Adolescent Opioid Addiction

What Pediatric Primary Care Providers Need to Know About Medication Assisted Therapy for Adolescent Opioid Addiction

• Diana Deister, MS, MD

• Child and Adolescent Psychiatrist

• Adolescent Substance Use and Addictions Program

• Division of Developmental Medicine BostonChildren’s Hospital

• October 24th, 2017

1

Disclosure

Diana Deister, MS, MD has no relationships with commercial companies to disclose.

2

Learning outcomes

• Review the neurobiology of opioids

• Review the epidemiology of opioid use in adolescents and

opioid related deaths in MA

• Review the evidence for appropriate use of medication- assisted therapy (MAT) for opioid use disorders in adolescents

• Understand how to monitor patients on MAT even if they are receiving MAT elsewhere

3

4

Opiates

Opioids

5

Opioid Pharmacology

Opioid μ-receptor and agonist

• The human body produces molecules called “endorphins” that bind to mu- opioid receptors.

• Binding in the CNS results in a sense of well-being, satisfaction and pleasure, all of which are important for homeostasis.

• Opioids mimic endorphins and bind to the same receptor.

6

The human body also has kappa and delta opioid receptors, though their role in addiction is not well defined.

CNS Areas with High Mu-Opioid

Receptor Density

Brain Region

Limbic System** Spinal Cord

Function

Pleasure and Reward Pain

Prefrontal Cortex

“Executive Functions”

Brain Stem

Respiration, Cough

** The limbic system is one of the “oldest” portions of the brain, is critical for adaptive memory and plays an important role in addiction.

7

A Dynamic System

• Immediately after tissue injury, spinal cord receptors become available, allowing injured patients to tolerate large opioid doses without euphoria or overdose.

• The same large dose could result in overdose in the same individual, once the pain has subsided and receptors are downregulated.

• Pain patients on appropriate treatment should not experience a euphoric “high,” which reduces the risk of developing an addiction.

8

Physiologic Adaptations: Tolerance

and Withdrawal

• Tolerance is the need for increasing amounts of the substance to achieve the desired effect.

• Withdrawal is a physiological response to a rapid decline in receptor binding, due to either rapidly decreasing concentrations of the opioid, or presence of a blocking agent.

• Symptoms are listed on the next slide.

American Psychiatric Association. DSM IV-TR. Diagnostic and Statistical Manual 18 of Mental Disorders Text Revision Fourth Edition ed. Washington DC; 2000.

Note that tolerance and withdrawal occur whenever there has been chronic exposure to opioids – whether for long term pain management or in addiction. Tolerance and withdrawal alone are not sufficient to make a diagnosis of addiction.

.

9

Opioid Withdrawal

Dysphoric Mood

Insomnia

Nausea/Vomiting

Diarrhea

Muscle aches/cramps

Sweating

Lacrimation

Rhinorrhea

Hypertension

Tachycardia

The signs listed above are all consistent with opioid withdrawal. These can be quantified using the “Clinical Opioid Withdrawal Scale,” or COW S. A COW S is used to follow patients who are detoxing.

10

Length and Timing of Withdrawal

Period

• Short-acting opioids (e.g., heroin, hydrocodone, oxycodone): withdrawal usually begins 6-12 hours after last dose, peaks at 36-72 hours, and lasts about 5 days

• Long-acting opioids (e.g., methadone, buprenorphine): withdrawal begins 36-72 hours after last dose, peaks at 4-5 days, and can last up to 2 weeks.

11

VIETNAM WAR

Civil War

METHADONE

HARRISON DRUG ACT

“PAIN” AS THE 5th VITAL SIGN

12

Increase in Opioid Rx, 1991-2013

Volkow ND. America’s Addiction to Opioids: Heroin and Prescription Drug Abuse. Natl. Inst. Drug Abus. 2014. Available at:

http://www.drugabus e.gov/about-nida/legis lative-activities /tes timony-to-congres s /2014/americas -addiction-to-opioids -heroin-pres cription- drug – a bus e .

13

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

No. of Rx’s (millions)

Monitoring the Future 2015 survey

th

Monitoring the Future 2015 – 8/10/12 graders, Past Month Use

Courtesy of NIDA: https://teens.drugabuse.gov/teachers/infographics

th

Monitoring the Future 2015 survey – 12 graders, Past Year Use

Courtesy of NIDA: https://teens.drugabuse.gov/teachers/infographics

Rates of opioid misuse by 12th

graders

Source: Johnston LD, et al., Monitoring the Future – National Results on Adolescent Drug Use: Overview of Key Findings, 2016

17

Mass Opioid Death Rate

Rate of Unintentional Opioid Deaths

In 2015, the estimated rate of unintentional opioid-related overdose deaths was 25.8 deaths per 100,000 residents. This represents a 26% increase from the rate of 20.4 deaths per 100,000 residents in 2014.

1Unintentional poisoning/overdose deaths combine unintentional and undetermined intents to account for a change in death coding that occurred in 2005. Suicides are excluded from this analysis.

2 Opioids include heroin, opioid-based prescription painkillers, and other unspecified opioids. This report tracks opioid-related overdoses due to difficulties in identifying heroin and prescription opioids separately.

30 25 20 15 10

5

0

20.4

5.6

7.6

9.3

7.9

7.7

8.6

9.0

8.0

Rate of Unintentional/Undetermined1 Opioid2-Related Deaths Massachusetts Residents: 2000-2015

9.1

9.9

9.6

9.3

10.5 13.7

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

25.8

2015

Rate

per 100,000 Residents

Confirmed Unintentional/Undetermined1 Opioid-related Deaths Compared to All Deaths by Age: January 2016-December 2016

http://www.mass.gov/eohhs/docs/dph/stop-addiction/current-statistics/opioid-demographic-february-2017. pdf

Reason for Opioid Misuse

Easy to get from medicine cabinet

62%

Available everywhere

52%

Not illegal

51%

Easy to get through other people’s prescription

50%

Can claim you have a prescription if caught

49%

Cheap

43%

Safer to use than illegal drug

35%

Less shame attached to using

33%

Easy to purchase over the Internet

32%

Fewer side effects than street drugs

32%

Parents don’t care as much if you get caught

21%

Partnership for a Drug-Free America. The Partnership Attitude Tracking Study (PATS): Teens in grades 7 through 12 2005; May 16, 2006

Lifetime opioid misuse rates rose dramatically between 1993 and 2003, and has subsequently leveled off near 13%. Nearly half of all new recreational users of prescription pain medications are under 18.

22

Heroin

• Heroin (di-acetyl morphine) rapidly crosses the blood brain barrier, where it is metabolized to morphine, resulting in very rapid delivery of morphine to the central nervous system.

• Because it is potent and relatively inexpensive, individuals who have become addicted to opioids may switch to heroin to combat tolerance

• Increased purity of heroin since the 1990s has made snorting or smoking practical alternatives to injecting, thus lowering the barrier to initiate use.

23

Age of onset of non-medical use of

prescription drugs

Source: McCabe SE et al. Does early onset of non-medical use of prescription drugs predict subsequent prescription drug abuse and dependence? Results from a national study. Addiction 2007 102(12):1920-1930.

24

Prescribed opioid use

Opioid misuse

Association between prescribed

opioids and opioid misuse

Source: Miech, et al. Pediatrics. (2015). 136(5):e1169-77.

Prescribed pain relief

AOR: 1.33

(95% CI 1.04-1.70)

Prescribed opioid use

Opioid misuse

Alc/MJ/tobacco use

Gateway to Opioid Misuse

Lifetime

Marijuana use

AOR: 2.44

(95% CI 2.22-2.67)

Lifetime Cigarette use

AOR: 1.25

(95% CI 1.16-1.36)

Lifetime Alcohol

AOR: 1.23

(95% CI 1.11-1.36)

Source: Fiellin et al. (2013) Prior use of alcohol, cigarettes, and marijuana and subsequent abuse of prescription opioids in young adults.

use

Younger age

Genetic vulnerability Mental health disorders

Motivation

Opioid addiction

Prescribed opioid use

Opioid misuse

Alc/MJ/tobacco use

Younger age*

Sources: McCabe et al. Addiction. (2007). 102(12):1920-30

*AOR decreases by 5% each year that non-medical use is delayed

(after one year, AOR: 0.95 with 95% CI 0.94-0.97)

Mental health and opioid use

Major depression,

anxiety disorder, or

panic disorder

Opioid use OR: 4.43 (95% CI 3.64-5.38)

Familial alcohol problem/drug use

Drug abuse/Dependence

OR: 7.89-7.92

PTSD

Drug abuse/Dependence

OR: 8.68

Sources: 1) Kilpatrick DG, Acierno R, Saunders B, Resnick HS, Best CL, Schnurr PP (2000). 2) Risk Factors for Adolescent Substance Abuse and Dependence:

Data From a National Sample. J Consult and Clin Psych 63(1):19-30. 3) Sullivan MD, Edlund MJ, Zhang L, Unützer J, Wells KB (2006). Association Between Mental Health Disorders, Problem Drug Use, and Regular Prescription Opioid Use. Arch Intern Med 166(19):2087-2093.

Motivations for opioid misuse

70 60 50 40 30 20 10

0

48.1%

51.9%

Used to relieve pain Source: McCabe et al. Add Behav. 2012. 37(5):651-6.

Used to get high/experiment

Percent

Association between motivation for use

and Opioid Use Disorder

Unprescribed pain relief

AOR: 1.8

(95% CI 1.20-2.60)

Sources : 1) Boyd et al. J. Addict Dis. 2009. 28(3):232-42. 2) Boyd et al. Pediatrics. (2006). 118(6):2472-80.

Recreational use

AOR: 3.42

(95% CI 1.45-8.07)

DSM-5 Criteria for Substance Use

Disorder

1. Use in larger amounts or for longer periods of time than intended 2. Unsuccessful efforts to cut down or quit.

3. Excessive time spent taking the drug

4. Failure to fulfill major obligations

5. Continued use despite knowledge of problems

6. Important activities given up

7. Recurrent use in physically hazardous situations

8. Continued use despite social or interpersonal problems 9. Tolerance

10.Withdrawal 11.Craving

Severity is designated according to the number of symptoms endorsed: 0 – 1: No diagnosis

2 – 3: mild SUD

4 – 5 : moderate SUD 6 or more: Severe SUD

34

Overview of Treatment for Opioid

Addiction

Non-pharmacologic

Intensive Outpatient/Partial

Individual, Group, or Family

Therapy

Therapeutic School/Community

Pharmacologic

Residential Treatment

Detox

methadone, buprenorphine, clonidine, “comfort meds”

Antagonist Therapy naltrexone PO or IM

12-Step Fellowships and other Peer support groups

Agonist Therapy methadone, buprenorphine

Opioid dependence is a chronic, relapsing neurological condition; patients who remain in long-term treatment generally do best. Supportive therapy combined with pharmacologic treatment seems to produce the best outcomes. Most efficacy studies have been done with adults, and little is known about the effects of treating developing adolescents with opioid agonists.

35

Pharmacologic Treatment Options

• Detoxification: eases discomfort associated with withdrawal. Can be achieved with opioids or non-opioid “comfort meds” such as ibuprofen, trazodone and clonidine for symptomatic relief.

• Opioid Antagonist Therapy: “blocks” opioid receptor so patients cannot get high. Naltrexone used for long-term treatment can be given PO or IM.

• Opioid Agonist Therapy: long-term treatment aimed at quelling cravings, improving functioning and reducing relapse rates. Options include methadone (full agonist) and buprenorphine (partial agonist).

36

Detoxification

Adult studies have recurrently found high relapse rates after detoxification without subsequent treatment. An NIH consensus statement regarding treatment of opioid dependent adults indicated detoxification alone is insufficient treatment.

National Institute of Health Consensus Development Conference Statement, 1997.

Kosten TR, Schottenfeld R, Ziedonis D, Falcioni J. Buprenorphine versus methadone maintenance for opioid dependence. Journal of Nervous and Mental Disease 1993;181(6):358-64.; Mattick et al., Buprenorphine versus methadone maintenance therapy: a randomized double-blind trial with 405 opioid- dependent patients., Addiction, 2003 Apr;98(4):441-52.; Gowing, L., Buprenorphine for the management of opioid withdrawal., Cochrane Database Syst

Rev. 2000;(3):CD002025.

Woody, GE., et al. Extended vs. Short-term Buprenorphine-Naloxone for T reatment of Opioid-Addicted Youth. JAMA 300(17) :2003-2011, 2008.

37

Medication Assisted Treatment

38

39

Opioid Function at Receptors

• Different exogenous molecules have varying levels of “fit” at the opioid receptor, resulting in different levels of receptor activity with binding

• Substances are divided into three groups: full agonists, partial agonists and antagonists.

• In general, antagonists have the highest receptor affinity and full agonists the lowest.

40

Methadone

• Methadone – very limited options for patients under age 18

• Schedule II

• Highly regulated

• Can only be prescribed through “methadone clinics”; very few can take patients under 18 years old.

• Methadone programs are highly structured, which offers an advantage for patients, especially with limited social support

• Some patients who are not successful with the partial agonist buprenorphine can be successful with methadone.

Studies in adults comparing methadone to buprenorphine have found nearly identical treatment retention and outcomes

41

Partial Agonist Therapy:

Buprenorphine

• Partial agonists occupy the receptor and blocks binding of full strength opioids.

• Receptors are only partially activated even with full occupancy

• Less reinforcing and less commonly abused than full agonists.

• The potential for misuse is not zero

42

Buprenorphine

• Buprenorphine – FDA indication for treating patients > 16 years

• Schedule III

• Can be prescribed from physician offices

• Combination product (with naloxone) limits misuse potential

• Antagonist properties may be therapeutically useful

• Safer than methadone in overdose

• Mildly reinforcing which may support medication adherence

Studies in adults comparing methadone to buprenorphine have found nearly identical treatment retention and outcomes

43

Buprenorphine

Preparations

Buprenorphine Naloxone

• Buprenorphine/naloxone combination product is the recommended formulation for treatment of opioid dependence

• Naloxoneispresentonlytoreduce diversion to injected abuse

• Whentakensublingually,naloxoneis poorly absorbed and has no physiologic effect

• Patientswhousethecombinationproduct IV or IN get primarily blocking from naloxone (and can precipitate withdrawal) rather than euphoria from a large dose of buprenorphine

44

Research Trials with Adolescents

Extended vs. Short-term Buprenorphine-Naloxone for Treatment of Opioid-Addicted Youth: A Randomized Trial

Study design

• Participants 15-21 years old with opioid dependence via DSM-IV, N=152

• Randomly assigned to 1 of 2 groups:

• 2-week detox w/ max dose of 14 mg/day buprenorphine

(n=78)

• 12-week treatment buprenorphine-naloxone w/ max dose of 24 mg/day for 5-7 days/ week for 12 weeks (n=74)

• All participants received group and individual counseling each week for 12 weeks

Woody, GE., et al. JAMA 300(17) :2003-11, 2008

45

Research Trials with Adolescents

Extended vs. Short-term Buprenorphine-Naloxone for Treatment of Opioid-Addicted Youth: A Randomized Trial

Summary of Findings

• Fewer Opioid positive urine screens in 12-week-treatment group

• Higher retention rates in 12-week-treatment group

Woody, GE., et al. JAMA 300(17) :2003-11, 2008

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Buprenorphine Waiver Training:

The Half and Half Course – specifically for Pediatricians and Family Physicians in addressing adolescent specific issues

http://www.cvent.com/d/l4q2mj

47

Treatment with Naltrexone:

Overview

• FDA indication for

• Naltrexone is a long-acting, high affinity, competitive opioid

receptor antagonist with an active metabolite (6-β-naltrexol)

• Naltrexone blocks the euphoric effects of opioid use.

• A study with adults aged 18 and over found that compared to placebo, patients who received naltrexone had less opioid use, better treatment retention and fewer cravings.

• There are no data regarding the efficacy or adverse effects profile in children.

Krupitsky et al., 201

48

Naltrexone: Pharmacology

• 5-40% bioavailability when administered orally

• Metabolized in the liver, renal excretion

• Effective opioid blockade lasts from 1-3 days depending on dose

• Recommended adult dose is 50 mg daily or 380 mg IM monthly

• Naltrexone can precipitate opioid withdrawal; start after the withdrawal period is completed – generally 7 days, longer if patient had been using long acting opioid such as methadone

49

Efficacy of Naltrexone: oral vs. XR

injection

• Retention in treatment is used as a primary outcome of treatment with NTX as a great majority of patients retained on NTX are abstinent from opioids

• Treatment retention rate in groups treated with XR preparations is twice that of the oral group, approximating 50-70% at 6 months

50

How long will my patient

be on MAT?

• SUD’s are like any chronic illness requiring maintenance treatment.

• Earlysobriety

• Longersobriety

• Relapse

• Early Sobriety, etc

• Patient response to treatment is individual, but should be multi-modal

• Changestolifestyle/diet/exercisehelp

• PsychosocialsupportshouldstartwithMATandcontinueafterits

discontinuation

• Individualmedicationneedsvaryinshorttermandlongterm

Monitor

52

MAT with outside provider

• Get a release to speak with the provider that specifically states substance abuse treatment is part of the information being communicated

• Notify external provider about critical medical updates

• Monitoring patients who get MAT somewhere else

• Drugtests–youcanorderthem!

• Buprenorphine/norbuprenorphine should be in the sample if patient is taking this medication

Conclusions

• Opioid use among adolescents and young adults is a serious problem with potentially life-threatening consequences

• Pediatric health care providers can have a significant impact on this problem by:

• Recognizing that adolescents can develop opioid use disorders

• Using caution in prescribing opioids

• Counseling patients and parents about prescription drug

misuse

• Supporting medication-assisted treatment for patients with severe opioid use disorders

54

Acknowledgements

Adolescent Substance Abuse Program (ASAP)

Clinicians

• Diana Deister, MD, MS

• Leslie Green, MSW, LICSW

• Scott Hadland, MD, MPH

• Sharon Levy, MD, MPH

• Shannon Mountain-Ray, MSW, LICSW

• Patricia Schram, MD

• Jesse Schram, LICSW

• Nicholas Chadi, MD

Research Assistants

• Dylan Kaye, BA

• Lily Rabinow, MS

• Parissa Salimian, BA

• Meghana Vijaysimha, MPH

• Rosemary Ziemnik, BS

Teaching Collaborators

• Pamela Burke, PhD, RN, FNP, PNP, FSAHM, FAAN

• Linda Malone, DNP, RN, CPNP

• Sarah Pitts, MD

• Marianne Pugatch, MSW, LICSW • Jennifer Putney, PhD, LICSW

Research Collaborators

• Co-principal investigators: Elissa Weitzman, ScD, Msc & Sharon Levy, MD, MPH

• Elizabeth Harstad, MD, MPH

• Lauren Wisk, PhD

Research Project Management

• Julie Lunstead, MPH, Program Manager • Erin Huang, MPH, Data Manager

PCSS MAT Training

Providers’ Clinical Support System for Medication Assisted Treatment

55

Questions?

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