Problematic alcohol use and its impact on liver disease quality of life in a multicenter study of patients with cirrhosis.

BACKGROUND: Management of cirrhosis is challenging and has been complicated by the COVID-19 pandemic due to decreased access to care, increased psychological distress, and alcohol misuse. Recently, The National Institute on Alcohol Abuse and Alcoholism has broadened the definition of recovery from alcohol use disorder to include quality of life (QoL) as an indicator of recovery. This study examined the associations of alcohol-associated cirrhosis etiology and problematic drinking with liver disease QoL (LDQoL). METHODS: Patients with cirrhosis (N=329) were recruited from 3 sites (63% from 2 Veterans Affairs Health Care Systems and 37% from 1 safety net hospital) serving populations that are economically or socially marginalized. Cirrhosis etiology was ascertained by chart review of medical records. Problematic drinking was defined by ≥8 on the Alcohol Use Disorders Identification Test. Multivariable general linear modeling adjusting for age, sex, race/ethnicity, site, pandemic-related stress, and history of anxiety/depressive disorder were conducted. Sensitivity analyses further adjusted for indicators of liver disease severity. RESULTS: Participants were on average 64.6 years old, 17% female, 58% non-White, 44% with alcohol-associated cirrhosis, and 17% with problematic drinking. Problematic drinking was significantly associated with worse LDQoL scores in the overall scale and in the memory/concentration and health distress subscales. These associations remained significant after adjusting for indicators of liver disease severity, including Model for End-Stage Liver Disease-Sodium score and decompensated cirrhosis status. CONCLUSIONS: Among patients with cirrhosis, problematic drinking was associated with worse LDQoL, especially in the domains of memory/concentration and health distress. Assessment and awareness of cognitive deficits and negative emotionality within the context of cirrhosis and problematic drinking may help clinicians provide better integrated care for this population.

N-acetylcysteine for smoking cessation among dual users of tobacco and cannabis: Protocol and rationale for a randomized controlled trial.

BACKGROUND: Tobacco and cannabis co-use is a growing public health problem. The synergistic effects of cannabis and nicotine on neurobiological systems that mediate reward and shared environmental cues reinforcing use may make tobacco smoking cessation more difficult. N-acetylcysteine (NAC), an FDA-approved medication and over-the-counter supplement, has shown promise in animal studies and randomized controlled trials (RCTs) in reducing tobacco and cannabis craving and use. NAC's potential efficacy in treating addiction may be attributable to its central nervous system effects in reducing excessive glutamatergic activity, oxidative stress, and inflammation. To date, no RCT has examined NAC for smoking cessation among dual users of tobacco and cannabis. METHOD: In a double-blind, placebo-controlled RCT, we will examine NAC for smoking cessation among dual users of tobacco and cannabis. Sixty adult cigarette-cannabis co-users are randomized to receive NAC 3600 mg per day or placebo over 8 weeks. Participants in both groups receive 8 weekly cognitive behavioral therapy sessions addressing smoking cessation and cannabis reduction. Outcomes are assessed at Weeks 0, 4, 8, and 12. Primary aims are to determine NAC's efficacy in decreasing cigarette craving, nicotine dependence, and use; and cannabis craving and use. Exploratory aims include examination of changes in neurocognition with NAC and their potential mediational effects on cigarette and cannabis use outcomes. CONCLUSION: Results will inform smoking cessation treatment among dual users of tobacco and cannabis. CLINICALTRIALS: gov Identifier: NCT04627922.

Effects of buprenorphine on opioid craving in comparison to other medications for opioid use disorder: A systematic review of randomized controlled trials.

BACKGROUND: Craving is a distressing symptom of opioid use disorder (OUD) that can be alleviated with medications for OUD (MOUD). Buprenorphine is an effective MOUD that may suppress craving; however, treatment discontinuation and resumed opioid use is common during the early phases of treatment. More information on the craving response through the high-risk period of initiating buprenorphine may provide meaningful information on how to better target craving, which in turn may enhance outcomes. This systematic review investigated buprenorphine doses and formulations on craving during the induction and maintenance phases of treatment, and for context also compared the craving response to other MOUD (i.e., methadone, extended-release naltrexone [XR-NTX]). METHODS: PubMed, PsycInfo, Embase, and Cochrane Central databases were searched for randomized trials of buprenorphine versus placebo, various buprenorphine formulations/doses, or other MOUD that included a measure of opioid craving. RESULTS: A total of 10 studies were selected for inclusion. Buprenorphine and buprenorphine/naloxone (BUP/NAL) were each associated with lower craving than placebo over time. Craving was greater among those prescribed lower versus higher buprenorphine doses. In comparison to other MOUD, buprenorphine or BUP/NAL was linked to greater craving than methadone in 3 of the 6 studies. BUP/NAL was associated with greater reported craving than XR-NTX. DISCUSSION: Craving is reduced over time with buprenorphine and BUP/NAL, although other MOUD may provide greater reductions in craving. Although there is currently considerable variability in the measurement of craving, it may be a valuable concept to address with individuals receiving MOUD, especially early in treatment.

Impact of Alcohol Use, Traumatic Stress, and Cigarette Smoking on Cognitive Functioning in Veterans With Co-occurring Alcohol Use Disorder and Posttraumatic Stress Disorder.

INTRODUCTION: Alcohol use disorder (AUD) and PTSD have high rates of co-occurrence in U.S. Military Veterans resulting in incrementally worse functional outcomes relative to having either one of these disorders alone. Cognitive dysfunction can impede one's ability to benefit from standard behavioral AUD and PTSD treatments. Cigarette smoking is also highly prevalent among U.S. Military Veterans, and cognitive dysfunction is associated with chronic cigarette use among individuals with AUD and PTSD independently. However, much less is known about to what extent cigarette smoking further impairs cognitive functioning in individuals with both co-occurring AUD and PTSD. MATERIALS AND METHODS: U.S. Veterans with co-occurring AUD and PTSD (n = 162) completed a comprehensive cognitive assessment covering various domains: working memory, processing speed, mental switching, cognitive inhibition, auditory-verbal learning, auditory-verbal memory, and verbal fluency. To examine the impact of alcohol use, traumatic stress, and cigarette smoking on cognitive function, we conducted a three-way interaction examining the moderated effects of smoking status on the association between alcohol use and PTSD symptoms on a composite domain of global cognition. RESULTS: Smoking status in Veterans with co-occurring AUD and PTSD moderated the relationship between alcohol use and global cognition (P = .042), such that higher levels of alcohol use in the past week were related to worse global cognitive function among Veterans cigarette smokers (P = .015) but not among nonsmokers (P = .833). On follow-up analyses of individual cognitive domains, greater alcohol use in the past week was associated with lower cognitive inhibition in smokers but not nonsmokers, with traumatic stress symptoms moderating this effect (P = .039). Additionally, smoking status moderated the relationship between alcohol use and auditory-verbal learning, such that there was a differential relationship between alcohol use and auditory-verbal learning between smokers and nonsmokers. CONCLUSIONS: Overall, results provide evidence for the compounding impact of alcohol use, traumatic stress, and cigarette smoking on cognitive functioning. Impaired cognitive performance on a global level as well as on individual domains of cognitive inhibition and auditory-verbal learning were evident. Cognitive dysfunction may impede a Veteran's ability to benefit from therapeutic treatment, and these cognitive domains may represent potential targets for cognitive training efforts. Further, study results support smoking cessation initiatives and smoke-free policies enacted at Veterans Affairs healthcare facilities and medical centers.

Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial.

Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment. Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes. Design, Setting, and Participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications. Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978). Main Outcomes and Measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters. Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45). Conclusions and Relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission. Trial Registration: ClinicalTrials.gov Identifier: NCT03170362.

The Impact of Exercise and Virtual Reality Executive Function Training on Cognition Among Heavy Drinking Veterans With Traumatic Brain Injury: A Pilot Feasibility Study.

Executive function (EF) underlies self-control deficits in alcohol use disorder (AUD) and traumatic brain injury (TBI). Cognitive training is a promising adjunctive treatment targeting TBI- and AUD- related cognitive dysfunction. However, major limitations related to compliance and generalizability in the field of cognitive training exist. Physical activity is associated with enhanced cognitive performance across several executive functions and may enhance the benefits of cognitive training. Virtual reality provides multisensory embodied experiences which are likely to engage brain networks more efficiently than standard cognitive training systems, ultimately resulting in greater near- and far-transfer effects. This pilot study aimed to obtain feasibility data and a preliminary assessment of an enriched virtual reality (VR) EF training (EFT) intervention combined with exercise (NCT03786276). Using an 8-week randomized adaptive design study, 30 AUD treatment seeking U.S. Veterans completed nine sessions of exercise-only (n = 15) or gameplay control (n = 15) over 3 weeks, followed by a week-4 repeat assessment in Phase 1. Twenty-three participants completed and moved onto Phase II, where they completed up to nine sessions of VR-EFT plus exercise and completed a week-8 end-of-study assessment. Primary outcomes included feasibility to retain participants, usability, and satisfaction of using VR-EFT. Secondary and exploratory outcomes included within group assessment of change in cognitive function, alcohol use, alcohol craving, and post-concussive symptoms among the three treatment conditions.VR-EFT was feasible with moderate usability and high acceptability ratings.The most common VR-related adverse effect was motion sickness (n = 2/16, 12.5%). The VR-EFT condition was associated with significant improvement in inhibition-switching and visual scanning (both p < 0.05) during Phase II. Exercise-only was associated with significant improvements in cognitive inhibition, cognitive flexibility, reductions in alcohol craving, and number of standard alcohol drinks per week (all p ≤ 0.05). The gaming-control condition was associated with improvement in cognitive flexibility and visuospatial immediate recall (both p < 0.05) during Phase 1. Recruitment and retention of U.S. veterans with AUD and TBI into an exercise plus VR-EFT intervention is feasible, but technological barriers may impact usability. VR-EFT was associated with improvement in executive function domains that were targeted in as little as 3-week and nine sessions of VR-EFT exposure. Results are promising and indicate the need for a larger controlled investigation to assess the efficacy of VR-EFT to enhance treatment outcomes among AUD treatment-seeking U.S. veterans with co-occurring AUD and TBI. Clinical Trial Registration: www.ClinicalTrials.gov, Identifier: NCT03786276.

Pilot study of extended-release lorcaserin for cocaine use disorder among men who have sex with men: A double-blind, placebo-controlled randomized trial.

OBJECTIVE: To determine if men who have sex with men (MSM) with cocaine use disorder (CUD) and actively-using cocaine could be enrolled and retained in a pharmacologic intervention trial of lorcaserin-a novel 5-HT2cR agonist-and determine the degree to which participants would adhere to study procedures. METHODS: This was a phase II randomized, double-blind, placebo-controlled pilot study with 2:1 random parallel group assignment to daily extended-release oral lorcaserin 20 mg versus placebo (clinicaltrials.gov identifier-NCT03192995). Twenty-two of a planned 45 cisgender MSM with CUD were enrolled and had weekly follow-up visits during a 12-week treatment period, with substance use counseling, urine specimen collection, and completion of audio-computer assisted self-interview (ACASI) behavioral risk assessments. Adherence was measured by medication event monitoring systems (MEMS) caps and self-report. This study was terminated early because of an FDA safety alert for lorcaserin's long-term use. RESULTS: Eighty-six percent completed the trial, with 82% of weekly study follow-up visits completed. Adherence was 55.3% (lorcaserin 51.6% vs. placebo 66.2%) by MEMS cap and 56.9% (56.5% vs. placebo 57.9%) by self-report and did not differ significantly by treatment assignment. Intention-to-treat analyses (ITT) did not show differences in cocaine positivity by urine screen between the lorcaserin and placebo groups by 12 week follow-up (incidence risk ratio [IRR]: 0.96; 95%CI = 0.24-3.82, P = 0.95). However, self-reported cocaine use in timeline follow-back declined more significantly in the lorcaserin group compared to placebo (IRR: 0.66; 95%CI = 0.49-0.88; P = 0.004). CONCLUSION: We found that it is feasible, acceptable, and tolerable to conduct a placebo-controlled pharmacologic trial for MSM with CUD who are actively using cocaine. Lorcaserin was not associated with significant reductions in cocaine use by urine testing, but was associated with significant reductions in self-reported cocaine use. Future research may be needed to continue to explore the potential utility of 5-HT2cR agonists.

Working memory and alcohol demand relationships differ according to PTSD symptom severity among veterans with AUD.

Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) are highly comorbid with complex and often unclear associations. Working memory deficits may represent a shared mechanism implicated in emotion regulation and control over impulsive alcohol use. Here we test whether PTSD symptoms and working memory correlated with performance on a behavioral economic assessment of alcohol demand. 113 veterans (mean age 51 years; 89% male) completed an Alcohol Purchase Task (APT) and were assessed for PTSD, alcohol use, and working memory. We examined the interaction of PTSD symptoms and working memory on four indices of alcohol demand measured from the APT; specifically, we used separate models to test whether associations between working memory and intensity (consumption at $0), Omax (maximum expenditure), Pmax (price at maximum expenditure), and elasticity (price sensitivity), differed as a function of PTSD symptoms. In a model controlling for hazardous drinking, average drinking levels, age, sex, marital status, occupation, and education, we observed a significant interaction between PTSD symptoms and working memory on elasticity, whereby greater working memory capacity was associated with greater elasticity for veterans with lower PTSD symptoms. Follow-up analyses regarding specific PTSD symptom domains indicated that this effect was strongest for avoidance symptoms. Taken together, working memory abilities correlated with subjective valuations of alcohol in a laboratory setting for veterans with less severe PTSD symptoms. This work highlights the conditions under which working memory may be a potential target for interventions geared toward reducing alcohol use in veterans with co-occurring PTSD and AUD. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Intranasal Oxytocin for Stimulant Use Disorder Among Male Veterans Enrolled in an Opioid Treatment Program: A Randomized Controlled Trial.

The increasing prevalence of illicit stimulant use among those in opioid treatment programs poses a significant risk to public health, stimulant users have the lowest rate of retention and poorest outcomes among those in addiction treatment, and current treatment options are limited. Oxytocin administration has shown promise in reducing addiction-related behavior and enhancing salience to social cues. We conducted a randomized, double-blind, placebo-controlled clinical trial of intranasal oxytocin administered twice daily for 6 weeks to male Veterans with stimulant use disorder who were also receiving opioid agonist therapy and counseling (n = 42). There was no significant effect of oxytocin on stimulant use, stimulant craving, or therapeutic alliance over 6 weeks. However, participants receiving oxytocin (vs. placebo) attended significantly more daily opioid agonist therapy dispensing visits. This replicated previous work suggesting that oxytocin may enhance treatment engagement among individuals with stimulant and opioid use disorders, which would address a significant barrier to effective care.

A randomized pilot trial of topiramate for alcohol use disorder in veterans with traumatic brain injury: Effects on alcohol use, cognition, and post-concussive symptoms.

BACKGROUND: Topiramate is an effective treatment for alcohol use disorder (AUD) and has also been used in the care of mild traumatic brain injury (mTBI). This pilot study aimed to obtain a preliminary assessment of topiramate's efficacy in reducing alcohol use and post-concussive symptoms, and its potential negative impact on cognitive function in 32 Veterans with co-occurring AUD and mTBI. METHODS: This was a prospective 12-week, randomized, double-blind, placebo-controlled pilot study of flexible-dose topiramate or placebo. Primary outcome was reduction of drinking days per week within the topiramate arm. Secondary outcomes included between group comparisons of alcohol use and craving, post-concussive symptoms, and cognitive function. RESULTS: Drinking days per week significantly decreased within both the topiramate and placebo arm. There were no significant treatment-by-week interactions on alcohol use/craving, or post-concussive symptoms in intent-to-treat analyses. In per-protocol analyses, topiramate significantly reduced number of drinks per week compared with placebo. Topiramate transiently impaired verbal fluency and working memory. Processing speed, cognitive inhibition, and mental flexibility significantly improved between weeks 1 and 12, regardless of treatment arm. CONCLUSIONS: Significant improvement occurred in both the topiramate and placebo groups over 12 weeks of treatment in alcohol use and post-concussive symptoms. Among treatment completers there was greater reduction of alcohol use in the topiramate arm. Topiramate was also associated with negative but transient effects on cognitive function. Results suggest both a possible benefit for topiramate treatment in reducing alcohol use and some potential for negative cognitive effects in Veterans with AUD and mTBI.

Acute cognitive effects of the hypocretin receptor antagonist almorexant relative to zolpidem and placebo: a randomized clinical trial.

STUDY OBJECTIVES: Hypnotic medications can adversely affect behavior during unanticipated awakenings during the night. Animals treated with the hypocretin (Hcrt) receptor antagonist almorexant (ALM) have less acute cognitive impairment compared to the GABAA receptor modulator zolpidem (ZOL). This study aimed to determine whether ALM produces less acute cognitive impairment than ZOL in human subjects. METHODS: Healthy, young adult, unmedicated male and female subjects participated in a controlled trial of a single dose of ALM 100 mg (N = 48), ALM 200 mg (N = 53), ZOL 10 mg (N = 49), and placebo (PBO, N = 52). RESULTS: ZOL and both doses of ALM produced similar levels of subjective sleepiness and impaired the ability of subjects to remain awake in a dark, low-stimulus setting relative to PBO. For most cognitive measures, performance under ZOL was significantly worse than ALM or PBO. For tasks involving verbal memory or visual-motor coordination, ZOL impaired performance, whereas the two doses of ALM were no different than PBO. For tasks involving higher-order executive function, ZOL produced impairment in processing speed and inhibitory control, whereas the two doses of ALM were no different than PBO. Performance decrements for ALM were less than ZOL but greater than PBO for some reaction time measures. CONCLUSIONS: The data provide support for the hypothesis that Hcrt receptor antagonists produce less functional impairment than a benzodiazepine receptor agonist (BzRA). These observations are particularly relevant to patients treated with sedative-hypnotics who are at elevated risk for falls and other untoward events during the intended hours for sleep.

Effects of Mirtazapine for Methamphetamine Use Disorder Among Cisgender Men and Transgender Women Who Have Sex With Men: A Placebo-Controlled Randomized Clinical Trial.

Importance: Methamphetamine use is increasingly prevalent and associated with HIV transmission. A previous phase 2a study of mirtazapine demonstrated reductions in methamphetamine use and sexual risk behaviors among men who have sex with men. Objective: To determine the efficacy of mirtazapine for treatment of methamphetamine use disorder and reduction in HIV risk behaviors. Design, Setting, and Participants: This double-blind randomized clinical trial of mirtazapine vs placebo took place from August 2013 to September 2017 in an outpatient research clinic in San Francisco, California. Participants were community-recruited adults who were sexually active; cisgender men, transgender men, and transgender women who (1) had sex with men, (2) had methamphetamine use disorder, and (3) were actively using methamphetamine were eligible. Participants were randomized to receive the study drug or placebo for 24 weeks, with 12 more weeks of follow-up. Data analysis took place from February to June 2018. Exposures: Mirtazapine, 30 mg, or matched placebo orally once daily for 24 weeks, with background counseling. Main Outcomes and Measures: Positive urine test results for methamphetamine over 12, 24, and 36 weeks (primary outcomes) and sexual risk behaviors (secondary outcomes). Sleep, methamphetamine craving, dependence severity, and adverse events were assessed. Results: Of 241 persons assessed, 120 were enrolled (5 transgender women and 115 cisgender men). The mean (SD) age was 43.3 (9.8) years; 61 (50.8%) were white, 31 (25.8%) were African American, and 15 (12.5%) were Latinx. A mean (SD) of 66% (47%) of visits were completed overall. By week 12, the rate of methamphetamine-positive urine test results significantly declined among participants randomized to mirtazapine vs placebo (risk ratio [RR], 0.67 [95% CI, 0.51-0.87]). Mirtazapine resulted in reductions in positive urine test results at 24 weeks (RR, 0.75 [95% CI, 0.56-1.00]) and 36 weeks (RR, 0.73 [95% CI, 0.57-0.96]) vs placebo. Mean (SD) medication adherence by WisePill dispenser was 38.5% (27.0%) in the mirtazapine group vs 39.5% (26.2%) in the placebo group (P = .77) over 2 to 12 weeks and 28.1% (23.4%) vs 38.5% (27.0%) (P = .59) over 13 to 24 weeks. Changes in sexual risk behaviors were not significantly different by study arm at 12 weeks, but those assigned to receive mirtazapine had fewer sexual partners (RR, 0.52 [95% CI, 0.27-0.97]; P = .04), fewer episodes of condomless anal sex with partners who were serodiscordant (RR, 0.47 [95% CI, 0.23-0.97]; P = .04), and fewer episodes of condomless receptive anal sex with partners who were serodiscordant (RR, 0.37 [95% CI, 0.14-0.93]; P = .04) at week 24. Participants assigned to mirtazapine had net reductions in depressive symptoms (Center for Epidemiologic Studies Depression Scale score, 6.2 [95% CI, 1.3-11.1] points lower; P = .01) and insomnia severity (Athens score, 1.4 [95% CI, 0.1-2.7] points lower; P = .04) at week 24. There were no serious adverse events associated with the study drug. Conclusions and Relevance: In this expanded replication trial, adding mirtazapine to substance use counseling reduced methamphetamine use and some HIV risk behaviors among cisgender men and transgender women who have sex with men, with benefits extending after treatment despite suboptimal medication adherence. Trial Registration: ClinicalTrials.gov identifier: NCT01888835.

Effects of Oxytocin Administration on Cue-Induced Craving in Co-occurring Alcohol Use Disorder and PTSD: A Within-Participant Randomized Clinical Trial.

BACKGROUND: Individuals with alcohol use disorder (AUD) are much more likely to meet criteria for posttraumatic stress disorder (PTSD) than the general population. Compared to AUD alone, those with comorbid AUD-PTSD experience worse outcomes. Prior literature suggests that oxytocin, a hypothalamic neuropeptide, may be effective in the treatment of both AUD and PTSD when administered intranasally, although specific mechanisms remain elusive. METHODS: Forty-seven male patients with comorbid AUD-PTSD were administered intranasal oxytocin in a randomized, double-blind, dose-ranging (20 IU, 40 IU, and matched placebo), within-participant design with study visits at least 1 week apart. A cue-induced craving paradigm was conducted using each participant's preferred alcoholic beverage versus a neutral water cue. Self-reported alcohol craving and heart rate (HR) were recorded and analyzed using linear mixed-effect models. RESULTS: While alcohol cues significantly induced self-reported craving and increased HR compared to neutral water cues, neither dosage of oxytocin compared to placebo reduced self-reported cue-induced alcohol craving nor cue-induced changes in HR in patients with PTSD-AUD. CONCLUSIONS: These preliminary findings suggest that oxytocin does not affect cue-induced craving. Our results contribute to an ever-growing field of research investigating the effects of intranasal oxytocin on the symptoms of substance use disorders and will help further refine methodology and streamline future inquiries in this area.

An electronic intervention to improve safety for pain patients co-prescribed chronic opioids and benzodiazepines.

BACKGROUND: Co-prescribing opioids and benzodiazepines increases overdose risk. A paucity of literature exists evaluating strategies to improve safety of co-prescribing. This study evaluated an electronic intervention to improve safety for patients co-prescribed chronic opioids for pain and benzodiazepines at 3 and 6 months. METHODS: A prospective cohort study was conducted from December 2015 through May 2016 at San Francisco Veterans Affairs Health Care System. A clinical dashboard identified 145 eligible patients prescribed chronic opioids and benzodiazepines. Individualized taper and safety recommendations were communicated to prescribers via electronic medical record progress note and encrypted e-mail at baseline. Primary outcome was number of patients co-prescribed chronic opioids and benzodiazepines. Secondary outcomes included daily dose of opioids and benzodiazepines and number prescribed ≥100 mg morphine equivalent daily dose. Safety outcomes included number with opioid overdose education and naloxone distribution, annual urine drug screening, annual prescription drug monitoring program review, and signed opioid informed consent. Linear mixed models and generalized estimating equations were used to examine within-group change in outcomes between baseline and 3 and 6 months. RESULTS: Among the 145 patients, mean (standard deviation) age was 62 (11) years and 91.7% (133/145) were male. Number co-prescribed significantly decreased from 145/145 (100%) at baseline to 93/139 (67%) at 6-month follow-up (odds ratio [OR] = 0.53, 95% confidence interval [CI]: 0.34-0.81, P = .003). Mean opioid and benzodiazepine doses significantly decreased from 84.61 to 65.63 mg (95% CI: 8.32-27.86, P < .001) and from 16.10 to 13.45 mg (95% CI: 1.6-3.9, P < .001), respectively, from baseline to 6-month follow-up. Patients prescribed ≥100 mg morphine equivalent daily dose significantly decreased from 39/145 (26.8%) at baseline to 26/139 (18.7%) at end of study (OR = 0.59, 95% CI: 0.44-0.78, P < .001), and patients with opioid overdose education and naloxone distribution significantly increased from 3/145 (2.1%) at baseline to 46/139 (33.1%; OR = 23.4, 95% CI: 7.61-71.99, P < .001) by the end of study. Number of patients with annual urine drug screening tended to increase from 123/145 (84.8%) at baseline to 132/145 (91.4%) by the end of study (OR = 1.89, 95% CI: 0.95-3.76, P = .07), and there were no significant changes across time in numbers of patients with annual prescription drug monitoring program review or signed opioid informed consent. CONCLUSIONS: Electronic interventions may provide an effective strategy to improve safety for patients co-prescribed chronic opioids for pain and benzodiazepines.

Mobile Technology for Treatment Augmentation in Veteran Smokers With Posttraumatic Stress Disorder.

INTRODUCTION: The purpose of this study is to examine the feasibility and acceptability of incorporating a mobile application, Stay Quit Coach, into an integrated care smoking-cessation treatment protocol for veterans with posttraumatic stress disorder (PTSD). METHODS: Participants included veteran smokers aged 18-69 years with PTSD. The integrated care protocol includes eight weekly PTSD-informed cognitive behavioral therapy sessions for smoking cessation, followed by monthly booster sessions and a prescription for standard smoking-cessation medications if desired. Participants used Stay Quit Coach as desired. Outcome measures at 3-month follow-up included: adherence (sessions attended), 30-day point-prevalence abstinence bioverified with carbon monoxide <6 parts per million, past-30 day mean daily cigarette use, exhaled carbon monoxide, nicotine dependence, and PTSD symptom severity. Repeated outcomes were analyzed with random-intercept linear mixed models. Data were collected in 2015-2016 and analyses were conducted in 2016-2017. RESULTS: Participants (n=20) were 95% male and 5% female; mean age 41.4 (SD=16.2) years. Thirteen participants (65%) attended all scheduled sessions, four (20%) did not adhere to the protocol on schedule, and three (15%) were lost to follow-up. At 3-month follow-up, six of 17 completers (35.3%) had bioverified 30-day point-prevalence abstinence. Nicotine dependence, carbon monoxide levels, and past 30-day cigarette use significantly decreased and PTSD symptoms were unchanged from baseline to follow-up. Participants self-reported using Stay Quit Coach 2.5 (SD=2.2) days/week; 15 of 17 (88.2%) reported using Stay Quit Coach <30 minutes/week; two of 17 (11.8%) reported using Stay Quit Coach 30-60 minutes/week. CONCLUSIONS: Although results must be interpreted with caution given the lack of control group and small sample size, findings indicate that integrating Stay Quit Coach into integrated care was feasible and acceptable.

Extended-release naltrexone for methamphetamine dependence among men who have sex with men: a randomized placebo-controlled trial.

BACKGROUND AND AIMS: Methamphetamine use is increasingly prevalent and associated with HIV transmission. Early-phase human studies suggested naltrexone reduced amphetamine use among dependent individuals. We tested if extended-release naltrexone (XRNTX) reduces methamphetamine use and associated sexual risk behaviors among high-risk methamphetamine-dependent men who have sex with men (MSM). DESIGN: Double-blind, placebo-controlled, randomized trial of XRTNX versus placebo over 12 weeks from 2012 to 2015. SETTING: San Francisco Department of Public Health, California, USA. PARTICIPANTS: One hundred community-recruited, sexually-active, actively-using methamphetamine-dependent MSM. Mean age was 43.2 years; 96% were male, 3% transfemale, and 1% transmale; 55.0% were white, 19.0% African American, and 18.0% Latino. INTERVENTIONS: XRNTX 380 mg (n = 50) or matched placebo (n = 50) administered by gluteal injection at 4-week intervals. MEASUREMENTS: Regression estimated average level and change in level of positive urines during the period 2-12 weeks (primary outcomes) and sexual risk behaviors (secondary outcome). FINDINGS: Ninety per cent of visits were completed. By intent-to-treat, participants assigned to XRNTX had similar differences during 2-12 weeks in methamphetamine-positive urines as participants assigned to placebo [incidence rate ratio (IRR) = 0.95, 95% confidence interval (CI) = 0.76-1.20; Bayes factor < 0.3]. Observed urine positivity declined from 78 to 70% in the XRNTX arm and 74 to 64% in the placebo arm. Adherence to injections was 96.7% in the XRNTX arm and 91.3% in the placebo arm. Sexual risk behaviors declined similarly among participants in both arms (all P > 0.05). There were no serious adverse events related to study drug and no differences in frequency of adverse events by treatment arm. CONCLUSIONS: Notwithstanding very high medication adherence for this study, extended-release naltrexone does not appear to reduce methamphetamine use or sexual risk behaviors among methamphetamine-dependent men who have sex with men compared with placebo.

Relations Between Cognitive Functioning and Alcohol Use, Craving, and Post-Traumatic Stress: An Examination Among Trauma-Exposed Military Veterans With Alcohol Use Disorder.

Cognitive dysfunction is commonly observed among individuals with alcohol use disorder (AUD) and trauma exposure and is, in turn, associated with worse clinical outcomes. Accordingly, disruptions in cognitive functioning may be conceptualized as a trans-disease phenomenon representing a potential high-yield target for intervention. Less is known though about how different cognitive functions covary with alcohol use, craving, and post-traumatic stress symptom severity among trauma-exposed individuals with AUD. Sixty-eight male and female trauma-exposed military veterans with AUD, entering treatment trials to reduce alcohol use, completed measures assessing alcohol use and craving, post-traumatic stress symptom severity, and cognitive functioning. In multivariate models, after controlling for post-traumatic stress symptom severity, poorer learning and memory was associated with higher alcohol consumption and higher risk taking/impulsivity was associated with stronger preoccupations with alcohol and compulsions to drink. Alcohol consumption and craving, but not performance on cognitive tests, were positively associated with post-traumatic stress symptom severity. Findings suggest that interventions to strengthen cognitive functioning might be used as a preparatory step to augment treatments for AUD. Clinicians are encouraged to consider a standard assessment of cognitive functioning, in addition to post-traumatic stress symptom severity, in treatment planning and delivery for this vulnerable and high-risk population.

Observational Evidence for Buprenorphine's Impact on Posttraumatic Stress Symptoms in Veterans With Chronic Pain and Opioid Use Disorder.

OBJECTIVE: Posttraumatic stress disorder (PTSD), chronic pain, and substance use disorders are prevalent co-occurring conditions that are challenging to treat individually, and there is no evidence-based treatment for all 3. Buprenorphine, used to treat opioid use disorder and chronic pain, is a partial nociceptin opioid receptor agonist. In preclinical studies, a nociceptin opioid receptor agonist was shown to mitigate PTSD symptoms in acute trauma. We compared buprenorphine to other opioid medications in its impact on PTSD symptoms in patients with chronic pain and opioid and/or other substance use disorders. METHOD: We assembled a retrospective cohort of 382 Iraq and Afghanistan veterans in US Department of Veterans Affairs health care from October 1, 2007, to July 29, 2013, with ICD-9-CM diagnoses of PTSD, chronic pain, and substance use disorders. We used time-varying general estimating equation models to assess the primary outcome, which was change in PTSD symptoms (measured using the PTSD Checklist and the Primary Care PTSD Screen) among veterans initiated on sublingual buprenorphine versus those maintained on moderately high-dose opioid therapy. RESULTS: Twice as many veterans in the buprenorphine group (23.7%) compared to those in the opioid therapy group (11.7%) experienced improvement in PTSD symptoms (P = .001). Compared to veterans in the opioid therapy group, veterans receiving buprenorphine showed significant improvement in PTSD symptoms after 8 months, with increasing improvement up to 24 months (incidence rate ratio = 1.79; 95% CI, 1.16-2.77; P = .009). There were no differences in the longitudinal course of pain ratings between groups. CONCLUSIONS: This observational study is the first to report an incidental effect of buprenorphine compared to opioid therapy in improving PTSD symptoms in veterans.

Feasibility, Acceptability, and Tolerability of Targeted Naltrexone for Nondependent Methamphetamine-Using and Binge-Drinking Men Who Have Sex with Men.

BACKGROUND: There are no effective pharmacologic strategies for nondependent methamphetamine (meth)-using and binge-drinking men who have sex with men (MSM) at high-risk for HIV. We sought to determine the feasibility of enrolling and retaining this population in a pharmacologic trial; the acceptability of pharmacotherapy study procedures; and the tolerability of targeted naltrexone versus placebo. METHODS: Thirty meth-using and binge-drinking MSM were randomly assigned 1:1 to 50 mg naltrexone or placebo for 8 weeks for targeted administration (ie, during craving or in anticipation of meth or alcohol use). Substance use counseling and behavioral assessments were conducted every 2 weeks. Medication use was measured using WisePill dispensers. RESULTS: Trial completion was 93%; visit completion rate was 95%. Mean weekly number of medication pills taken was 2.1 and was similar between arms. Participant satisfaction rate was 96%. There were neither serious adverse events nor differences in adverse event rates between arms. In exploratory intention-to-treat analyses, there were no differences in meth use and drinking. Naltrexone participants had greater reductions in serodiscordant receptive anal intercourse [incident rate ratio (IRR) = 0.15; 95% CI = 0.05 to 0.42] and serodiscordant condomless receptive anal intercourse (IRR = 0.11; 95% CI = 0.03 to 0.37), compared with placebo. In subgroup analyses among frequent meth users, naltrexone participants had greater reductions in meth-using days (IRR = 0.78; 95% CI = 0.62 to 0.99). In as-treated analyses, frequent study medication users in the naltrexone arm had greater reductions in binge drinking days (IRR = 0.72; 95% CI = 0.54 to 0.97). CONCLUSIONS: Targeted naltrexone is a feasible, acceptable, and tolerable intervention strategy for nondependent meth-using and binge-drinking MSM. Naltrexone was associated with significant sexual risk reductions; and for some individuals, naltrexone was associated with meth and binge-drinking reductions.