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Karran A. Phillips, MD, MSc NIDA Intramural Research Program AMERSA Annual Meeting November 8, 2014 Behavioral Pharmacology Laboratory Studies Treatment Section Technology Development GPS – Real Time Location Randomized Clinical Trials Archway - Outpatient Treatment Research Clinic EMA – Real Time Self Report Geographical Momentary Assessment Is there a role for Alpha-2 agonists in Relapse Prevention? • Opiate agonists effective treatments for opiate addiction block drug cue reinstatement no effect on stress-induced reinstatement patients still relapse • Alpha-2 agonists • block stress-induced reinstatement • possible effect on drug cue-induced reinstatement Alpha-2 agonists for Relapse Prevention If we combine clonidine with buprenorphine can we reduce time to lapse or relapse? Randomized Clinical Trial Clonidine for Relapse Prevention Archway Clinic Technology Development Opioid-dependent treatment seekers GPS – Real Time Location EMA – Real Time Self Report Clonidine 0 mg vs. 0.3 mg Geographical Momentary Assessment Relapse Prevention Baseline C-I Intervention Maintenance Counseling Buprenorphine (8-24 mg SL)/d Contingent Vouchers Clonidine 3 per week Urine/breath/ EMA 1 3 5 7 9 Quit deadline Randomization 11 13 15 weeks 17 19 21 23 25 C-I – clonidine induction 27 Ecological Momentary Assessment Environmental cues • In the past hour did you see heroin? (yes/no) • Right now, do you crave heroin? Stressors • Right now, are you stressed? • NO!! • no?? • yes?? • YES!! Asked at four randomly prompted times during participant’s waking hours Statistical Analysis Does clonidine prevent lapse? • Time to Lapse - first opiate positive or missed urine Does it prevent relapse? • Time to Relapse - any 2 or more consecutive positive or missed urines • Cox regression Does it increase duration of abstinence? • Longest period of consecutive opioid-negative urines • 2-way ANOVA Statistical Analysis Does clonidine decouple stress or cue exposure from craving? • Probability of reporting heroin/opiate craving (either yes? or YES!!) from: • Reports of stress • Reports of seeing heroin in the past hour • Generalized Linear Mixed Model (SAS PROC GLIMMX) Results: Participants Placebo (n = 57) Clonidine (n = 61) M (SD) / n (%) M (SD) / n (%) 38.3 (8.5) 39.2 (7.8) Gender: Male 46 (80.7%) 46 (75.4%) Race: Black 31 (54.4%) 40 (65.6%) Education (years) 12.0 (2.0) 11.9 (1.3) Heroin/Rx Opioid use 24.4 (7.9) 25.1 (8.0) 3.4 (7.5) 3.4 (7.3) 1.8 (1.8) 1.7 (1.4) Age (years) (days in the last 30) Cocaine use (days in the last 30) # of drug treatments Participants with no opioid lapse (%) Time to Lapse 100 Clonidine Placebo Hazard ratio = .67 95% CI = .45 – 1.0 p =.05 80 60 40 20 0 Induction Intervention 0 14 28 42 56 70 84 Days of clonidine/placebo Time to Relapse – not significant; p = .71 Hazard ratio 1.09; 95% CI .70 – 1.67 98 Days of consecutive opioid abstinence Longest Duration of Continuous Abstinence 80 70 60 50 40 * 30 20 10 0 Placebo t(109)=2.04, P≤0.05, Cohen’s d: 0.375 Clonidine Individual participant EMA: Stress and Heroin Craving Main effect of stress (F(3,257)=65.6, P≤0.001) Likelihood of reporting heroin craving (%) 30 25 20 15 * 10 5 0 Stress Rating EMA: Stress and Heroin Craving Likelihood of reporting heroin craving (%) 30 25 11.8% 6.3% Main effect of Clonidine (F(1,105)=71.5, P≤ 0.001) 20 15 * 10 5 0 Stress Rating EMA: Stress and Heroin Craving Likelihood of reporting heroin craving (%) 30 25 Drug X Stress interaction (F(3,257)=8.8, P≤0.001) 20 15 * 10 5 0 Stress Rating EMA: Drug Cues and Heroin Craving Likelihood of reporting heroin craving (%) 30 Main effect of exposure F(3,257)=65.6, P≤0.001 25 Main effect of clonidine F(3,257)=65.6, P≤0.001 20 Drug x Exposure Interaction, p=n.s. 15 * 10 5 0 Did Not See Heroin NO! Saw Heroin no? Cue Exposure Summary of Findings Does it work? • Yes, clonidine given in conjunction with buprenorphine increased duration of abstinence and time to lapse. Does clonidine work in humans using the same mechanism as in animals? • Evidence suggests yes. • Stress and craving were decoupled by clonidine, while cue exposure and craving were not. Discussion For clinicians and patients: The EMA results identify the circumstances under which clonidine maintenance is most likely to be beneficial: exposure to moderate (though not severe) levels of daily-life stress. Discussion For animal & human laboratory researchers: Our EMA results suggest that the seemingly contrived stressors used in the lab can indeed stand in for stressors encountered spontaneously by humans, outside the control of the investigator. Kenzie Preston David Epstein Udi Ghitza Bill Kowalczyk Michelle Jobes Ashley Kennedy Daniel Agage John Schmittner Yavin Shaham Archway Staff and participants Other Drug Use Marijuana Use 100 100 F(1,108)=6.32, P≤0.01, Cohen’s d=0.48 80 80 % Marijuana 60 Negative Urine Specimens 40 % Cocaine 60 Negative Urine Specimens 40 20 20 0 Placebo Clonidine 0 Cocaine Use P=.40 Placebo Clonidine