In laboratory animals, one of the major precipitants of relapsethat is, resumption of drug seekingis stress. For example, electric shock has been consistently shown to lead to reinstatement of heroin and cocaine seeking in rats (Shaham and Stewart, 1995;Erb et al., 1996;Shaham, 1996). This stress-induced reinstatement is blocked by the alpha-2 adrenergic receptor agonist clonidine (Erb et al., 2000;Shaham et al., 2000;Highfield et al., 2001). Because clonidine and other alpha-2 agonists prevent reinstatement for multiple drugs of abuse, they may be acting upon some final common pathway of stress-induced relapse, relevant to many or all addictions. To test the clinical utility and generalizability of our laboratory finding, we are continuing our clinical trial of clonidine for prevention of relapse to illicit opioid use in individuals in buprenorphine maintenance. The design of the trial is innovative. Most medication trials for substance abuse are conducted in patients who have ongoing drug use. Few studies have been designed as true relapse-prevention trials. This has been a major barrier to interpretability, because preclinical research suggests that cessation of ongoing use is very different biologically and behaviorally from prevention of relapse. In our clinical trial, abstinence initiation is facilitated with contingency management, a treatment method studied extensively in our laboratory. We are using real-time field monitoring with handheld electronic devices (a method we pioneered in this population) so we can prospectively evaluate the hypothesis that clonidines effects on relapse prevention will be through alteration of stress reactivity rather than cue reactivity in the daily environment. The trial is nearing its targeted evaluable sample size of 120. Positive results will provide an immediate treatment alternative that physicians can prescribe off-label, because clonidine is already FDA-approved and marketed. This would be a real innovation in addiction treatment: although clonidine is a familiar drug (currently used as a short-term adjuvent to opioid tapers), its use as a maintenance medication for relapse prevention would be entirely new. Our clinics experience so far, although we have not broken the blind, suggests that clonidine is well tolerated and is also not prone to misuse when prescribed for relapse prevention. Also, we tested clonidine simply as a prototypical drug of its class;if it prevents relapse, then other alpha-2 agonists should do the same. We have broken the blind early on a similarly designed trial of the atypical neuroleptic aripiprazole for prevention of relapse to cocaine addiction. Enrollment into that trial was slow because too few participants were achieving the initial cocaine-abstinence criterion for randomization to a study condition and because other studies were competing for the same pool of participants. Our preliminary analysis of the results suggests that aripiprazole might tend to delay relapse to cocaine addiction, but that the effect is too small to reach statistical significance, at least in the small sample we were able to enroll. We are also evaluating the role of stress in relapse in a large natural-history study in which real-time field monitoring of stressor exposure is combined with continuous location tracking via GPS. Preliminary analyses suggest some unexpected relationships between neighborhood environment and self-reported stress. As we collect more data, we should be able to determine how patterns of environmental-stressor exposure predict relapse. One of our goals is to supplement our ambulatory assessments with on-the-spot feedback, turning them into mobile interventions.
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