Addictive Disorders in India

CLINICAL PRACTICE GUIDELINES on Newer and Emerging

Published by Indian Psychiatric Society, India

Editors

Debasish Basu | P.K. Dalal | Y.P.S. Balhara

Indian Psychiatric Society
Specialty Section on Substance Use Disorders

CLINICAL PRACTICE GUIDELINES on Newer and Emerging Addictive Disorders in India

Indian Psychiatric Society
Specialty Section on Substance Use Disorders 2016

Editors

Debasish Basu P.K. Dalal Y.P.S. Balhara

Published by

Indian Psychiatric Society

INDIA

Clinical Practice Guidelines on
Newer and Emerging Addictive Disorders in India

Editors:

Debasish Basu P.K. Dalal Y.P.S. Balhara

First Edition: January, 2016

Price : Rs.500/-
Rs.100/- for IPS Members

Editorial Office:

Dr. Debasish Basu

Professor of Psychiatry, Drug De-addiction & Treatment Centre, Department of Psychiatry,
Postgraduate Institute of Medical Education & Research, Chandigarh-160012, India.

Email: db_sm2002@yahoo.com

Prepared by:

Indian Psychiatric Society

Speciality Section on Substance Use Disorders

For copies:

Dr. Gautam Saha

Chair, IPS Publication Committee

Printed at:

Repro Digital Pvt. Ltd.

192B S.P. Mukherjee Road, Kolkata 700026

An Official Publication of Indian Psychiatric Society

© All rights reserved.

No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, digital, recording or otherwise, without the prior permission of the publishers.

ii

INDIAN PSYCHIATRIC SOCIETY
OFFICE BEARERS AND EXECUTIVE COUNCIL MEMBERS (2015-16)

President : Dr. Vidyadhar Watve Vice-President : Dr. G. Prasad Rao General Secretary : Dr. N. N. Raju Hon. Treasurer : Dr. Vinay Kumar Hon. Editor : Dr. T.S.S. Rao

EXECUTIVE COUNCIL

Immediate Past President : Dr. T. V. Asokan Immediate Past Secretary : Dr. Asim Kumar Mallick

Executive Council Members (Direct)

Dr. Kishor Gujar
Dr. O P Singh
Dr. K K Mishra
Dr. Om Prakash
Dr. Mrugesh Vaishnav
Dr. Arabinda Brahma
Dr. (Surg Captain) Sunil Goyal

Zonal Representatives

Central Zone : Dr. Sarvesh Chandra, Dr. Jai Prakash Narayan East Zone : Dr. C L Narayan, Dr. Hiranya Goswami West Zone : Dr. D M Dhavle, Dr. Mukesh Jagiwala North Zone : Dr. R K Solanki, Dr. Chander Mohan South Zone : Dr. A J John, Dr. Abhay Matkar

INDIAN PSYCHIATRIC SOCIETY SPECIALTY SECTION ON SUBSTANCE USE DISORDERS

Chair : P. K. Dalal
Convener : Debasish Basu
Members :
Atul Ambekar | Y.P.S. Balhara | Kaustav Chakraborty
Prabhat Chand | Anju Dhawan | Shubh Mohan Singh | B. N. Subodh

IPS PUBLICATION COMMITTEE

Chair : Gautam Saha Convener : Sandeep Shah

iii

Clinical Practice Guidelines on
Newer and Emerging Addictive Disorders in India

INDIAN PSYCHIATRIC SOCIETY SPECIALTY SECTION ON SUBSTANCE USE DISORDERS 2016

AUTHORS

Atul Ambekar
Additional Professor
National Drug Dependence Treatment Centre
Department of Psychiatry
All India Institute of Medical Sciences (AIIMS), New Delhi 110029 atul.ambekar@gmail.com

Yatan Pal Singh Balhara
Assistant Professor
National Drug Dependence Treatment Centre
Department of Psychiatry
All India Institute of Medical Sciences (AIIMS), New Delhi 110029 ypsbalhara@gmail.com

Aniruddha Basu
Senior Resident and DM Addiction Psychiatry Candidate
Drug De-addiction & Treatment Centre
Department of Psychiatry
Postgraduate Institute of Medical Education & Research (PGIMER) Chandigarh 160012
draniruddhabasu@gmail.com

Debasish Basu
Professor of Psychiatry
Drug De-addiction & Treatment Centre
Department of Psychiatry
Postgraduate Institute of Medical Education & Research (PGIMER) Chandigarh 160012
db_sm2002@yahoo.com

Kaustav Chakraborty
Assistant Professor
Department of Psychiatry
College of Medicine and J.N.M. Hospital, Kalyani
West Bengal University of Health Sciences, West Bengal drkaustav2003@yahoo.co.in

            

iv

Prabhat Chand
Additional Professor of Psychiatry
Centre for Addiction Medicine
Department of Psychiatry
National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore 560029
prabhatkumarchand@gmail.com

P.K. Dalal
Professor and Head
Department of Psychiatry
King George’s Medical University Lucknow 226003 docpkdalal@gmail.com

Abhishek Ghosh
Senior Resident and DM Addiction Psychiatry Candidate
Drug De-addiction & Treatment Centre
Department of Psychiatry
Postgraduate Institute of Medical Education & Research (PGIMER) Chandigarh 160012
ghoshabhishek12@gmail.com

Shrigopal Goyal
Assistant Professor
Shiv Kishan Midaram Dammani Government Institute of Mental Health, Allied & Neuro Sciences (DIMHANS),
Department of Psychiatry & De-addiction, PBM Hospital
S.P. Medical College and Associated Groups Hospitals, Bikaner (Rajasthan) shrigopalgoyal@gmail.com

Arun Kandasamy
Assistant Professor of Psychiatry
Centre for Addiction Medicine
Department of Psychiatry
National Institute of Mental Health and Neuro Sciences (NIMHANS) Bangalore 560029
arunnimhans05@gmail.com

Ananya Mahapatra
Senior Resident
National Drug Dependence Treatment Centre Department of Psychiatry
All India Institute of Medical Sciences (AIIMS) New Delhi 110029
nnyaa09@gmail.com

              

v

Surendra K. Mattoo
Professor Psychiatry
Drug De-addiction & Treatment Centre
Department of Psychiatry
Postgraduate Institute of Medical Education & Research (PGIMER) Chandigarh 160012
skmattoo@ymail.com

Pratima Murthy
Professor of Psychiatry
Centre for Addiction Medicine
Department of Psychiatry
National Institute of Mental Health and Neuro Sciences (NIMHANS) Bangalore 560029
pratimamurthy@gmail.com

Subodh B.N.
Associate Professor of Psychiatry
Drug De-addiction & Treatment Centre
Department of Psychiatry
Postgraduate Institute of Medical Education & Research (PGIMER) Chandigarh 160012
drsubodhbn2002@gmail.com

Rajarshi Neogi
Assistant Professor
Institute of Psychiatry
Institute of Postgraduate Medical Education & Research and SSKM Hospital
Kolkata 700020
neogi123@gmail.com

Sathya Prakash
Senior Resident
National Drug Dependence Treatment Centre Department of Psychiatry
All India Institute of Medical Sciences (AIIMS) New Delhi 110029 dr.sathyaprakashtbts@gmail.com

Siddharth Sarkar
Assistant Professor
National Drug Dependence Treatment Centre Department of Psychiatry
All India Institute of Medical Sciences (AIIMS) New Delhi 110029
sidsarkar22@gmail.com

              

vi

Lekhansh Shukla
Senior Resident and DM Addiction Psychiatry Candidate
Centre for Addiction Medicine
Department of Psychiatry
National Institute of Mental Health and Neuro Sciences (NIMHANS) Bangalore 560029
drlekhansh@gmail.com

Shubh Mohan Singh
Associate Professor
Department of Psychiatry
Postgraduate Institute of Medical Education & Research (PGIMER) Chandigarh 160012

shubhmohan@gmail.com

  

vii

PREFACE

It gives me great pleasure to write the Preface of the book “Clinical Practice Guidelines on Newer and Emerging Addictive Disorders in India”, published by the Indian Psychiatric Society.

In 2014, the IPS Specialty Section on Substance Use Disorders had brought out an entirely new set of comprehensive Clinical Practice Guidelines (CPGs) on the assessment and management of common substance use disorders. This is a rich and updated

source of knowledge and skills, comprehensive in its width as well as depth of coverage. However, a need was felt to produce an evidence-based synopsis of the previous exhaustive reference book, targeted directly for the practitioners and students, for an easy checking and implementation. This brief “Synopsis” was published in 2015.

Moving on from there, this current set of CPGs focuses on four newer and emerging areas of direct concern to the Indian scenario: New Psychoactive Substances, emerging drugs in the Indian context, a more in-depth focus on dual disorders, and last but not the least, the new group of addictive disorders called “Behavioural Addictions.” All these are important for Indian psychiatrists as well as medical specialists likely to come across addictive disorders more often than ever. Despite the lack of rigorous evidence in some of these areas, the eminent authors of this book have done their best by highlighting the emergent gravity of the problems, collating the updated evidence to the extent possible, and making recommendations for practice concordant with the current state of knowledge and expertise.

I congratulate the IPS Specialty Section on Substance Use Disorders on this ambitious task. I also thank the Publication Committee of IPS for publishing this useful book with great care. I wish that IPS should come up with more such volumes on various important psychiatric topics in future, setting a healthy and helpful tradition.

Dr. Vidyadhar Watve

President, Indian Psychiatric Society January, 2016

viii

FOREWORD

It is a matter of pleasure to know that Indian Psychiatric Society is bringing out yet another useful book on “Clinical Practice Guidelines on Newer and Emerging Addictive Disorders in India”.

Drug addiction is an important psychosocial problem from time immemorial and is found amongst all cultures and civilizations across the world throughout history. Drug addiction causes immense human distress and unfortunately there is no part of the world that is free from it. Millions of people all over the world are

leading very miserable and pathetic lives. The drug abuse is a complex phenomenon with involvement of social, cultural, biological, geographical, historical and economic aspects.

All of us know that there are innumerable varieties of drugs which are abused but most commonly used include alcohol, nicotine, cannabis, opioids, inhalants, and benzodiazepines. Earlier, The IPS Specialty Section on Substance Use Disorders brought out Clinical Practice Guidelines (CPGs) on the assessment and management of these common substance use disorders in two volumes. The Comprehensive handbook was released at the Annual National Conference of the IPS (ANCIPS) in 2014, and the Synopsis of the same was released at ANCIPS 2015.

Of late there have been several developments in this area. Newer psychoactive substances have been emerging on the Indian scene, some of them old but used more often in India lately (like cocaine), and others are so new that they are not even mentioned in the legal statutory schedules of controlled drugs. Patients with co- occurring psychiatric disorders and drug addictions are seen and recognized more frequently. Finally, a newly designated group of behavioural problems, termed as ‘behavioural addictions’, is making the mark, most notable of them being Pathological Gambling and Pathological Internet Use (or Internet addiction), but there are many others although they are more controversial at present. It is difficult to treat these conditions, firstly because these are newer entities and challenges in the Indian scenario and secondly because strong evidence base is often lacking.

Given this important but difficult development, the IPS Specialty Section on Substance Use Disorders have again risen to the challenge and have produced a CPG book, written by experts in the field, to bring these issues to the forefront.

Indian Psychiatric Society is happy to involve in bringing out the latest developments in the field of addictions and I am sure the handbook will be very useful to experienced clinicians, young postgraduates and serious researchers. I thank Dr. P.K. Dalal, Dr. Debasish Basu, Dr. Gautam Saha and Dr. Sandeep Shah in addition to all authors for completing such a daunting task. Of course such a dream would not have been reality but for the support extended by Dr. Vidyadhar Watve and the EC members.

Long live IPS!

Dr. N.N. Raju

Indian Psychiatric Society

ix

FROM THE DESK OF IPS PUBLICATION COMMITTEE

 

Dear Member,

The landscape of medical education has
changed rapidly in recent years and will
continue to do so into the future. In addition,
the composition of our continuing medical
education will continue to change, with
increasing numbers and shares of the
population coming from communities of color. In this publication we use experimental clinical projection techniques to capture the impact of these changes on the size and ethnic composition of medical education to the members of each

state, each zone, and nationally the Indian Psychiatric Society as a whole.

A number of individuals were instrumental in the preparation of this publication. First and foremost among them were authors who played critical roles at several steps along the way to publication. Special thanks to Dr. P.K. Dalal and Dr. Debasish Basu who designed and produced the layout and graphics; who edited the text and helped proof the data; who built the interactive tool providing readers with customizable data and graphics for our Society; and we also like to design in the web environment for the online version of the publication.

We would also like to thank those individuals who gave of their time and expertise in serving on the technicalities over the past few months. Finally, our thanks go to all the senior members for their generous support of the preparation, publication, and dissemination of this edition.

IPS Publication Committee prepares the white paper that formed the foundation of themethodologyreviewcomponentofthiswork. Inshort,wehopethefutureisa brighter one than what we experience here – for all members.

All the authors earn our sincere gratitude for their efforts on this publication.

We thank our President Dr. Vidyadhar Watve, Vice-President Dr. G. Prasad Rao, Hony General Secretary Dr. N.N. Raju, Hony Treasurer Dr. Vinay Kumar, Hony Editor Dr. T.S.S. Rao, and grateful to all Council Members for helping and cooperating us to run the Publication Committee at ease.

Long live I.P.S.

Dr. Gautam Saha

Chairperson, Publication Committee Indian Psychiatric Society

Dr. Sandeep Shah

Convener, Publication Committee Indian Psychiatric Society

x

INDIAN PSYCHIATRIC SOCIETY –
SPECIALTY SECTION ON SUBSTANCE USE DISORDERS (IPS-SS-SUD)

CLINICAL PRACTICE GUIDELINES ON
NEWER AND EMERGING ADDICTIVE DISORDERS IN INDIA

CONTENTS

Title Author Page No.

Front Matter

Section A: General Overview

Clinical practice guidelines on newer and emerging addictive disorders: Overview of IPS guidelines 2016

Addiction – a hydra-headed problem

i-x

Debasish Basu, PK Dalal, 5 YPS Balhara

Pratima Murthy 15

Section B: Newer and Emerging Substances

New Psychoactive Substances:
An overview, with focus on synthetic cannabinoids and cathinones

Cocaine
Amphetamine-type Stimulants “Club Drugs”

Section C: Behavioural Addictions

Gambling disorder

Pathological Internet Use (“Internet Addiction”)

Other putative behavioural addictions

Section D: Dual Diagnosis

Dual Diagnosis: Psychotic disorders

Dual Diagnosis: Non-psychotic disorders

Debasish Basu, 27 Abhishek Ghosh

Subodh BN, 51 Aniruddha Basu

Atul Ambekar, 87 Shrigopal Goyal

Kaustav Chakraborty, 121 Rajarshi Neogi

Abhishek Ghosh, Debasish Basu, 181 PK Dalal

Prabhat Chand, Arun Kandasamy, 221 Pratima Murthy

Arun Kandasamy, 237 Lekhansh Shukla

YPS Balhara, Sathya Prakash, 263 Ananya Mahapatra, Siddharth Sarkar

Shubhmohan Singh, SK Mattoo 309

xi

SECTION A : GENERAL OVERVIEW

CLINICAL PRACTICE GUIDELINES ON NEWER AND EMERGING ADDICTIVE DISORDERS: OVERVIEW OF IPS GUIDELINES 2016

Debasish Basu P.K. Dalal Y.P.S. Balhara

On behalf of
Indian Psychiatric Society
Specialty Section on Substance Use Disorders

2016

Overview

BACKGROUND

Following the reconstitution of the Specialty Section on Substance Use Disorders of the Indian Psychiatric Society (IPS-SS-SUD) in 2011, the members of the Specialty Section strongly felt the need for formulating a set of evidence-based, methodologically sound and updated Clinical Practice Guidelines (CPG) for the assessment and management of the common substance use disorders in India. Following a long and rigorous process of development, a book was finally released at the Inauguration Ceremony of the 66th Annual National Conference of the Indian Psychiatric Society (ANCIPS) held in Pune in January 2014. It was an official publication of the IPS, brought out by IPS-SS-SUD, named “Clinical Practice Guidelines for the Assessment and Management of Substance Use Disorders” (referred hereafter as the “CPG-SUD book”).1 The following areas were covered in the CPG-SUD book of 2014: assessment of substance use disorders in general; alcohol use disorders; opioid use disorders; cannabis use disorders; sedative- hypnotic use disorders; tobacco use disorders; inhalant use disorders; and dual diagnosis. It was a comprehensive book running into 531 pages, with a masterly compendium of references and updated knowledge crystallized into practical recommendations.

Later, however, it was felt that there was a need for a more concise, practice-oriented, easy-to-follow “Synopsis” of the comprehensive CPG-SUD book as well, which would be a set of compact, precise, yet evidence- and expertise-based guidelines. Again an official publication of the IPS, the “Synopsis” book was released at the Inauguration Ceremony of the 67th Annual National Conference of the Indian Psychiatric Society (ANCIPS) held in Hyderabad in January 2015.2 Easy-to-carry in a pocketbook sized format, and easy-to-use with clear tables, panels, boxes and algorithms, it was a perfect supplementary companion of the comprehensive CPG-SUD book. It synthesized all the practice-relevant information necessary for the assessment and management of common substance use disorders and dual diagnosis. In order to maintain comparability and consistency with the CPG-SUD book, it contained the same chapters in the same order: assessment of substance use disorders in general; alcohol use disorders; opioid use disorders; cannabis use disorders; sedative-hypnotic use disorders; tobacco use disorders; inhalant use disorders; and dual diagnosis.

Since the publication of the CPG-SUD book in 2014 and the Synopsis book in 2015, both have been well received by clinical practitioners, researchers, academicians, and psychiatric students, i.e., by all the target groups these two books were meant for. They have provided the clinicians with updated and evidence-based guidelines for assessment and management of substance use disorders, and others with a comprehensive compendium of updated knowledge that can be a rich resource for academic purposes of teaching, learning, and research.

© Indian Psychiatric Society 2016 5

Need for the current volume of CPG

As mentioned above, the first two books were devoted to CPGs on common substance use disorders in India because it was the felt need of the Indian psychiatrists at that moment. However, the scenario of addictive disorders is never a static one. It witnesses continual kaleidoscopic changes, with newer substances, newer patterns, and indeed, newer ‘addictions’ emerging all the time.

Four broad changes have been noted in the landscape of addictive disorders in India of late. These are:

. (a)  Emergenceofaheterogeneousgroupofvarioussubstancesclubbedundertheterm “New Psychoactive Substances (NPS)”, which evade the existing regulatory legal framework but nonetheless, can be harmful;

. (b)  Emergence of long-known but so far less used substances in India in an emergent manner (such as cocaine and amphetamine-type stimulants), often in the context of rave parties or similar gatherings (the so-called “club drugs”);

. (c)  Appearance of novel, if somewhat controversial, patterns of maladaptive behavioural excess involving particular behaviours (gambling, use of technology like computer and Internet, eating, sexual activities, etc.), which do NOT primarily involve use of psychoactive substances as such (known as “behavioural addictions”); and finally,

. (d)  Enhancedprobabilityofclinicallyencounteringvariouscombinationsofsubstance use disorders with non-substance psychiatric disorders (known as dual diagnosis or dual disorders).

After the first-level basic coverage was completed in the first two books, it was felt appropriate now to move on to the next stage, or phase, of CPG development, focusing on these newer or emerging areas. This need was clearly foreseen in the Overview Chapter of the CPG-SUD book in 2014: “CPGs on stimulants and hallucinogens have not been incorporated, nor on ‘club drugs’ or ‘new psychoactive substances’, because we had to prioritize the content according to the currently existing predominant patterns of substance use in India. However, the scenario of substance use is always a fluid one, and newer drugs, including cocaine and other stimulants, and the so-called ‘club or rave’ drugs, have made entry into select circles of substance users in India. A future revised edition of this book may therefore add new CPGs on these SUDs as well.”3

This is the purpose of the current volume, which may be seen as the blossoming of the plant, the seed of which was sown in the 2014 volume!

The Process of Development of these CPGs

This CPG has followed the same process of development as the original CPG-SUD

6 © Indian Psychiatric Society 2016

Newer and Emerging Addictions in India

Overview

book. The CPG-SUD book was the culmination of intensive year-long efforts of a group of dedicated psychiatrists working in the field of substance use disorders in various reputed academic medical institutes of India. The development, refinement and finalizationoftheseClinicalPracticeGuidelines(CPGs) wastheresultofanarduous, long-drawn and rigorous process following a pre-defined iterative strategy involving progressively widening circles of peer review.

The pre-defined strategy for the process of development, refinement and finalization of these CPGs has been mentioned in details in the “Overview” chapter of the CPG-SUD book.3 The process is recapitulated briefly here.

Although all the members of the IPS-SS-SUD were variably involved in the process of development and/or refinement of the each of the CPGs, one senior author (a Faculty Member of a teaching medical institute with special interest and expertise in addictive disorders) was designated as the “Lead Author” for each of these CPGs. They co-opted additional contributors, not below the rank of a Senior Resident in psychiatry and working in the area of addictive disorders. These authors developed their respective CPG assigned to them.

In the process of development, we were guided by: (a) an extensive review of the relevant literature, including Indian data wherever available in published and retrievable form; (b) pre-existing recent guidelines in this area; (c) an awareness of the local needs and priorities whenever applicable (e.g., the need to focus on smokeless tobacco use in India); (d) need to balance the rigor and extensiveness of data coverage with the pragmatic considerations of condensing and filtering the data for practical use by clinicians; (e) need to rate the category of evidence and the strength of recommendations as per internationally accepted norms;4 and (f) the Appraisal of Guidelines for Research and Evaluation II (AGREE-II) instrument.5 These (strength of evidence and recommendations, and AGREE-II instrument, with degree of compliance displayed by most of these CPGs) are mentioned in the Appendix, and have been followed throughout all the CPGs.

The CPGs thus developed were finalized through an iterative process of progressively widening circles of peer review. Ethical issues and potential conflicts of interest were also taken care of, as mentioned explicitly in the “Overview” chapter of the CPG-SUD book.3

The Organization of the Book Chapters and the CPGs

Following this overview chapter, the next chapter is called “Addiction – a hydra headed problem.” Written by an eminent addiction psychiatrist who has been working in the area for many decades, it is really an experiential overview that sets the tone for the rest of the book, focusing on the essential roles and challenges of the psychiatrist in addiction psychiatry, especially in view of newer addictions and dual diagnosis.

© Indian Psychiatric Society 2016 7

The next Section of the book starts with an overview of the “New Psychoactive Substances (NPS)” and their relevance for the emerging Indian scenario. This chapter defines and classifies all categories of NPS but focuses on only those not covered in later chapters. It especially covers synthetic cannabinoids and synthetic cathinones (especially mephedrone, colloquially known as “meow meow”, which has already emerged as a major threat in several parts of India).

The following three chapters are on cocaine, amphetamine-type stimulants (ATS), and “club drugs” respectively. Together with the NPS overview, these chapters cover the (a) and (b) of the changes noted in the Indian substance use horizon as mentioned above. It is to be noted that these are not watertight mutually exclusive subjects. Cocaine and some older ATS drugs like amphetamines are not NPS because they are regulated under the schedules of the International Conventions and the Indian Narcotic Drug and Psychotropic Substances Act 1985. Club drugs comprise a loosely defined heterogeneous group of substances that can include cocaine and ATS. Thus, these chapters have been artificially carved out more out of practical necessities than for any basic underlying principles, except for the fact that these do cover the newer and emerging substances of use and their patterns of use in India.

The next Section focuses on the newer and again somewhat loosely defined entity called “Behavioural Addictions”. The first chapter in this Section, Gambling Disorder, is also the only one to have made the final mark by being included in the “Substance Use and Related addictive Disorders” section of the Diagnostic and Statistical Manual, 5th edition (DSM-5) of the American Psychiatric Association. Pathological Internet Use, also popularly known as “Internet addiction” could not make the final mark in DSM-5 as a definitive disorder but one sub-portion of it (Internet Gaming Disorder) has been relegated to the last section of DSM-5 as “conditions that need further study”. This has been covered in the next chapter in this book keeping in view its rising importance both in the popular media as well in the clinical and scientific circles. The last chapter in this section covers all those so-called behavioural addictions which are still best categorized as “putative” but nevertheless has an emerging body of research backup and can be a clinically encountered problem.

The final Section is on assessment and management of dual diagnosis disorders. Although covered in a general manner in the previous two CPG books,1,2 the need was felt to deliberate upon this area in a more comprehensive manner because of their increasing prominence in clinical setups. One chapter in this Section focuses on dual diagnosis psychotic disorders while the other focuses on non-psychotic disorders.

Each chapter begins with a clinically useful “Executive Summary” that summarizes the key recommendations and issues. Individual “Key Recommendations” are mentioned at the end of each major subsection of the chapters, occasionally also marking areas of present uncertainty. These summary points and recommendations come with the grading of evidence and strength as mentioned in the Appendix of this chapter.

8 © Indian Psychiatric Society 2016

Newer and Emerging Addictions in India

Overview

While not always possible or feasible, we have attempted to maintain a degree of uniformity and consistency in the structure and format across all the chapters. Each chapter is subdivided into several sections and sub-sections, which are numbered hierarchically in a numerical-point scheme (1, 1.1, 1.1.1, etc.) so that navigation along these subsections becomes easier and more meaningful for the reader. Scope and methodology including search strategies have been mentioned. Special attention has been paid to locate and highlight Indian studies and the applicability of the recommendations to the Indian situation. Certain special populations or situations have also been mentioned at the end of each chapter if available. Finally, along with pharmacological therapies, a conscious emphasis has been placed on non- pharmacological (psychosocial, cognitive and behavioural) interventions as well, to the extent possible.

Potential Readership, Utility, Scope, and Limitations of these CPGs

These are Clinical Practice Guidelines; hence the primary target audience for these CPGs is the practicing clinicians (especially psychiatrists but also non-psychiatric medical doctors and even non-medical professionals working in the area of addictive disorders). They should benefit from the Executive Summary and Key Recommendations to be applied in their clinical practice. Whoever is further interested can look up the relevant literature cited in the text as and when needed.

The secondary, but very important, audiences include, among others, medical teachers, postgraduate students, and researchers. These CPGs provide a comprehensive compendium of updated knowledge that can be a rich resource for academic purposes of teaching, learning, and research. Finally, these might be of benefit to medical institutes and to policy makers to inform healthcare related decisions in the area of SUDs (e.g., the decision to fund and implement opioid substitution treatment programmes in an institute or in a state or even national basis).

Like any CPG, along with their potential utility as outlined above, their scope and limitations need to be kept in mind so as to avoid their misuse, and encourage their correct use. Ever since the Institute of Medicine in 1990 defined CPGs as “systematically developed statements to assist practitioner and patient in decisions about appropriate health care in specific clinical circumstances”,6 the benefits, lack of benefits, and potential harms have been hotly debated, and the debate continues till date. Without going into details of these ‘pros and cons’ debates, our humble submission to the readers and potential users of this book and its individual chapters is: please remember that CPGs are “guidelines”, not mandates or obligatory standards required by law or by an institute, though mandates may later be derived from them as a policy matter. CPGs are meant to inform, assist and “guide” the clinician, not ask them to sacrifice their autonomy of clinical judgment, nor to be oblivious of the individual patient’s clinical situation and psychosocial context. Neither do we claim that these CPGs cover

© Indian Psychiatric Society 2016 9

everything under the sun related to SUDs. We had to necessarily prioritize the content and coverage of the areas, and, in this process, some sections might have been missed.

Another important limitation has to be kept in mind while interpreting the recommendations made in this book. Many of these subject areas are new and emerging, and rigorous ‘double-blind randomized controlled trials’ – the cornerstone of evidence-based medicine – are often absent, rare, or of small size or poor quality. Hence, the evidence ratings in many areas are of a low grade. Accordingly, the recommendations are necessarily of a “D” or “S” category, and many times no specific recommendations can be made at this level of knowledge and experience. Perhaps the situation may change by the time a later edition of this book is published. This statement does not reduce the value of this book but rather puts in proper perspective.

With this statement of the scope, declarations and limitations as a ‘disclaimer’, we would like to end by reiterating that if used for the correct purpose and in the correct manner, we hope that these CPGs should prove useful to both their primary as well as secondary readerships.

REFERENCES

1. Basu D, Dalal PK (eds). Clinical Practice Guidelines for the Assessment and Management of Substance Use Disorders. Delhi: Indian Psychiatric Society, 2014.

2. Dalal PK, Basu D (eds). Synopsis of the Clinical Practice Guidelines on Substance Use Disorders. Delhi: Indian Psychiatric Society, 2015.

3. Basu D, Dalal PK. Clinical practice guidelines for the assessment and management of substance use disorders: overview of IPS guidelines 2014. In, Basu D, Dalal PK (eds). Clinical Practice Guidelines for the Assessment and Management of Substance Use Disorders. Delhi: Indian Psychiatric Society; 2014, pp. 1-12.

4. Shekelle PG, Woolf SH, Eccles M, Grimshaw J. Clinical guidelines: developing guidelines. BMJ 1999; 318: 593–596.

5. Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, et al. AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ 2010; 182: E839-E842.

6. Field MJ, Lohr KN (eds). Clinical Practice Guidelines: Directions of a new Program. Committee to advise the Public Health Service on Clinical Practice Guidelines, Institute of Medicine. Washington DC: National Academy Press; 1990.

10 © Indian Psychiatric Society 2016

Newer and Emerging Addictions in India

Overview

APPENDICES
Appendix 1. AGREE-II instrument, and compliance of CPGs developed by IPS-SS-SUD

AGREE II Item

CPGs of IPS-SS-SUD 2016

Overall objective(s) of the guideline

To develop evidence-based and experience- based clinical assessment and management options for selected substance use disorders, behavioural addictions, and dual diagnosis.

The population (patients, public, etc.) to whom the guideline is meant to apply

Patients with substance use disorders, behavioural addictions, and dual diagnoses.

The target users of the guideline

The primary target users of these guidelines are practicing clinicians (especially psychiatrists but also non-psychiatric medical doctors and even non-medical professionals working in the area of addictions). The secondary, but very important, target users include medical teachers, postgraduate students, researchers and policy makers at various levels.

Systematic methods used to search for evidence

Existing guidelines, systematic reviews, RCTs and other clinical trials, and various observational studies were identified from PubMed, EMBASE, Google Scholar and other database searches, from the Cochrane Database as well as from guidelines and identification by experts in the field.

The methods for formulating the recommendations

This guideline is based on the synthesis and interpretation of available evidence obtained from studies across the world, especially in light of the Indian context, rating them on strength of evidence and combining this strength with the perceived importance and relevance in the Indian context to finally arrive at specific key recommendations as well as identifying current areas of uncertainty where applicable.

The health benefits, side effects, and risks have been considered in formulating the recommendations

Yes

There is an explicit link between the recommendations and the supporting evidence

Yes. Further, it has been clearly pointed out where no specific recommendations can be made at this time because of lack of supporting evidence of acceptable quality.

© Indian Psychiatric Society 2016 11

Appendix 2. Categories of Evidence and Strength of Recommendations (followed throughout these CPGs).4

Categories of evidence

. Ia  :

. Ib  :

. IIa  :

. IIb  :

III :

evidence from meta-analysis of randomised controlled trials

evidence from at least one randomised controlled trial

evidencefromatleastonecontrolledstudywithoutrandomisation

evidencefromatleastoneothertypeofquasi-experimentalstudy

evidence from non-experimental descriptive studies, such as comparative studies, correlation studies and case-control studies

12

© Indian Psychiatric Society 2016

Newer and Emerging Addictions in India

AGREE II Item

CPGs of IPS-SS-SUD 2016

A procedure for updating the guideline is provided

No, not at this stage. However, these CPGs may be updated every 5-7 years, or specifically added or modified recommendations may be made available online if major changes in evidence are witnessed in specific areas.

The recommendations are specific and unambiguous

Yes. However, these are not algorithmic or “cook-book recipe” recommendations to be followed blindly. Rather, major principles are recommended, which have to be applied along with clinical judgment in individual circumstances.

The different options for management of the condition or health issue are clearly presented.

Yes, to the extent possible.

Key recommendations are easily identifiable.

Yes, wherever available.

The guideline provides advice and/or tools on how the recommendations can be put into practice.

Yes, usually but not in very instance.

The guideline describes facilitators and barriers to its application.

This issue has not been specifically addressed in these CPGs.

The potential resource implications of applying the recommendations have been considered.

This issue has not been specifically addressed in these CPGs.

Competing interests of guideline development group members have been recorded and addressed.

All authors declared “No conflicts of interest.”

Overview

IV : evidence from expert committee reports or opinions and/or clinical experience of respected authorities

Strength of recommendations

. A  :

. B  :

. C  :

. D  :

S :

directly based on category I evidence

directly based on category II evidence or extrapolated recommendation from category I evidence

directly based on category III evidence or extrapolated recommendation from category I or II evidence

directly based on category IV evidence or extrapolated recommendation from category I, II or III evidence

Standard of care

© Indian Psychiatric Society 2016 13

ADDICTION – A HYDRA HEADED PROBLEM HERCULEAN CHALLENGES FOR THE PSYCHIATRIST

Pratima Murthy

On behalf of
Indian Psychiatric Society
Specialty Section on Substance Use Disorders

2016

Addiction

1. INTRODUCTION

The American Society of Addiction Medicine in 20111 redefined addiction as a chronic brain disorder. An editorial close on the heels of this proclamation in the Lancet2, cautioned that the over-medicalisation of addiction could have its downsides. Whatever the position, there is general agreement that being addicted is really like being in a maze, with confusing signals emitted both from within the individual (from biological predisposition and temperament) as well as from external factors (family, society and other aspects of the environment)3. An understanding of vulnerability, effect of substances on the body and mind, effective medical and psychosocial interventions, family support and follow-up support are all important for restitution and recovery. Who can better balance the science and art of addiction management than the psychiatrist!

2. ADDICTION – A COMPLEX HYDRA HEADED PROBLEM

During residency training in the 1980’s, my tryst with addiction was predominantly with alcohol dependence. We saw persons with alcohol dependence and treated them with disulfiram and psycho-social interventions. We saw nicotine dependence, but did precious little except giving half-hearted advice to quit smoking. A lot has changed in the three subsequent decades. In fact, change has been the only constant in the area of addiction and its management.

2.1 What has changed?

1. The nature of chemical addictions has changed- since the first case report of heroin use in India in the 1970’s, the problem of opiate use has been escalating throughout the country, and both illicit and pharmaceutical opioids dominate the landscape4. We are increasingly encountering sedative/hypnotic dependence, particularly benzodiazepine dependence in clinical practice5. Many young people are brought to treatment settings with inhalant misuse and dependence. Cannabis use and cannabis related problems continue to be present. Clinics are starting to see cocaine, LSD and stimulant abuse. The use of ketamine has been reported nearly two decades ago6 and continues to be prevalent. Instances of diversion of opioid substitution medications like buprenorphine, newer opioid drugs including tramadol abuse7 and news reports of novel psychoactive substances like mephedrone (colloquially known as “meow meow”)8 are increasing.

2. We have learnt that licit drugs like nicotine and alcohol are associated with greater public health problems in comparison to illicit drugs whose supply is more strongly controlled. There is now a national tobacco control programme and tobacco cessation clinics and treatments are becoming more readily available in hospitals and practice settings.

3. In the last two decades, the face of addiction has changed. The scenario has moved beyond chemical addictions to various kinds of behavioural addictions. These

© Indian Psychiatric Society 2016 17

include gambling, gaming, Internet addiction, food addiction, sex addiction, shopping addiction and other behavioural addictions9,10.

4. Gender and substance use is another area that is garnering greater attention, with more women being brought for the treatment of addiction, narrowing gender ratios, all underscoring the need to develop gender-sensitive treatment approaches11.

5. We are recognising the need to look at addiction on a developmental continuum, from the foetal effects of maternal substance use12, to the growing problem of substance use among the elderly13.

6. Cases of substance use are often complex to manage – with both physical and psychiatric co-morbidities. Dual diagnosis poses its own unique evaluation and management challenges.

7. The successful management of addiction includes not just the management of craving and relapse, but the effective management of co-morbidities.

8. Therapeutic nihilism is still very prevalent and many psychiatrists are hesitant, if not loath to treat persons with addiction. A large part of this nihilism stems from a lack of skills as to how to approach such persons and lack of a collaborative approach with the patient.

9. Addiction is recognised as a chronic, relapsing condition, with outcome rates similar to other chronic diseases14 and planned follow-up and aftercare yields better treatment retention and outcome15.

10. A range of pharmacotherapeutic and psychotherapeutic options have become available or used more often in the last two decades. Nicotine replacement strategies, bupropion, varenicline and re-emerging interest in cytisine for tobacco dependence; acamprosate, naltrexone, topiramate, baclofen, N-acetyl cysteine for alcohol and other addictions; buprenorphine and methadone (old drugs that have become popular in the armamentarium of harm reduction approaches), drugs used for co-morbidities (including atomoxetine, anti-depressants, mood stabilisers, anti- convulsants). Interactions between prescribed drugs and abused substances pose fresh challenges to the treating psychiatrist. Psychotherapeutic options including motivation enhancement, cognitive behavioural interventions, mindfulness interventions, relapse prevention strategies, among others. It is generally accepted that a combination of psychosocial and pharmacological interventions work better than either alone.

3. FOCUSING ON TWO OF THE NEWER CHALLENGES

Two broad areas in addiction that has captured both professional and public attention are the behavioural addictions and dual disorders. Both these have become areas of specialisation within addiction and deserve special attention.

18 © Indian Psychiatric Society 2016

Newer and Emerging Addictions in India

Addiction

3.1 Behavioural Addictions

Behavioural addictions resemble chemical addictions in many ways. What underlies these is a compulsion to repeatedly perform a rewarding behaviour – sometimes called a natural reward – despite negative consequences to the person’s physical, mental, social, and/or financial well-being. A variety of behavioural disorders, both old and new are now described16. These include, among a host of conditions, gambling, food, shopping, sex and technology addictions. The main challenge with behavioural addictions is that they are an extension of normal behaviours and behaviours that are normally reinforcing or rewarding. Sometimes the description of behavioural addictions is carried to the extreme, a case of nosologomania, not uncommon to psychiatry17, with every known behaviour (listening to music, praying, working) being described as a potential addiction.

Following the first published report of addictive use of the Internet appeared in the mid- 1990s18, there has been a plethora of published literature on the subject. Just as with the definition of case-ness in psychiatry, determining case-ness in such addictions poses a problem. This is because behavioural addictions involve ‘normal drives’, and are only considered addictions when the behaviours reach a certain degree of excess and harm. Griffith19 succinctly summarises that the difference between and excessive healthy enthusiasm and an addiction is that ‘health enthusiasms add to life whereas addictions take away from it. There are several schools of thought on whether behavioural addictions belong with other addictions, are part of a impulsive-compulsive spectrum disorder, or cross-cutting disorders that overlap with anxiety states, depression, obsessive compulsive disorders, attention-deficit hyperactivity disorders and personality disorder. There are, on the other hand, critics who raise the doubt of whether these are at all illnesses, or impulsive irresponsibility, or socio-cultural phenomena that should not be medicalised. Whatever the view-point, and whether or not these are disorders in their own right or epiphenomena of underlying psychiatric morbidity, it is nevertheless a clinical reality that we see patients who have serious problems with behaviours such as gambling, shopping, sex and the use of technology, causing much distress to others or themselves. DSM V recognises pathological gambling and gaming disorder as established behavioural addictions. The current focus has been to understand the factors that predispose such behaviours – genetic risk, temperament, co-occurring psychiatric illness, impaired decision making abilities, and so on.

There are several issues with behavioural addictions. Can the same criteria for chemical addiction be applied to behavioural addictions? Some of the supportive evidence comes from imaging studies that found similar brain imaging changes in alcohol users, cocaine users and persons with obesity20. Griffith19 suggests that apart from salience, tolerance, withdrawal symptoms and tendency to relapse, other hallmarks of a behavioural addiction include the mood modification properties of the behaviour and

© Indian Psychiatric Society 2016 19

the conflict associated with such behaviour.

Some researchers suggest a common diathesis across behaviour addictions. A high co- occurrence of compulsive sexual behaviour and gambling is a case in point21. Is then the wide spectrum of behaviour addictions a case of “diffr’nt strokes for diffr’nt folks” (sufferers, clinicians, epidemiologists and nosologists), or should we be take a more sensible unitary path? A unitary hypothesis is further supported by the fact that patients treated with dopaminergic agents for idiopathic Parkinsonism commonly developed new onset pathological gambling and sexual compulsivity22.

Engagement, treatment and follow-up retention are some important challenges in behavioural addictions.

3.2 Co-morbid Disorders

It would not be an exaggeration to say that addiction rarely occurs alone. There are invariably accompanying conditions which include psychiatric diagnosis, personality or temperament related issues, as well as medical co-morbidities.

In the narrow sense, dual disorders refer to the co-existence of addiction with a psychiatric disorder. There are multiple relationships between the use of substances and psychiatric symptomatology. Acute or chronic use of substances can produce symptomatology indistinguishable from independent psychiatric disorders; substance use can precipitate or worsen pre-existing psychiatric illnesses; substance use can be a method of coping with psychiatric symptoms; the two conditions may occur independent of each other; the emotional and social disturbances that occur in these two conditions may be indistinguishable from one another23. Most importantly, an underlying psychiatric illness can undermine interventions for substance use or behavioural addictions.

Prolonged heavy use of drugs and/or alcohol can result in an array of serious health conditions. When one adopts a much broader view of co-morbidity, a plethora of physical conditions including infections as well as non-communicable diseases fall in the rubric of co-morbidity.

There have been a few studies from India that have highlighted both psychiatric and medical co-morbidity among substance users24.

In respect of co-morbid disorders, there are several issues that merit attention and discussion. These include the exploration of shared vulnerability between substance use and other psychiatric disorders, the development of appropriate diagnostic approaches to co-occurring disorders and the development/ adaptation of treatments for such conditions.

The neurobiological interface between mental disorders and substance use has been gathering tremendous interest in the last couple of decades with a focus on shared molecular biology, neurotransmitter systems and neural circuits25.

20 © Indian Psychiatric Society 2016

Newer and Emerging Addictions in India

Addiction

Addressing SUDs from a life stage perspective with assessment and treatment approaches incorporating co-occurring disorders are necessary to successfully impact overall health26.

Treatment of dual diagnosis [co-occurrence of a substance use disorder (SUD) in patients with mental illness] poses several challenges for mental health professionals27. In spite of the high association between substance use and psychiatric disorders, there is a surprising paucity of studies related to treatment and outcome.

4. CHALLENGES BEFORE THE PSYCHIATRIST

With the definition of addiction broadening beyond the use of chemical substances to a range of behaviours that also possess similar characteristics, research is moving from a system that classifies addiction according to clinical symptoms to one more rooted in a mechanistic understanding of the disease, with a greater role for genetic imaging and cognitive science28.

Newer drug and behavioural addictions: Improving professional knowledge and competencies

Knowledge

Competencies

Training and Resource Mobilisation

Kinds of newer drugs, effects of use, intoxication, overdose, dependence and withdrawal

Clinical evaluation and symptomatic management of the various clinical presentations

Training of psychiatrists and other health professionals in the identification, assessment, engagement, treatment, crisis management, relapse prevention

Relevant Investigations

Use of appropriate investigations for detection in body fluids, assessment of systemic complications

Support for trained human resource and facilities for management including relevant pharmacotherapy

Pharmacology and interactions with other substances of abuse as well as medications

Symptomatic and specific management of underlying conditions including long- term management

Funding support for research on newer drugs of abuse and behavioural addiction including epidemiology, clinical presentations, treatment, course and outcome

Available pharmacotherapy and psychosocial management for newer drug addictions

Management of underlying vulnerability

Policy and advocacy to address and minimise the individual and public health impact from the use and addiction to newer drugs of abuse as well as behavioural addictions

© Indian Psychiatric Society 2016 21

Newer and Emerging Addictions in India

Knowledge

Competencies

Training and Resource Mobilisation

Complications associated with psychiatric and other medical co-morbidities and their management

Co-management of co- morbidities and liaison with other specialties

Behavioural addictions- similarities and divergence from chemical addictions, their co-morbidities and management

Effective recognition and management of behavioural addictions

Vulnerability including genetic risk, temperament, etc.

Management in different clinical and community populations including children and adolescents and in special settings like prison

However, while treatment options have expanded quite a bit in the last few decades, the generally established set of psychosocial and pharmacological approaches used for substance addiction form the mainstay of treatment even for the newer addictions. The current day psychiatrist is best advised to be well informed of the changing patterns of addictions, special populations requiring specialised care, behavioural and other newer addictions, co-morbidities and their management and the social and legal ramifications of the newer addictions. Thus contemporary psychiatry will have to constantly adapt itself to understanding the dynamic and hydra-headed problem of addiction in order to provide effective management.

REFERENCES

1. American Society of Addiction Medicine. Definition of Addiction. 2011. http://www.asam.org/pdf/Advocacy/PressReleases/20110815_DefofAddiction.PR.pdf

2. The Lancet. Addiction: a complex disorder. Editorial. The Lancet, 2011; 378:742.

3. Murthy P. Addiction: Is there light at the end of the tunnel? Indian Psychiatric Society mid-term CME publication, September 2011.

4. Larance B, Ambekar A, Azim T, Murthy P, Panda S, Degenhardt L, Mathers B. The availability, diversion and injection of pharmaceutical opioids in South Asia. Drug Alcohol Rev 2011; 30 (3): 246-254.

5. Chand PK, Murthy P. Megadose lorazepam dependence. Addiction 2003; 98 (11):1635-1636.

6. Singh S, Murthy P. Ketamine Dependence. Indian J Psychiatry 2001; 43(2):175-177.

22 © Indian Psychiatric Society 2016

Addiction

7. Chand PK, Jayaram N, Murthy P. Iatrogenic tramadol addiction. Indian J Med Sci 2015, in press.

8. Yahoo News. Meow Meow and the walking dead: India’s newest drug. November 12, 2015. http://news.yahoo.com/meow-meow-walking-dead-indias-080000387.html

9. Rosenberg KP and Feder LC. An introduction to behavioural addictions. In, Behavioural Addictions. First Edition. Criteria, Evidence and Treatment. Rosenberg KP and Feder LC (Eds). London: Academic Press, 2014.

10. Indian Council for Medical Research. Behavioural addiction in the community: an exploration. Sharma MK, Benegal V, Girish N, Thennarasu K. http://www.icmr.nic.in/final/Behavioural%20addiction%20in%20the%20community .pdf

11. Murthy P (Principal author and scientific editor). Women and Drug Use in India: Substance, Women and High-Risk Assessment Study. United Nations Office on Drugs and Crime, Ministry of Social Justice and Empowerment, United Nations Development Fund for Women 2008.

12. Nayak R , Murthy P, Girimaji S, Navaneetham J. Foetal alcohol spectrum disorders. J Trop Paediatr 2012; 58 (1): 19-24.

13. Nadkarni A, Murthy P , Crome IB, Rao R. Alcohol use and alcohol-use disorders among older adults in India: a literature review, Aging Ment Health 2013; 17 (8):979- 91.

14. McLellanAT,O’BrienCP,LewisD,KleberHD.Drugaddictionasachronicmedical illness: implications for treatment, insurance and evaluation. JAMA 2000; 284: 1689–1695.

15. Murthy P, Chand PK, Harish MG, Thennarasu K, Prathima S, Karappuchamy, Janakiramiah N. Outcome of alcohol dependence: The role of continued care. Indian J Community Med 2009; 34 (2): 148-151.

16. Rosenberg KP and Feder LC (Eds). Behavioural addiction. Criteria, evidence and treatment. London: Academic Press, 2014.

17. Van Praag HM. Impact of classification on psychiatry. Dialogues Clin Neurosci 1999; 3(1):141-151.

18. YoungK.Psychologyofcomputeruse: AddictiveuseoftheInternet:Acasethatbreaks the stereotype. Psychol Rep 1996; 79: 899-902.

19. GriffithM. A’components’modelofaddictionwithinabiopsychosocialframework.J Subst Use 2005; 10: 191-197.

20. Wang GJ, Volkow ND, Thanos PK, Fowler JS. Similarity between obesity and drug addiction as assessed by neurofunctional imaging: a concept review. J Addict Dis 2004; 23: 39-53.

21. GrantJE,SteinbergMA.Compulsivesexualbehaviourandpathologicalgambling.Sex Addiction Compulsivity 2005; 12: 235-244.

22. BostwickJM,HeckselKA,StevensSR,BowerJH,AhlskogJE.Frequencyofnew-onset

© Indian Psychiatric Society 2016 23

compulsive gambling or hypersexuality after drug treatment of idiopathic Parkinson Disease. Mayo Clinic Proc 2009; 84:310-316.

23. DHHS Publication No. (SMA) 95-3061. Printed 1994. Assessment and Treatment of Patients with Coexisting Mental Illness and Alcohol and Other Drug Abuse Treatment Improvement Protocol (TIP) Series 9.http://adaiclearinghouse.org/downloads/TIP-9- Assessment-and-Treatment-of-Patients-with-Coexisting-Mental-Illness-and-Alcohol- and-Other-Drug-Abuse-78.pdf

24. Murthy P, Manjunatha N, Subodh B N, Chand PK, Benegal V. Substance use and addiction research in India. Indian J Psychiatry 52(1), Supplement 2010.

25. Brady KT, Sinha R. Co-occurring mental and substance use disorders: the neurobiological effects of chronic stress. Am J Psychiatry 2005; 162: 1483-1493.

26. Schulte MT, Hser Y-I. Substance use and associated health conditions throughout the lifespan. Public Health Reviews. 2014.

27. MurthyP,ChandP.Treatmentofdualdiagnosisdisorders.CurrOpinPsychiatry2012; 25 (3): 194-200.

28. HolmesD.Addiction:fourbigquestions.Nature2015;522:s63.

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Newer and Emerging Addictions in India

SECTION B :
NEWER AND EMERGING SUBSTANCES

NEW PSYCHOACTIVE SUBSTANCES:
AN OVERVIEW, WITH FOCUS ON SYNTHETIC CANNABINOIDS AND CATHINONES

Debasish Basu Abhishek Ghosh

On behalf of
Indian Psychiatric Society
Specialty Section on Substance Use Disorders

2016

New Psychoactive Substances

CONTENTS

Executive Summary

1. Introduction

2. Scope and methodology of the guideline

3. Profile of NPS users

4. Assessment of suspected cases of NPS intoxication

. 4.1.  Clinical assessment

. 4.2.  Laboratory assessment

5. Management of synthetic cannabinoids/cathinone intoxication or toxicity

. 5.1.  Treatment setting

. 5.2.  Management of sympathomimetic toxidrome

. 5.3.  Management of psychiatric symptoms

. 5.4.  Management of withdrawal symptoms

6. Long term management for NPS use disorders

7. Conclusion

© Indian Psychiatric Society 2016 29

New Psychoactive Substances

EXECUTIVE SUMMARY

Introduction – New psychoactive substances (NPS) refer to a large and ever-increasing rubric of chemicals with pharmacological properties and clinical effects resembling a known illicit substance. During 2014, 500 psychoactive substances were officially notified for the first time in the European Union (EU). Since then, the EU’s early warning system has updated the list on a number of occasions. NPS are classified broadly into five categories: ketamine, piperazine, synthetic cathinones, synthetic cannabinoids, and plant based substances. These drugs might cause significant health hazards and also have the potential to cause addiction. Although there is no general population based survey on NPS, data from the emergency departments, poison research centers, and Internet surveys indicate an increasing trend of NPS use.

Methodology – This chapter focuses on two NPS, i.e. Synthetic cannabinoids and Syntheticcathinones. Therearenopublishedmeta-analysis,reviews,open-labeltrials, randomized double-blind trials, and placebo-controlled trials with regard to the management of NPS intoxication. Hence, the evidence of this guideline is based on case reports, case series, and expert opinions. Therefore as per the Appraisal of Guidelines for Research & Evaluation (AGREE) Instrument II the level of evidence is mostly at level D.

Profile of NPS users – NPS use has been observed in a distinctive group of population. Hence, identifying this group would be important for managing suspected NPS toxicity. Demographically most of them are adolescent or young adult males, with mostly homosexualorientation. Amajorityoftheseindividualsarealsoregularcannabinoids or cocaine users. A substantial majority uses these drugs in the night clubs and procures it through online purchasing.

Assessment of suspected case of NPS intoxication – Most of the patients with NPS use would be encountered in the emergency departments. Manifestations of the adverse effects due to these groups of drugs could be psychiatric or due to physiological. Detection of such cases with NPS intoxication/toxic effects depends on obtaining a recent intake of these substances. However, many a time history is not available or even there is a history of recent ingestion, effects of these drugs could be modified by other confounding variables due to simultaneous intake of other illicit substances. Nevertheless there are certain clinical indicators which suggest NPS toxicity. A sympathomimetic toxidrome is almost universal for all types of NPS (especially for synthetic cannabinoids/cathinones). NPS intoxication might also present with behavioural manifestations like, sudden onset unprecedented violence, suicidal behaviour and hallucinations. In addition to these, there are demographic indicators as mentioned already. In presence of these clinical indicators, laboratory analysis of biological specimens should be sent for identification of NPS or other illicit substances.

© Indian Psychiatric Society 2016 31

However, major limitations of these laboratory procedures are the availability and the time and expertise required to analyze and interpret results. In addition to direct detection of the chemical in the sample, there are certain laboratory changes (like hyperglycemia, hyponatremia, increased creatinine, changes in ECG) that have been detected in Spice/Bath salt intoxication. Although these all are non-specific changes which can happen in plethora of other medical conditions, in the presence of other clinical/historical evidence these laboratory parameters might have some supportive role to play.

Management of NPS intoxication/toxicity – Diagnosis of exposure, intoxication, and or toxicity can be challenging, as patients may be unable to share key historical details. The emergency and acute care physician must maintain a high index of suspicion for these toxins. No specific antidotes exist for NPS toxicity. Hence, management is always supportive. Most cases could be managed in the emergency with regular monitoring/observation. Patients need to be admitted in the intensive care unit, if they required to be intubated, with severe hyperthermia, recurrent seizures, coma, and arrhythmia. In case patients have predominant psychiatric symptoms, they could be transferred to a special psychiatric unit. Management might be grossly divided into three categories, treatment of sympathomimetic toxicity, behavioural/psychiatric problems, and withdrawal symptoms. The mainstay of treatment is benzodiazepines. Anti-psychotics are not the first preferred option for psychotic symptoms or violence, as these might lower the seizure threshold.

Treatment of withdrawal – Treatment of withdrawal symptoms is supportive and gradual dose reduction is not necessary.

Long term management – Evidence is limited to make any comments.

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Newer and Emerging Addictions in India

New Psychoactive Substances

1. INTRODUCTION

New psychoactive substance (NPS) is the term which encompasses a huge rubric of chemicals with pharmacological properties and clinical effects resembling a known illicit substance.1 The actual ‘image’ of these groups of psychoactive substances masquerades as common, apparently harmless consumer goods (like bath salts, incense, plant food, herbal products, etc.) or aura of science (research products) or substances which are ‘legal’ (hence also known as legal highs). The last point is important because many of these ‘NPS’s are still elusive to the legal watchdog agencies and thus could not be brought under proscription. This might be as a result of the discrepancy between ever emerging, fast growing innovative chemical tampering of NPS and slow, tedious, and convoluted drug policy.2 Thus the data regarding NPS are still underestimated and underappreciated.

Recognizing the salience of NPS, European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) was perhaps the first official organization to respond and furnish a special investigation report which described the new emerging phenomenon of NPS.3 During 2012, 57 psychoactive substances were officially notified for the first time in the European Union, with the EU’s early warning system reporting the appearance of more than one new psychoactive drug on the market every week.4 The recent number has reached up to 500.4 Moreover NPS are usually sold online through an amount of unregulated websites and are almost unknown to health professionals who may not be technically up to date/conversant, given the typical absence of up-to-date scientific literature and reliable sources of information.1,5,6 Thereafter classifying this ever increasing, broad, and mixed bag of NPS has been attempted by United Nations Office of Drug and Crimes (UNODC), as ketamine, Piperazines, Synthetic Cathinones, Synthetic cannabinoids, and plant based substances (Kratom, Salvia divinorum) (Panel 1).7 This could one hand improve research and recognition of these groups of substances but on the other might limit the exploration by drawing an artificial boundary.

The initial surveillance and tracking of NPSs took place in the European Union (EU) via an early warning network (Reitox), as well as an innovative Internet investigative project (Psychonaut) searching proactively for emerging patterns of drug abuse. A similarly coordinated early warning network exists in the USA called the Community Epidemiology Work Group (CEWG). The CEWG identified the emerging Synthetic cannabinoids (K2) epidemic in the Midwestern USA in 2010.7 In March 2011, the United States Drug Enforcement Administration (DEA) temporarily placed 5 synthetic cannabinoids (SC) into Schedule 1 of the Controlled Substances Act “to avoid imminent hazard to the public safety.8Amongst all exposures reported to American Association of Poison Control Centers between January 1, 2009, to April 30, 2012, Bath salts and synthetic THC exposures totaled 7467 and 11561, respectively. Bath salts exposures were 0 in 2009, 298 in 2010, and 6062 in 2011. Synthetic THC exposures were 14 in

© Indian Psychiatric Society 2016 33

2009, 2821 in 2010, and 6255 in 2011.9 This data although might represent the minuscule fraction of the actual threat definitely represent an increasing trend in the use of NPS (Bath salt and Spice to be precise).

For a clinician or a psychiatrist all these data could only be meaningful if the relevance of NPS in clinical practice could be demonstrated either in the form of health hazards or addictive potential. In the index chapter, we will be discussing about their health hazards at length. However, only handful of published literature addresses the issue regarding the addictive potential. A study amongst US dance drug users reported mephedrone, when used intranasal, to be perceived as more addictive and more risky than cocaine.10 A strong subjective ‘intoxicating effect’ of Spice has been demonstrated in another study.11 More studies are needed to settle this important issue.

Panel 1: Classification of New Psychoactive Substances (NPS) by UNODC4 (but see SPECIAL NOTES FOR INDIAN SCENARIO at the bottom of the panel)

Newer and Emerging Addictions in India

lKetamine1

lPiperazines- BZP, mcPP, TFMPP

lSynthetic cathinones (Commercial or colloquial name: Bath salt)- Mephedrone,2 Flephedrone, MDPV, Naphyrone

lSynthetic cannabinoids (Commercial or colloquial name: Spice)- JWH-018, JWH-073, JWH-200, CP-47,497, and (C8)-CP47,497

lPlant based substances- Kratom, Salvia divinorum

lAmino-indanes (Commercial or colloquial name: ‘pink champagne’)- 2-AI

lTryptamine(Commercial or colloquial name: ‘Foxy-methoxy’ or ‘alpha o alpha’)- 5-MeO-DMT, 5-MeO-DPT, AMT, 4-AcO-DMT

lOther substances- 1,3-dimethylamylamine (DMAA)

SPECIAL NOTES for Indian scenario:

1. Since November 2013, ketamine hydrochloride has been placed in the Schedule X of the Drugs and Cosmetics Rules (Sixth Amendment, 2013), meaning thereby that, in view of of its serious abuse potential, it is now placed under the most stringent schedule though still legal to prescribe with prescribed precautions

2. Since February 2015, mephedrone and its salts and preparations have been placed in Schedule I of the Psychotropic Substances of the Narcotic Drugs and Psychotropic Substances (Amendment) Rules, 2015, thus making their use etc. illegal other than for medicinal and scientific purposes as per the provisions of the NDPS Act 1985.

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New Psychoactive Substances

2. SCOPE AND METHODOLOGY OF THE GUIDELINE

In our opinion it might be too early to formulate a clinical practice guideline for the management of NPS as the evidence available so far is entirely based on case reports, case series and a few surveys. Hence, we thought of providing an overview on the profile of NPS users, methods of detection of NPS in body samples and the health hazards associated with the NPS use; all of which are relevant for the screening, assessment and treatment of NPS ‘intoxication’ which is practically the only formal diagnosis we could vouch for at the present moment. Moreover, as already has been defined, the index chapter will be focused on two NPS i.e. Synthetic cannabinoids and Synthetic cathinones.

We searched PubMed (http://www.ncbi.nlm.nih.gov/pubmed) to identify published meta-analysis, reviews, open-label trials, randomized double-blind trials, placebo- controlled trials, and case reports written in English, focusing on the synthetic cannabinoids and cathinones. In addition, we have searched Scopus, Google Scholar, and PsychInfo to identify any other study missed. The following keywords were used: synthetic cannabinoids, synthetic cathinones, Spice addiction, Bath salts addiction, New Psychoactive Substance (NPS). The search was conducted on 7th June, 2015. Only selection of synthetic cannabinoids and clinical trial had yielded no results relevant to this chapter (barring results on clinical efficacy of synthetic cannabinoids). When we customized and broadened our search by including all article types and tried to found out literature before 2011, once again there was no relevant result gathered; however, 2011 onwards we could locate total 600 studies (including 90 narrative reviews). However, more than half of these articles are on role of synthetic cannabinoids in various disorders. The keyword New psychoactive substance and synthetic cathinones yielded 586 and 152 results overall.

3. PROFILE OF NPS USERS

A central question is regarding the profile of users of NPS. The speculative users of NPS could be younger generation or professionals who might be using to obviate the risk of detection. The reason for using could be accidental or deliberate to have the legal high. Questions are asked whether NPS is a supplement or substitute of other illicit substances. To answer these questions maximum data are available for Spice (Synthetic cannabinoids). Studies across the Continents have revealed that Spice is an international phenomenon used primarily by adolescents and young adults and a gender gap, with men more than twice as likely to use Spice than women.12-13 Data from the American Poison Research Centre has almost demonstrated similar findings for Spice with a slightly young user profile (13-19 years). The same report has shown the most common usersofBathsaltstobeintheagerangeof20-29years. Intentionalabuseandinhalation were most common reason for and mode of exposure, respectively.9 Another survey on Spice revealed that in about one in five individual it was the preferred drug and primary

© Indian Psychiatric Society 2016 35

reasons for use were curiosity, positive drug effect, relaxation, and to get high without having a positive drug test.14 Moreover, acute subjective effects were reported to be similar to known effects of cannabis. In addition to this survey, a recent report has shown that use of Spice is widely prevalent amongst cannabis users.15 Whether NPS is a supplement or substitution for the existing illicit substance use, to find out an answer to this important issue, a study has been conducted in the UK. The results show that NPS are likely to be added to drug repertoires rather than replacing it, particularly amongst experienced users with consequent health risks for individuals and resource implications for services.16 As college goers fall in the vulnerable age group for Spice, studies amongst college students appear to be well justified. In a longitudinal study conducted in two colleges in the US has revealed that weighted lifetime prevalence of K2 and Spice use at college entry was 7.6%. An additional 6.6% of students reported first use during college. By the cohort’s fourth year, 17.0% reported lifetime K2 and Spice use. K2 and Spice use at college entry was associated with sensation seeking; hookah, marijuana, and illicit drug use; and low religiosity, which further substantiates the previous findings from the general population or poison centers.17 A potential space in which NPS might be used is in the discos. In a study from US night life scenes, 8.2% reported use of synthetic cannabinoids and 1.1% reported the use of mephedrone. Gay and bisexual men reported higher prevalence of mephedrone use. Latinos reported higher prevalence of synthetic cannabinoid use.18 A study of mephedrone use among dance drug users in the UK suggests that users of this substance are likely to be younger and male. Over 40% of these UK dance drug users reported the use of mephedrone. Additionally, other research indicates that many users in the UK continued the use of mephedrone after its ban despite a subsequent price increase, suggesting that the substance may be becoming entrenched within a broader class of club drugs within some scenes.10It has been cited as popular in some European nightclubs, such as in London, even after its prohibition with prevalence in one sample of attendees of gay- friendly clubs at 41%.9 From these studies it is quite apparent that in both sides of the Atlantic, Spice and mephedrone are used extensively by a special group of population. Due to difficulties with its detection through standard testing, it may be an attractive substance of abuse for military personnel. However, few studies have examined the consequences of its use in this population. In one of the US surveys conducted amongst treatment seeking military personnel, 11% reported using SC in the last 90 days and more than 65% of them reported Spice as their preferred drug.19 (Panel 2)

36 © Indian Psychiatric Society 2016

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New Psychoactive Substances

Panel 2: Profile of individual with New Psychoactive Substance (NPS) use

lAge – adolescents (Spice users are younger than others like users of Bath salt) lGender- Male> Female
lVulnerable users- people with cannabis/cocaine use
lSpecial demographic risk population- Gay and Lesbian, military personnel lImportant locus of use- night clubs

4. ASSESMENT OF SUSPECTED CASES OF NPS INTOXICATION

4.1 Clinical assessment

Most of the patients with NPS use would be encountered in the emergency departments. Manifestations of the adverse effects due to these groups of drugs could be psychiatric or due to physiological. Data regarding their ‘toxic’ effects and management are retrieved from the surveys conducted by National level Poison Centers and from case reports and case series. Hence the level of evidence is still a matter of debate and conjecture.

Detection of such cases with NPS intoxication/toxic effects depends on obtaining a recent intake of these substances. However, many a time history is not available or even there is a history of recent ingestion, effects of these drugs could be modified by other confounding variables due to simultaneous intake of other illicit substances.20 Nevertheless there are certain clinical indicators which suggest NPS toxicity (Panel 3). A sympathomimetic toxidrome is almost universal for all types of NPS (especially for synthetic cannabinoids/cathinones). Commonly reported effects include diaphoresis, palpitations, muscle tension or spasms, and bruxism (jaw clenching). In severe cases sympathomimetic toxicity is manifested by neurological and cardiovascular clinical features. The use of bath salts has been associated with cardiac arrhythmias.21 Acute drug toxicity is the leading cause of synthetic cathinone-induced fatality. Concomitant consumption of synthetic cathinones and other drugs have been reported in numerous fatalities.22-25 Concurrent use of synthetic cathinones with other stimulants leads to significantly greater monoamine toxicity, which may underlie the high frequency of polydrug use fatality associated with the synthetic cathinones.26 Other common and rare features of toxicity have been mentioned in the Table 1.

Toxicity of these substances depends on the amount and mode of intake, concomitant intake of other illicit substances, and time lapsed. Most designer stimulants are taken intranasally but may be consumed orally or via intravenous or intramuscular injection. Mephedrone is not suitable for smoking. Anecdotally, the effects generally start about 10-20 minutes after dosing, peak at 45-90 minutes, last 2-3 hours, and then decrease over 6-12 hours. Users may consume multiple doses during a session to prolong the desired effects.20 Synthetic cannabinoids are primarily smoked via a joint, bowl, or

© Indian Psychiatric Society 2016 37

water pipe, although they can be consumed orally or intranasally. Acute effects are similar to cannabis, including alteration in mood, conjunctival injection, and tachycardia. Effects are reported to start within 10 minutes after inhalation, and most effects appear to dissipate 2-6 hours after use.20

Following physical parameters must be examined in a suspected case of NPS use: body temperature, pulse (tachycardia), blood pressure (hypertension), monitoring urine output (oliguria/ anuria), general physical examination (for diaphoresis, needle marks, ecchymosis, conjunctival injection), ENT examination (nasal perforation, poor oral hygiene), examination for muscle tenderness (rhabdomyolysis), abdominal examination (hepatomegaly and tenderness),and neurological examination (clonus). Acute onset agitation or hallucination (or other psychotic symptoms) in a patient without any prior psychiatric history and with a history of recent drug/herbal product consumption must raise the suspicion of NPS toxicity. Synthetic cathinone hallucinations are frequently auditory and tactile in nature and paired with psychoses that can be severe and long lasting; many patients are admitted days after cessation of drug use and psychotic symptoms persist for several days thereafter while receiving treatment.27-28

Table 1. Physical findings associated with New Psychoactive Substance (NPS) use

Newer and Emerging Addictions in India

Body systems

Physical findings/ Clinical syndromes

Suspected NPS

Association with the NPS

General

Hyperthermia

Synthetic hallucinogens, bath salts

Intoxication

Cardiac

Tachycardia, Hypertension
Chest pain: might indicate cardiac ischaemia/myocarditis

Any NPS
Bath salts, synthetic cannabinoids

Recent use

Neurologic

Clonus Seizures

Synthetic hallucinogens Bath salts, synthetic hallucinogens, synthetic cannabinoids

Recent use Intoxication

Head & neck

Conjunctival injection Smoky chemical smell on breath
Epistaxis, nasal septal perforation

Jaw clenching, teeth grinding (bruxism)

Synthetic cannabinoids Any smoked NPS

Bath salts Bath salts

Recent use

Intra-nasal use Intoxication

Renal

Acute kidney injury

Synthetic cannabinoids

Recent use

38 © Indian Psychiatric Society 2016

New Psychoactive Substances

Body systems

Physical findings/ Clinical syndromes

Suspected NPS

Association with the NPS

Gastrointestinal

Nausea, vomiting Enlarged and/or tender liver: Acute hepatitis

Synthetic cannabinoids Any injected NPS

Recent use or withdrawal

Musculoskeletal

Muscle spasms
Limb swelling and pain: rhabdomyolysis

Bath salts
Bath salts, synthetic hallucinogens

Intoxication

Skin

Diaphoresis Ecchymosis
Fresh needle marks, track marks

Bath salts
Synthetic hallucinogens Any injected NPS

Recent use Recent use or intoxication

Psychiatric

Agitation
Psychosis (with or without hallucinations) Self mutilation

Any NPS
Synthetic cathinones

Recent use Recent use or intoxication

Adapted from Weaver et al., Designer drugs 2015: assessment and management. Addict Sci Clin Pract. 2015; 10(1): 8.20

Panel 3: When to suspect New Psychoactive substance (NPS) toxicity?

lHistorical evidence- recent intake of some unknown commercial herbal product purchased online or definitive history of consumption of Spice/Bath salts; individual with history of regular intake of cannabis, stimulants or other psychoactive substance

lDemographic pointers- young adults or adolescent males, with a homosexual orientation hailing from a night club

lEvidence from physical findings- conjunctival injection, odor of smoky chemical in the breath, perforated/ulcerated nasal septum, increased body temperature, palpitation, high blood pressure, decreased urine output, bruxism, muscle tenderness

lSuggestive clinical features- seizure in an individual, who is a known cannabis user; acute renal failure and rhabdomyolysis without any apparent physical cause

lBehavioural indicators- acute onset agitation, hallucination, self mutilating behaviour in an individual without any prior psychiatric history

4.2 Laboratory assessment

Detection of NPS is considered at two levels. First, in the suspected commercially available products and second which is important for clinicians, detection in biological

© Indian Psychiatric Society 2016 39

samples of subjects supposedly had consumed some of these products before landing up in the emergency. For the purpose of current practice guideline, by the phrase detection in laboratory, would be referred to the latter. Detection of NPS in the laboratory is always a challenging task. Whereas cases of intoxication and death have been reported, the phenomenon appears to be largely underestimated and is a matter of concern for Public Health. One of the major points of concern depends on the substantial ineffectiveness of the current methods of toxicological screening of biological samples to identify the new compounds entering the market.29 As stated earlier, the focus of the discussion would be on synthetic cannabinoids/cathinones (SC). There are a number of unique challenges to the laboratory detection of these substances present in the urine, oral fluid, and serum samples of people who have consumed Spice/Bath salt.

lContains synthetic cannabinoids/cathinones from different chemical classes lContains minimal amount of these substances
lComposition that is constantly changing

Therefore, a laboratory test that is to be of clinical utility would require a single or battery of tests that could detect cannabinoids/cathinones or their metabolites belonging to several chemical classes. The most common biological sample analyzed for the assessment of SCs is blood. Other samples which have been tested are urine and oral fluid.20

Several synthetic cannabinoids including JWH-018 and many of their downstream metabolites can be measured in the serum through liquid chromatography tandem mass spectrometry (LC-MS/MS) and gas chromatography mass spectrometry (GC/MS). However, LC-MS/MS and GC/MS methods require extraction, concentration, or derivation techniques that are time consuming. There are no commercially available laboratory tests for the detection of synthetic cannabinoids. These tests cannot be performed on-site at most institutions. Thus, the results would not be immediately available and would be unlikely to inform clinical decision-making.30-32 Synthetic cathinones can be identified using gas chromatography–mass spectrometry or liquid chromatography–mass spectrometry techniques. They can be measured in blood, urine, and stomach contents in both pre and postmortem specimens. Correlation of concentrations with clinical effects is not well understood. Blood concentrations of methedrone in specimens taken from suspected drug offenders ranged in one series from 0.2 to 4.8 ìg/g blood. Mephedrone concentrations in urine specimens taken after use in the preceding 24 h ranged from 0.6 to 7.35 mg/Ml. Synthetic cathinones can be analyzed in hair. A rat model suggests that cathinone and methcathinone are poorly incorporated into hair, but that methylone is well incorporated.33-36

As already mentioned one of the major limitations of these laboratory procedures is the time and expertise required to analyze and interpret results. A recent study has demonstrated the feasibility of a simple liquid chromatography-tandem mass

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New Psychoactive Substances

spectrometry (LC-MS/MS) screening procedure for NPS in blood. Simultaneous screening for 143 substances (including SCs) from different groups would be possible. The limits of detection (LODs) estimated for 104 compounds were in the range 0.01- 3.09 ng/mL, which is reasonably good. However, the extraction recoveries determined for 32 compounds were from 1.8 to 133%.37 Despite having some limitations, this study should promote further research.

In addition to direct detection of the chemical in the sample, there are certain laboratory changes which have been detected in Spice/Bath salt intoxication (Table 2). Although these all are non-specific changes which can happen in plethora of other medical conditions, in the presence of other clinical/historical evidence these laboratory parameters might have some supportive role to play.

Recommendations: If a patient presents with sympathomimetic toxidrome and presence of any red flag signs as mentioned in Panel 3 (Historical, demographic, physical, clinical, and behavioural), following investigations could be advised:

lSend a laboratory test for synthetic cannabinoids/cathinones (SC) [if available] lUrine drug screen for cannabinoids, amphetamines, cocaine, heroin
lA positive test for SC- substantiate the diagnosis
lNegative test for SC- not rule out NPS toxicity

lNegative other drug screen- suggestive evidence
Table 2. Laboratory changes associated with the use of

synthetic cannabinoids/cathinones

Laboratory findings

Observed values

Associated psychoactive substance

Hyperglycemia

170 to 220 mg/Dl

Synthetic cannabinoids

Hypokalemia

2.3 to 3.5 mmol/L

Synthetic cannabinoids

Hyponatremia

120-135 mmol/L

Synthetic cathinones

Hyperkalemia

>5.2 mmol/L

Synthetic cathinones

Elevated Creatinine

3.2-21.0 mg/dL

Synthetic cannabinoids, Synthetic cathinones

Acidosis

pH of 7.24 and a pCO2 of 63

Synthetic cannabinoids, Synthetic cathinones

Elevated Creatinine Phosphokinase

867 to 2649 U/L

Synthetic cannabinoids, Synthetic cathinones

Elevated White Blood Cell Count

13,000 to 19,000 cells per microliter

Synthetic cannabinoids

Adapted from Spadarna et al., Spicing thing up: synthetic cannabinoids. Psychopharmacology (Berl). 2013; 228(4): 525–540.33

© Indian Psychiatric Society 2016 41

5. MANAGEMENT OF SYNTHETIC CANNABINOIDS/CATHINONE INTOXICATION/TOXICITY

Diagnosis of exposure, intoxication, and or toxicity can be challenging, as patients may be unable to share key historical details. The emergency and acute care physician must maintain a high index of suspicion for these toxins when evaluating patients with signs and symptoms of sympathomimetic toxicity and all those pointers mentioned elsewhere (Panel 3) must be kept in mind. No specific antidotes exist for NPS toxicity. Hence, management is always supportive.

5.1 Treatment settings:

Usually cases of NPS toxicity are encountered in the emergency departments. Most cases could be managed in the emergency with regular monitoring/observation and till the disappearance of physical symptoms or correction of underlying metabolic/physiological disturbances. Patients could be discharged once they are stabilized.38 Those with persistent vital sign, neurologic, or psychiatric abnormalities should be admitted. Patients need to be admitted in the intensive care unit, if they required to be intubated, with severe hyperthermia, recurrent seizures, coma, and arrhythmia.39 In case patients have predominant psychiatric symptoms like hallucinations, hostility, suicidal tendencies, they could be transferred to a special psychiatric unit.40 Admission to the Medical ward might be necessary in case of renal failure and acute hepatitis. In a case series of 35 patients who presented to the ED after using “bath salts,” 26% were admitted to an intensive care unit, 14% to the medical floor, and 9% to the psychiatric unit.41

5.2 Management of sympathomimetic toxidrome:

Physical signs of most of the NPS intoxication (especially Synthetic cathinones) are consistent with sympathomimetic toxicity, which include hypertension, tachycardia, hyperthermia, dehydration, and psychomotor agitation. The most commonly reported adverse symptoms include palpitations, headache, chest pain, trismus, bruxism, tremors, and insomnia. Current practice is based on the treatment experience with other sympathomimetic agents, and supportive care is the mainstay of therapy. Aggressive sedation with benzodiazepines is indicated as needed for agitation, seizure, tachycardia, or hypertension. If hypertension persists, it is reasonable to treat with titratable vasodilators (i.e., nitroglycerin or sodium nitroprusside). Beta blockade should be avoided due to potential exacerbation of hypertension due to unopposed alpha-adrenergic stimulation. Significant hyperthermia may require passive or active cooling if not resolved with anxiolysis and sedation.42-43 The recommendations have been mentioned in the management algorithm.

5.3 Management of psychiatric symptoms:
Unprecedented hostility, violence, and suicidal behaviour could be present during

Spice or Bath salt intoxication. Although not systematically studied, during these

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New Psychoactive Substances

episodes the safety of the patient and the people around would inevitably become the cornerstone of treatment. Patients need to be isolated in a safe and calm place with minimal environmental stimulation. Benzodiazepines could be prescribed if violence could not be managed by conservative means. The dose and the choice of benzodiazepines remain speculative. However, based on the treatment experience with other violent patients, perhaps lorazepam in a slow intra-venous route with periodic monitoring of vitals might be considered.38,44

Psychosis due to synthetic cannabinoids (SC) and cathinone intoxication have been managed with monitored observation. For psychopathological clinical features, benzodiazepines have been used to treat anxiety, agitation, and seizures. Antipsychotics are second-line agents for agitation, due to the lowered seizure threshold with use of cathinone and phenethylamine designer drugs. Sedation may be required if the patient is markedly agitated and at risk for harm to self or health-care staff. Since some designer drug-associated psychosis may be severe and require prolonged inpatient treatment, psychiatric consultation is indicated, in particular for those with persistent symptoms.20,45

If marked psychiatric symptoms persist longer than one or more weeks after discontinuation, the patient should be evaluated carefully to determine whether he or she has a co-occurring primary psychiatric disorder, which then should be treated with specific therapy. Treatment of prolonged anxiety, depression, or psychosis is the same as when these conditions are not associated with recent designer drug use.46-47

The recommendations have been mentioned in the management algorithm.

5.4 Management of withdrawal symptoms:

Abrupt discontinuation of stimulants or hallucinogens does not cause gross physiologic sequelae, so they are not tapered off or replaced with a cross-tolerant drug during medically supervised withdrawal. Abrupt discontinuation of SC could result in withdrawal symptoms such as nausea and irritability, similar to that with cannabis cessation. However, there is no indication for pharmacologic replacement (e.g., dronabinol), since SC withdrawal is not life-threatening. Patients can be treated with supportive care by intravenous fluids and antiemetics if necessary.48-49

The recommendations have been mentioned in the management algorithm.

© Indian Psychiatric Society 2016 43

Management algorithm

Newer and Emerging Addictions in India

Patient in emergency with features of sympathomimetic toxidrome (high pulse, blood pressure, tremor, insomnia, anxiety) [D] What does this recommendation mean?

Send a laboratory test for synthetic cannabinoids/cathinones (SC) [if available]
Urine drug screen for cannabinoids, amphetamines, cocaine, heroin

A positive test for SC- substantiate the diagnosis Negative test for SC- not rule out NPS toxicity

Negative other drug screen- suggestive evidence [D]

 

Presence of any red flag signs as mentioned in Panel 3 (Historical, demographic, physical, clinical, and behavioural) [D]

       

(C) Shift to Medical unit lAcute hepatitis, lAcute renal failure [D]

(A) Shift to ICU lSevere hyperthermia, lRecurrent seizures, lComa, lArrhythmia [D]

 

(D) Manage in the emergency
If neither (A) nor (B) or (C) is present
[D]

(B) Shift to Psychiatry unit lViolence, hostility (if not managed conservatively)

lSuicidal behaviour lPsychotic symptoms

(especially if persistent)

   

Sympathomimetic toxidrome: Conservative management
lPhysical monitoring- blood pressure, pulse, urine output, body temperature
lInvestigations- ECG, Serum electrolytes, urea/creatinine, blood glucose
lSymptomatic management- Benzodiazepines [C/D] for agitation; nitroglycerine for hypertension

[D]

Psychiatric symptoms: (violence, hallucination, suicidal behaviour)
lConservative management- Providing a calm/supportive/non-threatening environment lIf not controlled- Benzodiazepines
lIf not controlled with benzodiazepines- Second generation anti-psychotics (Low dose) lFor persistent psychotic symptoms- consider possibility of an independent psychiatric disorder

[D]

Withdrawal symptoms:

lAbrupt stoppage of the substance (NPS) lManage anxiety with benzodiazepine lManage nausea/vomiting with anti emetics

[D]

44 © Indian Psychiatric Society 2016

New Psychoactive Substances

6. LONG TERM TREATMENT FOR NPS USE DISORDERS

Data are grossly insufficient to comment on the feasibility, necessity, and efficacy for the long term treatment of NPS use disorders. Although there has been some evidence suggesting the addictive (or dependence producing) potential of NPS, the current literature is inadequate to make a conclusive impression.10,11 However, hospitalization for the adverse effects of designer drugs affords an excellent opportunity (teachable moment) for advising patients to decrease their substance use and for engaging them in treatment.50 Explaining about the risks and the harms associated with such drug use, exploring about patient’s ambivalence and resolving the same, encouraging healthy choice and a special focus on harm reduction could be implemented during the time of hospitalization. Long-term treatment of designer drug use disorders likely involves similar components to that of other types of addiction treatment, including behavioural components, such as individual and group counseling with cognitive-behavioural therapy, motivational enhancement therapy, and 12-Step self-help group facilitation. Family members should be considered as part of the treatment program, in particular when treating adolescents or young adults. Unfortunately, pharmacologic treatment data to guide management of those with designer drug use disorders are unavailable. Although the empirical evidence needed to substantiate the effectiveness of these strategies is lacking, extrapolation of other literature related to this area provides an indirect validity.20,51

7. CONCLUSION

New psychoactive substance (NPS) includes a wide range of chemicals (either manufactured in the laboratory or derived from plant products) which are definitely physically harmful and perhaps addictive. The number and type of substances are rapidly growing and emerging, making the list ever proliferative and almost impossible to reproduce. Based on epidemiological data and clinical pragmatism, the index guideline had included two of the most important NPS namely, synthetic cannabinoids (Spice) and synthetic cathinones (Bath salts). No randomized controlled trials have been undertaken till date. Overall the area is riddled by gray and dark zones. Current research has been aimed at finding the profile of users, detection of these substances in biological fluids, manifestation and management of toxicity resulting from the intoxication/overdose of these substances. More research is required to give more than an impressionistic overview in these areas. New studies are warranted exploring the addictive potential and long term course, outcome and management of NPS users.

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37. Adamowicz P, Tokarczyk B. Simple and rapid screening procedure for 143 new psychoactive substances by liquid chromatography-tandem mass spectrometry. Drug Test Anal. 2015 May 14. doi: 10.1002/dta.1815. [E-pub ahead of print]

38. Simmons J, Cookman L, Kang C, Skinner C. Three cases of “spice” exposure. Clin Toxicol (Phila) 2011;49:431–433.

39. Synthetic cathinone derivatives. In: POISINDEX® System [Internet database]. Thomson Reuters (Healthcare) Inc. Accessed 20 June 2015

40. James D, Adams RD, Spears R, Cooper G, Lupton DJ, Thompson JP et al. Clinical characteristics of mephedrone toxicity reported to the UK National Poisons Information Service. Emerg Med J 2010; 28:686–9.

41. Rosenbaum CD, Carreiro SP, Babu KM. Here today, gone tomorrow…and back again? A review of herbal marijuana alternatives (K2, Spice), synthetic cathinones (bath salts), kratom, Salvia divinorum, methoxetamine, and piperazines. J Med Toxicol. 2012;8:15-32.

42. Center for Disease Control and Prevention Emergency department visits after use of a drug sold as “bath salts”—Michigan, November 13, 2010–March 31, 2011. MMWR. 2011;60:624–7.

43. Olives T, Orozeo B, Stellpflug S. Bath salts update: meow meow and MTV. ACEP Toxiciology Section 2011, Newsletter.

44. Hill SL, Doris T, Gurung S, Katebe S, Lomas A, Dunn M. Severe clinical toxicity associated with analytically confirmed recreational use of 25I-NBOMe: case series. Clin Toxicol (Phila) 2013;51:487–92.

45. Spiller HA, Ryan ML, Weston RG, Jansen J. Clinical experience with and analytical confirmation of “bath salts” and “legal highs” (synthetic cathinones) in the United States. Clin Toxicol (Phila) 2011;49:499–505.

46. Stellpflug SJ, Kealey SE, Hegarty CB, Janis GC. 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2- methoxyphenyl) methyl] ethanamine (25I-NBOMe): clinical case with unique confirmatory testing. J Med Toxicol. 2014;10:45–50.

47. Gunderson EW, Kirkpatrick MG, Willing LM, Holstege CP. Intranasal substituted cathinone “bath salts” psychosis potentially exacerbated by diphenhydramine. J Addict Med. 2013;7:163–8.

48. German CL, Fleckenstein AE, Hanson GR. Bath salts and synthetic cathinones: an emerging designer drug phenomenon. Life Sci. 2014; 97:2-8.

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49. Weaver MF, Schnoll SH. In Addictions: A Comprehensive Guidebook. In: McCrady BS, Epstein EE, editors. Stimulants: amphetamines and cocaine. New York: Oxford University Press USA; 1999. pp. 105–20.

50. Martins SS, Copersino ML, Soderstrom CA, Smith GS, Dischinger PC, McDuff DR. Sociodemographic characteristics associated with substance use status in a trauma inpatient population. J Addict Dis. 2007;26:53–62.

51. Weaver MF, Jarvis MA, Schnoll SH. Role of the primary care physician in problems of substance abuse. Arch Intern Med. 1999;159:913–24.

© Indian Psychiatric Society 2016 49

COCAINE

Subodh B.N. Aniruddha Basu

On behalf of
Indian Psychiatric Society
Specialty Section on Substance Use Disorders

2016

Cocaine

Executive Summary

1. Introduction

. 1.1  Epidemiology

. 1.2  Pharmacology

. 1.3  Mechanism of action

. 1.4  Consequences of cocaine use

2. Cocaine use disorders

3. Scope and methodology of the guideline

. 3.1  Scope of the Guidelines

. 3.2  Methodology of Guideline development

4. Review of treatment modalities

. 4.1  General Issues

. 4.2  Treatment Aims / Goals

5. Assessment of cocaine use disorders

. 5.1  Brief Overview

. 5.2  Clinical History

. 5.3  Physical Examination

. 5.4  Instruments

. 5.5  Investigations

6. Short term management

. 6.1  Management of cocaine intoxication

. 6.2  Management of cocaine withdrawal

7. Long term management of cocaine use disorders

7.1 Pharmacological agents 7.1.1 Topiramate

7.1.2 Modafinil
7.1.3 Disulfiram 7.1.4 Stimulants 7.1.5 Anticonvulsants 7.1.6 Antipsychotics 7.1.7 Antidepressants

CONTENTS

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. 7.1.8  Dopamine agonists

. 7.1.9  Cocaine Vaccine

7.1.10 Other medications
7.1.11 Use of Combination Pharmacotherapy

. 7.2  Psychosocial treatment

. 7.2.1  Behavioural approaches

. 7.2.2  Cognitive behavioural therapy

. 7.2.3  Twelve step facilitation program

. 7.2.4  Motivational enhancement therapy

. 7.2.5  Other psychotherapeutic approaches

. 7.3  Combined psychosocial and pharmacological management

8. Special Population

8.1 Pregnancy
8.1.1 Evidence Base

8.1.2 Conclusion
8.2 Attention Deficit Hyperactivity Disorder

8.2.1 Evidence base

8.2.2 Conclusion

9. Recommendations

54

© Indian Psychiatric Society 2016

9.1 9.2

Some issues to be considered before arriving at recommendations Recommendations

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Cocaine

EXECUTIVE SUMMARY

Cocaine a classic stimulant has emerged as one of the most common drugs used worldwide. Cocaine use disorders are associated with high mortality and morbidity worldwide. There is not much data on use of cocaine in India. Recently in last few years there are literature on use in media and one case series. As cocaine dependence syndrome like any other addictive disorders is a chronic relapsing and recurring condition, patients with cocaine use disorders will require a comprehensive multipronged care for continuous and prolonged period of time. An integrated bio- psychosocial approach to care is needed to address several aspects of the treatment. An active collaboration with the family while planning and delivering treatment is required.

The main goal of treatment is to maintain abstinence and if not possible decrease the frequency and severity of relapses and maximize functioning in between. The goals of treatment vary according to time frame, across individual patients and can be revised from time to time. It has been broadly divided into short term and long term goals. The short goals are management of intoxication, management of withdrawal symptoms, motivation enhancement, treatment of acute medical sequel and crisis intervention. Long term treatment goals are relapse prevention, maintenance of abstinence, occupational rehabilitation, social reintegration, abstinent life style and improving the quality of life of a person. This guideline will focus on the evidence available for the management of intoxication, management of withdrawal symptoms, and management of cocaine dependence. The current guideline used the AGREE II guidelines as template for proposing the guideline.

Assessment of Cocaine use disorders

A thorough and good assessment will help in diagnosing, establishing rapport, motivating the person and in formulating the plan of the management. The goal of assessment also varies in different phases of the treatment. During the first contact it is to establish rapport, diagnosis and plan of management, and during intervention it is monitoring the progress and assessing abstinence. The goal also depends on the context, motivation and cooperativeness of the client. If the client is uncooperative the aim of assessment is to retain the client in the treatment. During this time the information can be collected in pieces and information can be added when patient is co-operative.

A detailed assessment should include substance related factors (age of initiation, frequency, amount, tolerance, craving, withdrawal symptoms, salience, last dose, motivation, consequences of substance use), history of other substance use, physical and psychiatric comorbidity if any, abstinence related factors (past abstinence, duration, reasons for relapse, past treatment/s, methods used for controlling craving). It also includes history of high risk behaviours, presence of any externalizing disorders,

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physical and psychiatric comorbidity, family history of substance abuse and psychiatric illness, assessing social support, current living arrangements and reasons for current visit. A thorough physical examination is needed to assess for intoxication, withdrawal symptoms and evidence of physical damage due to alcohol use or other substance use. Investigations are used to confirm the presence of the cocaine, assess the degree of the physical damage and to confirm the presence of sexually transmitted disorders.

Some issues to be considered before arriving at recommendations

The proposed guideline is based on evidence obtained from developed countries (particularly USA) and none from India. Manifestations of cocaine intoxication and withdrawal are non- specific and are mostly self-limiting. Psychosocial interventions have reasonable evidence base and are recommended for cocaine use disorders.

Short term Management

The short term management is aimed towards medical stabilisation and engaging patient in process of treatment. The management of cocaine intoxication should include general assessment as described in ‘assessment’ with particular emphasis placed on physical status, mental status, substance use history and associated consequences. The acute effects of cocaine generally subside with time and they do not warrant any specific treatment. Specific pharmacological treatment is necessary when there is a history of recent use of other substance with physical consequences (e.g., respiratory depression, stroke, arrhythmias, etc.). In mild intoxicated state general measures like reassurance and maintenance in a safe and monitored environment do decrease external stimulation. Adequate hydration and nutrition should be provided. After the patient stabilizes then we need to assess the patient comprehensively and also assess for withdrawal and further management.

Management of cocaine withdrawal requires constant monitoring of signs and symptoms of withdrawal. The goals of the withdrawal are a) To relieve patient’s discomfort, prevent the occurrence of more serious symptoms, and forestall cumulative effects that might worsen future withdrawal; b) To utilise the withdrawal treatment opportunity to engage patients in long-term management. The withdrawal symptoms are self limiting. There are no well studied pharmacological agents to relieve symptoms of cocaine withdrawal. There is some evidence base for dopamine agonists like amantadine and bromocriptine, propranolol and other drugs. These drugs have given mixed results. The strength of evidence for these is at best (D) level and needs further studies for management of cocaine withdrawal.

Long term Management

Cocaine dependence is a chronic illness with lapses and relapses. Medications and psychosocial strategies are used for promoting abstinence and preventing relapse in

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patients with cocaine dependence. All the pharmacological agents used in cocaine use disorders have been studied along with psychosocial interventions. Hence patients should use whichever psychosocial approach they think beneficial or is available along with pharmacological agents.

Psychosocial treatments are the main stay of treatment – contingency management, community based reinforcement approaches and CBT have the highest efficacy (A). Other therapies like MET, mindfulness based therapies need further research (C).

Evidence for drug treatment is still preliminary – pharmacological treatment should be used in combination with psychosocial therapies (A). Modafinil and topiramate are emerging as prospective medications though currently evidence is not unequivocal and contradictory evidences exist (C). Currently disulfiram, dopamine agonists, antidepressants, anticonvulsants (except topiramate), psychostimulants, neither any combination of these medications are recommended. Cocaine vaccine has been found to be safe and shown promising results in Phase 1 & 2 research but not so promising response in Phase 3.

© Indian Psychiatric Society 2016 57

1. INTRODUCTION

Cocaine is one of the classic stimulants is a potent alkaloid derived from the leaves of coca plant grown by ancient Incas in Andes mountain1. Through explorers it travelled from South America to Europe. In the beginning of the twentieth century in the United States coca extracts was banned due to harmful consequences. In mid 1980s two new forms of cocaine emerged namely freebase cocaine and crack cocaine which are easily available ‘smokable’ forms making it easily available to the masses and thereby fuelling the ‘cocaine epidemic’2.

1.1 Epidemiology

Cocaine is one of the most common stimulant drugs used world-wide. The recent World Drug report states that 13.2 to 19.7 million cocaine users worldwide among adults aged 15 to 64 years (0.3%-0.4%)3. There is significant regional variation and cocaine is the second most common illicit drug in both the Americas. In Europe it is the most common illicit stimulant. In the Africa particularly in west and south it is common illicit drug4. For South Asia it has also entering into the scenario of drug problem. However, it is still restricted to mostly urban adolescents belonging to high socio-economic class who mostly visit rave parties or similar social gatherings. A case-series from India illustrates the recent development of such a problem5. Successive United Nations World Drug Report had cautioned about the emerging dangers of cocaine in south Asia. The indirect indicators like drug seizures and media highlights show that cocaine has already emerged in the India as burgeoning problem particularly among high risk groups like injection drug users6.

1.2 Pharmacology

Cocaine is extracted from the leaves of the erythroxylon coca by soaking leaves in organic solvent to form a thick paste7. If it is extracted with hydrochloric acid then the hydrochloride salt can be snorted, inhaled or taken by intravenous route8. The hydrochloride salt if treated with cocaine – benzoylmethylecgonine – is a naturally occurring crystalline alkaloid of the tropane family. It is a relatively small lipophilic molecule that is absorbed through mucous membranes and alveoli. About one-third of an oral or nasal dose of powered and up to 95% of an inhaled dose of freebase or crack cocaine may be bioavailable. Binding of cocaine to plasma proteins is minimal and its volume of distribution is low. Cocaine has a short half-life of 0.7 to 1.5 hours and is rapidly metabolized by plasma and liver cholinesterases to the major metabolites of benzoylecgonine and ecgonine-methyl ester. Benzoylecgonine is a neuropharmacologically active and cardiotoxic agent. These water-soluble metabolites are excreted in the urine. The time course of the physiologic effects of cocaine varies with the route of use, form of cocaine used, and concomitant use of other drugs9. The onset of effects occurs most rapidly with inhaled cocaine (3–5 seconds) followed by intravenous injection (10–60 seconds). The onset of effects is delayed with intranasal

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use (within 5 minutes) due to topical vasoconstriction. Conversely, the duration of effects is longest with intranasal cocaine use (60–90 minutes) and shortest with inhalation of crack cocaine (5–15 minutes). The short duration of effect with inhalation may lead to repetitive dosing to maintain desired effects. The frequent concomitant use of cocaine and ethanol results in the hepatic formation of the active metabolite, coca- ethylene, which has euphoric and sympathomimetic effects similar to cocaine but may also have greater toxicity. The longer half-life of cocaethylene (2.5 hours) may prolong the euphoric effects of cocaine10.

1.3 Mechanism of action

There are several mechanisms of action. The most commonly proposed mechanism is by acting at dopamine transporter (DAT) and increasing the concentration of extracellular dopamine in brain reward centres particularly the nucleus accumbens. This causes acute reinforcing effects11. Cocaine also has sympathomimetic actions in the peripheral tissues and quinidine like anaesthetic/ type I anti-dysrrhythmic properties. As a local anaesthetic, cocaine’s main effect is to block sodium channels in excitable tissues, and in massive doses it can interfere with the functioning of the potassium channels. The mechanism has been reviewed extensively in several reviews12.

1.4 Consequences of cocaine use

Cocaine affects different aspects of life of a person (medical, legal, financial, interpersonal etc.,) and their family members. Cocaine use is associated with high mortality and morbidity, reviewed extensively in several reviews13.

2. COCAINE USE DISORDERS

The current nosological approach to cocaine use disorders is14:

DSM-5

ICD-10

Substance use disorder

Substance dependence

Substance use disorders span a wide variety of problems arising from substance use, and cover 11 different criteria:

lTaking the substance in larger amounts or for longer than the time you meant to

lWanting to cut down or stop using the substance but not managing to

lSpending a lot of time getting, using, or recovering from use of the substance

lCravings and urges to use the substance

lNot managing to do what you should at work, home or school, because of substance use

At least three of the following six criteria which should have occurred together for at least one month or if persisting for periods of less than one month then they have occurred together repeatedly within a twelve month period):

A. A strong desire or sense of compulsion to take alcohol

B. Difficulties in controlling alcohol-taking behaviour in terms of its onset, termination, or levels of use

C. A physiological withdrawal state when alcohol use has ceased or been reduced, as evidenced by: the characteristic

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lContinuing to use, even when it causes problems in relationships

lGiving up important social, occupational or recreational activities because of substance use

lUsing substances again and again, even when it puts the you in danger

lContinuing to use, even when you know you have a physical or psychological problem that could have been caused or made worse by the substance

lNeeding more of the substance to get the effect you want (tolerance)

lDevelopment of withdrawal symptoms, which can be relieved by taking more of the substance.

withdrawalsyndromefor alcohol;oruse of the alcohol with the intention of relieving or avoiding withdrawal symptoms

D. Evidence of tolerance, such that increased doses of alcohol are required to achieve the effects originally produced by lower doses (clear examples of this are found in alcohol-dependent individuals who may take daily doses sufficient to incapacitate or kill non-tolerant users)

E. Progressive neglect of alternative pleasures or interests because of alcohol use, increased amount of time necessary to obtain or take alcohol or to recover from its effects

F. Persisting with alcohol use despite clear evidence of overtly harmful consequences

As per DSM-5cocaine use disorders are classified as mild, moderate and severe. As far this document is concerned most of the studies are based on cocaine dependence/ abuse/use – hence cocaine use disorder is used to include problem use, abuse and harmful use15.

3. SCOPE AND METHODOLOGY OF THE GUIDELINE

3.1 Scope of the Guidelines

These guidelines are neither comprehensive nor definitive. Cocaine use in India is rare but gradually in a transitional society like India it is being increasingly recognised as a problem. Currently it is used by only high socio-economic status of the society. Hence the treatment seeking is only restricted to private hospitals; hence large government hospitals, where most of the Drug Abuse Monitoring System is carried out, often miss them. This has led to very less research in this population. However, the growing importance of cocaine cannot be denied in the aftermath of globalization and increased availability. So we need guidelines and there is need to treat people suffering from cocaine dependence. Hence we have to depend mainly on research carried out in westernsetting. Indian psychiatristsandmentalhealthprofessionalscaringforpatients should consider the evidence base but not be limited by the recommendations made, as patients are cared in a number of different settings in our country. In the present form the guidelines are particularly applicable to De-addiction centres, and General hospital psychiatric centres. In this article we are not going to discuss about evidence base for management of dual diagnosis which requires a separate guidelines. Also this should not be considered as comprehensive enough to accommodate all know

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pharmacotherapy or behavioural interventions as around 60 medications have been tried. Equally important are the psychotherapeutic interventions – these need to be adapted to the Indian conditions for their best efficacy.

3.2 Methodology of Guideline development

The guideline seeks to summarise the recent data available on major treatments available for people with cocaine use disorder which might assist practitioners to ensure minimum standards of care. Relevant literature was identified through a PubMed literature search for publications related to this guideline. Searches were conducted; using the keywords like “cocaine abuse OR cocaine dependence OR cocaine use” The search yielded 35658 references till 20th Sep 2015. The search was restricted to human studies, written in the English language, and had abstracts, of which there were 21,568 studies. Among them relevant original articles, reviews of recent past were considered. Additionally, standard textbooks, bibliography of relevant articles and other guidelines like APA, NICE, BAP, WHO guideline for treatment of cocaine use disorders were also searched16,17. The Cochrane databases were also searched for relevant meta-analyses. The summary of treatment recommendations is keyed according to the level of evidences.

To maintain uniformity in standard and quality of guidelines, the Appraisal of Guidelines for Research & Evaluation II (AGREE II) Instrument has been used in preparing the guidelines. The strength of recommendation reflects not only the evidence but also the importance of the study.

4. REVIEW OF TREATMENT MODALITIES

4.1 General Issues

While treating patients with cocaine use disorders several factors should be taken into consideration. As cocaine dependence is a chronic relapsing and recurring condition, patients will require a comprehensive, continuous care for prolonged period. An integrated bio-psychosocial approach to care is needed to address several aspects of the treatment. An active collaboration with the family (particularly in India unlike in western countries) while planning and delivering treatment is required. Management of the cocaine use disorders should be sensitive to the needs and empirically titrated to the patient’s response and progress. The main goal of treatment is to maintain abstinence and if not possible then decrease the frequency and severity of relapses and maximize functioning in between. The specific goal depends on the stage at which patient presents.

4.2 Treatment Aims / Goals

The aims of treatment of cocaine dependence syndrome are:
Promote complete abstinence.
Stabilize acute medical (including cocaine intoxication/withdrawal) and psychiatric

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conditions, as needed.

Increase motivation for recovery.

Initiate treatment for chronic medical and psychiatric conditions, as needed.

Enhance coping and relapse prevention skills.

Improve occupational functioning, social support and assist in integrating to society on as needed basis.

Promote maintenance of recovery through ongoing participation in structured treatment or self-help groups.

The goals of treatment vary according to time frame, across individual patients and can be revised from time to time. It has been broadly divided into short term and long term goals. The short goals are management of intoxication, management of withdrawal symptoms, motivation enhancement, treatment of acute medical sequel and crisis intervention. Long term treatment goals are relapse prevention, to maintain abstinence, occupational rehabilitation, social reintegration, abstinent life style and improving the quality of life of a person. This guideline will focus on the evidence available for the management of intoxication, management of withdrawal symptoms, and management of dependence. Goals of treatment should be set and agreed between the patient and the clinician.

5. ASSESSMENT OF COCAINE USE DISORDERS

The assessment is very important as it forms the first point of contact and a thorough and good assessment will help in diagnosing, establishing rapport, motivating the person and in formulating the plan of the management.

5.1 Brief Overview

The assessment is very important as it forms the first point of contact and a thorough and good assessment will help in diagnosing, establishing rapport, motivating the person and in formulating the plan of the management. The goal of assessment also varies in different phases of the treatment. During the first contact it is to establish rapport, diagnosis and plan of management, and during intervention it is monitoring the progress and assessing abstinence. The goal also depends on the context, motivation of the client and cooperativeness of the client. If the client is uncooperative the aim of assessment is to retain the client in the treatment. During this time the information can be collected in pieces and information can be added when patient is co-operative.

5.2 Clinical History

A detailed assessment should include substance related factors such as age of initiation, frequency, amount, tolerance, craving, withdrawal symptoms, salience, loss of control, persistent despite harm, last dose, motivation, consequences of substance use (physical, psychological, financial, family problems, vocational and legal), history of other substanceuse, physicalandpsychiatriccomorbidityifany,abstinencerelatedfactors

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such as past abstinence, duration of abstinence, reasons for relapse, past treatments (pharmacological or non-pharmacological or both), methods used for controlling craving. It also includes history of high risk behaviours, presence of any externalizing disorders, physical and psychiatric comorbidity, family history of substance abuse and psychiatric illness, assessing social support, current living arrangements and reasons for current visit.

5.3 Physical Examination

A thorough physical examination to assess for intoxication, withdrawal symptoms and evidence of physical damage due to alcohol use or other substance use should be done. Also a thorough mental status examination and psychopathology in case of co-morbid psychiatric conditions should be done. Psychological or neuropsychological testing can be done for some individuals with history of cognitive impairment.

5.4 Instruments

Scales provide ways to structurally assess the individuals with cocaine use disorders. Some of the scales like ASSIST, Cocaine Selective Severity Assessment can be used to make diagnosis and identify the intensity of withdrawal symptoms.

5.5 Investigations

Investigations are used to confirm the presence of the cocaine, assess the degree of the physical damage and to confirm the presence of sexually transmitted disorders. Investigations such as liver function test, hemogram, GGT, VDRL, HIV in high risk cases can be used. Though not used routinely, in some cases, neuropsychological tests can be used to assess the cognitive function particularly in cases with medical, psychiatric complications or with co-morbid other substance use.

6. SHORT TERM MANAGEMENT

6.1 Management of Cocaine intoxication

Cocaine intoxication is commonly encountered in clinical settings particularly medical emergency settings. Diagnosis of intoxication can be made according to the criteria set up in ICD-10 or DSM-5. The clinical assessment should include general assessment as described in ‘assessment’ with particular emphasis placed on physical status, mental status, substance use history and associated consequences. If urine screens are available they can be screened and noted in the clinical history. The acute effects of cocaine intoxication generally subside with time and medications are needed for symptomatic management. Specific pharmacological treatment is necessary when there is a history of recent use of other substance use and with physical consequences (e.g., respiratory depression, stroke, arrhythmias, etc.,). If mildly intoxicated general measures like reassurance and maintenance in a safe and monitored environment do decrease external stimulation and provide orientation if necessary. Adequate hydration and nutrition should be provided. If patient is very anxious short acting low dose

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benzodiazepines and if severely agitated low dose antipsychotics can be used to control symptoms. While using benzodiazepines a close watch should be kept on respiratory difficulty and while using antipsychotics a close watch should be kept for occurrence of seizures and extrapyramidal symptoms. After the patient stabilizes then we need to assess the patient comprehensively and also assess for withdrawal and further management. The medical management of cocaine intoxication depending on the organ involved has been given in several medical guidelines18,19.

6.2 Management of cocaine withdrawal:

Though cocaine withdrawal does not produce the severe symptoms as seen in alcohol or heroin withdrawal and at one point of time its entity was debated, recent editions of Diagnostic and Statistical Manual and International Classification of Diseases have recognized it as a constellation of symptoms that occur after sudden cessation of cocaine intake. Since cocaine has a relatively short half-life of 90 minutes hence withdrawal symptoms may occur quite dramatically following the last dose particularly in the intravenous route. Initial pioneering study on cocaine withdrawal was done by Gawin and Klebel in 1980s. Using data from 30 out-patients they showed that there are three distinct phases of cocaine withdrawal namely ‘crash’, ‘withdrawal’ and ‘extinction’20. The phase one or ‘the crash’, developed rapidly following abrupt cessation of heavy cocaine use and is characterised by acute dysphoria, irritability and anxiety, increased desire for sleep, exhaustion, increased appetite, decreased craving to use. Phase two, ‘withdrawal’ is characterised by increasing craving to use, poor concentration, some irritability and some lethargy, which persisted for up to 10 weeks. Phase three, ‘extinction’, comprises intermittent craving to use in the context of external cues. Despite the relative persistence of this model to the clinical application of cocaine withdrawal results from several other studies have not supported this model and they rather predict a gradual return to the basal levels21. The withdrawal state is diagnosed as per DSM-V or ICD-10. The severity of cocaine withdrawal has been related to increased craving and early drop-out.

Management of cocaine withdrawal requires constant monitoring of signs and symptoms of withdrawal. The goals of the withdrawal are a) To relieve patient’s discomfort, prevent the occurrence of more serious symptoms, and forestall cumulative effects that might worsen future withdrawal; b) To utilise the withdrawal treatment opportunity to engage patients in long-term management.

There are no well-studied pharmacological agents to relieve symptoms of cocaine withdrawal. The evidence base is for dopamine agonists like amantadine and bromocriptine. Amantadine appears to primarily exert its therapeutic influence by releasing dopamine and norepinephrine from neuronal storage sites that are depleted by chronic cocaine dependence.22 Amantadine has been found to be effective in double blind placebo controlled studies to relieve the withdrawal symptoms in few studies23. One study has also showed that patients with more severe baseline withdrawal had

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more improvement compared to lower baseline24. The dose range used in these studies is from 100-400 mg/day. There is one negative placebo controlled study too23. Although amantadine is found useful in cocaine withdrawal but more studies are needed to settle its exact role. Thus the role for amantadine in cocaine withdrawal still remains unclear except in cases of severe withdrawal.

Bromocriptine acts as a dopamine agonist that stimulates dopamine receptors. Bromocriptine was found to be reducing cocaine withdrawal in few studies though recent studies have not proved its efficacy. When compared with amantadine, bromocriptine was associated with reduced tolerability and increased drop-out the dose range used in these studies is 2.5mg to 10mg.26

Propronolol is another drug which has been used with mixed efficacy.27 A recent trial which evaluated the efficacy of amantadine (300mg/day), propranolol (100mg/day) and their combination in cocaine dependent patients with severe cocaine withdrawal symptoms showed that none of the treatments were significantly more effective than placebo. Propranolol treatment was associated with better treatment retention and higher rates of cocaine abstinence compared to placebo.28

Though some drugs have been used the strength of evidence is at best ‘D’ and needs further research using well planned randomised controlled design.

7. LONG TERM MANAGEMENT OF COCAINE USE DISORDERS

Cocaine dependence syndrome like any other addictive disorders is a chronic illness with lapses and relapses. Medications and psychosocial strategies are used for promoting abstinence and preventing relapse in patients with cocaine dependence. All the pharmacological agents used in cocaine use disorders have been studied along with psychosocial interventions. Hence clinicians should use whichever psychosocial approach they think beneficial or is available along with pharmacological agents.

7.1 Pharmacological Agents

The pharmacological agents used broadly belong to psychostimulants, antiepileptics, disulfiram, antipsychotics and antidepressants class. The current guideline is based on evidence obtained from developed country (particularly USA) as there is none from India. There is little recent evidence for use of topiramate and modafinil for cocaine dependence.

7.1.1 Topiramate

7.1.1.1 Mechanism of action:

It is a fructose-related monosaccharide that is approved for the treatment of narcolepsy and epilepsy. Chronic cocaine use leads to malfunction of the GABAergic inhibitory pathways relative to the glutaminergic excitatory pathways in the dopaminergic excitatory pathway.29,30 Hence it may be helpful in cocaine dependence as it works through a multitude of mechanisms namely augmentation of the GABAergic pathways

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and inhibition of the glutaminergic kainite and AMPA receptors and also by blockade of voltage gated sodium and calcium channels-hence it is suitable for treating chronically low GABA signalling in cocaine users.

7.1.1.2 Dosage:

Dosage ranged from 200mg/day to 300mg/day in the clinical trials. The rate of dosage increase is 50 mg per week.

7.1.1.3 Evidence base

Efficacy of topiramate as an anti-craving agent has been seen in human volunteers under controlled conditions in the laboratory. A pilot study (n=40) showed that topiramate up to 200mg reduced cocaine usage in a 8 week trial.31 In another open-label RCT which was a feasibility study in Netherlands on crack cocaine users it has been shown that the efficacy of topiramate as an add-on to cognitive behavioural therapy (CBT) in crack- cocaine dependent patient was generally low.32 Although 82% of the patients in the experimental group agreed to start topiramate treatment), only 14% took topiramate for atleast11ofthe12-weeks. TherearetwodoubleblindplacebocontrolledRCT.Inone study which involved 170 cocaine and alcohol dependent subjects for 13 weeks duration after achieving a period of abstinence, subjects were randomized to topiramate, 300 mg daily, or identical placebo capsules in addition to weekly individual psychotherapy. It has been found that cocaine was not better than placebo in the primary outcome measures namely self-reported alcohol and cocaine use, and thrice weekly urine drug screens.33 In another study (n=142) it was seen that topiramate was more efficacious than placebo at increasing the primary outcome namely weekly proportion of cocaine non-use days as well as increasing the likelihood of urinary cocaine-free weeks as well as decreasing craving and improving observer-rated global functioning days34. So, overall, the evidence for topiramate in the treatment of cocaine dependence is mixed.

7.1.1.4 Conclusion:

Hence it can be said that though topiramate is now an emerging treatment; however, because of the contradictory findings it cannot be recommended as yet a first line therapy.

7.1.2 Modafinil

7.1.2.1 Mechanism:

Modafinil is a stimulant which is approved for the treatment of narcolepsy and shift work sleep disorder. Its proposed mechanism of action is by blocking the dopamine transporter and thereby increasing dopamine concentration in the extracellular space of nucleus accumbens.11 Hence, working as a mild stimulant it can reduce stimulant withdrawal and also suppress cocaine craving. Its action is, however, distinct from other stimulants and there are other mechanisms – modafinil’s effects in the brain involve

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hypocretin, histamine, epinephrine, γ-aminobutyric acid and glutamate35. Its actions on glutaminergic pathways are important as it is opposite to that of alcohol and this may have clinical relevance in patients of cocaine use disorder with co-morbid alcohol dependence.

7.1.2.2 Dosage: 200-400mg per day.

7.1.2.3 Evidence base:

Modafinil was found to block the euphoria arising out of cocaine use in human laboratory experiments and it has also been found to be medically safe when used along with intravenous cocaine36,37. A double blind placebo controlled RCT of modafinil at 400 mg showed self-reported abstinence of over 8-12 weeks verified by twice weekly urine benzoylecgonine tests compared to placebo38. Another 8-week, double blind, placebo controlled clinical trial, involving 94 cocaine dependent subjects without co- morbid alcohol dependence receiving 300 mg of modafinil or identical placebo daily, along with weekly individual therapy, reported significant improvement in terms of both the primary and secondary outcome measures39. There are few negative trials also. In an eight-week randomized, double blind, placebo-controlled study of modafinil treatment for cocaine dependence with patients (n=210), who were actively using cocaine at baseline, were randomized to 8- weeks of modafinil (0 mg/day, 200 mg/day or 400 mg/day) combined with once-weekly cognitive behavioural therapy, no significant benefit was found for modafinil40. A large government-funded multisite study done in 210 individuals reported that a 12 week trial did not show better efficacy for modafinil in terms of the primary outcome that is weekly percentage of cocaine non-use days41. Two secondary outcomes namely the maximum number of consecutive non-use days for cocaine, and a reduction in craving showed significant effects. However, the study also included patients with co-morbid alcohol dependence – hence when a separate analysis was done for cocaine users without other substance use co-morbidity there was increased efficacy for modafinil even in terms of the primary outcome.

Overall modafinil was quite well tolerated apart from minor adverse effects as reported in some of the trials namely anxiety, insomnia and headache and there were no reports of abuse in the trials conducted. Since modafinil is known to stimulate the DAT receptor there have been apprehension regarding its abuse potential. However, given its dopamine potentiating effects – caution should be maintained regarding its abuse potentia42.

7.1.2.4 Conclusion:

Modafinil is emerging as a prospective medication for cocaine dependence without co- morbid alcohol dependence though caution needs to be exercised in view of some negative trials and also probable abuse potential.

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7.1.3 Disulfiram

7.1.3.1 Mechanism of action:

Disulfiram is being used in alcohol dependence for long time and its use in cocaine dependence is of more recent onset. In cocaine dependence the proposed mechanism of actions are at the level of monoamine neurotransmitters. Disulfiram has been shown to chelate copper thereby inhibit dopamine beta hydroxylase resulting in excess of dopamine and reduced norepinephrine. Disulfiram also inhibits carboxylesterase and cholinesterase by unknown mechanisms43. This interferes with the metabolism of cocaine, increasing plasma levels which may potentiate its cardiovascular effects leading to adverse effects44.

7.1.3.2 Dosage: 62.5mg to 250mg. 7.1.3.3 Evidence base:

Randomized clinical trials of disulfiram as a treatment for cocaine dependence have been inconsistent. Most studies have found that treatment with disulfiram (250 mg/d) decreases cocaine use though one well-controlled study found that treatment with lower doses of disulfiram (62.5 and 125 mg/d) increased cocaine use significantly. A Cochrane review included seven controlled studies that randomised a total of 492 participants to receive disulfiram, a placebo, no pharmacological treatment or naltrexone in addition to psychosocial treatment. Disulfiram showed a trend toward fewer dropouts from psychosocial treatment when compared to placebo (three trials) or Naltrexone (three trials) but this was not statistically significant45.

7.1.3.4 Conclusion:

Disulfiram may be used in cocaine dependence though definite evidence is lacking regarding its efficacy.

7.1.4 Stimulants

7.1.4.1 Mechanism of Action:

In cocaine dependence agonist substitution or replacement therapy has also been tried. Here a similar but less harmful chemical with the intention of harm reduction as done in opioid has been tried for cocaine dependence. The ideal drug which should be used for replacement or substitution should have a similar mechanism of action and also there should be suppression of craving, act for a longer time and should not be as strongly reinforcing as the substance substituted for. Ideally a substituting agent should have a similar mechanism of action, onset of action should be slower but it should be longer acting. In fact preclinical animal studies and laboratory based studies show that the behavioural and reinforcing effects of cocaine, amphetamine, methylphenidate are similar46. Hence they can act as replacements.

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However, there are some neurobiological explanations also for example it has been proposed that methylphenidate improves the neurocognitive functioning in cocaine users who can therefore use it as a pre-requisite for psychosocial interventions.

The main drugs used are methylphenidate, amphetamine, modafinil, bupropion, mazindol, methamphetamine and selegeline47. Modafinil has been described already above.

7.1.4.2 Amphetamine
7.1.4.2.1 Mechanism of action:
Amphetamine acts as direct releasers of monoamines at the nerve terminals. 7.1.4.2.2 Dosage:
Dextro-amphetamine 15-30 mg
7.1.4.2.3 Evidence base:

Double blind RCT study have shown to decrease cocaine use though there were contradictory result48,49. One trial has also been conducted with methamphetamine sustained release and another pilot trial with lisdexamphetamine. The former showed significant improvement whereas the latter showed non-significant decrease in use50,51. These studies have only small number of cases and research is difficult with these drugs as they are all controlled drugs46.

7.1.4.2.4 Conclusion: No evidence currently for using methamphetamine or dextroamphetamine.

7.1.4.3.1 Methylphenidate (MPH):

MPH is currently used commonly for attention deficit hyperactive disorder (ADHD). MPH as per literature was first used by Khantzian to decrease cocaine use52.

7.1.4.3.2 Dosage:
60 – 90 mg/day 7.1.4.3.3 Evidence Base:

There are several open label studies which have showed that MPH is useful and there areequallygoodnumberofstudieswhichhaveshowednegativeresult53,54. Recently few double blind placebo controlled studies which have showed that MPH is useful in the fixed doses of up to 60mg/day. For heavy cocaine users more than 90mg have been advised. However, only a very few studies have tested high dosage of MPH46. These studies have several methodological problems- hence they are to be interpreted with caution.

7.1.4.3.4 Conclusion:

At present due to inadequate evidence methylphenidate cannot be recommended for long term treatment of cocaine dependence.

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7.1.5 Anticonvulsants:

7.1.5.1 Mechanism of Action:

The’seizurekindling’mechanismhas alsobeen hypothesizedtobean explanation foraddictivedisorder. Hence,almostallanticonvulsantsrangingfromcarbamazepine, tiagabine, gabapentin, lamotrigine, topiramate, valproate, phenobarbital, phenytoin and vigabatrin have been used56, 57,58,59, 60,61. These anticonvulsants potentiate the GABA- ergic mechanisms which may lead to decrease of dopaminergic tone of the nucleus accumbens thereby decreasing cocaine re-instatement and cocaine self- administration62. Topiramate as an anticonvulsant has shown some encouraging results so it has been discussed separately.

7.1.5.2 Evidence base:

A recent Cochrane review compared anticonvulsants with placebo and found no significantdifferences foranyoftheprimaryoutcomesmeasuresnamelydrop-out,use of cocaine by urinalysis or self-report, adverse effects and secondary outcomes namely compliance, craving, severity of dependence, depression and anxiety when anticonvulsants were compared with placebo63.

7.1.6 Antipsychotics:

7.1.6.1 Mechanism of action:

Acute cocaine use leads to an increase in dopamine secretion in certain brain areas

whereas chronic cocaine use leads to reduced dopamine tone. So anti-psychotics have

not been favoured much because of the proposition that they would decrease the

dopamine tone further and lead to more hedonic deficiency and subsequently further

increase in cocaine intake64. However, with the advent of the atypical anti-psychotics

there has been renewed interest in this topic as they are acting not only on the

dopaminergic pathways but also on the serotonergic pathways. Most of the older

studies have been conducted with haloperidol whereas the newer studies have been

conducted with olanzapine, risperidone, quetiapine and aripriprazole and have been

used in cocaine dependence in association with schizophrenia or bipolar illness65,66,67,68,69,70.

7.1.6.2 Dosage:

Olanzapine 5 – 10mg/day; Risperidone: 1mg to 4mg/day; Haloperidol: 4 and 10mg/day; Quetiapine: 400mg/day

7.1.6.3 Evidence base:

In few studies risperidone was effective in reducing the number of drop-outs and effective in treatment retention. Haloperidol and olanzapine were each found to reduce craving with respect to placebo though there were contradictory findings in other studies and the sample size was too small to be conclusive65,69. A cochrane review regarding the usefulness of anti-psychotics in the treatment of cocaine use disorder

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which included seven studies (N=293) found no significant differences for any of the efficacy measures comparing antipsychotics like haloperidol, risperidone and olanzapine with placebo. In a recent meta-analysis which included ten studies (risperidone=5, olanzapine=3, reserpine=2; N=562) with primary cocaine dependenceconcludedthatantipsychoticsdidnotdifferfromplacebowith regardto cocaine use days and lack of cocaine abstinence, severity of addiction, cocaine craving, Clinical Global Impressions-Severity of Illness (CGI-S) scores, depression, anxiety, compliance, all-cause discontinuation, and several side effects. However, antipsychotics caused more intolerability-related discontinuation than placebo. For quetiapine initial open-label studies showed efficacy when used at a dosage of 400mg/dayinsuppressingcocaineuseandcravinginnon-psychoticpatients. Thereis a double-blind, randomized, placebo-controlled study for 12-week, involving cocaine dependence syndrome with quetiapine (N=31) which showed that there is no significantbenefitofquetiapinecomparedtoplacebo(N=31)on self-reportofcocaine use and money spent on cocaine as well as urine drug screens73.

Methodology-wise most of studies had small sample sizes and measured treatment retention or drop-out as the main outcome measures though some studies measured craving as a secondary outcome measure. Also some of the studies had co-morbid heroin dependence and were maintained on methadone .

7.1.6.4 Conclusion:

Currently there is inadequate evidence to suggest the use of anti-psychotics in non- psychotic patients with cocaine use disorder.

7.1.5 Antidepressants:

7.1.5.1 Mechanism of action:

Acute cocaine use leads to increase of monoamines namely dopamine, serotonin and nor-epinephrine. However,withchronicusethereisdeficiencyofthemono-amines– so use of anti-depressants may lead to stabilization of the brain mono-amine levels and hence amelioration of the short and long-term symptoms related to cocaine abstinence. Also neuroimaging studies have shown that the areas of the brain activated are often common between cocaine use disorder and mood disorder – this is probably best illustrated by the mood symptoms during cocaine withdrawal. The most common anti- depressants which have been studied are desipramine, fluoxetine and bupropion74,75. Other antidepressants which have been studied are nefazodone, ritanserin, buspirone, gepirone, paroxetine, citalopram, venlafaxine, selegiline, tryptophan, sertraline, and imipramine76.

7.1.5.2 Dosage:
Desipramine: 75 -300mg/day; Fluoxetine: 20-60mg/day; Bupropion: 300mg/day

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7.1.5.3 Evidence base:

A Cochrane review included 37 studies (N=3551) concluded that there were significant heterogeneity in the studies in terms of design, instruments used, services and treatment delivered. Positive results obtained by antidepressants on mood-related outcomes are consistent with the primary effect of antidepressants. They do not seem to be associated with any effect on dropouts from treatment, cocaine use or side effects, which are direct indicators of cocaine abuse and dependence77. A recent systematic review compared antidepressants with dopamine agonists and showed that antidepressants were better for abstinence, based on two studies (N=44)78. The strength oftheevidenceisverylow. Boththereviewsmentionedthatcurrentevidencedoesnot support the use of antidepressants.

7.1.6 Dopamine agonists:

7.1.6.1 Mechanism of Action:

It has been described already in management of withdrawal state. The drugs commonly used are amantadine, bromocriptine, L-dopa/Carbidopa, pergolide, cabergoline, hydergine, and pramipexole.

7.1.6.2 Dose:

Amantadine 100-400mg/day; Bromocriptine=2.5-10mg/day; L-dopa/Carbidopa=75- 800mg/day/100-200mg/day; pergolide=0.1-0.5mg/day; Cabergolinehydergine = 0.5mg/week; and Pramipexole = 3mg/week.

7.1.6.2 Evidence Base:

A recent systematic review of 24 studies (N=2147 participants) concluded that current evidence from RCTs does not support the use of dopamine agonists for treating cocaine use78.

7.1.6.3 Conclusion:
At best currently there is no definite evidence for their efficacy. 7.1.7 Cocaine Vaccine
7.1.7.1 Mechanism of Action:

Cocaine vaccine is a newer approach. Here vaccinated individuals produce antibodies which bind to drug molecules and inhibit the passage across the blood brain barrier and reducing the subjective effects79.

7.1.7.2 Evidence Base: The Phase 1 and Phase 2 studies of cocaine vaccine have showed significant decrease in cocaine use in patients who have attained sufficient level of anti-cocaine antibodies80. The effect of anti-cocaine antibodies dropped off rapidly and its efficacy decreased after short time. A recent 6 site 24 week phase III randomized double blind placebo controlled study of around 300 patients at 16 weeks reported injection site reactions of induration and tenderness and around 29 serious

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adverse effects which did not lead to serious consequences or death. They concluded that the vaccine was safe. At 16 weeks there was no difference in abstinence rate as measured by cocaine positive urine rates with placebo81. Addressing the anti-cocaine antibodies level dropping further will have a role in anti-cocaine vaccine efficacy.

Conclusion:

Currently there is not much strong evidence to recommend the use of cocaine vaccine.

7.1.8 Other medications:

Other medications that have been used are ondansetron, baclofen, have found to be useful but need further RCTs to prove their efficacy82,83.

7.1.9.1 Combinations of medications:

Studies have been done using combination of pharmacotherapy. The combinations have been used as per the tentative underlying neurobiological basis of the medications.

7.1.9.2 Dosage:

Medications used have been a combination of naltrexone (50 mg) and isradipine(10 mg), bromocriptine and desipramine (200 mg/day), I-tryptophan (1 g/day) and I-tyrosine (1 g/day), amantadine (300mg/d) and propranolol (100mg/d), disulfiram (250 mg/day)and Naltrexone (100 mg/day) , metyrapone (500 mg/day) and oxazepam (20 mg/day) mixed amphetamine salts (60mg/day) and topiramate (300 mg/day) combined d-amphetamine(60mg/d) and modafinil, (400mg/day)84,85,28,86,87,88,89.

7.1.9.3 Evidence base:

Among the double blind randomized controlled trials done with the above combination of medications most are negative studies except the study with amphetamine salts and topiramate (3 months abstinence).90

7.1.9.4 Conclusion:

There is need for well conducted studies to recommend the use of combinations in cocaine dependence.

7.2 Psychosocial Treatment

As we have seen none of the pharmacotherapies have very good efficacy – hence psychosocial interventions take an important role in the treatment of cocaine dependence/ problem. A variety of psychosocial strategies have been used in cocaine dependence. The different approaches that have been taken for the treatment are behavioural approaches like contingency management, comprehensive strategies like community reinforcement approach, cognitive behaviour treatment, twelve step oriented treatment, self-help group and newer generation psychotherapies like mindfulness based therapy.

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7.2.1 Behavioural approaches:

It is based on the conventional behavioural paradigm. It recognized the strong natural rewarding effects of cocaine which allow it to be naturally re-enforcing. So in behavioural paradigm alternative rewards are created and patients tend to preferentially select them on producing drug free urine samples. This is particularly used for patients with co-morbid opioid dependence. In most of the studies patients receive reward at an intermittent schedule.

7.2.1.1 The most thoroughly studied method for treating cocaine dependence is the ‘fish-bowl’ approach where cocaine dependent patients are given the option to submit urine drug free samples and contingent upon it they are given the opportunity to draw for prizes or vouchers that vary in amount91. Beneficial results of such an approach have been demonstrated in patients with co-morbid cocaine and opioid use disorder on methadone as well as in the community. Also benefit has been shown in other patient populations like those with anti-social personality disorder, pregnant women and those exposed to tuberculosis. Overall behavioural therapies are very important in treatment of cocaine dependence as concluded by a meta-analysis which showed its effect size to be about 0.692.

7.2.1.2 In the community based reinforcement approach (CRA) apart from reinforcementbyrewardthereareothercomponentslike providingskillstraining(such as problems with drug refusal, problem solving or assertiveness) to minimise drug use, improving family relations, providing vocational and employment counselling, assisting with developing new recreational activities and social networks, and monitoring disulfiram therapy for those who abused alcohol. This concept of comprehensive care has been given by the matrix model- which gives an opportunity for the patients to develop themselves in lines with the CRA. It has shown promise in the maintenance of abstinence. In a study in 40 ambulatory cocaine-dependent adults were randomly assigned to behavioural treatment with or without an added incentive program – 75% of patients in the group with vouchers completed 24 weeks of treatment versus 40% in the group without vouchers – incentives delivered contingent on submitting cocaine-free urine specimens significantly improve treatment outcome93. Addition of voucher based interventions have specific advantages – in other study it has been shown that combining CRA with vouchers had therapeutic effects on substance abuse and psychosocial functioning during treatment and post-treatment follow-up in cocaine-dependent outpatients, although effects on cocaine use appear to be limited to the treatment period94.

7.2.2 Cognitive behavioural therapy (CBT): It is a combination of cognitive and behavioural approaches – it focuses particularly on the antecedents, behaviours and consequences of relapse in a structured manner. It is a goal-directed, flexible, structured therapy that focuses more on the maladaptive coping skills which have led to the relapse. It helps to identify the triggers of relapse and deal with it accordingly. It consists

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of multiple sessions focussing on social skills and involvement of the patient in the form of home-work assignments. Studies have shown that CBT is effective95.Others studies with larger sample sizes, have not found it to be uniquely effective. Studying the methodology of the individual studies it may be concluded that CBT was more effective when there have been a longer duration of use and that for shorter duration it may not be more effective96.

Among the important therapies namely contingency management, CRA and CBT it is worthwhile to compare amongst them. The Cochrane review observed that although the CBT seemed to be a promising however in the short term contingency based approaches appear to be more important. However, in the longer run CBT has more efficacy, though such studies are difficult, as was concluded by the Cochrane review where they highlighted the significant heterogeneity of the studies as well as the therapist specific issues97. This has led to the development of computer based CBT which can be used in longer term and which also holds promise in terms of efficacy98.

7.2.3 Twelve step facilitation program (TSF): It is based on the principles of twelve step program whereby spiritual elements are included in the self-help group intervention. Here the patients undergo a fellowship where under the guidance of a ‘sponsor’ they take a pledge whereby he surrenders to the Almighty and tends to discuss all causes of relapse and other hindrances faced in day to day dealing with substances. Similar programmes which deals with substances namely the alcohol anonymous, narcotics anonymous. Now evidence is also accruing favouring TSF. A randomized, placebo- controlled, double blind medication, with 4 treatment conditions: disulfiram plus TSF, disulfiram plus standard counseling only, placebo plus TSF, and placebo plus standard counseling in the context of a community-based methadone maintenance program on 112 participants showed that assignment to TSF was associated with less cocaine use throughout treatment and a higher number of cocaine-negative urines. Hence 12 steps therapy appears to be of benefit to methadone maintaining patients using cocaine99.

7.2.4 Motivational enhancement therapy (MET): This intervention is based upon Rogerian principles. MET is a client oriented, flexible, empathetic, non-judgemental approach which helps in motivational enhancement. Though has been an underlying principle in most of interviewing in substance use disorder yet structured intervention has also been done. Two sessions of motivational interventions showed that patients with poor coping skills decrease cocaine use irrespective of their poor motivation100. Another study using same design did not find any benefit – hence MET may not be efficacious in all scenarios though it needs to be an essential component of client interactions100.

7.2.5 Other psychotherapeutic approaches: Other newer psychotherapeutic approaches have been tried like “third wave” behavioural therapies, including Acceptance and Commitment Therapy (ACT), Dialectical Behaviour Therapy (DBT), Mindfulness-Based Stress Reduction (MBSR) and Transcendental Meditation (TM).

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These have not been empirically validated though holds promise in future102.

7.2.6 Conclusion: There are no data supporting a single treatment approach that is able to account for the multidimensional facets of addiction patterns and to significantly yield better outcomes to resolve the chronic, relapsing nature of addiction, with all its correlates and consequences. However, contingency management, community based reinforcement approaches and CBT have the highest efficacy in RCTs as per current evidence available.

7.3 Combined psychosocial and pharmacological management:

All the pharmacological agents used in cocaine use disorders have been studied along with psychosocial interventions. Many of the RCTs have given positive results92,31,103,104 and a few studies have given negative results75,54. Hence clinicians should use whichever psychosocial approach they think beneficial or is available along with pharmacological agents (A).

8.0 SPECIAL POPULATIONS

8.1 Pregnancy

A fallout of the ‘cocaine epidemic’ in western countries has been use of cocaine in pregnant mothers. Though initially it was reported from United States later it came to be reported from other countries including Europe. The epidemiological burden is illustrated by the fact that in a recent study of over 3,000 neonates – although 11% of the women reported using illicit drugs during pregnancy, 31% of the infants meconium tested positive for cocaine alone2. Apart from the direct effects of cocaine on the in utero fetus, other factors may also be responsible for the adverse outcome namely poor nutrition and poor antenatal care. A recent meta-analysis found that prenatal cocaine exposure is significantly associated with preterm birth, low birth weight, and small for gestational age infants105. The long-term effects of prenatal cocaine exposure on cognitive, motor, and language development have been inconsistent106. This inconsistency is likely related to the confounding effects of the postnatal environment, including dysfunctional parenting and unstable, chaotic home environments, and frequent poly-substance use in the mother107. Till date there are no published reports of cocaine related effects in the offsprings of cocaine using mothers from India.

8.1.1 Evidence base: Pregnancy itself is a great motivating force for women to quit and it was found that among pregnant women using cocaine before pregnancy, 73% were abstinent during pregnancy108. Most evidence in the treatment of cocaine using pregnant mothers is in the use of CBT, 12 step process and contingency management (CM). In a recent randomized trial comparing CM to community reinforcement approach and 12- step facilitation, CM was associated with significantly greater duration of cocaine abstinence, higher proportion of cocaine-negative urine tests and higher proportion of documented abstinence across the study period 109. Pharmacological treatments have

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not proved to be effective except the fact that a recent preliminary RCT with micronized progesterone have found some efficacy in achieving abstinence in the post-partum period110.

8.1.2 Conclusion:

Cocaine use in the pregnant women is through psychosocial interventions particularly contingency management.

8.2 Attention Deficit Hyperactivity Disorder

In the general population, the prevalence of adult ADHD is 4.4%, while in individuals with a substance use disorder, ADHD co-occurs at a rate of 10.8% with some studies showing a prevalence of up to 30%111. The reason of increased cocaine use in the ADHD population due to relief of depressive symptoms and anxiety arising out of the illness. Hence self-medication hypothesis by EJ Khantzian has been propounded to be the most important in establishing this co-morbidity. So use of stimulants as treatment is a usual choice in this population apart from other medications like bupropion46.

8.2.1 Evidence base:

Methylphenidate (MPH) is one of the most commonly used stimulant in ADHD with co- morbid cocaine use disorder. Among the three RCTs which have used, MPH in one study showed some efficacy with decreased intake of cocaine – however, that study was characterised by increased drop-out rate112. Also bupropion was not found to be more efficacious when compared to placebo in an RCT. Stimulant therapy of ADHD in childhood is associated with a reduction in the risk for subsequent drug and alcohol use disorders. However, caution needs to be maintained about the abusive potential of stimulants in this sub-group.

8.2.2 Conclusion:

At present there is no efficacy of any particular medication particularly stimulants (methylphenidate) in cocaine dependence with ADHD.

9. RECOMMENDATIONS

9.1 Some issues to be considered before arriving at recommendations

lThe proposed guideline is based on evidence obtained from developed country (particularly USA) and none from India.

lManifestations of cocaine intoxication and withdrawal are non specific and are mostly self- limiting.

lPsychosocial interventions have reasonable evidence base and are recommended for cocaine use disorders.

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9.2 Recommendations

9.2.1 Management of Intoxication and withdrawal

There is no convincing evidence supporting the use of pharmacological treatment for cocaine use disorder.

9.2.2 Management of cocaine dependence

Psychosocial treatments are the mainstay of treatment – contingency management, community based reinforcement approaches and CBT have the highest efficacy. Other therapies like MET, mindfulness based therapies needs further research.

Evidence for drug treatment is still preliminary – pharmacological treatment should be used in combination with psychosocial therapies (A). Modafinil and topiramate are emerging as prospective medications though currently evidence is not unequivocal and contradictory evidences exist (C). Currently disulfiram, dopamine agonists, antidepressants, anticonvulsants (except topiramate), psychostimulants, neither any combination of these medications are recommended. Cocaine vaccine has been found to be safe and shown promising results in Phase 1 & 2 research but not so promising response in Phase 3.

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75. Shoptaw S, Heinzerling KG, Rotheram-Fuller E, Kao UH, Wang P-C, Bholat MA, et al. Bupropion hydrochloride versus placebo, in combination with cognitive behavioural therapy, for the treatment of cocaine abuse/dependence. J Addict Dis. 2008;27(1):13-23.

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agonists for the treatment of cocaine dependence. Cochrane Database Syst Rev. 2015;5:CD003352.

79. Haney M, Gunderson EW, Jiang H, Collins ED, Foltin RW. Cocaine-specific antibodies blunt the subjective effects of smoked cocaine in humans. Biol Psychiatry. 2010 Jan 1;67(1):59-65.

80. Orson FM, Wang R, Brimijoin S, Kinsey BM, Singh RA, Ramakrishnan M, et al. The future potential for cocaine vaccines. Expert Opin Biol Ther. 2014 Sep;14(9):1271-83.

81. Kosten TR, Domingo CB, Shorter D, Orson F, Green C, Somoza E, et al. Vaccine for cocaine dependence: a randomized double-blind placebo-controlled efficacy trial. Drug Alcohol Depend. 2014 Jul 1;140:42-7.

82. Kahn R, Biswas K, Childress A-R, Shoptaw S, Fudala PJ, Gorgon L, et al. Multi-center trial of baclofen for abstinence initiation in severe cocaine-dependent individuals. Drug Alcohol Depend. 2009 Jul 1;103(1-2):59-64.

83. Johnson BA, Roache JD, Ait-Daoud N, Javors MA, Harrison JM, Elkashef A, et al. A preliminary randomized, double-blind, placebo-controlled study of the safety and efficacy of ondansetron in the treatment of cocaine dependence. Drug Alcohol Depend. 2006 Oct 1;84(3):256-63.

84. Sofuoglu M, Singha A, Kosten TR, McCance-Katz FE, Petrakis I, Oliveto A. Effects of naltrexone and isradipine, alone or in combination, on cocaine responses in humans. Pharmacol Biochem Behav. 2003 Jul;75(4):801-8.

85. Giannini AJ, Billett W. Bromocriptine-desipramine protocol in treatment of cocaine addiction. J Clin Pharmacol. 1987 Aug;27(8):549-54.

86. Pettinati HM, Kampman KM, Lynch KG, Xie H, Dackis C, Rabinowitz AR, et al. A double blind, placebo-controlled trial that combines disulfiram and naltrexone for treating co-occurring cocaine and alcohol dependence. Addict Behav. 2008 May;33(5):651-67.

87. Kablinger AS, Lindner MA, Casso S, Hefti F, DeMuth G, Fox BS, et al. Effects of the combination of metyrapone and oxazepam on cocaine craving and cocaine taking: a double-blind, randomized, placebo-controlled pilot study. J Psychopharmacol Oxf Engl. 2012 Jul;26(7):973-81.

88. Mariani JJ, Pavlicova M, Bisaga A, Nunes EV, Brooks DJ, Levin FR. Extended-release mixed amphetamine salts and topiramate for cocaine dependence: a randomized controlled trial. Biol Psychiatry. 2012 Dec 1;72(11):950-6.

89. Schmitz JM, Rathnayaka N, Green CE, Moeller FG, Dougherty AE, Grabowski J. Combination of Modafinil and d-amphetamine for the Treatment of Cocaine Dependence: A Preliminary Investigation. Front Psychiatry. 2012;3:77.

90. Mariani JJ, Pavlicova M, Bisaga A, Nunes EV, Brooks DJ, Levin FR. Extended-release mixed amphetamine salts and topiramate for cocaine dependence: a randomized controlled trial. Biol Psychiatry. 2012 Dec 1;72(11):950-6.

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91. Higgins ST, Alessi SM, Dantona RL. Voucher-based incentives. A substance abuse treatment innovation. Addict Behav. 2002 Dec;27(6):887-910.

92. Dutra L, Stathopoulou G, Basden SL, Leyro TM, Powers MB, Otto MW. A meta- analytic review of psychosocial interventions for substance use disorders. Am J Psychiatry. 2008 Feb;165(2):179-87.

93. Higgins ST, Budney AJ, Bickel WK, Foerg FE, Donham R, Badger GJ. Incentives improve outcome in outpatient behavioural treatment of cocaine dependence. Arch Gen Psychiatry. 1994 Jul;51(7):568-76.

94. García-Fernández G, Secades-Villa R, García-Rodríguez O, Sánchez-Hervás E, Fernández-Hermida JR, Higgins ST. Adding voucher-based incentives to community reinforcement approach improves outcomes during treatment for cocaine dependence. Am J Addict Am Acad Psychiatr Alcohol Addict. 2011 Oct;20(5):456-61.

95. Carroll KM, Nich C, Ball SA. Practice makes progress? Homework assignments and outcome in treatment of cocaine dependence. J Consult Clin Psychol. 2005 Aug;73(4):749-55.

96. Crits-Christoph P, Siqueland L, Blaine J, Frank A, Luborsky L, Onken LS, et al. Psychosocial treatments for cocaine dependence: National Institute on Drug Abuse Collaborative Cocaine Treatment Study. Arch Gen Psychiatry. 1999 Jun;56(6):493-502.

97. Knapp WP, Soares BGO, Farrel M, Lima MS. Psychosocial interventions for cocaine and psychostimulant amphetamines related disorders. Cochrane Database Syst Rev. 2007;(3):CD003023.

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99. Carroll KM, Nich C, Shi JM, Eagan D, Ball SA. Efficacy of disulfiram and Twelve Step Facilitation in cocaine-dependent individuals maintained on methadone: a randomized placebo-controlled trial. Drug Alcohol Depend. 2012 Nov 1;126(1- 2):224-31.

100. Stotts AL, Schmitz JM, Rhoades HM, Grabowski J. Motivational interviewing with cocaine-dependent patients: a pilot study. J Consult Clin Psychol. 2001 Oct;69(5):858-62.

101. Rohsenow DJ, Monti PM, Martin RA, Colby SM, Myers MG, Gulliver SB, et al. Motivational enhancement and coping skills training for cocaine abusers: effects on substance use outcomes. Addict Abingdon Engl. 2004 Jul;99(7):862-74.

102. Penberthy JK, Ait-Daoud N, Vaughan M, Fanning T. Review of treatment for cocaine dependence. Curr Drug Abuse Rev. 2010 Mar;3(1):49-62.

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104. Schmitz JM, Mooney ME, Moeller FG, Stotts AL, Green C, Grabowski J. Levodopa pharmacotherapy for cocaine dependence: choosing the optimal behavioural therapy platform. Drug Alcohol Depend. 2008 Apr 1;94(1-3):142-50.

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112. Dürsteler KM, Berger E-M, Strasser J, Caflisch C, Mutschler J, Herdener M, et al. Clinical potential of methylphenidate in the treatment of cocaine addiction: a review of the current evidence. Subst Abuse Rehabil. 2015;6:61-74.

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Newer and Emerging Addictions in India

AMPHETAMINE-TYPE STIMULANTS (ATS)

Atul Ambekar Shrigopal Goyal

On behalf of
Indian Psychiatric Society
Specialty Section on Substance Use Disorders

2016

Amphetamine-type Stimulants (ATS)

CONTENTS

Executive Summary

1. Introduction

. 1.1  History

. 1.2  Epidemiology
1.2.1 Global 1.2.2 Asia 1.2.3 India

. 1.3  Neuropharmacology

2. Who uses Amphetamine/Methamphetamine

2.1 Who are more prone? Population group at-risk of ATS use

3. Amphetamine use Disorders

. 3.1  Dependence

. 3.2  Routes of amphetamine administration and pattern of amphetamine use

. 3.3  Effects of ATS

. 3.3.1  Acute Effects

. 3.3.2  Consequences of amphetamine use

. 3.3.3  Health consequences of amphetamine use

. 3.4  Hazards-Psychological

3.4.1 Paranoid psychosis

3.4.2 Depression

. 3.5  Amphetamine withdrawal

. 3.6  Use during pregnancy and perinatal period

. 3.7  Death among ATS users

. 3.8  Consequences of amphetamine use in the context of polydrug use

4. Management

. 4.1  Amphetamine Psychosis

. 4.2  Treatment of ATS withdrawal

. 4.3  Treatment of amphetamine use disorders

4.3.1 Pharmacological treatment

© Indian Psychiatric Society 2016 89

4.4.1 4.4.2 4.4.3

5. Conclusion

Interventions in the community and in primary health- care setting Psychosocial treatment
Various type of Psychosocial treatment

90

© Indian Psychiatric Society 2016

4.3.1.1 Antagonist strategies

4.3.1.1.1 4.3.1.1.2 4.3.1.1.3

Naltrexone
Serotonin Dopamine antagonist Dopamine partial agonist

4.3.1.2 Agonist strategies
4.3.1.2.1 Dexamphetamine

4.3.1.2.2 Methylphenidate 4.3.1.2.3 Modafinil 4.3.1.2.4 Bupropion

4.4.1.3 Other treatment strategies

4.3.1.3.1 4.3.1.3.2 4.3.1.3.3 4.3.1.3.4 4.3.1.3.5

Serotonergic medications 5-HT3 antagonist (Ondansetron) Mirtazapine
GABAergic agents
N-acetyl cysteine

4.4 Psychosocial treatment and treatment approaches

Newer and Emerging Addictions in India

Amphetamine-type Stimulants (ATS)

EXECUTIVE SUMMARY

Amphetamine-type stimulants “(ATS)” or ‘psychostimulants’ are synthetic drugs that excite or speed up the nervous system and produce effects similar to adrenaline. They are highly euphoriogenic and consequently have a moderate degree of addictive potential. Use of these substances is associated with a wide variety of physical, psychological and social harms. Their use is growing in many parts of the world. In India, though the use remains low as of now, there is recent evidence that ATS use may be spreading in various parts of the country and hence clinicians need to be aware of management of ATS use disorders.

For management of acute amphetamine psychosis, dopamine antagonists or ‘anti- psychotics’ like chlorpromazine or haloperidol are indicated. The use of ascorbic acid can accelerate the renal elimination of amphetamines.

ATS withdrawal is generally not medically hazardous though it can be associated with depression. No medication has been demonstrated to be effective in alleviating amphetamine withdrawal, but some medications may be useful. Antidepressants have been used for withdrawal-induced depression with some benefit. Short-term use of benzodiazepines (diazepam 5 to 10mg QID SOS) and antipsychotics (olanzapine 2.5- 5mg BD SOS) for control of irritability and agitation can be helpful.

The evidence-base for the treatment of ATS dependence is rather limited. The evidence shows that various treatment agent like naltrexone, risperidone, modafinil, serotonin reuptake inhibitor, bupropion have been tried but demonstrate very limited benefits for amphetamine dependence. There are as yet no approved pharmacological treatments for ATS users which are based upon the philosophy and principles of substitution treatment (such as methadone or buprenorphine for opioid dependence). Maintenance on prescribed amphetamines has been demonstrated to reduce the use of street amphetamines.

Among psycho-social interventions, an eclectic “stepped-care approach” has been developed which aims to provide individualized, evidence-based and voluntary treatment.The services provided under the heading of “stepped care” include community-based prevention and health promotion, creating awareness that there are help/treatment options for ATS users, self-help groups, brief interventions of motivational interviewing and cognitive–behavioural therapy (e.g. one to four sessions), intensive individual counselling, detoxification and withdrawal services, crisis interventions and emergency care, as well as long term rehabilitation and reintegration services. Cognitive–behavioural therapy applied in a stepped-care approach is the treatment of best practice for ATS use.

Clearly, more research is needed in this area to expand the evidence-base globally, as well as in our country.

© Indian Psychiatric Society 2016 91

1. INTRODUCTION

Amphetamine-type stimulants“(ATS)”refer to a family of synthetic drugs that are chemically related to the parent compound amphetamine (phenylisopropylamine).1 Also referred to as ‘psychostimulants’, they excite or speed up the nervous system and produce effects similar to adrenaline. They are distinguishable from ‘botanical’ psychoactive drugs (e.g., heroin, cocaine, cannabis), which are derived from plants.2 Amphetamines act as central nervous system stimulants, which increase synaptic concentrations of monoamine neurotransmitters in the brain, namely, dopamine, serotonin and noradrenaline.3 The ATS group includes amphetamine, methamphetamine and methcathinone, fenetylline, ephedrine, pseudoephedrine, methylphenidate and MDMA or ‘Ecstasy’ – an amphetamine-type derivative with hallucinogenic properties.4

The type and form of ATS manufactured vary across regions. For example, in East and South-East Asia, manufacture of methamphetamine is primarily in tablet form (‘yaba’) and high purity crystalline form (‘ice’). Chemical precursors are necessary for the synthesis of amphetamine-type stimulants (ATS), and these chemicals commonly fall under international control. Their seizures are typically reported to the International Narcotics Control Board (INCB) and it provides some indications about trends in clandestine manufacturing. Ephedrine and pseudo ephedrine are precursor chemical for methamphetamine. phenyl-2-propoanone (P-2-P), Phenyl acetic acid and norephedrine are precursor chemical for both amphetamine and methamphetamine.5

Table 1 Common types of ATS5

Newer and Emerging Addictions in India

Drug

Common Name

Forms

Method of administration

Amphetamine

Speed, Whiz, Uppers, goey, dexies, pepe pills

White, yellow, Pink or brown powder, paste

Oral, intranasal, injection, anal

Dexamphetamine

Dexies, D-amp, dex

White, round tablets (marking ‘D5’)

Oral, intranasal, injection, anal

Methylamphetamine (‘cut’ or diluted formof Methylamphetamine hydrochloride salt)

Meth, speed, whiz, fast, uppers, goey, louee, LouReed, etc.

White, yellow or brown powder, paste, tablets or a red liquid

Oral, intranasal, injection, anal

Methylamphetamine hydrochloride (crystalline form – ‘uncut’, undiluted)

Small crystal particle size known as ‘crystal’- larger particle sizes known as ‘ice’; other terms include meth, d?meth, glass, crystal, batu, shabu (from the Philippines)

Crystalline- resembles crushed ice, particle size variable

Smoking, intranasal, Injection

92 © Indian Psychiatric Society 2016

Amphetamine-type Stimulants (ATS)

Drug

Common Name

Forms

Method of administration

3,4-methylenedioxy- methamphetamine (MDMA)

XTC, X, ecstasy, Adam, M&M, eccy, E, go, Scooby snacks, hug, beans

Tablet, powder, capsule, geltab (rare)

Oral, intranasal, smoking, injecting

3,4-methylenedioxy- ethylamphetamine (MDEA)

Eve

Tablet

Oral

N-methyl-1- (1,3-benzodioxol-5-yl) -2-butanamine (MBDB)

Eve

Tablet

Oral

The use of ATS is a global and growing phenomenon and in recent years, there has been a pronounced increase in the production and use of ATS worldwide. Over the past decade, use of amphetamine-type stimulants (ATS) has infiltrated its way into the mainstream culture in certain countries. Younger people in particular seem to possess a skewed sense of safety about ATS believing rather erroneously that these substances are safe and benign. Meanwhile, ATS are posing a serious threat to the health, social and economic fabric of families, communities and nations.

In many countries, the problem of ATS is relatively new, but quickly growing and is unlikely to be controlled soon. Though the geographical spread is widening, the awareness is limited and unfortunately there is a lack of integrated and consistent responses.

The market for amphetamine-type stimulants (ATS) in the Asia and the Pacific region has continued to grow in recent years, which is evident through recent seizures of methamphetamine in pill and crystalline forms in most countries in East and Southeast Asia. Illicit methamphetamine manufacture continued to spread throughout the region and new markets emerged for a variety of other synthetic substances.6,7

1.1 History

The earlier documentation of use of amphetamine was found in China, where the ma huang plant (Ephedra vulgaris) has been used to treat people with asthma.8This plant contains ephedrine which was first produced by chemical synthesis in 1887 in Germany.8 Subsequently, amphetamine came into medical and recreational use in the 1920s primarily for the treatment of colds and asthma. Methamphetamine, more potent and easier to make than amphetamine, was discovered in Japan in 1919.9 The crystalline powder was soluble in water, making it easy to inject. During the World War-

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II and the Vietnam War methamphetamine was widely used by the armed forces to increase alertness, confidence, feelings of increased strength and to suppress appetite. In the United States in the 1950s, legally manufactured tablets of bothdextroamphetamine (Dexedrine) and methamphetamine (Methedrine) were used by college students, truck drivers, and athletes. By the 1960s the market in methamphetamine had changed from being predominantly licit to illicit. This was followed by the synthesis, manufacture and distribution of methamphetamine by ‘motor cycle’ and other criminal gangs in United States.9 Subsequently, they were widely prescribed for weight control and treatment of attention deficit disorders. However, since the 1970s, amphetamines have been manufactured in clandestine laboratories and increasingly used as recreational drugs. Because of their high potential for abuse, amphetamines became a Schedule II controlled drug following the 1971 Convention on Psychotropic Substances.4

1.2 Epidemiology

1.2.1 Global

In 2009–10, it was estimated that between 13.7 and 52.9 million people used substances belonging to the amphetamines group at least once in the preceding year. Data for East and South-East Asia suggest that between 4.4 and 37.9 million people have used amphetamines in the past year, no estimates were available for South Asia.10According to the world drug report, 2012 between 2008–2010, about 1.3% of adults worldwide reported use of amphetamine type stimulants (ATS) involving compounds that range from amphetamine to an array of amphetamine analogues, but exclude 3,4-methylenedioxy-N-methylamphetamine or ‘ecstasy.11A retrospective audit of patients admitted between 2008 to 2013 at Albany Health Campus, western Australia was found One hundred and fifty two ATS-related hospital episodes were identified during the study period, 55% male and 45% female, with an age range from 16 to 50.12

The ATS market continues to evolve and grow. Globally, it remains the second most widely used illicit drug after cannabis. In 2012, the World Customs Organization reported an increase in border detections of ATS in North America, Western Europe and the Middle East, with large quantities also detected in the Asia-Pacific region. During 2012, customs agencies reported a global increase in the number and weight of methylamphetamine and MDMA detections. The largest methylamphetamine border detections by weight were reported by customs agencies in Asia-Pacific, Western Europe and North America.13

Iran is a growing source of methylamphetamine destined for both domestic and international markets. Iran-based methylamphetamine trafficking networks have become leading domestic market suppliers, in addition to supplying user markets across the Middle East and Asia-Pacific region. The Bureau for International Narcotics and Law

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Enforcement Affairs (BINLEA) reported that while Iranian seizures of opium and heroin have remained stable, seizures of methylamphetamine are increasing, with 2012 figures reportedly increasing eleven-fold from 2008 to 2011.14 North America remains both a transit and a source region for methylamphetamine. Canada is source for methamphetamine and having many laboratories for production (Criger 2013).15 Mexico remains the primary source for methylamphetamine in the United States of America (US), with media reporting indicating that more than 80 per cent of themethylamphetamine seized in the US is manufactured in Mexico.16

Since 2010, however, surging ATS seizures point to a rapid expansion of the global market, with total ATS seizures rising by more than 80 per cent to more than 135 tons in 2012. The increase of ATS seizures is primarily attributable to the growing amount of global methamphetamine seizures, which have more than doubled over the same period, reaching 107 tons in 2012. The growing importance of methamphetamine is a new feature of the global ATS market. The high level of global methamphetamine seizures in recent years has been primarily due to the rise of seizures in East and South- East Asia and North America.17

1.2.2 ASIA
UNODC (2010) estimated that up to 20.7 million individuals in Asia and pacific region

used ATS in the past one year.18

Methamphetamine continues to dominate the ATS market in East and South-East Asia, Oceania and the Pacific. ATS seizures in the region have annually increased from about 13 tons in 2008 to just under 40 tons in 2012. The rapid rise of ATS seizures over the years is primarily attributable to the increase of methamphetamine seizures which about tripled from less than 12 tons in 2008 to 36 tons in 2012.17,18

Review conducted in china based on the literature identified from searches of the China national knowledge infrastructure (1979-2013), PubMed databases, hand-picked references, and online references with emphasis on epidemiology, treatment and traditional Chinese medicine. The epidemiological trends of ATS in China have led to its being 2.2 times the rate of morphine abuse and second only to marijuana abuse.19

1.2.3 India

In general, ATS use has remained very low in India, compared to other illicit drugs. In India, the extent, pattern and consequences of ATS use has not been studied. Over the last few years, laboratories producing amphetamine-group substances have been unearthed by law enforcement agencies from several parts of the country. India along with China is the most frequently mentioned source country of seized illicit shipments of ephedrine and pseudoephedrine which can be used to manufacture ATS. Anecdotal reports and clinical data indicate the emergence of use of these substances in several parts of the country.

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However, National household survey (NHS) reported the prevalence of ever use of ATS to be 0.03% Current use according to DAMS (National Survey) was 0.2%. Though, Current use according to RAS (National Survey) was nil but in the thematic “Border study” (as a part of National Survey),some ATS userswere detected.20 More recently UNODC has commissioned a study on ATS use in India. This study was conducted in the five states of Manipur, Mizoram, Punjab, Tamil Nadu and West Bengal, in India. The study also assessed the adverse health consequences related to the use of ATS. The findings of the study revealed that methamphetamine pills and powder were the most commonly used forms of ATS. Most users were in their early twenties. The usersreported a general feeling of euphoria and happiness, making it very attractive and deeplydesirabletoconsume. Nearlyhalfoftheparticipantsofthestudywerefoundto be dependent users and a quarter of them reported to have experienced mental problems after ATS use including paranoia, hallucinations, depression and panic attacks. The study also established a link between ATS use and crime, with 18 percent of the participants confirming that they had been apprehended by the police after ATS use. Study found 55 percent were ecstasy ever user, methamphetamine pills were ever used by 42 percent of the respondents followed by methamphetamine powder (36 percent) and amphetamines (35 percent) (UNODC,2015)21 Ecstasy was reported to be last used in the past one month by 13.1 percent amphetamine by 8.2 percent. Among reasons for initiation of ATS, more than half (57%) reported curiosity followed by peer influence (17%). While citing reasons for their current use 30.8 percent reported, “to be more energetic”.21

Thus, it is clear that ATS use though is low in India at present, in the coming years, the clinicians are likely to encounter more cases affected by ATS use disorders and hence, it is imperative for the clinicians to remain prepared to deal with this newer clinical and public health problem. 22

1.3 Neuropharmacology

Amphetamines are sympathomimetic central stimulants. Their pharmacological action is exerted indirectly by sustaining high levels of catecholamine in the synaptic cleft and directly by binding to the postsynaptic adrenergic receptors. It acts as indirect catecholamine agonist and releases serotonin and also blocks reuptake of dopamine.

Amphetamine undergoes extensive renal excretion and significant amounts are present in urine as the unchanged parent drug. The concentration of amphetamine in urine is about 200 times greater than the concentration in blood. Other factors could impact on the urine-blood amphetamine relationship, such as urinary pH, creatinine, route of administration, pattern of voiding and time elapsed after use of the drug.

2. WHO USES AMPHETAMINE/METHAMPHETAMINE?
Recent UNODC study conducted in India found that most of the respondents were

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youths with the median age of 25 years. A quarter of the respondents (25%) were females. About two third (63%) of the respondents had received college level education and more than half were engaged in full time employment with about one fifth (19%) reporting being in business. A similar proportion (19%) reported earning more than Rs. 30,001/- per month. Majority (62%) were single.21

There is no definitive profile of a “typical” user. ATS are used for many reasons. For example, sportspersons may use ATS to enhance their performance, long-distance truck drivers may use it to keep awake on long journeys, labourers and porters engaged in heavy physical activities may take ATS to make them feel stronger, and students may use it to help them stay awake and study. Another group of ATS users comprises those who take ATS for social reasons such as at parties, nightclubs or gatherings of friends and acquaintances. Some are heavy and regular users who smoke or inject potent forms of methamphetamine and also use a variety of other drugs. They are thus likely to experience poor mental and physical health and may become dependent on amphetamines. However, the majority of non-medical use is by young people who use low-potency ATS, swallow or snort the drug, do not inject and are not dependent.

2.1 Who are more prone? Population groups at-risk of ATS use

lChildren with ADHD

lThose suffering from PTSD

lThose suffering from mood disorders (self medication hypothesis)

lThose adolescent and adults already using inhalants, cigarettes, cannabis , alcohol (gate way hypothesis)

lMen for sexual pleasure, indiscriminate sexual Behaviour
lThose with social phobia
lThose withconductdisorderorantisocialpersonalitydisorder lThose who are impulsive and engage in high risk taking behaviour lWith personality traits of physical fearlessness and reward sensitivity lAdolescent females with abnormal weight control behaviour lWorking/homeless children;

lIncarcerated and institutionalized youth;

lSexually abused children

lUnemployed youth

lSex workers and other workers in the entertainment/hospitality industry (e.g. clubs and casinos)

lYoung people frequenting places of entertainment such as clubs and discothèques © Indian Psychiatric Society 2016 97

lMen who have sex with men (MSM), lesbian, bisexual and transgender youth, who have higher rates of drug use including ATS than the rest of the community.22,23,24

3. AMPHETAMINEUSEDISORDERS

Amphetamines produce feelings of euphoria and relief from fatigue, may improve performance on some simple tasks, increase activity levels, and produce anorexia. The dependence liability of the amphetamines is thought to be primarily related to their euphorigenic effects.25 However, their dependence and misuse are viewed as resulting from a process in which multiple interacting factors (social, psychological, cultural, and biological) influence drug-using behaviour.26

Amphetamines have been used almost since their introduction. Taken intravenously, the dependence potential of amphetamines is comparable to that of heroin or cocaine.27 The ease of synthesis frominexpensive and readily available chemicals makes possible the wide spread of amphetamine dependence and abuse.

3.1 Dependence

Dependence on ATS is characterized by increasing tolerance to the drug, occurrence of withdrawal symptoms, a preoccupation with the drug and an inability to reduce ATS use despite signi?cant negative social, health or psychological consequences and impairment.

lTolerance can sometimes be observed when ATS users transit from non-injecting to injecting as they begin to use higher doses of ATS per episode.

lWithdrawal from ATS is marked by fatigue, lethargy, sleep disturbances, appetite disturbances, depression, irritability, psychomotor retardation or agitation and strong craving.

The degree of methamphetamine dependence is strongly related to the route of administration: injecting route of intake is associated with a high likelihood of dependence.

3.2 Routes of amphetamine administration and patterns of amphetamine use

The patterns of amphetamine use may be classified as follows.28

lInstrumental use: amphetamines are exploited by the users to achieve desired goals, such as improve concentration and ward off fatigue.

lSubcultural/recreational use: amphetamine stimulant properties are exploited to allow the user to remain active for longer periods in social/recreational settings, such as at music and dance events.

lChronic use: for several reasons, such as craving, tolerance and withdrawal, some amphetamine users turn to be chronic users to relieve unwanted effects of abstinence.

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Amphetamine may be ingested, snorted or smoked and, less commonly, injected. In powder form, methamphetamine is generally swallowed or snorted. The crystalline form of methamphetamine, which looks like glass and is often referred to as “ice”, is typically smoked. When smoked or injected, ice reaches the brain rapidly and is associated with a high risk of dependence. There is growing evidence that smoking crystal methamphetamine has more harmful psychological effects and a higher addictive potential than other forms of methamphetamine. Furthermore, methamphetamine is sometimes mixed with other drugs and sold as “ecstasy” 3,4 (methylenedioxymethamphetamine – MDMA), a drug with hallucinogenic properties that is frequently used in clubs and entertainment venues.

Within the dependence/harmful use continuum, there are several discernable patterns of use. None are without potential risks though it is not clear whether occasional use inevitably leads to regular or dependent use. These include a pattern of experimental occasional use, usually with friends and in social settings. The pattern of intermittent heavy binge use is more serious; it generally occurs on weekends and is precipitated by party-going and the desire to stay awake. Such binge use may be occasional with large gaps between binges. Some people use ATS regularly – daily or almost daily – and such use may be accompanied by physical and psychological dependence. In addition, polydrug useis very common among methamphetamine users. Alcohol, cannabis and other psychostimulant drugs (such as ecstasy) are the most frequently used drugs.

3.3 Effects of ATS

Due to slight structural differences, methylamphetamine produces a stronger nervous system response than amphetamine. Short-term effects of amphetamine and methylamphetamine use may include sweating, headaches, insomnia, anxiety and paranoia. High doses can result in blurred vision, hallucinations, tremors and stroke. Long-term use may result in severe dental problems, reduced immunity, high blood pressure, depression, impaired memory and concentration, deficits in motor skills, aggressive or violent behaviour, anxiety, cardiovascular problems and kidney failure.29-31

3.3.1 Acute Effects
Immediately after smoking the drug or injecting it- extremely pleasurable ‘rush’ or

‘flash’.
lEnhanced mood and body movement lEuphoria
lIncreased respiration
lInsomnia
lIncreased heart rate

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lIncreased blood pressure
lReduced appetite
lDilated pupils
lPerceptualabnormalities-visualandtactile hallucinationsorillusions

3.3.2 Consequences of amphetamine use
A range of harms is associated with amphetamine use. Some are predominantly dose

related and others are a combination of dose and length of use.33

Table 2: Various Consequences of amphetamine use

Newer and Emerging Addictions in India

Physical consequences of low-dose use

Physical consequences of high-dose use

Physical consequences of short-term use

Physical consequences of long-term use

Physical consequences of ATS use

Sweating

–  Intoxication

–  Palpitation

–  Chest pain

–  Headache

–  Hot and cold
flushes

–  Reduced appetite

–  Increase in blood pressure

–  Euphoria

–  Alertness

–  Reduction of
fatigue

–  Talkativeness

–  Improved
physical performance

Overdose

–  Intoxication

–  High blood
pressure

–  Seizures

–  Nausea

–  Vomiting

–  Cerebral
haemorrhage and death

Intoxication

–  Dehydration

–  Cardiovascular
problems (i.e. rapid heart rate, irregular heartbeat and increased blood pressure and death from a cardiac event)

–  Overdose

–  Hyperthermia
and convulsions

–  Decreased
appetite and
weight loss

–  Skin and teeth
problems

–  Sleep disorders

–  Feelings of
invincibility
while intoxicated

–  Increased
high-risk behaviours such as unsafe sex

Drug dependence – Poor nutrition
– Poor sleep
– Susceptibility to

illness including cardiovascular problems

– Potential death from arrhythmias or myocardial infarction

or stroke

Precipitates psychiatric problems

–  Exacerbates
existing
problems

–  Mood disorders:
confusion, paranoia, anxiety, depression, suicidal ideation, panic attacks, obsession, psychosis

–  Cognitive impairment

–  Sleep disorders, fatigue

–  Agitation

–  Increased
impulsivity

–  Aggression and
violence

–  Social and
family disruption/ breakdown

–  Unemployment

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3.3.3 Health consequences of amphetamine use

A. Physicalandneurologicaldisordersduetoamphetaminese.g.,

–  Excitation syndrome: hyperthermia and tachycardia followed by circulatory collapse with eventually fatal outcome,

–  Vascular accidents: due to increased blood pressure, cerebral hemorrhage may occur, but also myocardial infarction, both with an increased mortality risk,

–  Cerebral convulsions and coma, followed by cardiovascular shock, an eventually fatal outcome, and stereotype movements and choreic syndrome.

B. Amphetamine-inducedmentaldisordersincluding

–  Amphetamine Use Disorders (formerly Dependence and abuse as per DSM IV)

–  Intoxication

–  Withdrawal

–  Intoxication delirium

–  Psychotic disorders

–  Mood disorders

–  Anxiety disorders

–  Sexual dysfunctions

–  Sleep disorders
C. Health consequences of amphetamine use, e.g.,






D. Social consequences of amphetamine use – Violence

Human immunodeficiency virus infection Hepatitis
Other sexually transmitted diseases Tuberculosis

Other bacterial, fungal, and viral infections

– Crime
– Accidents

3.4 Hazards- Psychological

3.4.1 Paranoid psychosis (following long-term use)

lResembles schizophrenia

lPersecutory delusion followed by auditory hallucinations, strange or unusual beliefs, and thought reading.

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lVivid visual or tactile hallucinations

lAtypical paranoid psychosis – single dose exposure

lIn vulnerable individuals, dose-independent ecstasy abuse can lead to unpredictable and potentially dangerous neuropsychiatric sequelae.34

During the phase of chronic, high-dose consumption of amphetamines, many amphetamine users may have the experience of paranoia and hallucination.35 This conclusion has been supported by at least two experiments, which found that most amphetamine users became psychotic within a week after a continuous administration of amphetamines.36,37

The main characteristics of this psychosis are delusion of persecution, delusion of reference, auditory hallucination, and visual hallucination.38 With further consumption, the individual becomes increasingly exhausted, loses insight into his or her actions, and may become violent and increasingly psychotic.39 Although amphetamine psychosis may last longer than cocaine psychosis, it usually abate rapidly (within days) with the cessation of amphetamine intake and the excretion of amphetamines.40 However, about 5-15% of the users who develop an amphetamine psychosis fail to recover completely.41

There is very little evidence about the risk factors of amphetamine psychosis. However, the results of a recent study found that mental health problems, including hallucinations and paranoia, significantly correlated with 4 factors.42 Those are: i) increasing severity of dependence on amphetamines, ii) a larger number of mental health symptoms experienced before starting to use amphetamines, iii) a larger average quantity of amphetamine used in a day of use, and iv) a greater number of days on which benzodiazepines had been used in the previous 6 months.

3.4.2 Depression – as part of withdrawal can occur
lMixed affective state is more common in bipolar patients, poor outcome of episode lSocial withdrawal –in intoxicated state or due to psychosis

lAbnormal motor activity – stereotyped behaviour such as repeatedly assembling and dissembling electronic equipment may occur in intoxicated or withdrawal state, in delirium or in actively hallucinating persons

lAggression

3.5 Amphetamine withdrawal

Amphetamine withdrawal has been less studied although it is a common problem with a prevalent rate of 87% among amphetamine users.43,44 This prevalence is as high as those of opiate withdrawal (91%) and cocaine withdrawal (86%). Although the duration of amphetamine withdrawal tends to be much longer than cocaine withdrawal, the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnostic criteria for

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amphetamine withdrawal are the same as those for cocaine withdrawal.32 The findings of a factor analysis of amphetamine withdrawal symptoms suggest that this clinical condition may be comprised of three factors.45 The hyperarousal factor comprises drug craving, agitation, and vivid or unpleasant dreams. The reversed vegetative factor comprises decreased energy, increased appetite, and craving for sleep. The anxiety factor comprises loss of interest or pleasure, anxiety and slowing of movement. Depressive mood is a prevalent symptom and should be considered as a symptom incorporated in more than one factor or more. Although the symptoms occurring during amphetamine withdrawal may be over in four or five days, some of the symptoms may continue for weeks or months.41, 46

Table 3: Phases of ATS withdrawal

Phases

Time duration

Common sign and symptoms

Crash

Start at 12-14 hours after last amphetamine use and subsides by 2-4 days

Fatigue, agitation, irritability, Depression, muscle ache, Sleep disturbance

Withdrawal

Between 2-4 days to 2-4 weeks, peak in severity over 7-10 days

Strong craving ,Fluctuating between irritability, anxiety, restlessness and agitation, low energy

Extinction

Weeks to months

Gradual resumption of normal mood with episodic fluctuation in mood and energy levels alternating between irritability, restlessness, anxiety, agitation , fatigue, lack of energy -episodic craving and disturbed sleep

3.6. Use during pregnancy and perinatal period lRelated with more pregnancy complications lAnaesthesia relatedcomplications lSmall for gestational age children

lInfants are also psychosocially disadvantaged and are at greater risk for abuse and neglect47, 48

3.7. Death among ATS users
lMost common complication – Hyperthermia lRhabdomyolysis with acute renal failure lOverdose, toxicity49,50

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3.8. Consequences of amphetamine use in the context of polydrug use lMethamphetamine toxicity is increased when taken in combination with

alcohol, cocaine or opiates.

lUse of alcohol and methamphetamine in tandem can be dangerous – it increases the blood pressure, placing a greater burden on the heart. Methamphetamine can also disguise the effects of alcohol, which may increase the risk of alcohol poisoning and accidents due to a false sense of feeling sober and in control.

lUse of cannabis and methamphetamine in tandem has been shown to increase psychotic symptoms in some users.

lHeroin and methamphetamine used together can cause respiratory depression which may induce cardiac failure. Methamphetamine can also increase the risk of heroin overdose.

lThe combination of methamphetamine and cocaine has been shown to substantially increase the cardiotoxic effects of both drugs.

4. MANAGEMENT

4.1 AMPHETAMINE PSYCHOSIS

It has been estimated that the prevalence of psychosis is 11 times higher among regular ATS users than among the general population, and that 23% of regular ATS users will experience symptoms of psychosis within a given year. The treatment of ATS-induced psychosis is short-term antipsychotic medication; symptoms usually abate rapidly within days of stopping ATS intake.

It has long been believed that dopamine antagonists, such as chlorpromazine, haloperidol, and thioridazine, are effective for the treatment of this psychosis [III].51, 52 In addition, the use of ascorbic acid can accelerate the renal elimination of amphetamines.[III]53

4.2 Treatment of ATS withdrawal

ATS withdrawal is generally not medically hazardous and fatalities directly attributable to ATS withdrawal are rare. The severity of withdrawal is dependent upon the dose and frequency of use, type of stimulant used, mode of administration, other drug use, current health problems and the duration of use. Supervision by health-care staff is indicated only in severe cases. During and after withdrawal, users must be regularly monitored for their physical and mental state as withdrawal can lead to severe depression. Different symptoms become evident at different stages of the withdrawal. However, no medication has been demonstrated to be effective in alleviating amphetamine withdrawal, but some medications may be useful with some symptoms. Antidepressants have been used for withdrawal-induced depression with some benefit,

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although onset of action is delayed and relapse to use while taking antidepressants can result in hypertension or serotonin syndrome. Mirtazapine is used at Drug and Alcohol Services South Australia and has resulted in some improvement in symptoms. It may be continued for depressive symptoms if response to treatment is evident. Short-term use of benzodiazepines (diazepam 5 to 10mg QID SOS) and antipsychotics (olanzapine 2.5- 5mg BD SOS) for control of irritability and agitation can be helpful, particularly in the inpatient setting. Care should be taken to limit access to large quantities of medications and to avoid development of benzodiazepine dependence. These medications should be prescribed for a maximum of seven to 10 days. Modafinil is also used at Drug and Alcohol Services South Australia and has been demonstrated to result in some improvement in symptoms, but this is not an approved medication for amphetamine withdrawal treatment. The mainstay of treatment is supportive care and counselling.54

4.3 Treatment of amphetamine use disorders 4.3.1 Pharmacological treatment

Pharmacotherapies for amphetamine or methamphetamine dependence are based on different underlying mechanisms that may:

a. altertheneurobiologyofreinforcementor rewardfromthedrug,

b. attenuate the negative reinforcing effects of withdrawal from and craving for the drug, or

c. ameliorate comorbid psychiatric vulnerabilities that co-occur and that can interfere with recovery

The medications evaluated in trials for pharmacotherapies for amphetamine or methamphetamine dependence have mechanisms of action that can be categorized as antagonists or agonists. Antagonist therapy approaches use medications that block the action of the agonist to attenuate or eliminate the positive reinforcing effects of acute methamphetamine intoxication. Antagonists compete with endogenous monoamines but have no intrinsic activity at the receptor site. In contrast, agonist therapies are medications that bind to and trigger responses from receptors involved in the addiction process, often mimicking the action of monoamines involved in the reinforcement, withdrawal symptoms and motivational aspects of methamphetamine or amphetamine use.55

4.3.1.1 Antagonist strategies

4.3.1.1.1 Naltrexone: It is an opioid receptor antagonist. Since, the primary positive reinforcing effects of ATS are mediated by dopamine, and opioid receptors partially modulate dopaminergic effects these receptors may act as a relevant pharmacological target. The results of an open-label trial of naltrexone for amphetamine dependence were encouraging.56 A Swedish randomized trial included 80 treatment-seeking

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amphetamine-dependent adults who were grouped to placebo or 50 mg of naltrexone.57 In an intention-to-treat analysis, naltrexone outperformed placebo in terms of both mean numbers of negative urine samples and continuous abstinence rates. However, the limitation of study was that the retention and adherence was suboptimal. It is important to note the exclusion criteria: the trial required a two-week period of abstinence prior to randomisation, which might have excluded severely dependent patients.55

Tiihonen et al, (2012) assessed the naltrexone implant in a 10-week trial in randomized manner for individuals with comorbid opioid and amphetamine dependence. The results were encouraging for naltrexone in term of retention and proportion of drug-free urine samples.58

4.3.1.1.2 Serotonin Dopamine antagonist: Two small open-label trials evaluated risperidone in methamphetamine-dependent adults to show acceptability and decreases in weekly methamphetamine use that correlated with plasma risperidone levels.59,60 A randomised trial of quetiapine and risperidone in 80 adults hospitalised with bipolar disorder and co-occurring cocaine or methamphetamine dependence reported that both equally reduced bipolar symptoms and drug cravings, with reductions in cravings associating with reductions in stimulant use . However, in experimental condition, neither haloperidol nor risperidone attenuated the euphorigenic effects of methamphetamine in healthy volunteers, dampening rationale for further evaluation of dopamine antagonists.61,62

4.3.1.1.3 Dopamine partial agonist: Studies on partial agonist aripiprazole have not observed any difference in methamphetamine use.55

4.3.1.2 Agonist strategies (Oral substitution approaches)

There are as yet no approved pharmacologicaltreatments for ATS users which are based upon the philosophy and principles of substitution treatment (such as methadone or buprenorphine for opioid dependence). Potential oral substitution/ pharmacotherapeutic interventions are still in the experimental stage but could be useful when they become available for chronic and dependent ATS users who are unable to cease use or even ameliorate their high-risk behaviours.

The efficacy of substitution therapy for ATS users is not known, even though the practice appears to have gained a degree of clinical acceptance at least in the United Kingdom. The literature is not extensive and controlled trials are few. There is a strong and growing case for rigorous evaluation of substitution therapies combined with tailored psychosocial interventions to achieve improved outcomes for amphetamine users. (IV).63 A randomized study included 41 long-term dependent amphetamine user seeking treatment. Half of treatment seekers were given amphetamine and another half were kept on counseling only. There was reduction in use of street amphetamine, howevertreatmentsubjectsappearedattendedcounselingsessionregularly. (Ib)64

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4.3.1.2.1 Dexamphetamine: Agonist therapies produce behavioural and neurobiological effects that are comparable or identical to the drug of addiction.65 Dexamphetamine increases extracellular levels of dopamine through a carrier- mediated exchange at presynaptic vesicles.A 12 weeks randomized trial assigned methamphetamine-dependent participants to receive up to 110 mg/day sustained- release dexamphetamine (N = 23) or placebo (N = 26) for 12 weeks. Those in the dexamphetamine condition completed an average of 86 days compared with the placebo condition (49 days) but no effect on methamphetamine use was observed. Although some decrease in craving for methamphetamine was observed with dexamphetamine treatment, no improvement in drug use or retention were observed in a subsequent trial.66

4.3.1.2.2 Methylphenidate: Additional support for an agonist approach is available from the study by Tiihonen (2007).58 In this 20-week, randomised, double-blind, placebo-controlled trial of aripiprazole, methylphenidate or placebo among participants dependent upon injection use of amphetamine, participants assigned to the 54 mg/day slow-release methylphenidate condition (N = 17) had significantly fewer amphetamine-positive urine samples than placebo-treated patients (N = 19; odds ratio=3.77; 95% confidence interval 1.55, 9.18).

4.3.1.2.3 Modafinil: Studies on modafinil – both open-label and randomized – conducted in HIV –positive patients and methamphetamine dependent adults found few adverse effects and no indications that medication was habit-forming or a diversion risk. However modafinil was no more effective than placebo in retention of treatment.67 Anderson et al, (2012) completed a trial of 210 methamphetamine dependent individuals randomised to placebo, or 200 mg, or 400 mg of modafinil. There was no evidence of benefit for either medication condition in terms of percentage of participants with a week of abstinence or retention. The authors caution, however, that due to poor medication compliance, the trial does not represent a definitive test of the efficacy of modafinil.68

4.3.1.2.4 Bupropion: Although not strictly considered an agonist, bupropion functions

as a mild stimulant and antidepressant. Bupropion is a nonselective inhibitor of the

dopamine and norepinephrine transporters and also acts as an antagonist at nicotinic

acetylcholine receptors. Bupropion increases dopamine transmission in both the

nucleus accumbens and the prefrontal cortex through inhibition of the dopamine

transporter. Various randomized placebo-controlled double-blind trials with sample

sizes between 30-150 in different type of population are available.69-71 On primary

outcomes of retention and Methamphetamine-free urine samples, Methamphetamine

useandcravings, bupropionsustainedreleasedidnotoutperformplacebo.However,

recruitment and retention were ‘feasible’ and bupropion was well tolerated, as

indicated by the absence of adverse events and acceptable medication adherence.55, 68,72,73,

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4.3.1.3 Other treatment strategies

4.3.1.3.1 Serotonergic medications: A study assessed the selective serotonin reuptake inhibitor sertraline (50 mg twice daily) in a four-arm randomised design. Two hundred and twenty-nine participants were assigned to sertraline only, sertraline and contingency management, placebo and contingency management, or placebo only. Contingency management significantly improved methamphetamine use outcomes, while participants assigned to the sertraline-only condition resulted in poorer retention and lower likelihood of sustained abstinence than the other treatment conditions.5

The evidence-base for the treatment of amphetamine use disorders is rather limited. The small number of treatment studies may reflect the fact that this issuehas been received less attention than the treatment for other substances, e.g., alcohol, heroin, or cocaine.

The evidence shows that fluoxetine, amlodipine, imipramine and desipramine have been tried but demonstrate very limited benefits foramphetamine dependence and abuse. Fluoxetine may decrease craving in short-term treatment. Imipramine mayincrease duration of adherence to treatment in medium-term treatment. Apart from these distal benefits, no otherbenefits, in particular the proximal ones can be found. This limited evidence suggests that no treatment has been conclusively demonstrated to be effective for the treatment of amphetamine dependence and abuse.

A review by (WHO, 2001) (I)74 for treatment of amphetamine dependence and abuse included the results of four studies (Batki et al, 2000; Batki et al, 2001; Galloway et al, 1996; Tennant et al, 1986). While two studies compared fluoxetine 40 mg/day (Batki et al, 2000), amlodipine 10 and 5 mg/day (Batki et al, 2001) and desipramine 100-150 mg/day (Tennant et al, 1986) with placebo, the other compared imipramine 150 mg/day with imipramine 10 mg/day (Galloway et al, 1996). Three included studies (Batki et al, 2000; Batki et al, 2001; Tennant et al, 1986), therefore, should be considered as placebo, randomised, double-blind controlled studies. The other study should be considered as a randomised, doubleblind controlled study of imipramine 150 mg/day and imipramine 10 mg/day although the investigators considered that imipramine 10 mg/day was a placebo.

Short-term, proximal outcomes presented in three studies were: i) number or percentage of amphetamine positive urines (Batki et al, 2000; Galloway et al, 1996); ii) number or percentage of amphetamine-use days (Batki et al, 2000; Galloway et al, 1996); iii) frequency of amphetamine use (Batki et al, 2000) and iv) amount of amphetamine consumed (Batki et al, 2001).

Short-term, distal outcomes presented in four studies were: i) craving (Batki et al, 2000; Batki et al, 2001; Galloway et al, 1996); ii) severity of dependence, abuse or addiction as measured by Addiction Severity Index (ASI) (Batki et al, 2001); iii) discontinuation rate

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(Batki et al, 2000) and iv) days of adherence to treatment (Batki et al, 2000; Batki et al, 2001; Tennant 1986).

4.3.1.3.2 5-HT3 antagonist (Ondansetron): Johnson and colleagues assessed three doses of ondansetron in a double-blind placebo-controlled trial with 150 methamphetamine-dependent participants. Significant differences were not observed for the medication at any of the doses in reducing methamphetamine use or any reports of withdrawal, craving or severity of dependence.75

4.3.1.3.3 Mirtazapine: Colfax reported outcomes of a trial of mirtazapine (15 mg twice daily) in 60 men who have sex with men showing men assigned to receive mirtazapine showed fewer methamphetamine-positive urine samples compared to those assigned to placebo.76

4.3.1.3.4 GABAergic agents: The GABA system activation exerts an inhibitory effect on the reward system of dopaminergic tract. This feature suggests that GABA agents may have some efficacy in attenuating the reinforcing effects of stimulants. Some preclinical evidence suggested modest efficacy for cocaine dependence of the selective GABAB agonist baclofen, and a clinical trial found some support as a treatment for cocaine dependence.77

In a randomised, placebo controlled trial of a proprietary concoction of flumazenil injections (a benzodiazepine antagonist), gabapentin and hydroxyzine in 120 methamphetamine-dependent adults78, no effects were seen on methamphetamine use, treatment retention or drug craving. Elkashef et al. (2012)79 assessed topiramate with a target dose of 200 mg/day in 140 methamphetamine dependent adults. There was no clear evidence of efficacy for the medication; however, among individuals who were abstinent at the beginning of treatment, topiramate appeared to facilitate abstinence during the second half of the trial.

4.3.1.3.5 N-acetyl cysteine: Recently, a double blind randomized cross over study conducted to evaluate efficacy of N-acetyl cysteine in treatment of methamphetamine dependence found that this drug is effective in suppressing methamphetamine craving.80

4.4 Psychosocial treatment approaches

Only few controlled trials of a psychosocial intervention for amphetamine dependence and abuse have been found.81 However, recently web based intervention has been used for treatment of users of amphetamine type stimulant.82 To meet the challenge of ATS treatment, an eclectic “stepped-care approach” has been developed which aims to provide individualized, evidence-based and voluntary treatment. The “stepped-care” approach uses psychosocial interventions at various stages of drug use. It aims to increase access to treatment, provide support to help users reduce or cease use, and

© Indian Psychiatric Society 2016 109

mitigate the social, health and legal problems associated with continued use.

The services provided under the heading of “stepped care” include community-based prevention and health promotion, creating awareness that there are help/treatment options for ATS users, self-help groups, brief interventions of motivational interviewing and cognitive–behavioural therapy (e.g. one to four sessions), intensive individual counselling, detoxification and withdrawal services, crisis interventions and emergency care, as well as long term rehabilitation and reintegration services. Research suggests that cognitive–behavioural therapy applied in a stepped-care approach is the treatment of best practice for ATS use.

There are many activities, which need to be undertaken at every step. Thus, case management and counselling are important at every stage – though different techniques and different intensities are indicated for ATS users, depending on their profiles. Also important is the provision of opportunities for ATS users to undergo vocational training and assistance to gain employment, as well as in improving family relations, dealing with legal problems and assisting in the development of new recreational activities and social networks in the community.

4.4.1 Interventions in the community and in primary health-care settings (Steps one and two)54

Providing services for ATS users in the community is the first step. Many ATS users are occasional users who require information and education about the risks of ATS use, as all ATS users may at some time require emergency care and management of acute withdrawal. All ATS users should be provided with condoms since ATS use tends to increase libido and hence the risk of unsafe sex. Needles and syringes should be provided to all ATS injectors.

Providing services for ATS users in the community and in primary health-care settings has many benefits including help in dispelling the stigma and discrimination as ATS users are not singled out.

ATS users are exposed to a range of evidence- and community-based psychosocial interventions as appropriate, without necessarily providing a specific therapeutic approach. It is a setting where knowledge of community resources is available so that referral can easily be made to specialized drug treatment facilities or other ancillary services. It is the setting to which drug users are likely to return if referred to specialist care. It is in the community that resources for rehabilitation and reintegration are mobilized. It is the most cost-effective option for ATS users due to the lower costs of transportation to such health facilities as well as for the health sector in the delivery of services to ATS users and associated costs of referral to other standard health services such as HIV/ AIDS and tuberculosis.

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Table 4 : Stepped care approach54

Steps for ATS Users

Types of ATS User

Types of activities

One

Occasional ATS users believed to be at relatively low risk

Personal care activities: Self/family Care,Self-help groups, informal communitybased care

NGO activities: Information about the risks of drug use, brief counselling, peer outreach and education, drop-in centres, skills and vocational training, rehabilitation and reintegration services

Two

“Problem” ATS users

Drug services in primary health-care settings: assessment, brief counselling, harm reduction information, needle and syringe programmes, referral to specialist services if required, assistance with basic symptomatic detoxification and withdrawal. Referral

back to the community for support, rehabilitation and reintegration services and/or to expert care

Three

Heavy/dependent ATS users

Specialized, voluntary drug dependence clinical care: Assessment of dependence, pharmacologically assisted withdrawal, harm reduction, needle and syringe programmes, outpatient and/or inpatient or residential treatment and specialized counselling, referral to rehabilitation and reintegration services, and back to the community for support

4.4.2 Psychosocial treatment
The key features of successful psychosocial treatment interventions for drug problems

are as follows:

a. Seek the input of drug users to determine what works

b. Do not blindly apply what seems to work for other drug treatment. Interventions must be appropriate. Adopt evidence-based approaches.

c. Adopt a holistic approach that addresses the broader socioeconomic issues rather than only the drug use.

4.4.3 Various types of Psychosocial treatment54 lCognitive–behavioural therapy(CBT)

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lMotivational interviewing (MI) lContingency management (CM) lHarm reduction and risk reduction lBrief interventions (BI)

lMatrix model lTwelve-step programme

Table 5 : Psychosocial intervention54

Newer and Emerging Addictions in India

Intervention

Types of activities

Cognitive-behavioural therapy (CBT)

lBased on Social Learning Theory9
lKey concepts include: encouraging and reinforcing

behaviour change
lRecognizing and learning to avoid high-risk settings lImproving coping skills
lManaging and avoiding trigger situations associated with

drug-use behaviours
lLearning to deal with drug craving.

Motivational interviewing (MI)

lAssumptions are that people change their thinking and behaviour according to a series of identifiable stages

lIt is possible to influence the natural change process with “motivational” interviewing techniques.

lKey concepts include establishing a “therapeutic alliance” showing empathy, providing feedback, helping the client to reframe his/her behaviour and thus reinforcing change.10

Contingency management (CM)

lContingency management is the systematic application of reinforcement/conditioning principles.

lBasic assumptions include the belief that drug use behaviour can be controlled using reinforcement procedures.

lPositive reinforcement takes the form of verbal praise, earning programme privileges or rewards.

lTypically, the individual can earn larger-value rewards for longer periods of continuous abstinence from drugs.

Harm reduction and risk reduction

lDesigned to help drug users minimize the adverse consequences of their drug use.

lThe interventions that make up the package of harm/risk reduction include provision of information, education and counselling, peer outreach, distribution of condoms and

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clean needles and syringes, ensuring easy access to primary health care, e.g. services for HIV/voluntary counselling and testing (VCT) and antiretroviral medication, drug counselling and treatment, crisis management etc.

Matrix model

lDeveloped in the 1980s by the Matrix Institute on Addictions group in Southern California, USA

lIt is a comprehensive behavioural treatment approach that combines behavioural therapy and family education including cognitive–behavioural therapies (see above), relapse prevention techniques, positive reinforcement for the abstinence-using components of motivational interviewing, contingency management, provision of accurate psychoeducational information, and introduction to the 12-step recovery programme (see below).

lIt employs regular urine testing.
lThe programme thus focuses on encouraging behaviour

change and not on dealing with the underlying causes of drug use or psychopathology.13,14,15

Twelve-step programme

lThe “12-step programme” is a self-help programme based on a fellowship of ex-drug and/or alcohol users and plays a key role in relapse prevention by offering mutual support.

5. CONCLUSION

ATS is a rather new category of substance for most Indian professionals. At present the clinical experience is limited. Even globally, there is scanty evidence-base about effectiveness of various treatment approaches. Clearly, more research is needed in this area to expand the evidence-base globally, as well as in our country.

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DISORDERS ASSOCIATED WITH USE OF “CLUB DRUGS”

Kaustav Chakraborty Rajarshi Neogi

On behalf of
Indian Psychiatric Society
Specialty Section on Substance Use Disorders

2016

Club Drugs

CONTENTS

Executive Summary

1. Introductory section

. 1.1  Introduction

. 1.2  Scope and methodology of developing the guideline

. 1.3  Data Search Methodology

2. Club drugs

. 2.1  Epidemiology of club drugs

. 2.2  MDMA

. 2.2.1.  Clinical pharmacology

. 2.2.2.  Neurobiology

. 2.2.3.  Clinical and adverse effects

. 2.2.4.  Management
2.2.4.1. Management of acuteMDMA toxicity
2.2.4.2. Management of harmful use and dependence of MDMA

. 2.3  Ketamine

. 2.3.1.  Clinical pharmacology

. 2.3.2.  Neurobiology

. 2.3.3.  Clinical and adverse effects

. 2.3.4.  Management
2.3.4.1. Management of acute toxicity of Ketamine
2.3.4.2. Management of Ketamine dependence and withdrawal

. 2.4  Gamma-hydroxybutyrate (GHB)

. 2.4.1.  Clinical pharmacology

. 2.4.2.  Neurobiology

. 2.4.3.  Clinical and adverse effects

. 2.4.4.  Management
2.4.4.1. Management of acute GHB toxicity 2.4.4.2. Management of GHB withdrawal 2.4.4.3. Management of GHB dependence

© Indian Psychiatric Society 2016 123

2.5. Flunitrazepam

. 2.5.1.  Clinical pharmacology

. 2.5.2.  Neurobiology

. 2.5.3.  Clinical and adverse effects

2.5.4 Management

2.5.4.1. Toxicology and detection

2.5.4.2. Management of Flunitrazepamintoxication/dependence 2.6. Lysergic acid diethylamide (LSD) and related hallucinogens

. 2.6.1.  Clinical pharmacology

. 2.6.2.  Neurobiology

. 2.6.3.  Clinical and adverse effects

. 2.6.4.  Management
2.6.4.1. Management of hallucinogen toxicity 2.6.4.2. Management of hallucinogen dependence 2.6.4.3. Management of HPPD

3. General principles in the management of club drugs intoxication / harmful use/ dependence

4. Club drugs: Indian scenario

5. Conclusion

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Club Drugs

EXECUTIVE SUMMARY

Club drugs are a group of newer synthetic addictive substances which are increasingly used in ‘clubs’ or ‘raves’ along with loud, electronic ‘techno rock’ music and all night dancing by the sensation seeking youths and/ or adults. There is very little data regarding the prevalence of club drugs harmful use/ dependence particularly from India. The data is only in the form of case reports or case series, news paper reports, crime bureau or narcotics department data. But it can definitely be said that their use is on the rise and clinicians will be challenged by the various health problems that are known to arise from the use of these substances. In our discussion we will use the term ‘club drugs’ in reference to MDMA, Ketamine, GHB, Flunitrazepam, and LSD/related substances. We have developed a clinical practice guideline based on existing evidence, with emphasis on available Indian data, to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances, e.g., acute intoxication, harmful use, dependence and withdrawal state due to use of club drugs.

MDMA (3,4-METHYLENEDIOXYMETHAMPHETAMINE or ECSTASY)

Management of acute MDMA toxicity

Laboratory identification of MDMA is difficult. As many as one-third of immunoassay urine screens have failed to detect it in standardized specimens. In acute MDMA toxicity short period of hospital stay is recommended (C). Severely dehydrated patients may require intravenous fluid (C). Patients with severe hyponatremia may require fluid restriction (C). Gastric decontamination with active charcoal is indicated if presentation is within 1 hour of ingestion (D). Hyperthermia can be treated with Dantrolene (C) or benzodiazepine sedation (D).

Management of harmful use and dependence of MDMA

Psychosocial treatment is the mainstay for chronic harmful use of MDMA (D, S). No speci? c guidelines for psychosocial intervention have been described and validated for chronic ecstasy users. For those that do seek help, typical treatment approaches include individual and group counselling, cognitive behavioural therapy, and relapse prevention technique.

KETAMINE

Management of acute toxicity of Ketamine

The diagnosis of ketamine should be considered when people (especially young people) present with agitation, tachycardia and either visual hallucinations or nystagmus. No antidote exists for ketamine overdose. Supportive care with special attention to cardiac and respiratory function is the mainstay of treatment as the effects of the drug are usually short lived (S). Patient should be kept in a quiet environment with

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minimum external stimulus (S). Activated charcoal can be used in the presence of co- ingestant or if the patient presents very early (D). Benzodiazepines cane be used for agitated or hyperthermic patients (D).

Management of Ketamine dependence and withdrawal

Psychosocial treatments are mainstay of ketamine dependence (D). Ketamine withdrawal is characterized by anxiety, shaking, sweating, palpitations and carving for the drug. This can be treated with tapering dose of diazepam modified from alcohol detoxification regimen (D).

GAMMA-HYDROXYBUTYRATE (GHB)

Management of acute GHB toxicity

It may be difficult to differentiate GHB poisoning from other sedative hypnotic intoxications. GHB is detected by routine urine screens in the western countries which are not available in India now. A sensitive and specific GC-MS method using selective ion monitoring has been developed for the quantification of GHB in blood. Supportive care is the mainstay of treatment. Endotracheal intubation may be required if vomiting is present (D,S). Decontamination with activated charcoal should be considered in patients who are alert, stable and have a protected airways (D). Atropine can be used for hemodynamically unstable patients (D). Myoclonic movements and seizures may be treated with lorazepam or diazepam (D). There are no specific antidotes for GHB poisoning

Management of GHB withdrawal

The GHB-related withdrawal syndrome seems consistent with other hypnotic/sedative withdrawal syndromes. Benzodiazepines are the first line of treatment for GHB withdrawal (D). Baclofen and barbiturates can be used as second-line adjuncts (D). Valproic acid, carbamazepine, gabapentin, chloral hydrate, baclofen, clonidine, paroxetine, beta blockers, bromocriptine, trazadone, fentanyl, propofol, and antipyschotics have been tried sporadically (D).

Management of GHB dependence

Psychosocial interventions are the mainstay of treatment of GHB dependence (D). Motivatonal counselling, contingency management, CBT based relase prevention techniques, group therapy, occupational therapies can be tried.

FLUNIRAZEPAM

Management of flunitrazepamintoxication / dependence

Management of Flunitrazepamoverdose/dependence is similar to other benzodiazepine overdose/dependence which has been elaborately dealt in the

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previous volume of IPS-CPG which provided the guidelines for the management of sedative-hypnotic use disorders. Decontamination with activated charcoal is done for patients with secured airways and who present early (D,S). Flumazenil can be used to reverse the effects of Flunitrazepamtoxicity (D). Flunitrazepamdependence is managed by titrating doses of long acting benzodiazepines similar to other benzodiazepine dependence (D).

LSD AND OTHER RELATED HALLUCINOGENS

Management of hallucinogen toxicity

The management of acute toxicity resulting from the use of hallucinogens will in part depend on the hallucinogenic substance consumed.Attempts to ‘talk the patient down’ first must be instituted. Sympathetic, non-judgemental reassurance, support and observation are often sufficient.Patient should be placed in a quiet, well lit room with minimal external stimuli (S). Benzodiazepines, diazepam or lorazepam are the mainstay of treatment, particularly in presence of agitation (D). Antipsychotics can be considered as second line treatment (D).

Management of hallucinogen dependence

The use of LSD or other classic hallucinogens does not appear to lead to dependence. Typically there is no persistent and compulsive pattern of use and the use of hallucinogens is not associated with any recognized withdrawal syndrome.

Management of HPPD (Hallucinogen persisting perception disorder)

Hallucinogen persisting perception disorder (HPPD) and ‘flashbacks’ have been associated with use of classic hallucinogens in particular, although these concepts remain uncertain. HPPD can persist for months or years after the use of hallucinogens.Several classes of antidepressants, anxiolytics, antipsychotics, COMT inhibitor, naltrexone, levodopa, clonidine, lamotrigine and citalopram can be used to treat HPPD (B). Lamotrigine may be a promising agent in the treatment of HPPD (D).

GENERAL PRINCIPLES IN THE MANAGEMENT OF CLUB DRUGS INTOXICATION / HARMFUL USE / DEPENDENCE

No standard treatment protocol has been identified for club drug overdose. Basic management should include cardiac monitoring, pulse oximetry, urinalysis, and performance of a comprehensive chemistry panel to check for electrolyte imbalance, renal toxicity, and possible underlying disorders. Harm reduction strategies have been proposed which emphasizes that buildings meet safety and health standards, adequate security is provided to accommodate the large number of attendees and “ravers” are educated about health effects by trained volunteers.Suspicion of a club drug overdose or toxicity is essential. Except for GHB, club drugs cannot be detected through routine toxicological screens. Airway, breathing and circulation should be maintained (S).

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Gastrointestinal decontamination with activated charcoal is recommended if ingestion has happened within last 1 hour (S). Hyperthermia and Serotonin syndrome should be managed with tepid sponging and cyproheptadine/chlorpromazine respectively (S). Flumazenil may be administered to reverse the effects of flunitrazepamtoxicity (D, S). Psychosocial interventionsin various forms e.g. motivational interviewing, contingency management, CBT based relapse prevention, community reinforcement approach, behavioural therapies, socialbehaviour network therapy, supportive expressive psychotherapy can be effective for the management of club drugs dependence (D). Long term community intervention programs e.g. ‘Club against Drugs’ has shown some promise (C).

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1. INTRODUCTORYSECTION

1.1 INTRODUCTION

‘Raves’ are parties with loud, electronic “techno-rock” music, laser light shows, and all- night dancing held in clandestine locations, including warehouses, nightclubs, and farm fields.1 They first became popular in Great Britain in the late 1980s.The underground or noncommercial music featured at raves which is produced by computers and include little or no vocals is distinct from the music played at conventional nightclubs. Following bans in some countries the rave parties moved in to legitimate nightclubs. A “raver” is a person who has an exciting and uninhibited social life and regularly goes to raves. Not all ravers use drugs; however, many illicit drugs are available at raves and are used liberally to enhance the “vibe”.2 Here, it would be worthwhile to clarify that words like ‘rave drugs’, ‘club drugs’ and ‘party drugs’ have been used interchangeably in the literature. The U.S. National Institute on Drug Abuse (NIDA) in its “Community Alert on Club Drugs,” defined “club drugs” as MDMA (3,4- methylenedioxymethamphetamine, or Ecstasy), Ketamine, Gamma-hydroxybutyrate (GHB), Flunitrazepam, Methamphetamine, and Lysergic Acid Diethylamide (LSD).3 On the other hand, the U.S. Office of National Drug Control Policy identifies four specific club drugs: MDMA, Ketamine, GHB, and Flunitrazepam.4 Methamphetamine and LSD have been inconsistently included in the category of the club drugs. In addition, these two drugs have a longer history of misuse in comparison to the other four which came to the scene much later (MDMA being first reported in 1985).

In our discussion we will use the term ‘club drugs’ in reference to MDMA, Ketamine, GHB, Flunirazepam, and LSD/related substances to avoid further confusion. Methamphetamine has been deliberately left out because it will dealt in a separate chapter on amphetamine like stimulants. These drugs are being used in an expanding variety of venues by groups who differ in terms of age, gender, sexual orientation, and race/ethnicity5. Each of these drugs has very different pharmacologic properties, physiological and psychological effects, and potential consequences (Table 1).

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Manner of use

Tablet/Capsule; ingested orally, can be crushed/snorted/ dissolved/injected6

Liquid – injected, added to items to be smoked. Powder – dissolved in drinks, smoked, snorted or dissolved and injected16

Liquid; often mixed with alcohol – effects amplified6

Tablet; typically ingested orally; crushed and snorted

Tablet; typically ingested orally; sublingually/ buccally

Onset of action; T1/2

30 to 60 minutes; 5.8 ± 2.2 hours

Variable; elimination t1/2is ~2 hours

15-30 minutes after an oral dose; 22-28 minutes

15-20 minutes; 18 – 26 hours

LSD ~ 60 mins

Therapeutic use

Not strongly supported

Veterinary anaesthetic, also used as anaesthetic in India for Humans

To treat cataplexy associated with narco- lepsy

To treat insomnia

Earlier to treat alcohol dependence; now not licensed for clinical use

Clinical effects

Feelings of empathy, energy, psychomotor drive, self-confidence, depression, derealization, depersonalization, well- being, positive mood, heightened perception & sensory awareness, increase in the sensuality of sexual experiences, inhibition of orgasm and erectile dysfunction, mydriasis7-11

Low dose: relaxation (K-land); Higher dose: dream-like state, hallucinations, visual distortions, sensation of near-death experiences (K-land)16- 18, nystagmus, increased tone, purposeful movements, amnesia,

10 mg/kg: euphoria, amnesia, and hypotonia; 20–30 mg/kg: somnolence; > 50 mg/kg: unconsciousness and coma; anxiety reduction, increases relaxation, enhances libido, agitation, nystagmus, ataxia,

1- or 2-mg dose: reduces anxiety, inhibition, and muscular tension; Higher doses: anterograde amnesia, lack of muscular control, and loss of consciousness.23

Euphoria, mild stimulation, enhanced appreciation of musicand lights, visually appealing distortions,
intensi? cation of sensual or sexual feelings,altered sense of time and place, and a sense of shared and heightened signi? cance of the situation24

MDMA

Ketamine

GHB

Flunitrazepam

LSD/related hallucinogens

Table 1: Pharmacological and clinical profile of club drugs

Club Drugs

                       

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Toxic effects

Irritability, fatigue, nausea, loss of appetite, weight loss, tachycardia, hypertension, tremors, tics, jaw clenching, serotonin-syndrome, anxiety, bruxism, thought disorder/psychosis, difficulty concentrating, hyperthermia, hyponatremia, hypertension, dysrhythmias, liver toxicity, ataxia, neurotoxicity, rhabdomyolysis, disseminated intravascular coagulation (DIC), seizures, death12-15.

Increased heart rate, hypertension, cognitive and psychomotor impairment, nausea, respiratory depression, immobility, anxiety, dissociation, depression, recurrent flashbacks, delirium, amnesia, schizophrenic symptoms, loss of consciousness, respiratory depression, catatonia, death1,16,17,19,20

Sleep induction, tremors, agitation, seizures, GI symptoms, CNS & respiratory depression, dizziness, confusion, hallucinations, apnea, bradycardia, unconsciousness, sudden reversible coma with abrupt awakening and violence, death16,22

Decreased body temperature and blood pressure, sedation, cognitive & psychomotor impairment, visual disturbances, dizziness, confusion, GI disturbances, urinary retention.

‘Bad trip’, characterised by anxiety, fear/panic, dysphoria and/or paranoia. Distressing effects can be sensory (e.g. frightening perceptions), somatic (e.g. distressing awareness of physiological processes), personal(e.g. troubling thoughts or feelings) or even metaphysical (e.g. feelings about evil force; tachycardia, tachypnoea, agitation, hyperpyrexia and hypertension

Dependence

No dependence

No dependence

Can produce physical dependence

Can produce physical dependence

No dependence

Long term sequelae

Possible: cognitive deficiencies, brain neurotoxicity

Cognitive difficulties (attention, learning, memory)

Unknown

Depression, memory loss, mental confusion, paradoxical agitation, stomach disorders

No potential long term neurotoxic effect

MDMA

Ketamine

GHB

Flunitrazepam

LSD/related hallucinogens

Adapted from Chakraborty K, Neogi R, Basu D. Club drugs: Review of the ‘rave’ with a note of concern for the Indian scenario. Indian J Med Res 2011;133:594-604.25

Scientific studies about the uses of these club drugs and their short-term and long-term effects on animals have shown these drugs can be damaging in multiple ways, and some drugs (particularly MDMA) can damage specific neurons in the brain5. Moreover, routine drug screens do not pick up various club drugs, and gas chromatography-mass spectrometry (GC-MS) testing must be requested to confirm the presence of the specific drug, otherwise many cases of sexual assault and driving under the influence go undetected. In this guideline we attempt to discuss the epidemiology, clinical pharmacology, neurobiology, clinical and adverse effect profile, and treatment strategies of club drugs with a section contributing to the Indian scenario.

1.2. SCOPE AND METHODOLOGY OF DEVELOPING THE GUIDELINE

The index guideline covers the epidemiology, clinical pharmacology, neurobiology, clinical and adverse effects, and management of acute intoxication, harmful use, withdrawal and dependence state due to use of club drugs wherever applicable. In general the ICD-10 classification for mental and behavioural disorders was followed as the point of reference. Mental and behavioural disorders due to use of hallucinogens can be coded under F16 of ICD-10, whereas mental and behavioural disorders associated with other club drugs can be coded under F19 (Mental and behavioural disorders due to multiple drug use and use of other psychoactive substances).The discussion on management mainly focuses on five types of club drugs which has already been referred to in the previous section. The general principles in the management of club drugs intoxication, harmful use, withdrawal and dependence are presented later in this chapter. This guideline assumes importance because consistent treatment protocols are lacking which the clinicians can follow when confronted with users of club drugs as newer generation of youths are increasingly opting for these drugs to get the desired ‘kick’ particularly in club/ rave settings. In index guideline ‘acute intoxication’ means, a transient condition following the administration psychoactive substance, resulting in disturbances in level of consciousness, cognition, perception, affect or behaviour, or other psychophysiological functions and responses; ‘harmful use’ means, a pattern of psychoactive substance use that is causing damage to health, the damage may be physical or mental; ‘dependence syndrome’ means, a cluster of physiological, behavioural, and cognitive phenomena in which the use of a substance or a class of substances takes on a much higher priority for a given individual than other behaviours that once had greater value; and ‘withdrawal state’ means A group of symptoms of variable clustering and severity occurring on absolute or relative withdrawal of a substance after repeated, and usually prolonged and/or high-dose, use of that substance.

1.3. DATASEARCHMETHODOLOGY

The data search strategies for this review included electronic databases as well as hand- search of relevant publications or cross-references. The electronic search included PUBMED and other search engines (e.g. Google Scholar, PsychINFO). The data search

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strategies for this review included electronic databases as well as hand-search of relevant publications or cross-references. The electronic search included PubMed and other search engines (e.g. Google Scholar, PsychINFO etc.). Cross-searches of other electronic (e.g., online newspapers and magazines) and hand-search of key references often yielded other relevant material. The search terms used, in various combinations, were: club drugs, rave drugs, recreational drugs, rave parties, Ecstasy, Ketamine, Rohypnol, GHB, LSD, hallucinogens, street names, pharmacology, toxicology, psychiatric disorders, guidelines and management. Much of the clinical evidence is derived from review articles, individual case reports and case series and a small number of prospective observational studies, retrospective audits and analysis of patient records.

2. CLUB DRUGS

2.1. EPIDEMIOLOGY OF CLUB DRUGS

Despite evidence that suggests an increase in the population level use of these drugs, research on the population prevalence of their use is limited, most probably because of the relative recency of their recreational use. For Ecstasy the prevalence has been estimated between 0.9% in France to 19.7% in Australia.26,27 The others are much less prevalent – 0.9-4.7% and 0.7-2.6% for GHB and Ketamine respectively, depending upon the population and age group studied.28-30 One study reported 20% of youths aged 16–23 having ever used one or more of these club drugs.31In the US, data from the 2011 National Survey on Drug Use and Health estimate that about 14.5 million individuals aged 12 or older had used ecstasy at least once in their lifetime; about 2.4 million had used the substance at least once in the previous year; and about 540,000 were current users (defined as use during the previous month).32

The data on dependence potential of club drugs is relatively sparse. In a study of 400, 18- to 20 year old club going young adults, majority (58.5%) met the criteria for club drug dependence.33 In a cross-nation study using the computerized Substance Abuse Module for Club Drug (CD-SAM) 15% and 59% of the subjects met MDMA abuse and dependence, respectively.34 Club drug toxicity is a common reason for presentation to the emergency department from a nightclub environment.35-37 Wood et al.38 reported that, out of 173 individuals with club drug toxicity requiring medical attention in a large urban nightclub, the majority of individuals were frequent club drug users, and a signi? cant proportion had recurrent club drug toxicity requiring assistance.

Some researchers have argued that men experience more opportunities to try drugs.39 However, it is likely that frequenting dance clubs, in which there are many opportunities to experiment with drugs, may result in comparable opportunities for females to initiate use and, thus, minimize prevalence differences across gender. Meanwhile, young adult females have been found to be at the greatest risk of

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experiencing harm from club drugs and to report negative consequences.40-41 Other studies have not found gender differences in club drug use.33,42,43

Further, polysubstance abuse is common among users of club drugs, often used in combination, particularly with marijuana or alcohol.31,44,45 In a survey of 23,780 middle school students in New York City, it was found that Black students were less likely than White students to useclub drugs. The use of alcohol and/or marijuana predicted club drug use regardless of the timeframe of use, and lifetime cigarette use predicted lifetime club drug use.46 It has been found that, club drug use is common among youths in treatment for substance abuse and has spread beyond the rave culture.47 In a retrospective review of 38,350 case records from 1998 through 2003 of persons admitted with problems with club drugs were compared against users of alcohol or other drugs. Club drug users were more impaired on ? ve of six Addiction Severity Index (ASI) indices at admission and they were more likely to use multiple substances more often. They were more likely than users of alcohol or other drugs to complete treatment, but this varied by drug. At follow-up 90 days after discharge, club drug users continued to report more ASI problems. Pro? les of these clients show that ecstasy use has spread beyond the club culture, as indicated by the changes in client demographics over time. GHB clients presented a mixed picture of severe problems at admission and good response to treatment. Hallucinogen clients were young and less likely to complete treatment.48

Much of the available literature on the epidemiology of “club drugs” among men who have sex with men (MSM) derives from studies conducted on the west coast of the United States (Reback and Grella, 1999; Lewis and Ross, 1995; Frosch et al., 1996), with additional studies in Australia (Kippax et al., 1998) and Western Europe (Henry, 1992). 49-53 In a study of 569 MSM youths, recruited during 2000 and 2001, high rates of lifetime exposure to a variety of club drugs(including methamphetamine, ketamine, and MDMA) was observed. Among those who used club drugs on a chronic basis (N = 145), there was high rates of a prior suicide attempt (including high rates of multiple suicide attempts), high rates of lifetime exposure to multiple types of drugs, high rates of current poly drug use (including multiple types of club drugs), and high rates of current depressive symptoms.54 MSM who had ever used MDMA were more likely to report unprotected anal sex and were more likely to be diagnosed with an STD than MSM who had never used MDMA.55A study assessing the pattern of club drug initiation among gay and bisexual men suggests that the sequencing of club drug use may be better explained by socialization processes in the gay community than by Gateway Theory, which has been traditionally used to explain patterns of drug use in the population.56

The epidemiological studies on club drugs are shown in Table 2.

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Table 2: Epidemiological studies on club drugs

Author

Country

Population

Drug

Percentage

Survey on “Drug affinity among young people in the federal republic of Germany”57

Germany

Youth aged 12-25 years

Ecstasy (MDMA) LSD

4% 2%

Kraus & Augustin58

Germany

18-59 year old

MDMA LSD

1.5% 2%

Tossmann& Heckmann59

Germany

1664 adolescents and young adults attending techno parties

MDMA
LSD and related hallucinogens

44.4% 37%

Tossmann et al60

Germany

1412 young adults attending techno parties

MDMA
LSD and related hallucinogens

40.1% 33.6%

Wilkins et al61

New Zealand

15-45 years

MDMA Ketamine GHB

5.4% 0.7% 4.7%

Abraham et al62

Netherlands

15-64 years

MDMA

3.6%

National Plan on Drugs, 200163

Spain

Household survey

MDMA

4.2%

Beck et al64

France

15-64 years old

MDMA

0.9%

Centre for Addiction and Mental Health65

Canada, Ontario

Students of grade 7-12

MDMA Ketamine GHB

5.6% 2.6% 1%

Aust66

United Kingdom

15-59 years

MDMA

5.9%

Australian Institute of Health and Welfare67

Australia

14+ years

MDMA

6.1%

SAMSHA68

United States

12th grade students

MDMA MDMA

3.3% 15.1%

Johnston et al69

United States

12-17 years 18-25 years

MDMA Ketamine GHB

4.5% 2.1% 1.4%

Gripenberg-Abdon et al70

Sweden

401 cruise ship passenger of a
40 hour electronic dance music event

MDMA+ Amphetamines

10.1%

Havere et al71

Belgium

775 visitors of clubs, dance events, and rock festivals

MDMA

19.1%

Banta-Green et al55

Seattle, USA

310 Rave party attendees

MDMA

74.19%

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2.2. MDMA(3,4-METHYLENEDIOXYMETHAMPHETAMINEorECSTASY)

Ecstasy (also called X, M, E, XTC, rolls, beans, Clarity, Adam, lover’s speed, hug drug) is a synthetic, psychoactive drug with both stimulant and hallucinogenic properties similar to methamphetamine and mescaline. MDMA was developed in 1914 as an appetite suppressant, but animal tests were unimpressive, and it was never tested in humans.23 In the 1970s and 1980s, MDMA was thought to be a useful adjunct to psychotherapy due to the altered state of consciousness it produced.72 Despite the lack of scientific evidence, the Multi disciplinary Association for Psychedelic Studies (MAPS) is currently supporting the progression of research to investigate the effectiveness of MDMA as a therapeutic adjunct to psychotherapy.73 It has been a Schedule I drug in USA since 1985 having a high potential for abuse. There is no currently accepted medical use of this drug in treatment in the USA, and there is a lack of accepted safety for use of this drug under medical supervision.74 Prevalence has varied over time but data from the Crime Survey for England and Wales (CSEW) shows that in 2013-14 it was the third most prevalent illicit drug after cannabis and cocaine, with 1.6% of adults aged 16–59 and 3.9% of young adults(16–24 years) having used it in the last year.24 A multi site study exploring the psycho economic factors of Ecstasy consumption has found that monetary and opportunity cost, but not income, significantly predicted Ecstasy use.75 A recent study has found that, low risk perception, high perceived behavioural control of obtaining Ecstasy (an estimated Ecstasy procurement time less than 24h), and current Ecstasy dependence predicted future Ecstasy use.76 Another study among young women found that high stress level is positively correlated with ecstasy use and indulgence in high risk sexual behaviour.77

2.2.1. Clinical Pharmacology

MDMA can be taken through various routes (Table 1). 25 Most tablets containing MDMA are produced in clandestine laboratories in Belgium, Luxemburg, or in Asia. The simplest method of manufacturing MDMA is through 3,4-methylenedioxyphenyl-2- propanone (PMK), a commercially available ketone. Other common precursors include saffrol, isosaffrol, piperonal, and safrole (often from sassafras oil).78 A review of surveys on the contents of Ecstasy tablets found in the 1980s and early 1990s showed that the ingredients of the “MDMA” sold as “esctasy” could include other psychoactive substances as well.79 MDMA is being increasingly used in combination with ketamine and selective serotonin reuptake inhibitors (SSRIs) like fluoxetine and sertraline, which produces a rush initially, prolongs the pleasurable effect, and results in easier comedown following a high.80,81

2.2.2. Neurobiology
The principle effects are on the serotonin system where it is an indirect serotonin

agonist. MDMA inhibits tryptophan hydroxylase, which decreases serotonin

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production.82 It induces the release of serotonin and also blocks serotonin re- uptake.These effects are thought to be related to the observed depression, anorexia, agitation, and marked feelings of empathy reported in association with use of the drug. Because MDMA depletes serotonin stores in neurons, subsequent doses produce diminished euphoria and increase adverse effects such as depression and agitation.83 In addition to its effects on serotonin neurotransmission, MDMA has also been shown to affect the noradrenergic, dopaminergic, and cholinergic neurotransmitter systems.6,84,85

2.2.3. Clinical and adverse effects

Clinical effects of MDMA have been varied ranging from increased energy to depression (Table 1).7-11 Partygoers are motivated primarily by the energetic and euphoric effects they expect from MDMA.86 MDMA has been shown to increase energy and psychomotor drive, self-con?dence, and well-being, and to produce a positive mood, heightened sensory awareness (such as intensi? ed perceptions), derealization, depersonalization, and to increase responsiveness toemotions and sense of closeness to others.83 MDMA increases sexual arousal and there are reports where MDMA was specifically used to increase the sexual vigour.87,88 No withdrawal syndrome from MDMA has been reported.82 Regular ecstasy users often report diminished responsiveness to the drug and a consequent need for dose escalation, both of which imply the development of tolerance.32

Ecstasy use can also bring about a range of negative physical side effects while under the influence of the drug and during the comedown period (Table 1)12-15. Adverse effects include anxiety and thought disorder, jaw clenching (bruxism), lack of appetite, difficulty concentrating, disturbance of balance, and an increase in blood pressure. In a study of MDMA administration, some of these effects were still reported by some subjects after 24 hours.9 Women reported more undesirable acute subjective effects (e.g. physical illness, depressed mood, anxiety, thought disorder and perceptual changes) with greater intensity relative to males.89 In addition, studies have found a relationship between MDMA use (but not use of other drugs) and high risk sexual behaviour (unprotected anal intercourse) among homosexual and bisexual men attending dance clubs.55, 90

There are numerous reports of Ecstasy producing severe acute toxicity resulting in death usually related to severe dehydration, strokes, hyperthermia, and hyponatremia.91 These cases involved seizures, tachyarrhythmias, hypertension, diaphoresis, and pupillary dilation. In addition, body temperatures rangedfrom 104–110?F, which was associated with a variety of complications including kidney failure and death. Evidence of possible liver toxicity is also suggested as another severe outcome related to MDMA use. MDMA ingestion directly causes a rise in antidiuretic hormone. Heat from the exertion of dancing in a crowded room coupled with the MDMA-induced hyperthermia

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can lead easily to excessive water intake and severe hyponatremia, to which young women appear to be particularly susceptible.92,93 Cases have also been reported of damage to the neurological system including cerebral infarctions and hemorrhage, accompanied by neurological impairment. MDMA ingestionhas also been implicated in the experience of psychiatric disturbances such as depression, panic attacks, and ? ash backs of hallucinations. It is likely that these disturbances emergein individuals who are already “at-risk” for mental illness; however, it has been suggested that because MDMA has demonstrated neurotoxicity it might actually be able to induce chronic psychosis in the absence of such individual risk.83Long-term use of MDMA has been related to brain neurotoxicity (lower density of serotonin transporter sites) even after periods ofabstinence.94,95

There is also a substantial risk for fetal exposure from women who are, or become pregnant, while using MDMA. Pregnant women who use MDMA tend to be young, single, and report psychological morbidity and have a clustering of risk factors that may compromise the pregnancy and fetus. Pregnant rats exposed to MDMA during a period that was developmentally equivalent to the human ? rst trimester days had pups with signi? cant neurochemical and behavioural alterations, which is the ? rst report of its kind following a prenatal MDMA exposure.5,96

2.2.4. Management

Laboratory identification of MDMA is difficult. MDMA is excreted as unchanged drug, 3,4-methylenedioxyamphetamine (MDA), and free and glucuronidated/sulfated 4- hydroxy-3-methoxymethamphetamine (HMMA), and 4-hydroxy-3- methoxyamphetamine (HMA) metabolites.Identification of HMMA as well as MDMA through gas chromatography-mass spectroscopy (GC-MS) increases the ability to identify positive specimens but requires hydrolysis.97,98.

2.2.4.1. Management of acute MDM Atoxicity

The most common interventions requiredare clinical monitoring, observation and reassurance, and symptomatic treatment, including ? uids (D).99 The average duration of hospital stay reported by the Australian study was three hours (III).100 Dehydration should be addressed. Following ecstasy-related presentation to a hospital emergency department, intravenous ? uids were administered to 31% of patients in a UK study,130 and to 71% of cases in a Swiss study, but it is important to note that symptoms following ecstasy use range from severe dehydration to severe hyponatraemia; the latter patients require?uidrestriction,soitisdangeroustogivehypotonic ?uidsornormalsalineto patients prior to proper assessment (III).101,102 There is no evidence to support gastric decontamination with activated charcoal, but it may be appropriate for cases of presentation within 1 hour of ingestion (IV).24

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Patients presenting with body temperatures above 39°C need aggressive coolingmeasures, such as ice baths or internal cooling, and benzodiazepine sedation

(IV).24 It has been suggested that dan trolene may be considered when hyperthermia persists. However, this has been contested by some. No clinical trials have been conducted but a review has reported better survival rates for patients with temperatures above 40°C who received dan trolene, with minimal adverse effects (III).103 Referral to an intensive care unit may need to be considered for monitoring and ventilation (IV).24.

Recommendations:

lIn acute MDMA toxicity short period of hospital stay is recommended (C)

lSeverely dehydrated patients may require intravenous fluid (C)

lPatientswithseverehyponatremiamayrequirefluidrestriction (C)

lGastric decontamination with active charcoal is indicated if presentation is within 1 hour of ingestion (D)

lHyperthermia can be treated with Dantrolene (C) or benzodiazepine sedation (D)

2.2.4.2. Management of harmful use and dependence of MDMA

The treatment of harmful ecstasy use is primarily psychosocial. Nospeci? c guidelines for psychosocial intervention have been described and validated forchronic ecstasy users. For those that do seek help, typical treatment approaches include individual and group counselling, cognitive behavioural therapy, and relapse prevention technique.104

Recommendations:

lPsychosocial treatment is the mainstay for chronic harmful use of MDMA (D, S)

2.3. KETAMINE

Ketamine, a derivative of phencyclidine, is an anaesthetic that has been approved for human and animal use, both in trauma and emergency surgery as well as veterinary medicine. Illicit ketamine is also known as Special K, Vitamin K, K, kit-kat, keets, super acid, super K, cat valiums and jet.It can be taken through various routes (Table 1).16 A typical method uses a nasal inhaler, called a “bullet” or “bumper”; an inhalation is called a “bump”. Ketamine often is taken in “trail mixes” of methamphetamine, cocaine, sildenafil citrate (Viagra), or heroin.105 Both popular and research accounts indicate that the recreational use of ketamine has widened in the context of nightclubs, dance parties, and raves.106 Cases of Ketamine dependence have also been reported among anesthesiologists who have easy access to the agent.107,108 Leung et al.109 conducted a focus group with club drug users and noted that there was a special drug use sequence widely practiced by Taiwanese poly-drug users. In a single drug use episode, MDMA was usually the first drug used, followed by ketamine and then marijuana. This unique

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sequence of polydrug use in a single episode is called “Trinity”.110 Chinese Severity of Dependence Scale for Ketamine (C-SDS-K) has been found to be a reliable and valid tool for measuring the severity of dependence in the treatment-seeking population of Chinese ketamine users.111

2.3.1. Clinical Pharmacology

Koesters et al.112 brie? y reviewed reports of the uses of ketamine for human anaesthesia,

indicating that its use was associated with hallucinations after waking up, which led to

discontinuation of ketamineas an anesthetic agent in humans. Recently there has been

renewed interest in its use as an anesthetic agent in brief painful procedures. Ketamine is

a potent analgesic which prevents ‘wind-up’, where neurons in the spinal cord become

sensitized to painful stimuli.113 In this way, low doses of ketamine given before, during

and after surgery improves post-operative pain relief. In humans low doses (0.1–0.5

mg/kg/hour) of ketamine can be used as local anaesthetics and co-analgesics, and are

particularly effective for neuropathic pain114 which is notoriously dif? cult to treat. Low-

dose ketamine is also effective in treating complex regional pain syndrome.115,116

Intravenous Ketamine is now being increasingly used for treatment of refractory

depression in the dose of 0.5 mg/kg as a slow intravenous infusion.117,118 Intravenous

Ketamine also has short lasting effect on suicidal cognition of depressed patients.119

Ketamine is a Schedule III controlled substance in USA whereas in India it is placed

under Schedule H. Ketamine is a well-known immune modulator and, as for most club

drugs, it behaves as an immunosuppressive drug.120 Anaesthesia doses are 2-10 mg/kg

while recreational doses can range between 50–100 mg.112 Frequent users often take

ketamine in a pattern of cyclical binges similar to cocaine or amphetamine dependence.

Tolerance builds rapidly and can be very high.121 Users can become psychologically

dependent, with craving and a high tolerance.121,122 Ketamine withdrawal symptoms

characterized by anxiety, shaking, sweating, palpitations and carvings seem to be key

problems in frequent ketamine users and have been published by many case studies.110,123-125.

2.3.2. Neurobiology

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist. It binds to the same NMDA receptor site as phencyclidine, located in the calcium channel, leading to a blockade in calcium flow through these channels. Decreased excitatory amino acid neurotransmission mediated by NMDA receptors through calcium channel blockade has been associated with altered perception, memory, and cognition.126 NMDA blockade is associated with increased dopamine release in prefrontal cortex and midbrain. It has also been suggested that ketamine, through its binding to the NMDA receptor, can inhibit the reuptake of serotonin, dopamine, and norepinephrine, although the mechanism underlying this action is not entirely clear.14

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2.3.3. Clinical and adverse effects

When misused, subjective experience depends on the dose of the drug consumed (Table 1) 1,16,17,19,20. Acute adverse effects are many (Table 1). These include increased heart rate, hypertension, impairment of motor functioning, respiratory depression, nausea, immobility that leads to abnormally low body, temperature, anxiety, dissociation, depression, recurrent ? ash backs, delirium (confusion disordered speech, hallucinations), amnesia, impaired attention, learning disability, and symptoms of schizophrenia. Effects due to chronic misuse include cognitive difficulties in areas such as attention, learning, and memory.17 Taffe et al.127 concluded that recreational exposure to sub anaesthetic doses of ketamine was likely to induce wide-ranging compromise of cognitive function ranging from memory to attentional to motor domains. In another cross-sectional study, frequent users of ketamine displayed impairments in working and episodic memory and executive functions and experienced reduced psychological wellbeing.128 A neuroimaging study by Liao et al.129 has found white matter changes in bilateral frontal and left temporoparietal cortices. There was also evidence that frontal white matter fractional anisotropy correlated with the severity of drug use.

When misused, low doses are associated with feelings of relaxation called “K-land,” while higher doses can produce dreamlike states, hallucinations, visual distortions, and sensation of near-death experience called a “K-hole”.1,16 Its use has also been associated with unintentional injuries that can occur because the user is insensitive to pain.1 In addition it has been associated with sexual assault because of its dissociative effect in humans.83 There are very few deaths by “pure” ketamine overdose recorded. Of 87 ketamine-linked deaths in New York City, none was purely due to the use of ketamine.130 Parke-Davis has reported that there are cases of accidental injections with 10 times the amount required for surgery, with no obvious, lasting effects.131

Ketamine withdrawal symptoms characterized by anxiety, shaking, sweating, palpitations and carvings seem to be key problems in frequent ketamine users and have been published by many case studies.123-125.

2.3.4. Management

Ketamine is not tested for in standard or advanced drug tests. It is not included on the list of drugs the Substance Abuse and Mental Health Services Administration (SAMHSA) uses for employee drug testing purposes. However if a specific test was requested, norketamine, the breakdown product of Ketamine, is detectable in blood and urine for 7-14 days and “sometimes far longer” in heavy users through high performance liquid chromatography (HPLC).14,94.

2.3.4.1 Management of acute toxicity of Ketamine
The diagnosis of ketamine should be considered when people (especially young

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people) present with agitation, tachycardia and either visual hallucinations or nystagmus, although the absence of the latter two ?ndings does not rule out the possibility of ketamine misuse. No antidote exists for ketamine overdose. Activated charcoal is not necessary after ketamine acute intoxication, unless there is evidence that a co-ingestant may be contributing to the patient’s symptoms or, in thecase of a large ingestion, if the patient presents very early (IV).24

Although randomised controlled trials and other robust studies are not available, there is consistency in case reports and series that patients are best managed with standard supportive care, with special attention to cardiac and respiratory functions, as the effects of the drug are usually short-lived (IV).132,133 Benzodiazepines can be used for agitated patients (IV).24 Patient should be kept in a quiet environment, with minimal external stimuli which prevents excessive agitation (IV).24 Profoundly obtunded patients may require airway support, intravenous ? uids and titrated benzodiazepine therapy if they are agitated, hyperthermic or show overt sympathomimetic signs (IV).134

Recommendations:

lSupportive care with special attention to cardiac and respiratory function is the mainstay of treatment (S)

lPatient should be kept in a quiet environment with minimum external stimulus (S) lActivated charcoal can be used in the presence of co-ingestant or if the patient

presents very early (D)
lBenzodiazepines cane be used for agitated or hyperthermic patients (D)

2.3.4.2. Management of Ketamine dependence and withdrawal

A small number of ketamine-speci? c psychosocial studies have also been conducted. Copeland et al.135 suggest that the harms that require further investigation are the association of ketamine use with unsafe sex and injecting behaviours and its neurotoxic effects. Effective brief and early interventions are needed for those who are at risk of harm because of ketamine intoxication and/or excessive and regular consumption (IV). Critchlow described the treatment of a person with dependence on ketamine that involved three motivational interviewing sessions in the ?rst instance (IV).136 An abstinence-oriented approach can be used for ketamine, similar to that used for psychostimulants (IV).137

Only one case report of ketamine withdrawal is available and describes medically assisted detoxi?cation carried out in conjunction withthree sessions of motivational interviewing. Detoxi? cation was carried out usinga reducing regimen of diazepam over three days. The regimen was successful and eliminated the majority of withdrawal symptoms (IV).136

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Recommendations:

lPsychosocial treatments are mainstay of ketamine dependence (D)
lKetamine withdrawal can be treated with tapering dose of diazepam modified from

alcohol detoxification regimen (D)

2.4. GAMMA-HYDROXYBUTYRATE (GHB)

GHB is available as a clear liquid, white powder (dissolved in water), tablet, or capsule and can be made in private residences with ingredients and recipes obtained on the Internet (DEA 04). Street names include “G”, “Liquid Ecstasy,” “Scoop,” “Easy Lay,” “Georgia Home Boy,” “Grievous Bodily Harm,” “Liquid X,” “Goop,” “Gib,” “Soap,” “Blue Nitro”, “Blue Verve”, “Caps”, “Chemical X”,“Cherry Meth”, “Date Rape Drug”, “Drogue du Cambriolage Sexuel Parfait”, “Ellie”, “Ever Clear”, “EZ Lay”, “Fantasy”, “G”, “Gamma-OH”, “Get-her-to-Bed”, “Great Hormones at Bedtime”, “Grievous Bodily Harm”, “G-Riffic”, “Jib”, “Liquid Dream”, “Liquid E”, “Liquid Ectasy”, “Liquid G”, “Liquid X”, “Liquid-XTC”, “Natural Sleep 500”, “Organic Quaalude”, “Salty Water”, “Scoop”, “Scoop Her”, “Sleep”, “Soap”, “Somatomax”, “Somatomax PM”, “Vita-G”, “Water” and “Nitro”.23.

GHB was suggested for medical use in anaesthesia, obstetrics, and psychiatry138 (including possible use for alcohol and narcotic withdrawal symptoms) in the 1960s and also in the treatment of alcohol and opiate withdrawal, fibromyalgia, and narcolepsy.23,139-142 By the 1990s, GHB was being marketed for illicit use in weight control management and its purported anabolic properties and associated muscle growth that made it a popular drug with body builders.6,14 In addition, GHB has been implicated for its use in association with sexual assault because victims have difficulty resisting the assault due to the level of intoxication produced. The associated memory problems and the fact that it clears from the body quickly (within 12 h) make detection difficult and increase the complexity of attempts to prosecute for which GHB derived its infamous label of ‘date rape’ drug.16 Much interest has been generated regarding driving difficulties caused by GHB. In has been found that, two symptoms that most commonly caused driving difficulties were rapid loss of consciousness or onset of stupor, known among users as “G-napping” and periods of anterograde amnesia.24 GHB is now a Schedule I drug in the U.S. and Schedule IV of the 1971 UN Convention. In 2002, sodium oxybate, a formulation of GHB, was approved for the treatment of narcolepsy and classified as schedule III.23

2.4.1. Clinical Pharmacology

Gamma-hydroxybutyric acid (GHB) is a short-chain fatty acid occurring naturally in mammals. GHB can form salts (e.g. sodium and potassium salts), which are soluble in water and alcohol. It is colourless and easily mixes in aqueous solutions; however, a

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salty taste may be noticeable.143 Illegal GHB and its precursors, GBL (gamma butyrolactone) and 1,4-BD (1,4-butanediol), can be obtained over the Internet and sometimes are marketed as solvents such as ink jet printer fluid or as GHB alternatives in health food stores, gyms, raves, and nightclubs. GHB and GBL are subject to interconversion in aqueous media.

GHB pharmacokinetics have been studied in healthy volunteers, narcoleptics, alcoholics, and patients with liver impairment. A further study monitored GHB kinetics following 1,4-butanediol administration to healthy volunteers. When healthy adult volunteers and patients with biopsy-proven liver cirrhosis were compared, there was a marked reduction in clearance following oral administration and significant prolongation of elimination half-life.144 GHB is metabolized via succinic acid and the citric acid cycle (TCA cycle/Krebs cycle), ultimately producing carbon dioxide and water. GHB conversion to succinic semi-aldehyde can be catalysed by cytosolic GHB- dehydrogenase or mitochondrial GHB-etoacid transhydrogenase. At low doses, GHB is eliminated through the respiratory system, with higher doses via renal clearance. While the half-life of GHB is short after low doses, high doses (such as those associated with overdose) result in slow and prolonged absorption and a much longer half-life in animal studies.23 The related chemicals, 1,4-BD and GBL, are metabolized endogenously to GHB. 1,4-BD is metabolized by alcohol dehydrogenases to gamma- hydroxybutyraldehyde and then by aldehyde dehydrogenase to form GHB; ethanol can inhibit this metabolism as it acts as a competitive substrate to alcohol dehydrogenase. Less than 2% of GHB is eliminated unchanged through urine. GBL is converted to GHB by serum lactonase; this enzyme is not present in brain tissue.145, 146 Following the oral administration of 1,4-BD 25 mg/kg, the mean elimination half- life was reported to be about 39.3 minutes in healthy adult volunteers.147

2.4.2. Neurobiology

GHB acts as a neurotransmitter or neuromodulator and bind to GABA-B receptors; GHB is both a metabolite and a precursor of the inhibitory neurotransmitter gammahydroxybutyrate (GABA), and acts as a neuromodulator in the GABA system.23 GHB does not readily pass the blood brain barrier. The highest density of these receptors is in the hippocampus, cortex, and dopaminergic areas (striatum, olfactory tracts, and substantia nigra). GHB inhibits dopamine release and activates tyrosine hydroxylase, that together act to increase central dopamine levels, which could be associated with the reinforcing effects of GHB.148

2.4.3. Clinical and adverse effects
Clinical and toxic effects of GHB can be found in Table 1.2,16,22 The symptoms typically

occur within 15-45 minutes, and resolve within a relatively short interval of time; CNS

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depression usually persists for 1-3 hours with patients making a complete recovery typically within 4-8 hours. Other common neurological effects include ataxia, disorientation, dizziness, confusion, hallucinations, somnolence, slurred speech, dysarthria, confusion, headache, incoordination, euphoria, amnesia, hypotonia, hyporeflexia, tremor, and myoclonus. Seizures or seizure-like activity have also been reported agitation, bizarre behaviour, and combativeness has been noted in some patients, either at presentation to the treatment facility or upon wakening. Patients can also alternate between agitation and somnolence.

Table 3: Clinical effects of GHB at different doses

Dose range

Clinical effects

10 mg/kg
20 – 30 mg/kg 50mg/kg >50mg/kg

Short-term anterograde amnesia, hypotonia, and euphoria Drowsiness, sleep, and myoclonus
Coma
Coma, bradycardia, and/or respiratory depression

Other less common neurological effects may include bruxism, vertigo, disinhibition, increased sexual arousal, delusions, extrapyramidal side effects, dystonias, and athetoid posturing. Miosis is common while mydriasis and horizontal and vertical gaze nystagmus may also occur. Pupils may also be sluggish or nonreactive. Common cardiovascular effects include bradycardia, and hypotension. Chest tightness or palpitations may also occur. The major respiratory effects of GHB include dose-related respiratory depression, bradypnoea, periodic (Cheyne-Stokes) respirations, and apnoea and respiratory failure. Metabolic features include hyperglycaemia, hypokalaemia, and potentially hypernatremia if large doses of the sodium salt are ingested. Elevated creatine kinase activity/rhabdomyolysis may also occur. Nausea and vomiting are common gastrointestinal symptoms following oral or intravenous administration of GHB. Death is normally due to respiratory failure. GHB use alongside other CNS depressant drugs may increase toxicity by producing synergistic CNS depression. and co-ingestants may also contribute to fatalities involving GHB.21,147

The Drug Enforcement Administration (DEA) has documented deaths related to GHB.15 Several issues to note were the presence of other substances (particularly alcohol and opiates e.g. heroin, codeine, dihydrocodeine and morphine); the presence of GHB in postmortem blood specimens, in cases where there has been no evidence of GHB use and the GHB concentration found is sometimes low despite the user dying due to GHB use.

Dependence on GHB has been described as developing after regular use, i.e., every 2h round-the-clock for 2 months to 4 year.23 Withdrawal symptoms include insomnia,

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muscular cramping, tremor, perspiration, anxiety, and feelings of doom.149 Withdrawal from higher doses includes bowel bladder incontinence and blackouts.148

2.4.4. Management

2.4.4.1. Management of acute GHB toxicity

A diagnosis of GHB intoxication is typically made on the basis of the patient’s history and presentation. However, as such symptoms are not specific, it may be difficult to differentiate GHB poisoning from other sedative hypnotic intoxications, especially if no history of GHB use is available to the clinician. GHB is detected by routine urine screens in the western countries which are not available in India now, but other immunoassays for GHB and GBL are not available. These are reliably detected by specific requests for GC-MS, but timing is important, as GHB is rapidly excreted as carbon dioxide through exhalation.21 GHB has a half-life of 27 min and it is virtually undetected in the urine 12 h after ingestion.133 Since GHB continues to be produced after death, it should be collected in tubes containing sodium fluoride.150 In cases of chemical submission, both urine and blood should be analyzed, since GHB is present longer in urine than in blood, and a detailed case history should be obtained. A sensitive and specific GC-MS method using selective ion monitoring has been developed for the quantification of GHB in blood.151

Decontamination is unlikely to be beneficial in the majority of cases because of the drug’s rapid absorption, particularly when consumed in a liquid form. Activated charcoal (50-100 g) should only be considered in patients who are alert, stable, and cooperative, or have a protected airway (IV).152,153 Supportive care is the mainstay of management, with primary emphasis on respiratory and cardiovascular support. Initial treatment includes securing intravenous access and continuous cardiac and blood pressure monitoring along with pulse oximetry and arterial blood gas monitoring. Airway protection including rapid sequence induction with endotracheal intubation and/or assisted ventilation is indicated (IV).24 Atropin may be needed for patients with haemodynamically unstable hypotension which is treated with crystalloids (IV).24 Myoclonic movements typically do not require any specific treatment but benzodiazepine administration may be useful (IV).24 Seizures may be treated with lorazepam or diazepam only if the patient has seizures and is well ventilated (IV).24

There are no specific antidotes for GHB poisoning. However, some pharmaceuticals have been investigated as potential antidotes.147 They are Physostigmine, Naloxone, Flumazenil and GABA-B antagonist, SCH 5091.147

Recommendations

lSupportive care is the mainstay of treatment. Endotracheal intubation may be required if vomiting is present (D,S)

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lDecontamination with activated charcoal should be considered in patients who are alert, stable and have a protected airways (D)

lAtropine can be used for hemodynamically unstable patients (D)
lMyoclonic movements and seizures may be treated with lorazepam or diazepam (D)

2.4.4.2. Management of GHB withdrawal

The GHB-related withdrawal syndrome seems consistent with other hypnotic/sedative withdrawal syndromes. Commonly reported symptoms include auditory and visual hallucinations, tremors, tachycardia, hypertension, sweating, agitation, anxiety, paranoia, insomnia, disorientation, confusion, and aggression/combativeness. Patients may also suffer depression, miosis, nystagmus, cardiac palpitations, dyspnea, tachypnoea, nausea and vomiting, diarrhoea, and abdominal pain, though this is less common. Withdrawal can occur rapidly following the last dose taken by the user; in one case series, it developed within 1-12 hours. The duration of these clinical effects may continue for three to twenty-one days.23 In severe cases, delirium, psychosis, rhabdomyolysis, and seizures, are observed which may become life-threatening.

To date, there have been no rigorous prospective clinical trials investigating GHB withdrawal treatments. Combined evidence suggests that benzodiazepines are the ? rst line of treatment, but adjuncts may be helpful to control symptoms (IV).154 Baclofen and barbiturates have been described as second-line adjuncts.24 TOXBASE recommends that withdrawal symptoms can be effectively treated with a combination of diazepam and baclofen and this has been used successfully in clinical practice, as part of medically assisted detoxi? cation (IV).152,155-158 A wide range of medications have been used and described as potentially helpful in GHB withdrawal management. However, supporting evidence for any of these medications is mainly based on a small number of case reports and case series. These agents include barbiturates, valproic acid, carbamazepine, gabapentin, chloral hydrate, baclofen, clonidine, paroxetine, beta blockers, bromocriptine, trazadone, fentanyl, propofol, or antipyschotics (IV).24

Recommendations

lBenzodiazepines are the first line of treatment for GHB withdrawal (D)

lBaclofen and barbiturates can be used as second-line adjuncts (D)

lValproic acid, carbamazepine, gabapentin, chloral hydrate, baclofen, clonidine, paroxetine, beta blockers, bromocriptine, trazadone, fentanyl, propofol, and antipyschotics have been tried sporadically (D)

2.4.4.3. Management of GHB dependence
General psychosocial interventions for the use of club drugs are applicable to the

management of the chronic harms of GHB use, as well as aftercare and support (IV). 24

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Recommendations

lPsychosocial interventions are the mainstay of treatment of GHB dependence (D)

2.5. FLUNITRAZEPAM

Street names of Flunitrazepam include Roofies, Rophies, Roche, Forget-me Pill, Circles, Mexican Valium, Rib, Roach-2, Roopies, Rope, Ropies, Ruffies, Roaches, Circles, Forget Pill, LA Rochas, Lunch Money, Mexican Valium, Mind Erasers, Poor Man’s Quaalude, Pingus, R-2, Roches, Roofies, Roopies, Rope, Rophies, Ruffies, Trip-and- Fall, Whiteys, Forget me drug, Reynolds, Rolpes, Reffies, Ruffles, Sedexes, wolfies.23,159

Flunitrazepamis a benzodiazepine manufactured by Roche Laboratories, is available in more than 60 countries in Europe and Latin America for preoperative anaesthesia, sedation, and treatment of insomnia. In the United States where it is not legally available, imported Flunitrazepamcame to prominence in the 1990s as an inexpensive recreational sedative and a “date rape” drug.160It is odourless and tasteless and is easily dissolved in beverages, allowing a perpetrator to add it to the beverage of a potential victim. Flunitrazepam has had a long history of abuse by heroin and cocaine addicts. The manufacturers, Hoffman-La Roche, are now adding a blue dye to the pill that will be visible if added to a beverage though the generic flunitrazepam available in the grey market do not have the dye.159

Flunitrazepamcomes in pill form and is typically taken orally, although reports of it being ground and snorted are also available. Users swallow or chew the tablets or allow them to dissolve under the tongue. The act of adding such substances to drinks is known as “drink spiking”. They also crush pills and snort the powder to feel the effects more quickly, the powder can also sprinkled on marijuana and smoked or dissolved and injected. Users feel the effects 15-20 minutes after ingestion, and they may last for 12 or more hours.159

In 1996, the U.S. government prohibited the import of the drug, but it remains available in other countries and continues to be illegally brought into the U.S. Since 2001, only the 1mg Roche tablet has been available, although generic products continue to be available in the 2mg strength, which has been the strength preferred for misuse, since word around the street and in the sub-culture maintains that the 2mg pill produces a quicker and a better “high” than two 1mg pills.161 Although the generic/grey market pills may be white and round, the original manufacturer has reformulated the 1mg pill to be a greyish-green oval tablet.

2.5.1. Clinical Pharmacology
Chemical formula and structure of Flunitrazepam is C16H12FN3O3-5-(2-

Fluorophenyl) 1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepine. It is a white solid,

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with a melting point of between 166-167°C, a molecular weight of 313.3, and is soluble in ethanol.159

2.5.2. Neurobiology

Similar to other benzodiazepines, Flunitrazepam is a GABA agonist. As such, it mediates inhibitory neurotransmission in the brain and spinal cord.162 Benzodiazepines bind to the GABA receptor, opening the chloride channels of neurons and resulting in an influx of chloride and hyperpolarization of the cell. This decreases the excitability of the cell producing sedation, anticonvulsant activity, and anxiety reduction.162

2.5.3. Clinical and adverse effects

Clinical effects of Flunitrazepam are similar to benzodiazepines.23 The effects are much greater with the concurrent ingestion of alcohol or other sedating drugs.23 Flunitrazepam has been suggested to have a higher abuse liability than other benzodiazepines.163 Clinical effects of Flunitrazepam include disinhibition, amnesia, and muscle relaxation, but individual effects vary.164 The amnesia is commonly of anterograde type, that is, it involves memory loss for events that occur after the medication is taken.23

Adverse effects of Flunitrazepam include decreased body temperature and blood pressure, sedation, cognitive & psychomotor impairment, visual disturbances, dizziness, confusion, GI disturbances, urinary retention.23 The effects of Flunitrazepam can be felt within 30 minutes of being drugged and can last for several hours. If an individual is drugged, he/she might look and acts like someone who is drunk. Flunitrazepam overdose may result in excessive sedation, impairment of balance and speech, and may progress in severe overdoses to respiratory depression, coma, and possibly death.162

Cessation of Flunitrazepamuse can result in benzodiazepine withdrawal syndrome. The withdrawal syndrome includes headache, tension, anxiety, restlessness, muscle pain, photosensitivity, numbness and tingling of the extremities, and increased seizure potential.165 Gradual discontinuation may result in withdrawal symptoms including seizures, psychosis, severe insomnia, amnesia, loss of concentration, rebound insomnia, mood swings, depression and severe anxiety. Abrupt and rapid discontinuation may result in suicidal or homicidal ideations, mania, delirium, convulsions, violence, catatonia and coma. As withdrawal weans off over days to weeks patients often find that their physical and mental health improves with improved mood and improved cognition.162

2.5.4. Management
2.5.4.1. Toxicology and detection
While a standard component of most urine drug screens is testing for benzodiazepines,

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Flunitrazepam is administered in such small amounts and distributed so rapidly that detection methods commonly fail. Typical toxicological tests can only detect Flunitrazepamin blood and urine for up to 72 h after ingestion due to quick metabolism and elimination.5 Laboratory identification of Flunitrazepam is very difficult to achieve due to only a 72 hour period of time to test for it before the drug is metabolized in the body. There are only insignificant traces after that time which is nearly impossible to detect. Flunitrazepam is not detected with routine toxicological screening. After ingestion it can be found in the blood stream for 24 hours and in urine samples for 48 hours. A sensitiveurine test can detect the presence of Flunitrazepam up to 60 hours after ingestion. Flunitrazepam and its active metabolite 7-amino-flunitrazepam may be detected by gas chromatography/mass spectrometry testing up. Hairs can also be used as a possible source of detection of Flunitrazepam and its metabolites.159

Rohypnol Rapid Drug Test (Benzodiazepines Dip Test)–Flunitrazepam Urine Drug test, a simple one step dip and read urine test card for detection of Benzodiazepines in urine. This test card detects presence of Flunitrazepam in urine.

Micro-Plate Enzyme Immunoassay- Micro-plate enzyme immunoassay method allows to detect Flunitrazepamand related compounds in urine at least up to 5 days after administration of a single dose of Flunitrazepam (like in drug-facilitated sexual assault scenarios). This significant increase in the detection time interval is possible if the enzymatic hydrolysis of urine and solid-phase extraction is applied.159,166

Mass Spectrometry – Application of mass spectrometry with negative ion monitoring chemical ionization allows detecting 7- aminoflunitrazepam, major metaboliteof Flunitrazepam, in urine 14 days after administration of a single dose of Flunitrazepam. The maximum concentration of 7-aminoflunitrazepam in urine was observed 6 to 24 hours after administration of a single dose of Flunitrazepam. The concentrations of 7- aminoflunitrazepam in hair are much higher than concentrations of the parent drug, Flunitrazepam. The metabolite remains in hair for at least one month after administration of a single dose of Flunitrazepam.159,166

2.5.4.2. Management of Flunitrazepamintoxication/dependence

Management of Flunitrazepamover dose/dependence is similar to other benzodiazepine overdose/dependence which has been elaborately dealt in the previous volume of IPS-CPG which provided the guidelines for the management of sedative-hypnotic use disorders.167 Supportive measures include use of activated charcoal to absorb drug in the gastrointestinal tract as well as respiratory support (IV).165 Flumazenil is a specific benzodiazepine antagonist that may be administered to reverse the effects of Flunitrazepam toxicity (IV).165

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Recommendations

lDecontamination with activated charcoal is done for patients with secured airways and who present early (D,S)

lFlumazenil can be used to reverse the effects of Flunitrazepamtoxicity (D) lFlunitrazepamdependence is managed by titrating doses of long acting

benzodiazepines similar to other benzodiazepine dependence (D) lPsychosocial interventions are also useful for Flunitrazepam dependence (D)

2.6. LSD AND RELATED HALLUCINOGENS

LSD is the best-known synthetic hallucinogenic drug among the class of the hallucinogens. Although LSD does not occur in nature, a similar analogue, lysergic acid amine (LSA), is found in seeds of Argyreia nervosa and Ipomoea violacea used in Central America for ceremonial purposes.168 Synthesized by Hofmann in 1938, LSD’s consciousness-altering properties were discovered accidentally a few years later.169 Its molecular structure and mechanism of action present similarities with serotonin, which prompted the evaluation of its potential therapeutic use in alcoholics and patients with mental disorders.170 In 1966, LSD was banned and in 1970 was reclassified as a Schedule I controlled substance in an attempt to avoid its growing recreational use.171

The most common hallucinogenic fungi containing tryptamine derivatives are the Psilocybe spp. mushrooms, which are widely distributed around the world, being extremely used by indigenous people for centuries in sacred rituals, especially in South American countries (particularly in Colombia), Mexico, India, Japan, New Guinea and Australia.172,173,174 Psychoactive mushrooms soon became known worldwide as ‘magic mushrooms’ and have turned famous among recreational users in the USA, Europe and Japan. Psilocybe mushrooms, psilocybin and psilocin are classified as Schedule I drugs in the USA, although the spores of mushrooms remain legal except California.168

Another very commonly known and used natural tryptamine is bufotenine or 5- hydroxy-N,N-dimethyltryptamine (5-OH-DMT), an N-alkylated derivative of serotonin and also a structural isomer of psilocin.175-178

LSD and other related hallucinogens are summarised in Table 4.

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Table 4: LSD and related hallucinogens (Adapted from NEPTUNE, 2015)24

Newer and Emerging Addictions in India

Chemical name

Abbreviation

Street products and names

(6aR,9R)-N,N-diethyl-7-methyl- 4,6,6a,7,8,9-hexahydroindolo- [4,3-fg]quinoline-9-carboxamide (N,N-diethyl-D-lysergamide)

LSD

‘Acid’, ‘A tab’, ‘Blotter’ (LSD on blotting paper squares, ~1 cm2), ‘Geltabs’, ‘Windowpane’ (LSD in gelatine squares/ pieces), ‘Microdots’ (very small pills)

(8β)-9,10-didehydro-6- methylergoline- 8-carboxamide

LSA (ergine)

‘Morning Glory seeds’ and ‘Hawaiian Baby Wood rose seeds’ (seeds containing LSA and other alkaloids)

Other LSD related compounds

ALD-52, ETH- LAD, PRO- LAD, AL-LAD, LSZ

‘Morning Glory seeds’ and ‘Hawaiian Baby Wood rose seeds’ (seeds containing LSA and other alkaloids)

O-phosphoryl-4-hydroxy- N,Ndimethyltryptamine

Psilocybin

‘Magic mushrooms’, ‘Mushies’ or ‘Shrooms’ contain psilocybin and related tryptamines

4-hydroxy-N,N- dimethyltryptamine

Psilocin

‘Liberty caps’ or ‘Libs’ are the most common wild UK species of magic mushroom, Psilocybesemilanceata. Also occurring in the UK are Panaeoluscinctulusand ‘Wavy caps’, Psilocybecyanescens’Cubes’ or ‘Boomers’ are the most commonly home-cultivated species, Psilocybecubensis’Truffles’ or ‘Philosopher’s stones’ are cultivated nodular growths (technically ‘sclerotia’) from other Psilocybespecies.

N,N-dimethyltryptamine

DMT

‘Dimitri’ and ‘Spice’ are terms sometimes used for the white, yellow or brown DMT crystals or powder, often used for smoking (technically vapourising). This should not be confused with ‘spice’ also commonly used for synthetic cannabinoids. ‘Ayahuasca’ and ‘Yagé’ are decoctions that include a DMT-containing

plant and another plant containing a monoamine oxidase inhibitor, which allows DMT to be orally bioavailable

alpha-methyltryptamine

αMT

‘AMT’

N,N-diisopropyltryptamine

DiPT

‘Foxy’

5-methoxy-N,N- diisopropyltryptamine

5-MeO-DiPT

‘Foxy Methoxy’

3,4,5- trimethoxyphenethylamine

Mescaline

‘Hallucinogenic cacti’ contain psychoactive alkaloids, principally mescaline. ‘Peyote’, ‘San Pedro’ an ‘Peruvian Torch’ are the common names for the three predominant species

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Chemical name

Abbreviation

Street products and names

2C Series, and their derivatives

2C-B has various close analogues; bk-2C-B, and 25B-NBOMe

‘Bees’ are tablets or capsules containing 2C-B. ‘Nexus’ is also 2C-B ‘Tripstasy’ was 2C-T-7, but could be used for any drug combining hallucinogenic effectswith MDMA-like effects ‘N- Bomb’ drugs are the NBOMe analogues series, so 25I-NBOMe may also be called ‘NBOMe 2C-I’

Hallucinogenic amphetamines,DOx series and their derivatives

DOM, DOI, DOB, TMA-2

‘STP’ (for ‘serenity, tranquillity and peace’) was the original name for pills of DOM

Tetrahydrodifranyl compounds

2C-B-FLY, bromodragonfly

They are called ‘FLY’ because their molecular structure resembles the insect

2.6.1. Clinical Pharmacology
In general, classical hallucinogens can be divided into two main structural classes:

1. Phenylalkylamines

2. Indolamines.

The chemical backbone of hallucinogenic phenylalkylamines is a phenethylamine group, which is a prevalent structure in a range of endogenous compounds, including the neurotransmitters dopamine and norepinephrine.179 Indolamines contain an indole nucleus as basic structure, having a high structural similarity with 5-hydroxytryptamine (5-HT or serotonin), a monoamine neurotransmitter that modulates human mood and behaviour. 179,180

Indolamines can be subclassified into two main groups:

i. The simple tryptamines (including substances like DMT and psilocybin) that can be subdivided according to the site of the modification.

ii. TheergolinessuchasLSD.179

Following absorption, tryptamine analogues undergo phase I and phase II metabolism. The ergoline LSD is extensively metabolized and <1% of the ingested dose is eliminated unchanged in urine. The analysis of urine from LSD users identified five metabolites, namely the 2-oxo-LSD, 2-oxo-3-hydroxy-LSD, N-desmethyl-LSD, 13- and 14-hydroxy-LSD glucuronides.181 Psilocybin (a 4-substituted indolamine) is rapidly dephosphorylated by phosphatases in the digestive tract, in kidney and probably in the humanblood to generate its pharmacologically active metabolite psilocin. Oxidative deamination of psilocin to form 4-hydroxyindole acetic acid (4-OH-IAA) constitutes a minor metabolic pathway.182 Psilocin is further metabolized by phase II enzymes to give the psilocin-O-glucuronide, which is the main metabolite detected in human urine.182 Like 5-HT itself, some tryptamine derivatives including DMT, 5-OH-DMT and 5-MeO-

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DMT are extensively metabolized through oxidative deamination to their corresponding indole acetic acid (IAA) derivatives mediated by monoamine oxidase A (MAO-A).183

2.6.2. Neurobiology

There is high correlation between the affinity to 5-HT2 receptors and hallucinogenic potency in humans.184 Radio-ligand binding studies showed that phenylalkylamine hallucinogens such as mescaline are typically selective for 5-HT2 receptors, including
the 5-HT2A, 5-HT2B and 5-HT2C subtypes.184 Like phenylalkylamines, the tryptamine hallucinogens such as LSD, psilocin, DMT or 5-MeODMT act as 5-HT2 receptor agonists, but they are much less selective, binding to a variety of 5-HT1 and 5-
HT2 receptor subtypes (including 5-HT1A, 5-HT1B, 5-HT1C, 5-HT2A and 5-HT2C receptors) with different affinities.179,185 Tryptamine derivatives, in general, exert their effects by binding to and activating primarily the serotonin 5-HT2A receptor, which is mainly responsible for the effects of hallucinogens.179 DMT is described as sigma-1 (σ1) receptor agonist with moderate affinity, although this is not its main interaction, since DMT affinity for 5-HT1A and 5-HT2A receptors is twice greater than for σ1.186 Dopaminergic and adrenergic receptors play an additional role in mediating certain aspects of the behavioural effects provoked by these compounds.186 Ibogaine interacts strongly the NMDA receptor, σ–receptors, μ-opioid receptors, and muscarinic receptors.187 It also causes serotonin and dopamine reuptake inhibition at their transporters (SERT and DAT).188

2.6.3. Clinical and adverse effects

Users experience euphoria, mild stimulation, enhanced appreciation of music and lights, visually appealing distortions, intensification of sensual or sexual feelings, altered sense of time and place, and a sense of shared and heightened significance of the situation with the intake of hallucinogens. The effects of the hallucinogens are dose dependent. One hallucinogen i.e. 2C-B has been described as inducing ‘perceptual enhancement’ and euphoria (hence more used in raves/clubs and popular as a dance drug), but these are milder than those of classical hallucinogens such as LSD and the drug lacks the potent hallucinogenic effects of LSD.

Unwanted psychological effects of hallucinogens are referred to as a ‘bad trip’, and are characterised by anxiety, fear/ panic, dysphoria and/or paranoia. Distressing effects can be sensory (e.g. frightening perceptions), somatic (e.g. distressing awareness of physiological processes), personal (e.g. troubling thoughts or feelings) or even metaphysical (e.g. feelings about evil forces). In very rare cases, fear and paranoid delusions may lead to erratic behaviour and potential aggression against self and others.189 Even when a user is not experiencing a ‘bad trip’, unwanted effects can include confusion, disorientation, anxiety and unwanted thoughts, emotions and memories.

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Symptoms of hallucinogen overdose involve almost all the organ systems of the body which is shown in Table 5.

Table 5: Symptoms of overdose and toxicity of LSD and related hallucinogens

Organ system

Symptoms

Central nervous system

Dilated pupils, mydriasis, (common with psilocybin), sensory distortions, visual & auditory illusions, synaesthesia &tactile hallucinations, e.g. formication, affect lability, euphoria dysphoria, acute panic, paranoia, ideas of reference, depersonalisation, anxiety disorientation dissociation agitation, aggression, combativeness delirium depression, suicidal ideation, attempted suicide, psychosis, delusions, hallucinations seizures confusion ataxia ‘bizarre behaviour’ lightheadedness, headaches, paraesthesias, abnormal sensations of heat and cold, chills, restlessness and excitement

Cardiovascular system

Tachycardia and hypertension

Musculoskeletal system

Myalgia, twitching, shaking,muscle tension and jaw clenching

Respiratory system

Tachypnoea

Metabolic

Metabolic acidosis

Gastrointestinal system

Nausea, vomiting (psilocybin commonly) and diarrhoea

Renal

Acute kidney injury/acute kidney failure, rhabdomyolysis

Others

Hyperthermia, pyrexia, hypoglycaemia, flushing and sweating

A study using data from the large representative sample of the US National Survey on Drug Use and Health found that the use of hallucinogenic drugs appears not to be causally linked to the de novo development of chronic disorders of mental health such as schizophrenia or depression.190 Hallucinogens are rarely a cause of substance- induced psychosis, where the drug triggers a psychotic episode that may persist hours, days or even weeks after the acute intoxication should have run its course.191 Nonetheless, psychotic symptoms in the context of LSD use have been reported. Salvia can trigger psychosis in people with existing psychotic illnesses or predispositions. Psilocybin mushrooms can cause an exacerbation of psychosis. A greater psychotic response to LSD in persons with a genetic predisposition to schizophrenia has been observed.192

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Hallucinogen persisting perception disorder (HPPD) and ‘flashbacks’ have been associated with use of classic hallucinogens in particular, although these concepts remain uncertain. HPPD as a diagnosis has been embraced by a group of people experiencing longer-term symptoms resulting from hallucinogen use. HPPD can persist for months or years after the use of hallucinogens. For some, this long-term change to vision and hearing is much less problematic than for others, for whom it can cause substantial morbidity.193,194

The diagnostic criteria of HPPD as defined by DSM-5 (292.89) are as follows:

A. Following cessation of use of a hallucinogen, the re-experiencing of one or more of the perceptual symptoms that were experienced while intoxicated with the hallucinogen (e.g. geometric hallucinations, false perceptions of movement in the peripheral visual fields, flashes of colours, intensified colours, trails of images of moving objects, positive afterimages, halos around objects, macropsia, and micropsia).

B. The symptoms in Criterion A cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

C The symptoms are not due to a general medical condition (e.g. anatomical lesions and infections of the brain, visual epilepsies) and are not better accounted for by another mental disorder (e.g. delirium, dementia, schizophrenia) or hypnopompic hallucinations.

In contrast, ICD-10 views this disorder within the wider paradigm of a psychotic disorder (F1x.5) and specifically considers ‘flashbacks’ (F1x.70) within the context of ‘residual and late-onset psychotic disorder’ (F1x.7). ICD-10 also specifies that ‘flashbacks’ ‘may be distinguished from psychotic disorders partly by their episodic nature, frequently of very short duration (seconds or minutes) and by their duplication (sometimes exact) of previous drug-related experiences’.

LSD has been involved in a small number of fatalities attributed to ‘excited delirium’, more commonly associated with cocaine. Excited delirium has also been associated with 5-MeO-DALT and alpha-MT. It has been argued that, in some instances, fatalities attributed to excited delirium may reflect underlying serotonergic and/or sympathomimetic toxicity.24

2.6.4. Management

2.6.4.1. Management of hallucinogen toxicity

The management of acute toxicity resulting from the use of hallucinogens will in part depend on the hallucinogenic substance consumed. It has been suggested that monitoring and supportive treatment is all that is required for the majority of patients including airway management.195

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Attempts to ‘talk the patient down’ first must be instituted. Sympathetic, non- judgemental reassurance, support and observation are often sufficient. Where possible, the patient should be placed in a well lit room with minimal disturbance. Patients may be prone to mistrust and paranoid ideation and early efforts in empathising, expressing understanding of their fears and establishing confidence have been shown to be beneficial.189

Benzodiazepines, particularly diazepam or lorazepam195,196 have been reported by some studies to be first-line choice if pharmacological interventions are needed and in cases of agitation (IV).189 In most of the case 10 mg oral doses of diazepam (0.1–0.3 mg/kg body weight) is sufficient (IV).24 Doses of 15–30 mg per hour or as needed have been suggested for cases of ‘bad trips’ that do not respond to reassurance in an emergency department setting.189 Larger doses may be required. Antipsychotics should be considered as a second line if benzodiazepines do not produce adequate sedation (IV).24 In cases of severe agitation or ‘excited delirium’, physical restrain should be avoided, as this is associated with sudden cardiovascular collapse.197

Recommendations

lPatient should be placed in a quiet, well lit room with minimal external stimuli (S) lBenzodiazepines, diazepam or lorazepam are the mainstay of treatment,

particularly in presence of agitation (D)
lAntipsychotics can be considered as second line treatment (D) 2.6.4.2. Management of hallucinogen dependence

The use of LSD or other classic hallucinogens does not appear to lead to dependence. Typically there is no persistent and compulsive pattern of use and the use of hallucinogens is not associated with any recognised withdrawal syndrome.198 Hallucinogens do not appear to show classic patterns of tolerance, but, on the contrary, areassociatedwithtachyphylaxis.179 ThismeansthatsensitivitytotheeffectsofLSDand other hallucinogens appears to be strongly attenuated for a period after use. It may therefore prove difficult for a user to achieve desired effects from LSD if taken two days in a row, or indeed to get a desired effect from other hallucinogens.168,179

2.6.4.3. Management of HPPD

Pharmacological interventions for HPPD have been used but many of the studies (especially older ones) had methodological limitations. These interventions have included several classes of antidepressants, anxiolytics and antipsychotics, a COMT inhibitor, naltrexone, levodopa, clonidine, lamotrigine and citalopram (IIb).24 Over the years, there have been reports of treatment using haloperidol, diphenylhydantoin, trifluoperazine, barbiturates, benzodiazepines, carbamazepine, sertraline, naltrexone, clonidine, and a combination of olanzapine and fluoxetine(IIb).24 Hermle et al. have

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suggested that the anti-epileptic lamotrigine may be a promising new medication for HPPD (IV).24,199

Recommendations

lSeveral classes of antidepressants, anxiolytics, antipsychotics, COMT inhibitor, naltrexone, levodopa, clonidine, lamotrigine and citalopram can be used to treat HPPD (B)

lLamotrigine may be a promising agent in the treatment of HPPD (D)
3. GENERAL PRINCIPLES IN THE MANAGEMENT OF CLUB DRUG

INTOXICATION / HARMFUL USE / DEPENDENCE

Because club drugs are illicitly obtained and often are adulterated or substituted, they are usually known as unknown substances. In the ever-changing world of illegal drug distribution, Internet Web sites can be helpful in identifying the rapidly changing appearances of these substances.23 Urine and serum toxicology screens may not be able to detect club drugs. For example, urine screening does not detect MDMA, though it does detect its metabolite, MDA. Ravers often present with concurrent ingestion of drugs with different pharmacological profile, which may include stimulant and depressant drugs. Therapist should always make an attempt to gather information from as many sources as possible regarding what was ingested and in what form.

Table 6 : Treatment strategies for Club Drugs (adapted from Gahlinger, 2004)23

Newer and Emerging Addictions in India

  

Not sure

What drug was taken?

Positive identification of drug

   

Ask for sample, description, or visual identification

Consider adulteration, or drug substitution

   

Cardiac monitoring
Pulse oximetry
Urinalysis
Chemistry panel
Toxicology screen if available Seizure precautions

Consider escape and self-injury

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If less than 60 minutes since ingestion, consider gastric lavage

Stimulants: MDMA
Ketamine (Ketalar)

Depressants: Flunitrazepam GHB

Anxiety or agitation: Benzodiazepines e.g. Diazepam/Lorazepam/Midazolam

Severe hypertension: Labetalol/ Phentolamine/Nitroprusside

Hyperthermia: rapid cooling\ Serotonin syndrome: Cyproheptadine/

Chlorpromazine

Rhabdomyolysis: alkaline IV fluids (5% D with Sodium Bicarbonate)

Provide supportive care. Consider flight risk.
Consider psychiatric consultation Provide education to patient and

No standard treatment protocol has been identified for club drug overdose. Basic management should include cardiac monitoring, pulse oximetry, urinalysis, and performance of a comprehensive chemistry panel to check for electrolyte imbalance, renal toxicity, and possible underlying disorders (Table 6).23 Every effort should be made to control seizures. Gastrointestinal decontamination with activated charcoal and a cathartic may be useful in acute exposures if the drug was taken orally within the previous 60 minutes. Severe hypertension can be treated with labetalol, phentolamine, nitroprusside, or similar agents. Hyperthermia should be treated immediately with tepid water bathing and fanning. The serotonin antagonists chlorpromazine and cyproheptadine appear to be effective in mild to moderate cases of serotonin syndrome.200 There are no specific antidotes for ingestion of club drugs, except for Flunitrazepam, which has already been mentioned.165 In view of the above, an alternative is to encourage harm reduction strategies (Table 7)2 by ensuring that buildings meet safety and health standards, adequate security is provided to

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accommodate the large number of attendees and ravers are educated about health effects by trained volunteers. NIDA website (www.clubdrugs.org) also provides useful information regarding club drugs.

Table 7: Harm reduction strategies for raves (adapted from Weir, 2000)2

Newer and Emerging Addictions in India

lReplenish fluids and sodium (500 mL/h if dancing, 250 mL/h if inactive) lTake breaks from dancing
lKnow the risks of adulterated drugs and the inaccuracies of logos lKnow the signs and symptoms of toxicity

lAvoid alcohol
lEnsure medical centre and team is on-site
lDon’t attend a rave alone; contract with a friend to look out for each other

As with other psychoactive substances, various psychosocial interventions can be planned for the management of club drugs dependence. These include motivational interviewing, contingency management, CBT based relapse prevention, community reinforcement approach, behavioural therapies, social behaviour network therapy, supportive expressive psychotherapy so on and so forth (IV).201,202 However, in the absence of any controlled clinical trial of psychosocial interventions for the management of club drugs dependence, specific recommendation cannot be made. UNODC’s Global Synthetics Monitoring: Analyses, Reporting and Trends (SMART) Programme aims to provide quality information on ATS, such as patterns of trafficking and use, and will provide the international community with the evidence needed to take more targeted action in areas of weakness.203 An illicit club drug community intervention programme, ‘Clubs against Drugs’, was initiated in 2002 in Stockholm, Sweden. The illicit club drug intervention was based on a systems approach top revention.204,205 The programme included community mobilization, drug training, increased enforcement,policy work, environmental changes and media advocacy and public relation (PR) work [18,21] In a pre- (2003) and post-intervention study (2004 & 2008) design The ‘Clubs against Drugs’ community-based intervention programme, appeared to increase the frequency and effectiveness of club doormen’s interventions regarding obviously drug-intoxicated guests (III).206

4.1. RECOMMENDATIONS

lSuspicion of a club drug overdose /toxicity is essential

lExcept for GHB, club drugs cannot be detected through routine toxicological screens, so one should not waste valuable time

lMaintainairway, breathing and circulation (S)
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lGastrointestinal decontamination with activated charcoal is recommended if ingestion has happened within last 1 hour (S)

lHyperthermia and Serotonin syndrome should be managed with tepid sponging and cyproheptadine/chlorpromazine respectively (S)

lFlumazenil may be administered to reverse the effects of flunitrazepam toxicity (D, S)

lPsychosocial interventions in various forms can be effective for the management of club drugs dependence (D)

lLong term community intervention programs e.g. ‘Club against Drugs’ has shown some promise (C)

4.CLUB DRUGS:INDIANSCENARIO

Indian data related to club drugs are very limited with little efforts being made to gather systematic data regarding the same. The first nationwide survey to obtain information on extent, pattern and magnitude of substance abuse in the country indicated new emerging trend of substance use in India with amphetamine like substances (ATS) are being more used in regions like Goa and Ahmedabad.207 Most reports regarding club drugs are from newspaper articles; hence there is an urgent need for verified, authentic research data.

A recent assessment by United Nations Office on Drugs and Crime (UNODC)203 has found that after substantial increases in the late 1990s, the use of synthetic drugs (e.g., amphetamines and Ecstasy) in North America, Europe and Oceania has stabilized, albeit at high levels. But the problem has shifted to new markets, particularly in East and South-East Asia and the Middle East over the past few years. With technological advancement and particularly the information technology sector coming up in a big way in India (often as outsourcing for overseas-based multinational companies), suddenly there is a neo-rich young generation. This is often coupled with the need to escape temporarily from the severe work pressure and social isolation created by this lifestyle. With drug licensing and controlling authorities focusing more on licit and traditional illicit drugs (e.g. opioid, cannabis), club drugs have caught the fancy of this neo-rich young generation. Table 8 lists the various factors/reasons behind the significance of this new and emerging phenomenon in the Indian drugs scenario and why we should be concerned.

Table 8 : Why India should be concerned about Club Drugs?

1. These are often associated with status symbol amongst the neo-rich youth

2. These are often perceived to be safe or benign compared to the “hard drugs” such as heroin, cocaine etc.

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Adapted from Chakraborty K, Neogi R, Basu D. Club drugs: Review of the ‘rave’ with a note of concern for the Indian scenario. Indian J Med Res 2011;133:594-604.25

The rave parties of Goa are said to be started by the Hippies.208 Earlier Rave parties meant loud music, alcohol and cannabis abuse. Since the late eighties, psychedelic culture in the northern village of Anjuna became increasingly concentrated on free out-door parties with a particular subgenre of electronic dance music, which by 1994 was known as Goa trance and later became much darker, more minimal and aggressive, called psy- trance.208 Rave parties in Goa happen every tourist season (November to May) which are attended mainly by foreigners from the UK, Israel, Germany, France and Japan.209 The bars organizing such parties sell Ecstasy or LSD.210 In last few years upper-class Indians have massively taken to Ecstasy and clubbing and there are more women amongst them.208 The CK1 pill is one of the trendy party drugs manufactured locally in Goa. The pill is a combination of cocaine and the anaesthetic ketamine. CK1, also known by its street names Blizzard and Calvin Klein, is easily available in the north Goa beach belt. Customs officials admit that the clandestine production and smuggling of ketamine is turning Goa into a transit point for an international drug mafia.211

Thanks to its booming software industry, Bangalore is baptized the Silicon Valley of India and has turned into a rave hotspot.212 The spot lights in the clubs create an atmosphere between cosy and disco, everybody drinks, most smoke and a few take psychedelic drugs.212,213

In Pune, 280 people were arrested during a pre-dawn raid on a rave party in March 2007. The ravers were allegedly using California drops.214 A California drop is acid that

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3. Some of these drugs (e.g., GHB, Rohypnol) are notorious as “rape drugs” and their use is associated with crimes like date-rape, party rape, robbery, etc.

4. Unlike cannabis, opium or heroin, these are usually imported or smuggled from neighboring countries

5. Some of these (e.g., MDMA) are directly neurotoxic in short and long term use

6. Contrary to their popular perception, all these drugs can have substantial toxic effects on several systems of the body and can be potentially lethal (see Table 1,
‘Toxic effects’, for details)

7. These are difficult to detect through routine toxicological screening (GHB is an
exception);

8. These are notorious for spreading sexually transmitted diseases (STDs) and HIV
infection because of their intravenous route of administration

9. These are devoid of any antidote (flunitrazepam is an exception)

10. Managementneedstobestartedearlyandcanbedifficult(seeTable6fordetails)

Club Drugs

is put on a stamp, which is then chewed; the cost of each drop is put between INR 350 and 500.

Also known as white magic, drone, and mephedrone, “meow meow” is the latest and cheapest street drug hitting Mumbai which was not even in the list of government- banned drugs until February 2015.215 A very recent newspaper article reported that African connection to drug peddling in the city of Hyderabad seems to be on the wane. Records from the Narcotics Control Bureau revealed that drug rackets have moved closer home, with suppliers now mostly hailing from Nepal and Myanmar.216

Sometimes police directly raid rave parties in plain clothes and catch ravers red-handed. People who are found in the Rave Party are often booked under Section 27 of the Narcotic Drugs and Psychotropics Substances Act of 1985 and Section 294 of the Indian Penal Code.

5. CONCLUSION

Club drugs are a menace to the society. Their use, other than for strictly medical or approved research purposes, should be prohibited through legislation and awareness generation. Eventhoughthe“clubdrug”phenomenonwasidentifiedearly,scientific information about these drugs, their identification, and short- and long-term effects are still evolving. The lack of research-based information on the adverse effects of these drugs has led to the emergence of a range of web sites that may or may not provide accurate information. India has a huge teenage population which is being targeted by foreign drug peddlers to flourish their business. Club drugs continue to be modified and evolve, making them very difficult to monitor. As health professionals we should remain well informed regarding club drugs and their management protocol. To the best of our knowledge this is the only guideline which solely focuses on the management of club drugs toxicity, dependence and withdrawal and makes specific recommendations to manage those conditions. There is another guideline24 which deals with the management of acute and chronic harms of club drugs along with other psychoactive substances. Therefore, this guideline provides us with a unique opportunity to make ourselves familiar with various club drugs available in the market and enable us to deal more effectively with the medical problems arising out of using these substances.

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180. Brandt SD, Freeman S, McGagh P, Abdul-Halim N, Alder JF. An analytical perspective on favoured synthetic routes to the psychoactive tryptamines. J Pharm Biomed Anal 2004; 36:675–691

181. Sklerov JH, Magluilo J Jr, Shannon KK, Smith ML. Liquid chromatography-electrospray ionization mass spectrometry for the detection of lysergide and a major metabolite, 2- oxo-3-hydroxy- LSD, in urine and blood. J Anal Toxicol 2000; 24:543–554.

182. Hasler F, Bourquin D, Brenneisen R, Vollenweider FX. Renal excretion profiles of psilocin following oral administration of psilocybin: a controlled study in man. J Pharm Biomed Anal 2002; 30:331–339.

183. Sitaram BR, Lockett L, Talomsin R, Blackman GL, McLeod WR. In vivo metabolism of 5-methoxy-N,N-dimethyltryptamine and N,N-dimethyltryptamine in the rat. BiochemPharmacol 1987; 36:1509–1512.

184. Titeler M, Lyon RA, Glennon RA. Radioligand binding evidence implicates the brain 5- HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens. Psychopharmacology 1998; 94:213–216.

185. Blair JB, Kurrasch-Orbaugh D, Marona-Lewicka D Cumbay MG, Watts VJ, Barker EL, et al. Effect of ring fluorination on the pharmacology of hallucinogenic tryptamines. J Med Chem 2000; 43:4701–4710.

186. Halberstadt AL, Geyer MA. Multiple receptors contribute to the behavioural effects of indoleamine hallucinogens. Neuropharmacology 2011; 61:364–381.

187. Ray TS. Psychedelics and the human receptorome. PLoS One 2010; 5:e9019.

188. Bulling S, Schicker K, Zhang YW, Steinkellner T, Stockner T, Gruber CW, et al. The mechanistic basis for noncompetitiveibogaine inhibition of serotonin and dopamine transporters. J BiolChem 2012; 287:18524–18534.

189. Johnson M, Richards W, Griffiths R. Human hallucinogen research: guidelines for safety. J Psychopharmacol 2008; 22:603–620.

190. Krebs TS, Johansen PO. Psychedelics and mental health: a population study. PloS One. 2013; 8:e63972.

191. Keshavan MS, Kaneko Y. Secondary psychoses: an update. World Psychiatry 2013; 12:4-15.

192. van Amsterdam J, Opperhuizen A, van den Brink W. Harm potential of magic mushroom use: a review. RegulToxicolPharmacol 2011; 59:423–429.

193. Baggott MJ, Coyle JR, Erowid E, Erowid F, Robertson LC. Abnormal visual experiences in individuals with histories of hallucinogen use: A web-based questionnaire. Drug Alcohol Depend 2011; 114:61–67.

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194. Halpern JH, Pope HG Jr. Hallucinogen persisting perception disorder: what do we know after 50 years? Drug Alcohol Depend 2003; 69:109-119.

195. Williams RH, Erickson T. Evaluating hallucinogenic or psychedelic drug intoxication in an emergency setting. Lab Med 2000; 31:394–401.

196. Meehan TJ, Bryant SM, Aks SE. Drugs of abuse: the highs and lows of altered mental states in the emergency department. Emerg Med Clin North Am 2010; 28:663–682.

197. Huesgen K. Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1: excited delirium syndrome and sudden death. Emerg Med J 2013; 30:958– 960.

198. Griffiths RR, Johnson MW, Richards WA, Richards BD, McCann U, Jesse R. Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology 2011; 218:649–665.

199. Hermle L, Simon M, Ruchsow M, Batra A, Geppert M. Hallucinogen persisting perception disorder (HPPD) and flashback – are they identical? J Alcoholism Drug Depend 2013; 1:121.

200. Martin TG. Serotonin syndrome. Ann Emerg Med 1996; 28:520-526.

201. Smedslund G, Berg RC, Hammerstrøm KT, SteiroA, Leiknes KA, Dahl HM, et al. Motivational interviewing for substance abuse. Cochrane Database Syst Rev 2011; (5):CD008063.

202. Knapp WP, Soares BG, Farrel M, Lima MS. Psychosocial interventions for cocaine and psychostimulant amphetamines related disorders. Cochrane Database Syst Rev 2007; (3):CD003023

203. UNODC Annual Report 2009 [Online]. 2009 [cited 2015 Sept 15]; Available from: URL:http://www.unodc.org/documents/about-unodc/AR09_LORES.pdf

204. Holder HD. Alcohol and the Community: A Systems Approach to Prevention. Cambridge: Cambridge University Press; 1998.

205.Birckmayer J, Fisher DA, Holder HD, Yacoubian GS Jr. Prevention of methamphetamine abuse: can existing evidence informcommunity prevention? J Drug Educ 2008; 38:147–165.

206. Abdon JG, Wallin E, Andreasson S. Long-term effects of a community-based intervention: 5-year follow-up of ‘Clubs against Drugs’. Addiction 2011; 106:1997–2004

207. Ray R. The Extent, Pattern and Trends of Drug Abuse in India, National Survey. New Delhi: UNDCP-ROSA; 2004.

208. Saldanha A. Trance and visibility at dawn: racial dynamics in Goa’s rave scene. Soc Cult Geogr 2005; 6:707-721

209. Raves: the foreign hand [Online]. 2007 [cited 2015 Sept 15]; Available from:

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URL:http://www.telegraphindia.com/1070311/asp/7days/story_7490754.asp

210. Saldanha A. Vision and viscosity in Goa’s psychedelic trance scene. ACME: An International E-Journal for Critical Geographies 2006; 4:172-193.

211. Drug trade may increase during tourist season: Goa police [Online]. Available from: URL:http://www.indiaenews.com/india/20091111/230963.htm

212.Saldanha A. [Online]. [cited 2015 Sept 15]; Available from: URL: http://www.snarl.org/youth/arun-msi.pdf

213. Rave Heart. The Times of India. [Online]. 2004 [cited 2015 Sept 15]; Available from: URL:http://timesofindia.indiatimes.com/city/bangaloretimes/RaveHeart/articleshow/ 928759.cms

214. Rave party, revellers, drugs, and aftermath. The Hindu. [Online]. 2007 [cited 2015 Sept 15]; Available from:
URL:http://www.thehindu.com/2007/03/06/stories/2007030610260100.htm

215. Meow Meow and the walking dead: India’s newest drug [Online]. 2015 [cited 2015 Sept 15]; Available from:
URL:http://www.ozy.com/fast-forward/meow-meow-and-the-walking-dead-indias- newest-drug/62142

216. Drug rackets move closer home [Online]. 2015 [cited 2015 Sept 15]; Available from: URL:http://timesofindia.indiatimes.com/city/hyderabad/Drug-rackets-move-closer home/articleshow/47919137.cms

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SECTION C : BEHAVIOURAL ADDICTIONS

GAMBLING DISORDER

Abhishek Ghosh Debasish Basu P.K. Dalal

On behalf of
Indian Psychiatric Society
Specialty Section on Substance Use Disorders

2016

Gambling Disorder

Executive Summary

1. Introduction

2. Scope and methodology of the guideline

3. Assessment of gambling disorder/ pathological gambling (GD/PG)

. 3.1  Diagnosis of GD

. 3.1.1  Screening questionnaire

. 3.1.2  Structured interviews

. 3.2  Exploration for co-morbidity

. 3.3  Exploration for psycho-social consequences

4. Treatment setting

5. Treatment for gambling disorder (GD)/ pathological gambling (PG)

5.1 Pharmacological management for gambling disorder (GD) 5.1.1 Opioid antagonists

. 5.1.2.  Antidepressants

. 5.1.3.  Mood stabilizers

. 5.1.4.  Other group of medications

5.2 Psychosocial treatment for gambling disorder (GD) 5.2.1 Gamblers Anonymous

. 5.2.2.  Self help measures

. 5.2.3.  Cognitive behaviour therapy

. 5.2.4.  Brief intervention and motivational intervention

. 5.2.5.  Family therapy

. 5.2.6.  Combined psycho-social approach

5.3 Combined psychotherapy and drug treatment 6. Caveats in the proposed guideline

CONTENTS

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Gambling Disorder

EXECUTIVE SUMMARY

Introduction- Gambling, as a ubiquitous method of entertainment is present since antiquity. However, gambling is mostly recreational, only in a minority it causes significant socio-occupational dysfunction, and in a further smaller fraction of individuals it becomes an uncontrollable pre-occupation that persists despite significant negative consequences, resulting in a disorder. Gambling disorder (GD) was introduced in the Psychiatric nosology in 1980’s in the 3rd Edition of DSM [and also in ICD-9] as pathological gambling. In DSM-5, it is included in the section of substance use and related addictive disorders as Gambling Disorder. It is reasonably common in clinical setting. Gambling disorder leads to devastating psychosocial consequences and is associated with poor quality of life. Cumulative evidence for the treatment of gambling disorder, which ranges from psychosocial to pharmacological, has demonstrated significant efficacy in reducing the severity and consequences of gambling.

Assessment for GD- Assessment and diagnosis of GD is entirely clinical and hence based upon a detailed history and mental status examination. History from the individual must be corroborated from the family members where ever possible. A comprehensive assessment of GD must consist of the following:

lScreening and establishing confirmed diagnosis lExploration for co-morbidity
lExploration for psychosocial consequences

Screening and diagnostic instruments are reviewed in the guideline. The frequency and pattern of co-morbidity have been discussed. The adverse psycho-social consequences, the exploration of which are deemed necessary an additional have been mentioned.

Treatment setting- Although no systematic assessment has been conducted so far, the usual locus for the treatment of GD is the out-patient clinics. Inpatient treatment is most likely to take place if the individual is hospitalized for another psychiatric disorder, including substance use disorders.

Pharmacological treatment for GD – Various treatment options have been investigated for pharmacotherapy of gambling disorder, namely the opioid antagonist, antidepressants, mood stabilizers, and glutamatergic agents. Naltrexone could be considered as the first line pharmacological treatment for gambling disorder (GD). Dosage required could be more than the usual dose used for the treatment of alcohol dependence. [A] N-acetyl-cysteine (NAC) could be another promising first line agent following naltrexone [A]. Second line agents: fluvoxamine (~200 mg/day) [B], paroxetine (~50 mg/day) [B], memantine (~20mg/day), tocapone, and acamprosate [C]. Although treatment of GD in presence of co-morbidity has not been investigated

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systematically, evidence suggests that escitalopram and lithium could be used for concurrent anxiety disorder and bipolar disorder respectively.

Psychosocial treatment for GD – Research in the area of psychological treatment for GD is probably better developed as opposed to the pharmacological treatment. Several treatment options for gamblers have been explored, ranging from self-help and peer support, to brief and motivational interventions, to more intensive therapy approaches. In depth motivational intervention (MI) or short term (~4 sessions) motivation enhancement therapy could be first line treatment options as a sole form of treatment [A] or brief motivational intervention could be used in conjunction with other forms of intensive interventions (especially CBT) to improve treatment retention [A].More intensive intervention especially CBT could be considered for long term engagement [A].CBT could be delivered in both individual and group format [A]. Components of CBT includes: cognitive restructuring, relapse prevention [A], skill training, behavioural interventions (like cue conditioning/extinction) [B]. Bibliotherapy (proving workbooks) could be used along with either MI or CBT [A]. Second line therapy options could be: twelve step facilitation (TSF) [A], Exposure based therapy [B], and family therapy [C]. The overall empirical evidence for the efficacy of psychological intervention in terms of both quantity and quality of studies is better than pharmacological treatment. Hence, it must be offered to all patients seeking treatment for GD.

The document ends with important caveats that should be borne in mind while interpretingandfollowingtheguideline. .

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1. INTRODUCTION

Gambling, as a ubiquitous method of entertainment is present since antiquity. In gambling, the individual places something of value at stake in the hope of getting something of greater value. Perhaps, it originated in Korea, and spread across the Europe,USA,andAsia. IntheancientandmedievalIndia,itwaspresentasdicegames; in the pre-independence and colonial era horse racing was a highly cherished activity amongst the relatively affluent Indian communities.1 In the 90’s lotteries was the legalized form of ‘gambling’. Presently perhaps cricket betting has become the ‘state of the art’ gambling! However, most of the gambling are recreational, only minority causes significant socio-occupational dysfunction and in further smaller fraction of individual it becomes a pre-occupation and uncontrollable and persists despite significant negative consequences, resulting into disorder.2 Gambling disorder (GD) was introduced in the Psychiatric nosology in 1980’s in the 3rd Edition of DSM [and also in ICD-9] as pathological gambling (PG) along with other impulse control disorders like kleptomania, pyromania, and trichotillomania.3-5 However, the diagnostic criteria laid down for pathological gambling were based on criteria for substance dependence. Because there is no substance involved in gambling, it could not be incorporated under the section of substance use disorders, despite its clinical-phenomenological, biological, and even treatment related similarities with the latter.6 This limitation has been subverted in DSM-5 which has brought about a significant change in the section of substance use disorders by incorporating addictive disorders (includes behavioural addictions).7 Henceforth, pathological gambling which was ‘out of place’ for more than three decades after its inception could be included in this section as gambling disorder. The elimination of the pre-fix pathological is to reduce stigma associated with the word and perhaps to establish a phonemic similarity with other substance use disorders (for e.g. alcohol related disorders).6 This recent change in the nosology is likely to improve recognition of the disorder, especially among substance users who are at high-risk for GD.8 However, in ICD-10 it is still specified as Pathological Gambling (PG). Hence, both these terms have been used interchangeably in the current document.

Prevalence of PG varies widely depending upon the locus and modus of the study. The first three national level survey conducted in the US were telephone based and the prevalence ranged from 0.8-2% .9-11 The first in-person national level study done as a part of National Epidemiological Survey of Alcohol and Related Conditions (NESARC) revealed a prevalence figure of 0.4% in general population.12 A large body or research also exists across the continents 13and across a diverse population (college students, adults, children, and specific ethno-cultural group. The figures of PG hover around 0- 4% and 1.7-8.5% amongst adults and child/adolescent respectively.13 Prevalence of PG is significantly more in substance using population. A meta-analysis of 18 studies amongst the treatment seeking substance users, the lifetime rate of PG was 14%.14 Other

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large scale individual studies focusing on the substance users observed a prevalence figure ranging from 10-13%.15 One Indian study which assessed problem gambling(not PG/GD) in treatment seeking substance using population observed a prevalence of 7.4% in the past year.1

Gambling disorder leads to serious psycho-social consequences. It is associated with poor quality of life, high rates of bankruptcy, divorce, and incarceration. Gambling losses might lead to psychiatric hospitalizations because of secondary depression and suicidality.16 The overwhelming financial consequences and guilt associated with GD places the individual at higher risk of suicidal attempts. A study among Gamblers Anonymous (GA) participants has revealed suicidal attempt as high as 25% .17 Despite all these negative consequences the rate of treatment seeking is a very low in GD. The likely cause ranges from external barriers for seeking help to personal factors.18 People who seek treatment mostly do so for their substance use or psychiatric problems and seldom for gambling per se.

Although a couple of decades ago treatment literature regarding GD revolved around case reports, case series and controlled trials with serious methodological limitations,19 over the last decade there has been several methodologically validated research in this area. Cumulative evidence for the treatment of gambling disorder, which ranges from psycho-social to pharmacological, has demonstrated significant efficacy in reducing the severity and consequences of gambling. To the best of our knowledge, till now there is no published clinical practice guideline (CPG) dedicated in this important area. The objective of the current guideline is to study the available evidence, determine its strength and finally to recommend practical treatment options especially suited to the Indian context.

2. SCOPEANDMETHODOLOGYOFTHEGUIDELINE

We searched PubMed (http://www.ncbi.nlm.nih.gov/pubmed) to identify published meta-analysis, reviews, open-label trials, randomized double-blind trials, placebo- controlled trials, and case reports written in English, focusing on the pharmacotherapy of pathological gambling. In addition, we have searched Scopus, Google Scholar, and PsychInfo to identify any other study missed. The following keywords were used: gambling disorder, pathological gambling, problem gambling, pharmacotherapy, psychological therapy and treatment. The search was conducted on 4th June, 2015. Only selection of clinical trial had yielded 203 results; inclusion of reviews had increased the number of results to 509.

We have used the term gambling disorder (GD) and pathological gambling (PG) interchangeably throughout the document.

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2. ASSESSMENT OF GAMBLING DISORDER/ PATHOLOGICAL GAMBLING (GD/PG)

Assessment and diagnosis of GD is entirely clinical and hence based upon a detailed history and mental status examination. History from the individual must be corroborated from the family members where ever possible. A comprehensive assessment of GD must consist of the following:

lScreening and establishing confirmed diagnosis lExploration for co-morbidity
lExploration for psycho-social consequences

3.1 Diagnosis of GD
The diagnosis of GD is primarily based on exploring and establishing the diagnostic

criteria laid down for this disorder in the current nosology. [Panels 1, 2 and 3]

Panel 1

ICD-10 criteria for PG
lIndividuals have frequent and repeated episodes of gambling despite adverse

consequences
lIndividuals put their jobs at risk, acquire large debts, and lie or break the law lIndividuals have intense urges to gamble, which are difficult to control lIndividuals have preoccupation with ideas and images of the act of gambling lShould be distinguished from gambling and betting (frequent gambling for

excitement or in an attempt to make money), excessive gambling by manic patients, and gambling by sociopathic personalities

Panel-2

DSM-IV TR criteria for PG
Persistent and recurrent maladaptive gambling behaviour is indicated if the individual has five (or more) of the following:
lIs preoccupied with gambling
lNeeds to gamble with increasing amounts of money
lHas repeated unsuccessful efforts to control, cut back, or stop gambling
lIs restless or irritable when attempting to cut down or stop gambling lGambles as a way of escaping from problems or of relieving a dysphoric mood lAfter losing money gambling, often returns another day to get even (i.e.,

“chasing one’s losses”)

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lLies to conceal the extent of involvement with gambling
lHas committed illegal acts to finance gambling
lHas jeopardised or lost an important relationship, job, or educational or career

opportunity because of gambling
lRelies on others to provide money to relieve a desperate financial situation

caused by gambling
The gambling behaviour is not better accounted for by a manic episode

Panel-3

DSM-5 criteria for GD

Persistent and recurrent problematic gambling behaviour leading to clinically significant impairment or distress, as indicated by the individual exhibiting four (or more) of the following in a 12-month period:
lNeeds to gamble with increasing amounts of money in order to achieve the

desired excitement.
lIs restless or irritable when attempting to cut down or stop gambling.
lHas made repeated unsuccessful efforts to control, cut back, or stop gambling. lIs often preoccupied with gambling (e.g., having persistent thoughts of reliving

past gambling experiences, handicapping or planning the next venture, thinking

of ways to get money with which to gamble).
lOften gambles when feeling distressed (e.g., helpless, guilty, anxious,

depressed).
lAfter losing money gambling, often returns another day to get even (“chasing”

one’s losses).
lLies to conceal the extent of involvement with gambling.
lHas jeopardized or lost a significant relationship, job, or educational or career

opportunity because of gambling.
lRelies on others to provide money to relieve desperate financial situations

caused by gambling
The gambling behaviour is not better accounted for by a manic episode Current severity:
Mild: 4–5 criteria met.
Moderate: 6–7 criteria met.
Severe: 8–9 criteria met.

NOTE: “Has committed illegal acts to finance gambling” has been removed from the diagnostic criteria

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3.1.1 Screening questionnaire

There are several screening instruments developed for PG, which can be applied both for clinical and for general population. For a detailed review the readers are suggested to go through the chapter written by Stinchfield et al. (2007).20 The purpose of a brief screen is to identify individuals who may have a gambling disorder; it helps to narrow down the number of people who will be referred for more time-intensive and costly comprehensive assessment. The mean time required for administering a screening instrument ranges from 1-5 minutes.

Amongst them South Oaks Gambling Screen (SOGS) which is based on DSM-III criteria for PG and has 20 questions is perhaps the most widely used screening questionnaires.21 This instrument has been translated into several languages without affecting its reliability and can be administered both in the interview or self-report format. It has three versions for the lifetime, past year, and past 3 months diagnosis of PG. The sensitivity (0.99) of the instrument overshadows its specificity (0.75), which has made it as one of the reliable screening instruments.22 A relatively brief screening instrument Problem gambling Severity Index (PGSI) which has 9 items is based on DSM-IV criteria of PG. The use of this instrument is gradually increasing in recent times. It has both high sensitivity (0.83) and an excellent specificity (1.0) for the diagnosis of problem gambling (score>8 is indicative of PG).23 A third screening instrument for gambling is known as Massachusetts Gambling Screen (MAGS). This test looks for signs and symptoms of PG and psychological and social problems associated with gambling disorders as in DSM- IV. It is a 14-item questionnaire and seven items are scored with a past year time frame. MAGS items are scored by multiplying each item times a discriminant function coefficient, and then added together with a constant. A score between 0 and 2 labels a “transitional gambler” or PPG. A score greater than 2 indicates PG.24 Another instrument is the 17-item National Opinion Research Center DSM-IV Screen for Gambling Problems (NODS), which was originally developed for a US national gambling telephone survey and was based on past-year and lifetime DSM-IV diagnostic criteria for pathological gambling.25 The diagnosis of PG is based on a cut-off score, the validity of which is yet to be established systematically.26 A 3-item short version of NODS, known as NODS-CLiP observed to have excellent sensitivity (0.94) and specificity (0.96), when tested in the community sample. This screening instrument explores three areas, loss of control, lying and preoccupation and positive response in any one of the items calls for a detailed evaluation.25 Brief Biosocial Gambling Screen (BBGS) a recently developed screening instrument which also has 3 questions assesses PG over last one year as opposed to the NODS-CLiP which is for the lifetime diagnosis of PG. An alternative four-item screen that demonstrates improved sensitivity, good positive and negative predictive power and invariance across key demographic groups had been developed. As it is derived from NODS, It is known as Preoccupation, Escape, Risked Relationships

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and Chasing (PERC).27 Given high rates of comorbidity, routine and accurate identification of gambling-related problems among individuals seeking help for substance abuse and related disorders is important. BBGS was derived from the NESARC study and was based on DSM-IV PG.28 It also has similar high sensitivity and specificity like the NODS-CLiP. However, the validity of these 2 instruments has not been established yet from different sample and for clinical population. A recent study has compared the brief screening instruments with the DSM-5 criteria for GD. Both NODS-CLiP and NODS-PERC had been found to have excellent accuracy at all cut-off points. However, BBGS had the best accuracy.29 The shortest possible screening tool for PG is the Lie/Bet scale. Its Items determine if individual lies to others about gambling behaviours or bets more and more money. There are 2 items with “yes/no” response options in a lifetime time frame. Answering “yes” to one or both items indicates PG.30

3.1.2 Structuredinterviews

For a more comprehensive assessment, the Gambling Treatment Outcome Monitoring System (GAMTOMS) is a multidimensional self-report or interview assessment instrument. GAMTOMS incorporates SOGS and also assesses various domains pertaining to treatment planning and outcome monitoring, including gambling frequency, mental health, financial problems, legal problems, and motivation. Additionally, this system has a ten-item DSM-IV measure that is relevant for diagnostic purposes. GAMTOMS has been used for several psychometric evaluations in clinical samples, whereby DSM-IV categorical diagnosis of pathological gambling had good sensitivity (0·96) and specificity (0·95) for distinguishing clinician-diagnosed cases from non-cases, as well asgood sensitivity (0·96) and specificity (1·0) distinguishing SOGS- positive cases from SOGS-negative cases. GAMTOMS also includes a follow-up version that measures treatment outcome via self-report.31Another comprehensive instrument for the diagnosis of GD is Diagnostic Interview for Gambling Schedule (DIGS). This instrument measures demographics, gambling involvement, treatment history, onset of gambling, gambling frequency, amounts of money bet and lost, sources of borrowed money, financial problems, legal problems, mental health screen, other impulse disorders, medical status, family and social functioning and diagnostic symptoms (lifetime and past year). It has total 20 items and is based on DSM-IV TR diagnostic criteria. If respondent endorses either of the two items per criterion, the criterion is considered endorsed.32 The details of all instruments have been summarized in Table 1.

However, an interview by a qualified psychiatrist is always the gold standard for the diagnosis of GD. Other diagnostic/screening instruments mentioned so far can supplement an interview but can and should never replace it. These instruments are proven to be highly useful for research purpose, to have an idea about the baseline severity of gambling and to monitor the progress with treatment.

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Table 1: Instruments for screening and diagnosis of gambling disorder

Instrument

Number of items

Time to administer

Screening instruments

Lie/Bet

Two items; “yes/no” response options

One-minute interview

South Oaks Gambling Screen (SOGS)

20 scored items

10- to 20-minute paper and pencil

Massachusetts Gambling Screen (MAGS)

14-item questionnaire; seven items are scored

Five- to 10- minute paper and pencil

NODS-CLiP

Three items; “yes/no” response options

One-minute interview

NODS-PERC

Four items; “yes/no” response options

One-minute interview; intended for use in clinical settings

Brief Biosocial Gambling Screen (BBGS)

Three items; “yes/no” response options

One-minute interview

Diagnostic instruments

Gambling Treatment Outcome Monitoring System (GAMTOMS)

142-item Gambling Treatment Admission Questionnaire has a 10-item measure of DSM-IV diagnostic criteria

30- to 45-minute paper and pencil questionnaire

Diagnostic Interview for Gambling Schedule (DIGS)

20 diagnostic symptom items to measure the two DSM-IV diagnostic criteria

30-minute interview

3.2 ExplorationforCo-Morbidity

Internationally, the co-occurrence between problem gambling and co-morbid psychiatric conditions has been empirically examined in both epidemiological and clinical samples. A systematic review and meta-analysis of co-morbid disorders in population-representative samples of problem gamblers revealed high rates of psychiatric disorders, including nicotine dependence (60%), alcohol and substance use disorders (58%), mood disorders (38%) and anxiety disorders (37%). A recent meta- analysis of 36 studies has reported a lifetime and current co-morbidity as ~75%. In order of frequency co-morbid disorders are mood disorders (23%), alcohol use disorders (21%), anxiety disorders (18%) and non-alcohol substance use disorders (7%).33 Evidence suggests that the presence of co-morbid disorders in treatment-seeking PGs is associated with an increased severity of gambling behaviour, gambling-related consequences, psychiatric symptoms, impulsivity and other psychosocial difficulties.34-36 The presence of co-morbid psychiatric conditions therefore has

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implications for individual case formulation, treatment planning and selection, the proposed objectives and expectations of the selected treatment, and the even length of treatment. Psychiatric co-morbidity may also affect an individual’s compliance with treatment, the success of treatment, the likelihood of relapse and the number of treatment attempts.37-38

Therefore following presence of disorders must be explored by clinical interview and (if needed diagnostic instruments):

lSubstance use disorders
lMood disorders
lAnxiety disorders
The process of diagnosing these disorders is outside the purview of the chapter.

3.3 Exploration for Psychosocial Consequences

GD incurs a lot of negative effect on the individual and on the family-society. It has been estimated that for one person suffering from GD, at least 10 people get affected by its negative consequences.39 Exploration of negative consequences is mostly historical and following dimensions must be incorporated:

lLegal
lMarital relationship
lInterpersonal relationship with significant others in the family lFinancial
lOccupational
lOverall quality of life

Gambling Treatment Outcome Monitoring System (GAMTOMS), as mentioned earlier is a comprehensive instrument which can assess the adverse psycho-social effects of gambling. This instrument can supplement the clinical history. Such an assessment could be extremely helpful in planning treatment and to monitor the progress of it.

4. TREATMENT SETTINGS

Gambling disorder might be encountered both in the psychiatric or addiction treatment clinic.Theorientationandphilosophyoftheseclinicsaredifferent. However,asGDis currently a part of addictive disorder and most of the research conducted so far was based on substance use disorder treatment clinics and done by a group of researchers with substance use disorder orientation and allegiance, this clinical practice guideline would be predominantly guided by addiction treatment principles. Although no systematic assessment has been conducted so far, the usual locus for the treatment of GD is the out-patient clinics. Inpatient treatment is most likely to take place if the individual is hospitalized for another psychiatric disorder, including substance use

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disorders. Research had revealed that individual with either psychiatric or substance use co-morbidity tends to have higher severity and poorer outcome for both gambling and the other disorder.40-42

Following could be indications for inpatient treatment: lPatients with depressive disorder and suicidality lPatients with severe substance use disorders lPoor social support

lCourt mandated admissions
5. TREATMENT FOR GAMBLING DISORDER (GD) / PATHOLOGICAL GAMBLING

(PG)

Surveys in the general population indicate that only about 10% of those who are suffering from GD seek formal treatment. Reasons for their non-treatment seeking are a desire to handle their problem on their own, shame, and denial.43-44 Despite low treatment seeking both direct and indirect evidence indicate that the recovery rate of GD is around 30-40%. And most of the individual recovers without treatment from professional sources. Hence GD is not always a chronic, persistent and severe disorder.45 Moreover, it has been seen that individual with more legal complications, preoccupation with gambling and with co-morbid mood disorders seeks treatment.46 In depth interviews of those who were recovered had revealed use of behavioural strategies like, engaging in activities incompatible with gambling and avoidance of conditioned cues, which are quite similar with those who had undergone professional treatment.47 These facts don’t question the necessity for the treatment of GD rather point towards some important considerations regarding those who seek treatment (the subset of patients for whom this CPG is applicable):

lMore severe form of GD (severity might be in terms of more psycho-social consequences or presence of severe co-morbidity)

lBrief treatment model might aid in the self-recovery process of the individual lIt is important to dispel stigma and resultant myth regarding gambling lThere is always a hope for recovery

Goal of treatment for GD: Gambling as has been conceptualized as addictive disorder the standard goal and standard outcome measure remain complete abstinence. However, research does not support the contention that abstinence-based goals are more advantageous than moderation goals.48 In fact, research has demonstrated the viability of non-abstinent treatment goal and popularity of the same amongst those in naturalortreatmentassistedrecovery. AstudyconductedamongstthefemalewithPG in Australia has shown that those with older age and with a strong belief that complete abstinence is not required for recovery opt for moderation as treatment goal.49

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Nevertheless, the definition of moderation or non-abstinence is still a point of contention and most of the treatment research in this area is based on complete abstinence. Hence, in our CPG we recommend complete abstinence as the goal of treatment for GD.

5.1 Pharmacological Treatment for GD

The different pharmacological approaches currently considered for GD derive from the various psychopathological and phenomenological perspectives of the disorder. GD may be considered as belonging to the impulse control or obsessive compulsive spectrum, as a behavioural addiction or as the result of an emotional dysregulation closely related to mood disorders. In the first case, pharmacological approach is based on anti-obsessive or antidepressant drugs, in order to improve serotonergic transmission. Drug dose is usually medium-high and the treatment lasts longer than in depression. According to the second perspective, the most used compounds are opioid antagonists, as in the treatment of alcoholism or other forms of addiction. In particular, controlled studies have been conducted for naltrexone and nalmefene on larger samples. In the third approach, therapy is based on mood stabilizers such as lithium and atypical antipsychotics, as in the treatment of resistant depression and bipolar disorder. We shall be discussing the efficacy of these groups of agents subsequently.50

The outcome measures decided for each study are also based on the rationale behind using that group of medication. For example, trials of antidepressants had used reduction Y-BOCS (gambling), anxiety-depression rating as the primary outcome, whereas trials with opioid antagonists mostly had used reduction in gambling frequency and dollars lost in gambling as primary outcome measures. Secondary outcome mostly was change in the CGI scale. Details of all pharmacological treatment trials have been summarized in Table 2.

5.1.1 Opioidantagonists:51-55

The trial of this group of drugs could be justified by conceptualizing GD as behavioural addiction, which is the most acceptable and empirically validated stance at the present moment. Most of the studies have tried naltrexone and only few are on nalmefene. Overall, Naltrexone has shown more consistent efficacy compared to SSRIs in reducing gambling urges and excitement related to gambling. Naltrexone does not usually result in intolerable side effects despite the dosage of naltrexone which was used in these trials was more than that is used for alcohol or opioid dependence. Studies published so far have been discussed in tabular format.

5.1.2 Antidepressants:56-62

A variety of antidepressant drugs have been studied and tested for the treatment of GD banking on the hypothesis that GD could be a disorder of obsessive-compulsive spectrum. The efficacy of both SSRI and non-SSRI group of drugs have been

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investigated. Amongst SSRI fluvoxamine, paroxetine, and escitalopram have shown some promising results, whereas results for sertraline and bupropion are negative. Most of the trials were double blind and randomized but sample size ranged from 15-76. Duration of treatment ranged from 2-6 months.

5.1.3 Mood stabilizers:63-66

Mood stabilizers showed anti-impulsive properties as well as efficacy in reducing craving and preventing relapse in different substance-related disorders. Considering GD as disorder of emotional dysregulation and lying on the mood disorder spectrum, several studies have been conducted to evaluate their usefulness in the treatment of GD. Trial with lithium carbonate was shown to be effective. However, this study was conducted in patients with bipolar disorder. Studies using olanzapine did not find it superior than placebo.

5.1.4 Other group of medications:67-74

Clinical trials have also been conducted with agents which modulates the glutamatergic neurotransmission. Glutamatergic neurotransmission-modulating agents which are tried in GD include N-acetylcysteine (NAC), memantine, amantadine, acamprosate, topiramate, lamotrigine, baclofen, and modafinil. Manipulation of glutamatergic neurotransmission is a relatively young but promising avenue for the development of improved therapeutic agents for the treatment of drug and behavioural addictions. Substantial evidence has accumulated indicating that ligands acting on glutamatergic transmissionarealsoofpotentialutilityinthetreatmentofdrugaddiction. Evidenceis overall mixed. However, NAC is emerging as a promising agent.

Table 2 : Pharmacological treatments for gambling disorder (GD)

Study

N

Dose/day; Duration of use

Design

Results

Opioid antagonists (naltrexone/nalmefene)

Kim et al. 200151

89

Naltrexone
mean dose 188mg/day; duration: 12 weeks

Randomized Double- blind Placebo- controlled

Outcome: gambling frequency and loss of dollar
Naltrexone is significantly superior to placebo

Grant et al. 200852

77

Naltrexone
dose range: 50-150mg/day; duration: 18 weeks

Randomized Double- blind Placebo- controlled

Outcome: Scores of urge and behaviour subscales of the PG- YBOCS and Gambling symptom assessment scale

Naltrexone is significantly superior to placebo

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*Patients with co-morbid anxiety

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Study

N

Dose/day; Duration of use

Design

Results

Toneatto et al. 200953

52

Naltrexone
mean dose: 59mg/day; duration: 11 weeks

Randomized Double- blind Placebo- controlled

Outcome: gambling frequency and loss of dollar
Naltrexone is significantly superior to placebo

Grant et al. 200654

207

Nalmefene dose range: 25-100mg/day; duration:16weeks

Randomized Double- blind Placebo- controlled

Outcome: gambling frequency and loss of dollar
Naltrexone is significantly superior to placebo

Grant et al. 201055

233

Nalmefene dose range: 20-40mg/day; duration:16weeks

Single blind for 1 week with placebo then
Double-blind for next 15 weeks

Outcome: Outcome: Scores of urge and behaviour subscales of the PG-YBOCS
Nalmefene 40?mg/day is significantly superior to placebo

Antidepressants

Hollander et al. 200056

15

Fluvoxamine (SSRI) mean dose 195mg/day; duration: 16 weeks

Double-blind cross- over placebo-controlled

Outcome: overall score in PG- YBOCS and PG-CGI Fluvoxamine is superior to placebo

Blanco et al. 200257

32

Fluvoxamine (SSRI) mean dose 200mg/day; duration: 24 weeks

Randomized Double- blind Placebo- controlled

Outcome: reduction in money and time spent in gambling per week
Fluvoxamine is not significantly superior to placebo

Kim et al. 200258

45

Paroxetine (SSRI) with dose range: 20–60mg/day; duration: 8 weeks

Randomized Double- blind Placebo- controlled

Outcome: scores on Gambling symptom assessment scale and CGI
Paroxetine is superior to placebo

Grant et al. 200359

76

Paroxetine (SSRI) 10–60mg/day; duration:16 weeks

Randomized Double- blind Placebo- controlled

Outcome: overall score in PG- YBOCS and Gambling symptom assessment scale Paroxetine is not significantly superior to placebo

Saiz-Ruiz et al. 200560

60

Sertraline (SSRI) 50–150mg/day; duration: 24 weeks

Randomized Double- blind Placebo- controlled

Outcome: Criteria for Control of Pathological Gambling Questionnaire (CCPGQ) Sertraline is not significantly superior to placebo

Grant et al. 200661

13*

Escitalopram (SSRI) mean dose 25mg/day; duration: 20 weeks

Open label trial for 12 weeks then Double-blind Placebo-controlled for 8 weeks

Outcome: overall score in PG- YBOCS and score on HAM-A Escitalopram is superior to placebo

Gambling Disorder

Study

N

Dose/day; Duration of use

Design

Results

Black et al. 200762

39

Bupropion (NDRI) mean dose 325mg/day; duration: 12 weeks

Randomized Double- blind Placebo- controlled

Outcome: Yale-Brown Obsessive-Compulsive Scale modified for PG, the Gambling Severity Assessment Scale, the Clinical Global Impression Improvement

Bupropion is not significantly superior to placebo

Mood stabilizers

Hollander et al. 200563

40*

Lithium carbonate mean dose 1170mg/day; duration: 10 weeks

Randomized Double- blind Placebo- controlled

Outcome: total pathological gambling scores on the Yale- Brown Obsessive Compulsive Scale and Clinical Global Impression severity of pathological gambling scale Clinical Global Impression severity of pathological gambling scale

Lithium is significantly superior to placebo

Berlin et al. 201364

42

Topiramate 25–300mg/day ;duration:
14 weeks

Randomized Double- blind Placebo- controlled

Outcome: change in the obsessions subscale of the Yale- Brown Obsessive-Compulsive Scale Modified for Pathological Gambling and scores on Barratt’s impulsiveness scale Topiramate is not significantly superior to placebo

McElroy et al. 200865

42

Olanzapine 2.5–15mg/day; duration:12 weeks

Randomized Double- blind Placebo- controlled

Outcome: change in the obsessions subscale of the Yale- Brown Obsessive-Compulsive Scale Modified for Pathological Gambling
Olanzapine is not significantly superior to placebo

Fong et al. 200866

23

Olanzapine 2.5–10mg/day; duration: 7 weeks

Randomized Double- blind Placebo- controlled

Outcome: self-reported urges for gambling, frequency of gambling behaviour, and self- reported mood and anxiety levels

Olanzapine is not significantly superior to placebo

*Patients with bipolar comorbid

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*With nicotine dependence #Patients with Parkinson’s disease

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Study

N

Dose/day; Duration of use

Design

Results

Other medications

Zack & Poulos, 200867

20

Modafinil: 200mg/day

Placebo-controlled, double-blind, counterbalanced, repeated measures design

Outcome: differential effects in the high-impulsive (H-I) vs. low- impulsive (L-I) PGs
In H-I subjects, the drug decreased desire to gamble, salience of Gambling words, disinhibition and risky decision- making; worsening in the L-I sub- group

Grant et al. 200768

27

N-acetyl cysteine (NAC) mean effective dose of NAC was 1477mg/day); duration: 14 weeks

Open label trial for 8 weeks then double blind trial for the next 6 weeks

Outcome: Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling [PG-YBOCS] total score
NAC is superior to placebo

Grant et al. 201469

28*

N-acetyl cysteine (NAC) dose: 1200- 3000mg/day; duration:12 weeks

Randomized Double- blind Placebo- controlled

Outcome: scores on Fagerström test for nicotine dependence and Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling [PG- YBOCS] total score

During the 3-month followup, NAC was superior to placebo on PG severity and NAC facilitates long-term behavioural therapy

Grant et al. 201070

29

The mean effective dose of memantine was 23mg/day; duration: 10 weeks

Open label study

Outcome: Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling [PG-YBOCS] total score and also gambling frequency/duration Improved scores than the baseline

Thomas et al. 201171

17#

The mean dose of amantidine: 200mg/day

Open label placebo controlled study

Outcome: Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling [PG-YBOCS] total score and daily expenditure reduction
Amantadine is better than placebo

Gambling Disorder

Study

N

Dose/day; Duration of use

Design

Results

Black et al. 201172

26

Dose of Acamprosate: 999- 1998mg/day; duration: 10 weeks

Open label placebo controlled study

Outcome: Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling [PG-YBOCS] total score
Acamprosate is well tolerated and may be effective in the treatment of PG (not statistically significant than placebo)

Dannon et al. 201173

17

Acamprosate vs. bacofen; duration: 6 months

Open label trial No placebo

Outcome: diagnosis as per semi-structured instrument No improvement with either acamprosate or baclofen

Grant et al. 201374

24

Tolcapone dose: 100mg/day; duration: 8 weeks

Open-label trial explored

Outcome: reductions in GD severity, depression, anxiety and disability and improvement in quality of life

Tolcapone is better than placebo

Recommendation

lNaltrexone can be considered as the first line pharmacological treatment for gambling disorder (GD). Dosage required could be more than the usual dose used for the treatment of alcohol dependence. [A]

lN-acetyl-cysteine (NAC) could be another promising first line agent following naltrexone [A]. Dosage to be administered ranged from 1200-3000 mg/day. [B]

lSecond line agents: fluvoxamine (~200 mg/day) [B], paroxetine (~50 mg/day) [B], memantine (~20mg/day), tolcapone, and acamprosate [C].

lEscitalopram could be an option for those with co-morbid anxiety disorder [B]. lFor individual with high impulsiveness modafinil could be an alternative treatment

option [B].

lResponse to treatment could be seen between 1-8 weeks, depending upon the type of medication (opioid antagonist ~1 week; NAC ~8 weeks). Any medications must be continued for this duration before changing it. Duration of treatment though not well defined, medications could be safely used for 6 months.

Nalmefene, though found out to be effective in randomized double blind trials [A], is not available in India.

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Key uncertainties

lDuration of treatment is not defined.
lTreatment effect or strategies for those with co-morbid substance use disorders needs

to be evaluated.
lThough there few narrative reviews, no meta-analysis has been conducted till date. 5.2 PsychosocialTreatmentforGamblingDisorder(GD)

Research in the area of psychological treatment for GD is perhaps better developed as opposed to the pharmacological treatment. Several treatment options for gamblers have been explored, ranging from self-help and peer support, to brief and motivational interventions, to more intensive therapy approaches. Involvement in peer support programs seems to be optimal when combined with professional treatment; however, engagement and retention in peer support is limited. In majority of the studies, primary outcomes were measures of gambling symptom severity, financial loss from gambling and frequency of gambling. Secondary outcomes were occurrence of pathological gambling diagnoses and depression and anxiety symptoms. Retention in the treatment, one of the significant determinants of the outcome for any psychological treatment, is another parameter which has been frequently studied. Overall retention rates range from 50% to 90%. Treatment effects were defined by comparisons between therapy and control conditions at post-treatment assessments (conducted from 0 to 3 months following completion of treatment) and follow-up assessments (conducted from 9 to 12 months following completion of treatment). Details of all psycho-social interventions have been reviewed in Table 3.

5.2.1 Gamblers Anonymous (GA)75

GA which is modeled on Alcoholics Anonymous 12-step programs strongly advocates complete abstinence from gambling. Like its sister programs, GA has adopted the disease model and views disordered gambling as a lifelong affliction that can be controlled via gambling abstinence, but not cured. Gamblers Anonymous were started in 1957 in Los Angeles, CA, USA, and are now operating in at least 55 countries worldwide (http://www.gamblersanonymous.org/mtgdirTOP.html.). The groups promote a sense of common purpose and understanding and reinforce each consecutive day of abstinence from gambling. As with Alcoholics Anonymous, periods of success are marked with celebrations and rewards.75 Twelve-step-facilitation (TSF) is a professionally led structured form of psychological intervention derived from the treatment philosophy of 12 step programs and aims increasing referral to, involvement in, and understanding of 12 step programs. TSF has been tried for gambling also. The effectiveness studies are mentioned in the Table 3.

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5.2.2 Cognitive behaviour therapy (CBT)76-86

It is one of the widely researched and practiced forms of psycho-social intervention. CBT is conducted by a trained professional and is an intensive psychological treatment. Its treatment model focuses specifically on modifying distorted cognitions associated with gambling, including overestimating probabilities of winning, illusions of control over the outcome of a gamble, the belief that a win is due after a series of losses (i.e., thegambler’s fallacy), and memory biases in favor of remembering win. The cognitive errors have been enumerated in the Panel 4. CBT also includes problem-solving training, social skills training, and relapse prevention. Behavioural models conceptualize gambling disorders as learned patterns of reinforcement within a functional framework. Continued gambling behaviours stem from a variable pattern of reinforcement with respect to antecedents (e.g., external gambling cues, positive or negative emotions), behaviours (e.g., chasing of losses, strategizing to attain money), and consequences (e.g., financial loss). CBT treatments focus on modifying one or more components of this functional relationship in order to modify the learned patterns. Although a small number of trials have evaluated the efficacy of a purely cognitive approach, the largest number and the most rigorously designed trials have evaluated a combined CBT model. The rubric of CBT, however, encompasses a wide range of therapeutic approaches.

5.2.3 Brief and motivational interventions 87-95

As already mentioned elsewhere in this CPG, treatment seeking is very low in GD. Additionally those who are seeking either professional treatment or attending GA almost half of them could not be retained in the treatment or in the self help groups.76-78 This poor retention rate is perhaps a reflection of internal ambivalence for change or is indicative of treatment seeking due to external factors like persuasion by family and friends. Moreover, poor long term retention reiterates the need for brief intervention. Motivational approaches attempt to address client ambivalence towards change, for example by weighing the advantages and disadvantages of changing their gambling behaviour. Some motivational therapies provide personalized and/or normative feedback. Motivational approaches have also been explored as an avenue to engage problem or at-risk gamblers who have not yet met diagnostic criteria for gambling disorder, in an attempt to prevent escalation of gambling behaviour and related negative consequences.75

5.2.4 Other self-help measures88-90

Some individuals may prefer individual, self-directed options such as bibliotherapy (eg, workbooks), Internet-based interventions relative to GA, or in-person therapy. The workbook materials have been evaluated as stand-alone interventions and in combination with telephone or in-person support. Evidence base for bibliotherapy though minimal has been mentioned in the Table 3.

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5.2.5 Family therapy96

Advances in family therapy interventions for treating substance abuse problems have been adapted for gambling disorders. A self-help workbook of the Community Reinforcement and Family Therapy (CRAFT) model, adapted for gambling, has been evaluated in two randomized controlled trials. In CRAFT, family members are trained to use behavioural principles to reinforce non-gambling behaviour and not to reinforce inadvertently the gambling behaviour in individuals who are not addressing their gambling problem.

5.2.6 Combined psychosocial approach97-100

Most commonly combined psychosocial therapies are motivational intervention/brief therapy with an intensive psychological treatment like CBT. This makes intuitive sense to combine these forms of treatment because of their putative additive effects; i.e., motivational intervention will improve treatment retention which is an important mediator in the effectiveness of any intensive therapy. Though not a usual part of standard CBT, cue exposure therapy is sometime combined with traditional CBT.[2] Another combination which is widely practiced for its pragmatic value is combining motivational therapy with bibliotherapy (like proving CBT workbooks). Sometime online or telephonic brief sessions or e-mail reminders are used in conjunction with other forms of intervention.

There are a couple of narrative reviews in the area of psychological treatment for GD. However, we could locate only one meta-analysis conducted by Cochrane collaboration. Eleven studies compared CBT with control and comparisons at 0 to 3 months post-treatment showed beneficial effects of therapy that ranged from medium to very large. Only one study compared groups at 9 to 12 months follow-up and produced smaller effects that were not significant. Four studies of motivational interviewing therapy were identified and mainly considered samples demonstrating less severe gambling (relative to studies of pathological gamblers). Data suggested reduced financial loss from gambling following motivational interviewing therapy at 0 to 3 months post-treatment. Studies compared groups at 9 to 12 months follow-up and found a significant effect of motivational interviewing therapy in terms of frequency of gambling, with comparisons on other outcomes that were not significant. One study (n = 18) considered another psychological therapy (i.e.Twelve-Step Facilitated Group Therapy) and suggested beneficial effects in terms of most outcomes at 0 to 3 months post-treatment. This review supports the efficacy of CBT in reducing gambling behaviour and other symptoms of pathological and problem gambling immediately following therapy. However, the durability of therapeutic gain is unknown.

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5.3 Combined Psychotherapy and Drug Treatment

Combination of both modalities of treatment has been rarely studied systematically. A recent randomized controlled trial compared the effectiveness of combined escitalopram (20mg/day) and CBT versus CBT alone for the treatment of GD, and found no evidence for improved outcomes among those receiving both escitalopram and CBT in comparison to those receiving CBT only(Jun. 2013 http://clinicaltrials.gov/ct2/ show/NCT00927563). In another study combined NAC and imaginal desensitization therapy has been found to reduce nicotine dependence and improve longer-term GD treatment outcome.69 Further research into combined behavioural and pharmacotherapy with respect to different medication types (e.g., opioid antagonists) is needed.

Panel-4

Distorted cognitions in GD

Magnification of gambling skill

lOverrating one’s ability to win at gambling

Superstitious beliefs

lTalismanic superstitions include beliefs that the possession of certain objects increases the probability of winning (eg, ring, hat)

lBehavioural superstitions include beliefs that certain actions or rituals can increase the probability of winning (eg, playing only certain slot machines or placing smaller bets if they do not throw the dice themselves)

lCognitive superstitions include beliefs that certain mental states can affect the probability of winning (eg, prayer, hope, positive expectancies)

Interpretative biases

lAttributional biases refer to the tendency to overestimate dispositional factors (e.g., skills, abilities) to explain wins and to underestimate situational factors (e.g., luck, probability)

lGambler’s fallacy refers to the belief that a win is due after a series of losses lChasing refers to the belief that the only way to recover financial loss is to

continue to gamble

lAnthropomorphism is the tendency to attribute human characteristics to non- animate or non-human gambling objects (e.g., slot machine, lottery card, bingo card, horses)

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lLearning from losses refers to the belief that continuing to gamble is highly justifiable because losses are perceived as valuable learning experiences, which can ultimately lead to winning

lHindsight bias refers to retrospectively evaluating gambling decisions as correct or incorrect on the basis of whether they lead to wins or losses

Temporal telescoping

lThe belief that wins are actually nearer, temporally, than further, especially if the gambling is relying on superstitious behaviour or gambling systems to win; the gambler makes the additional assumption that they (rather than other gamblers) will win, even if other gamblers have also incurred serious losses and are expecting to win

Selective memory

lSelectively recalling wins, especially large ones, and having difficulty recalling losses

Predictive skill

lMaking gambling decisions on the basis of interpretations or meanings assigned to subjectively salient or important cues; cues can be internal (e.g., bodily perceptions, gut sensations, intuitions, feelings) or external (eg, omens, weather phenomena, serendipitous events) or behaviour by other gamblers

Illusions of control over luck

lLuck can be perceived as an important variable and regarded as an uncontrollable variable (ie, luck oscillates between periods of good and bad luck and cannot be manipulated directly), a controllable variable (ie, luck can be manipulated through superstitious behaviours or systems), a trait variable (ie, people are characteristically lucky with certain games and unlucky with others), or a contagion (ie, luck is affected by other areas of their life or by other people)

Illusory associations

lPerceiving illusory associations or assigning causality to salient features of the environment believed to be associated with gambling outcomes (eg, noticing more frequent winning at night, noticing that certain days of the week are more likely to lead to wins, believing that watching a sports game on television will favor a specific team)

Toneatto T, Ladoceur R. Treatment of pathological gambling: a critical review of the literature. Psychol Addict Behav. 2003; 17:284-92.19

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Table 3 : Psychosocial therapies for gambling disorder (GD)

Study

N

Number and duration of sessions

Design

Results

Cognitive behaviour therapy (CBT) and CBT-plus- other intervention

Sylvain et al. (1997)76

40 enrolled 14 vs. 22 in treatment groups completed

30 sessions with six-month follow- up

Cognitive therapy (CT) + relapse prevention vs. wait list (WL) Randomized controlled trial

Outcome: Gambling symptom assessment scale to measure gambling severity
CT is better than WL control

Ladoucer et al. (2001)77

88 enrolled 35 vs. 59 in treatment groups completed

20 sessions with 12-month follow- up

Cognitive therapy + relapse prevention vs. wait list Randomized controlled trial

Outcome: Gambling symptom assessment scale to measure gambling severity
CT is better than WL control

Ladouceur et al. (2003)78

81 enrolled 34 vs. 46 in treatment groups completed

10 weeks with two-year follow- up

Group cognitive therapy (GCT) + relapse prevention vs. wait list Randomized

Outcome: Gambling criteria based on structured interview CBT vs. WL: 65 percent no longer met PG criteria vs. 20 percent on wait list

Echeburua et al. (2000)79

64 enrolled 50 completed

Six weeks with 12-month follow- up

Groups: Stimulus control with in vivo exposure and relapse prevention (SCERP), cognitive restructuring, combined treatment and wait list

Outcome: Abstinence from gambling or reduction in gambling frequency SCERP>CT=Combined treatment

Milton et al. (2002)80

40 assigned to treatment; 20 completed

Eight sessions with a 9 month follow-up

Individual CBT vs. CBT + interventions to improve treatment compliance (motivational interventions) Randomized controlled trial

Outcome: Gambling symptom assessment scale to measure gambling severity and treatment retention

Addition of motivational intervention improves treatment

Melville et al. (2004)81

Group CBT: 13 vs.
group + interactive written assignments: 19; (>80% females)

Two 90-minute sessions each week for eight weeks

Group CBT, group + interactive written assignments (mapping) vs. wait- list control Combined group included co-morbid mood disorders

Outcome: Gambling criteria based on structured interview and treatment retention Combined treatment is better in terms of reduction of GD symptoms

Co-morbidity reduced treatment retention

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Study

N

Number and duration of sessions

Design

Results

Petry et al. (2006)82

231 enrolled; 181 completed

Eight sessions with one-year follow-up

Manualized CBT in individual counseling vs. CBT workbook vs. GA referral Randomized controlled trial

Outcome: Abstinence from gambling or reduction in gambling frequency
At the end of the session: Individual CBT> CBT workbook> GA referral

At the end of 1 year: no difference amongst treatment groups

Wulfert et al. (2006)83

CMBT group: 9 TAU group: 8 (100 percent male)

16 sessions with three-, 6 and 12- month follow-up

Cognitive- Motivational Behaviour Therapy (CMBT) vs. treatment as usual (TAU) Randomized controlled trial

Outcome: Gambling criteria based on structured interview CMBT>TAU
Improvement maintained at 12 months follow up

Echeburúa, Gómez, & Freixa, (2001)84

44 enrolled 41 completed

20 sessions with three-, six and 12-month follow- up

Behaviour therapy vs. cognitive restructuring/relapse prevention Psycho-education, stimulus control, gradual exposure and relapse prevention

Outcome: gambling frequency, money lost in gambling
CBT is better than TAU Efficacy is less robust at 6 and 12 months

Jimenez- Murcia et al., 201285

352 males

16 weekly group CBT sessions

Comparison of CBT+ERP vs. CBT alone Quasi-experimental non-randomized study

Outcome: Scores on the Symptom Checklist-Revised (SCL-90-R) and the South Oaks Gambling Screen (SOGS); rate of relapse
No difference between the groups
CBT+ERP: poorer retention rate

Smith et al., 201586

87 (CT= 44, ET=43); completers: CT=30, ET=21)

1, 3, and 6 month follow-up

differential efficacy of CT and Exposure therapy (ET) for adult problem gamblers Randomized controlled trial

Outcome: rated by participants using the Victorian Gambling Screen (VGS)
Both groups experienced comparable reductions (improvement) in VGS scores both at the end and after 12 months

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Study

N

Number and duration of sessions

Design

Results

Brief intervention or motivational interviewing (-plus-other psychological therapy)

Dickerson et al. (1990)87

29 enrolled

Providing CBT based workbook and single in- depth session

CBT workbook vs. workbook + a single in-depth interview

Outcome: not well defined Both groups improved at six months

Hodgins et al. (2001)88

102 enrolled 85 available at 12 months

Single session of motivational enhancement

CBT workbook vs. workbook + motivational enhancement intervention via telephone vs. wait list (WL)

Outcome: Clinical global impression modified for PG No statistical difference between motivational enhancement and workbook Both better than WL

Hodgins & Holub, (2007)89

Unclear

Single session with 12 months follow up

Single-session motivational interview (MI) with self-help workbook vs. workbook alone.

Outcome: Gambling frequency and money spent in gambling MI> Self-help workbook

Hodgins et al. (2007)90

169 enrolled 142 available at 12- month follow-up

Mailings done once for first group (n=85) vs. seven mailings for second group (n=84), with 12- month follow- up

Relapse-prevention bibliotherapy – single mailing vs. repeated mailings over a 12- month period

Outcome: criteria met in South Oaks Gambling Screening questionnaire (SOGS)
The repeated-mailing group improved more than the single- mailing group but not significantly

Carlbring & Smit, (2008)91

66 enrolled 60 with post- treatment data

Six-, 18- and 36- month follow up

Web-based CBT with telephone support and online workbook materials vs. waitlist control

Outcome: criteria met in South Oaks Gambling Screening questionnaire (SOGS) Intervention group: moderate to large improvements maintained at 36-month follow-up

Hodgins et al. (2009)92

314 enrolled 267 completed 12-month follow-up

Six-, nine- and 12-month follow- up completed

Motivational interview + mailed self-help workbook vs. six-week waitlist control or workbook- only control

Outcome Gambling frequency and money spent in gambling MI+ workbook=Workbook only> WL

Diskin & Hodgins, (2009)93

81 enrolled 69 completed 12-month follow-up (>40% female)

One-, three-, six- and 12- month follow-up

Single in-person motivational interviewing vs. control interview

Outcome: Gambling severity MI significantly better than control interview Improvement persisted after 12 months

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Study

N

Number and duration of sessions

Design

Results

Petry et al. (2009)94

117 enrolled 114 completed Week 6 evaluation 113 completed 9-month follow-up

Nine-month follow-up

Four conditions: Brief advice vs. motivational enhancement therapy (MET) vs. MET + CBT vs. no-treatment control

All treatment conditions provided significant symptom improvement although MET had the most significant effect relative to the control group

Carlbring et al. (2010)95

150 enrolled

Group CBT: 12 sessions
MI: 4 sessions Six- and 12- month follow-up

Group CBT (eight sessions) vs. motivational interviewing (four sessions) vs. no treatment control group

Outcome: severity of PG, symptoms of anxiety and depression CBT=MI>Control group

Gamblers Anonymous (GA)/Twelve-step facilitation (TSF) [-plus- other psycho-social interventions]

Grant et al. (2009)97

68 patients

Six sessions of intervention

Imaginal desensitisation plus motivational interviewing (IDMI) vs. Gamblers Anonymous

Outcome: Yale-Brown Obsessive Compulsive Scale Modified for Pathological Gambling total scores, gambling urges and gambling behaviour IDMI>GA
Those who did not respond to GA, responded later to IDMI

Stewart et al. (1988)98

232

One and 2 year follow up

Retrospective and prospective arms of GA attendees Observational study

Outcome: abstinence from gambling
Rate of abstinence: 8% of all comers at one year from first attendance and by 7% at two years

Toneatto & Dragonetti, (2008)99

CBT:65 TSF:61

CBT/TSF: 8 sessions each

CBT vs. TSF

Outcome: Key gambling variables (eg, frequency, abstinence rates, money wagered)

TSF=CBT
Participants who attended more

sessions and chose an initial abstinent treatment goal appeared to achieve better outcomes

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Study

N

Number and duration of sessions

Design

Results

Marceaux et al. (2011)100

TSF
(n = 11), CBGT- mapping (n = 18), and Wait-List control
(n = 9)

6 months follow up

Group based CBT vs. TSF vs. WL

Outcome: number of DSM-IV criteria met, perception of control/self-efficacy, desire to gamble, and frequency of gambling episodes CBGT-mapping and TSF had no significant differences on any outcome measure at follow-up assessments

Gamblers Anonymous (GA)/Twelve-step facilitation (TSF) [-plus- other psycho-social interventions]

Hodgins et al. (2007)96

186 enrolled

Three- and six- month followup

Intervention groups (based on CRAFT): Self-help workbook vs. workbook + telephone support vs. control group

Outcome: gambling frequency Intervention groups had less days gambled but behavioural principles too complicated for family members to implement

Recommendations

lIn depth motivational intervention (MI) or short term (~4 sessions) motivation enhancement therapy could be first line treatment options as a sole form of treatment [A] or brief motivational intervention could be used in conjunction with other forms of intensive interventions (especially CBT) to improve treatment retention [A].

lMore intensive intervention especially CBT could be considered for long term engagement [A]. Number of sessions could range from 10-30 (mean 20) [A]. CBT could be delivered in both individual and group format [A]. Components of CBT includes: cognitive restructuring, relapse prevention [A], skill training, and behavioural interventions (like cue conditioning/extinction) [B].

lBibliotherapy (proving workbooks) could be used along with either MI or CBT [B].

lSecond line therapy options could be: twelve step facilitation (TSF) [A], Exposure based therapy [B], and family therapy [C].Family therapy (CRAFT) could be useful when the individual is not ready to seek treatment.

lBrief telephonic MI could be an option for those not willing to commit for long term engagement or not willing to come to treatment facilities [B].

lCombination of N-acetyl-cysteine with exposure based therapy might have some additive effect [B].

lGA referral unlikely to be effective alone, if not coupled with other professionally led interventions [A].

© Indian Psychiatric Society 2016 211

lBecause of the lack of empirical evidence, therapy for GD with a co-morbid psychiatric disorder is still speculative. CBT could be an option [B].

The overall empirical evidence for the efficacy of psychological intervention in terms of both quantity and quality of studies is better than pharmacological treatment. Hence, it must be offered to all patients seeking treatment for GD.

Key uncertainties

lDurability of the effectiveness of psycho-social intervention is still a matter of debate lCo-morbidity in GD is exceptionally common but no studies so far have addressed

this important issue systematically.

lEssential components of CBT need to be incorporated are still elusive.

lFeasibility, and efficacy of combined drug and psychological therapy needs to be investigated in the future

lCountries like India in which majority of the treatment of substance use disorder is clinic based and where there is a substantial scarcity of mental health professionals, effective delivery of psychosocial management remains elusive.

lCost effectiveness of these psychosocial interventions has not been researched extensively.

6. CAVEATS OF THE PROPOSED GUIDELINE
Some research gaps have already mentioned in the section of key uncertainties. However, in our mind there are other limitations which must have been kept in mind while following and analyzing the index guideline. This practice guideline is purported to help clinicians to manage patients attending their clinics. However, the abysmally low treatment seeking might raise doubt regarding its pragmatic utility.43 Research directed towards exploring the reasons behind low treatment seeking and improving the same must be undertaken in near future. The second problem which could make this guideline ineffectual is the problem of poor treatment retention.101Though there has been some evidence that adding motivational interviewing could improve treatment retention it needs to be replicated and systematically researched to find out other strategies. Thirdly, combination of drug and psycho-social intervention which is perhaps the most widely practiced strategy for the management of GD has been studied minimally. Due to the lack of empirical validation, the effectiveness of this most commonly practiced modality of treatment in real world setting could not be commented upon. Fourthly, the psychological interventions which have maximum empirical support are labor intensive and require special expertise. The existing resources which are already struggling to keep up with the treatment of substance use disorders might face further difficulty if ‘burdened’ with the challenge of treating behavioural addiction too. This could question the practicability of these intensive

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interventions. Next, this guideline is based on the literature from the West. The generalizability of such recommendations for our Indian population might be debated. However, in absence of any treatment related research from India, we did not have any better alternative than to extrapolate our recommendations from the Western literature. Lastly, The Pathways Model explicated by Blaszczynski & Nower102 (although not as yet fully validated) hypothesizes three routes into disordered gambling. Individuals in the first group have no predisposing vulnerabilities; rather their gambling problems have been conditioned by the psychological properties of the games themselves, and perhaps by the experience of a ‘big win’ early in their gambling careers. The second subgroup is prone to depression or anxiety, and these individuals begin gambling as a means of escape or to otherwise alleviate these emotional difficulties. The third group present with antisocial and impulsive tendencies, accompanied by neuropsychological evidence of frontal cortex involvement. This model indicates that there could be an opportunity for patient treatment matching. This area needs to be explored in the future.

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PATHOLOGICAL INTERNET USE (“INTERNET ADDICTION”)

Prabhat Chand Arun Kandasamy Pratima Murthy

On behalf of
Indian Psychiatric Society
Specialty Section on Substance Use Disorders

2016

Pathological Internet Use (“Internet Addiction”)

Executive Summary

1. Introduction

2. Assessment

. 2.1  Assessment of Internet use

. 2.2  Assessment of comorbidity

. 2.3  Assessment of temperament

3. Management

3.1 Psychological Intervention
3.1.1 Cognitive Behaviour Therapy 3.1.2 Others
3.1.3 Effectiveness

3.2 Pharmacological
3.2.1 Anti-depressants

3.2.2 Stimulants

4. Psychological versus Pharmacological

5. Conclusion

CONTENTS

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Pathological Internet Use (“Internet Addiction”)

EXECUTIVE SUMMARY

The literature regarding Internet addiction or pathological Internet use has been increasing very fast along with increasing presence of Internet dependent activities in the day-to-day life. There are different terms being used by different researchers about excessive use of Internet i.e. pathological Internet use, compulsive Internet use, problematic Internet use, Internet addiction, Internet dependency etc. The common theme in all these terminology is inability to control one’s use of the Internet which leads to negative consequences in daily life. Disagreement regarding diagnostic criteria and the lack of large epidemiological studies have resulted difficulty in establishing true prevalence as well as assessment of pathological Internet use.

Assessment of temperament and comorbidities along with the nature of Internet use is essential in the clinical practice. Excessive Internet use can also be expression of ongoing emotional difficulty and ongoing poor coping mechanism. There is lack of evidence based research in the management of Internet addiction. Cognitive behavioural therapy for Internet addiction (CBT-IA) has been commonly used in clinical settings. The initial stage of CBT-IA is on modifying the behaviour i.e. setting up realistic goals, daily log of Internet use, structuring use, creating a new schedule and to learn to control Internet usage. The second stage aims at reducing maladaptive cognitions. The last stage focusses on real problems existing in their lives that lead to addiction. Various other types of psychological interventions like Reality Therapy, Short term treatment of Internet and computer addiction (STICA) has also been proposed.The pharmacological treatment specific to Internet addiction are mostly based on case series and studies from comorbid conditions like ADHD. Escitalopram, Bupropion, Methylphenidate has shown promise. The effective therapy for IA/PIU needs an individual approach and best results are expected on combined psychological and pharmacological treatment.

© Indian Psychiatric Society 2016 225

1.INTRODUCTION

Pathological Internet use (PIU), also known as problematic Internet use (PIU), has been increasingly reported by clinicians across the world. This rise of PIU and related research is associated with the unprecedented growth and access to the Internet across the world.1 At this point, neither the diagnosis of PIU nor Internet addiction (IA) appears in any official diagnostic system as a number of researchers feel this as a manifestation of an underlying problem and the Internet is only a medium of expression. At the same time, there are researchers who have argued that IA/PIU is a separate psychiatric entity like other addictions or akin to compulsive-impulsive disorders.

Specifically symptoms of Internet addiction include a) preoccupation with Internet activities; b) increasing tolerance; c) development of psychological dependency and withdrawal symptoms; d) inability to reduce Internet use; e) Internet use to cope with negative moods and reduce stress; and f) replacing other activities and relationships with recurrent Internet use despite awareness of the deleterious consequences.2,3 Block (2008) suggested four diagnostic criteria essential to a possible diagnosis of PIU as an addictive behaviour: (1) excessive Internet use, often associated with a loss of sense of time or a neglect of basic drives; (2) withdrawal, including feelings of anger, depression and tension when Internet is not accessible; (3) tolerance, including the need for better computer equipment, more software, or more hours of use; and (4) adverse consequences, including arguments, lying, poor school or vocational achievement, social isolation, and fatigue.4

2. ASSESSMENT

There are no standard diagnostic criteria for diagnosing IA/PIU. There are already about 50 screening/ diagnostic instruments for IA/PIU which different researchers have used in their studies. A comprehensive review of these scales5 suggests that a few scales like the Internet Addiction Diagnostic Questionnaire (IADQ)6, Internet Addiction Test (IAT)3, Compulsive Internet Use Scale7 are frequently used while others have been largely restricted to single research groups. Even for the frequently used scales, the psychometric properties need further exploration. Most of them have been used for research-based screening for IA/PIU. The prevalence estimate of IA/PIU varies depending on types of criteria used.8 However, for a clinician, the clinical interview and a thorough mental state examination still remains the gold standard for assessment. Based on the evidence available to date, the authors would like to suggest a framework for the assessment of pathological Internet use in this clinical practice guideline as follows: (i) assessment of the Internet use, (ii) assessment of comorbidity, and (iii) assessment of temperament.

2.1 Assessment of Internet use:

lQuantity of time and frequency of Internet use has been a common factor assessed 226 © Indian Psychiatric Society 2016

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in traditional settings. Unfortunately this may not be of use in our setting because of the Internet access through the mobile phone 24/7. Therefore it would be more useful to give importance to the form and content of Internet use.

lNature of Internet use: The assessment should be about essential and non-essential or recreational use of the net. This information will be useful because it will help us understanding whether there is any pathology at all, and if it is pathological, what is the severity. This information needs to be incorporated into the management plan.

lType of use: Whether the individual is gaming or gambling, using pornography (Cyber sexual), getting into virtual relationships through social networking sites (Cyber relationship), online shopping, bullying, hacking, etc.

lFactors motivating use: This information will be helpful to understand how Internet is helping the patient psychologically. It will also provide insights into what are the motivation factors that maintain the excessive use of the Internet. For example, an adolescent who has difficulty in communicating in the real world feels more confident of making relationships on social networking sites as the perceived threat is lesser from a virtual world. Such motivations can guide therapy. Temperament plays an important role in deciding the nature of games they choose.9

2.2 Assessment of comorbidity:

Psychiatric comorbidity can both be a cause and consequence of the IA/PIU. The temporal relation is difficult to establish like in the case in other addictive disorders. But gamers with IA/PIU have high risk of comorbidity like depression and anxiety.10-12 Carlie et al.13 reviewed 20 studies and reported that among people with IA/PIU, 75% had depressive symptoms, 57% had anxiety symptoms, 100% had ADHD symptoms, 60% had OCD symptoms and 66% had aggression. Many studies have found association of substance use disorders with IA/PIU14-16. In view of all the above findings, a thorough psychiatric interview is advised in all the patients reporting with IA/PIU. Repetitive strain injury (RSI), computer vision syndrome, fatigue, obesity etc. have been reported with excessive computer use.

2.3 Assessment of temperament:

Certain personality traits may contribute to the initiation, and maintenance of IA/PIU17. They need to be evaluated for both internalizing and externalizing temperaments. The emerging evidences indicate that most of the adolescents presenting with IA/PIU has significant temperamental issues which contribute to the abnormal behaviour.

This assessment will be helpful in reframing the problem, developing a rapport and develop a holistic management plan rather than focusing on the IA/PIU.

3. MANAGEMENT

The research on psychological and pharmacological management for IA/PIU is

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hampered by the inconsistencies in definition, lack of reliable criteria and inadequate sampling methods. The preliminary evidence largely stems from open label trials, case records and treatment responses of the comorbid disorders. In 2009, Petersen et al.18 argued that it is not possible to develop any suitable clinical recommendationsdue to lack of studies. However over the last few years, a number of psychological and pharmacological modalities has been tried to help people with IA/PIU.

3.1 Psychological interventions

Most of the intervention work has been developed in the area of psychological interventions.

3.1.1. Cognitive Behaviour Therapy

Internet addiction has been proposed as a type of compulsive disorder. Hence CognitiveBehaviourTherapy forInternetAddiction(CBT-IA)hasbeensuggestedasan effective treatment for Internet addiction19. Internet being a daily necessity of modern life, the focus of the CBT-IA is one of harm reduction rather than complete abstinence of Internet use.

The CBT-IA as proposed by Young20 consists of three phases of treatment lasting for approximately twelve weeks.

First Phase: Behavioural

The behavioural modification is the main goal of this phase. This consists of keeping a diary of Internet use and other behaviours with a primary goal of abstinence from problematic online use. The controlled use of Internet for work or other legitimate purpose is allowed. Patient will keep a daily log of Internet usage i.e. day, duration, event, activity, etc. The therapist, with inputs from the patient, builds up a structured activity schedule incorporating other activities or new habits and streamlining the online activity.Time management online and offline is the main focus.

Second Phase: Cognitive interventions

The target in this phase is to correct the maladaptive cognitions and triggers that initiate excessive Internet usage. The distortive thoughts, i.e., “I am hopeless in my study but only good at gaming” / “I am useless in offline but my online avatar (online game character) can achieve everything”, etc. are often reported by patients. Pathological Internet users may also develop thoughts that they are treated with dignity and respect only in the virtual space than in the real world like school or home. They may feel dissatisfaction or be unhappy with their real lives.

During cognitive therapy, the clinician identifies the distortions, challenges them and allows re-scripting of the distorted thoughts. Cognitive restructuring allows the client to re-evaluate how rational are his/her interpretations of these thoughts. For example, a young boy having difficulty in making friends or socializing, uses massive multiple

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online games to build his self-esteem, gradually realizes how his use of gaming is to satisfy socializing emotional needs that are not fulfilled in real life.

Recognizing these patterns of faulty thinking helps the client to break the cycle of Internet use and to restrict use of the Internet.

Third Phase: Harm reduction interventions

The associated problems related to personal, social and occupational functioning are targeted in this phase. Identification and treatment of co-existing psychiatric and other substance use helps in continued recovery and prevent relapse. The recovery process in case of pathological Internet useis not just decreasing use but also addressing and handling the underlying cause that leads to the compulsive use. Otherwise the chance of relapse is very high.

Table 2 : Cognitive Behaviour Therapy for Internet Addiction (CBT-IA)20

. (a)  Practice the opposite: reorganization of the time or time management, assessment of current habits and re-adapt to new time pattern. For example, patient’s Internet habit involves checking E – mail the first thing in the morning. Suggest that the patient take a shower or start breakfast first instead of logging on.

. (b)  External stoppers: Use external controls like alarm or prompters events to help log off from the computer. Cultivate an alternative activity

. (c)  Set goals: Set reasonable and practical goals for use of Internet. Keep Internet sessions brief and frequent. Aim is to have sense of self-control rather than allowing the Internet to take control

. (d)  Abstain from a particular application: In case a particular application like chat, game or networking is specifically more problematic and moderation has failed, then abstinence from that is appropriate. He may use other activities like email or web surfing. Abstinence is strictly advised for people who have past history of drug or alcohol addiction problems.

. (e)  Reminder cards: The focus is here of self-reminding in a concrete way the five major problem and five benefits for cutting down the usage.

. (f)  Personal inventory: Make an inventory of short term, medium term and long term goals. Keep that in mind as a motivating factor to change current behaviour.

. (g)  Supportgroup:Self-helpgroup

(h) Family therapy: Educate the family members, reduce the blame, improve on communication and assist with addiction recovery.

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3.1.2 Other Psychological Interventions

There are multiple other psychological interventions like Multi-level Counselling Program (MLC), Social competence training (SoCo), Solution-focused Brief Therapy (SFBT), Cognitive Therapy (CT), Reality Therapy (RT) that have used for the treatment of IA. The MLC is usually a combination of different psychological therapieslike CBT & Psychoeducation, CBT & parent training with medications etc. The reality therapy proposed by Kim among Korean students, includes techniques such as: control theory, five basic needs, total behaviour, friendly involvement, and making a plan, along with a few components of CBT. In Germany, CBT based short term treatment of Internet and computer addiction (STICA) consisting both individual and group therapy for four monthsdurationisproposedforIA. ArecentpilotstudydescribingthestepsofSTICA, reported significant improvement in IA related symptoms among 42 outpatients.21 The readers can go through an excellent review and meta-analysis of these studies by Winkler 201322.

Table 3 : Short-term Treatment for Internet and Computer Game Addiction (STICA)21

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Probatory

Psychological diagnostic of IA
Anamnesis of current and life-time media use Identification of problematically used online contents Diagnosis of comorbid disorders

Assessment of psychopathological symptoms and psychosocial resources

Initial stage

Initializing trustful patient-therapist alliance and therapy commitment

Assessment and enhancement of motivation for behavioural change

Development of proximal and distal therapy aims Psycho education

Behaviour modification

Psycho education

Identification of triggers (situations, cognitions, beliefs, emotions, and psychophysiological reactions) of Internet use

Develop of SORKC-schemes and cognitive restructuring Development of an individual model of IA
Training module: discrimination of emotional states Social skills training

Reestablishment of alternative behavioural strategies and interests

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Stabilization and relapse prevention

Reestablishment of alternative behavioural strategies and interests

Exposure training and habituation training

Individual relapse prevention, stopping techniques, and emergency plans

3.1.3 Effectiveness

There is robust evidence to suggest the effectiveness of various forms of psychological intervention for IA.The effect size of CBT alone is 0.84-2.13(95% CI) and other psychological treatments is 1.12-2.67 (95%CI) indicating the effectiveness as well as no significant differences between the interventions. CBT group performed significantly better with regard to “time spent online” and recovery from depression compared to other groups. A higher number of female participants, older patients, or an American sample had larger effect sizes for some outcome variables.22

3.2. Pharmacological

Pharmacological treatment for IA is mostly extrapolated from the treatment of comorbidities i.e. depression, ADHD or substance use. Recent neuroimaging studies point towards the involvement of limbic and prefrontal cortex just as in other addictions, indicating the possible effectiveness of anti-craving drugs like opioid and glutamate antagonists.

3.2.1. Anti-depressants

Escitalopram in the dose range of 20-30 mg/day for 10 weeks in an open label study on 19 patients as well as acase-report was associated with significant reduction of time spentonline23. Thebeneficialeffectpersistedevenafterpatientswererandomizedto drug or placebo group. Bupropion, used among patients with gaming addiction with or without depression, resulted in considerable degree of reduction in craving and time spent on gaming. This improvement was not associated with any change in depression.24 Neuroimaging studies on brain activity of patients treated with Bupropion (left dorsolateral prefrontal cortex, left occipital lobe) did not differ from that of healthy control.25, 26

3.2.2. Stimulants

In view of the high comorbidity of ADHD i.e. 30-50% with IA, methylphenidate has been used for ADHD children addicted to video gaming. Methylphenidateinthe dose rangeof 18-54mg/dayusedamongsixtytwodrugnaïvechildrenshowedsignificant benefit on both IA scale, ADHD rating score and Visual continuous performance test (CPT)12

Other drugs like memantine, a glutamate agonist, naltrexone, an opioid antagonist,

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mood stabilizers, atypical antipsychotics have been tried without much benefit.27

4. PSYCHOLOGICAL VERSUS PHARMACOLOGICAL

Winkler et al. in a recent meta-analysis of sixteen methodologically sound studies reported that there is no significant difference in the efficacy of improvement between both the interventions with regard to outcome parameters like time spent online, depression and anxiety. The effect sizes for psychological treatment (95%CI: 1.22-2.33) and pharmacological treatment (95% CI: 0.28-2.23) were similar. At the same time there are only three methodologically sound studies on pharmacological treatment.22

Key Recommendations
(based on limited number of studies n=16 and meta-analysis)22,27

Newer and Emerging Addictions in India

Psychological

Cognitive Behaviour Therapy for Internet Addiction is useful in reducing time spent online, recovery from depression (A)

Other psychological therapies that include individual CBT along with family therapy or group therapy etc. are also effective (B)

Individual therapy is better in the initial part of intervention compared to group therapy. (C )

The short term gains achieved in the therapy are maintained over long period (almost upto a year) (B)

Pharmacological (based on three studies)

Preliminary evidence shows that Pharmacological treatments alone (Escitalopram, Bupropion, Methylphenidate) are effective in short term (C ).

Lack of robust and methodologically sound studies focusing on IA.

Others

Combination of these two therapies may be recommended presently as the most effective intervention approach

In view of high comorbidity, effective therapy requires individual approach and must be adjusted according to the patient’s needs

5. CONCLUSION

In summary, the validity of Internet Addiction as a separate diagnostic entity still remains to be established. Nevertheless, pathological use of the Internet is a problem that is increasingly brought to the attention of the clinician. The assessment includes assessment of the time spent on Internet-related activities, the kind of Internet activity,

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the motivating factors for pathological use of the Internet, consequent disruption to functioning and health, presence of co-morbidity and an assessment of temperament. Engagement in treatment can pose a challenge, particularly when the individual’s occupation is Internet-based. Management includes a combination of psychological interventions and appropriate pharmacotherapy.

References

1. Chakraborty K, Basu D, Kumar KGV. Internet Addiction: Consensus, Controversies, and theWayAhead.EastAsianArch Psychiatry2010;20:123-32.

2. Spada MM. An overview of problematic Internet use. Addictive Behaviours 2014;39:3-6.

3. Young KS. Internet addiction: The emergence of a new clinical disorder. CyberPsychol Behaviour1998;1:237-244.

4. Block JJ. Issues for DSM-V: Internet addiction. Am J of Psychiatry 2008; 165:306-307.

5. Laconi Sp, Rodgers RF, Chabrol H. The measurement of Internet addiction: a critical review of existing scales and their psychometric properties. Comput Human Behav 2014;41:190-202.

6. Young KS. Psychology of computer use: XL. Addictive use of the Internet: a case that breaks the stereotype. Psychol Reports 1996;79:899-902.

7. Meerkerk GJ, van Den Eijnden RJJM, Vermulst AA, Garretsen HFL. The compulsive Internet use scale (CIUS): some psychometric properties. CyberPsychol Behaviour 2009;12:1-6.

8. Grover S, Chakraborty K, Basu D. Pattern of Internet use among professionals in India: Critical look at a surprising survey result. Ind Psychiatry J2010;19:94-100.

9. Demetrovics Z, Urban R, Nagygyorgy K, et al. The development of the problematic online gaming questionnaire (POGQ). PLoS One 2012;7:e36417.

10. Batthyany D, Muller KW, Benker F, Woelfling K. [Computer game playing: clinical characteristics of dependence and abuse among adolescents]. Wien Klin Wochenschr2008;121:502-509.

11. Bioulac Sp, Arfi L, Bouvard MP. Attention deficit/hyperactivity disorder and video games: A comparative study of hyperactive and control children. Eur Psychiatry2008;23:134-141.

12. HanDH,LeeYS,NaC,etal.TheeffectofmethylphenidateonInternetvideogame play in children with attention-deficit/hyperactivity disorder. Compr Psychiatry. 2009;50:251-256.

13. Carli V, Durkee T, Wasserman D, et al. The association between pathological Internet use and comorbid psychopathology: a systematic review. Psychopathology. 2013;46(1):1-13.

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14. Korkeila J, Kaarlas S, Jaaskelainen M, Vahlberg T, Taiminen T. Attached to the web—harmful use of the Internet and its correlates. Eur Psychiatry. 2010;25(4):236-241.

15. Fisoun V, Floros G, Siomos K, Geroukalis D, Navridis K. Internet addiction as an important predictor in early detection of adolescent drug use experience—implications for research and practice. J Addict Med2012;6 :77-84.

16. Yen J-Y, Ko C-H, Yen C-F, Wu H-Y, Yang M-J. The comorbid psychiatric symptoms of Internet addiction: attention deficit and hyperactivity disorder (ADHD), depression, social phobia, and hostility. J Adolesc Health2007;41:93-98.

17. Mehroof M, Griffiths MD. Online gaming addiction: the role of sensation seeking, self-control, neuroticism, aggression, state anxiety, and trait anxiety. Cyberpsychol Behav Soc Netw 2010;13:313-316.

18. Petersen KU, Weymann N, Schelb Y, Thiel R, Thomasius R. [Pathological Internet use–epidemiology, diagnostics, co-occurring disorders and treatment]. Fortschr Neurol Psychiatr2009;77:263-271.

19. Young KS. The Evolution of Internet Addiction. Addict Behav. 2015.(in press) Available online 29 May 2015).

20. Young KS. Internet Addiction: Symptoms, Evaluation and Treatment. L. VandeCreek & Jackson (eds). Innovations in Clinical Practice: A Source Book, vol. 17, 1999:19-31.

21. WolflingK,BeutelME,DreierM,MullerKW.TreatmentOutcomesinPatientswith Internet Addiction: A Clinical Pilot Study on the Effects of a Cognitive-Behavioural Therapy Program. Biomed Res Int 2014:8 pages.

22. Winkler A, Dorsing B, Rief W, Shen Y, Glombiewski JA. Treatment of Internet addiction: a meta-analysis. Clin Psychol Rev2013;33:317-329.

23. Dell’Osso B, Hadley S, Allen A, Baker B, Chaplin WF, Hollander E. Escitalopram in the treatment of impulsive-compulsive Internet usage disorder: an open-label trial followed by a double-blind discontinuation phase. J Clin Psychiatry2008;69:452-456.

24. Han DH, Hwang JW, Renshaw PF. Bupropion sustained release treatment decreases craving for video games and cue-induced brain activity in patients with Internet video game addiction. Exp Clin Psychopharmacol 2010;18:297- 304.

25. HanDH,RenshawPF.Bupropioninthetreatmentofproblematiconlinegameplayin patients with major depressive disorder. J Psychopharmacol2012;26:689-696.

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26. Han DH, Kim SM, Renshaw PF. Functional Brain Changes in Response to Treatment of Internet Gaming Disorder. C. Montag & M Reuter (eds) Internet Addiction (ed.) Springer; 2015:77-91.

27. Przepiorka AMg, Blachnio A, Miziak B, Czuczwar SaJ. Clinical approaches to treatment of Internet addiction. Pharmacol Rep2014;66:187-191.

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OTHER PUTATIVE BEHAVIOURAL ADDICTIONS

Arun Kandasamy Lekhansh Shukla

On behalf of
Indian Psychiatric Society
Specialty Section on Substance Use Disorders

2016

Other Putative Behavioural Addictions

CONTENTS

Executive Summary

1. Introduction

. 1.1  Current understanding and principles

. 1.2  Epidemiology – Global and Indian scenario

. 1.3  Consequence and disease burden

. 1.4  Syndromes under study

. 1.5  Comorbidity and related considerations

2. Scope and methodology of guidelines

. 2.1  Methodology of Guideline development

. 2.2  Scope of guidelines

. 2.3  Limitations

3. Food addiction

. 3.1  Introduction and current understanding

. 3.2  Assessment

. 3.3  Pharmacological management – evidence and recommendation

. 3.4  Non-pharmacological interventions – evidence and recommendation

4. Sex addiction

. 4.1  Introduction and Current understanding

. 4.2  Diagnostic criteria

. 4.3  Assessment

. 4.4  Pharmacological management – evidence and recommendation

. 4.5  Non-pharmacological interventions – evidence and recommendation

. 4.6  Ethical and legal concerns

5. Compulsive buying disorder

. 5.1  Introduction and current understanding

. 5.2  Assessment

. 5.3  Pharmacological management – evidence and recommendation

. 5.4  Non-pharmacological interventions – evidence and recommendation

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6. Exercise addiction

. 6.1  Introduction and current understanding

. 6.2  Assessment

. 6.3  Management

7. Conclusion

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EXECUTIVE SUMMARY

Introduction: Behavioural addiction is an emerging field. There are certain similarities between substance use disorder and behavioural addictions. Components model of addictions suggest that any behavioural excess should be evaluated on six parameters; salience, mood modification, tolerance, withdrawal symptoms, conflict and relapse. Existence and prevalence of these disorders in Indian population require further studies. Food addiction, sex addiction and compulsive buying are backed by prevalence studies while other proposed behavioural addictions have only case reports/case series as evidence. There is high comorbidity with mood, substance use disorders and temperamental traits of externalizing or internalizing spectrum.

Scope and Methodology of Guidelines: A literature search of PubMed and Google Scholar database was done, references of review articles and monographs were also included. These guidelines are meant to support clinicians and are limited by the scarcity of evidence available in this field.

Food addiction: Repeated binges of hyper-palatable (high fat or sugars) foods, loss of control, negative affective states are features suggestive of food addiction. There are no instruments which can be suggested for routine use in Indian population. Treatment of comorbidities is strongly recommended. Combination of psychological and pharmacological therapy is essential. Fluoxetine or Topiramate can be chosen as first line agents along with cognitive behaviour therapy. Lifestyle modification and dietary counselling should be provided in all cases of food addiction and/or obesity.

Sex addiction: Non-paraphilic compulsive sexual activity with features of loss of control, tolerance, withdrawal symptoms and relapses is conceptualized as sex addiction. PATHOS is a brief screening instrument that can be used in routine clinical care. Treatment of comorbid mood disorder, Attention deficit hyperactive disorder (ADHD) is recommended. Fluoxetine or Sertraline can be used as first line agents however, evidence is not strong. Similarly, there is lack of evidence for psychotherapy models.

Compulsive buying disorder: Irrepressible, uncontrolled excessive buying that continues despite negative consequences is suggested as hallmark of compulsive buying disorder. Evaluation and treatment of comorbid disorders is strongly indicated. There is insufficient evidence to recommend any pharmacotherapy. Cognitive behavioural therapy has shown promising improvement and is recommended as a first line intervention.

Exercise addiction: Excessive exercise with features of salience, withdrawal, loss of control and tolerance is proposed as exercise addiction. It should be differentiated from eating disorders (anorexia nervosa, bulimia nervosa) and body dysmorhophobia. There is insufficient evidence to recommend any pharmacological or non-pharmacological treatment.

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1. INTRODUCTION

1.1 Current understanding and principles

The area of behavioural addictions is an evolving field. This chapter will address syndromes that are less established than pathological gambling and Internet use disorder but need mention due to emerging evidence. It is emphasized that every ‘behavioural excess’ is not conceptualized as an addiction. Mark Griffith’s components model of addiction gives the most studied and convergent set of criteria for diagnosing behavioural addiction. It consists of six core components: salience, mood modification, tolerance, withdrawal symptoms, conflict, and relapse (Panel1). It should be noted that some of the syndromes discussed in this chapter are included in official classifications with a different name while some are not included in any official classification currently.

Newer and Emerging Addictions in India

PANEL 1 – COMPONENTS MODEL OF BEHAVIOURAL ADDICTION

Salience – behaviour becomes the most important activity in a person’s life and tends to dominate his or her thinking, feelings, and behaviour.

Mood modification – the emotional effect the behaviour has on the individual which often serves as a coping strategy and is reported as the arousing “rush” or the numbing or the tranquilizing “escape” the behaviour provides.

Tolerance – process whereby increasing amounts of the behaviour are required to achieve the former mood-modifying effects, often meaning greater periods of time are spent engaging in the behaviour, and/or there is a desired escalation in the intensity, recklessness, destructiveness, and ego-dystonic nature of the behaviour.

Withdrawal symptoms – unpleasant feeling states and/or physical effects (e.g., the shakes, moodiness, irritability) that occur when the person is unable to engage in the behaviour.

Conflict – discord between the person and those around him or her (i.e., interpersonal conflict), conflicts with other activities (i.e., social life, work, hobbies, and interests) or from within the individual him- or herself (i.e., intrapsychic conflict and/or subjective feelings of loss of control) that are concerned with spending too much time engaging in the addictive behaviour.

Relapse – tendency for repeated reversions to earlier patterns of excessive behaviour to recur and for a common return to the most extreme patterns of excessive behaviour soon after periods of control.

1.2 Epidemiology – Global and Indian scenario.

There is a dearth of epidemiological studies and it is premature to speculate on prevalence rates. A review shows prevalence of food addiction (2%), love addiction

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(3%), sex addiction (3%), exercise-addiction (3%), work addiction (10%) and shopping addiction (6%) in US population.1 A longitudinal study reports similar one year prevalence rates where eleven percent responders reported ‘at least one excessive behaviour’. Specifically, food addiction (7.4%), shopping addiction (4.5%), sex addiction (2.5%) and exercise addiction (3.3%) were identified through self-diagnosis.2 In India, an ICMR funded survey identified food addiction (1.6%; 2% male & 1.2% female), Shopping addiction (4%; male-3.2% & female-4.8%), Sex addiction (2%; 0.3% male&0.1% female) and Exercise addiction (5.6%; 7.5% males & 3.8% females).3

1.3 Consequence and Disease Burden

Since these syndromes are relatively recent concepts they do not lend themselves to traditional estimates of morbidity and mortality. However, they indirectly contribute to significant disease burden globally. For example, there is a link between obesity and food addiction. Obesity accounts for 3·4 million deaths, 3·9% of years of life lost, and 3·8% of disability-adjusted life-years (DALYs) worldwide.4 Further research is needed to quantify disease burden due to other behavioural addictions.

1.4 Syndromes under study

Since behavioural addiction is an evolving concept there are a number of excess behaviours that are being conceptualized in this rubric. It’s noted that while some of these syndromes have other names in official classifications, most are not diagnosable using DSM-5 or ICD-10. It is necessary to view these conditions in perspective of available evidence and there place in diagnostic systems. A list of these conditions along with the literature supporting them and their relationship with existing diagnoses is presented in Table 1.

Table 1 : List of proposed behavioural addictions

Behavioural Excess

Proposed ‘Addiction’

Evidence

Related DSM5 Diagnoses

Related ICD10 Diagnoses

Food Consumption

Food addiction

Self-report surveys. Prevalence and follow up studies. (Convenient samples)

Feeding and Eating disorders.
Binge eating disorder.

Atypical Bulimia Nervosa.
Other eating disorder.

Sexual activities

Sex addiction

Self-report surveys. Prevalence and follow up studies. (Convenient samples)

Nil

Excessive sexual drive.

Shopping and spending.

Compulsive buying/ Shopping addiction

Self-report and prevalence studies. (Convenient samples)

Nil

Other habit and Impulse disorders.

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Behavioural Excess

Proposed ‘Addiction’

Evidence

Related DSM5 Diagnoses

Related ICD10 Diagnoses

Exercise.

Exercise addiction.

Self-report surveys.

Nil

Nil

Work/Occupationa l activities

Work addiction.

Self-report surveys.

Nil

Nil

Tanning

Indoor tanning addiction.

Case reports.

Nil

Nil

Romantic Pursuits

Love addiction

Theoretical Postulates.

Nil

Nil

1.5 Comorbidity and related considerations

There is a high comorbidity of substance use disorders and other mental disorders in this group of patients. Specifically affective disorders, attention deficit hyperactivity disorder and anxiety disorders are commonly reported. In addition temperamental factors like externalizing or internalizing temperaments are more common in this population. Finally, behavioural addictions can co-exist and often interact with each other which has been called addiction interaction disorder.5 Thus it is essential to take a detailed history, perform toxicology screening and rule out other conditions.

2. SCOPE AND METHODOLOGY OF GUIDELINES

2.1 Methodology of Guideline development

Relevant literature was identified through a PubMed literature search for publications related to this guideline. Searches were conducted using two sets of keywords. First a literature search was conducted using “Behavioural addictions OR Process addictions OR Impulsive compulsive disorders”. This was followed by specific search terms namely: “Food addiction OR eating addiction”, “Shopping addiction OR compulsive buying”, “Sex addiction OR sex dependency OR excessive sexual drive OR nymphomania OR satyriasis” and “Tanning addiction”. Results were filtered with language- English, species-human and availability-abstract. Additionally bibliographic references of review articles and monographs were reviewed.

2.2 Scope of guidelines

These guidelines are neither comprehensive nor definitive. Psychiatrists caring for patients should consider the evidence base but not be limited by the recommendations made here. Further these guidelines are limited by the scarce scientific evidence available in this field. It’s an emerging field riddled with controversies thus guidelines will require revision as new evidence appears.

3. FOOD ADDICTION

3.1 Introduction and Current understanding.
A recent conceptualization of obesity (due to excessive calorie consumption) and

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inability to alter this behaviour is that hyper-palatable foods are addictive.6 This concept is more pertinent for patients with binge eating and clear loss of control regarding certain calorie dense hyper-palatable food items (high fat, high sugar foods).7 There are two important caveats to this conceptualization. Firstly, obesity is not always due to disordered eating, other endocrine causes should be ruled out. Secondly, overeating itself does not indicate an addictive process, for many individuals it is due to large potions, liberal snacking and poor food choices.8

3.2 Assessment

3.2.1 Brief Overview

First Assessment is an opportunity of establishing rapport and further engagement which is required for a more nuanced understanding of patient’sproblems. There can be different contexts in which patient presents for example; referral by a physician or specialist, pre-bariatric surgery referral, self-referral or being brought by family for ‘disordered eating’. A final formulation may not be reached till a number of interviews are conducted. This should be communicated to patient and family.

3.2.2 Clinical History

A detailed history should include; purpose and context of current visit, comorbid psychiatric or physical disorders, current medications if any, substance use history, history of other behavioural addictions, premorbid personality and temperament. Family history of substance use disorders, obesity, metabolic disorders and current living arrangement is important. Important findings that demand a more detailed evaluation for food addiction, based on available literature are highlighted in Panel2. There are certain differential diagnoses that should be considered and are highlighted in Panel3. It should be kept in mind that Binge eating disorder and Food addiction are competing formulations and cannot be delineated at present.9

PANEL 2 – FEATURES SUGGESTING FOOD ADDICTION

1. Recurrent Binge eating episodes: Bouts of unusually large food intake in relatively short periods of time.

2. Periodicpoorcontrol:increasedbingesafterperiodsofrelativedeprivation.

3. Lossofcontrol:diminishedabilityorwillingnesstocutdownfoodconsumption.

4. Hyper-palatablefoods:highfatandhighsugarfoods.

5. Highernegativeaffectandemotionaldysregulation.

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PANEL 3 – DIFFERENTIAL DIAGNOSIS OF FOOD ADDICTION

1. Other eating disorders: presence of purging, compensation and body image disturbance.

2. Atypicaldepression:presenceofhypersomniaanddepressivesymptoms.’

3. ‘Comfortfoods’:lackofmultiplebinges,clearstressors.

4. Adonis complex/muscle dysmorphia: body-image disturbances, high protein foods.

5. Drug induced hyper-phagia: atypical anti-psychotics, cyproheptidine, cannabinoids, and steroids.

6. Endocrine disorders: thyrotoxicosis, recurrent hypoglycaemia due to medications or brittle diabetes.

7. Neurologicaldisorders:KleineLevinsyndrome.

8. Raregeneticsyndromes:Prader-WillisyndromeandBardetBiedlSyndrome.

3.2.3 Physical examination

A thorough physical examination specially focusing on body mass index, waist to hip ratio, acanthosis nigricans, stigmata of substance use disorders, blood pressure, peripheral pulses and circulation, stigmata of purging or repeated vomiting (erosion of enamel, callosities on knuckles) and stigmata of endocrine illnesses (skin changes, tachycardia, moon facies) should be done. Body weight and waist to hip ratio can be used during the course of treatment to monitor improvement and enhance motivation.

3.2.4 Instruments

Yale Food addiction scale (YFAS) developed by Gearhardt, Corbin, & Brownell in 2009 is the most widely used instrument for food addiction.10 However this has not been validated in Indian population. Since the scale involves culturally determined items (name of food items with high fat and sugar content for example Pretzel, Bacon) it may not hold valid in Indian scenario. It is not recommended for routine clinical use.

3.2.5 Investigations

If the psychiatrist is the first point of contact and referral to physician is not planned, a number of investigations are advised to rule out metabolic syndrome. Fasting and post prandial blood sugar, fasting lipid profile, haemogram, renal function tests and hepatic function tests should be reviewed. If hepatic functions are deranged in absence of alcohol use abdominal ultrasound should be done to evaluate non-alcoholic steatotic hepatitis (NASH). A toxicology screen can be used depending on index of suspicion. Similarly, sexually transmitted infections should be ruled out if there is a history of high risk sexual encounters. In females, Polycystic ovary disease may be a pre-existing or

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comorbid condition and mid-cycle follicle stimulating hormone (FSH), Luteinizing hormone (LH), Testosterone and sex hormone binding globulin (SHBG) can be done before referral to an endocrinologist.

3.3 Pharmacological Management- evidence and recommendations.

Identification and treatment of comorbid conditions – ADHD, depression and anxiety disorders is recommended. There are no well-studied pharmacotherapies for food addiction as it is not a recognized diagnosis. Pharmacotherapy for binge eating disorder and obesity are worth reviewing in this context – Table 2. In summary anti-depressants (SSRI and SNRI) decrease frequency of binges in short term, anti-epileptic medications decrease both the frequency of binges and promote weight loss while anti-obesity drugs only promote weight loss.11,12 There are a number of drugs and combinations that are in various phases of development and may be available shortly. They are summarized in Panel 4.

Table 2: Pharmacotherapy for binge eating disorder and anti-obesity drugs

Pharmacological agent(s)

Dose

Evidence

Strength of recommendation

Expected Improvement

Common side effects

Fluoxetine

20 to 60 mg per day.

1B

A

Decreased frequency of binges.

Gastrointestinal discomfort.

Sertraline

50 to 200 mg

1B

A

Decreased frequency of binges.

Gastrointestinal discomfort.

Fluvoxamine

50 to 300 mg

1B

A

Decreased frequency of binges.

Anticholinergic symptoms. Discontinuation syndrome.

Citalopram

20 to 60 mg

1B

A

Decreased frequency of binges.

Gastrointestinal symptoms.

Topiramate

25 to 300 mg

1A

A

Decreased binges and weight loss.

Cognitive deficits.

Atomoxetine

10 to 80 mg

1B

A

Decreased binges.

Gastrointestinal symptoms.

Orlistat

60 to 360 mg

1A

A

Weight loss through decreased fat absorption.

Steatorrhea and vitamin deficiencies.

Metformin

500 mg to 2000mg

2A

B

Weight loss.

Gastrointestinal symptoms.

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3.4 Non-pharmacological interventions – evidence and recommendation.

3.4.1 Overview

Pharmacological treatment has modest and short-lasting benefit. Current expert opinion is that a combination of pharmacotherapy and psychotherapy is optimal management strategy.13 Similar to pharmacological management, there is an absence of literature pertaining to psychotherapy of food addiction per se. However, there is extensive literature on psychotherapy of binge eating disorder which will be reviewed. Summary of evidence for psychotherapeutic interventions is presented in Panel 5. Major modalities and recommendations are summarized in Table 3.

Table 3 : Psychotherapeutic interventions in food addiction

Newer and Emerging Addictions in India

PANEL 4 – EMERGING ANTI-OBESITY TREATMENTS

1. Lorcaserin:5HT2Cagonism,satietypromotingagent.Dose:10mgtwiceaday. Significant interaction with anti-depressants.

2. Fixed dose Combination of Phentermine and Topiramate:3.75 mg phentermine/23 mg topiramate to 7.5 mg/46 mg combination.

3. FixeddosecombinationofBupropionandNaltrexone.

4. FixeddosecombinationofBupropionandzonisamide.

5. Tesofensine: tri-monoamine reuptake inhibitor, inhibits reuptake of serotonin, nor-epinephrine and dopamine.

Psychotherapeutic intervention

Category of evidence

Strength of recommendation

Lifestyle and Dietary counselling

1A

A

Cognitive Behaviour therapy

1B

A

Interpersonal Therapy

1B

A

Dialectical Behaviour Therapy

1C

A

Self Help

4

D

Peer Support

4

D

3.4.2 Lifestyle modification and dietary modification

Following assessment a counselling session focusing on dietary habits, physical activity, and behaviour modification must be offered to all clients. (Strength of recommendation: S). Involving a dietician or general physician for comprehensive care can be considered based on resources, severity of obesity and presence of comorbidities like vascular disease, diabetes or hypertension. Obesity is a disease of energy imbalance, counselling should address energy consumption (diet), energy expenditure (physical activity), and

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how to incorporate this information into daily lives (behaviour therapy). Lifestyle management has been shown to result in a modest (typically 3–5 kg) weight loss compared with no treatment or usual care.14

PANEL 5 – FOOD ADDICTION PSYCHOTHERAPY- SALIENT POINTS

Types of interventions: Lifestyle and dietary modification, CBT, DBT, IPT, peer support (Overeaters anonymous) and self-help.

lAny intervention is better that no-intervention.
lCBT/DBT/IPT have comparable efficacy in reducing binges in short term. lMinimal effect on body weight with any psychotherapeutic intervention. lCBT and DBT can be given in individual or group format.

3.4.3 Cognitive behavioural therapy (CBT)

No CBT program for food addiction currently exists, although CBT is a relatively well- established psychological treatment for BED.15 CBT for BED consists of three stages spanning approximately 20 sessions. Stage one consists of establishing a therapeutic relationship and on educating the patient on the rationale underlying the CBT approach. Stage two emphasizes replacing binge eating with a regular pattern of eating and address cognitive distortions including dichotomous reasoning, low self-esteem, and extreme perfectionism. The third stage ensures that progress is maintained it also includes formulating relapse plans.

3.4.4 Dialectical Behavioural therapy (DBT)

DBT proposes that individuals who struggle with BED may lack the skills necessary to cope with their affective states and, therefore, may use food as a means to avoid or escape from emotional distress. DBT for BED (DBT-BED involves the following modules: mindfulness skills, emotional regulation, and distress tolerance. DBT-BED is effective at enhancing patients’ overall level of emotional regulation and may be superior to CBT in terms of abstinence from binge eating.16

3.4.5 Interpersonal Therapy (IPT)

IPT typically focuses on the connection between current symptoms and interpersonal (i.e., relationship) problems and holds the assumption that the condition is maintained by interpersonal problems. IPT may be comparable to CBT in reducing binges and better in maintaining improvement.17

3.4.6 Self-help

For milder cases a manualized CBT format administered in a guided or purely self-help format may be useful.18 Considering that it does not demand many resources it is a feasible first step towards therapy.

© Indian Psychiatric Society 2016 249

3.4.7 Peer support

12 step programs like overeaters-anonymous may be beneficial for some patients. Systematic evidence of efficacy is lacking currently.19

Newer and Emerging Addictions in India

FOOD ADDICTION
lKey Features: Repeated binges, loss of control, consumption of hyper-palatable

foods, and relapses.

lOverlaps with: Binge eating disorder.

lComorbidities: Mood disorders, anxiety disorders, substance use disorders, other behavioural addictions, ADHD.

lAlways recommended: Treatment of comorbidities, lifestyle and nutritional counselling, follow-up and weight monitoring.

lRecommended: Fluoxetine 20-60mg/day OR Topiramate 25-200mg/day AND Cognitive behavioural therapy.

lCan be considered: Sertraline 50-200mg/day, Zonisamide 100-600mg/day, Atomoxetine 25-60mg/day anti-obesity drugs, Interpersonal therapy, dialectical behavioural therapy.

lTreatment Goals: control of binges in short term, sustained weight loss in long term.

4. SEX ADDICTION

4.1 Introduction and current understanding.

Excessive, compulsive sexual desire and activities have been variously named as – sex addiction, compulsive sexual behaviour, sex dependency and impulsive-compulsive sexual disorder. Despite being reported and postulated since 1812 by Benjamin Rush it was not included in DSM 5 due to lack of adequate evidence.20 Current conceptualization of sex addiction is a non-paraphilic excessive sexual behaviours with features of impulsivity, compulsivity and causing significant personal distress, social or medical comorbidity. This conceptualization and resultant criteria has high internal consistency, inter-rater reliability and cross-validity with measures of hyper-sexuality, impulsivity, stress-proneness and emotional dysregulation.21

4.2 Diagnostic criteria

There are multiple sets of criteria proposed by different groups working in the field. There is a significant similarity between these criteria and criteria for substance use disorders. Criteria proposed by Carnes et al is mentioned in Panel6 as it has been studied most extensively and has longitudinal stability.22

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PANEL 6 – SEXUAL ADDICTION DIAGNOSTIC CRITERIA

A. Aminimumofthreecriteriametduringa12-monthperiod:

. 1)  Recurrent failure to resist impulses to engage in specific sexual behaviour.

. 2)  Frequent engaging in these behaviours to a greater extent or longer duration than intended.

. 3)  Persistent desire or unsuccessful efforts to stop, to reduce, or to control behaviours.

. 4)  Inordinate amount of time spent in obtaining sex, being sexual, or recovering from sexual experiences.

. 5)  Preoccupation with the behaviour or preparatory activities.

. 6)  Frequently engaging in the behaviour when expected to fulfil occupational, academic, domestic, or social obligations.

. 7)  Continuation of the behaviour despite knowledge of having a persistent or recurrent social, financial, psychological, or physical problem that is caused or exacerbated by the behaviour.

. 8)  Need to increase intensity, frequency, number, or risk of behaviours to achieve the desired effect or diminished effect with continued behaviours at the same level of intensity, frequency, number, or risk.

. 9)  Giving up or limiting social, occupational, or recreational activities.

. 10)  Distress, anxiety, restlessness, or irritability if unable to engage in the behaviours.

B. Has significant personal and social consequences (such as loss of partner, occupation, or legal implications).

4.3 Assessment

4.3.1 Brief overview

There are multiple considerations during assessment like – context of assessment, confidentiality, privacy, legal implications and need to remain non-judgmental. Context of assessment can be self-referral, marital conflict, under duress or for other psychiatric problems. Multiple interviews may be required to establish adequate comfort level.

4.3.2 Clinical History

Clinical history should focus on detailed sexual and relationship history, fantasies, internal conflict and compulsivity. A clear understanding of gender identity, sexual orientation and sexual preferences is necessary to avoid misdiagnosis. A frank discussion regarding sexual preferences and conflicts with law is required.

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Externalizing temperamental traits of impulsivity, emotional dysregulation are frequently present. Comorbidity of substance use disorders, attention deficit hyperactivity disorder and mood disorder is also common. A medical history focusing on symptoms of sexually transmitted infections should be collected. Finally if patient is in a long term relationship, relationship problems should be looked for. Differential diagnoses for sexual addiction are mentioned in Panel 7 and should be ruled out.

Newer and Emerging Addictions in India

PANEL 7 – DIFFERENTIAL DIAGNOSIS OF SEXUAL ADDICTION

1. Paraphilias: Deviant sexual preference is the primary complaint. Paraphilic tendencies can be present in sexual addiction also but they are not the primary symptom.

2. Affective disorders: hypomania, mania and rarely atypical depression can be accompanied by hyper-sexuality but it is characteristically episodic and accompanied by other symptoms.

3. Substanceusedisorders:stimulant,anabolicsteroidsandothersubstanceabuse can be accompanied by periods of excessive sexual activity.

4. Mentalretardation:lackofinhibitionandabilitytomodulateimpulses.

5. Dementia:hyper-sexualitycanbeseeninfronto-temporaldegeneration.

6. Neurologicaldamageduetovariouscauseslikeheadinjury,multiplesclerosis.

7. Endocrine:hyper-testosteronismduetotumour.

8. Drug induced: testosterone supplementation, GnRH analogues, levodopa and dopamine agonists.

9. Raregeneticdisorders:KleineLevinsyndrome.

4.3.3 Physical examination

Special focus should be given to genital examination and stigmata of substance use disorder.

4.3.4 Investigations

Important investigations in addition to routine are serology for sexually transmitted infections, toxicology screen and in atypical cases a sex hormone profile (serum FSH, LH, free testosterone and sex hormone binding globulin).

4.3.5 Instruments

Sexual addiction screening test – revised (SAST-R) has 20 core items and 25 subscale items. It is valid in homosexual patients and has a good reliability at a cut-off of 6.23 However it has a total of 45 items and is time consuming. Recently, a screening instrument called PATHOS was developed to aid in the identification of those who may

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have sexual addiction. Similar to the CAGE, this mnemonic six- item screener (extracted from the SAST-R) was found to have acceptable internal consistency (0.94–0.77) and using the cut-off score of 3, demonstrated good sensitivity and specificity ratings.24 See Panel 8 for a list of PATHOS items.

PANEL 8 – PATHOS ITEMS
1. Doyouoftenfindyourselfpreoccupiedwithsexualthoughts?(Preoccupied) 2. Doyouhidesomeofyoursexualbehaviourfromothers?(Ashamed)
3. Haveyoueversoughthelpforsexualbehaviouryoudidnotlike?(Treatment) 4. Hasanyonebeenhurtemotionallybecauseofyoursexualbehaviour?(Hurt) 5. Doyoufeelcontrolledbyyousexualdesire?(Outofcontrol)
6. Whenyouhavesex,doyoufeeldepressedafterwards?(Sad)
A positive response to more than 3 questions indicate need for further assessment.

4.4 Pharmacological management – evidence and recommendation.

Pharmacological management should be a component of multi-faceted plan including individual psychotherapy and marital therapy. Most importantly if a comorbidity like ADHD or mood disorder is identified it should be treated in earnest. Evidence for treatment of sexual addictions (conceptualized as non-paraphilic sexual compulsivity) is sparse. Pharmacotherapy aimed at reducing libido has much evidence in paraphilias and sex-offenders24-26; however this evidence cannot be extrapolated to sex addiction. Treatment of sex addiction aims to improve control over sexual desire rather than complete suppression of it. A summary of pharmacological agents and evidence supporting their use is summarized in Table 6.

Table 6 : Pharmacotherapy for sex-addiction

Pharmacological agent(s)

Dose

Evidence

Strength of recommendation

Disorder studied

Common side effects

Fluoxetine27

20 to 80 mg per day

2B

B

Paraphilias and non-paraphilic hyper sexuality

Gastrointestinal discomfort.

Sertraline

50 to 200 mg

2B

B

Paraphilias

Gastrointestinal discomfort.

Naltrexone28

100 mg

3

C

Non-paraphilic hyper sexuality

Fatigue, anhedonia

4.5 Non Pharmacological interventions – evidence and recommendation. Components of non-pharmacological management as described by Carnes et al22 are

© Indian Psychiatric Society 2016 253

summarized in Panel 9. It is noted that there is a lack of controlled comparative data. (Category of evidence – 4, strength of recommendation- D).

4.6 Ethical and legal concerns

Hyper-sexuality can lead to conflict with law. However, it is neither necessary nor sufficient for diagnosis. A discussion with patient regarding legal implications of his/her behaviour should be undertaken and recorded. Clinicians are advised to be mindful of potential medico-legal issues and ethical dilemmas when dealing with sexual addiction. A potential scenario could be about disclosure to spouse during therapy sessions. Some legal statutes may require obligatory reporting of ongoing sexual abuse like ‘The Protection of Children from Sexual Offences Act, 2012’.29

Newer and Emerging Addictions in India

PANEL 9 – PSYCHOSOCIAL INTERVENTION FOR SEXUAL ADDICTION

PHASE I – INTERVENTION
lSurvey extent of problematic behaviour lTeach about illness
lReferral to 12-Step Program
lConfront denial
lAgree on behaviour contract
PHASE II- INITIAL TREATMENT
l12-Step attendance
lComplete first step of 12-step process lAgree on writing an abstinence definition lWritten relapse-prevention plan lComplete period of celibacy
lDevelop a sex plan
lPartner and family involvement lMultiple addiction assessment lTrauma assessment
lGroup therapy
lShame reduction
PHASE III- EXTENDED THERAPY lComplete steps 2 – 4 of 12-step process lDevelopmental issues lFamily-of-origin issues
lGrief resolution
lMarital and family therapy
lCareer issues
lTrauma therapy

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SEX ADDICTION
lKey Features: Failure to resist impulses, desire to control or stop, increasing time

spent, continued despite adverse consequences.

lOverlaps with: Disorders of sexual preference.

lComorbidities: Substance use disorders, ADHD.

lAlways recommended: Treatment of comorbidities, engagement in long term therapy.

lRecommended: Fluoxetine 20-60mg/day.

lCan be considered: Augmentation with Naltrexone 100-200mg/day.

lTreatment Goals: Control of high risk contacts and commitment to long term therapy.

5. COMPULSIVE BUYING DISORDER (CBD)

5.1 Introduction and current understanding

Compulsive buying disorder or shopping addiction has been variously conceptualized as impulse control disorders, obsessive-compulsive and related disorders, behavioral and substance addictions, and mood disorders.30 Most of the epidemiological data is from western and high income group countries.31

5.2 Assessment

A focused assessment to evaluate ‘excessive buying’ is required prior to diagnosing CBD. Current conceptualization and diagnostic features of CBD are summarized in Panel10. Temperamental traits of impulsivity, distractibility and cognitive schemas which place high value on materialism are considered to be risk factors.32 Comorbidity of mood disorder, anxiety disorders, substance use disorders and other behavioural addictions should also be evaluated. Differential diagnoses to be considered are summarized in Panel 11.

5.3 Pharmacological management – evidence and recommendation

Treatment of comorbid mood disorder, attention deficit hyperactivity disorder should be optimized. There is insufficient evidence to recommend pharmacotherapy in patients with no comorbidities. In a study comparing Tab Fluvoxamine 300mg and placebo there was no difference in response.33

5.4 Non-Pharmacological interventions – evidence and recommendation

Cognitive behavioural therapy (CBT) focusing on actual shopping behaviour problems, financial management, emotions and feelings associated with buying behaviour, self- esteem and consequences has shown preliminary improvement in two studies.34,35

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Group therapy and individual psychodynamic therapy has also been proposed but with no efficacy data for comparison. Thus CBT is recommended as a treatment for compulsive buying disorder. (Evidence category 1B, strength of recommendation A).

Newer and Emerging Addictions in India

PANEL 10 – FEATURES SUGGESTING COMPULSIVE BUYING DISORDER

1. IrrepressibleBuying:individualmustbeengrossedinshoppinginacompulsive way. He or she will spend hours shopping and spending each week, and the shopping activity is coupled with an intense urge to purchase one or multiple items. This unavoidable urge to shop and purchase is overpowering and irrepressible, and is precisely what leads to uncontrollable shopping behaviours.

2. UncontrollableBuying: mostindividualswithCBDhaveoverwhelmingurges to buy products, and it is nearly impossible for individuals to successfully resist these urges.

3. Negative Consequences of Buying: most individuals fail to change this behaviour despite negative consequences in all different domains of individuals’ lives, including financial, familial and occupational.

PANEL 11 – DIFFERENTIAL DIAGNOSIS OF EXCESSIVE SHOPPING
1. Affective disorders: hypomanic or manic episodes, clearly episodic with

accompanying symptoms.

2. Hoardingdisorder:presenceofclutterandpoorinsight.

3. Obsessive compulsive disorder: obsessions/magical thinking/need for completion or just right phenomenon.

4. Dementia:Diogenessyndrome

6. EXERCISE ADDICTION

6.1 Introduction and current understanding.

Exercise addiction has been variously referred to as compulsive exercise, obligatory exercise or exercise abuse. Initially believed to be a ‘positive addiction’33 it is increasingly realized that some individuals have patterns of exercise that are dysfunctional.34 It remains a rare condition but is more common in individuals related to professional sports. In such cases it is difficult to delineate it from high levels of commitment and competitiveness. Further, there is substantial debate if this entity exists separate from eating disorders.35

6.2 Assessment
Excessive exercise should be evaluated keeping in mind the components model of

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addiction. An important distinction should be made between primary exercise addiction where exercise itself is the objective and other disorders like eating disorders, muscle dysmorphia where objectives are different. A history of anabolic steroid abuse, repeated overuse injuries, disruption of social and familial ties is important.

6.3 Management

There is insufficient evidence to recommend pharmacological or non-pharmacological management. It is proposed that approaches like CBT which are effective for eating disorders may be effective in exercise addiction.

7. CONCLUSION

Almost all the pathological behaviours named above do not have enough evidence to get into the mainstream diagnostic criteria as of now. There is also a lack of evidence towards a standard protocol of management. But the clinicians come across such cases regularly. Inviewofthesefacts,theauthorsareoftheopinionthat:

1. A detailed assessment of the behaviour under investigation along with assessment of comorbid psychiatric and medical disorders and the temperament will be useful to arrive at the focus of management in these disorders.

2. Management should include an individualized treatment plan which would comprise of rapport building, motivational intervention, management of temperamental issues and comorbidities along with management of the problem behaviour. The role of pharmacotherapy other than treating co-morbidities still needs to be established.

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2. Konkoly Thege B, Woodin EM, Hodgins DC, Williams RJ. Natural course of behavioural addictions: a 5-year longitudinal study. BMC Psychiatry. 2015;15:4.

3. Manoj Sharma, Vivek Benegal, Rao T. Behavioural and Technology addiction survey. Bangalore: National Institute of Mental Health and Neurosciences 2013.

4. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384(9945):766-81.

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6. Volkow ND, Wise RA. How can drug addiction help us understand obesity? Nat Neurosci. 2005;8(5):555-60.

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7. Gearhardt AN, White MA, Masheb RM, Morgan PT, Crosby RD, Grilo CM. An examination of the food addiction construct in obese patients with binge eating disorder. Int J Eat Disord. 2012;45(5):657-63.

8. Moreno C, Tandon R. Should overeating and obesity be classified as an addictive disorder in DSM-5? Curr Pharm Des. 2011;17(12):1128-31.

9. Gearhardt AN, White MA, Masheb RM, Grilo CM. An Examination of Food Addiction in a Racially Diverse Sample of Obese Patients with Binge Eating Disorder in Primary Care Settings. Compr Psychiatry. 2013;54(5):500-5.

10. Gearhardt AN, Corbin WR, Brownell KD. Preliminary validation of the Yale Food Addiction Scale. Appetite. 2009;52(2):430-6.

11. Reas DL, Grilo CM. Review and Meta-analysis of Pharmacotherapy for Binge-eating Disorder. Obesity. 2008;16(9):10.1038/oby.2008.333.

12. Reas DL, Grilo CM. Current and Emerging Drug Treatments for Binge Eating Disorder. Expert Opin Emerg Drugs. 2014;19(1):99-142.

13. Crow S. Treatment of Binge Eating Disorder. Curr Treat Options Psychiatry. 2014;1(4):307-14.

14. Wadden TA, Butryn ML, Wilson C. Lifestyle modification for the management of obesity. Gastroenterology. 2007;132(6):2226-38.

15. Hay PJ, Bacaltchuk J. Psychotherapy for bulimia nervosa and binging. Cochrane Database Syst Rev. 2003(1):Cd000562.

16. Telch CF, Agras WS, Linehan MM. Group dialectical behaviour therapy for binge-eating disorder: A preliminary, uncontrolled trial. Behaviour Therapy. 2000;31(3):569-82.

17. Hilbert A, Bishop ME, Stein RI, Tanofsky-Kraff M, Swenson AK, Welch RR, et al. Long- term efficacy of psychological treatments for binge eating disorder. Br J Psychiatry. 2012;200(3):232-7.

18. Wilson GT, Vitousek KM, Loeb KL. Stepped care treatment for eating disorders. J Consult Clin Psychol. 2000;68(4):564-72.

19. Ronel N, Libman G. Eating Disorders and Recovery: Lessons from Overeaters Anonymous.Clin.Soc.WorkJ. 2003;31(2):155-71.

20. Kafka MP. Hypersexual disorder: a proposed diagnosis for DSM-V. Arch Sex Behav. 2010;39(2):377-400.

21. Reid RC, Carpenter BN, Hook JN, Garos S, Manning JC, Gilliland R, et al. Report of findings in a DSM-5 field trial for hypersexual disorder. J Sex Med. 2012;9(11):2868-77.

22. Carnes PJ. Sexual addiction and compulsion: recognition, treatment, and recovery. CNS Spectr. 2000;5(10):63-72.

23. CarnesP,GreenB,&,CarnesS.Thesameyetdifferent:RefocusingtheSexualAddiction Screening Test (SAST) to reflect orientation and gender. Sexual Addiction Compulsivity. 2010;17(1):7-30.

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24. Carnes PJ, Green BA, Merlo LJ, Polles A, Carnes S, Gold MS. PATHOS: A brief screening application for assessing sexual addiction. J Addict Med. 2012;6(1):29-34.

25. Assumpção AA, Garcia FD, Garcia HD, Bradford JMW, Thibaut F. Pharmacologic Treatment of Paraphilias. Psychiatric Clinics of North America. 2014;37(2):173-81.

26. Khan O, Ferriter M, Huband N, Powney MJ, Dennis JA, Duggan C. Pharmacological interventions for those who have sexually offended or are at risk of offending. Cochrane Database Syst Rev. 2015;2:Cd007989.

27. Kafka MP, Prentky R. Fluoxetine treatment of nonparaphilic sexual addictions and paraphilias in men. J Clin Psychiatry. 1992;53(10):351-8.

28. Raymond NC, Grant JE, Coleman E. Augmentation with naltrexone to treat compulsive sexual behaviour: a case series. Ann Clin Psychiatry. 2010;22(1):56-62.

29. Model Guidelines under Section 39 of The Protection of Children from Sexual Offences Act, 2012 New Delhi: MINISTRY OF WOMEN AND CHILD DEVELOPMENT 2013 [cited 2015 15/09/2015]. Available from: http://wcd.nic.in/act/POCSO%20- %20Model%20Guidelines.pdf.

30. Dittmar H. Compulsive buying–a growing concern? An examination of gender, age, and endorsement of materialistic values as predictors. Br J Psychol. 2005;96(Pt 4):467-91.

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35. Blaydon MJ, Lindner KJ. Eating disorders and exercise dependence in triathletes. Eat Disord. 2002;10(1):49-60.

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SECTION D : DUAL DIAGNOSIS

DUAL DIAGNOSIS : PSYCHOTIC DISORDERS

Yatan Pal Singh Balhara Sathya Prakash Ananya Mahapatra Siddharth Sarkar

On behalf of
Indian Psychiatric Society
Specialty Section on Substance Use Disorders

2016

Dual Diagnosis : Psychotic Disorders

CONTENTS

Executive Summary

1. Introduction

. 1.1.  Concept of dual diagnosis

. 1.2.  Epidemiology of dual diagnosis: psychotic disorders

. 1.3.  Importance of dual diagnosis: psychotic disorders

2. Scope and methodology of the guideline

. 2.1.  Overview of the guidelines

. 2.2.  Scope of the guidelines

2.2.1. Psychotic dual diagnosis
2.3. Methodology of guideline development

3. Assessment and formulation

. 3.1.  General issues

. 3.2.  Treatment aims / goals

. 3.3.  Deciding treatment setting

. 3.4.  Assessment of dual diagnosis: psychotic disorders

. 3.4.1.  General overview

. 3.4.2.  Clinical history

. 3.4.3.  Physical examination

. 3.4.4.  Assessing risk
3.4.4.1. Violence
3.4.4.2. Suicidality

. 3.4.5.  Rating scales

. 3.4.6.  Investigations

. 3.5.  Recommendations for practice

4. Interventions in psychotic dual diagnosis

. 4.1.  Motivation enhancement intervention

. 4.2.  Pharmacological measures

4.2.1. For substance use disorder 4.2.1.1. Short term management

4.2.1.1.1. Interaction of anti-psychotic medications with substance of abuse and medicines

used for its short term management (management of withdrawals)

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4.3.

4.2.2.5. Psychosocial measures

4.3.1.

4.3.2.

4.3.3.

4.3.4.

4.3.5.

4.3.6.

Combined Motivational Interviewing and Cognitive Behavioural Interventions

4.3.1.1. Basic principle
4.3.1.2. Evidence base
Modified Cognitive-Behavioural Therapy (CBT) 4.3.2.1. Basic principle
4.3.2.2. Evidence base
Dual Recovery Therapy (DRT)
4.3.3.1. Basic principle
4.3.3.2. Evidence base
Modified Motivational Enhancement Therapy 4.3.4.1. Basic principle
4.3.4.2. Evidence base
The Substance Abuse Management Module (SAMM) 4.3.5.1. Basic principle
4.3.5.2. Evidence base
Self-help groups

4.2.1.2.

Long term 4.2.1.2.1. 4.2.1.2.2. 4.2.1.2.3. 4.2.1.2.4. 4.2.1.2.5.

management
For alcohol use disorders
For opioid use disorders
For tobacco use disorders
For cocaine and other stimulant use disorders For cannabis use disorders

4.2.2. For psychotic disorder

4.2.2.1. 4.2.2.2. 4.2.2.3. 4.2.2.4.

First generation anti-psychotics

Second generation anti-psychotics

Electroconvulsive therapy (ECT)

Interaction of anti-psychotic medications with substance of abuse and medicines used for its management

4.3.6.1. 4.3.6.2.

Basic principle Evidence base

Duration of use of anti-psychotics

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. 4.4.  Integrated interventions

. 4.4.1.  Basic principle

. 4.4.2.  Evidence base

. 4.5.  Assertive outreach

. 4.5.1.  Basic principle

. 4.5.2.  Evidence base

. 4.6.  Recommendations for practice

5. Service delivery related issues

. 5.1.  Service delivery formats

. 5.2.  Cost effectiveness related issues

. 5.3.  Recommendations for practice

6. Special populations

. 6.1.  Prison population

. 6.2.  Homeless population

. 6.3.  Recommendations for practice

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EXECUTIVE SUMMARY

The term ‘dual diagnosis’ refers to the co-occurrence of at least one psychoactive substance use disorder and at least one non-substance psychiatric disorder. Persons with dual diagnoses, in general, pose certain unique assessment and management challenges. This is also true for persons with dual diagnoses who have psychotic disorder as the psychiatric disorder. With respect to the management of persons with dual diagnosis (having psychotic disorder as the psychiatric disorder) the following recommendations can be made –

lDetailed history and physical examination should be undertaken (S)

lRisk for violence towards self or others need to be evaluated (S)

lRating scales should be applied (B)

lRoutine and special investigations should be performed as appropriate (B)

lMotivational interviewing can be used to improve retention in treatment and outcome (A)

lMotivational interviewing techniques may be modified to suit needs of psychotic dual diagnosis patients (C)

lMost of the medications used for management of substance use disorders remain to be systematically studied in psychotic dual diagnosis patients

lNaltrexone (A), acamprosate (A) and disulfiram (A) are effective in management of alcohol use disorders

lVarenicline (A) and Bupropion (sustained release) (A) are effective in management of tobacco use disorders

lMost of the first generation anti-psychotics and many of the second generation anti- psychotics remain to be systematically studied in psychotic dual diagnosis patients

lAtypical antipsychotics are considered the first line of management in psychotic dual diagnosis patients (D)

lRisperidone (A), olanzapine (A) and flupenthixol (B) are effective in management of psychotic dual diagnosis patients

lHaloperidol (A), risperidone (A), olanzapine (A) and flupenthixol (B) are effective in reducing substance use among psychotic dual diagnosis patients

lLong acting depot preparations may be used in case of compliance issues (D)
lThere is some support for use of electroconvulsive therapy, but there is a need to

further research its role in psychotic dual diagnosis patients (C)

lIntegrated psychosocial management is found to be better than individual stage-wise management (B)

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lAssertive outreach to improve engagement with treatment services has been found to be helpful (B)

lCognitive behavioural interventions, social skills training and group interventions have also shown benefit in dual diagnosis patients with psychotic disorders (B)

lVarious Psychosocial treatments work to similar extent for dual diagnosis patients with psychosis (A)

lContingency management may be useful for homeless dual diagnosis patients (A) lHousing first approach requires further consideration as a harm reduction approach

in homeless population (B)

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1. INTRODUCTION

1.1 CONCEPTOFDUALDIAGNOSIS

The term ‘Dual diagnosis’ has been defined in various ways. It generally refers to the presence of at least one (psychoactive) substance use disorder (SUD) and one psychiatric disorder in the same person.1,2 Previously various terms have been used to represent this co-occurrence of substance use disorders and psychiatric disorders. These include Mentally Ill Chemical Abusers (MICA), Chemical Abusing Mentally Ill (CAMI), Mentally Ill Substance Abusers (MISA), and Substance Abusing Mentally Ill (SAMI). Over the past few years the terms ‘Individuals with Co-occurring Psychiatric and Substance Use disorders (ICPSUD)’ and’Co-occurring disorders’ are beign increasingly used to represent those having both substance use disorders and psychiatric disorders. For the purpsoe of the current guidelines the term ‘dual diagnosis’ shall be used to represent this set of population as it coninues to be one of the most commonly used terms in medical lietrature.

Individuals with a wide range of psychiatric disorders are more likely to have a co- morbid substance use disorders (SUD) compared to the general population. Similarly, those having a substance use disorder have increased chances of having a co-morbid psychiatric disorder. Substance use disorders and psychotic disorders tend to co-occur together3,4,5 and this co-morbidity is the focus of the current chapter.

The co-occurrence rate of SUD and psychotic disorders is greater than what would be expected by chance. There are different possible reasons for this greater by chance association of SUD and psychiatric disorders.6 These are represented by the common factor model, bidirectional model, secondary substance use disorder model and secondary psychiatric disorder models. The general issues and concepts of dual diagnosis are applicable to the co-morbidity of substance use disorders and psychotic disorders. These have been covered in the previous clinical practice guidelines for the assessment and management of substance use disorders published by Indian Psychiatric Society.7

1.2 EPIDEMIOLOGYOFDUALDIAGNOSIS:PSYCHOTICDISORDERS

Studies conducted worldwide have shown high rates of co-occurrence of SUD associated with any psychiatric disorder. This is especially true for the clinical population based studies. The rate of co-occurrence of SUD and psychiatric disorders has varied from 15% in the general population to 80% in clinical samples from both mental health and addiction treatment settings. However, few of these studies have specifically calculated the prevalence of the co-morbidity of SUD with a psychotic disorder. Even the studies that have analyzed the rate of this co-occurrence have been limited by small sample size. Epidemiological studies that have assessed co-morbidity of substance use disorders with psychotic disorders and found that alcohol and drug dependence are twice as common in persons with a psychotic disorder.9

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The Epidemiological Catchment Area (ECA) study revealed that 37% of people with alcohol use disorders and 53% with other drug use disorders had co-morbid psychiatric conditions. Amongstpeoplewiththediagnosisofschizophrenia,47%hadasubstance abuseordependencedisorder. Individualswithadiagnosisofschizophreniawerealso three times more likely to be alcohol abusers and six times more likely to abuse other substances as compared to those without schizophrenia.10 It also estimated that even after adjusting for baseline psychopathology and socio-demographic variables a lifetime diagnosis of alcohol abuse/dependence predicted an eight-fold increased risk of reporting at least one psychotic symptom in the follow-up period. Rates of cigarette smoking among people with schizophrenia were between 70 and 88%.10

The National Co-morbidity Survey (NCS) also reported that alcohol and drug use disorders are quite often co-morbid with other psychiatric disorders. In the revised NCS (NCS-R), the prevalence rate for co-morbid SUD with non-affective psychosis over the lifetime was 26.8% and prevalence in the year prior to the assessment was 15.6%.11

The studies that have focused specifically on psychotic disorders (including schizophrenia) also have found high co-morbidity of psychotic disorders12 and substance use disorders.12 In the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study,12 at least one substance abuse or dependence was reported in 60.3% of the sample.In an epidemiologically representative British sample of patients with first episode psychosis Barnett et al.13 found the prevalence of substance use to be twice as much as in the general population. Cannabis and alcohol were the most frequently abused substances with 38% reporting polysubstance abuse. Kavanaghet al.14 reported on substance use related variables in an Australian sample of patients with both affective and non-affective psychosis. The prevalence of substance use disorders was comparable in both groups with men having greater prevalence than women. Younger age group was associated with use of illicit drugs whereas lower educational attainment was associated with cannabis use. Addington et al.15 studied patients admitted to an early psychosis program in Canada and confirmed earlier reports of greater prevalence in men and younger age groups. The most prevalent substances were alcohol and cannabis, in keeping with several previous observations.

There is a relative paucity of studies from India with regard to epidemiology co- occurring SUD and psychotic disorders. Though characteristics of Hemp Insanity had been described from India more than 80 years ago,16 there have been no epidemiological studies that have systematically assessed the prevalence of co-morbid SUD and psychotic disorders in general population. The prevalence of SUD among persons diagnosed with psychotic disorders has been found to vary across clinical population based studies. In a study conducted in central India, 54.3% of consecutively admitted male schizophrenia patients were found to have an additional substance use

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disorder17. Another study found substance use disorders apart from tobacco to be present in less than 20% of the sample of patients with psychotic disorders.22 A study by Basu et al found that psychotic disorders were present in about 3% of patients treated for substance use disorders in a de-addiction centre. Another study found that psychotic disorders was present in about 2% of patients being treated for alcohol use disorder.19 The course of the psychotic disorder had been reported not to be associated with substance use in a previous study from India.20 The varied findings observed across these studies are, in part, reflection of the different settings across which these studies have been carried. Additionally, the study criteria, diagnostic paradigms used and sample selection were also different across these studies. There is a need for representative community based epidemiological studies to ascertain the rates of co-morbid substance use disorders and psychotic disorders in the country.

1.3 IMPORTANCE OF DUAL DIAGNOSIS: PSYCHOTIC DISORDERS

Substance misuse has been identified as both a risk factor for onset as well as progression of psychiatric disorders.11 On the other hand, impaired psychological status may also contribute to relapse or an increase in substance use. Substance abuse is associated with a wide range of deleterious effects in persons with a psychotic disorder. Co-morbid SUD in persons with psychotic disorders (including schizophrenia) makes them vulnerable even to premature death due to various factors such as vulnerability to medical illnesses, accidental deaths, and suicide.21,22 Thus, appropriate recognition and management of dual diagnosis is of paramount importance.

Additionally, co-morbid SUD and psychotic disorders poses various clinical challenges during management. First, the motivation of patients with substance use disorders and psychotic disorders may be low.23 This has been attributed to the perceived benefits as a consequence of substance use including relaxation, elevation of mood, and countering dysphoria in some of the previous studies.24,25 Second, engagement into the treatment process might be difficult on the account of paranoia towards treatment services, and fear of forced detention and coercive treatment. Also, patients with dual diagnosis that includes psychosis may have poor insight into their illness or may not regard the substance use as a problem. Additionally, stigma associated with both the disorders may deter the patients from utilizing the available services.26 The risk of suicide, violence and the presence of medical co-morbidities may be higher among patients with dual diagnosis as compared to the patients with the either of the two disorders.22,27,28,29 The risk of therapeutic non-adherence is high,30 and so is the chance of occurrence of social problems like homelessness and social isolation.31 The patients with substance use and psychotic disorders have a poorer prognosis as compared to patients with either SUD or psychosis, as they are likely to be hospitalized at an earlier age, have longer durations of illness and hospital stay, and frequent relapses and hospitalizations.,32,33 These factors

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make the treatment of patients with substance use disorders and psychosis more challenging than that of either disorder alone. This justifies the need for separate guidelines for the treatment of co-occurring SUD and psychotic disorders. The dual diagnosis of SUD and psychotic disorders shall be referred to as ‘psychotic dual diagnosis’ or ‘dual diagnosis: psychotic disorders’ in the subsequent sections.

2. SCOPEANDMETHODOLOGYOFTHEGUIDELINE

2.1. OVERVIEW OF THE GUIDELINES

Management of dual diagnoses in general and psychotic dual diagnoses in particular, can be challenging. The current guidelines aim to offer guidance to clinicians who manage patients diagnosed with both substance use disorders (SUD) and psychotic illnesses. This shall include persons who have both SUD and psychotic disorders irrespective of the nature of association between these two disorders.

2.2. SCOPE OF THE GUIDELINES

The current guidelines are aimed primarily at clinicians who deal with patients with co- morbid SUD and psychotic disorders. However, the clinicians should keep in mind the specific characteristics of the patients and the treatment setting before applying these guidelines to individual patient. In other words, some degree of fine tuning or individualization may be needed on a case to case basis. Finally, the treating clinician must take into consideration the more recent evidence that would have accumulated since writing of these guidelines.

These guidelines are meant for application by qualified and trained clinicians in de- addiction centers and general hospital treatment settings, though it may be applicable in other settings as well. The guidelines mainly focus on management, although some relevant discussion on assessment is also included. The guidelines shall address the issues specific to the psychotic dual diagnosis. The issues related to assessment and management of SUD, in general, have been covered in the ‘Clinical Practice Guidelines for the Assessment and Management of Substance Use Disorders Treatment’ published by Indian Psychiatric Society (IPS) and can be accessed from there.34 Also, general issues related to assessment and management for dual diagnosis have also been covered in ‘Clinical Practice Guidelines for the Assessment and Management of Substance Use Disorders Treatment’ published by Indian Psychiatric Society (IPS) and can be accessed from there.7

2.2.1. PSYCHOTIC DUAL DIAGNOSIS

For the purpose of the current guidelines ‘psychotic dual diagnosis’ shall refer to the co- occurrence of one SUD and a psychotic disorder in the same individual. The dual diagnosis of SUD and psychotic disorders shall be referred to as ‘psychotic dual

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diagnosis’ or ‘dual diagnosis: psychotic disorders’ in the subsequent sections. The psychotic disorders shall include different non-affective psychotic disorders including schizophrenia.

2.3. METHODOLOGY OF GUIDELINE DEVELOPMENT

The guideline attempts to collate the findings from studies relating to psychotic dual diagnosis and draw conclusions and recommendations from them. Relevant literature was identified through a search on PubMed, PsycINFO, EMBASE and Google Scholar. The search was carried out in June 2015. Using MeSH terms “Diagnosis, Dual (Psychiatry)” and “Psychotic Disorders”, “Schizophrenia”, “Induced Psychosis”, “Persistent Delusional Disorder”, and Boolean operator AND, 1066 abstracts were identified. Of these, 39 were clinical trials, 11 were randomized trials, and 2 were meta- analysis. Only English language peer-reviewed articles were included for the preparation of the guidelines. Further studies were identified through cross references and searching through other guidelines like that of the National Institute of Clinical Excellence (NICE), Royal Australian and New Zealand College of Psychiatrists (RANZP) guidelines, American Psychiatric Association (APA) guidelines, Queensland Guidelines, publications of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). The Cochrane database was also searched for relevant meta-analyses. The treatment recommendations have been made in accordance with the quality of evidence. To maintain uniformity and quality, the Appraisal of Guidelines for Research & Evaluation II (AGREE II) instrument was used in preparing the guidelines. The strength of recommendation was based on the study design and other merits of the publication (table 1).

Table 1 : Methodology of guideline development – Salient Features

Data base searched

lPubMed lPsycINFO lEMBASE lGoogle Scholar

Search terms used^

lDiagnosis, Dual (Psychiatry)” lPsychotic Disorders” lSchizophrenia”
lBipolar disorder”
lInduced psychosis” lPersistent delusional disorder”

Other sources of information

lNational Institute of Clinical Excellence (NICE) guidelines

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Other sources of information

lRoyal Australian and New Zealand College of Psychiatrists (RANZP) guidelines

lAmerican Psychiatric Association (APA) guidelines

lQueensland Guidelines
lPublications of the National Institute on Alcohol

Abuse and Alcoholism (NIAAA)

lPublications of the National Institute on Drug Abuse (NIDA)

Framework for writing the guidelines

lAppraisal of Guidelines for Research & Evaluation II (AGREE II) Instrument

^MeSH (Medical Subject Headings) search terms

3. ASSESSMENT AND FORMULATION

3.1. GENERAL ISSUES

For a detailed description on clinical assessment of substance use disorders and dual diagnosis one is advised to refer to the ‘Clinical Practice Guidelines for the Assessment and Management of Substance Use Disorders Treatment’ published by Indian Psychiatric Society (IPS).7 The current section presents only the salient aspects relevant to the patient with psychotic dual diagnosis.

The assessment of patients with psychotic dual diagnosis patients encompasses both substance use and psychiatric disorder related issues. Prioritizing treatment strategies based on the relative urgency of various issues and needs has to be carefully undertaken. It is also influenced by the preference and expertise of the treating psychiatrist. The psychotic symptoms may resemble those of an acute psychotic episode to one of a more chronic psychosis with variable affective content. Moreover, the severity and quality of the substance use disorder also varies across patients. Finally, the directionality of ’cause and effect’ of substance use and psychosis in itself adds another dimension to the complexity.21

A simple way of prioritizing the various aspects of patient care in a case of psychotic dual diagnosis is based on Ries typology for dual diagnosis.35 This approach shall entail consideration of all symptoms and clinical needs under two heads – substance use related and psychotic disorder related. Each of these categories is then considered as being high priority and low priority, yielding four possibilities. These shall include- ‘high severity psychotic disorder – high severity substance use disorder’; ‘low severity psychotic disorder – high severity substance use disorder’; ‘high severity psychotic disorder – low severity substance use disorder’; and ‘low severity psychotic disorder –

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low severity substance use disorder’. This approach although simple, provides valuable guidance on prioritizing the various clinical needs of the patient.1

3.2. TREATMENT AIMS / GOALS
The aims of treatment of psychotic dual diagnosis are as follows:36,37,38

lAddress acute and life threatening conditions (substance intoxication and withdrawal, acutepsychiatricsymptomslikesuicidality,co-morbidmedicalillness)

lPromote reduction/abstinence from substance of use lControl the symptoms of psychiatric disorder lAddress the co-morbid medical illnesses, if any lAddress psychosocial issues

lIncrease motivation

lEnhance coping and inculcate relapse prevention skills

lProvide psycho-education regarding illness, ensure compliance, regular follow-ups

lImprove socio-occupational functioning

lPromote maintenance of recovery through continued treatment and/orparticipation in self-help groups

lEnsure community re-integration and social/occupational rehabilitation

The goals of treatment may be divided into short and long term goals for the sake of convenience36. The short term goals include management of acute psychotic phase (with management of associated agitation, aggression and disruptive behaviour) along with management of intoxication, withdrawal and imminent medical issues. A rather unique problem faced in treating psychotic dual diagnosis patients is their lesser engagement in treatment and low motivation to reduce substance use.39 Presence of acute psychotic symptoms and impaired judgment result in lower levels of motivation to reduce substance use which in turn can destabilize the psychotic symptoms. This can initiate a vicious feed-forward cycle were psychotic disorders and accompanying substance use fuel each other and hamper improvement. Motivation enhancement and efforts to retain the patient in the treatment facility thus assume significant importance in this group of patients. However one must chose the appropriate time for such interventions. Long term treatment goals are maintenance of abstinence, relapse prevention, control of features of psychotic disorders and socio-occupational rehabilitation.

3.3. DECIDING TREATMENT SETTING

Outpatient setting, inpatient setting, day care setting amongst others are some of the common settings where patients with psychotic dual diagnosis are likely to be treated. This, in turn, could be located in an exclusive de-addiction facility, a general psychiatric

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care facility or a specialized dual diagnosis treatment setting. The decision about treatment setting needs to take care into account various factors. These include-

lNatureofacutepsychiatricsymptomsi.e. activepsychoticsymptoms lSuicidality and self-harm attempts
lHistory or likelihood of future violence
lSeverity of withdrawal symptoms/ intoxication

lAssociated medical illnesses lSeverity of substance dependence lPrior abstinence attempts lLevel of motivation of the patient lPresence of social supports lPatient and physician preference

In psychotic dual diagnosis patients, presence of active psychotic symptoms, associated aggressionandunmanageabilitycanposeathreattopatientand/orothers. Hencean inpatient treatment setting is often warranted in such situations.

3.4. ASSESSMENT OF DUAL DIAGNOSIS: PSYCHOTIC DISORDERS

3.4.1 GENERAL OVERVIEW

Assessment is a continuous process as new information may emerge at any point in the course of treatment. Initial assessments are carried out with an aim to reach at a working (definitive/ provisional or tentative) diagnosis and formulate a management plan. The subsequent assessments are made to confirm the diagnosis (if not definitive), fill in the gaps in information, carry out specialized assessment (as family dynamics etc.), and observe response to interventions (including effects and side effects).Special attention must be paid in cases of psychotic dual diagnosis patients with regards to the risk of harm to self or others. Assessment typically includes history taking, physical examination, mental status examination, use of scales and instruments, psychological assessment, and relevant investigations. These steps are summarized in Figure 1.

3.4.2. CLINICAL HISTORY

In psychotic dual diagnosis patients, clinical history should be obtained from multiple sources including patient, family members, significant others including friends and medical records). Other sources of information like previous medical records should be carefully reviewed. Efforts should be made to obtain information from co-workers, law- enforcement officials (in case of legal repercussions related to substance use, violent behaviour) to obtain a clear picture of the clinical symptoms and dysfunction.

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History

Sources of information: Patient, Family Members, Significant others including friends, Medical records, etc.

Physical examination

Signs of intoxication, withdrawal; medical complications

Mental status examination

Psychotic disorder; co-morbid psychiatric disorders; risk of violence (towards self and others); level of motivation

 

Investigations (biochemical/neuro imaging, etc)

For detection of substance; for medical complications

Psychological assessment

For additional information on relevant psychological issues

Rating scales

For rates severity; monitor response to therapy

Fig 1 : Assessment of a case of psychotic dual diagnosis

A detailed history regarding substance use should typically include the age of initiation, frequency and amount of use, development of various features of ‘addiction’, last dose, motivation, complications due to substance use in various domains (physical, psychological, financial, social, familial, vocational and legal), abstinence attempts and reasons for relapse. History of psychiatric illness should be ascertained including onset, progression, course, severity and dysfunction.

Short lasting psychotic symptoms can be seen in the context of intoxication and must be carefully delineated from a psychiatric disorder. Additionally, efforts should be made to ascertain the possibility of any causal association (and directionality of causation) between the SUD and psychotic disorder. Efforts should be made to delineate the presence of an independent psychotic disorder from a substance induced psychotic disorder. Temporal sequence of development of symptoms, and the course of psychiatric symptoms in a controlled setting ensuring abstinence provide valuable clues in establishing this distinction. This can have relevant treatment implications as substance induced psychotic disorders tend to be self remitting once the offending substance use stops. Relevant history to negate the possibility of delirium or organic diseases presenting with psychiatric manifestations must also be clearly obtained.

Other aspects of the history like treatment history, medical history, family history, early

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To be repeated as needed and indicated

developmental history, educational, occupational history, marital history and personality profile can help gain valuable insights into the patient’s background. The social supports and key figures in patient’s life can also be assessed. The family dynamics, family members’ understanding of the patient’s psychotic disorder and the presence of expressed emotions, interpersonal conflicts and familial dysfunction consequent to patient’s illness need to be assessed. The chief care giver(s) of the patient must be identified in order to ensure their participation in the treatment process, ensure compliance to medications and regular follow up and to psycho-educate them regarding the expected course and prognosis of the patient.

Though the first contact may yield a considerable part of the history, crucial elements may also emergence later with improved therapeutic alliance with the patients and information from other sources.

3.4.3. PHYSICAL EXAMINATION

Detailed physical examination forms an important part of evaluation of the patient with psychotic dual diagnosis. Signs of intoxication and withdrawal are to be carefully looked into. Findings would depend upon the nature of substance used. Thus typical findings may include injection marks in case of an injecting drug user, tremors in alcohol withdrawal, and discoloured teeth in case on nicotine use. Neurological examination must also be carried out to rule out presence of focal deficits and other neuropsychiatric manifestations.

3.4.4. ASSESSING RISK

In psychotic dual diagnosis patients assessing risk of violence and suicide forms an important part of assessment (table 2).

Table 2 :
Risk factors for violence and suicidality among psychotic dual disorder patients

Newer and Emerging Addictions in India

Risk factors for violence

Risk factors for suicidality

lCo-morbid substance use and psychotic disorder

lMale gender lPersonality disorder lPast history of violence lPresence of stressors lPresence of delusions and

hallucinations with threatening and

persecutory content lCommand hallucinations

lCo-morbid substance use and psychotic disorder

lPresence of intoxication or severe withdrawal lMale gender
lExtremes of age
lPresence of chronic co-morbid medical

conditions, particularly painful lPresence of depressive symptoms, lHopelessness
lPersonality disorder and impulsivity lPrevious history of suicidal attempts lPresence of clear suicidal plans

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3.4.4.1 VIOLENCE: Presence of co-morbid substance use29 along with a psychotic disorder has been identified as a risk factor for violent behaviour.41 Some of the other risk factors for violence include male gender, presence of personality disorder, past history of violence, presence of stressors, presence of delusions and hallucinations with threatening and persecutory content and command hallucinations.41

3.4.4.2 SUICIDALITY: A number of risk factors for suicide have been identified in patient with dual diagnosis. As stated above for risk of violence, the presence of co- morbid substance use disorder along with a psychotic disorder in itself is known risk factor for suicide. Presence of intoxication or severe withdrawal, male gender, extremes of age, presence of chronic co-morbid medical conditions, particularly painful, presence of depressive symptoms, hopelessness, personality disorder and impulsivity, previous history of suicidal attempts and presence of clear suicidal plans are some of the other risk factors.22

3.4.5 RATING SCALES

Rating scales are useful for assessing the severity of problems and monitoring treatment response over time. Some of these scales have been valid ated in a population of patients with dual diagnoses as well. The Dartmouth Assessment of Lifestyle Instrument (DALI) is an 18-item interviewer administered tool42 that can be used as a screening instrument for substance use disorder in the psychiatric population. It takes about 6 minutes to complete and was formed from the most validated questions of 10 robust screening questionnaires for substance use disorders. It primarily screens for alcohol, cannabis and cocaine use disorders. Thought disorder subscale of Brief Psychiatric Rating Scale (BPRS) and Beck’s Depression Inventory (BDI) can be used validly in dual diagnosis populations.43

The Chemical Use, Abuse and Dependence (CUAD) scale is a brief, reliable and validated tool for the identification of substance use disorders in severely mentally ill in- patients and takes about 20 minutes to administer.44

Diagnostic instruments such as the Psychiatric Research Interview for Substance and Mental Disorders (PRISM) may also be used. PRISM also attempts to differentiate between substance induced and independent psychiatric disorder and has been validated in large epidemiological studies.45 Other specific scales and interview schedules46 used for either psychotic disorders or substance use disorders may obviously be used in combination. Some of the commonly used scales are listed in box 1. However, there is limited information on use of these instruments in Indian settings.

3.4.6 INVESTIGATIONS

Investigations of various kinds may be indicated among patients with psychotic dual diagnosis.27 While these investigations play little role in establishing in refuting the

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diagnosis for with SUD or psychotic disorders these are important to identify presence of co-morbid medical disorders (as a complication of SUD or otherwise); confirming(or refuting) presence of substance in body fluids, monitoring treatment adherence, monitoring side effects of treatment among others.

The investigations for SUD are guided mainly by the nature and route of substance being used. Complete hemogram, renal function tests, liver function tests, blood sugar and electrolytes are some of the commonly requested investigations. In patients with alcohol use disorders, liver function tests may need to be supplanted by additional investigations such as ultrasound abdomen, serum ammonia, upper GI endoscopy. In case of injecting drug users, tests for hepatitis B and C, HIV may be indicated. A urine screen for various substances in case of an unclear history or to additionally buttress historical findings may also need to be performed. Those prescribed anti-psychotic medications need to be monitored for blood glucose, lipid profile and liver function.

3.5 RECOMMENDATIONSFORPRACTICE

Newer and Emerging Addictions in India

Box 1. Commonly used rating scales/ diagnostic instruments for the assessment of dual diagnosis patients

lDartmouth Assessment of Lifestyle Instrument (DALI)
lBrief Psychiatric Rating Scale (BPRS)
lBeck’s Depression Inventory (BDI)
lChemical Use, Abuse and Dependence (CUAD) scale
lPsychiatric Research Interview for Substance and Mental Disorders (PRISM)

Box 2. Recommendations for practice with regards to assessment for psychotic dual diagnosis

lDetailed history and physical examination. (S)
lRisk for violence towards self or others need to be evaluated. (S) lApplication of rating scales. (B)
lPerforming routine and special Investigations as appropriate. (B)

The alphabet in parenthesis represents strength of evidence (for details refer to the introductory chapter)

4. INTERVENTIONSINPSYCHOTICDUALDIAGNOSIS

The current section deals with salient aspects of management of psychotic dual disorders. This includes management of SUD and management of psychotic disorder.

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Only the issues specific to the psychotic dual diagnosis shall be discussed in this section. Management of various SUD and dual diagnosis have been addressed in the ‘Clinical Practice Guidelines for the Assessment and Management of Substance Use Disorders Treatment’ published by Indian Psychiatric Society (IPS) and can be accessed from there.7

4.1 MOTIVATION ENHANCEMENT INTERVENTIONS

A common factor contributing to the refusal or avoidance of treatment by psychotic dual diagnosis patients is their low motivation to reduce substance use. Lack of insight consequent to presence of psychotic illness, strong emotions, and the continuing resort to alcohol and other readily available substances as self-medication are some of the reason why these patients exhibit resistance to quitting substance use. Motivational Interviewing (MI) has been recommended as an essential intervention in the early stages of working with the patients with dualdiagnosis. Such an approach acknowledges that individuals may not be aware that their substance use is causing problems for themselves and others. They may not consider that they have a problem; even if they do, decreasing or stopping use may not be on their agenda.44 Accessing treatment is not considered equivalent to being motivated and activated to manage their own problems with living. Hence, people living with SUD and psychotic disorders may require assistance to move from the stage of pre-contemplation to that of contemplating of change49,50,51,52,53 Motivational Interviewing (MI) emphasizes personal choice, responsibility, and awareness of the risks and benefits of continued substance use and helps the individual move towards the action stage and consequently bring about changes with regards to their substance use behaviour.

4.2. PHARMACOLOGICALMEASURES 4.2.1 FORSUBSTANCEUSEDISORDER 4.2.1.1 SHORTTERMMANAGEMENT

The short term management goals include treatment strategies to deal with intoxication and withdrawal states and detoxification. Treatment of withdrawals should be initiated along with the treatment of psychotic disorder.54

There are no empirical studies for withdrawal management for patients with psychotic dual diagnosis. Use of typical withdrawal management regimens has been mentioned forpsychoticdualdiagnosispatients. Alsoinpatientdetoxificationisrecommendedfor patients who are unable to stop/ reduce their substance use from out-patient.55 The clinicians are advised to refer to the previous clinical practice guidelines for the assessment and management of substance use disorders published by Indian Psychiatric Society for detailed information on short term management of SUD.7

Cocaine and stimulant intoxication may present with symptoms of psychosis (e.g.

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persecutory delusions). There are no approved pharmacological agents with clear benefit in this condition. Acutely agitated patients are generally managed with decreased exposure to external stimuli, reassurance, reorientation, and short term use of benzodiazepines, if necessary.

4.2.1.1.1. INTERACTION OF ANTI-PSYCHOTIC MEDICATIONS WITH SUBSTANCE OF ABUSE AND MEDICINES USED FOR ITS SHORT TERM MANAGEMENT (MANAGEMENT OF WITHDRAWALS)

One must take in to consideration the possible interactions (pharmacokinetic and pharmacodynamic) between the medications used for management of withdrawals and the anti-psychotic medications. Some of these interaction have been summarized in table 5. 56,57

4.2.1.2 LONGTERMMANAGEMENT

The general principles and outline of management of SUD can be accessed from the previous clinical practice guidelines for the assessment and management of substance use disorders published by Indian Psychiatric Society (IPS).7

4.2.2.1.1 FOR ALCOHOL USE DISORDERS

Acamprosate, naltrexone and disulfiram (more recently baclofen as well)are commonly used medicines for long term management of alcohol use disorders. Selective Serotonin Reuptake Inhibitors (SSRIs) and anticonvulsants such as topiramate have little evidence to support their use as anti-craving agents. However, there is limited literature on effectiveness of these medicines among patients with co-morbid alcohol use disorders and psychotic disorders.

Naltrexone has been studied in patients with alcohol use disorders and schizophrenia.58,59,60 In a retrospective study on 72 psychiatric patients treated with naltrexone for alcohol use disorders, 82% significantly reduced their drinking.61 Open label trial62 as well as randomized placebo-controlled double-blind trial have also suggested that naltrexone maybe helpful in decreasing alcohol use in patients with psychotic disorders and alcohol dependence.58,60

Clinical reports have suggested that disulfiram can precipitate a number of psychiatric symptoms, including delirium, depression, anxiety, mania, and psychosis.62 Caution has been expressed about the use of disulfiram in patients with psychosis due to risk of psychosis and is a risk-benefit analysis must be conducted before taking the final decision. Notably, a retrospective study with psychosis and alcohol use disorder suggested beneficial effects of disulfiram in most patients with no suggestion of increased psychosis.64 Disulfiram was found to be comparable to naltrexone (and better than placebo) in a randomized controlled trial among patients with co-morbid

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psychotic spectrum disorders and alcohol abuse.65 However, one must ensure that the patient is capable of providing written informed consent before disulfiram therapy is instituted.66

Acamprosate was found to be safe in a randomized trial among patients with co-morbid schizophrenia spectrum disorders and comorbid alcohol dependence. However, the trial failed to establish superiority of acamprosate over placebo in this trial.67

Limited evidence suggests utility of baclofen in the treatment of dual diagnosis patients.64,68,69,70

In spite of limited published literature on effectiveness of medications used in long-term management of alcohol in patients with co-morbid psychotic dual diagnosis, these medications are commonly used in this population.71

4.2.2.1.2 FOR OPIOID USE DISORDERS

Buprenorphine and methadone72 are the primary agents used for opioid substitution whereas naltrexone,62,73 is the main antagonist agent used in long term management of opioid use disorders.

Opioid substitution therapy with methadone and buprenorphine remains to be systematically studied among psychotic dual diagnosis patients. In a small study of methadone maintenance therapy among people with opiate dependence and schizophrenia, the best improvement was observed among those who were prescribed a combination of methadone and clozapine.74 In a retrospective study on buprenorphine treatment outcome in dually diagnosed heroin dependent patients with psychotic dual disorders were found to have comparatively lower retention rates.75 Consensus recommendations from west have supported both methadone and buprenorphine as safe treatment options.66

4.2.2.1.3 FOR TOBACCO USE DISORDERS

Bupropion, varenicline and nicotine replacement therapy (NRT) have all been studied for the management of tobacco dependence in patients with psychotic dual diagnosis.76,77,78 Bupropion (sustained release) has been found to increase smoking abstinence rates in smokers with schizophrenia.79,80 Also, it does not increase the risk of seizures in this population group.78 However, there is limited evidence to support use of NRT in this population with lower than expected benefits, although it has been found to be safe and well tolerated.66 There are randomized controlled trials and observational studies that have established efficacy of varenicline in smoking cessation among patients with psychotic dual disorders.81,82 However, one needs to be cautious with regards to psychiatric adverse effects reported with use of varenicline.78 There are reports of emergence and worsening of psychosis associated with use of veranicline.83

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4.2.2.1.4. FOR COCAINE AND OTHER STIMULANT USE DISORDERS

There are no approved medications for use for long term management of cocaine and other stimulant use disorders.

4.2.2.1.5. FOR CANNABIS USE DISORDERS

There are no approved medications for use for long term management of cannabis use disorders.

Box 3 summarizes the various pharmacological options along with the strength of evidence in management of SUD among patients with psychotic dual disorders.

Newer and Emerging Addictions in India

Box 3. Recommended pharmacological agents for management of SUD among patients with psychotic dual diagnosis
lBuprenorphine (D)
lMethadone (C)

lNaltrexone (For opioid dependence) (D) lNaltrexone (For alcohol dependence) (A) lAcamprosate (D)
lDisulfiram (A)

lVarenicline (A)
lBupropion(sustained release) (A) lNicotine Replacement Therapy (NRT) (D)

The alphabet in parenthesis represents strength of evidence (for details refer to the introductory chapter)

4.2.2 FOR PSYCHOTIC DISORDER

The general principles and outline of management of dual diagnosis can be accessed from the previous clinical practice guidelines for the assessment and management of substance use disorders published by Indian Psychiatric Society (IPS).7

As has already been suggested, there are a number of limitations to the available literature. Most of the studies assessing effectiveness of antipsychotic medicines tend to exclude patients with co-morbid SUD and psychotic disorders.84 At present, large scale randomized controlled trials comparing efficacy and acceptability of different antipsychotics for management of co-occurring psychosis and substance use disorder are lacking. Studies vary in their sample size, choice of substance use and psychotic disorder and methodology limiting comparability. Moreover, schizophrenia remains the commonly studied psychotic disorders in these studies and information is lacking on

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other psychotic disorders. The clinicians are advised to read these guidelines in conjunction with guidelines on management of psychotic disorders.

The management of psychotic disorder includes starting an antipsychotic agent85,86,87,88,89,90,91 and optimal titration of dose based on the improvement of baseline target symptoms.

4.2.2.1. FIRST GENERATION ANTI-PSYCHOTICS

There is limited literature that has explored effectiveness of first generation anti- psychotics among patients with psychotic dual disorders. However, in spite of concerns with regards to propensity of first generation antipsychotics to exacerbate substance use consequent to extrapyramidal side effects and worsening of negative symptoms and dysphoria, small open label trials have suggested favorable outcomes with regards to co-morbid SUD among patients with psychotic dual diagnosis who were treated with flupenthixol.92,93 Improvement in SUD was reported in spite of limited improvement in psychotic features in one of these studies.93 However, long-acting injectable depot risperidone was found to be associated with better substance use and psychosis outcomes over six months in an open label randomized trial among patients with co- morbid SUD and schizophrenia.94 Another randomized trial reported a significantly higher reduction in craving for cocaine patients treated with haloperidol compared with patients treated with olanzapine. However, there were no differences in SUD and psychosis outcomes in this study.89 On the other hand, another study found olanzapine to be associated with significant reductions in craving and SUD as compared to haloperidol in a randomized trial among individuals with co-morbid cocaine use disorder and psychotic disorder.86

4.2.2.2. SECOND GENERATION ANTI-PSYCHOTICS

Second generation antipsychotics have been considered as first line agents in primary psychotic disorders because of the decreased risk for extrapyramidal side effects and tardive dyskinesia. Some evidence suggests additional utility of these agents in treating substance use disorders.87,90,91 Only clozapine,90,91 has been shown to be clearly more effective than other agents, that too in those who have failed previous trials of other medications. Some evidence, mainly from case reports and series, suggest clozapine’s beneficial role in psychotic dual diagnosis as it has additional beneficial effects on substance use as well.95,96 However, there are no prospective, randomized controlled trials that have established superiority of clozapine in such population.55

Risperidone was found to be associated with significantly less cue-elicited craving and substance related relapses in a six week open label study among patients with co- morbid cocaine use disorder and schizophrenia.97 However, there was no significant improvement in psychotic features.A double-blind, randomized controlled trial over 14

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weeks comparing the efficacy of olanzapine with risperidone in patients with co-morbid cocaine/cannabis use disorder and schizophrenia found comparable treatment adherence rates in the two groups. Risperidone was associated with a significantly greater reduction in cannabis craving.98 Olanzapine has also shown to improve retention in treatment and SUD during opioid agonist maintenance treatment in the patients with co-morbid opioid use disorders and psychotic disorders.99 However, long- acting injectable depot risperidone was found to be associated with better substance use and psychosis outcomes over six months in an open label randomized trial among patients with co-morbid SUD and schizophrenia.94 Another study found olanzapine to be associated with significant reductions in craving and SUD as compared to haloperidol in a randomized trial among individuals with co-morbid cocaine use disorder and psychotic disorder.86

Similarly, there is some evidence that second generation anti-psychotics can have some beneficial effect among those with psychotic disorder when used in conjunction with nicotine replacement therapy.100

Other antipsychotics like aripiprazole and quetiapine have also been found to control substance use and psychosis although the evidence is limited by its quantity as well as quality.87,88

Second generation anti-psychotics have been recommended as a first line agents in management of psychotic dual disorders.55 While there is some evidence to suggest benefit of second generation antipsychotic over first generation antipsychotics, comparison of various atypical antipsychotics has not established or refuted superiority of one medicine over another equivocally. In view of the potentially life threatening adverse effects associated with use of clozapine, other second generation anti- psychotics such as olanzapine and risperidone have been recommended as preferred medications for this population.55 Among these agents, choice of a particular agent may depend upon the desired side-effect profile, availability and cost of the medications. Long-acting injectable antipsychotic medication may be considered for patients with recurrent relapses related to therapeutic non-adherence.93,94

The recommendations with regards to use of anti-psychotics in management of psychotic dual diagnosis have been presented in Table 3. These recommendations need to be seen in light of limitations of the existing evidence (including limited research on anti-psychotics in this population) as highlighted earlier.

4.2.2.3 ELECTROCONVULSIVE THERAPY (ECT)

The efficacy of ECT has been well established in patients with psychotic disorders.101,102 ECT is often reserved for patients who do not respond to less invasive methods of treatment. It is also considered as a viable treatment option for patients who present with catatonia or have high risk of suicide or violence. The literature on dual diagnosis

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psychotic patients has also supported the use of ECT as an effective treatment modality, but has been restricted to case reports and case series.103,104

Table 3 :
Recommended anti-psychotic medications and Electroconvulsive Therapy (ECT) for management of SUD among patients with psychotic dual diagnosis

A. Effectiveness with regards to psychotic features

lFlupenthixol (B)
lOther First generation anti-psychotics (D) lClozapine (C)
lOlanzapine (A)
lRisperidone (A)
lAripiprazole (C)
lQuetiapine (C)
lOther second generation anti-psychotics (D) lDepot anti-psychotics (A) lElectroconvulsive Therapy (ECT) (C)

B. Effectiveness with regards to SUD

lFlupenthixol (B) lHaloperidol (A) lClozapine (C) lOlanzapine (A) lRisperidone (A)

SUD- Substance Use Disorder
The alphabet in parenthesis represents strength of evidence (for details refer to the introductory chapter)

4.2.2.4. INTERACTION OF ANTI-PSYCHOTIC MEDICATIONS WITH SUBSTANCE OF ABUSE AND MEDICINES USED FOR ITS MANAGEMENT

Anti-psychotic medicines used for management of psychosis can have potential interactions with substance of abuse as well as medicines used for its management.66

Opioid agonists and partial agonists can contribute to the sedation and constipation with anti-psychotic medications. Naltrexone has not been found to have any significant interaction with anti-psychotic medications.66 Medications such as ziprasidone (that prolong the QT interval) should better be avoided in patients with prolonged baseline QTc intervals and co-occurring alcohol and cocaine use. Tobacco smoking increases the rate of metabolism of the antipsychotic medications (such as clozapine, olanzapine,

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haloperidol, fluphenazine, chlorpromazine, thioridazine) metabolized through the P450 1A2 isoenzyme by about 50%. Anti-psychotic medicines that are likely to lead on to liver disease, cardiac disease or lowering of seizure threshold should be used cautiously among those patients with SUD whose substance of abuse has lead to impaired functioning of these bodily systems and organs. While presence of these medical conditions is not an absolute contraindication to use of anti-psychotics one must make a risk-benefit- analysis prior to instituting treatment with these medications. In case use of such anti-psychotics is warranted in such patients, it should be initiated under close medical supervision with regular monitoring of the functioning of such bodily systems and organs. Interactions of anti-psychotic medications with substance of abuse and medicines used for its management have been summarized in tables 4&5.

Table 4 : Interaction between psychoactive substances and anti-psychotics

Newer and Emerging Addictions in India

Psychoactive substance

Anti-psychotic

Interaction

Alcohol and cocaine

Ziprasidone

Prolonged baseline QTc intervals specially among those with prolonged baseline QTc intervals

Tobacco smoking

Clozapine, olanzapine, haloperidol, fluphenazine,

chlorpromazine, thioridazine

Increased metabolism

Various psychoactive substance impacting bodily systems and organs

Various anti-psychotics impacting bodily systems and organs

Aggravated insult to bodily systems and organs

Table 5 :
Interaction between medications used for management of withdrawal from substances and anti-psychotics

Medication used for management of withdrawal

Anti-psychotic

Interaction

Benzodiazepines

Antipsychotics with sedating effect

Increased sedation cognitive dysfunction

Methadone

Quetiapine

Increased plasma methadone concentrations^

Methadone

Antipsychotics with sedating effect

Increased sedation cognitive dysfunction

Buprenorphine

Antipsychotics with sedating effect

Increased sedation cognitive dysfunction

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Medication used for management of withdrawal

Anti-psychotic

Interaction

Methadone

Risperidone, other phenothiazines

Possibly increased plasma concentrations^

Baclofen

Antipsychotics with sedating effect Clozapine#

Increased sedation cognitive dysfunction

Nicotine/ tobacco smoking*

Clozapine, haloperidol

Decreased concentration of\ antipsychotics

^ pharmacokinetic interaction
*Polycyclic aromatic hydrocarbons in tobacco smoke primarily implicated; nicotine alone has

some evidence from animal studies as enzyme inducer.

#Clozapine and baclofen additionally interact at the GABA B receptor, exact clinical implications not known.

4.2.2.5 DURATION OF USE OF ANTI-PSYCHOTICS
Following the first psychotic episode, antipsychotic medication is usually continued for a period of around 1-2 years, although long-term therapy is commonly recommended for patients with recurrent illness.105,106,107 Antipsychotics prevent relapse in patients with remitted positive and mood symptoms, and maintenance treatment helps to reduce symptoms in patients with chronic illness. These drugs enable many patients who previously would have been institutionalized to live in the community. Regular physical examination and relevant investigations must be carried out to monitor the side-eff\ects.108,109,110

4.3 PSYCHOSOCIAL MEASURES
In comparison to those with substance abuse alone, patients with co-morbid SUD and psychotic disorders have relatively less motivation to change, are harder to engage, drop out of long-term programs more easily, and make slow progress. In addition to pharmacotherapy, psychosocial interventions are considered important to improve motivation, treatment adherence and prevent relapse.48,51,52,53 The details on psychosocial measures in management of SUD can be accessed from the previous clinical practice guidelines for the assessment and management of substance use disorders published by Indian Psychiatric Society (IPS).7

In context of psychotic dual disorders (among those diagnosed with schizophrenia) Combined Motivational Interviewing and Cognitive Behavioural Interventions, Modified Cognitive-Behavioural Therapy (CBT), Dual Recovery Therapy (DRT), Modified Motivational Enhancement Therapy, The Substance Abuse Management Module (SAMM), self help groups, social support interventions have been studied/ recommended.

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4.3.1 COMBINED MOTIVATIONAL INTERVIEWING AND COGNITIVE BEHAVIOURAL INTERVENTIONS

4.3.1.1 Basic principle

Motivational Interviewing is an empathic, nonjudgmental, and supportive approach to examine the patient’s ambivalence about changing substance use behaviours and help achieve behaviour change. Cognitive Behavioural Interventions are based on the cognitive and behavioural theories with an aim to improve self-control and social skills.

4.3.1.2 Evidence base

In the UK, Barrowclough et al.[86] conducted a randomized controlled trial of family intervention in psychosis with substance misuse. The intervention, which comprised five weekly sessions of motivation interviewing, six sessions of cognitive therapy held every 2 weeks, and 10–16 sessions of family intervention was more effective than routine care in improving general functioning, symptoms and days of abstinence from substance misuse over 12 months. Another trial that involved 29 sessions of Cognitive Behavioural Interventions and Motivational Interviewing over 9 months, with subsequent follow-up assessments at intervention completion (9 months), one year later, and again at 18 months post-intervention in 18 schizophrenia patients, found significant improvements in psychiatric well-being on the DSM-IV Global Assessment Functioning scale and fewer negative symptoms in comparison to routine care.[87]

4.3.2 ModifiedCognitive-BehaviouralTherapy(CBT)

4.3.2.1 Basicprinciple

Modified Cognitive-Behavioural Therapy (CBT) includes information about cravings and triggers of drug use, and the unique difficulties associated with substance abuse for people with schizophrenia; includes relapse prevention; motivational interviewing strategies; social skills improvement; problem-solving strategies.111

4.3.2.2 Evidencebase

It has been recommended by expert group on improving the care of individuals with schizophrenia and substance use disorders.66

4.3.3 DualRecoveryTherapy(DRT)

4.3.3.1 Basic principle

Dual Recovery Therapy (DRT)integrates substance abuse relapse prevention, psychiatric social skills training, Motivational Enhancement Therapy and the principles of 12-step programs in linked group and individual treatment sessions.112

4.3.3.2 Evidencebase
It has been recommended by expert group on improving the care of individuals with

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schizophrenia and substance use disorders.66
4.3.4 ModifiedMotivationalEnhancementTherapy 4.3.4.1 Basicprinciple

In Modified Motivational Enhancement Therapy, traditional Motivational Enhancement Therapy is modified for the patient with schizophrenia as specific strategies are matched to different motivational levels.113

4.3.4.2 Evidencebase

It has been recommended by expert group on improving the care of individuals with schizophrenia and substance use disorders.66

4.3.5 TheSubstanceAbuseManagementModule(SAMM)

4.3.5.1 Basicprinciple

The Substance Abuse Management Module (SAMM) is based on relapse prevention, harm reduction, and social skills training.114

4.3.5.2 Evidencebase

It has been recommended by expert group on improving the care of individuals with schizophrenia and substance use disorders.66

4.3.6 Self-helpgroups

4.3.6.1 Basicprinciple

Self-help groups for dual diagnosis provide support and education about addiction recovery concepts. The members learn to see recovery as a way of living a meaningful life within the limitations of their dual diagnoses. Specifically targeted self-help groups, such as Dual Recovery Anonymous or Double Trouble in Recovery have been reported to play an important and meaningful role in the lives of people with dual diagnoses.115 These groups offer essential social support that comes from others who fully understand the difficulties of remaining sober, and they provide a structure for daily living, along with a commitment to stopping substance use.

4.3.6.2 Evidencebase

Research reveals that clients who consistently attend these self-help groups for a year or more achieve reduced substance use outcomes. The traditional 12-step programs on which these programs are based may need modification for the people with dual diagnoses; the limitations of social and emotional expression among many people with schizophrenia do not fit with the Alcoholics Anonymous custom of talking about intimate aspects of oneself in a group.116

A Cochrane review of 32 RCTs failed to find compelling evidence to support any of the

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psychosocial interventions over another to remain in treatment or to reduce substance use or improve mental state in people with serious mental illness.117 Also, none of the aforementioned psychosocial interventions for psychotic dual disorders (among those diagnosed with schizophrenia) have been studied in Indian setting.

4.4 INTEGRATEDINTERVENTIONS

4.4.1 Basicprinciple

The integrated approach involves individually tailored treatments. It is focused on

preventing anxiety, emphasizes trust, understanding and learning. It is aimed at

reducing harm from substance use rather than achieving abstinence. Case management,

close monitoring, substance misuse treatment, rehabilitation, housing and

pharmacotherapy have been identified as components of integrated approach.118,119,120,121,122

4.4.2 Evidencebase

Integrated out-patient treatment has been found to be effective in engaging patients in services, reducing substance use and sustaining remission among dual diagnosis patients.118

4.5. ASSERTIVEOUTREACH

4.5.1. Basic principle

Assertive community treatment (ACT) is described as a structured health care service approach to working with dual-diagnosis clients.123 The case managers are central to client engagement, treatment, and retention. The usual case-manager responsibilities include development of a working alliance with patients, link them into relevant other services, and function as their advocate vis-a-vis these services and other health professionals.

4.5.2. Evidencebase

Assertive community treatment (ACT) has been found to be associated with better outcomes with regard to substance use, quality of life, reduced hospitalization (when baseratewashigh) ascomparedtothestandardout-patientmanagementoverathree year period.123,124

4.6. RECOMMENDATIONS FOR PRACTICE

Newer and Emerging Addictions in India

lMotivational interviewing to improve retention and outcome. (A)
lFamily motivational intervention in case of adolescents with psychotic dual

diagnosis. (A)
lModification of motivational interviewing techniques to suit needs of dual

diagnosis patients. (C)

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lAtypical antipsychotics are considered the first line of management in dual diagnosis patients with psychotic disorders (A)

lClozapine is the only antipsychotic shown to have superior efficacy compared to other atypical and typical agents (A)

lLong acting depot preparations may be used in case of compliance issues (B)
lRole of ECT needs to be further researched in dual diagnosis patients with

psychotic disorders (C)
lLithium and valproate may have some efficacy in reducing substance use and

controlling psychiatric symptoms in patients with substance use disorder and

bipolar disorder (B)
lAcamprosate and naltrexone may be of benefit in alcohol use disorder among dual

diagnosis patients by reducing alcohol use (A)
lIntegrated psychosocial management is found to be better than individual stage-

wise management (B)
lAssertive outreach to improve engagement with treatment services has been found

to be helpful for patients with dual diagnosis (B)
lCognitive behavioural interventions, social skills training and group interventions

have also shown some benefit in dual diagnosis patients with psychotic disorders(B) lThere is no compelling evidence to support any one psychosocial treatment over another to remain in treatment or to reduce substance use or improve mental state

in people with serious mental illness (A)

5 SERVICEDELIVERYRELATEDISSUES

5.1. SERVICE DELIVERY FORMATS

Sequential, parallel and integrated formats are the three main types of service delivery for patients with psychotic dual diagnosis. Sequential format refers to treatment of either substance use or psychotic disorder first followed by the other. The parallel format means simultaneous treatment for SUD and psychotic disorder but by different teams. Integrated format means that the same team with full coordination and integration treats both disorders simultaneously (table 6).

Of the three formats, integrates format is regarded as the best.125 It is reported to be more efficient and involves a flexible combination of treatment for SUD and psychiatric disorder.

Matrix Model has been developed with an aim to manage dual diagnosis comprehensively across a range of service delivery agencies. Psychiatric and SUD professionals work in partnership across services and commissioning structures and create ‘nodes of integration’. These nodes of integration create a matrix by linking through parallel-working. Although promising in its approach, further research is required to test the effectiveness of this service-delivery model.

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Table 6 : Components of integrated care for patients with dual diagnosis

Newer and Emerging Addictions in India

Component

Description

Case management

lMultidisciplinary case management lAssertive outreach

Close monitoring

lMedication supervision lUrine drug screening lCoercive approaches

Substance misuse treatment

lMotivational approaches lHarm reduction
lCognitive behavioural therapy in

individual, group and family settings lSelf-help groups
lSocial skills training

Rehabilitation

lProvision of long-term support in the community

Housing

lSupported and independent

Pharmacotherapy

lProvision of antipsychotic medication,

lImprovement of compliance by providing education and medication supervision

5.2. COST EFFECTIVENESS RELATED ISSUES

Compared with either SUD or psychiatric patients, patients with dual diagnosis tend to utilize more services.126 However, interventions developed for dual diagnosis patients (Assertive Community Treatment) have been found to be comparable to standard management in terms of cost-effectiveness.126 The benefits in terms of cost-effectives are even more marked for those with high severity of disorder.127 However, more research is needed to ascertain whether the added benefits of high-intensity acute care justify the extra costs. Psychotic dual diagnosis patients are more likely to be towards the high severity of the spectrum and are expected to benefit from such interventions for dual diagnosis.

5.3 RECOMMENDATIONSFORPRACTICE

lIntegrated treatment of dual diagnosis clearly leads to better outcomes than other formats of service delivery (A)

lHigh-intensity service delivery improves outcomes in more severe cases (C)

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6. SPECIAL POPULATIONS

6.1. PRISON POPULATION

Studies have reported that more than 90% of prison inmates reported drug or alcohol use. In spite of this, only limited research on dual diagnosis has been carried out in the prison setting. A recent review of mental health care in prisons from the Sainsbury Centre for Mental Health (SCMH) found a ‘big gap’ in dual diagnosis services in prison and a ‘lack of co-ordinated care’ in prison and on release for those with a dual diagnosis.

It has been found feasible to use instruments such Addiction Severity Index and Mini International Neuropsychiatric Interview (MINI) to assess patients with dual diagnosis in prisonsetting. Areviewofexistingprisonbasedtreatmentsofdualdiagnosisreported that well-run treatment programs often ease the burden of correctional administration.128,129,130 However, it has been recommended that dual diagnosis patients should be treated in specialized facilities rather than in the jails itself.

However, management of dual diagnosis in this population group remains unexplored in Indian setting.

6.2. HOMELESS POPULATION

Patients with a dual diagnosis are more likely to have had difficulties with education, employment, accommodation, and hence more liable to social exclusion and homelessness as compared to those with either a SUD or a psychiatric disorder.131 Co- morbid substance disorder and schizophrenia has been shown to be associated with a variety of poorer outcomes, including housing instability and homelessness. Integrated care involving mental health, substance abuse, and housing interventions has been reported to be beneficial among this population group.118 In fact, housing first programs favoring immediate housing and consumer choice have been recommended as viable alternative to standard care in this population group.131,132

However, management of dual diagnosis in this population group remains unexplored in Indian setting.

6.3. RECOMMENDATIONS FOR PRACTICE

lJail diversion services may reduce time spent in jail without increasing risk to the public (B)

lService utilization of jail diversion services is required to be improved (B)

lContingency management may be useful for homeless dual diagnosis patients (A)

lHousing first approach requires further consideration as a harm reduction approach in homeless population (B)

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DUAL DIAGNOSIS : NON-PSYCHOTIC DISORDERS

SK Mattoo Shubh Mohan Singh

On behalf of
Indian Psychiatric Society
Specialty Section on Substance Use Disorders

2016

Dual Diagnosis : Non-Psychotic Disorders

CONTENTS

Executive Summary
1. Introduction
2. Scope and introduction of guideline 3. Results

. 3.1  General considerations and treatment setting

. 3.2  Screening, assessment and treatment

. 3.3  Mood disorders

. 3.3.1  Major depressive disorder (MDD) and Bipolar disorder (BPAD)

. 3.3.2  Pharmacotherapy

. 3.3.3  Psychotherapeutic and psychosocial management

. 3.3.4  Conclusions

. 3.4  Anxiety disorders

. 3.4.1  General considerations

. 3.4.2  Pharmacotherapy

. 3.4.3  Psychotherapeutic and psychosocial management

3.5. Personality disorders

. 3.5.1  General considerations

. 3.5.2  Borderline personality disorder

. 3.5.3  Antisocial personality disorder

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Dual Diagnosis : Non-Psychotic Disorders

EXECUTIVE SUMMARY

Dual diagnosis disorders (DD) denotes the co-existence of substance use disorders (SUD) and other non-substance use psychiatric disorders in the same individual. Non- psychotic DD include the co-occurrence of substance use disorders with mood disorders, anxiety disorders, and personality disorders. The presence of DD predicts poor prognosis with respect to both the SUD and the non-SUD. Therefore, treatment options for DD need to be carefully considered. There is some evidence to show that the traditional treatment models of consecutive or insulated care of the SUD and the non- SUD may not be as effective as integrated or simultaneous care of the DD. The authors have attempted to review this are keeping in view the requirements of the mental health professional in India.

A review of literature reveals that there is scarcity of data. However, the following recommendations can be made.

All patients should be screened for the possibility of DD at initial assessment unless acute stabilization is required when this may be deferred. For this purpose, screening instruments may be used. If there is any indication of DD, then a more thorough assessment to confirm the diagnosis and get other relevant details should be done. The treatment of DD should be conceptualized in two phases, acute and maintenance or stabilization phase.

In DD with mood disorders, literature search indicates the following recommendations. In alcohol SUD and major depressive disorder (MDD), mirtazapine, add-on naltrexone or alone, add-on naltrexone to sertraline and add-on disulfiram as second choice can be tried. In alcohol SUD with bipolar disorder, add-on naltrexone as first choice followed by add-on lamotrigine or alone, add-on valproic acid or alone, add-on disulfiram as second-choice and add-on gabapentin, add-on topiramate, lithium as third choice can be recommended. In cannabis SUD with Bipolar disorder, add-on valproic acid to lithium as first choice and lithium, or add-on valproic acid as second-choice may be recommended. In Cocaine SUD with MDD, add-on risperidone or alone can be recommended. In Cocaine with Bipolar disorder, add-on valproic acid to lithium as first choice followed by add-on lamotrigine or alone, lithium, add-on valproic acid or alone, add-on quetiapine or alone, add-on rispridone or alone as second choice can be recommended. In Opioid SUD with MDD/Bipolar disorder no evidence based recommendation is possible. However, treatment as usual for the affective disorder is likely to be effective. As regards psychotherapy, in MDD and bipolar disorder, motivational interviewing and Contingency management may be useful.

In DD with anxiety disorders, the evidence base is again scarce. Selective serotonin reuptake inhibitors are likely to be affective. Benzodiazepines should not be withheld

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indiscriminately. Specific psychotherapies for anxiety disorders are also likely to be useful.

In DD with personality disorders, recommendations are possible for borderline personality disorder and antisocial personality disorders. Interventions for SUD in presence of personality disorders are likely to be as effective in those without personality disorders. Dialectical behaviour therapy can be recommended for borderline personality disorder and contingency management can be recommended in antisocial personality disorder.

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Dual Diagnosis : Non-Psychotic Disorders

1. INTRODUCTION

Dual diagnosis disorders (DD) denotes the co-existence of substance use disorders (SUD) and other non-substance use psychiatric disorders in the same individual.1 This co-occurrence is observed to be much higher than that would be expected by chance alone and about 50% of people with severe mental disorders are affected by SUD.2 This finding has been borne out in epidemiological studies done across the world across different diagnostic groups.3 The reasons for this association are complex and various etiological theories have been proposed.4 It is also been observed that people with DD have higher rates of negative outcomes such as relapses, involvement in crime, homelessness, infections and hospitalization.5 Traditional models of psychiatric care in which services for mental disorders and SUD run separately and parallel to each other often prove to be less than effective in the optimum management of people with DD. Thus, despite the heterogeneity inherent in individuals with DD, the current trend is to consider patients with DD as belonging to a distinct group with special needs and to integrate services in such a way that both the SUD and the psychiatric disorder are managed simultaneously by one service with equal importance paid to both.6 Notwithstanding the clinical and public health importance of DD, research in this area has suffered due to lack of standardised definitions and nomenclature.1,7 Major nosological systems do not have any special category for DD and stress upon the group of substance-induced disorders in which there is evidence of a plausible association between substance intoxication and/or withdrawal and the mental disorder with proof of the symptoms of the latter not being due to an independent mental disorder.8,9

In addition, other than some notable exceptions, major treatment guidelines for mental disorders have not given adequate importance to DD.10 There are some treatment guidelines that are exclusively devoted to DD11-14 and its assessment.15 Indian data in this field are scarce with regards to both epidemiology and treatments.16 However, given the rates of mental disorders and SUD in the Indian population, it is likely that DD represent a major source of psychiatric morbidity in India as well.17

This guideline attempts to synthesize available data regarding the management of non- psychotic DD in the form of clinical practice guidelines (CPG) that are especially applicable to the Indian context.

2. SCOPEANDMETHODOLOGYOFTHEGUIDELINE

CPGs are systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances. The authors have tried to maintain a high standard and quality for these guidelines. Thus, the Appraisal of Guidelines for Research & Evaluation (AGREE) Instrument II has been used as a template for this exercise as far as possible.18 AGREE instrument is a tool that assesses the methodological rigor and transparency in which a guideline is developed.

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We have prepared this guideline in accordance to AGREE II, the newer revised version. We endeavoured to follow a structured and rigorous development methodology, to conduct an internal assessment to ensure that the guidelines are sound, and to evaluate guidelines by other groups for potential adaptation to our own context. Categories of strength of evidence available are based upon the AGREE II guideline.19

For the purpose of this guideline, non-psychotic disorders include the group of affective disorders, anxiety disorders and personality disorders.

We have reviewed the available literature with regards to non-psychotic disorders, DD, substance abuse and clinical management up to July 2015. Through a process of consultation between the authors, relevant data were retained. Treatment guidelines were then generated on the basis of available level of evidence.

3. RESULTS

The following sections present the results of the literature review. Each section will be followed by a section of recommendations along with strength of available evidence. This is presented with reference to the Indian context and the proposed audience in mind.

3.1 Generalconsiderationsandtreatmentsetting

The presentation and management of patients with DD can take place in varied settings. These include dedicated substance abuse services, mental health services, or dedicated DD services. The literature review reveals that there are subtle differences in recommendations with respect to different treatment settings.12,14,15 However, the authors opine that considering the state of mental health services in India, our recommendations will be common with regards to treatment setting. These recommendations can be considered appropriate for an inpatient, outpatient or emergency mental health service that is manned by psychiatrists and other mental health professionals.

3.2 Screening,AssessmentandTreatment

Screening is the process for evaluating the possibility of the presence of a particular problem. Assessment on the other hand is the process of evaluating the nature of that problem and developing specific strategies.

While it is perhaps intuitive that screening and assessment should be an integral and important part of any management protocol in DD, objective data is scarce in this population. Treatment guidelines however explicitly mention and advocate screening and assessment of all patients presenting at mental health and substance abuse services for the possibility of DD unless there are immediate contraindications such as intoxication, pain, distress, or need of emergency treatment.14,15 If present, these need to be managed immediately.

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The process should start with a proper history taking including family history, past history, a physical examination and necessary laboratory investigations. As mentioned before, the high degree of co-occurrence should ensure that the clinicians have a high index of suspicion so that necessary details are enquired into and a clinical diagnosis is possible. In case there is history of substance use in a setting of psychiatric symptoms, the possibility of substance-induced disorders should be entertained and ruled out. This is because these disorders are generally self-limiting.

In addition to clinical assessment, the use of appropriate screening instruments may be recommended. These can include instruments such as K-10, PsyCheck, or MINI for patients presenting with substance abuse related complaints or instruments such as CAGE, ASSIST, AUDIT for patients presenting with complaints related to psychiatric disorders other than substance use disorders.15 Indian data in this area are scarce. There are some data with regard to use of screening instruments especially with respect to alcohol use disorders20 and also the development of screening questionnaires in vernacular for detection of common mental disorders21, depressive disorders22 and alcohol dependence.23 However, these have not specifically addressed populations with DD.

If clinical assessment, and/or screening indicate the presence of DD, a comprehensive diagnostic assessment should be carried out for all patients.24 Several authors have pointed out that diagnosis in DD may be difficult and may require multiple assessments.24 This should be followed by treatment planning and outcome evaluation. Treatment planning can vary on a case-to-case basis. Outcome evaluation should also include documentation of current substance use patterns to evaluate the severity of current use and to serve as a baseline for the future and pre-morbid baseline functionality.24 The temptation to consider one of the other diagnosis as primary should be avoided.25

Phases of treatment can be divided into acute treatment and stabilization followed by maintenance and rehabilitation.25 Acute management involves observation, making a diagnosis, management of acute conditions such as intoxication or withdrawal, management of psychiatric symptoms and stabilization to as close to the baseline as possible. Maintenance phase seeks to prevent relapse and recurrence through continued medical and psychosocial interventions.25

Recommendations

Strength of all recommendations for this section: D

lAll patients should be comprehensively assessed and screened unless acute stabilization is required

lInitial assessment should include a proper history, clinical and laboratory evaluation lRelevant screening instruments can be used

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lPositive screening or clinical evaluation should suggest DD and a comprehensive assessment for the same should be carried out

lAssessment of DD should include patterns of substance abuse, psychiatric symptomatology, estimation of pre-morbid functioning

lIt is useful to consider management of DD in two phases, namely acute management and maintenance phase and rehabilitation

3.3 Mooddisorders

3.3.1 Major Depressive Disorder (MDD) and Bipolar Disorder (BPAD)

MDD is commonly comorbid with SUD.26 The odds ratio for developing SUD in those with a life time history of MDD is 1.8.27 This comorbidity also increases the cost of treatment when compared to non-DD patients.28 The comorbidity of BPAD and SUD is even more obvious. Early-onset BPAD seems to be strongly associated with the development of SUD.29 The odds ratio for developing SUD in patients with BPAD can be as high as 6.9.30 A review of literature in this area revealed that other than a recent Canadian management guidelines for patients with mood disorders and SUD11, there is a paucity of well-designed, randomized and controlled clinical trials in patients with DD. Therefore, robust guidelines are difficult to arrive at.

3.3.2 Pharmacotherapy

With regards to pharmacotherapy in patients with comorbid SUD and mood disorders, the literature review suggests that outcome measures have included the symptoms of the mood disorder and the craving or use of substance. The literature review is as follows.

Anticonvulsants:

There is little evidence for the use of anticonvulsants in DD patients with MDD. There are negative Ib studies with regards to the use of carbamazepine in patients with MDD and cocaine use.31-33 There is level 4 evidence for the use of valproate in alcohol DD.34

The evidence base for the use of anticonvulsants in DD with BPAD is no better. An open-label, non-blinded study with 9 participants with different SUD showed the utility of valproate in acute BPAD.35 There is a negative study for the use of carbamazepine in cocaine users.31 There is some level II, III and IV evidence for the use of add-on gabapentin in alcohol SUD36,37, add-on or alone lamotrigine in alcohol and cocaine DD38-40, and add-on topiramate in alcohol DD.36,41,42

Lithium:

The evidence base suggests that lithium is not useful in MDD comorbid with alcohol and cocaine SUD (level Ib and IV respectively).43,44

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There is somewhat greater evidence for the use of lithium alone or in association with other drugs in BPAD DD. Lithium has been shown to be effective in adolescents with BPAD and secondary SUD (Level Ib).45 There is also some evidence base for the use of lithium as add-on with valproic acid or alone in DD with alcohol, cannabis and cocaine SUD (Level Ib).44-46

Antidepressants:

There is some evidence for the use of antidepressants in MDD comorbid with DD. No studies were found for BPAD comorbid with SUD.

Among the tricyclic antidepressants, the evidence base is as follows. There is level Ib evidence supporting the use of amitriptyline, desipramine and imipramine in DD with alcohol SUD.47-50 Imipramine has also been used with benefit as add-on to methadone in opioid dependence with MDD.51,52

The evidence base for selective serotonin reuptake inhibitors is also confined to MDD. There is level Ib evidence supporting the use of fluoxetine, escitalopram, nefazodone and sertraline in alcohol SUD comorbid with MDD.53-58

Level IB evidence also exists for the use of mirtazapine for the same indication.47, 59

Level Ib evidence exists for the use of sertraline in cocaine SUD comorbid with depressive symptoms.60 There is also a negative study for the use of venlafaxine in patients cocaine SUD comorbid with MDD.61

Antipsychotics:

The evidence base for the use of antipsychotics in DD MDD is meagre. There is a level 4 study supporting the use of risperidone in cocaine SUD.62

Antipsychotics have been studied more often in the context of DD BPAD. There is evidence supporting the use of add-on and alone quetiapine and risperidone in polysubstance abuse (level 3), alcohol, cocaine, amphetamines and methamphetamines (level 2).62-68 However, there are negative studies with quetiapine as well.69

Others:

The other agents that have been studied in DD MDD are buprenorphine in heroin SUD (level 4)70, disulfiram in alcohol SUD (level 2)71, memantine in alcohol SUD (level 2)53,54 and naltrexone add-on or alone (level 2)58,72, naltrexone with sertraline.58

The other agents that have been studied in BPAD DD are add-on disulfiram in alcohol SUD (level 2)72,73, methadone in heroin SUD (level 3)74 and add-on naltrexone in alcohol SUD (level 2).72,75,76

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3.3.3 Psychotherapeuticandpsychosocialmanagement

There is some evidence for the role of psychotherapy and psychosocial methods of intervention. There is an increasing use of technology and novel methods in delivering these interventions.77-79 However, given the nature of interventions, blinding and placebo-controlling is impossible.

Contingency management was found to be useful for improving treatment retention in both MDD and BPAD with comorbid SUD.80

The evidence base for different psychotherapies in patients with MDD or BPAD comorbid with SUD is as follows.

Cognitive behaviour therapy (CBT):

There are negative results reported for studies conducted for both MDD and BPAD with comorbid SUD.81-83

Interpersonal therapy (IPT):

A preliminary report has supported the use of IPT in women with alcohol SUD and MDD.84

Motivational interviewing (MI):

There is level 2 evidence for the use of MI in DD85,86 and level 3 evidence for use in BPAD.85 However, when combined with CBT, MI has not been shown to be effective.87

3.3.4 Conclusions

There is a paucity of well-designed studies regarding the effectiveness of various interventions in DD with mood disorders.

Recommendations

lAlcohol and MDD
uFirst choice: mirtazapine, add-on naltrexone or alone, add-on naltrexone to

sertraline.
uSecond choice: add-on disulfiram
uThird choice: Valproic acid, amitriptyline, imipramine, escitalopram

lAlcohol with Bipolar disorder

uFirst choice: Add-on naltrexone

uSecond choice: add-on lamotrigine or alone, add-on valproic acid or alone, add- on disulfiram

uThird choice: add-on gabapentin, add-on topiramate, lithium lCannabis with Bipolar disorder

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uFirst choice: add-on valproic acid to lithium

uSecond choice: Lithium, add-on valproic acid lCocaine with MDD

uAdd-on risperidone or alone lCocaine with Bipolar disorder

uFirst choice: add-on valproic acid to lithium
uSecond choice: add-on lamotrigine or alone, lithium, add-on valproic acid or

alone, add-on quetiapine or alone, add-on rispridone or alone lOpioid SUD with MDD/Bipolar disorder:

uNo evidence base recommendation is possible. However, treatment as usual for the affective disorder is likely to be effective.

lPsychotherapy
uMajor depressive disorder: Motivational interviewing and Contingency

management may be useful.

uBipolar disorder: Motivational interviewing and Contingency management may be useful.

3.4 AnxietyDisorders

Anxiety disorders and SUD are commonly comorbid.88 This has been borne out in all large scale epidemiological surveys.30 The presence of this comorbidity is predictive of poor prognosis and recovery from either condition.89 Generalized anxiety disorder and panic disorder were found to have the highest comorbidity with SUD.90 The pattern of these comorbidities has been confirmed in a recent review.91 As with mood disorders, the evidence base for interventions in DD with anxiety disorders is meagre. As far as the authors are aware, no treatment guidelines explicitly exist for this indication. However, there is a recent review in this area.92

3.4.1 General considerations

As anxiety symptoms are commonly associated with substance use, withdrawal and MDD, a careful diagnostic exercise to confirm comorbidity is essential (level 4).92 This is often difficult.

3.4.2 Pharmacotherapy

The evidence base for use of pharmacotherapy alone in this group of DD is sparse. A category II study that investigated the use of paroxetine in subjects with alcohol dependence and social anxiety disorder found improvement in anxiety but not so much in alcohol quantity or frequency.93 In another category I b study of paroxetine in subjects with similar pathology, somewhat similar results were seen.94 Another category I b study

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with sertraline or placebo in alcohol SUD and posttraumatic stress disorder (PTSD) was equivocal.95 There are studies that have investigated the possible utility of buspirone. A category II a study in subjects with generalized anxiety disorder (GAD) and alcohol SUD showed that buspirone was useful in measures of anxiety and drinking.96 A couple of studies with buspirone in subjects with alcohol SUD and GAD, and subjects with opioid dependence on methadone found no significant improvements in substance or anxiety outcome parameters.97,98

The use of benzodiazepines in this group of patients is controversial. Whereas a common sense approach would indicate that such agents should be used with circumspection, actual data is sparse. Some studies suggest that those with SUD are more prone to abusing and developing dependence to benzodiazepines.99 However there are some studies to the contrary as well which suggest that with careful monitoring and selection, benzodiazepines can be gainfully used in patients with SUD and anxiety disorders.100,101

3.4.3 Psychotherapeutic and psychosocial management

While there is ample evidence for the use of non-pharmacological therapies in the form of behaviour therapies (BT) in anxiety disorders, the evidence base for the use of BT in DD is mixed. A category III study showed that subjects with panic disorder with and without agoraphobia and SUD had worse outcomes than those without when subjected to CBT.102 Similarly, a category IIa study investigating the use of CBT in patients with panic disorder and alcohol SUD found that CBT performed no better than treatment as usual.103 Another category Ib study investigating the role of CBT in patients with alcohol SUD and comorbid anxiety disorders showed that while CBT was effective in improving anxiety outcomes, alcohol outcomes were not significantly different.104 Another category Ib study showed that evidence based psychotherapy for PTSD in patients with alcohol SUD did not perform better than supportive counselling and pharmacotherapy.105 On the other hand, studies have shown that subjects with various anxiety disorders and alcohol SUD respond equally well when compared to those without alcohol SUD when subjected to various forms of BT.106-108 However these studies were not as robust as the former.

Another interesting development is the testing of integrated treatments designed specifically for comorbid anxiety disorders and SUD. These include the following. An integrated CBT protocol for alcohol SUD and panic disorder has been developed.109 A category 1b trial showed that integrated treatment was associated with reductions in anxiety and alcohol use.110 Other integrated therapies have been devised for PTSD comorbid with alcohol SUD. Therapies devised in this population group are seeking safety111, integrated CBT112 and COPE (concurrent treatment of PTSD and substance use disorders using prolonged exposure).113 Evidence base suggests that these treatments are

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well tolerated and do not worsen PTSD symptoms.92 However, much more research evidence is needed before these therapies enter the mainstream. The issue of paucity of trained personnel to deliver these therapies in a country such as India is also pertinent.

Recommendations

lGiven the association of anxiety symptoms and different phases of substance use, a proper diagnostic exercise is essential before making a diagnosis of DD.

lSelective serotonin reuptake inhibitors may be useful in anxiety disorders with SUD. lBenzodiazepines should be used with caution but should not be withheld when

indicated.

lNon-pharmacological methods of treatment in form of integrated, specific behaviour therapies are recommended.

3.5 Personalitydisorders(PD)

PD, specially the antisocial personality disorder are commonly comorbid with substance abuse.2 Similar findings have been reported for borderline personality disorder as well.114 People with SUD are found to have a higher prevalence of PD than the general population and the comorbidity of these conditions is associated with greater impairment.114 While the comorbidity of PD and SUD is beyond doubt, there are very few well-designed studies that have specifically looked at treatment protocols for thesame. MoststudiesconcernwithtreatmentstrategiesforindividualswithPDwhere somemembersofthepopulationhaveSUD. Therefore,mostguidelinesinthissection are extrapolated rather than from direct evidence. There are some well-regarded Cochrane reviews of management strategies for borderline and antisocial PD.115-119 The British Association of Psychopharmacology has also issued updated guidelines on treatment options for substance abuse and comorbidities that includes PD.120 Health Canada also has a section on management options for the treatment of this DD.121 There is a recent review on the treatment considerations in DD with borderline PD.122

3.5.1 General considerations

It is a commonly held notion that people with PD do not respond well to treatment strategies for SUD. However, this has been refuted and it has been suggested that people with PD and SUD can benefit as much as people without this comorbidity to standard treatments for SUD.123 There is some evidence to suggest that this is the case across different PD, SUD and outcomes120 (level 4 evidence). These outcomes include measures of substance abuse, high-risk behaviours, overall mortality and suicidality. However, evidence also suggests that treatment for this DD does not improve the symptoms of the PD per se and that such patients should also have dedicated treatment for the PD120 (level 4 evidence). Whether any particular treatment modality is specifically useful for both the SUD and the PD simultaneously is uncertain. There is

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some evidence to suggest that successful treatment of SUD in patient with this DD may predict improvement in the PD.124

As with other disorders, it is essential to make a proper diagnostic assessment. However, screening instruments for PD are not easily available. Diagnosis would mostly require a proper clinical interview and to gather as much information from as many informants as possible (Level 4 evidence). Issues of anger and impulse control are often clues to the presence of PD. As in other DD, concurrent, integrated treatment is the best choice for this DD121 (level 4 evidence).

3.5.2 Borderline Personality Disorder

The 5 evidence base for treatment options in borderline PD and SUD DD is scant. Psychotherapy: Dialectical behaviour therapy (DBT) has some evidence base in this population. There are a couple of RCTs that have examined DBT in this population with significant results125,126 (Level Ib evidence). In addition, there is one study of dynamic deconstructive psychotherapy in this population.127

Pharmacotherapy: There is some evidence to suggest that disulfiram and naltrexone can be used in patients with borderline and antisocial PD and alcohol SUD128 (Class Ib evidence).

3.5.3 Antisocial Personality Disorder

The evidence base for treatment options in antisocial PD and SUD DD is scant. Psychotherapy: there is some evidence (Level IIb) regarding the usefulness of contingency management in abstinence from substance use in patients with cocaine SUD.129 A similar study found that structured behavioural approach improved behavioural measures but not necessarily substance related measures in patients with opioid SUD (level Ib evidence).130

Pharmacotherapy: In double blind placebo controlled study, nortriptyline was found to be useful in patients with antisocial PD and alcohol SUD.131 Desipramine was found to be inferior to placebo in patients with cocaine SUD and antisocial PD.132

Recommendations

lThe evidence base in this area is scanty.
lInterventions for SUD in patients without PD are likely to be as effective in patients

with PD.
lSuccessful treatment of SUD may benefit symptoms of PD.
lDialectical behaviour therapy can be recommended in borderline PD with SUD. lContingency management can be recommended in antisocial PD with SUD.

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The Clinical Practice Guidelines for the Assessment and Management of Substance Use Disorders (CPG-SUD) was prepared by the Indian Psychiatric Society Specialty Section on Substance Use Disorders and published by IPS in January 2014. The following year, in January 2015, a more concise, practice- oriented, easy-to-carry and easy-to-follow supplementary companion of the comprehensive CPG-SUD book was published (“The Synopsis”). Since their publication, both the CPG-SUD and its Synopsis books have been well received by clinical practitioners, researchers, academicians, and psychiatric students, i.e., by all the target groups these books were meant for.

However, the scenario of addictive disorders is never a static one. It witnesses continual kaleidoscopic changes, with newer substances, newer patterns, and indeed, newer ‘addictions’ emerging all the time. Four broad changes have been noted in the landscape of addictive disorders in India of late. These are:

. (a)  Emergence of a heterogeneous group of various substances clubbed under the term “New Psychoactive Substances (NPS)”, which evade the existing regulatory legal framework but nonetheless, can be harmful;

. (b)  Emergence of long-known but so far less used substances in India in an emergent manner (such as cocaine and amphetamine-type stimulants), often in the context of rave parties or similar gatherings (the so-called “club drugs”);

. (c)  Recent recognition of patterns of maladaptive behavioural excess involving particular behaviours (gambling, use of technology like computer and Internet, eating, sexual activities, etc.), which do NOT primarily involve use of psychoactive substances as such (known as “behavioural addictions”); and finally,

. (d)  Enhanced probability of clinically encountering various combinations of substance use disorders with non-substance psychiatric disorders (known as dual diagnosis or dual disorders).

Thus, this year, the Specialty Section decided to focus on “Newer and Emerging Addictive disorders in India”.

CPGs are meant to inform, assist and “guide” the clinician, not to ask them to sacrifice their autonomy of clinical judgment, nor to be oblivious of the individual patient’s clinical situation and psychosocial context. With this disclaimer and caveat, however, we believe that this new set of the CPGs, when properly used along with clinical training in addiction psychiatry, can be a very useful and handy companion to the students, clinicians and even teachers in their day-to-day practice.

Debasish Basu, P.K. Dalal, Y.P.S. Balhara (Editors)

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