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.
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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
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4
Opiates
Opioids
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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.
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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.
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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.
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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.
.
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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.
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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.
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VIETNAM WAR
Civil War
METHADONE
HARRISON DRUG ACT
“PAIN” AS THE 5th VITAL SIGN
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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 .
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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
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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
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.
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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.
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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.
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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
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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.
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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).
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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.
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Medication Assisted Treatment
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Questions?
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