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Emergence of Medication Assisted Therapy (MAT) in Addiction Treatment George Woody, MD Department of Psychiatry, Treatment Research Institute, and Delaware Valley Node of NIDA Clinical Trials Network University of Pennsylvania. Disclosures. NIDA funding

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  1. Emergence of Medication Assisted Therapy (MAT) in Addiction Treatment George Woody, MDDepartment of Psychiatry, Treatment Research Institute, and Delaware Valley Node of NIDA Clinical Trials NetworkUniversity of Pennsylvania

  2. Disclosures • NIDA funding • Reckitt Benckiser provided medication for buprenorphine studies via NIDA • Alkermes is providing VIVITROL® (naltrexone for extended-release injectable suspension) & matching placebo for amphetamine treatment project • Some slides from Drs. O’Brien, Ling and Dackis

  3. Overview of Presentation • Background • Counseling & medications • Alcohol medications • Opioid medications • Amphetamine medications • Nicotine medications • Cocaine medications • Vaccines • Psychiatric medications for co-morbidities

  4. Most Important Point of Talk(If you remember nothing else) • New medications are being developed • Old medications are being used and studied for new indications • Keep informed about what is going on and try to apply it • Though there is no “magic bullet”, these medications can help your patients

  5. Background • The Big Book says members should take advantage of medical advances • Somehow, this message changed to a “no medication” philosophy, probably based on: • Observations that abuseable substances often precipitate relapse, even if used in small amounts • Ambivalence about addiction as a personality/social/motivational problem rather than a medical disorder • Historical absence of medical profession from addiction treatment

  6. Background (continued) • Result was generalization to any medication, even those with no addiction risk (lithium, antidepressants, others) • Addiction treatment became based (entirely) on psychosocial therapies + 12-Step participation • But, with two exceptions • Benzodiazepines for alcohol withdrawal • Evidence it prevents DTs • Antabuse for preventing relapse to alcohol • Things have been changing (slowly!) • “Evidence-based medicine” an important factor

  7. Background (continued) • Methadone maintenance the first “breakthrough” • But opposition continues • Not allowed in a few states and countries • Data show no real problem combining psychosocial therapy with medication • In fact, medication magnifies counseling effect • i.e. Methadone and Suboxone – no meds=no patients • And, counseling magnifies medication effects – Especially for patients with many psychosocial problems

  8. Example: Methadone Only vs. Methadone + Counseling in Maintenance Rx - Positive Urines

  9. Previous Slide Example of Counseling Magnifying Methadone Effect • But – important to consider: • Patients were veterans; many had psychiatric, medical, family/social, legal problems • 30% did OK with methadone alone • Probably those with fewer co-morbidities • Patients seeking Suboxone may be more similar to these 30% and do fine with medication alone because: • More working • Shorter period of addiction • Fewer co-morbidities

  10. Alcohol Medications • Benzodiazepines for withdrawal • Antabuse - not popular with patients or most clinicians: • Drug interactions – inhibits drug metabolism • Cardiovascular events possible if drink • Naltrexone for relapse prevention • Attenuates reward by reducing transmission in the dopamine/endorphin system • Works best if used after patient detoxified • Seems to work mainly in persons with a certain genetic alteration, not in those without it

  11. Pharmacological Treatments for Alcoholism Craving Scores by Week Mean (SEM) Craving Score (0-9) 0 1 2 3 4 5 6 7 8 9 10 11 12 Weeks on Medication

  12. Subjective “high” in Naltrexone and Placebo Subjects 0.1 0 - 0.1 - 0.2 - 0.3 - 0.4 - 0.5 mean “high” rating * Naltrexone Placebo * p<.05

  13. Non-relapse “Survival” 1.0 0.9 0.8 0.7 Cummulative Proportion with No Relapse 0.6 0.5 0.4 0.3 Naltrexone HCL (N=35) Placebo (N=35) 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 No. of Weeks Receiving Medication Volpicelli et al, Arch Gen Psychiatry, 1992; 49: 876-880

  14. Rates of Never Relapsing According to Treatment Group (n=97) Naltrexone/coping skills Naltrexone/supportive therapy Placebo/coping skills Placebo/supportive therapy 100 80 60 40 n=97 20 0 0 20 40 60 80 Days O’Malley et al, Arch of Gen Psychiatry, Vol 49, Nov 1992

  15. Hypothesis: Why it Works Dopamine release necessary for “rewarding” effects of alcohol Alcohol causes release of endogenous opioids which release dopamine Naltrexone blocks endogenous opioid release

  16. Change in bEndorphin Levels after Alcohol Consumption % change in plasma b-endorphin levels Minutes after alcohol consumption

  17. 1.0 1.0 1.0 .9 .9 .9 Naltrexone / Naltrexone / Naltrexone / .8 .8 .8 Asp40 Allele (A/G, G/G) Asp40 Allele (A/G, G/G) Asp40 Allele (A/G, G/G) .7 .7 .7 Naltrexone Naltrexone Naltrexone .6 .6 .6 ProportionNonrelapsed Asn40 Allele (A/A) Asn40 Allele (A/A) Asn40 Allele (A/A) Placebo / Placebo / Placebo / .5 .5 .5 Asp40 Allele (A/G, G/G) Asp40 Allele (A/G, G/G) Asp40 Allele (A/G, G/G) .4 .4 .4 Placebo / Placebo / Placebo / Asn40 Allele (A/Al) Asn40 Allele (A/Al) Asn40 Allele (A/Al) .3 .3 .3 .2 .2 .2 .1 .1 .1 0.0 0.0 0.0 0 0 0 14 14 14 28 28 28 42 42 42 56 56 56 70 70 84 84 84 Relapse Rate by Genotype Days

  18. Alcohol Medications (cont.) Topiramate • Multiple mechanisms of action • 1. Na+ and CA++ channel blockade • 2. GABA potentiation • 3. Glutamate antagonism • 4. Carbonic anhydrase inhibition

  19. Results: alcohol use Days of Alcohol Use (in Heavy Drinkers) P = .04

  20. Results: abstinence rates % Patients with 3 Consecutive Abstinent Weeks p < .05

  21. Conclusions • Topiramate • Well tolerated with slow dose titration • Reduces cocaine use & promotes stable abstinence • May be beneficial in cocaine /alcohol dependence

  22. Alcohol Medications (cont.) • Acamprosate (Campral) - A synthetic compound similar to homotaurine, a naturally-occurring amino acid • Reduces CNS excitability associated with alcohol withdrawal, possibly by blocking glutamatergic (excites) N-methyl-D-aspartate receptors (NMDA) while activating gamma-aminobutyric acid (GABA; calms) receptors • NMDA receptors excite; GABA receptors calm • European studies show relapse prevention effect • U.S. studies do not • Possibly because most European patients had residential rx before outpatient rx

  23. Final Thought on Alcohol Medications • A way to “controlled drinking” for some? • BIG controversy! • VIVITROL® - extended release naltrexone • Blood level for 28 days • Aetna found it reduced ER and other expensive services for a net saving

  24. Opioid Addiction Medications • Methadone and Suboxone (buprenorphine/naloxone) - Work for maintenance & detox • When used for maintenance • Reduce drug use, HIV risk, overdose death, crime • Improve quality of life, psychiatric symptoms • Buprenorphine implants for maintenance (Probuphine) • Inserted under skin on inner part of arm • Last 6 months; must be removed • Effective in one study & 2nd underway • May get FDA approval

  25. Opioid Addiction Medications: Detox • Methadone & buprenorphine work best in short term • Poor results in long-term • Other medications • Clonidine (an antihypertensive) • sedating; suppresses autonomic signs of withdrawal but not subjective distress • Lofexidine – similar to clonidine • Less hypotension • Approved in Europe but not in U.S.

  26. Clonidine vs. Buprenorphine: Percent Present and Clean from Inpatient detox at Days 13-14 (Ling et al)

  27. Clonidine vs. Buprenorphine: Percent Present and Clean from Outpatient Detox at Days 13-14 (Ling et al)

  28. Opioid Addiction – Relapse Prevention • Naltrexone – oral, injectable (VIVITROL® ), and implant (Vivitrol only approved for alcohol dependence; no naltrexone implants approved in US) • Interest and adherence to oral naltrexone in US has been low except for: • Highly motivated patients • Those threatened by severe consequenses if relapse (health care professionals in monitoring programs, probation/parole)

  29. Opioid Relapse Prevention: Naltrexone Implants –Emerging Data • NIDA sponsored implant studies in early 1970s, but no preparations were safe and effective • New technologies improved the situation • Example: PRODETOXONE - Approved in Russia, 2005 - 1000 mg naltrexone - 2-3 cm incision; insert under skin of abdominal wall - Blocks opioids for 3 months

  30. Naltrexone Implant Study in St. Petersburg(Interim analysis of 191 patients) • 6- month randomized trial • Ntx implant + ntx oral placebo • Ntx oral + ntx implant placebo • Ntx oral placebo/ntx implant placebo

  31. 60% 40% 20% 68% 60% 15% 0% OP+PI ON+PI OP+NI 6 Month Relapse Rate (end of treatment) OP+NI < OP+PI (P<0,001) OP+NI < ON+PI (P<0,001)

  32. Naltrexone Implants (cont) • Effects similar in final sample of 306 patients • No serious adverse events • But, more superficial infections in implant patients • Australia, China also have implants • Australian implant used in over 3000 patients • None yet approved by their governments • Alkermes study of Vivitrol for relapse prevention to opioid addiction recently completed in Russia • Results show strong effect of Vivitrol over placebo • Could result in US approval for opioid relapse prevention

  33. Amphetamine Medications • No pharmacotherapy found effective until recent Swedish trial • Significant effect with oral naltrexone in randomized, placebo-controlled trial of 80 patients (Jayaram-Lindstrom et al, 2008)

  34. Amphetamine in Iceland:Dependent Patients Admitted to Vogur: 1984-2008

  35. % of Patients Admitted to Vogur with Diagnosis of Amphetamine Addiction: 1984-2008

  36. Iceland Study (NIDA Funding; Vivitrol Provided by Alkermes) • 100 amphetamine dependent patients starting outpatient treatment • Randomized 1:1 to VIVITROL® or VIVITROL® placebo • Randomization stratified according to male/female; injecting/non-injecting • Medication continued for 6 months • Primary outcome – proportion of amphetamine negative urine tests during weeks 1-24 of outpatient treatment • Results available in 2 years

  37. Other Outcomes: HIV Risk • Results should provide signal if Vivitrol helps prevent relapse to amphetamine addiction • Some in Iceland are injecting • Though HIV prevalence low in Iceland, it can change rapidly if injecting continues • Effective treatments reduce HIV risk • Best shown for methadone, but any effective treatment will do it • Example - naltrexone

  38. HIV Risk Assessment Battery Data: Naltrexone for Relapse to Opioid Addiction in St. Petersburg Sex risk Drug risk 8,00 ] 6,00 Score ] ] 4,00 2,00 ] remission relapse remission relapse

  39. Cocaine Addiction Medications • Meds may be different than those for amphetamine • Many studies & leads • No clearly positive results • Very important problem, so we keep trying • Most promising current medication is modafinil (Provigil) • Releases dopamine, norepinephrine and histamine • Low abuse liability – Schedule IV • Approved for treatment of narcolepsy but being used “off label” to counteract daytime sleepiness, fatigue, etc

  40. ModafinilEfficacy in Cocaine Dependenceand Abuse Potential Universityof Pennsylvania - Center for Studies in Addiction

  41. Blocks cocaine-induced euphoria Three controlled human laboratory studies Reverses cocaine-induced neuroadaptations Agonist Therapy Minimal abuse potential Promotes abstinence in 2/3 clinical trials Not effective in alcohol dependence Possible gender effect Modafinil for Cocaine Dependence

  42. Dopamine transporter antagonist Slow onset after oral administration (4 hrs to peak) Low water solubility (IV not feasible) Unstable at high temperatures (Smoking not feasible) Relatively low potency vs psychostimulants Methylphenidate 20 mg vs. modafinil 200 mg Abuse Characteristics of Modafinil Low potency DAT antagonist with a slow onset of action

  43. 6 5 4 3 2 1 -1 0 1 2 3 4 5 6 7 8 Modafinil Subjective Effects in Humans Amphetamine 15 mg Modafinil 300 mg Caffeine 300 mg Placebo ARCI: Amphetamine Scale Hours Postdose Warot 1993

  44. Post-marketing modafinil surveillance • Modafinil has little potential for abuse • Limited reports of euphoric effects • Increased mainstream publicity • Extensive Internet postings on off-label use • Several reports of decreased efficacy over time Post-Marketing Experience with Modafinil “Information to date continues to support the conclusion that the abuse liability of modafinil, if it exists, is low.” Myrick 2004

  45. Nicotine Addiction Medications “Smoking is the leading preventable cause of disease and death in the United States” 440,000 premature deaths per year Cost to the nation, $157 billion dollars Report of Surgeon General on the Health Effects of Smoking, 2004

  46. Pharmacology of nicotine addiction % of Individuals Exposed to a Drug Who Become Addicted O’Brien, Goodman and Gillman, 1996

  47. Current treatments Cold turkey Self-help Cessation counseling Medications Nicotine replacement Bupropion SR (Zyban®) Varenicline (Chantix®) Combination of counseling + medication

  48. Current treatments Self-help approaches Cold turkey 5% long-term abstinence* Leaflets, internet, posters 3-14% long-term abstinence** *Fiore et al., JAMA, 288(14):1768-71, 2002 **Curry et al., J.Consult. & Clin. Psychology, 61(5):305-19 1993

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