Sleep reductions associated with illicit opioid use and clinic-hour changes during opioid agonist treatment for opioid dependence: Measurement by electronic diary and actigraphy.

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.

End-of-day reports of daily hassles and stress in men and women with opioid-use disorder: Relationship to momentary reports of opioid and cocaine use and stress.

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.

Assessment of pioglitazone and proinflammatory cytokines during buprenorphine taper in patients with opioid use disorder.

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.

Before and after: craving, mood, and background stress in the hours surrounding drug use and stressful events in patients with opioid-use disorder.

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 h 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 1-h-bin time resolution, suggesting that if such benefits exist, they are brief.

Exacerbated Craving in the Presence of Stress and Drug Cues in Drug-Dependent Patients.

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

Context and craving during stressful events in the daily lives of drug-dependent patients.

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

Real-time assessment of alcohol drinking and drug use in opioid-dependent polydrug users.

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.

Effects of Prereactivation Propranolol on Cocaine Craving Elicited by Imagery Script/Cue Sets in Opioid-dependent Polydrug Users: A Randomized Study.

OBJECTIVES: Relapse to drug misuse may follow exposure to drug cues that elicit craving. The learned associations, or "emotional memories," that underlie responses to cues may be attenuated or erased by the ß-adrenergic antagonist propranolol during a "reconsolidation window" shortly after the memories are reactivated by cues. METHODS: We evaluated the effects of propranolol on cue-induced drug cravings in healthy opioid-dependent individuals who used cocaine while receiving methadone maintenance (n = 33). Participants were asked to recall specific cocaine use and neutral events in an interview; these events were used to develop personalized auditory script/cue sets. Approximately 1 week later, propranolol (40 mg) or placebo (random assignment, double blind) was administered orally before presentation of the script/cue sets; the presentation of the script/cue sets were tested 1 week and 5 weeks after the propranolol/placebo session. Ongoing drug use was monitored via urine screens and self-report in twice-weekly visits. RESULTS: Cue reactivity, as assessed by craving scales and physiological responses, was unexpectedly greater in the propranolol group than in the placebo group. This counterhypothesized group difference was present acutely during propranolol administration and seemed to persist (without reaching statistical significance) during the subsequent test sessions. CONCLUSIONS: Our results do not support the use of propranolol for cue-induced cocaine craving in opioid-maintained patients.

Some of the people, some of the time: field evidence for associations and dissociations between stress and drug use.

RATIONALE: Stress's role in drug use is supported by retrospective interview and laboratory studies, but prospective data confirming the association in daily life are sparse. OBJECTIVES: This study aims to assess the relationship between drug use and stress in real time with ambulatory monitoring. METHODS: For up to 16 weeks, 133 outpatients on opiate agonist treatment used smartphones to report each time they used drugs or felt more stressed than usual. They rated stress-event severity on a 10-point scale and as a hassle, day spoiler, or more than a day spoiler. For analysis, stress reports made within 72 h before a reported use of cocaine or opioid were binned into 24-h periods. RESULTS: Of 52 participants who reported stress events in the 72-h timeframe, 41 reported stress before cocaine use and 26 before opioid use. For cocaine use, the severity of stressors, rated numerically (r effect = 0.42, CL95 0.17-0.62, p = 0.00061) and percent rated as "more than a day spoiler" (r effect = 0.34, CL95 0.07-0.56, p = 0.0292)], increased linearly across the three days preceding use. The number of stressors did not predict cocaine use, and no measure of stress predicted opioid use. In ecological momentary assessment (EMA) from the whole sample of 133, stress and drug use occurred independently and there was no overall relationship. CONCLUSIONS: EMA did not support the idea that stress is a necessary or sufficient trigger for cocaine or heroin use after accounting for the base rates of stress and use. But EMA did show that stressful events can increase in severity in the days preceding cocaine use.

Continuous in-the-field measurement of heart rate: Correlates of drug use, craving, stress, and mood in polydrug users.

BACKGROUND: Ambulatory physiological monitoring could clarify antecedents and consequences of drug use and could contribute to a sensor-triggered mobile intervention that automatically detects behaviorally risky situations. Our goal was to show that such monitoring is feasible and can produce meaningful data. METHODS: We assessed heart rate (HR) with AutoSense, a suite of biosensors that wirelessly transmits data to a smartphone, for up to 4 weeks in 40 polydrug users in opioid-agonist maintenance as they went about their daily lives. Participants also self-reported drug use, mood, and activities on electronic diaries. We compared HR with self-report using multilevel modeling (SAS Proc Mixed). RESULTS: Compliance with AutoSense was good; the data yield from the wireless electrocardiographs was 85.7%. HR was higher when participants reported cocaine use than when they reported heroin use (F(2,9)=250.3, p<.0001) and was also higher as a function of the dose of cocaine reported (F(1,8)=207.7, p<.0001). HR was higher when participants reported craving heroin (F(1,16)=230.9, p<.0001) or cocaine (F(1,14)=157.2, p<.0001) than when they reported of not craving. HR was lower (p<.05) in randomly prompted entries in which participants reported feeling relaxed, feeling happy, or watching TV, and was higher when they reported feeling stressed, being hassled, or walking. CONCLUSIONS: High-yield, high-quality heart-rate data can be obtained from drug users in their natural environment as they go about their daily lives, and the resultant data robustly reflect episodes of cocaine and heroin use and other mental and behavioral events of interest.

Clonidine Maintenance Prolongs Opioid Abstinence and Decouples Stress From Craving in Daily Life: A Randomized Controlled Trial With Ecological Momentary Assessment.

OBJECTIVE: The authors tested whether clonidine blocks stress-induced seeking of heroin and cocaine. The study was also intended to confirm translational findings from a rat model of drug relapse by using ecological momentary assessment of patients' stress to test hypotheses about clonidine's behavioral mechanism of action. METHOD: The authors conducted a randomized double-blind placebo-controlled clinical trial with 208 opioid-dependent patients at an outpatient buprenorphine clinic. The 118 participants (57%) who maintained abstinence during weeks 5-6 were continued on buprenorphine and randomly assigned to receive clonidine (N=61) or placebo (N=57) for 14 weeks. Urine was tested thrice weekly. Lapse was defined as any opioid-positive or missed urine test, and relapse as two or more consecutive lapses. Time to lapse and relapse were examined with Cox regressions; longest period of abstinence was examined with a t test, and ecological momentary assessment data were examined with generalized linear mixed models. RESULTS: In an intent-to-treat analysis, clonidine produced the longest duration (in consecutive days) of abstinence from opioids during the intervention phase (34.8 days [SD=3.7] compared with 25.5 days [SD=2.7]; Cohen's d=0.38). There was no group difference in time to relapse, but the clonidine group took longer to lapse (hazard ratio=0.67, 95% CI=0.45-1.00). Ecological momentary assessment showed that daily-life stress was partly decoupled from opioid craving in the clonidine group, supporting the authors' hypothesized mechanism for clonidine's benefits. CONCLUSIONS: Clonidine, a readily available medication, is useful in opioid dependence not just for reduction of withdrawal signs, but also as an adjunctive maintenance treatment that increases duration of abstinence. Even in the absence of physical withdrawal, it decouples stress from craving in everyday life.

Real-time tracking of neighborhood surroundings and mood in urban drug misusers: application of a new method to study behavior in its geographical context.

BACKGROUND: Maladaptive behaviors may be more fully understood and efficiently prevented by ambulatory tools that assess people's ongoing experience in the context of their environment. METHODS: To demonstrate new field-deployable methods for assessing mood and behavior as a function of neighborhood surroundings (geographical momentary assessment; GMA), we collected time-stamped GPS data and ecological momentary assessment (EMA) ratings of mood, stress, and drug craving over 16 weeks at randomly prompted times during the waking hours of opioid-dependent polydrug users receiving methadone maintenance. Locations of EMA entries and participants' travel tracks calculated for the 12 before each EMA entry were mapped. Associations between subjective ratings and objective environmental ratings were evaluated at the whole neighborhood and 12-h track levels. RESULTS: Participants (N=27) were compliant with GMA data collection; 3711 randomly prompted EMA entries were matched to specific locations. At the neighborhood level, physical disorder was negatively correlated with negative mood, stress, and heroin and cocaine craving (ps<.0001-.0335); drug activity was negatively correlated with stress, heroin and cocaine craving (ps .0009-.0134). Similar relationships were found for the environments around respondents' tracks in the 12h preceding EMA entries. CONCLUSIONS: The results support the feasibility of GMA. The relationships between neighborhood characteristics and participants' reports were counterintuitive and counter-hypothesized, and challenge some assumptions about how ostensibly stressful environments are associated with lived experience and how such environments ultimately impair health. GMA methodology may have applications for development of individual- or neighborhood-level interventions.

Differential sensitivity of Pak5, Pak6, and Pak5/Pak6 double-knockout mice to the stimulant effects of amphetamine and exercise-induced alterations in body weight.

OBJECTIVES: PAK5 and PAK6 are protein kinases highly expressed in the brain. Previously, we observed that Pak6 knockout mice gained significantly more weight during development than Pak5 knockout mice as well as wild-type controls and double-knockout mice lacking both Pak5 and Pak6. In this study, we assessed the effects of exercise on food intake and weight gain of these mice as well as their sensitivity to the stimulant effects of amphetamine. METHODS: Mice of each genotype were placed in cages with free access to run wheel exercise or in cages without run wheels for a total of 74 days. Food and fluid intake as well as body weight of each mouse were measured on a weekly basis. Finally, mice were given a high dose of amphetamine and activity levels were observed immediately thereafter for 90 minutes. Brains and testes of mice were assayed for protein levels of the estrogen alpha and progesterone receptors. RESULTS: While run wheel mice consumed significantly more food, they weighed less than non-run wheel mice. In addition, although Pak6 knockout mice consumed the same amount of food as wild-type mice, they were significantly heavier regardless of run wheel condition. Pak5 knockout mice were found to be more active than other genotypes after amphetamine treatment. Finally, protein levels of the progesterone and estrogen alpha receptors were altered in brain and testes of the Pak6 knockout mice. DISCUSSION: Collectively, these data suggest that PAK6 play a role in weight gain unrelated to exercise and caloric intake and that Pak5 knockout mice are more sensitive to the stimulant effects of amphetamine.

Functional deficits in PAK5, PAK6 and PAK5/PAK6 knockout mice.

The p21-activated kinases are effector proteins for Rho-family GTPases. PAK4, PAK5, and PAK6 are the group II PAKs associated with neurite outgrowth, filopodia formation, and cell survival. Pak4 knockout mice are embryonic lethal, while Pak5, Pak6, and Pak5/Pak6 double knockout mice are viable and fertile. Our previous work found that the double knockout mice exhibit locomotor changes and learning and memory deficits. We also found some differences with Pak5 and Pak6 single knockout mice and the present work further explores the potential differences of the Pak5 knockout and Pak6 knockout mice in comparison with wild type mice. The Pak6 knockout mice were found to weigh significantly more than the other genotypes. The double knockout mice were found to be less active than the other genotypes. The Pak5 knockout mice and the double knockout mice performed worse on the rotorod test. All the knockout genotypes were found to be less aggressive in the resident intruder paradigm. The double knockout mice were, once again, found to perform worse in the active avoidance assay. These results indicate, that although some behavioral differences are seen in the Pak5 and Pak6 single knockout mice, the double knockout mice exhibit the greatest changes in locomotion and learning and memory.

Clonidine blocks stress-induced craving in cocaine users.

RATIONALE: Reactivity to stressors and environmental cues, a putative cause of relapse in addiction, may be a useful target for relapse-prevention medication. In rodents, alpha-2 adrenergic agonists such as clonidine block stress-induced reinstatement of drug seeking, but not drug cue-induced reinstatement. OBJECTIVE: The objective of this study is to test the effect of clonidine on stress- and cue-induced craving in human cocaine users. METHODS: Healthy, non-treatment-seeking cocaine users (n = 59) were randomly assigned to three groups receiving clonidine 0, 0.1, or 0.2 mg orally under double-blind conditions. In a single test session, each participant received clonidine or placebo followed 3 h later by exposure to two pairs of standardized auditory-imagery scripts (neutral/stress and neutral/drug). Subjective measures of craving were collected. RESULTS: Subjective responsivity ("crave cocaine" Visual Analog Scale) to stress scripts was significantly attenuated in the 0.1- and 0.2-mg clonidine groups; for drug-cue scripts, this attenuation occurred only in the 0.2-mg group. Other subjective measures of craving showed similar patterns of effects but Dose × Script interactions were not significant. CONCLUSIONS: Clonidine was effective in reducing stress-induced (and, at a higher dose, cue-induced) craving in a pattern consistent with preclinical findings, although this was significant on only one of several measures. Our results, though modest and preliminary, converge with other evidence to suggest that alpha-2 adrenergic agonists may help prevent relapse in drug abusers experiencing stress or situations that remind them of drug use.

Targeted disruption of the Pak5 and Pak6 genes in mice leads to deficits in learning and locomotion.

PAK6 is a member of the group B family of PAK serine/threonine kinases, and is highly expressed in the brain. The group B PAKs, including PAK4, PAK5, and PAK6, were first identified as effector proteins for the Rho GTPase Cdc42. They have important roles in filopodia formation, the extension of neurons, and cell survival. Pak4 knockout mice die in utero, and the embryos have several abnormalities, including a defect in the development of motor neurons. In contrast, Pak5 knockout mice do not have any noticeable abnormalities. So far nothing is known about the biological function of Pak6. To address this, we have deleted the Pak6 gene in mice. Since Pak6 and Pak5 are both expressed in the brain, we also generated Pak5/Pak6 double knockout mice. These mice were viable and fertile, but had several locomotor and behavioral deficits. Our results indicate that Pak5 and Pak6 together are not required for viability, but are required for a normal level of locomotion and activity as well as for learning and memory. This is consistent with a role for the group B PAKs in the nervous system.