1. Karran A. Phillips, MD, MSc NIDA Intramural Research Program AMERSA Annual Meeting November 8, 2014

2. Effect of Clonidine on Response To Stress and Drug Cues Cocaine users not seeking treatment randomly assigned to:  Clonidine 0 mg (placebo)  Clonidine 0.1 mg  Clonidine 0.2 mg AdmissionDosingBaseline Measures Script Procedures10 min. Guided Relaxation Session 3 hours Behavioral Pharmacology Laboratory Studies Randomized Clinical Trials Archway - Outpatient Treatment Research Clinic Technology Development GPS – Real Time Location EMA – Real Time Self Report Geographical Momentary Assessment Treatment Section

3. 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 Is there a role for Alpha-2 agonists in Relapse Prevention?

4. Alpha-2 agonists for Relapse Prevention with buprenorphineIf we combine clonidine can we reduce time to lapse or relapse?

5. Randomized Clinical Trial Clonidine for Relapse Prevention Archway Clinic Clonidine 0 mg vs. 0.3 mg Opioid-dependent treatment seekers EMA Technology Development GPS – Real Time Location EMA – Real Time Self Report Geographical Momentary Assessment Relapse Prevention 11 9 C-I – clonidine induction Contingent Vouchers Maintenance Counseling Buprenorphine 5 21 (8-24 mg SL)/d weeks Clonidine 3 7 13 15 17 19 23 25 27 Baseline Intervention Quit deadline Randomization Urine/breath/ 3 per week C-I 1

6. 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 Ecological Momentary Assessment

7. 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

8. 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) Statistical Analysis

9. Results: Participants Placebo (n = 57) Clonidine (n = 61) M (SD) / n (%) Age (years) 38.3 (8.5)39.2 (7.8) Gender: Male46 (80.7%)46 (75.4%) Race: Black31 (54.4%)40 (65.6%) Education (years) 12.0 (2.0)11.9 (1.3) Heroin/Rx Opioid use (days in the last 30) 24.4 (7.9)25.1 (8.0) Cocaine use (days in the last 30) 3.4 (7.5)3.4 (7.3) # of drug treatments1.8 (1.8)1.7 (1.4)

10. Time to Lapse Time to Relapse – not significant; p =.71 Hazard ratio 1.09; 95% CI.70 – 1.67 Hazard ratio =.67 95% CI =.45 – 1.0 p =.05

11. Longest Duration of Continuous Abstinence t (109) =2.04, P≤0.05, Cohen’s d: 0.375 * Individual participant

12. * Stress Rating Main effect of stress (F (3,257) =65.6, P≤0.001) EMA: Stress and Heroin Craving Likelihood of reporting heroin craving (%) 30 20 25 15 5 10 0

13. * Likelihood of reporting heroin craving (%) Stress Rating Main effect of Clonidine (F (1,105) =71.5, P≤ 0.001) 6.3% 11.8% EMA: Stress and Heroin Craving 30 20 25 15 5 10 0

14. * Stress Rating Drug X Stress interaction (F (3,257) =8.8, P≤0.001) EMA: Stress and Heroin Craving Likelihood of reporting heroin craving (%) 30 20 25 15 5 10 0

15. * Cue Exposure Did Not See Heroin Saw Heroin Main effect of exposure F (3,257) =65.6, P≤0.001 Main effect of clonidine F (3,257) =65.6, P≤0.001 EMA: Drug Cues and Heroin Craving Likelihood of reporting heroin craving (%) 30 20 25 15 5 10 0 Drug x Exposure Interaction, p=n.s.

16. 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. Summary of Findings

17. 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

18. 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. Discussion

19. Kenzie Preston David Epstein Udi Ghitza Bill Kowalczyk Michelle Jobes Ashley Kennedy Daniel Agage John Schmittner Yavin Shaham Archway Staff and participants

20. Other Drug Use F (1,108) =6.32, P≤0.01, Cohen’s d=0.48 P=.40