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BACKGROUND: Preliminary evidence suggested that the PPARγ agonist pioglitazone reduces opioid-withdrawal symptoms, possibly by inhibiting increases in proinflammatory cytokines. METHODS: 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/day), then randomized to receive oral pioglitazone (up to 45 mg/day) 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. RESULTS: 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 (r = 0.70, p = 0.038) and plasma (r = 0.77, p = 0.015). Participants having higher levels of plasma MCP-1 reported higher SOWS, most notably after the buprenorphine taper ended. CONCLUSIONS: 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. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01517165

In addiction, risk factors for craving and use include stress and drug-related cues. Stress and cues have additive or more-than-additive effects on drug seeking in laboratory animals, but, surprisingly, seem to compete with one another (ie, exert less-than-additive effects) in human laboratory studies of craving. We sought heretofore elusive evidence that human drug users could show additive (or more-than-additive) effects of stress and cues on craving, using ecological momentary assessment (EMA). Outpatients (N=182) maintained on daily buprenorphine or methadone provided self-reports of stress, craving, mood, and behavior on electronic diaries for up to 16 weeks. In three randomly prompted entries (RPs) per day, participants reported the severity of stress and craving and whether they had seen or been offered opioids, cocaine, cannabis, methamphetamine, alcohol, or tobacco. In random-effects models controlling for between-person differences, we tested effects of momentary drug-cue exposure and stress (and their interaction) on momentary ratings of cocaine and heroin craving. For cocaine craving, the Stress × Cue interaction term had a positive mean effect across participants (M=0.019; CL95 0.001-0.036), denoting a more-than-additive effect. For heroin, the mean was not significantly greater than 0, but the confidence interval was predominantly positive (M=0.019; CL95 -0.007-0.044), suggesting at least an additive effect. Heterogeneity was substantial; qualitatively, the Stress × Cue effect appeared additive for most participants, more than additive for a sizeable minority, and competitive in very few. In the field, unlike in human laboratory studies to date, craving for cocaine and heroin is greater with the combination of drug cues and stress than with either alone. For a substantial minority of users, the combined effect may be more than additive.

Knowing how stress manifests in the lives of people with substance-use disorders could help inform mobile “just in time” treatment. The purpose of this paper is to examine discrete episodes of stress, as distinct from the fluctuations in background stress assessed in most EMA studies. For up to 16 weeks, outpatients on opioid-agonist treatment carried smartphones on which they initiated an entry whenever they experienced a stressful event (SE) and when randomly prompted (RP) three times daily. Participants reported the severity of stress and craving and the context of the report (location, activities, companions). Decomposition of covariance was used to separate within-person from between-person effects; r effect sizes below are within-person. Participants (158 of 182; 87%) made 1787 stress-event entries. Craving for opioids increased with stress severity (r effect = 0.50). Stress events tended to occur in social company (with acquaintances, 0.63, friends, 0.17, or on the phone, 0.41) rather than with family (spouse, −0.14; child, −0.18), and in places with more overall activity (bars, 0.32; outside, 0.28; walking, 0.28) and more likelihood of unexpected experiences (with strangers, 0.17). Being on the internet was slightly protective (−0.22). Our prior finding that being at the workplace protects against background stress in our participants was partly supported in these stressful-event data. The contexts of specific stressful events differ from those we have seen in prior studies of ongoing background stress. However, both are associated with drug craving.