Kenzie L. Preston - US grants

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.

Assessment of episodes of drug use and psychosocial stress is complicated by the fact that each is often transient and difficult to recall accurately. Assessment of their causal connections with one another, and of their genetic and environmental determinants, is complicated by the complexity of the causal connections and by the elusive nature of what constitutes the environment. In this project, we are assessing drug use and psychosocial stress in near-real time through ecological momentary assessment (EMA), in which participants use handheld electronic diaries to record events as they occur and to report recent or ongoing events in response to randomly timed prompts throughout the day. We are also maintaining real-time records of where the reported events occur by collecting GPS data to track their whereabouts with a spatial resolution of several meters. We use these data collectively in a method we are calling geographical momentary assessment (GMA). Our goal with GMA has little to do with knowing the specific Baltimore locations where drug-related behaviors occur, and everything to do with gaining generalizable knowledge about how activity spaces (the spaces in which daily activities occur) are associated with such behaviors and their precipitants. We are currently analyzing GMA data from 190 opioid/cocaine users in opioid-agonist maintenance. An innovation that we introduced in our project was to investigate stressful events in patients with opioid use disorder by asking them to report the events in real time on smartphones. Knowing how stress manifests in the lives of people with substance-use disorders could help inform mobile just in time treatment. The objective was to examine discrete episodes of stress, as distinct from the fluctuations in background stress assessed in most EMA studies. Participants reported the severity of stress and craving and the context of the report (location, activities, companions) in each stress event entry. Craving for opioids increased with stress severity. Stress events tended to occur in social company (with acquaintances, friends, or on the phone) rather than with family and in places with more overall activity and more likelihood of unexpected experiences. Being on the internet was slightly protective. 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. EMA reports of specific events usually focus more on antecedents and concomitants than on aftermaths. We examined mental state reported in thrice daily randomly prompted entries both before and after discrete episodes of stressful events (SE) and lapses to drug use (DUs). In RPs, participants rated their stress, opioid craving, cocaine craving, and moods. Randomly prompted (RP) entries within 5 hrs of an event were analyzed and compared to other RPs. Stress, negative mood, and craving were generally higher before and after DUs and SEs compared to background levels in participants with at least one DU (n=149) or SE (n=158). Before DUs, there were increases in negative mood, opioid craving, and cocaine craving, but not background stress. Before SEs, there were increases in background stress, opioid craving, and cocaine craving, but not negative mood. These changes were more variable after events than before. Neither DUs nor SEs were significantly related to positive mood. Stress increased before stressful-event entries, but was less evident before drug use. Craving increased in the hours before drug use and stressful eventsand remained elevated in the hours after either event. These results suggest a stronger link between drug use and craving than between drug use and stress. Lapses to drug use did not improve mood or reduce stress, at least not at our 1-hr-bin time resolution, suggesting that if such benefits exist, they are brief. 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 (i.e., 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 EMA. In RPs, 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 x Cue interaction term had a positive mean effect across participants, denoting a more-than-additive effect. For heroin, the mean was not significantly greater than 0, but the confidence interval was predominantly positive, suggesting at least an additive effect. Heterogeneity was substantial; qualitatively, the Stress x 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. Responses to stress and drug craving differ between men and women. Differences in the momentary experience of stress in relation to craving are less well-understood. We used EMA data to examine sex differences in two areas: 1) causes and contexts associated with stress, and 2) the extent to which stress and drug cues are associated with craving. For these analyses, we analyzed the entries initiated when participants felt more stressed than usual (stress event) and randomly prompted entries. The causes reported for stress events did not differ significantly by sex. Women reported arguing and being in a store more often during stress events, and men reported working more often during stress events, compared to base rates (assessed via RPs). Women showed a greater increase in opioid craving relative to men in the presence of both stress and cues compared to either alone. Men showed a greater increase in cocaine craving relative to women when stress was present. The effect of cues on cocaine craving was greater when stress was also present (more apparent in men). EMA methods provide evidence based on real-time activities and moods that opioid-dependent men and women experience similar contexts and causes for stress, with different responses. One of our other mHealth activities is evaluation of the effects of drug use on circadian rhythm and sleep. We are currently analyzing data from a mobile device that monitors light exposure and activity to assess circadian disruption and its relation to treatment outcome. We are also conducting a study of sleep in opioid-maintained outpatients with and without chronic pain.