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Objective Evidence suggests that blunted reward responsiveness may account for poor clinical outcomes in both opioid use disorder (OUD) and chronic pain. Understanding how individuals with OUD and comorbid chronic pain (OUD+CP) respond to rewards is, therefore, of clinical interest because it may reveal a potential point of behavioral intervention. Methods Patients with OUD (n = 28) and OUD+CP (n = 19) on opioid agonist treatment were compared on: 1) the Probabilistic Reward Task (an objective behavioral measure of reward response bias) and 2) ecological momentary assessment of affective responses to pleasurable events. Results Both the OUD and the OUD+CP groups evidenced an increase in reward response bias in the Probabilistic Reward Task. The rate of change in response bias across blocks was statistically significant in the OUD group (B = 0.06, standard error [SE] = 0.02, t = 3.92, P Conclusions Overall, findings across objective and subjective measures were mixed, necessitating follow-up with a larger sample. The results suggest that although there is a reward response bias in patients with OUD+CP treated with opioid agonist treatment relative to patients with OUD without CP, it is modest and does not appear to translate into patients’ responses to rewarding events as they unfold in daily life.

AIM To assess the role of momentary pain on opioid craving and illicit opioid use among individuals receiving opioid agonist treatment. DESIGN Observational study using ecological momentary assessment. SETTING The National Institute of Drug Abuse Intramural Research Program in the United States. PARTICIPANTS Fifty-six adults who qualified for opioid agonist treatment. MEASUREMENTS Participants completed randomly prompted assessments of pain severity, stress, negative mood, opioid craving and illicit opioid use for a mean of 66 days [standard deviation (SD) = 27]. Urine samples were collected two to three times/week throughout. FINDINGS Almost 70% of participants reported moderate average pain severity in the past 24 hours at intake and 35% of participants reported chronic pain. There were no significant differences in percent of opioid-positive urine samples (P = 0.73) and average level of opioid craving during the study period (P = 0.91) among opioid agonist treatment only patients versus opioid agonist treatment patients with chronic pain. However, momentary pain severity significantly predicted concurrent opioid craving [B = 0.02, 95% confidence interval (CI) = 0.01, 0.04], over and above stress and negative mood. Momentary opioid craving, in turn, significantly predicted illicit opioid use that was assessed in the next moment [odds ratio (OR) = 1.72, 95% CI = 1.12, 2.64), while controlling for autocorrelation and the effects of pain, negative mood and stress. Momentary opioid craving significantly mediated the prospective association between momentary pain and illicit opioid use (95% CI = 0.003, 0.032). Exploratory analysis revealed that momentary pain severity also significantly moderated the momentary association between stress and opioid craving (B = 0.02, 95% CI = 0.00, 0.04), such that when momentary pain severity increased, the association between the two intensified. CONCLUSIONS Among people receiving opioid agonist treatment, momentary pain appears to be indirectly associated with illicit opioid use via momentary opioid craving.

RATIONALE: Many people being treated for opioid use disorder continue to use drugs during treatment. This use occurs in patterns that rarely conform to well-defined cycles of abstinence and relapse. Systematic identification and evaluation of these patterns could enhance analysis of clinical trials and provide insight into drug use. OBJECTIVES: To evaluate such an approach, we analyzed patterns of opioid and cocaine use from three randomized clinical trials of contingency management in methadone-treated participants. METHODS: Sequences of drug-test results were analyzed with unsupervised machine-learning techniques, including hierarchical clustering of categorical results (i.e., whether any samples were positive during each week) and K-means longitudinal clustering of quantitative results (i.e., the proportion positive each week). The sensitivity of cluster membership as an experimental outcome was assessed based on the effects of contingency management. External validation of clusters was based on drug craving and other symptoms of substance use disorder. RESULTS: In each clinical trial, we identified four clusters of use patterns, which can be described as opioid use, cocaine use, dual use (opioid and cocaine), and partial/complete abstinence. Different clustering techniques produced substantially similar classifications of individual participants, with strong above-chance agreement. Contingency management increased membership in clusters with lower levels of drug use and fewer symptoms of substance use disorder. CONCLUSIONS: Cluster analysis provides person-level output that is more interpretable and actionable than traditional outcome measures, providing a concrete answer to the question of what clinicians can tell patients about the success rates of new treatments.

Sleep problems are commonly reported during opioid agonist treatment (OAT) for opioid use disorders. Inpatient studies have found both sleep disturbances and improved sleep during OAT. Illicit opioids can also disrupt sleep, but it is unclear how they affect sleep in outpatients receiving OAT. Therefore, we used electronic diary entries and actigraphy to measure sleep duration and timing in opioid-dependent participants (n = 37) treated with methadone (n = 15) or buprenorphine (n = 22). For 16 weeks, participants were assigned to attend our clinic under different operating hours in a crossover design: Early hours (07:00–09:00) vs. Late hours (12:00–13:00) for 4 weeks each in randomized order, followed for all participants by our Standard clinic hours (07:00–11:30) for 8 weeks. Throughout, participants made daily electronic diary self-reports of their sleep upon waking; they also wore a wrist actigraph for 6 nights in each of the three clinic-hour conditions. Drug use was assessed by thrice-weekly urinalysis. In linear mixed models controlling for other sleep-relevant factors, sleep duration and timing differed by drug use and by clinic hours. Compared to when non-using, participants slept less, went to bed later, and woke later when using illicit opioids and/or both illicit opioids and cocaine. Participants slept less and woke earlier when assigned to the Early hours. These findings highlight the role OAT clinic schedules can play in structuring the sleep/wake cycles of OAT patients and clarify some of the circumstances under which OAT patients experience sleep disruption in daily life.

Background Treatment with opioid agonists is effective for opioid use disorder, but early discontinuation of treatment is a major obstacle to success. Intensive longitudinal methods — which take many repeated measurements over time, usually in the field— have provided unique insight into the effects of stress, mood and craving on drug use while people are being treated; these methods might also be useful for studying the processes that lead people to drop out of treatment. Methods Ecological momentary assessment (EMA) was conducted for up to 17 weeks by obtaining multiple electronic diary entries per day from 238 participants being treated with methadone or buprenorphine-naloxone. Survival analysis was used to study two outcomes: dropping out of treatment and noncompliance with EMA self-report requirements. Self-reports of stress, craving, and mood were used as time-varying predictors. Demographic and psychosocial variables measured with the Addiction Severity Index at the start of treatment were used as time-invariant predictors. Results Dropping out of treatment was more likely in participants with more reported hassles (a measure of stress), higher levels of cocaine craving, lower levels of positive mood, a recent history of emotional abuse, a recent history of being bothered frequently by psychological problems, and with buprenorphine rather than methadone as their medication. In contrast, study noncompliance was not significantly associated with any of the variables analyzed. Conclusions Assessment of stress, craving and mood during treatment might identify people who are at greater risk of dropping out, and therapeutic interventions targeting these processes might increase retention.

Allostatic load, an operationalization for cumulative strain on physiology from adaptation (allostasis) to stress over a lifetime, can manifest as damage to cardiovascular, neuroendocrine, and metabolic systems. The concept of allostatic load may be particularly useful in research on substance-use disorders (SUDs) because SUD researchers have sought to better understand the relationship between chronic stressors and drug use. Theoretical models hold that SUDs can be conceptualized as a spiral toward a state of persistent allostasis (i.e., allostasis so persistent as to represent homeostasis at a new, unhealthy set point). Regardless of the extent to which those models are accurate, increased allostatic load could be a mechanism by which frequent drug administration increases risk for adverse outcomes. We conducted two secondary analyses to evaluate allostatic load in the context of drug use, including alcohol use, in a locally recruited sample with a high proportion of illicit substance use (N = 752) and in a nationally representative sample from the NHANES 2009–2016. We hypothesized that after controlling for age and other potential confounds, people with longer histories of drug use would have higher allostatic-load scores. Multiple regression was used to predict allostatic load from participants' drug-use histories while controlling for known confounds. In the locally recruited sample, we found that longer lifetime use of cocaine or opioids was related to increased allostatic load. In NHANES 2009–2016, we found few or no such associations. Lengthy histories of problematic non-medical substance use may facilitate more rapid increases in allostatic load than aging alone, and, together with findings from previous investigations, this finding suggests increased risk for chronic disease.

Background We previously showed, in people starting treatment for opioid use disorder (OUD), that stress is neither necessary nor sufficient for lapses to drug use to occur, despite an association between the two. Both theoretical clarity and case-by-case prediction accuracy may require initial differentiation among patients. Aim To examine: (a) evidence for distinct overall trajectories of momentary stress during OUD treatment, (b) relationships between stress trajectory and treatment response, and (c) relationships between stress trajectory and momentary changes in stress and craving prior to lapses. Methods We used ecological momentary assessment (EMA) to collect ratings of stress and craving 3x/day for up to 16 weeks in 211 outpatients during agonist treatment for OUD. With growth mixture models, we identified trajectories of stress. We used mixed effect models to examine trajectory-group differences in the dynamics of stress and craving just before lapses to any drug use. Results We identified four trajectories of stress: Increasing (13.7 %); Moderate and Stable (23.7 %); Declining and Increasing (18 %); and Low (44.6 %). Overall drug use and opioid craving were lowest in the Low Stress group. Overall drug use was highest in the Moderate and Stable group. Alcohol use and opioid craving were highest in the Increasing Stress group. Opioid craving increased before lapse for most groups, but stress increased before lapses for only the Moderate and Stable group. Conclusion There are natural groupings of participants with distinct patterns of stress severity during OUD treatment. Momentary stress/craving/lapse associations may be better characterized when these groupings are considered first.

RATIONALE: Given that many patients being treated for opioid-use disorder continue to use drugs, identifying clusters of patients who share similar patterns of use might provide insight into the disorder, the processes that affect it, and ways that treatment can be personalized. OBJECTIVES AND METHODS: We applied hierarchical clustering to identify patterns of opioid and cocaine use in 309 participants being treated with methadone or buprenorphine (in a buprenorphine-naloxone formulation) for up to 16 weeks. A smartphone app was used to assess stress and craving at three random times per day over the course of the study. RESULTS: Five basic patterns of use were identified: frequent opioid use, frequent cocaine use, frequent dual use (opioids and cocaine), sporadic use, and infrequent use. These patterns were differentially associated with medication (methadone vs. buprenorphine), race, age, drug-use history, drug-related problems prior to the study, stress-coping strategies, specific triggers of use events, and levels of cue exposure, craving, and negative mood. Craving tended to increase before use in all except those who used sporadically. Craving was sharply higher during the 90 minutes following moderate-to-severe stress in those with frequent use, but only moderately higher in those with infrequent or sporadic use. CONCLUSIONS. People who share similar patterns of drug-use during treatment also tend to share similarities with respect to psychological processes that surround instances of use, such as stress-induced craving. Cluster analysis combined with smartphone-based experience sampling provides an effective strategy for studying how drug use is related to personal and environmental factors.

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

Whereas substance-use researchers have long combined self-report with objective measures of behavior and physiology inside the laboratory, developments in mobile/wearable electronic technology are increasingly allowing for the collection of both subjective and objective information in participants’ daily lives. For self-report, ecological momentary assessment (EMA), as implemented on contemporary smartphones or personal digital assistants, can provide researchers with near-real-time information on participants’ behavior and mood in their natural environments. Data from portable/wearable electronic sensors measuring participants’ internal and external environments can be combined with EMA (e.g., by timestamps recorded on questionnaires) to provide objective information useful in determining the momentary context of behavior and mood and/or validating participants’ self-reports. Here, we review three objective ambulatory monitoring techniques that have have been combined with EMA, with a focus on detecting drug use and/or measuring the behavioral or physiological correlates of mental events (i.e., emotions, cognitions): (1) collection and processing of biological samples in the field to measure drug use or participants’ physiological activity (e.g, hypothalamic-pituitary-adrenal axis activity); (2) global positioning system (GPS) location information to link environmental characteristics (disorder/disadvantage, retail drug outlets) to drug use and affect; (3) ambulatory electronic physiological monitoring (e.g., electrocardiography) to detect drug use and mental events, as advances in machine learning algorithms make it possible to distinguish target changes from confounds (e.g., physical activity). Finally, we consider several other mobile/wearable technologies that hold promise to be combined with EMA, as well as potential challenges faced by researchers working with multiple mobile/wearable technologies simultaneously in the field.

BACKGROUND: In a recent clinical trial (NCT00295308), we demonstrated that clonidine decreased the association between opioid craving and moderate levels of stress and affect in patients receiving buprenorphine-based opioid agonist therapy. OBJECTIVES: To examine the relationship between illicit opioid use and craving and affect during the evaluation of clonidine as an adjunct medication in buprenorphine treatment for opioid use disorder. Secondarily, to examine whether those relationships are driven by within- or between-participant factors. METHODS: This was a secondary data analysis from our original trial. Participants (N = 108, female: n = 23, male n =85) receiving buprenorphine were randomized to receive adjunct clonidine or placebo. Participants used portable electronic devices to rate stress, mood, and craving via ecological momentary assessment (EMA) four times randomly each day. To associate the EMA data with illicit opioid use, each EMA report was linked to participants’ next urine drug screen (thrice weekly). We used generalized linear mixed models to examine the interaction between treatment group and illicit opioid use, as well as to decompose the analysis into within- and between-participant effects. RESULTS: Craving for opioids and cocaine was increased when participants were using illicit opioids; this effect was greater in the clonidine group. For affect, mood was poorer during periods preceding opioid-positive urines than opioid-negative urines for clonidine-treated participants, whereas there was no difference for placebo participants. CONCLUSION. This secondary analysis provides evidence that illicit opioid use was linked to stronger negative affect and craving in participants maintained on clonidine in opioid agonist therapy.

OBJECTIVE In a clinical trial examining daily clonidine as an adjunct to buprenorphine treatment for opioid dependence, we found that clonidine increased opioid abstinence and decoupled stress from craving. From a personalized-medicine perspective, the next step is to identify people for whom clonidine would be beneficial. To that end, using data from the same clinical trial, we examined the associations of daily-life activities with treatment success. METHODS Outpatients (N = 118) received clonidine (0.3 mg/d) or placebo during 18 weeks 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. RESULTS Participants in the buprenorphine-only (buprenorphine plus placebo) 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. CONCLUSIONS 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.

Adherence monitoring is a vital component of clinical efficacy trials, as the regularity of medication consumption affects both efficacy and adverse effect profiles. Pill-counts do not confirm consumption, and invasive plasma assessments can only assist post hoc assessments. We previously reported on the pharmacokinetics of a potential adherence marker to noninvasively monitor dosage consumption during a trial without breaking a blind. We reported that consumption cessation of subtherapeutic 15 mg acetazolamide (ACZ) doses showed a predictable urinary excretion decay that was quantifiable for an extended period. The current study describes the clinical implementation of 15 mg ACZ doses as an adherence marker excipient in distinct cohorts taking ACZ for different "adherence" durations. We confirm that ACZ output did not change (accumulate) during 18-20 days of adherence, and developed and assessed urinary cutoffs as nonadherence indicators. We demonstrate that whereas an absolute concentration cutoff (989 ng/mL) lacked sensitivity, a creatinine normalized equivalent (1,376 ng/mg ACZ) was highly accurate at detecting nonadherence. We also demonstrate that during nonadherent phases of three trials, creatinine-normalized urinary ACZ elimination was reproducible within and across trials with low variability. Excretion was first order, with a decay half-life averaging ~ 2.0 days. Further, excretion remained quantifiable for 14 days, providing a long period during which the date of last consumption might be determined. We conclude that inclusion of 15 mg ACZ as a dosage form adherence marker excipient, provides a reliable and sensitive mechanism to confirm medication consumption and detect nonadherence during clinical efficacy trials.

BACKGROUND: Treatment with methadone is effective in reducing heroin use, HIV risk, and death; however, not all patients respond to treatment. Better outcomes may emerge with personalized treatment based on factors that influence treatment courses. OBJECTIVES: to investigate psychosocial variables contributing to treatment response, using a comprehensive definition of treatment response. METHODS: Seventy participants seeking treatment for heroin and cocaine addiction completed up to 40 weeks of daily methadone. At week 22, we administered a semi-structured interview for DSM-IV symptoms. We defined opioid treatment responders as people still enrolled at 22 weeks, not meeting past-30-day criteria for DSM-IV opioid abuse or dependence or DSM-5 opioid-use disorder, and providing ≥ 75% opioid-negative urine samples in the 30 days prior to week 22. The same criteria were applied to assess cocaine treatment response. RESULTS: Sample was 71% male, 41% White, and averaged 39.4 ± 7.9 years old. Opioid treatment response was more likely in participants who had been employed over the past 3 years (OR 8.1, 95% CI 1.2–55) and less likely in those who spent more time on hobbies (OR 0.45, 95% CI 0.23–0.88). Cocaine treatment response was more likely in participants who had a good relationship with their father (OR 5.3, 95% CI 1.2–24) and less likely if positive for hepatitis C (OR 0.15, 95% CI 0.03–0.75). CONCLUSIONS: Pretreatment characteristics differentially predict treatment response for heroin and cocaine use. Similar research in diverse patient groups may aid in the development of personalized treatment combining biologic treatment with targeted psychosocial interventions.

In rodents, antagonism of receptors for corticotropin-releasing factor (CRF) blocks stress-induced reinstatement of drug or palatable food seeking. To test anticraving properties of the CRF1 antagonist pexacerfont in humans. We studied stress-induced eating in people scoring high on dietary restraint (food preoccupation and chronic unsuccessful dieting) with body-mass index (BMI) >22. In a double-blind, between-groups trial, 31 “restrained” eaters were stabilized on either pexacerfont (300 mg/day for 7 days, then 100 mg/day for 21 days) or placebo. On day 15, they underwent a math-test stressor; during three subsequent visits, they heard personalized craving-induction scripts. In each session, stress-induced food consumption and craving were assessed in a bogus taste test and on visual analog scales. We used digital video to monitor daily ingestion of study capsules and nightly rating of food problems/preoccupation on the Yale Food Addiction Scale (YFAS). The study was stopped early due to an administrative interpretation of US federal law, unrelated to safety or outcome. The bogus taste tests suggested some protective effect of pexacerfont against eating after a laboratory stressor (r effect = 0.30, 95 % CL = −0.12, 0.63, Bayes factor 11.30). Similarly, nightly YFAS ratings were lower with pexacerfont than placebo (r effect = 0.39, CI 0.03, 0.66), but this effect should be interpreted with caution because it was present from the first night of pill ingestion, despite pexacerfont’s slow pharmacokinetics. The findings may support further investigation of the anticraving properties of CRF1 antagonists, especially for food.

Background Individual trajectories of drug use and drug-related problems are highly heterogeneous. There is no standard taxonomy of these trajectories, but one could be developed by defining natural categories based on changes in symptoms of substance-use disorders over time. Methods Our study was conducted in a community sample in Baltimore, Maryland. At baseline, all participants were using opioids and/or cocaine, but none were in treatment. Drug use and symptomatology were assessed again at 12 months (N = 115). Results We defined Quitters as participants who had not used for at least 30 days at follow-up (17%). For the remaining participants, we performed longitudinal cluster analysis on DSM symptom-counts, identifying three trajectory clusters: newly or persistently Symptomatic (40%) participants, Chippers (21.5%) with few symptoms, and Converted Chippers (21.5%) with improved symptom counts. Logistic regression showed that profiles of Quitters did not resemble Chippers, but instead resembled Symptomatic participants, having high probability of disorderly home neighborhood, nonwhite race, and negative mood. Quitters tended to have two protective factors: initiating opioid-agonist treatment during the study (reffect = 0.25, CL95 0.02–0.48) and lack of polydrug use (reffect = 0.25, CL95 0.004–0.49). Converted Chippers tended to be white, with orderly home neighborhoods and less negative mood (reffects 0.24 to 0.31, CL95 0.01–0.54). Conclusions Changes in DSM symptomology provided a meaningful measure of individual trajectories. Quitters shared psychosocial characteristics with Symptomatic participants, but not with participants who continued to use with few symptoms. This suggests that Quitters abstained out of necessity, not because their problems were less severe.

Background and aims Stress can be validly assessed “live” or by a summary evaluation of the very recent past. Using smartphone-based ecological momentary assessment (EMA) combined with end-of-day (EOD) entries, we assessed the association between daily hassles, stressful events and use of opioids and cocaine, in opioid- and cocaine-using men and women. Methods For up to 16 weeks, 161 outpatients in opioid-agonist treatment who reported cigarette smoking carried smartphones on which they reported stressful events (SEs) and drug use (DU) and completed an EOD questionnaire to report hassles encountered throughout the day, current perceived stress, cigarettes/day, and current mood. We compared EOD responses on days with and without SE and DU reports and on days when thrice-weekly urine drug screens indicated opioid or cocaine use or abstinence. Results Participants (N = 161) made 11,544 EOD entries; EMA SEs were reported on 861 (7.5%) days, and DUs on 1685 (14.6%) days. The most frequently reported hassles in EOD entries were “not enough money” (31.4% of daily reports) and maintaining abstinence (18.7%). Total EOD hassles showed small but statistically significant associations [odds ratios (95% CIs)] with EMA SEs [1.09 (1.06–1.13)], DUs [1.08 (1.06–1.10)], and urine-positive opioid [1.06 (1.04–1.09)] and cocaine [1.03 (1.00–1.06)] results. Men and women had similar rates (mean/day (SD)) of hassles: men 2.25 (3.55); women 2.55 (3.76) (F1,159 = 0.53, p = 0.47). Conclusions Daily hassles, reported at the end of the day, are associated with both same-day stressful events and drug use. Monitoring hassles and devising specific coping strategies might be useful therapeutic targets.

Location data are becoming easier to obtain and are now bundled with other metadata in a variety of biomedical research applications. At the same time, the level of sophistication required to protect patient privacy is also increasing. In this article, we provide guidance for institutional review boards (IRBs) to make informed decisions about privacy protections in protocols involving location data. We provide an overview of some of the major categories of technical algorithms and medical–legal tools at the disposal of investigators, as well as the shortcomings of each. Although there is no “one size fits all” approach to privacy protection, this article attempts to describe a set of practical considerations that can be used by investigators, journal editors, and IRBs.

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.Using ecological momentary assessment (EMA), we examined sex differences in real-time in two areas: (1) causes and contexts associated with stress, and (2) the extent to which stress and drug cues are associated with craving.Outpatients on opioid-agonist treatment (135 males, 47 females) reported stress, craving, and behavior on smartphones for 16 weeks. They initiated an entry each time they felt more stressed than usual (stress event) and made randomly prompted entries 3 times/day. In stress-event entries, they identified the causes and context (location, activity, companions), and rated stress and craving severity.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 random prompts). Women showed a greater increase in opioid craving as a function of stress (p 0.0001) and had higher stress ratings in the presence of both stress and drug cues relative to men (p 0.01). Similar effects were found for cocaine craving in men (p 0.0001).EMA methods provide evidence based on real-time activities and moods that opioid-dependent men and women experience similar contexts and causes for stress but differ in stress- and cue-induced craving. These findings support sex-based tailoring of treatment, but because not all participants conformed to the overall pattern of sex differences, any such tailoring should also consider person-level differences.

Background Helping patients control obesity remains a clinical challenge for internists, and African Americans experience obesity rates higher than other racial/ethnic groups. Purpose To investigate whether a behavioral theory-based mobile health intervention would enhance weight loss when added to standard care among overweight/obese African American adults. Methods A randomized controlled trial of 124 adults recruited from Baltimore-area African American churches. Participant follow-up ended March 2013. Participants were randomized to standard care (included one-on-one counseling sessions with a dietitian and a physician) or standard care plus daily tailored text messages for 6 months. Text messages were delivered in phases: preparation, reinforcement of participant-selected diet and exercise goals, reflection, goal integration, weight loss methods, and maintenance. There were follow-up visits at 3, 6, and 12 months. Primary outcome was weight change from baseline to end-intervention at 6 months. Secondary outcomes included weight change at 3 months, engagement, and satisfaction with the intervention. Results Sixty-three participants were randomized to the mobile health intervention and 61 to standard-care control. Weights were collected in-window for 45 (36.3%) at 3 months and 51 (41.1%) at 6 months. Mean weight loss at 3 months was 2.5 kg greater in the intervention group compared with standard care (95% confidence interval [CI], −4.3 to −0.6; P P = .001) at 6 months. Degree of engagement with messages was correlated with weight loss. Conclusions While attrition was high, this study supports a tailored, interactive text-message intervention to enhance weight loss among obese African-American adults.

Background and Objectives To support medication development with cannabinoids, smoked cannabis has been said to alleviate symptoms of opioid withdrawal. We evaluated that hypothesis. Methods We analyzed data from the methadone-taper phase of a clinical trial we had conducted. Participants were 116 outpatient heroin and cocaine users (of whom 46 were also cannabis users) who stayed for the 10-week taper. Main outcome measures were weekly urine screens for cannabinoids, plus every-two-week assessments of opioid-withdrawal symptoms. Results Opioid-withdrawal scores did not differ overall between users and nonusers of cannabis. In a lagged analysis in the 46 users, there was a slight (not statistically significant) indication that weeks of higher opiate-withdrawal symptoms preceded weeks of cannabis use (effect-size r = .20, 95% CI −.10 to .46, p = .52). Even if this finding is taken to suggest self-medication with cannabis, a lagged analysis in the other temporal direction showed no indication that cannabis use predicted lower opiate-withdrawal symptoms the next week (effect-size r = .01, 95% CI −.28 to .30, p = .69). These findings persisted in sensitivity analyses controlling for each of 17 potential confounds. Discussion and Conclusion With our findings, the clinical evidence for smoked cannabis as a reducer of opioid-withdrawal symptoms moves slightly further from “inconclusive” or “mixed” and closer to negative, at least in the context of a methadone dose taper like the one used here. Scientific Significance This finding may remove one rationale for medication development using cannabinoids to treat opioid withdrawal, but leaves other rationales intact. (Am J Addict 2015;XX: XX–XX)

Many patients with opioid use disorder do not have successful outcomes during treatment but the underlying reasons are not well understood. An OPRD1 variant (rs678849) was previously associated with methadone and buprenorphine efficacy in African–Americans with opioid use disorder. The objective of this study was to determine if the effect of rs678849 on opioid use disorder treatment outcome could be replicated in an independent population. Participants were recruited from African–American patients who had participated in previous studies of methadone or buprenorphine treatment at the outpatient treatment research clinic of the NIDA Intramural Research Program in Baltimore, MD, USA between 2000 and 2017. Rs678849 was genotyped retrospectively, and genotypes were compared with urine drug screen results from the previous studies for opioids other than the one prescribed for treatment. Genotypes were available for 24 methadone patients and 55 buprenorphine patients. After controlling for demographics, the effect of rs678849 genotype was significant in the buprenorphine treatment group (RR = 1.69, 95% confidence interval (CI) 1.59–1.79, p = 0.021). Buprenorphine patients with the C/C genotype were more likely to have opioid-positive drug screens than individuals with the C/T or T/T genotypes, replicating the original pharmacogenetic finding. The effect of genotype was not significant in the methadone group (p = 0.087). Thus, the genotype at rs678849 is associated with buprenorphine efficacy in African–Americans being treated for opioid use disorder. This replication suggests that rs678849 genotype may be a valuable pharmacogenetic marker for deciding which opioid use disorder medication to prescribe in this population.

RATIONALE: Ecological momentary assessment (EMA) of specific events usually focuses more on antecedents and concomitants than on aftermaths. OBJECTIVES: To examine mental state both before and after discrete episodes of stress and drug use. METHODS: For up to 16 weeks, outpatients on opioid-agonist treatment carried smartphones on which they initiated entries for stressful events (SEs) or lapses to drug use (DUs), and thrice daily when randomly prompted (RPs). Participants rated their stress, opioid craving, cocaine craving, and moods. RP entries within 5 hours of an event were analyzed and compared to other RPs. RESULTS: 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. CONCLUSIONS: Stress increased before stressful-event entries, but was less evident before drug use. Craving increased in the hours before drug use and stressful events—and 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 one-hour-bin time resolution, suggesting that if such benefits exist, they are brief.

Background Sleep disturbance is common in patients with opioid use disorder (OUD) receiving medication for addiction treatment. Differences between patients on the two primary agonist medications—methadone and buprenorphine—are not well understood. Methods In patients receiving either methadone or buprenorphine treatment for OUD, we examined sleep continuity and architecture using ambulatory monitoring to gather both an objective measure (daily sleep EEG; M = 5.76 days, SD = 1.46) and a subjective measure (daily sleep diary; M = 54.10 days, SD = 25.10) of sleep. Results Patients treated with buprenorphine versus methadone did not differ on any measure of sleep continuity or architecture. Women had longer EEG-derived total sleep time than men (d = -0.68, 95 % CI -1.32 to -0.09), along with lower %N2 (d = 0.94, 95 % CI 0.34–1.64) and greater %N3 (d = -0.94, 95 % CI -1.61 to -0.32). Self-reported sleep differed from EEG-derived estimates: wake after sleep onset was greater by EEG than by diary (d = 2.58, 95 % CI 1.74–3.63), and total sleep time and sleep efficiency were lower by EEG than by diary (d for sleep time = 2.93, 95 % CI 2.06–4.14; d for efficiency = 1.69, 95 % CI 0.98–2.49). Conclusions Patients treated with buprenorphine or methadone did not substantively differ in ambulatory measures of sleep. With both medications, there was a discrepancy between objective and subjective sleep measures. Further confirmatory evidence would inform the development of sleep-related recommendations for OUD patients undergoing agonist treatment.

Introduction The subjective experience of drug craving is a prominent and common clinical phenomenon for many individuals diagnosed with opioid use disorder (OUD), and could be a valuable clinical endpoint in medication development studies. The purpose of this scoping review is to provide an overview and critical analysis of opioid craving assessments located in the published literature examining OUD. Method Studies were identified through a search of PubMed, Embase, and PsychInfo databases and included for review if opioid craving was the focus and participants were diagnosed with or in treatment for OUD. Results Fifteen opioid craving assessment instruments were identified across the 87 studies included for review. The most common were the Visual Analog Scale (VAS, 41 studies), Desires for Drug Questionnaire (DDQ, 12 studies), Heroin Craving Questionnaire (HCQ, 10 studies), and Obsessive-Compulsive Drug Use Scale (OCDUS, 10 studies). Craving assessments varied considerably in their format, content, time frame, and underlying subscales, and only 6 of 15 had been psychometrically evaluated. Discussion This review identified a variety of opioid craving assessments, but few had been evaluated for their psychometric properties making it difficult to ascertain whether craving is being assessed optimally in studies of OUD. Thus, the development of a reliable and valid opioid craving assessment would be worthwhile and could be guided by recently published Food and Drug Administration Clinical Outcome Assessment (COA) guidelines. Importantly, a COA focused on opioid craving could be a valuable addition to research studies designed to evaluate novel treatments for OUD.

Objectives People with substance use problems living in neighborhoods with high levels of disorder are disproportionately likely to experience trauma and develop PTSD symptoms. We sought to evaluate the relationships between objective neighborhood disorder, perceptions of neighborhood, and the use of maladaptive coping behaviors among both non-substance-using and substance-using participants with and without PTSD symptoms. Methods Participants (255 non-drug users [NDUs], 168 marijuana and/or alcohol users [MAUs], and 273 opioid and/or stimulant users) completed the Addiction Severity Index, PTSD Checklist-Civilian Version, The COPE Inventory, and the Perceived Neighborhood Scale. The Neighborhood Inventory for Environmental Typology (NIfETy) was used to objectively assess neighborhood disorder at participants' home addresses. Regression modeling was used to assess within-group predictors of PTSD and test for mediation in the relationships between PTSD, perceptions of neighborhood, and coping behaviors. Results In NDUs, lower sense of community partially mediated the relationship between PTSD symptoms and using mental disengagement to cope. In MAUs, higher levels of perceived crime partially mediated the individual relationships between PTSD symptoms and using mental disengagement, focusing on and venting emotions, and using substances to cope. Opioid and/or stimulant users with PTSD symptoms reported using higher levels of mental disengagement, focusing on and venting emotions, and substances to cope and perceived a higher degree of crime; no mediation was inferred. Conclusion Perceptions of community and crime may be more predictive of PTSD symptoms than objectively measured neighborhood disorder. These perceptions partially mediate the relationship between maladaptive coping behaviors and PTSD symptoms.

We sought to develop and deploy a video-based smartphone-delivered mobile HIV Risk Reduction (mHIVRR) intervention to individuals in an addiction treatment clinic. We developed 3 video modules that consisted of a 10-minute HIVRR video, 11 acceptability questions, and 3 knowledge questions and deployed them as a secondary study within a larger study of ecological momentary and geographical momentary assessments. All 24 individuals who remained in the main study long enough completed the mHIVRR secondary study. All 3 videos met our a priori criteria for acceptability “as is” in the population: they achieved median scores of ≤2.5 on a 5-point Likert scale; ≤20% of the individuals gave them the most negative rating on the scale; a majority of the individuals stated that they would not prefer other formats over video-based smartphone-delivered one (allP<0.05). Additionally, all of our video modules met our a priori criteria for feasibility: ≤20% of data were missing due to participant noncompliance and ≤20% were missing due to technical failure. We concluded that video-based mHIVRR education delivered via smartphone is acceptable, feasible and may increase HIV/STD risk reduction knowledge. Future studies, with pre-intervention assessments of knowledge and random assignment, are needed to confirm these findings.

Aripiprazole blocks psychostimulant seeking in a rat model of relapse. However, in humans, it may increase ongoing use. We tested aripiprazole specifically for relapse prevention. Methadone-maintained outpatients who were abstinent from cocaine in weeks 11-12 were randomized to double-blind aripiprazole (15 mg daily) or placebo in weeks 13-27 after 12 weeks of contingency management. Participants reported craving through ecological momentary assessment. We stopped the trial because very few (18/41) participants fulfilled the abstinence criterion. The results suggested that aripiprazole delayed lapse [hazard ratio (HR)=0.45, 95% confidence interval (CI)=0.14-1.42, P=0.17] and relapse (HR=0.31, 95% CI=0.07-1.27, P=0.10), but the effects did not reach statistical significance. Unexpectedly, the proportion of participants reporting cocaine craving was higher in the aripiprazole group (Fisher's exact P=0.026), although the frequency of craving was similar in the aripiprazole and placebo groups (1.89 vs. 1.16%, reffect=0.43, 95% CI=-0.08-0.76). The results suggest that in recently abstinent cocaine users, aripiprazole might delay relapse, but might also slightly increase craving. Difficulty in trial implementation underscores the fact that initial abstinence from cocaine is not a trivial hurdle.

We investigated relationships between drinking, other drug use, and drug craving, using ecological momentary assessment (EMA), in a sample of polydrug users who were not heavy drinkers. In a prospective longitudinal cohort study, 114 heroin and cocaine users on methadone-maintenance treatment carried handheld electronic diaries during waking hours and were screened for drug and alcohol use for up to 25 weeks. Individuals who fulfilled the Diagnostic and Statistical Manual of Mental Disorders criteria for alcohol abuse or dependence were excluded. Participants responded to 2-5 random prompts per day to report on their moods, cravings, and activities and initiated entries when they used or acutely craved heroin or cocaine. Drinking alcohol was assessed in both types of entries. Breath alcohol was measured three times weekly. Participants reported drinking alcohol in 1.6% of random-prompt entries, 3.7% of event-contingent entries when craving cocaine and/or heroin, and 11.6% of event-contingent entries when using cocaine and/or heroin. Alcohol drinking was also associated with higher craving ratings and prestudy alcohol use. More drinking was detected by ambulatory self-report than by in-clinic breath testing. Even though we had screened out heavy drinkers from our sample of polydrug users, drinking was associated with heroin and cocaine craving and actual use. Language: en

Oral naltrexone's effectiveness as an opioid antagonist has been limited due to poor patient adherence. A long-acting naltrexone formulation may be beneficial. This study evaluated the effects of extended-release injectable naltrexone (XR-NTX), targeted for a one-month duration of action, in blocking opioid agonist challenge effects in humans.Outpatient non-dependent opioid abusers (N=27) were randomly assigned to a single double-blind IM administration of 75, 150, or 300 mg XR-NTX. To assess the extent of opioid blockade, hydromorphone challenges (0, 3, 4.5, 6 mg IM in ascending order at 1-h intervals [up to 13.5 mg total]) were given at pretreatment baseline and on days 7, 14, 21, 28, 42, and 56. Opioid blockade was assessed via (1) tolerability of the ascending hydromorphone doses; (2) visual analog scale (VAS) ratings of subjective opioid effects and (3) pupil diameter. Effects on the VAS and pupils were assessed via the slope of the time-action function over ascending hydromorphone doses, with zero slope indicating complete blockade.Blockade of the VAS "any drug effect" response to 3 mg hydromorphone was complete for 14, 21, and 28 days, respectively, for the XR-NTX doses of 75, 150, and 300 mg. Subjective effects were more readily blocked than was pupil constriction. Higher hydromorphone doses produced only modest increases in agonist effects. With the 300 mg XR-NTX dose the slope of VAS responses remained at or near zero for one month even with maximal cumulative hydromorphone dosing.These data quantify the month-long opioid blockade underlying XR-NTX's efficacy in opioid dependence treatment.

Aims Clinical trials test the safety and efficacy of behavioral and pharmacological interventions in drug-dependent individuals. However, there is no consensus about the most appropriate outcome(s) to consider in determining treatment efficacy or on the most appropriate methods for assessing selected outcome(s). We summarize the discussion and recommendations of treatment and research experts, convened by the US National Institute on Drug Abuse, to select appropriate primary outcomes for drug dependence treatment clinical trials, and in particular the feasibility of selecting a common outcome to be included in all or most trials. Methods A brief history of outcomes employed in prior drug dependence treatment research, incorporating perspectives from tobacco and alcohol research, is included. The relative merits and limitations of focusing on drug-taking behavior, as measured by self-report and qualitative or quantitative biological markers, are evaluated. Results Drug-taking behavior, measured ideally by a combination of self-report and biological indicators, is seen as the most appropriate proximal primary outcome in drug dependence treatment clinical trials. Conclusions We conclude that the most appropriate outcome will vary as a function of salient variables inherent in the clinical trial, such as the type of intervention, its target, treatment goals (e.g. abstinence or reduction of use) and the perspective being taken (e.g. researcher, clinical program, patient, society). It is recommended that a decision process, based on such trial variables, be developed to guide the selection of primary and secondary outcomes as well as the methods to assess them.

Background Opioid Use Disorder (OUD) is a significant public health issue in the United States and globally. FDA-approved treatment for OUD includes Opioid Substitution Therapy (OST) with medications such as methadone and buprenorphine. While OST has been shown to be effective, a meta-analysis of outcome data from OST studies indicated that a significant percentage of opioid dependent patients treated with OST do not sustain abstinence or reduce their illicit opioid use. Understanding the factors that predict reductions in illicit opioid use during treatment would allow clinicians to make more informed therapeutic decisions, selecting medications that are most likely to benefit individual patients. Methods The START trial was a 24-week open-label randomized trial of methadone and buprenorphine for the treatment of OUD. Weekly urine drug screens were performed. Treatment efficacy was defined by the proportion of opioid positive urine tests. A Generalized Estimating Equation (GEE) was used to determine if variants in the OPRD1 gene were associated with treatment efficacy in African-Americans (AA; n=77). A replication population (n=75) was collected from AA patients who had previously participated in OST trials in Baltimore. Urine drug screens were performed three times per week. For a meta-analysis, weeks 21–24 were analyzed since they represent the last month of data available for both data sets. Responders were defined as patients who a) were retained in treatment until at least week 21 and b) were opioid positive for less than 50% of their urine drug screens in weeks 21–24. For in vitro analysis, 15 bp regions surrounding the C or T allele of rs678849 were cloned into luciferase vectors and transfected into neuroblastoma cells. Luciferase activity was measured by dual-luciferase reporter assay system. Results In the START trial, rs678849 was associated with the efficacy of methadone (p=0.001) and buprenorphine (p=0.008) in treating OUD in AA patients. The pharmacogenetic effect on buprenorphine (p=0.01), but not methadone (p=0.23), was replicated in the independent AA population from Baltimore. In a meta-analysis of weeks 21–24 of both data sets, patients with the C/C genotype had a significantly higher proportion of opioid positive urine drug screens (59%) than T allele carriers (26%, p Discussion These data suggest that a variant in the OPRD1 gene has a large pharmacogenetic effect on buprenorphine efficacy in the AA population and that the variant may have effects on expression. We hypothesize that the C allele of rs678849 functions as a silencer element, binding transcriptional repressors and downregulating OPRD1 expression. We also hypothesize that the T allele of the variant is an enhancer element and upregulates OPRD1 expression through interactions with a unique group of transcription factors. Further in vitro studies will be needed to dissect the complete mechanism and a prospective clinical trial that confirms this pharmacogenetic effect will be necessary before rs678849 can be used to guide treatment decisions.

To determine the electrocardiographic effects of coadministration of lofexidine and methadone.Prospective, double-blind study.Outpatient drug treatment research clinic.Fourteen adults (mean +/- SD age 34.9 +/- 5.3 yrs) with physical dependence on opioids.Participants were stabilized on methadone maintenance therapy, reaching a target dose of 80 mg/day. After 3 weeks of methadone stabilization, participants received lofexidine 0.4 mg or placebo once/day, each for 1 week, administered at the same time as methadone. From weeks 3-8, all subjects received lofexidine, with the dose escalated each week in 0.2-mg increments so that by week 8, participants were receiving lofexidine 1.6 mg/day. Electrocardiograms (ECGs) were obtained at baseline (before methadone), after stabilization with methadone, and after lofexidine coadministration during peak plasma lofexidine levels.Prespecified outcome measures of mean and maximal changes in heart rate, and PR, QRS, and QTc intervals were obtained after stabilization with methadone and after lofexidine 0.4 mg coadministration. Repeated-measures regression showed no significant changes in heart rate or PR, QRS, or QTc interval after methadone stabilization, but a significant decrease in heart rate (mean +/- SD -8.0 +/- 7.3 beats/min, p=0.0006) after starting lofexidine. When data were analyzed by using maximal ECG response, again, no significant changes were noted during methadone induction compared with baseline, but significant changes did occur in all four ECG parameters when lofexidine was coadministered: decreased heart rate (mean +/- SD -9.6 +/- 5.8 beats/min, p0.0001) and increased PR interval (+11.1 +/- 19.8 msec, p=0.026), QRS interval (+3.7 +/- 4.3 msec, p=0.002), and QTc interval (+21.9 +/- 40.8 msec, p=0.018). In three female participants, the change in QTc interval from baseline was clinically significant (40 msec).Our preliminary data suggest that coadministration of lofexidine and methadone induces QTc interval prolongation. This drug combination should be prescribed cautiously, with ECG monitoring. Furthermore, because the participants with the largest changes in QTc interval in our study were female, women may be at highest risk.

Introduction and Aims. A challenge in treatment research is the necessity of adhering to protocol and regulatory strictures while maintaining flexibility to meet patients' treatment needs and to accommodate variations among protocols. Another challenge is the acquisition of large amounts of data in an occasionally hectic environment, along with the provision of seamless methods for exporting, mining and querying the data. Design and Methods. We have automated several major functions of our outpatient treatment research clinic for studies in drug abuse and dependence. Here we describe three such specialised applications: the Automated Contingency Management (ACM) system for the delivery of behavioural interventions, the transactional electronic diary (TED) system for the management of behavioural assessments and the Protocol Workflow System (PWS) for computerised workflow automation and guidance of each participant's daily clinic activities. These modules are integrated into our larger information system to enable data sharing in real time among authorised staff. Results. ACM and the TED have each permitted us to conduct research that was not previously possible. In addition, the time to data analysis at the end of each study is substantially shorter. With the implementation of the PWS, we have been able to manage a research clinic with an 80 patient capacity, having an annual average of 18 000 patient visits and 7300 urine collections with a research staff of five. Finally, automated data management has considerably enhanced our ability to monitor and summarise participant safety data for research oversight. Discussion and Conclusions. When developed in consultation with end users, automation in treatment research clinics can enable more efficient operations, better communication among staff and expansions in research methods. [Vahabzadeh M, Lin J-L, Mezghanni M, Epstein DH, Preston KL. Automation in an addiction treatment research clinic: Computerised contingency management, ecological momentary assessment and a protocol workflow system. Drug Alcohol Rev 2009;28:3–11]

Background The development and approval of an efficacious pharmacotherapy for stimulant use disorders has been limited by the lack of a meaningful indicator of treatment success, other than sustained abstinence. Methods In March, 2015, a meeting sponsored by Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) was convened to discuss the current state of the evidence regarding meaningful outcome measures in clinical trials for stimulant use disorders. Attendees included members of academia, funding and regulatory agencies, pharmaceutical companies, and healthcare organizations. The goal was to establish a research agenda for the development of a meaningful outcome measure that may be used as an endpoint in clinical trials for stimulant use disorders. Results and conclusions Based on guidelines for the selection of clinical trial endpoints, the lessons learned from prior addiction clinical trials, and the process that led to identification of a meaningful indicator of treatment success for alcohol use disorders, several recommendations for future research were generated. These include a focus on the validation of patient reported outcome measures of functioning, the exploration of patterns of stimulant abstinence that may be associated with physical and/or psychosocial benefits, the role of urine testing for validating self-reported measures of stimulant abstinence, and the operational definitions for reduction-based measures in terms of frequency rather than quantity of stimulant use. These recommendations may be useful for secondary analyses of clinical trial data, and in the design of future clinical trials that may help establish a meaningful indicator of treatment success.

We investigate needs, challenges, and opportunities in visualizing time-series sensor data on stress to inform the design of just-in-time adaptive interventions (JITAIs). We identify seven key challenges: massive volume and variety of data, complexity in identifying stressors, scalability of space, multifaceted relationship between stress and time, a need for representation at multiple granularities, inter-person variability, and limited understanding of JITAI design requirements due to its novelty. We propose four new visualizations based on one million minutes of sensor data (n=70). We evaluate our visualizations with stress researchers (n=6) to gain first insights into its usability and usefulness in JITAI design. Our results indicate that spatio-temporal visualizations help identify and explain between- and within-person variability in stress patterns and contextual visualizations enable decisions regarding the timing, content, and modality of intervention. Interestingly, a granular representation is considered informative but noise-prone; an abstract representation is the preferred starting point for designing JITAIs.

While a majority of cocaine research focuses on identification of therapies targeting dependence, few detection strategies exist to aid in clinical determination of susceptibility or likelihood of relapse. To enhance our understanding of the full spectrum of cocaine-induced effects, we used a lipidomics approach to investigate the ability of cocaine to remodel the blood lipidome. Lipids were extracted from 190 human blood samples (123 drug users, 67 non-users) and analyzed using electrospray ionization-mass spectrometry. The resulting data were assessed using multivariate analysis, which indicated differences in the lipid profiles of drug users compared to non-users. Identification of m/z features suggested alterations in glycerolipids, fatty acids, phosphatidylcholines, and phosphatidic acids. A subset of repeat abusers were asked to rate the positive and negative effects following their first cocaine exposure in comparison to their most recent use. These scores were used to assess the extent of enhanced...

Sublingual buprenorphine, a long-acting, partial mu-opioid agonist, is as effective as methadone in the treatment of heroin dependence, with a better safety profile due to its antagonist activity. However, the safety of therapeutic doses (8 to 16 mg) that might be diverted for intravenous (i.v.) use has not been demonstrated. To evaluate the safety and possible ceiling effects of buprenorphine administered i.v. to experienced opioid users, buprenorphine was administered to 6 nondependent opioid abusers residing on a research unit; the doses tested, in separate sessions, were 12 mg buprenorphine sublingual, i.v./sublingual placebo, and escalating i.v. buprenorphine (2, 4, 8, 12, and 16 mg). Physiologic and subjective measures were collected for 72 hours post-drug administration. Buprenorphine minimally but significantly increased systolic blood pressure. Changes in heart rate or oxygen saturation among the 7 drug conditions were not statistically significant. The mean maximum decrease in oxygen saturation from baseline was greatest for the 8-mg i.v. dose. Buprenorphine produced positive mood effects, although with substantial variability among participants. Onset and peak effects occurred earlier following i.v. administration: peak i.v. effects occurred between 0.25 and 3 hours; peak sublingual effects occurred at 3 to 7 hours. Duration of effects varied among the outcome measures. The dose-response curves were flat for most parameters, particularly subjective measures. Side effects were mild except in one participant who experienced severe nausea and vomiting after the 12-mg i.v. dose. Buprenorphine appears to have a ceiling for cardiorespiratory and subjective effects and a high safety margin even when taken by the i.v. route.

Buprenorphine is a partial μ-opiate agonist and κ-opiate antagonist marketed in the United States and worldwide as a parenteral or sublingual analgesic1 and as maintenance treatment for opiate dependence.2 However, its efficacy for treatment of dually (cocaine and heroin) dependent individuals has not been established. For the treatment of opiate dependence, sublingual doses of 8 to 16 mg daily of buprenorphine are as effective as 55 to 80 mg of oral methadone in reducing opiate use.3,4 There is some evidence that sublingual doses as low as 2 mg daily may reduce opiate use.5 Because buprenorphine has a relatively long duration of action, every-other-day and 3-times-weekly dosing have also shown efficacy.6-9 A large proportion of opiate users use cocaine, even during opiate agonist substitution treatment for opiate dependence. Cocaine use during opiate agonist maintenance treatment is associated with increased opiate use, poorer treatment outcomes, and premature dropout from treatment.10 Methadone and levomethadyl acetate (INN, levacetylmethadol) do not seem efficacious for the treatment of cocaine dependence in opiate-dependent individuals. Thus a medication that effectively reduced both opiate and cocaine use would offer a therapeutic advantage over methadone or levomethadyl acetate alone for the many patients who are using or are dependent on both opiates and cocaine. Buprenorphine was found to have such potential in preclinical studies. It significantly reduced cocaine self-administration in monkeys without interfering with appetitive behaviors such as eating.11-14 However, attempted replications of these effects in humans have yielded inconsistent results. In some human laboratory studies, buprenorphine treatment reduced self-reported cocaine craving and cocaine self-administration; other studies have failed to replicate those results.15-18 Currently, there is no consensus in the literature about the clinical efficacy of buprenorphine for treatment of concurrent cocaine and heroin dependence. In some clinical trials with opiate-dependent subjects, buprenorphine treatment has been associated with reductions in cocaine use,19-21 whereas other trials have found no evidence of efficacy.18,22 One negative trial used buprenorphine doses of 4 mg and 12 mg/d22; the other used a mean dose of 11.2 mg.18 The positive studies have used buprenorphine doses up to 16 mg daily, with more reduction of cocaine use at higher doses. The purpose of this study was to evaluate the efficacy of sublingual buprenorphine maintenance (10 weeks) in reducing cocaine and opiate use in dually (cocaine and opiate) dependent outpatients.

We examined gender differences in drug use patterns and in medical presentation among 520 hospitalized, HIV-infected African-Americans. Substance abuse history was self-reported, and medical data were obtained by chart review. Overall, 321 (65%) reported ever having used heroin, with equivalent rates in men and women. Women were more likely to report current use, to have sought treatment, and tended to feel more dependent on heroin than men. Among heroin users, women were more likely to be admitted for conditions related to drug use, rather than AIDS, and to have CD4 counts > 200/mm3. These gender differences in opioid dependency and medical comorbidity may indicate a need for alternative treatment approaches for men and women.(Am J Addict 2004; 13:281–291)

With the growing role of intravenous drug use in the transmission of HIV infection, HIV-infected patients frequently present with comorbid opioid dependence. Yet, few empirical evaluations of the efficacy and consequences of opioid detoxification medications in medically ill HIV-infected patients have been reported. In a randomized, double-blind clinical trial, we evaluated the impact of three medications on the signs and symptoms of withdrawal and on the pain severity in heroin-dependent HIV-infected patients (N=55) hospitalized for medical reasons on an inpatient AIDS service. Patients received a 3-day pharmacologic taper with intramuscular buprenorphine (n=21), oral clonidine (n=16), or oral methadone (n=18), followed by a clonidine transdermal patch on the fourth day. Observed and self-reported measures of opioid withdrawal and pain were taken 1-3 times daily for up to 4 days. Opiate administration used as medically indicated for pain was also recorded. Observer- and subject-rated opiate withdrawal scores decreased significantly following the first dose of medication and overall during treatment. Among all 55 subjects, self-reported and observer-reported pain decreased after treatment (on average observer-rated opioid withdrawal scale (OOWS) scores declined 5.6 units and short opioid withdrawal scale (SOWS) declined 4.8 units, P

Contingency management (CM) rapidly reduces cocaine use, but its effects subside after treatment. Cognitive-behavioral therapy (CBT) produces reductions months after treatment. Combined, the 2 might be complementary. One hundred ninety-three cocaine-using methadone-maintained outpatients were randomly assigned to 12 weeks of group therapy (CBT or a control condition) and voucher availability (CM contingent on cocaine-negative urine or noncontingent). Follow-ups occurred 3, 6, and 12 months posttreatment. Primary outcome was cocaine-negative urine (urinalysis 3 times/week during treatment and once at each follow-up). During treatment, initial effects of CM were dampened by CBT. Posttreatment, there were signs of additive benefits, significant in 3- versus 12-month contrasts. Former CBT participants were also more likely to acknowledge cocaine use and its effects and to report employment.

Aims—To determine whether cannabinoid-positive urine specimens in heroin-dependent outpatients predict other drug use or impairments in psychosocial functioning, and whether such outcomes are better predicted by cannabis-use disorders than by cannabis use itself. Design—Retrospective analyses of three clinical trials; each included a behavioral intervention (contingency management) for cocaine or heroin use during methadone maintenance. Trials lasted 25–29 weeks; follow-up evaluations occurred 3, 6, and 12 months posttreatment. For the present analyses, data were pooled across trials where appropriate. Setting—Urban outpatient methadone clinic. Participants—408 polydrug abusers meeting methadone-maintenance criteria. Measurements—Participants were categorized as nonusers, occasional users, or frequent users of cannabis based on thrice-weekly qualitative urinalyses. Cannabis-use disorders were assessed with the Diagnostic Interview Schedule III-R. Outcome measures included proportion of cocaine- and opiate-positive urines and the Addiction Severity Index (at intake and follow-ups). Findings—Cannabis use was not associated with retention, use of cocaine or heroin, or any other outcome measure during or after treatment. Our analyses had a power of .95 to detect an r 2 of .11 between cannabis use and heroin or cocaine use; the r 2 we detected was less than .03 and nonsignificant. A previous finding that cannabis use predicted lapse to heroin use in heroin-abstinent patients did not replicate in our sample. However, cannabis-use disorders were weakly associated with psychosocial problems at posttreatment follow-up. Conclusions—Cannabinoid-positive urines need not be a major focus of clinical attention during treatment for opiate dependence, unless patients report symptoms of cannabis-use disorders.

Combinations of medications are often used in neuropsychiatry to enhance treatment efficacy. This 8-week, open-label study tested the combination of bupropion (or =300 mg) and bromocriptine (or =7.5 mg) daily in 34 cocaine-dependent (DSM-IIIR) outpatients also receiving weekly individual counseling. The first 18 subjects spent one week at maximum dose; the next 16 spent three weeks. Both groups showed significant reductions in self-reported cocaine use, with no significant change in proportion of urine toxicology tests positive for cocaine. There were no significant differences in outcome between groups. These results suggest that the combination of bupropion and bromocriptine is safe in cocaine addicts, but provide ambiguous evidence of its efficacy.

Infection with hepatitis C virus (HCV) is a complex public health problem with a high prevalence of chronic infection, an increasing prevalence of HCV-associated disease, low rates of testing and treatment, and the prospect of increasing incidence associated with intravenous drug use (IVDU; Smith, Jorgensen, Zibbell, & Beckett, 2012). IVDU is a major risk factor for HCV, and HCV prevalence is exceedingly high among intravenous drug users (Schreuder et al., 2010). A study conducted in Baltimore, MD, found that the seroprevalence of HCV among intravenous drug users was 77%, with most individuals becoming positive within the first year of initiating IVDU (Garfein, Vlahov, Galai, Doherty, & Nelson, 1996). IVDU does not directly influence HCV progression despite the potential for multiple repeat exposures to various HCV genotypes, but HCV progression may be accelerated by several factors associated with IVDU, including excess alcohol intake, reduced access and adherence to treatment, and poor nutrition (Cooper & Mills, 2006). Given the adverse public health consequences of HCV infection and its link to HIV, improved approaches to reducing the spread of HCV, particularly among intravenous drug users, are needed. Although there is strong evidence that medication-assisted addiction treatment reduces drug misuse, HIV-risk behaviors, and HIV infection rates (Metzger, Woody, & O’Brien, 2010; Millson et al., 2007), the corresponding evidence for HCV remains controversial (Crofts, Nigro, Oman, Stevenson, & Sherman, 1997; Selvey, Denton, & Plant, 1997; Thiede, Hagan, & Murrill, 2000), suggesting that approaches beyond medication-assisted treatment alone are needed to curb HCV-risk behaviors and infection rates. Given that risk behaviors persist during addiction treatment (Chaudhry et al., 2011) and are more likely among patients who do not know their HCV status (Vidal-Trecan, Coste, Varescon-Pousson, Christoforov, & Boissonnas, 2000), one approach might be to test people for hepatitis C upon addiction-treatment admission and inform them of the results. Unawareness of HCV status is common. In one study, 72% of HCV+ and 46% of HCV− intravenous drug users were unaware of their HCV status (Hagan et al., 2006). However, even after diagnosis with HCV, high-risk behaviors continue (Hagan et al., 2006; Ompad, Fuller, Vlahov, Thomas, & Strathdee, 2002). The initial diagnosis of HCV had a strong, negative emotional effect in almost half of a patient group that was not primarily composed of intravenous drug users (Fabris et al., 2006). For intravenous drug users, an HCV diagnosis is sometimes thought to be less momentous than for nonintravenous drug users, but that may not always be true (Treloar & Rhodes, 2009). As for possible emotional effects of the disease process itself, there seems to be no published research; phenomenological studies of hepatitis C focus on patients who have begun antiviral treatment, which can produce psychiatric side effects of its own (Sgorbini, O’Brien, & Jackson, 2009). What is unknown is whether ongoing risk behavior is increased by the negative emotional effect of HCV diagnosis itself or by other factors in the lived experience of HCV+ individuals not on antiviral treatment. The analyses presented here are part of a project to better understand the factors influencing drug use and lapse and improve approaches to reducing high-risk behaviors. We have followed up on prior research in our laboratory showing that HCV+ patients in methadone maintenance report higher drug-related HIV-risk behaviors and are more likely to test positive for opioids compared with HCV− patients (Willner-Reid, Belendiuk, Epstein, Schmittner, & Preston, 2008). Our treatment-research clinic uses ecological momentary assessment (EMA), a technique for collection of in-the-field, first-person data using handheld computers. EMA largely eliminates recall bias by collecting self-report in near real time and produces time-stamped data that are amenable to statistical aggregation (Shiffman, Stone, & Hufford, 2008). We have previously reported success with EMA in a study of over 100 heroin- and cocaine-using methadone-maintained patients and shown that cocaine-use events are preceded by increasing exposure to drug-use triggers and are associated with craving, stress, and tobacco use (Epstein, Marrone, Heishman, Schmittner, & Preston, 2010; Epstein & Preston, 2010; Epstein et al., 2009; Preston et al., 2009). In the analyses reported here, we determine whether HCV+ and HCV− individuals are differentially exposed, in their daily lives, to triggers of craving and drug use, and we explore the relationship of HCV status with demographics and momentary moods in patients whose HCV is not yet overtly symptomatic in an effort to inform treatment interventions for reduction of HCV-risk behavior and infection rates.

Cocaine-using methadone-maintenance patients were randomized to standard contingency management (abstinence group, n = 49) or to a contingency designed to increase contact with reinforcers (shaping group, n = 46). For 8 weeks, both groups earned escalating-value vouchers based on thrice-weekly urinalyses: The abstinence group earned vouchers for cocaine-negative urines only; the shaping group earned vouchers for each urine specimen with a 25% or more decrease in cocaine metabolite (first 3 weeks) and then for negative urines only (last 5 weeks). Cocaine use was lower in the shaping group, but only in the last 5 weeks, when the response requirement was identical. Thus, the shaping contingency appeared to better prepare patients for abstinence. A 2nd phase of the study showed that abstinence induced by escalating-value vouchers can be maintained by a nonescalating schedule, suggesting that contingency management can be practical as a maintenance treatment.

Seven cocaine-abusing volunteers were trained to discriminate 50 mg oral cocaine vs placebo across 50 2-h sessions. Discriminative, subjective and autonomic effects were assessed with a procedure developed for precise characterization of their acute time-course. Subjective effects of oral cocaine began 10-15 min post-drug, peaked at 40-50 min and took up to 100 min post-drug to return nearly to baseline. Autonomic effects also began 10-15 min post-drug, peaked at 40-50 min and typically returned to baseline by 120 min post-drug; for most participants, peak heart rate and blood pressure remained within the range seen with placebo. Six out of seven participants acquired the discrimination (although this typically required 15-30 sessions, and there were some intriguing dissociations between the ability to discriminate oral cocaine from placebo and the ability to identify it as a stimulant). In most participants, oral cocaine produced increases in ratings of 'liking', 'alertness' and 'good effects', and in motor performance. Overall, the results support the sensitivity of the behavioral-testing procedure used, and show that 50 mg oral cocaine can serve as a discriminative stimulus in adult humans.