1. Medication Assisted Treatment Vijay Amarendran, MD, Dip ABAM 08/01/16

2. Together We’re Stronger Overview Epidemiology of opiate addiction Neurobiology of opioid addiction History of MAT Pharmacology of Medications Evidence for effectiveness Questions

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9. Abuse versus Addiction versus Dependence

10. Together We’re Stronger Choice or disease

11. Together We’re Stronger Reward Pathway

12. Together We’re Stronger Other brain changes

13. Together We’re Stronger History of MAT Methadone developed in 1930s Heroin epidemic in large American cities 1950-1961, rapidly increasing death rates of heroin injectors drastically from 7.2 deaths per 10,000, the number grew to 35.8 deaths per 10,000

14. Together We’re Stronger History Initially used to detox heroin addicted patients over a week or 10 days. (90% relapsed) Rehab facilities data showed relapse rates of 86% to 97% Researchers at the Rockefeller Foundation(early 1960’s)- developed dosing heroin addicted patients with methadone. Proposed to the administrators of New York City, where approximately half the country’s heroin users lived, that methadone programs be established to treat these patients and get them off the illicit drug.

15. Together We’re Stronger History In early 1970's more Methadone maintenance programs were opened around the country with public funding The findings of major early studies(60s and 70s) have been consistent. Methadone maintenance reduces and/or eliminates the use of heroin, reduces the death rates and criminality associated with heroin use, and allows patients to improve their health and social productivity

16. Together We’re Stronger History Late 1980s Naltrexone, an opiate antagonist developed and used in alcohol and opiate addiction. Modest efficacy, compliance remained as major issues Long acting injectable approved by FDA in 2010 In 2002, sublingual buprenorphine/ naloxone (Suboxone) and buprenorphine (Subutex)was approved to treat opiate addiction as a prescription

17. Together We’re Stronger Opioid withdrawal symptoms Flu like symptoms Nausea and vomiting Diarrhea Runny nose and eyes Rapid breathing Tremors Increased heart rate and blood pressure Chills and hot flashes Enlarged pupils Sweating Goosebumps Stomach cramps Muscle and joint aches Drooling Yawning

18. Together We’re Stronger Psychological symptoms Long lasting Fluctuating intensity Severe cravings Poor sleep Irritability Restlesness Anxiety Mood fluctuations Confusion Lack of energy Agitation Poor concentration Low motivation

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20. Advantages of MAT Decreased cravings and withdrawal symptoms Significantly reduced drug use, if not cessation Significantly less chances of contracting HIV, Hepatitis B, Hepatitis C and ?tuberculosis Decreased chance of overdose death Decreased crime and jail time Better chances of gainful employment Reduction of number of days hospitalized Better pregnancy outcomes

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23. Methadone versus Buprenorphine (Suboxone) Similarities Opiate receptor agonists Long acting Effectively treat withdrawals and quench cravings Relatively less likely to produce euphoric effects Less likely to cause fluctuating blood levels Differences Partial versus full agonist Plateau effect with Buprenorphine Risk of respiratory depression with overdose Mu receptor affinity Lower risk of abuse addiction and side effects Sublingual Regulatory requirements

24. Together We’re Stronger Methadone Pharmacology Long acting opioid Half life 24 to 36 hours Peak blood levels in 2 to 4 hours Pain relief for 4 to 6 hours Metabolized by liver enzymes Rapid metabolism in some patients and during pregnancy- can split dose to counter this

25. Together We’re Stronger Pharmacology Therapeutic doses attenuate or block euphoric effects of heroin Does not have any active metabolites Steady state reached in 5 to 7 days

26. Together We’re Stronger Side Effects Sedation Overdose risk Weight gain Swelling of legs Heart Rhythm abnormalities Liver toxicity Constipation Neonatal abstinence syndrome Sexual side effects ?teeth cavities Insomnia Dry mouth Nausea and vomiting Itching

27. Together We’re Stronger Federal regulatory requirements 1 year of addiction 18 or older Must provide medical, counseling, educational, nursing assessment Must provide or refer to prenatal services Must provide HIV/HBV/HCV testing and prevention counseling Must test for drugs at least 8 times a year Must maintain records confidentially Initial dose cannot exceed 30 mg Dispense 365 days a year(in Maine) Courtesy dosing “Take home” doses Treatment plan must be updated every 3 months

28. Together We’re Stronger 8 point criteria Absence of recent abuse of drugs Regularity of clinic attendance Absence of serious behavioral problems at the clinic Absence of known recent criminal activity Stability of the patient's home environment and social relationships Length of time in comprehensive maintenance treatment Assurance that take-home medication can be safely stored within the patient's home Whether the rehabilitative benefit the patient derived from decreasing the frequency of clinic attendance outweighs the potential risks of diversion.

29. Together We’re Stronger Cochrane review 2009 To evaluate the effects of methadone maintenance treatment (MMT) compared with treatments that did not involve opioid replacement therapy (i.e., detoxification, offer of drug-free rehabilitation, placebo medication, wait- list controls) Methadone appeared statistically significantly more effective than non-pharmacological approaches in retaining patients in treatment and in the suppression of heroin use as measured by self report and urine/hair analysis (6 RCTs, RR = 0.66), but not statistically different in criminal activity (3 RCTs, RR=0.39) or mortality (4 RCTs, RR=0.48)

30. Together We’re Stronger Trials reviewed N=32 to 382 Duration 45 days to 2 years

31. Together We’re Stronger Cochrane review 2009 Methadone is an effective maintenance therapy intervention for the treatment of heroin dependence as it retains patients in treatment and decreases heroin use better than treatments that do not utilise opioid replacement therapy. It does not show a statistically significant superior effect on criminal activity or mortality.

32. Together We’re Stronger SAMHSA AEB series Analysed studies from 1995-2012 Rated the level of evidence (high, moderate, and low) based on bench marks for the number of studies and quality of their methodology

33. Together We’re Stronger SAMHSA AEB series 7 RCTs 2 Quasi-experimental studies

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37. AEB Series

38. Together We’re Stronger ASAM National Practice Guideline 2015 49 guidelines identified, 34 used in review, 21 addressed Methadone treatment. Methadone is a treatment option recommended for patients who are physiologically dependent on opioids, able to give informed consent, and who have no specific contra- indications

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40. Buprenorphine/Naloxone (Suboxone) High Affinity Low Intrinsic activity Oral bioavailability Abuse potential Weaker pain killer Metabolized by the liver Special license Cap of 100 patients Milder withdrawal Slower onset Naloxone to deter abuse Subutex (Buprenorphine) in pregnancy

41. Together We’re Stronger Side effects Respiratory depression Liver toxicity (IV use) Neonatal abstinence syndrome Precipitated withdrawal Constipation Diversion

42. Together We’re Stronger Buprenorphine Cochrane review 2014 Effective medication in the maintenance treatment of heroin dependence, retaining people in treatment at any dose above 2 mg Suppresses illicit opioid use at doses 16 mg or greater Compared to methadone, retains fewer people when doses are flexibly delivered and at low fixed doses At fixed medium or high doses, as effective as methadone in retention and suppression of illicit opioid use Methadone is superior to buprenorphine in retaining people in treatment, and methadone equally suppresses illicit opioid use

43. Together We’re Stronger Oral Naltrexone- Cochrane review 2011 Not better than placebo for reincarceration rate Retention rate low (28%) Overall inconclusive and not yet considered a proven treatment

44. Together We’re Stronger Factors influencing treatment response Childhood trauma Co-morbid psychiatric illness Poor psychosocial support network Children Professionals Religious affiliation Older age Marital status Criminal history Drug use pattern

45. Together We’re Stronger Conclusions Opioid addiction is a neurobiological disorder that affects decision making, reward processing and behavioral inhibition Traditional treatment has led to and continues to lead to high relapse rates Relative safety and efficacy of Methadone and Buprenorphine well established Access to treatment is an issue

46. Together We’re Stronger More information for patients and families http://store.samhsa.gov/product/The-Facts-about- Buprenorphine-for-Treatment-of-Opioid- Addiction/SMA15-4442http://store.samhsa.gov/product/The-Facts-about- Buprenorphine-for-Treatment-of-Opioid- Addiction/SMA15-4442 http://store.samhsa.gov/product/Medication-Assisted- Treatment-for-Opioid-Addiction-Facts-for-Families-and- Friends/SMA15-4443http://store.samhsa.gov/product/Medication-Assisted- Treatment-for-Opioid-Addiction-Facts-for-Families-and- Friends/SMA15-4443 http://store.samhsa.gov/product/What-Every-Individual- Needs-to-Know-About-Methadone-Maintenance/SMA06- 4123http://store.samhsa.gov/product/What-Every-Individual- Needs-to-Know-About-Methadone-Maintenance/SMA06- 4123

47. Together We’re Stronger References Review of Neurobiology of addiction George and Koob 2010 Methadone maintenance therapy: A review of historical and clinical issues Joseph et al 2000 Methadone Maintenance Therapy Cochrane review 2009 SAMHSA AEB series 2012 ASAM practice guidelines 2015 Buprenorphine Cochrane Review 2014 Oral Naltrexone Cochrane Review 2011

48. Together We’re Stronger Questions