Update on Relapse Prevention Medications for Addiction. Outline. A partial catalog of the future. Treatment Misadventures

Transcription

1 Update on Relapse Prevention Medications for Addiction Marc Fishman MD Johns Hopkins University Mountain Manor Treatment Center Tuerk Conference 5/10/11 Outline Conceptual framework for anti-addiction medications Some biology and potential mechanisms The present: What we already have A partial catalog of the future: New developments and the pipeline Delivery, logistics, barriers, implementation Discussion Treatment Misadventures A partial catalog of the future New uses for existing meds Vigabatrin for cocaine XR-Naltrexone for opioids XR-Naltrexone for stimulants Pregabalin for benzos New meds Cocaine vaccine Implant naltrexone Implant buprenorphine Cannabinoid antagonists NK-1 antagonists for stress-induced relapse Disulfiram for cocaine Metabolic enzymes Buspirone for stimulants What we already have Methadone Buprenorphine Nicotine replacement What we already have (but don t use enough) Disulfiram Nicotine anti-craving Naltrexone for alcohol Acamprosate 1

2 What we recently got % Abstinent 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% weeks 9-12 weeks 9-24 weeks 9-52 Varenicline Bupropion Placebo XR-naltrexone for opioids Naltrexone Pure competitive antagonist of opioid receptors Very effectively prevents and reverses all opioid effects FDA approved for Oral NTX for opioid dependence 1984 Oral NTX for alcohol dependence 1996 Injectable XR-NTX for alcohol dependence 2004 Injectable XR-NTX for opioid dependence 2010 Conceptual Issues Conceptual framework for addiction medications Should medications be used in the treatment of addiction? Is this a philosophical question? Is this a scientific question? Is this a practical question? 2

3 Rationale for medication Reduce craving Impact the physiology of dependence Protect against lapses, which should be expected Reduce high rates of relapse Improve treatment retention Improve outcomes of current psychosocial treatments Anti-addiction medications - potential effects Block the effects of action Reduce reward Prevent withdrawal Act as non-impairing substitute Enhance negative consequences Prevent relapse after abstinence Vocabulary Agonist - drug that activates a receptor Antagonist - drug that blocks a receptor Partial agonist/antagonist - drug that does some of both Vocabulary Craving - subjective sense of hunger for substance Triggers salience of environmental cues, associated with behaviors (conscious or unconscious) Reinforcement - response that increases likelihood of behavior Positive reinforcement - positive stimulus (reward craving) that increases likelihood of behavior Negative reinforcement - removal of noxious stimulus (relief craving) that increases likelihood of behavior Punishment - noxious stimulus that decreases likelihood of behavior Multiple Mechanisms of Action Agonists Antagonists Modulators of reinforcement pathways Aversive agents Modulators of metabolism Immunization Modulators of sustaining or re-instatement pathways Others? 3

4 Any meds for cocaine? A partial catalog for the future New developments and pipeline We ve tried everything A few things are fair at best Bupropion Desipramine Modafenil Long-acting ADHD stimulants (Adderall-XR) Can we create synergy by adding contingency management? CM is one of the most potent treatments we have, but many adoption and sustainability barriers Some suggestion that the combination is more than additive 2 complimentary approaches to the reward system? jumpstarting the meds? Vigabatrin Currently approved for certain types of epilepsy Anti-craving properties for cocaine Works by enhancing GABA (blocks enzyme that breaks down GABA) Side effects: peripheral vision problems with ongoing use > 2 years VTA Nucleus Accumbens For more information or to refer a patient Call Erin Curran

5 Naltrexone for Amphetamine Relapse Prevention? 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) Cannabinoid antagonists Endogenous cannibinoid system: receptors and ligands (receptor binders) Active in pain, hunger, reward, bone growth Cannabinoid antagonists decrease animal self-administration of cocaine, and reinstatement of cocaine seeking after extinction CB-1 gene deletion nearly eliminate cocaine effects and addiction in rats Cannabinoid antagonists Could cannabinoid antagonists have a role in cocaine or MJ addiction? Various compounds being studied agonists, antagonists, reuptake inhibiotrs, synthesis inhibitors, etc One (rimonabant) came close to approval, but rejected because of side effects Implant Naltrexone for Opioid Dependence Is an implantable extended release naltrexone formulation effective for treatment of opioid dependence? Arch Gen Psychiatry. 2009;66(10): Implant naltrexone Background The pure opioid antagonist naltrexone has good lab efficacy for opioid dependence but terrible effectiveness in standard community treatment because of noncompliance Injectable XR-NTX formulations are a huge advance the best study to date showed 62% opioid neg urine over 2 months (vs 25% placebo), but nevertheless 18% did not return for a 2 nd dose at 1 month and 32% dropped out by 2 months 5

6 Implant naltrexone Intervention Implant of slow release naltrexone tablets delivered with abdominal incision as SQ injection of 2.3 g NTX, with previous lab estimates of 5.5 month duration Implant naltrexone Method Implant of slow release naltrexone tablets delivered with abdominal incision as SQ injection of 2.3 g NTX, with previous lab estimates of 5.5 month duration Heroin dependent subjects (n=69) randomized to a 6 month trial of single dose of NTX implant + placebo pills vs. placebo implant plus oral NTX 50 mg/d Follow up monthly for 6 months Designated helper to supervise oral medication compliance Implant naltrexone Results Implant naltrexone Results Results Naltrexone blood levels Men Women >2ng/mL 56d 43d >1ng/mL 101d 124d Hulse, G. K. et al. Arch Gen Psychiatry 2009;66: Copyright restrictions may apply." Cocaine vaccine Summary question Can we treat cocaine dependence immunologically with a vaccine? Arch Gen Psychiatry. 2009;66(10): Cocaine vaccine Background What about using antibody clearance of active drug through vaccination as a strategy? Cocaine derivative molecule linked to protein subunit of cholera toxin (chosen for immunogenicity and safety) -- Produces cocaine specific IgG Cocaine produces euphoria at very low levels (0.5µM), so strategy requires high concentrations and effectiveness of antibody (estimate 43µg/mL) Previous work predicts need for series of 5 vaccinations to produce those levels with peak antibody levels at week 12-16, also predicts 25-30% make low antibody levels 6

7 Cocaine vaccine Results 38% of vaccine receivers achieved sufficient antibody Of those, 76% required > 3 doses, and 38% required > 4 doses 62% of vaccine receivers did not achieve sufficient Ab after 5 doses All Ab levels decline after week 16 Cocaine vaccine Results From weeks 9-16 high Ab group has greater # cocaine free UDS than low Ab group and than placebo No difference weeks Exclude early dropouts (insufficient vaccine exposure) and early abstinence achievers (abstinence not related to vaccine) -- rate of achieving no new cocaine use >50% of the time is greater in the high Ab group (53%) than in the low Ab group (23%) Cocaine vaccine Results Cocaine vaccine Conclusions Modest results, hard to get adequate Ab levels, response not sustained, feasibility unclear However very exciting proof of concept opens up an entire new world of therapeutics (also being pursued with nicotine, angiotensin) Bottom line: we want it eventually, not yet ready for prime time, keep working out the kinks Copyright restrictions may apply." Martell, B. A. et al. Arch Gen Psychiatry 2009;66: Dronabinol for MJ dependence No difference in MJ use Looking for boosting effects of other meds? Pregabalin for alcohol and benzodiazepines Pregabalin activates the GABA system (which are central to action of alcohol and BZDs) Some promising early research Gabapentin also of some interest for symptom reduction during detox 7

8 Long-acting buperenorphine - probuphine Subcutaneous buprenorphine rods implanted in upper arm 6 months duration Dosing adjustable by # of rods Significant reduction in opioid positive urines Disadvantage: requires removal Look for approval this year or next Lofexidine for opioid detox Cousin of clonidine but better side effect profile, easier to use Available currently in UK May be alternative to opioid agonist detox, especially in transition to naltrexone induction Relapse and stress sensitivity Alcoholics are more stress sensitive Shock and hot plate in rates Negative emotional stimuli in humans Stress response is major risk for reinstatement of drinking (relapse) following post-dependent abstinence NK-1 antagonist for possible anti-stress relapse prevention Substance P (neurokinin) acts at NK-1 receptor peripherally mediates pain, centrally mediates emotional stress reactions, negative emotional over-reaction in alcoholics NK-1 antagonist reduces stress-induced alcohol craving, reduces stress hormone response to challenge, reduces response to negative emotional stimuli, increases response to positive emotional stimuli Buspirone for cocaine Buspirone is a dopamine D3 antagonist Very safe, well tolerated Modest benefit for anxiety Some modest reduction in cocaine effects Little reduction in ongoing use More robust reduction of relapse following abstinence 8

9 Disulfiram (and cousins) for cocaine Disulfiram blocks dopamine beta hydoxylase, enzyme involved in metabolism of dopamine and synthesis of norepinephrine Disulfiram (and more specific cousin nepicastat) block post-dependent reinstatement of drug seeking but not initial self-administration Metabolic enzyme treatments Human enzyme butyrylcholinesterase involved in normal metabolism of cocaine Creation of new enzyme cocaine hydrolase 1000 times more efficient through recombinant DNA mutations Prevents cocaine toxicity and reinstatement of drug seeking in postdependent rats Pharmacogenetics 9

10 There will be a quiz tomorrow Delivery, Implementation, Logistics The devils in the practical details Barriers to effectiveness and adoption Cost Knowledge and training Prejudice and misunderstanding Lack of medical involvement in treatment Lack of delivery system models Limited potency of medications Side effects Problems with adherence and compliance Emerging context for delivery of relapse prevention medication An example in youth opioid dependence treatment Youth opioid treatment chart review Patient characteristics Age, mean Gender, male 53% Race, caucasian 94% Duration of opioid use 18.2 years 2.8 years Rate of injection use 61% 10

11 Youth opioid treatment chart review Medication treatment Cumula&ve reten&on by medica&on Treated with: Any medication 61% Buprenorphine 39% Extended release naltrexone 19% Oral naltrexone 3% No medication 39% * = p < 0.01 compared to no medication Opioid- free weeks by medica&on Combining urine and self report Youth opioid treatment chart review Opioid free weeks above the median Opioid free weeks > median (8): No medication 34% Any medication 60% Buprenorphine 51% Extended release naltrexone 80% * = p < 0.01 compared to no medication Why medication? Can you be in recovery on medicines Medicines just a crutch or band-aid Maybe. Like meetings or group. If the patients like it so much, there must be something wrong. But if they don t like it, it doesn t matter how good it is. If medications are an easy fix will patients refuse needed psychosocial treatments and supports. Actually, they come to psychosocial treatment more. Why medication? Can you be in recovery on medicines If medications eliminate cravings will patients miss opportunity for needed cravings management? Academic if they relapse. Postpone until later when stronger. Open question - maybe need later high intensity counseling. Abuse and diversion Real issue, needs to be managed, but not as problematic as scare stories make it out to be. 11

12 Is everything on the menu? Why medication? Can you be in recovery on medicines Medicines just a crutch or band-aid Maybe. Like meetings or group. If the patients like it so much, there must be something wrong. But if they don t like it, it doesn t matter how good it is. If medications are an easy fix will patients refuse needed psychosocial treatments and supports. Actually, they come to psychosocial treatment more. Why medication? Can you be in recovery on medicines If medications eliminate cravings will patients miss opportunity for needed cravings management? Academic if they relapse. Postpone until later when stronger. Open question - maybe need later high intensity counseling. Abuse and diversion Real issue, needs to be managed, but not as problematic as scare stories make it out to be. Pharmacological Treatment Question: Which is better - medications or counseling? Answer: Yes We ve come a long way Case (1) 16 F injection heroin and depression Initial tx suboxone, oral NTX, ineffective 2º nonadherence despite close parental monitoring, even went as far as liquid Received 8 doses XR-NTX, substantial improvement (despite sporadic lapses) Extreme conflict with mother, moved in with heroin-using boyfriend Insisted on stopping XR-NTX 2º injection site pain 5 d oral NTX then immediate relapse and dropout 12

13 CASE (2) 1 yr later presented back to us after stabilized on methadone 1 month, re-initiated therapy and Rx for depression After 4 months on methadone, switched to bupe Erratic course over 4 months with sporadic medication non-compliance and lapses leading to progressive full relapse Work with family to arrange inpatient treatment and detox with plan for switch back to NTX Surreptitious use of bupe and cheeking of NTX at residential program Precipitated withdrawal Case (3) Course of XR-NTX with company-sponsored sample program for 6 months Half way house and strong engagement in 12 step fellowship Titration of anti-depressant with gradual remission of depression and anxiety Switch to oral naltrexone for 2 months, but tired of meds Oral naltrexone back-up as needed 18 months sober 13