Even for patients who have maintained long-term abstinence from drugs, relapse remains a substantial risk. As we have shown using ecological momentary assessment (EMA), lapses to drug use may follow acute increases in stress. In the rat reinstatement model of relapse, stress-induced seeking of heroin, cocaine, speedball (heroin-cocaine combination), alcohol, or nicotine is blocked by alpha-2 adrenoceptor agonists such as lofexidine, guanfacine, and clonidine. Thus, alpha-2 agonists may act on a final common pathway of stress-induced relapse, relevant to multiple drugs of abuse. In a randomized, placebo-controlled laboratory study, with non-treatment-seeking cocaine users, we have shown that clonidine was effective in reducing stress-induced (and, at a higher dose, cue-induced) craving in a pattern consistent with the findings from the reinstatement model. We have since shown, in a double-blind, randomized trial in abstinent opioid users receiving agonist maintenance, that adjuvant clonidine maintenance increase time to lapse and longest duration of abstinence. EMA data showed that heroin craving increased with increasing severity of stress; clonidine decoupled that association, and participants in the clonidine group reported less heroin craving. In contrast, clonidine did not alter craving responses to drug-cue exposure. We are continuing to analyze data from this completed trial to learn more about the behavioral mechanisms through which clonidine maintenance prevents lapses. We have continued to analyze data from the randomized clinical trial examining daily clonidine as an adjunct to buprenorphine treatment for opioid dependence. We had found that clonidine increased opioid abstinence and decoupled stress from craving (Kowalczyk et al., 2015). From a personalized-medicine perspective, the next step is to identify people for whom clonidine would be beneficial. To that end, we examined the associations of daily-life activities with treatment success. Outpatients (N = 108, female: n = 23, male n = 85) received clonidine (0.3 mg/d) or placebo during 18 wks of buprenorphine treatment. Participants carried a smartphone that randomly prompted them 4 times per day to report their moods and activities. Using generalized linear mixed models, we assessed the likelihoods of different types of daily activity as a function of clonidine versus placebo, days of longest continuous opioid abstinence, and their interaction. Participants in the buprenorphine-only (placebo plus clonidine) control group who engaged in more responsibilities (work and child/elder care) had longer streaks of abstinence, whereas those who engaged in more unstructured-time activities had shorter streaks of abstinence. Conversely, for participants in the buprenorphine-plus clonidine group, longer streaks of abstinence were associated with higher frequencies of activities associated with unstructured time. The study replicates findings that engaging in responsibilities is related to positive treatment outcomes in standard opioid agonist therapy. The pattern of results also suggests that clonidine helped participants engage in unstructured-time activities with less risk of craving or use than they might otherwise have had. In additional analyses to determine whether the decoupling of affect from craving was accompanied by decoupling of affect and craving from actual use of illicit opioids, we linked each EMA report to the participants next urine result (thrice weekly), determining whether the report was made during a time the participant used an illicit opioid. We used generalized linear mixed models to examine the interaction between treatment group and illicit opioid use, and broke the analysis into within- and between-participant effects. Craving for opioids and cocaine was increased when participants were using illicit opioids. For affect, there was an interaction between treatment group and illicit opioid use: for clonidine-treated participants, mood was poorer during periods preceding opioid-positive urines than opioid-negative urines, whereas for placebo participants there was no difference. This secondary analysis provides evidence that clonidine minimized the impact of moderate levels of negative affect and craving on participants in opioid agonist therapy. Preliminary evidence suggested that the PPAR agonist pioglitazone reduces opioid-withdrawal symptoms, possibly by inhibiting increases in proinflammatory cytokines. A randomized, placebo-controlled clinical trial was conducted utilizing two different study designs (entirely outpatient, and a combination of inpatient and outpatient) to evaluate the safety and efficacy of pioglitazone as an adjunct medication for people with opioid physical dependence undergoing a buprenorphine taper. Participants were stabilized on buprenorphine/naloxone (sublingual, up to 16/4 mg/d), then randomized to receive oral pioglitazone (up to 45 mg/d) or placebo before, during, and after buprenorphine taper. Outcome measures included the Subjective Opiate Withdrawal Scale (SOWS) and Clinical Opiate Withdrawal Scale, use of rescue medications to alleviate opioid withdrawal symptoms, and opioid-positive urine specimens. Cerebrospinal fluid (CSF) and plasma were collected during the taper in a subset of participants for measurement of proinflammatory cytokines. The clinical trial was prematurely terminated due to slow enrollment; 40 participants per group were required for adequate statistical power to test study hypotheses. Twenty-four participants enrolled; 17 received at least one dose of study medication (6-pioglitazone, 11-placebo). SOWS scores were higher in the pioglitazone arm than in the placebo arm after adjusting for use of rescue medications; participants in the pioglitazone arm needed more rescue medications than the placebo arm during the post-taper phase. SOWS scores were positively correlated with monocyte chemoattractant protein-1 (MCP-1) in CSF and plasma. Participants having higher levels of plasma MCP-1 reported higher SOWS, most notably after the buprenorphine taper ended. Results from this study provide no evidence that pioglitazone reduces opioid withdrawal symptoms during buprenorphine taper. High correlations between MCP-1 and opioid withdrawal symptoms support a role of proinflammatory processes in opioid withdrawal. Finally, we continue to develop Geographical Momentary Assessment (GMA), an approach to measurement and understanding of the relationships among mood, drug use, and environmental exposure to psychosocial stressors in participants daily travels. GMA is largely a descriptive technique, but we remain committed to transforming description into intervention. For example, we have shown that electronic-diary studies can provide amazing insight into the daily lives of substance abusers during treatment and data that are sensitive to behavioral changes during even brief periods of abstinence. The technologies that enable us to collect data on drug use, craving, and stress in the field may also be used for delivery of treatment in the field, perhaps in response to the patients movement toward previously identified triggers. 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. Our 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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