1. 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 Boston Children’s Hospital
October 24th, 2017

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

3. 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

5. Opiates Opioids 20 mg Oxycodone
Adolescent Substance Abuse: New Strategies for Primary Care 5

6. Opioid Pharmacology
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.
Opioid µ-receptor and agonist
The human body also has kappa and delta opioid receptors, though their role in addiction is not well defined.

7. CNS Areas with High Mu-Opioid Receptor Density
Brain Region
Function
Prefrontal Cortex
“Executive Functions”
Limbic System**
Pleasure and Reward
Brain Stem
Respiration, Cough
Spinal Cord
Pain
** The limbic system is one of the “oldest” portions of the brain, is critical for adaptive memory and plays an important role in addiction.

8. 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.

9. 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.
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. .
American Psychiatric Association. DSM IV-TR. Diagnostic and Statistical Manual
of Mental Disorders Text Revision Fourth Edition ed. Washington DC; 2000. 18

10. 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 COWS. A COWS is used to follow patients who are detoxing.

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

12. VIETNAM WAR Civil War METHADONE HARRISON DRUG ACT
“PAIN” AS THE 5th VITAL SIGN
Civil War
1914
1974
1860’s
1970’s
1999
METHADONE
HARRISON DRUG ACT

13. Increase in Opioid Rx, 1991-2013 No. of Rx’s (millions)
Nearly threefold increase in 22 years from 76 million to 207 million prescriptions.
Volkow ND. America’s Addiction to Opioids: Heroin and Prescription Drug Abuse. Natl. Inst. Drug Abus Available at:

14. Monitoring the Future 2015 survey
Monitoring the Future is an annual survey of 8th, 10th, and 12th graders conducted by researchers at the University of Michigan, Ann Arbor, under a grant from the National Institute on Drug Abuse, part of the National Institutes of Health. Since 1975, the survey has measured drug, alcohol, and cigarette use and related attitudes in 12th graders nationwide. Eighth and 10th graders were added to the survey in 1991.
Overall, 44,892 students from 382 public and private schools participated in the 2015 survey.

15. Monitoring the Future 2015 – 8/10/12th graders, Past Month Use
Courtesy of NIDA:

16. Monitoring the Future 2015 survey – 12th graders, Past Year Use
Courtesy of NIDA:

17. 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

19. Mass Opioid Death Rate

21. Confirmed Unintentional/Undetermined1 Opioid-related Deaths Compared to All Deaths by Age: January 2016-December 2016
1 Unintentional poisoning/overdose deaths combine unintentional and undetermined intents to account for a change in death coding that occurred in Suicides are excluded from this analysis.
Note: Due to rounding, percentages under “All Deaths” do not add up to 100%.

22. 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
Parents don’t care as much if you get caught
21%
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.
Partnership for a Drug-Free America. The Partnership Attitude Tracking Study
(PATS): Teens in grades 7 through ; May 16, 2006

23. 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.

24. 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 (12):

25. Prescribed opioid use
Opioid misuse

26. Association between prescribed opioids and opioid misuse
Prescribed pain relief
AOR: 1.33
(95% CI )
McCabe (2017): Of those adolescents who reported both medical and nonmedical use of opioids, most reported medical use prior to NUPO. (Can’t find AOR)
Source: Miech, et al. Pediatrics. (2015). 136(5):e

27. Prescribed opioid use
Opioid misuse
Alc/MJ/tobacco use

28. Gateway to Opioid Misuse
Lifetime Marijuana use
AOR: 2.44
(95% CI )
Lifetime Cigarette use
AOR: 1.25
(95% CI )
What does exposure mean here?
What type of opioid use – misuse, opioid use disorder, pills, heroin, any opioid
*summarize study here
Lifetime Alcohol use
AOR: 1.23
(95% CI )
Source: Fiellin et al. (2013) Prior use of alcohol, cigarettes, and marijuana and subsequent abuse of prescription opioids in young adults.

29. Opioid addiction Opioid misuse Prescribed opioid use Younger age
Genetic vulnerability
Mental health disorders
Motivation
Opioid misuse
Opioid addiction
Alc/MJ/tobacco use

30. Younger age*
AOR = adjusted odds ratio
*AOR decreases by 5% each year that non-medical use is delayed (after one year, AOR: 0.95 with 95% CI )
Sources: McCabe et al. Addiction. (2007). 102(12):

31. Mental health and opioid use
Familial alcohol problem/drug use
Drug abuse/Dependence
OR:
Major depression, anxiety disorder, or panic disorder
Opioid use OR: 4.43
(95% CI )
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): ) 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):

32. Motivations for opioid misuse
11.1% of 12th graders have misused prescription opioids in their lifetime
Source: McCabe et al. Add Behav (5):651-6.

33. Association between motivation for use and Opioid Use Disorder
Unprescribed pain relief
AOR: 1.8
(95% CI )
Boyd et al., 2009: Refers to the increased odds of “general substance or opioid abuse/dependence disorder.” (abstract) but later only refers to substance use disorder.
“For every additional motive endorsed, the odds of a positive score on the DAST-10 (positive score meaning moderate level of risk for substance abuse/self-treatment with opioids) increased by a factor of 1.8.” (Boyd et al., 2006)
Recreational use
AOR: 3.42
(95% CI )
Sources : 1) Boyd et al. J. Addict Dis (3): ) Boyd et al. Pediatrics. (2006). 118(6):

34. DSM-5 Criteria for Substance Use Disorder
Use in larger amounts or for longer periods of time than intended
Unsuccessful efforts to cut down or quit.
Excessive time spent taking the drug
Failure to fulfill major obligations
Continued use despite knowledge of problems
Important activities given up
Recurrent use in physically hazardous situations
Continued use despite social or interpersonal problems
Tolerance
Withdrawal
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

35. Overview of Treatment for Opioid Addiction
Non-pharmacologic
Pharmacologic
Residential Treatment
Detox
methadone, buprenorphine, clonidine, “comfort meds”
Intensive Outpatient/Partial
12-Step Fellowships and other Peer support groups
Antagonist Therapy
naltrexone PO or IM
Individual, Group, or Family Therapy
Agonist Therapy
methadone, buprenorphine
Therapeutic School/Community
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.

36. 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).

37. 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): ; Mattick et al., Buprenorphine versus methadone maintenance therapy: a randomized double-blind trial with 405 opioid-dependent patients., Addiction, 2003 Apr;98(4): ; Gowing, L., Buprenorphine for the management of opioid withdrawal., Cochrane Database Syst Rev. 2000;(3):CD
Woody, GE., et al. Extended vs. Short-term Buprenorphine-Naloxone for Treatment of Opioid-Addicted Youth. JAMA 300(17) : , 2008.

38. Medication Assisted Treatment

40. 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.

41. 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

42. 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

43. 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

44. Buprenorphine Preparations
Buprenorphine/naloxone combination product is the recommended formulation for treatment of opioid dependence
Naloxone is present only to reduce diversion to injected abuse
When taken sublingually, naloxone is poorly absorbed and has no physiologic effect
Patients who use the combination product IV or IN get primarily blocking from naloxone (and can precipitate withdrawal) rather than euphoria from a large dose of buprenorphine
Buprenorphine
Naloxone

45. Research Trials with Adolescents
Extended vs. Short-term Buprenorphine-Naloxone for Treatment of Opioid-Addicted Youth: A Randomized Trial
Study design
Participants 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
Methods
Randomized-controlled trial
Participants years old, N=156
2-week detox vs 12-week treatment
All patients also received 2 counseling sessions (1 individual and 1 group) for 12 weeks
Results
Compared to patients who received 2 week detox, those who received 12 weeks of medication assisted treatment
Had better treatment retention
Had fewer positive opioid drug tests at 4 and 8 weeks and fewer positive opioid tests overall :
No differences by 12 weeks
The authors concluded that based on their study, longer-term opioid replacement is superior to short term.
Department of Pschiatry UPENN:
JAMA.†2008;300(17):
Woody, GE., et al. JAMA 300(17) : , 2008

46. 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
Methods
Randomized-controlled trial
Participants years old, N=156
2-week detox vs 12-week treatment
All patients also received 2 counseling sessions (1 individual and 1 group) for 12 weeks
Results
Compared to patients who received 2 week detox, those who received 12 weeks of medication assisted treatment
Had better treatment retention
Had fewer positive opioid drug tests at 4 and 8 weeks and fewer positive opioid tests overall :
No differences by 12 weeks
The authors concluded that based on their study, longer-term opioid replacement is superior to short term.
Department of Pschiatry UPENN:
JAMA.†2008;300(17):
Woody, GE., et al. JAMA 300(17) : , 2008

47. Buprenorphine Waiver Training:
The Half and Half Course – specifically for Pediatricians and Family Physicians in addressing adolescent specific issues
Prescriber’s Clinical Support System

48. 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

49. 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

50. 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

51. How long will my patient be on MAT?
SUD’s are like any chronic illness requiring maintenance treatment.
Early sobriety
Longer sobriety
Relapse
Early Sobriety, etc
Patient response to treatment is individual, but should be multi-modal
Changes to lifestyle / diet / exercise help
Psychosocial support should start with MAT and continue after its discontinuation
Individual medication needs vary in short term and long term

52. Monitor Directly observed induction All medication observed by parents
Pill counts at each visit
Small prescriptions, no early refills
Random drug testing to monitor for medication compliance and use of illicit drugs

53. 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
Drug tests – you can order them!
Buprenorphine/norbuprenorphine should be in the sample if patient is taking this medication

54. 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

55. Adolescent Substance Abuse Program (ASAP)
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

56. Questions?