OPIOID AGONISTS FOR TREATMENT OF OPIOID DEPENDENCE (OATOD)

OPIOID AGONISTS FOR TREATMENT OF OPIOID DEPENDENCE (OATOD): GUIDELINES FOR IMPLEMENTATION IN THE STATE OF PUNJAB

A. Background

B. RationaleandScopeofthisdocument

C. Objectives

D. Basic facts about opioid agonist treatment of opioid dependence (OATOD)

E. Essentialpre-requisitesforstartingOATOD

F. Guidelines on OATOD for opioid withdrawal (vis-à-vis clonidine)

G. Guidelines on OATOD for opioid maintenance (Opioid Substitution Therapy, OST) (vis-à-vis naltrexone)

H. Regulatory aspects

Prepared by: Dr. Debasish Basu and Dr. Ajit Avasthi, Professors, Department of Psychiatry, PGIMER, Chandigarh

Date Submitted to the Govt. of Punjab: 9th October 2014

Date Accepted for implementation by the Govt. of Punjab:

Date of Revision of these Guidelines: Two Years from the date of acceptance/ implementation

ABBREVIATIONS USED IN THIS DOCUMENT

BN: Buprenorphine sublingual preparations

BNX: Buprenorphine-naloxone fixed dose combination sublingual preparations

DCGI: Drug Controller General of India

DHS: Directorate of Health Services

DOT: Directly Observed Treatment

IDU: Injecting Drug Use, or Injecting Drug User

IRCA: Integrated Rehabilitation Centre for Addicts

NACO: National AIDS Control Organization

NCB: Narcotics Control Bureau

NDPS Act: Narcotic Drugs and Psychotropic Substances Act, 1985

NGO: Non-Governmental Organizations

OATOD: Opioid Agonist Treatment of Opioid Dependence, or Opioid Agonists for Treatment of Opioid Dependence

OST: Opioid Substitution Treatment

PGIMER: Postgraduate Institute of Medical Education & Research, Chandigarh

A. BACKGROUND

Opioids are chemical substances (“drugs” in common parlance) that are psychoactive (i.e., they alter mood, thinking, judgment, perception or other mental functions) and are highly addictive (i.e., with their regular intake, the user becomes dependent on them psychologically and physically, as manifest from any three of the following):

· having repeated strong craving for the substances,

· loss of control in regulating their use of these substances,

· needing progressively higher doses of the substances to achieve the same effect

[tolerance],

· experiencing very unpleasant psychophysiological reactions upon abruptly stopping their

use [withdrawal syndrome],

· neglecting alternative pleasures, interests and responsibilities of life in favour of spending

time on seeking, using or recovering from the effect of these substances [salience], and

· persistence with the use of these substances despite psychological or physical harm

because of their use [e.g., depression, venous ulcers, HIV and other infections, etc.]

Common examples of opioids include crude opium (afeem), poppy husk (bhukki), poppy seeds (khuskhus), heroin (impure street version of brownish colored powder known locally as “smack”, and relatively pure white powder often used by injecting, locally known as “chitta”, “white” or simply “heroin”), and a list of “pharmaceutical” or “prescription” opioids (often locally called “medical nasha”) including morphine, pentazocine (Fortwin), pethidine, buprenorphine, codeine (in cough syrups such as Corex, earlier Phensedyl and Rexcoff), tramadol and dextropropoxyphene (Proxyvon, Spasmoproxyvon or “Neela”, Dexovon, etc).

Opioid dependence causes severe harm to the:

· Individual (addiction, overdose, health problems including several infections, academic/work loss, financial loss, and higher mortality due to a combination of factors including overdose toxicity, accidents, infections and other medical reasons, crime and other antisocial consequences, etc.),

· Family (family burden, disruption, marital discord, financial drain, social stigma)

· Society (higher crime rates, loss of productivity, social disruption), and

· State/nation (blocked progress, economic backwardness, instability, and general

disrepute).

The state of Punjab has been grappling with the problem of drug addiction for quite some time now, of which alcohol and opioids are the major substances of use. Although no exact state-wide direct estimate is available, the magnitude of the problem is apparent to people living in Punjab and can be gauged by indirect estimators such as drug-related crime rates, bookings under the NDPS Act, and drug seizure records. The reasons for this state of affairs are complex and multifaceted, and these are beyond the scope of this document, but the magnitude of the problem is undeniable. It is a “clear and present danger” to the very rubric of the society.

In view of this, the present Government of Punjab has taken several interlinked multi-level systematic state-wide proactive steps to curb the menace, including measures of supply reduction, demand reduction and harm reduction. Again, the details of these measures are beyond the scope of this document, but one particular facet of this battery of steps is of direct relevance to serve as the background of this document. This concerns the supply and use of buprenorphine (BN), buprenorphine-naloxone combination (BNX) and tramadol as opioid agonist treatment of opioid dependence (OATOD).

OATOD is a recognized, effective, evidence-based, and generally safe option for treating opioid dependence worldwide. OATOD essentially involves the medically assessed and supervised administration of safer and longer-acting opioid drugs for either short-term use in opioid detoxification, or, in selected cases, for longer-term use as opioid substitution treatment (OST) for preventing relapse of use of illicit opioids and for helping the users to re-build their lives while on the cover of OST. It is especially useful in the context of injecting drug use (IDU) to prevent HIV and other infections, and also in non-IDU of severe, chronic, multiple-relapsing nature associated with crimes and other major complications.

So far, there is no problem. But we have to remember that opioid agonists like BN, BNX and tramadol are themselves opioids, with all the psychoactive and addictive properties of opioids outlined above. Thus, use of OATOD is a double-edged sword. When used properly,

it can save and re-build lives. When used improperly, it can cause damage just like any other opioids. Hence the whole issue rests upon a “proper”, “balanced” or “rational” use of OATOD.

In this regard, of late, serious concerns have been raised regarding the ways in which OATOD is being used in Punjab. Several issues have been brought to the notice of the authorities, which, if unchecked, can bring the entire philosophy and practice of OATOD to disrepute, and can cause more harm than OATOD purports to reduce. These issues are mentioned in the following section (Rationale and Scope of this document). Given this background, the present document provides guidelines for the rational use of OATOD so that it reaches the needy, while minimizing the improper and irrational use of opioids in the name of so-called OATOD.

It has to be emphasized that Guidelines are not made in vacuum or in absolute terms. They have to be sensitive to the social context so as to strike a right balance between the “benefits” versus the “risks” of any given approach. Further, the risk-benefit ratio is not a stable parameter. It is fluid, and often reflects the current practice. Guidelines have to recognize this shift of balance between risks and benefits of a particular approach, and have to be modulated accordingly; lest the “use” of an otherwise excellent treatment can rapidly swing into its “misuse” or even “abuse”, eventually harming the very excellence of the approach, unless proper cautions, regulations and monitoring standards are set in place by Guidelines. Medical history is replete with such instances, starting from thalidomide and digitalis, to lithium, to clozapine, and others. These Guidelines, thus, are NOT meant for disparaging OATOD by any means but rather to encourage its rational use and discourage otherwise.

B. RATIONALEANDSCOPEOFTHISDOCUMENT

While a clearly evidence-based effective approved therapy for opioid dependence, OATOD, if misused, has the potential of causing similar harm that it is supposed to reduce.

Some of these harms include:

· Creating – and maintaining – an iatrogenic (= caused by the treatment itself) dependence

(which may precipitate withdrawal when the supply of the drug is suddenly withdrawn),

· Fostering addiction by overuse of the opioid agonist drugs (post-marketing surveillance survey of buprenorphine showed that 44.5%, or nearly half, of those maintained on therapeutic buprenorphine, reported “a sense of high (nasha)”, which means that if used in a higher dose, these drugs can cause opioid induced addictive effects),

· Endangering the lives of people with combined overdose of buprenorphine and other nervous system depressants such as alcohol or benzodiazepines (as abundantly evidenced in several countries where high-dose buprenorphine has been used for years, e.g., France, Australia, New Zealand)

· Most worryingly, generating a parallel market of these potentially addictive drugs by diversion of legally obtained buprenorphine (through prescription of doctors) for abuse by self or others. This can be done in a number of ways, e.g.,

o Asking for a much higher dose of buprenorphine than actually needed or for a much longer period – often for 30-day refills – and thus siphoning off extra medication;

o Getting prescriptions written from multiple doctors (same patient registered at multiple places);

o ‘Faking’ opioid addiction (falsely claiming that one takes heroin and hence needs buprenorphine);

o Even ‘proxy’ patients (‘uncle’ getting prescriptions for his ‘opioid addict nephew’), etc.

o The system has become such that the prescribing doctor sells the medicine at a higher price (2-3 times higher) and then these are further sold off in the “market” at a further much higher price.

Unfortunately, there is evidence – both from practising doctors and from many patients – that these practices are in existence. The exact extent of such practices is difficult to ascertain, but from anecdotal evidence converging from multiple sources, it appears to be substantial.

More importantly, there does not appear to be any proper ‘check’ or regulatory measures to monitor the situation. Hence there is apprehension that the actual extent of these harms could be much higher than anticipated, and may create a situation of uncontrollable chaos if the tide is not stemmed right now.

The other major harms of the ‘misused’ OATOD system is that:

· Patients who are in genuine need of long-term opioid maintenance treatment may be left

out because of the huge siphoning off of buprenorphine in the parallel market, and,

· Finally, bringing the whole philosophy and practice of OST into disrepute; this will be very unfortunate indeed.

As mentioned in the earlier section of this document, there is no absolute ‘right’ or ‘wrong’ about any Guidelines. They have to be sensitive to the social context so as to strike a right balance between the “benefits” versus the “risks” of any given approach. The risk-benefit ratio is not a stable parameter. It is fluid, and often reflects the current practice. Guidelines have to recognize this shift of balance between risks and benefits of a particular approach, and have to be modulated accordingly. The rationale of this document is guided by the current grave concerns raised because of the unregulated and often irrational way OATOD and particularly OST (or whatever goes in the name of OST) is being used in Punjab and its vicinity.

The ‘target population’ of these guidelines in this document is comprised of:

· The Government of Punjab (particularly its Drug Control Section, Govt. Drug warehouses and Mental Health/De-addiction Cell of DHS)

· The manufacturers and suppliers of sublingual buprenorphine (BN) and sublingual buprenorphine-naloxone combination (BNX)

· The doctors working in both government and private sectors who prescribe sublingual BN and BNX and also tramadol for opioid dependence

This document does NOT target the NGOs and government hospitals which run NACO- accredited and NACO-funded OST Centres for IDU patients (because there are already existing

detailed Practice Guidelines and Standard Operating Procedures produced by NACO which are mandatory for these OST Centres).

· However, the Government might consider writing to NACO flagging up its concerns and requesting NACO or its State Wing (Punjab State AIDS Control Society – PSACS) to ensure that those guidelines and procedural safeguards are actually in place, or even asking for data regarding the same).

The jurisdiction of these guidelines will be limited to the State of Punjab, though other States and Union Territories of India may consider using or adopting these guidelines for their own implementation as well. Eventually, the Government of India might consider formulating its own policy.

It is worthwhile to mention here that currently there are no existing guidelines at the national level on OATOD in general and OST in particular. The National Policy on NDPS Act (2012) does have a small section called “Harm Reduction”, which takes a rather narrow and disparaging view that has been called into question and are under revision. It makes some general overview statements, which are summarized in the Clause 73 of the National Policy (quoted below).

“73. In view of the above, the approach towards harm reduction will be as follows:

a) Drug addicts including injecting drug users (IDUs) will be identified and treated and their drug-using habit will not be supported or incentivised.

b) However, in cases where it is not possible to convince an IDU to undergo de-addiction, as a first step, clean needles and syringes or oral substitution may be provided to him.

c) Harm reduction techniques as indicated in (b) above may be practiced only by hospitals or centres set up or supported by or recognized by the Central Government or any State Government.

d) If anyone or any organisation other than those indicated in (c) above distributes needles and syringes or drugs for oral consumption to addicts, it shall be treated as abetting consumption of drugs and such person or organisation will be treated accordingly under the NDPS Act, 1985.

e) The centres indicated in (c) above promoting ‘harm reduction’ shall maintain records of each of the addicts and shall switch them to de-addiction as soon as possible preferably within one year but in no case later than two years.”

These statements have been criticized as focusing only on IDUs, and taking a rather strict and narrow view of the complex issue. However, because this is still the National Policy in force, we have taken note of them and have tried to accommodate them as much as possible without eroding the scientific evidence base.

Levels of Recommendation used in these Guidelines

Based on the extensive scientific literature, existing guidelines and position papers of national and international bodies, policies in other countries where OST is practiced, experience of using OATOD in our country and relevant publications, an iterative consultation from multiple stakeholders, and – last but not the least – emerging issues and concerns about the real-world practice of OATOD in the State of Punjab and its vicinity as evidenced in recent times – these Guidelines are formulated so as to provide THREE levels of recommendations in order of their strength. Three verbs are used for statements of recommendation, in decreasing order of strength of recommendation, as follows:

I. “MUST / MUST NOT” – it refers to recommendations that are felt to be mandatory. It implies that, if not followed, penal or other administrative sanctions may be imposed by the relevant authorities.

II. “SHOULD / SHOULD NOT” – it refers to recommendations that, although not mandatory, are felt to be desirable. These should be followed to the extent possible, as a matter of good practice.

III. “MAY / MAY NOT” – it refers to recommendations that, though generally advisable, are felt to be optional. It will depend upon the individual or the agency concerned to act upon these recommendations based upon their evaluation of other options.

C. OBJECTIVES

1. To ensure proper and rational use of OATOD and especially OST for opioid dependence in Punjab.

2. To discourage and minimize improper and irrational use of the same.

3. To evolve a state-wide mechanism for achieving the above two objectives.

D. BASIC FACTS ABOUT OPIOID AGONIST TREATMENT OF OPIOID DEPENDENCE (OATOD)

The basic premises of using an opioid agonist agent for treating opioid dependence are:

· The licit (medically given) opioid would block the withdrawal and craving for illicit opioids (i.e., reduce ‘drug hunger’).

· The licit (medically given) opioid would block the intoxicating and rewarding effects of illicit opioids (i.e., reduce ‘drug reinforcement’).

· The licit (medically given) opioid, being long-acting and relatively safe (because of proper dose and lack of toxic adulterants, lack of injection and sharing related adverse consequences), would reduce the harms associated with use of illicit opioids.

· Because of the above factors, the person on OATOD does not have to spend time, money and efforts to procure or use of illicit opioids, including indulging in petty crimes, drug smuggling, harming others, etc. The person can now focus on re-building one’s life, lead a stable life, move towards rehabilitation, and eventually come out of the drug habit, including the temporary dependence on the medically given opioid.

As of now, the only opioid agonist approved for the treatment of opioid dependence is

buprenorphine via sublingual route, either alone (BN) or in a fixed-dose combination with naloxone (BNX). Oral tramadol is the other opioid commonly used for this purpose. Dextropropoxyphene is now banned in India, and other opioids including methadone and slow- release morphine are still not available other than research settings.

Of the two preparations of buprenorphine available in India, BNX is safer from the angle of abuse than plain BN, because BN can be abused by injection but BNX causes unpleasant withdrawal reaction if injected. Plain BN can only be advised if administered in front of one’s own eyes and ensured that the patient has completely dissolved the entire tablet in saliva (known as Directly Observed Treatment or DOT). DOT is administered in NACO-accredited OST centres for IDUs. For all other purposes and in other settings especially take-home doses in outpatient settings, BNX is a safer bet (though this too can be abused if taken in a higher dose than required).

It is to be further noted that oral substitution treatments are approved for treatment of opioid dependence only “by hospitals or centres set up or supported by or recognized by the Central Government or any State Government” (National Policy on NDPS Act). The Drug Controller General of India (DCGI) has further stipulated that BN and BNX can be supplied by the manufacturers only to “designated de-addiction centres set up by the Govt. of India funded by the Ministry of Health and Ministry of Social Justice & Empowerment and hospitals with De-addiction facilities”, and further that “a list of the centres to whom supply of the drug is made should be submitted to this Directorate periodically indicating the quantity supplied to each centre.” (DCGI)

Tramadol, though outside the purview of these directions, and though available with retail chemists against valid prescriptions, is used widely for opioid dependence. Although effective in treating opioid withdrawal, tramadol has certain disadvantages, such as a short duration of action and propensity to cause seizures when used in higher doses.

It is important to emphasize that OATOD is used for two very different indications and different scenarios:

· Short-term Treatment of opioid withdrawal during detoxification phase

· Long-term treatment of opioid dependence during maintenance phase

The short term treatment is for acute opioid withdrawal during detoxification phase. This is usually given for 7-14 days, where the dose of BN / BNX is built up to 6-8 mg/day (occasionally up to 10-12 mg/day) and is tapered off without prolonging its use beyond this period after the

acute withdrawal is over. This is the current standard of treatment for opioid withdrawal during detoxification phase. It is unlikely to cause major concerns regarding abuse and diversion.

The long term treatment is for opioid dependence during maintenance phase, also known as opioid substitution treatment (OST). Most often this phase of treatment may be directly continued from the initial (detoxification) phase. OST is long-term maintenance of the illicit opioid user in a illicit-opioid-free but licit-opioid dependent state, for as long as the patient is stabilized, crime-free, finds a job, gets into a stable relationship, has no longer craving and preoccupation with drug seeking as an issue, can find enjoyment in an illicit-drug-free lifestyle, has generated alternative interests and responsibilities, and has generally re-built his life and re- integrated into mainstream society. OST typically employs lower opioid doses in Indian settings (2-8 mg/day) but is continued for a longer period, typically 6 months to 2 years and occasionally longer. The final aim is to gradually taper off OST after this period, with or without alternative (non-opioid) medications.

In sum, the objectives of OST are:

· to reduce illegal and other harmful drug use, including repeated relapses,

· improve the patient’s health and well-being,

· reduce the risk of transmission of blood-borne infectious diseases,

· reduce death and other medical morbidities associated with drug use,

· reduce crime committed by patients,

· facilitate an improvement in the patient’s occupational and social functioning,

· improve the economic status of patients and their families, and, finally,

· to achieve abstinence from drug use, including cessation of the substitution treatment.

It is the OST phase of treatment that generates lots of controversies and is often misunderstood, by the policy-makers, and often by doctors as well as by the patients. Perusal of the objectives of OST stated above will clarify some of these misunderstandings. OST is NOT simply substituting one addiction with another. It is about giving a chance to the patient to organize and lead a stable illicit-drug-free lifestyle.

Neither doctors nor patients should take OST as a “Short-cut” or “Easy-way-out” to obtaining illicit drugs in a licit manner and living indefinitely in this manner. To give an analogy, when a leg bone is fractured, one has to use a plaster casing and a crutch to support the leg as long as it takes for the internal stabilization and recovery takes place till such time the bone heals and the leg again becomes functional. Then the plaster casing and the crutch is taken off. The crutch is for providing support to enable the recovery taking place, though it performs the work of the leg as long as it is used. The crutch is not the leg!

This brings us to the next section: Essential pre-requisites for starting OATOD.

E. ESSENTIALPRE-REQUISITESFORSTARTINGOATOD

1. The first essential pre-requisite of starting any OATOD (whether for short-term or long- term use) is ESTABLISHING OPIOID DEPENDENCE. This may sound like stating the obvious, but often is neglected, perhaps because it is too obvious!

2. The second essential pre-requisite is CHARACTERIZING OPIOID DEPENDENCE. This includes the exact type(s) of opioid, route of use, quantity typically consumed, the severity of dependence, and the adverse consequences of opioid dependence.

3. The third essential pre-requisite is CONSIDERING CAUTIONS AND CONTRAINDICATIONS FOR OATOD. This includes exploring concomitant use of other substances (especially other CNS depressants), and medical conditions that require caution before starting OATOD (e.g., bronchial asthma, severe respiratory or hepatic impairment, phaeochromocytoma, inflammatory bowel disease, and hypothyroidism).

4. The fourth essential pre-requisite is DOCUMENTING PREVIOUS ATTEMPTS AT QUITTING (spontaneous and medically aided, including outdoor- and indoor-based de- addiction treatments, with opioid or non-opioid medications).

5. The fifth essential pre-requisite is to have a PSYCHOSOCIAL MANAGEMENT MODALITY, which is mandatory along with OATOD. This may be, at the minimum, provision of a Counselor, and at best, a multidisciplinary team of psychiatric social worker, psychologist, vocational instructor and psychiatric nurse. The point is that OATOD is not complete without concurrent psychosocial management.

6. The sixth essential pre-requisite is to have a QUALIFIED PSYCHIATRIST to start, monitor and terminate OATOD. Only psychiatrists must start OATOD (after proper assessment and documentation and after meeting the other essential pre-requisites). Other professionals (medical, nursing, counselors and others) should, however, be involved in monitoring various aspects of OATOD as part of a multidisciplinary team.

7. The final essential pre-requisite is to have a VALID AND ACCOUNTABLE SET-UP within which OATOD can be carried out. This includes (a) a designated de-addiction centre or other valid treatment facilities, (b) a valid and documented supply of the opioid agonist drug from the manufacturers, and (c) a valid and documented system of dispensing of the opioid agonist drug to the opioid dependent patients.

ALL THESE PRE-REQUISITES MUST BE FULFILLED.

F. GUIDELINES ON OATOD FOR OPIOID WITHDRAWAL (VIS-À-VIS CLONIDINE)

I. Role of buprenorphine (BN)/ buprenorphine-naloxone combination (BNX). (a) Inpatient.

1. Inpatient treatment of opioid withdrawal is indicated in the following circumstances: • Individuals with drug overdoses

• Individuals at risk for a severe or complicated withdrawal syndrome • Individuals with acute or chronic general medical conditions

• Individuals with a documented history of not engaging in or benefiting from treatment in a less intensive setting

• Individuals with marked psychiatric comorbidity who are an acute danger to themselves or others

• Individuals manifesting opioid use or other behaviors who are an acute danger to themselves or others

· Individuals who have not responded to less intensive treatment efforts and whose opioid use disorder poses an ongoing threat to their physical and mental health

· Patients on OST who want to discontinue their sublingual opioid but cannot do so in outpatient setting

2. Plain sublingual buprenorphine (BN) may be used in INPATIENT SETTINGS ONLY, TO BE ADMINISTERED UNDER DIRECT SUPERVISION OF NURSING STAFF. However, fixed-dose combination of buprenorphine-naloxone (BNX) should be PREFERRED because of lower potential for diversion and injectable abuse. Plain BN must not be used in any other settings (other than NACO-accredited OST Clinics for IDUs under DOT scheme, which is beyond the mandate of these Guidelines).

3. BN treatment should start after mild opioid withdrawal has started (usually 6-12 hours after last intake of illicit opioids).

4. The usual starting dose is 2-4 mg sublingual. It may be increased by another 2 mg increment after 3-4 hours if needed. Once-daily morning dose is sufficient in most cases.

5. In the Indian setting, the usual daily dose of BN is 4-10 mg.

6. The dose of BN can often be tapered off in 10-14 days in the inpatient setting. However, in certain circumstances (high-dose high-potency opioid dependence) it may be extended up to 3-4 weeks. It must not be extended beyond 4 weeks for detoxification purpose in any case.

7. Psychosocial management must be continued.

8. Towards the end of detoxification (once the acute withdrawal symptoms have settled down), various options for long-term management should be discussed with the patient and family. These include: only psychosocial management (no medicines), long-term management with oral naltrexone (plus psychosocial management), and long-term management with sublingual BNX or oral methadone if available (plus psychosocial management). The final choice depends upon various factors including medical condition, social and occupational stability, financial aspects, patient preference and family preference. It is NOT NECESSARY to prescribe OST to each and every patient (see next section).

(b) Outpatient.

II.

A large number of opioid dependent patients can be detoxified on outpatient basis.

ONLY THE FIXED-DOSE COMBINATION OF BUPRENORPHINE- NALOXONE (BNX) MUST BE USED FOR OUTPATIENT DETOXIFICATION BECAUSE OF ITS LOWER POTENTIAL FOR DIVERSION AND INJECTABLE ABUSE.

The dosage and duration remain largely the same as above (for inpatients), except that the total duration of detoxification may be slightly longer (14-21 days) in the outpatient setting. It must not be extended beyond 4 weeks for detoxification purpose in any case. Other notes and recommendations remain the same as above.

Role of Tramadol.

BN/BNX is not available in many centres/clinics as of now. Tramadol, a relatively weak opioid agonist with adjunct monoaminergic action, may be used in such circumstances as a second-level option where the severity of opioid dependence and withdrawal merits an opioid agonist.

The major advantage of tramadol is that it is available on prescription from retail pharmacists, unlike buprenorphine which has to be supplied by (or purchased from) bona fide de-addiction centres or hospitals with de-addiction facilities.

The major disadvantages of tramadol are: (a) its short duration of action, necessitating three to four times dosing per day (even long-acting preparations are administered twice a

day), and (b) its epileptogenic potential, especially at higher doses. Further it has

addictive liability of its own, being an opioid.

4. HENCE, TRAMADOL MUST NOT BE USED FOR LONG-TERM THERAPY. IT CAN ONLY BE USED FOR SHORT-TERM TREATMENT OF OPIOID WITHDRAWAL AS A SECOND-LEVEL OPTION.

5. The dose of tramadol should be tapered as follows: 50 mg tablets 2 tabs 4 times daily (8 tablets daily) for the first 3 days, then 2 tabs 3 times daily (6 tablets daily) for the next 4 days, then 1-1-2 (4 tablets daily) for the next 4 days, then 1-0-1 (2 tablets daily) for the next 3 days, to be stopped after 14 days. Thus, in a typical case, 70 tablets of tramadol 50 mg would be sufficient for one person’s detoxification. Of course, in individual severe cases the requirement may go up to a maximum of 100 tabs for a 3-week course. The central purchases have to be toned up accordingly. This state is likely to persist for the next few months at least, till the current spate of thousands of patients with their supply line of opioids suddenly cut down are taken care of.

6. Tramadol should be prescribed to patients with INJECTABLE OPIOIDS USE or NON-INJECTED BUT PURE HEROIN (“Chitta”) OR PURE OPIUM USE ONLY. IT SHOULD NOT BE USED FOR ANY AND ALL CASES OF OPIOID USE, like bhukki, doda, low-quality opium, codeine cough syrups (Rexcoff etc.), propoxyphene capsules (Proxyvon, Spasmoproxyvon, “Neela”, etc.). In such cases clonidine 0.1 mg tablets should be used instead, along with symptomatic treatment. [Note: Tramadol must not be used for patients with epilepsy or seizures due to any cause. Clonidine should be used instead. On the other hand, BNX or tramadol may be preferred for detoxification if clonidine is judged to be medically risky for use, e.g., in an elderly person with long- standing poppy husk use where use of clonidine might lead to hypotension and bradycardia. In the end, it is a clinician’s medical judgment considering the benefits vs. risk of use a particular medication for detoxification.]

7. In case a patient fails detoxification with the above, he should be referred to district or other designated drug de-addiction centres, where he can be prescribed buprenorphine- naloxone combination for further treatment.

III.

1. 2.

3. 4. 5. 6.

Role of clonidine.

Clonidine is a non-opioid medicine used for withdrawal management.

It is better than no active medicines, and somewhat less effective than buprenorphine or methadone.

Its major advantage is lack of abuse liability. Another advantage is smooth induction on naltrexone immediately after detoxification.

Its major disadvantage is risk of hypotension and bradycardia at higher doses, though at the usual dose range (0.3 to 0.6 mg per day in three divided doses) the risk is minimal.

It can definitely be used in inpatient setting, with monitoring of blood pressure and pulse rate.

In the outpatient setting, though some guidelines discourage the use of clonidine in the outpatient setting, there is a large clinical experience from many centres in India on the safe use of clonidine over more than last three decades.

Based on this, it is recommended that both BNX and clonidine are viable options for treatment of opioid withdrawal. Clonidine is preferred in: (a) inpatient setting, especially when there is no plan for long-term opioid maintenance, and (b) outpatient setting in selected cases where the severity of opioid dependence is low or where OATOD is risky or contraindicated (see E.3 above). BNX is indicated in circumstances other than above.

It is re-emphasized that only BNX sublingual preparation and no other preparation of buprenorphine (e.g., plain sublingual BN, injectable BN, BN transdermal patch) must be used for this purpose, except in inpatient setting where sublingual BN may be administered under direct supervision and ensuring that the tablets are fully dissolved in the mouth.

This brings us to the next and the most important section, on long-term opioid maintenance.

G. GUIDELINES ON OATOD FOR OPIOID MAINTENANCE (OPIOID SUBSTITUTION THERAPY, OST) (VIS-À-VIS NALTREXONE)

I. OPIOID SUBSTITUTION THERAPY (OST)

1. ONLY THE FIXED-DOSE COMBINATION OF SUBLINGUAL BUPRENORPHINE-NALOXONE (BNX) MUST BE USED BECAUSE OF LOWER POTENTIAL FOR DIVERSION AND INJECTABLE ABUSE. No other preparation of buprenorphine (e.g., plain sublingual BN, injectable BN, BN transdermal patch) must be used for this purpose. Similarly, no other opioids (e.g., tramadol, tapentadol, dextropropoxyphene, codeine, etc.) must be used for this purpose, with the exception of methadone in selected centres on pilot basis under direct observation only (i.e., no take-home dose).

2. Before starting OST, ALL the essential pre-requisites as mentioned in Section E above MUST be fulfilled. OST may be started in the inpatient or outpatient setting but is always continued in the outpatient setting only.

3. The indications for OST: Candidates for OST MUST meet criteria (a) or (b), AND all the other criteria (c) through (i):

a. Injecting opioid use (i.e., opioid use through parenteral routes by injection like IM, IV, SC, etc.) as the predominant route of use.

b. In case of non-injecting opioid use, the predominant opioid should be either relatively pure white heroin (“Chitta”), other varieties of heroin like impure street- variety brownish heroin (“smack”), pure opium, or other potent opioids. OST SHOULD NOT BE USED FOR ANY AND ALL CASES OF OPIOID USE, especially low-potency opioids like poppy husk (bhukki, doda), low-quality opium, codeine cough syrups (Rexcoff etc.), propoxyphene capsules (Proxyvon, Spasmoproxyvon, “Neela”, etc.).

c. An established diagnosis of opioid dependence, as confirmed by direct history taking from the patient himself and corroborated independently from family

members, physical and mental examination of the patient, and, if possible, urine analysis for presence of opioids. Diagnosis by “proxy” (e.g., diagnosis made only from history given by people claiming to be family members or friends) is not acceptable.

d. Duration of opioid dependence for at least two years or more.

e. At least two failed de-addiction attempts with other medications.

f. Serious medico-legal or psychosocial consequences due to opioid use/seeking

behavior.

g. Lack of social support.

h. Craving being significant reason for multiple past relapses.

i. Patient providing informed consent and undertaking for OST (see APPENDIX).

4. OST must NOT be started:

a. Without confirming and documenting opioid dependence

b. For any other substance dependence

c. With concomitant use of high doses of sedative-hypnotics or alcohol

d. In those below 18 years of age

e. With known hypersensitivity to buprenorphine or naloxone

f. In the presence of severe respiratory or hepatic impairment, or in any

circumstances where the CNS depressant effect of opioids may be accentuated

g. Without obtaining informed consent and undertaking for OST (see APPENDIX).

[Note: OST should be avoided, or may be started with caution and close medical monitoring in the presence of pregnancy, during breastfeeding, and select medical conditions such as bronchial asthma, pheochromocytoma, inflammatory bowel disease, and hypothyroidism.]

5. The patient should be started on 2-4 mg of BNX (1-2 tablets), at a time when he is in mild withdrawal, in the presence of the doctor/nurse and ensured that he uses the medication properly and completely.

6. The correct dose of BNX is that which adequately suppresses withdrawal and craving, blocks the effect of illicit opioids, but does not induce a sense of euphoria or ‘high’ or ‘kick’.

7. If withdrawal is not suppressed within 2 hours of intake, another 2 mg may be given.

8. The usual sufficient dose in Indian population is 4 mg – 8 mg (i.e., 2-4 tablets of BNX) daily. Dose requirements in excess of 10-12 mg (5-6 tablets) per day should necessitate careful medical re-evaluation or alert the clinician to a possibility of diversion.

9. BNX combination can be given as a “Take-Home” dose, with the following ESSENTIAL CLAUSES:

a. The patient must be registered in an OST Clinic with some unique identification number by which he can be linked with a computerized database.

b. The exact total number of BNX tablets dispensed to the patient must be documented in (a) patient’s treatment card, (b) patient’s case file), and (c) dispensing register maintained by the nursing staff.

c. The BNX tablets should be dispensed by pharmacist or nursing staff in the same place where the prescription is made, ideally in the same or adjacent room, or as close to it as possible.

d. The usual take-home dose should be for one week (7 days) only.

e. In case the patient asks for a take-home dose longer than 7 days, the doctor must be convinced about the genuineness and unavoidability of the situation. This can be done by detailed questioning of the patient, inspection of supporting documents if any, and confirmation from family members. The reason must be

documented in the patient’s case file, with corroborating facts.

f. Even with this exception as above, the maximum duration for which take-home

dose of BNX can be supplied is for two weeks (14 days).

g. Under such extraordinary circumstances where even this 14-day period has to

be breached (e.g., patient developing a fracture or needing an emergency surgery when his BNX consumption may go higher, or he cannot attend the OST Clinic

because of physical restrictions of movement), the doctor must personally satisfy such need, with documentary evidence in the case file, and be held accountable, for dispensing beyond the 14-day period.

10. Psychosocial management must be continued during the entire duration of OST. Depending upon the resources available, this will include (a) relapse prevention counseling, (b) motivation building, (c) coping skills improvement, (d) assertiveness training, (e) vocational guidance, counseling and liaison, (f) facilitating alternative interests and hobbies, family involvement, lifestyle modification, etc. and finally (g) constantly reminding the patient that OST is only a “Crutch” or a “Stepping Stone” for enabling full recovery to take place, when OST may be terminated. This last bit is especially vital, so that the ultimate goal of OST is not lost. The management may be provided in an individual, group or even family setting.

11. The typical duration of OST is a contentious issue. The decision regarding duration of treatment and treatment-completion (i.e., tapering of agonist maintenance medication to make patient opioid free) should only be arrived at in consultation with the patient and involves evidences that patient is stabilized, is leading an illicit opioid-free life and is socially and occupationally rehabilitated. Till such criteria are evident, the OST should continue, if required, for very long duration (running into years). However, there is evidence that unless a clear “goal for termination of OST” is maintained, there is a risk that OST may become interminable, especially in government settings with free supply of the opioid medication. Many doctors feel helpless in the situation where they feel they have simply been reduced to “legal drug peddlers” prescribing buprenorphine but the patients not showing any progress in their socio-occupational rehabilitation. Thus it is better to keep a “goalpost” in view, which may be flexible to an extent.

12. With this background, and also keeping in view the National Policy on NDPS Act recommendation, it is recommended that OST should be terminated “preferably within one year but in no case later than two years.” However, in exceptional cases,

select patients may need it for longer periods, perhaps for another year or so. In such cases, the exceptional need must be clearly documented in the case file.

13. Weaning off from buprenorphine can be difficult. Many patients find it difficult to completely discontinue buprenorphine, especially after prolonged use. In such cases, inpatient admission may be necessary for a short period (7-10 days) when detoxification is done using clonidine followed by induction on oral naltrexone for 6-12 months.

14. A system of monitoring the OST is pivotal for ensuring its success as well as minimizing its abuse. This is dealt with in the next section (Regulatory Aspects).

II. Role of Naltrexone.

1. Naltrexone is an opioid antagonist that (a) blocks the effect of illicit opioids, and (b) has purported ‘anti-craving’ effects. It is available as 50 mg oral tablets. The standard dose is 1 tablet/day, though occasionally 2 tablets/day can also be given. Periodic liver function monitoring is important.

2. The major advantage of naltrexone is that it is non-addictive, and has a long duration of action.

3. The major disadvantage of naltrexone is that patients do not like it (unlike OATOD, which is liked by the patients for obvious reason). Hence treatment retention is often low, resulting in relapse.

4. However, it has been found to be reasonably acceptable (though much less than OATOD) in Indian patients, many of whom have relatively milder opioid dependence (compared to western patients).

5. It has been suggested that the following may be good indicators of attempting naltrexone therapy rather than OST:

a. Shorter duration (less than two years) lesser severity of opioid dependence

b. Lesser severity of opioid dependence (as suggested by less withdrawal, tolerance and craving; less adverse medico-legal and/or psychosocial adverse effects; no evidence of injecting drug use; use of lower potency opioids such as poppy husk,

codeine, dextropropoxyphene or tramadol)

c. Coming to treatment for the first or second time

d. High motivation

e. Better social and occupational support

f. Higher levels of education; professionals; white-collared occupation

g. Patients on parole or probation from prison

h. Patients with co-morbid alcohol use disorders for whom treatment with anti- craving agents may be indicated

i. Patients who express a desire for remaining free of any kind of opioids including OST

j. Where the regulatory aspects of OATOD are absent.

This brings us to the final part of the OATOD, i.e., Regulatory Aspects.

H. REGULATORY ASPECTS

In order to strike the right balance between the correct use of OATOD and to minimize its improper use, certain regulatory aspects are a must. These involve the role of central and state governments, suppliers of opioid medications, and individual treatment centres and prescribers.

I. Central Govt.

1. The Drug Controller General of India (DCGI) must keep surveillance on the manufacture, supply and utilization of opioid agonist drugs (especially BN, BNX, and methadone).

2. Similarly, the Narcotics Control Bureau (NCB) should maintain similar surveillance.

II. State Govt.

1. The State Govt. must endeavor to establish OST CLINIC IN EACH DISTRICT/SUBDIVISIONAL HOSPITAL AS A PART OF THE DE- ADDICTION CENTRES. This is absolutely vital to ensure that the genuine

patients with genuine needs receive their OST in a proper way from a bona fide source. This is a pivotal step to weed out dishonest practices, black marketing, illicit diversion and abuse of buprenorphine.

2. The State Govt. should ensure adequate supply of BNX in its drug warehouses all the time.

3. The State Govt. may provide BNX free-of-cost to the patients of the Govt.-run OST Clinics.

4. The State Govt. (Drugs Control) should keep surveillance on the manufacture, supply and utilization of opioid agonist drugs (especially BN, BNX, and methadone). This may be done by evolving a system of monthly tally of such drugs purchased by the Govt., drug warehouse ‘mother’ stocks, quantity of drugs supplied to individual de-addiction centres or OST Clinics, and utilization of these drugs at these centres/clinics.

5. The State Govt. (Drugs Control) should keep surveillance on the manufacture, box labeling, licensing, and sale of various strengths of sublingual buprenorphine tablets (and its combinations with naloxone) in accordance with DCGI approval.

6. The State Govt. (Directorate of Health Services, DHS) should keep similar surveillance on the functioning of the de-addiction centres (both in the Govt. Sector AND in the private sector) and the opioid prescription bulk and patterns of individual prescribers.

III. Manufacturers and Suppliers of opioid medications

1. They must comply with DCGI directions in this regard, and provide the details of supply of drugs to various treatment centres and doctors to DCGI and DHS on a monthly basis.

IV. Individual de-addiction centres

1. The de-addiction centres, or hospitals with de-addiction facilities, must be:

a. Set up/funded/approved/recognized by the Government, under the Ministry of Health & Family Welfare (Drug De-addiction Centres, or NACO funded OST Clinics attached with Govt. Hospitals), or the Ministry of Social Justice &

Empowerment (Integrated Rehabilitation Centre for Addicts (IRCA), or

NACO-funded NGOs running OST Clinics); or

b. In case of privately run Hospitals and Nursing Homes or any other Health

Establishments, these must be monitored and approved by the State formulated Guidelines for “Minimum Standards of Care” as mentioned in the Punjab Govt. Gazette Notification in December 2010.

2. These de-addiction facilities must maintain immaculate and detailed records of opioid medications purchase from the manufacturers and supply or sale to the patients. They must maintain at least three registers:

a. Entry of each purchase of the opioid drugs in the Central Consumable Stock Register;

b. Disbursement of stock to the OST Clinic Drug Register; and

c. Supply/sale of these medicines (with exact quantity disbursed at each visit) to individual patients in the Patient Register maintained at the OST Clinic. These

three Registers must tally regarding the total quantity.

3. They must also maintain a registry of OST patients, with their identifying numbers.

There should be some mechanism to ensure that these numbers can be matched with those of other Centres, in order to ensure that the same patient does not get opioid medication from multiple sources.

4. Each patient registered in the OST Clinic must have an individual case file which would document their diagnosis (and how it was established), indications and cautions for OST, details of dosing, dispensing, and status of the patient; and psychosocial management. Termination plan from OST should also be mentioned.

5. They must issue specific quantity of BNX tablets to individual patients, which must be mentioned on their OPD/OST Clinic Cards.

6. They must be vigilant for any suspicious activity alerting to the possibility of diversion or abuse of BNX, such as:

a. Repeated requests for increased quantity of BNX in the absence of withdrawal

b. “Losing” OPD cards and asking for refill prescriptions

c. Proxy family members turning up instead of the patient for refills

d. Asking for prescriptions for long periods (beyond 7 days) without convincing circumstances or corroboration

e. Appearing drowsy or under influence of opioids at follow-up visits, etc.

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APPENDIX: INFORMED CONSENT FORM FOR OST

(Given on the following pages: English, Hindi, and Punjabi versions)

[NOTE: The English is the generic version, and the Hindi and Punjabi versions are being used in Drug De-addiction and Treatment Centre, Department of Psychiatry, PGIMER, Chandigarh, hence bearing its name. These serve as models which may be adopted by replacing the name of the Centre suitably.]