Primary Care Associated With Follow Up Viral Load Testing in Patients Cured of Hepatitis C Infection With Direct Acting Antivirals at a Multidisciplinary Addiction Treatment Program: Insights From a Real-World Setting.

OBJECTIVES: Treatment of hepatitis C virus infection (HCV) with direct acting antiviral therapy is encouraged regardless of substance use status. Patients with substance use disorder are at risk of HCV reinfection after cure. Follow up viral load testing (FUVL) with HCV RNA is recommended. We investigated factors associated with adoption of FUVL in real-world clinical settings. METHODS: Medical records of all patients with SUD who achieved HCV cure with direct acting antivirals at a multidisciplinary addiction treatment program between 2014 and 2019 were reviewed as part of a quality improvement initiative. Demographic and clinical characteristics including SUD treatment, urine toxicology results, and medical service use were collected. Factors associated with FUVL were analyzed and the rate of HCV reinfection was determined. RESULTS: Among 149 patients, 58.4% received FUVL. Receipt of FUVL was associated with engagement in ongoing primary medical care after cure (AOR 4.39, 95% CI [1.67, 11.49]). The HCV reinfection rate among those who received FUVL was 1.95 per 100 person-years of follow up (95% CI [0.64, 5.98]). There was no significant difference in the percentage of negative urine toxicology results before and after cure. CONCLUSIONS: Over half of a cohort of patients with substance use disorder cured of HCV received FUVL. The relationship between FUVL and engagement in primary medical and substance use treatment highlights the importance of integrated systems in providing longitudinal care for patients cured of HCV. Standardized interventions that facilitate FUVL testing and management of infectious complications of SUD in addiction treatment settings are needed.

Saracatinib Fails to Reduce Alcohol-Seeking and Consumption in Mice and Human Participants.

More effective treatments to reduce pathological alcohol drinking are needed. The glutamatergic system and the NMDA receptor (NMDAR), in particular, are implicated in behavioral and molecular consequences of chronic alcohol use, making the NMDAR a promising target for novel pharmacotherapeutics. Ethanol exposure upregulates Fyn, a protein tyrosine kinase that indirectly modulates NMDAR signaling by phosphorylating the NR2B subunit. The Src/Fyn kinase inhibitor saracatinib (AZD0530) reduces ethanol self-administration and enhances extinction of goal-directed ethanol-seeking in mice. However, less is known regarding how saracatinib affects habitual ethanol-seeking. Moreover, no prior studies have assessed the effects of Src/Fyn kinase inhibitors on alcohol-seeking or consumption in human participants. Here, we tested the effects of saracatinib on alcohol consumption and craving/seeking in two species, including the first trial of an Src/Fyn kinase inhibitor to reduce drinking in humans. Eighteen male C57BL/6NCrl mice underwent operant conditioning on a variable interval schedule to induce habitual responding for 10% ethanol/0.1% saccharin. Next, mice received 5 mg/kg saracatinib or vehicle 2 h or 30 min prior to contingency degradation to measure habitual responding. In the human study, 50 non-treatment seeking human participants who drank heavily and met DSM-IV criteria for alcohol abuse or dependence were randomized to receive 125 mg/day saracatinib (n = 33) or placebo (n = 17). Alcohol Drinking Paradigms (ADP) were completed in a controlled research setting: before and after 7-8 days of treatment. Each ADP involved consumption of a priming drink of alcohol (0.03 mg%) followed by ad libitum access (3 h) to 12 additional drinks (0.015 g%); the number of drinks consumed and craving (Alcohol Urge Questionnaire) were recorded. In mice, saracatinib did not affect habitual ethanol seeking or consumption at either time point. In human participants, no significant effects of saracatinib on alcohol craving or consumption were identified. These results in mice and humans suggest that Fyn kinase inhibition using saracatinib, at the doses tested here, may not reduce alcohol consumption or craving/seeking among those habitually consuming alcohol, in contrast to reports of positive effects of saracatinib in individuals that seek ethanol in a goal-directed manner. Nevertheless, future studies should confirm these negative findings using additional doses and schedules of saracatinib administration.

Randomized pilot trial of Web-based cognitive-behavioral therapy adapted for use in office-based buprenorphine maintenance.

Background: Despite the clear success of office-based buprenorphine treatment in increasing availability of effective treatment for opioid use disorder, constraints on its effectiveness include high attrition and limited high-quality behavioral care in many areas. Web-based interventions may be a novel strategy for providing evidence-based behavioral care to individuals receiving office-based buprenorphine maintenance. This report describes modification and initial pilot testing of Web-based training in cognitive-behavioral therapy (CBT4CBT) specifically for use with individuals in office-based buprenorphine. Methods: Twelve-week randomized pilot trial evaluating effects of CBT4CBT-Buprenophine in retaining participants and reducing drug use with respect to standard office-based buprenorphine alone was carried out. Twenty individuals meeting DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) criteria for current opioid use disorder were randomized to standard buprenorphine treatment or buprenorphine plus access to CBT4CBT-Buprenorphine. Results: There were promising findings regarding rates of urine toxicology screens negative for opioids (91% versus 64%; P = .05, effect size d = 0.88) and all drugs (82% versus 30%; P = .004, d = 1.2). Individuals randomized to CBT4CBT-Buprenorphine completed a mean of 82.6 (SD = 4.4) days of treatment (of a possible 84) compared with 68.6 (SD = 32.6) for those assigned to standard buprenorphine treatment. Conclusions: Although preliminary and limited by the small sample size, this trial suggests the feasibility and promise of validated, Web-based interventions, tailored for this specific patient population, for improving outcomes in office-based buprenorphine.

Pilot investigation of the effect of carvedilol on stress-precipitated smoking-lapse behavior.

INTRODUCTION: Separate α1- and ß-adrenergic antagonists have shown efficacy in reducing nicotine-motivated behaviors in rodents and humans, supporting a role for the noradrenergic system in mediating the reinforcing properties of drugs of abuse. However, the effect of the combined α1- and ß-adrenergic antagonist, carvedilol, on stress-related smoking is unknown. METHODS: Using a well-established human laboratory model of stress-precipitated smoking-lapse behavior, we examined whether carvedilol (0 or 50 mg/day; between subject, n=17 per group), administered to steady-state, would attenuate the ability to resist smoking following stress imagery (vs. neutral imagery) and reduce subsequent smoking self-administration in nicotine-deprived smokers ( n = 34 total). Tobacco craving, withdrawal, and physiologic reactivity were also assessed. RESULTS: Latency to start smoking and number of cigarettes smoked during the self-administration period did not differ by medication condition. Counter to our hypothesis, tobacco craving demonstrated a medication × time effect, with greater craving in the carvedilol condition. Systolic blood pressure and heart rate demonstrated lower values in the carvedilol versus placebo group, consistent with known effects of carvedilol. CONCLUSION: While carvedilol attenuated physiologic reactivity consistent with its clinical indication, beneficial effects on smoking outcomes were absent in this preliminary investigation and may suggest possible worsening. Future work may benefit from discerning the single versus combined effects of α1- and ß-adrenergic antagonism on smoking outcomes.

Effects of Varenicline Alone and in Combination With Low-dose Naltrexone on Alcohol-primed Smoking in Heavy-drinking Tobacco Users: A Preliminary Laboratory Study.

OBJECTIVES: Heavy-drinking tobacco users are less likely to successfully quit smoking than their moderate-drinking counterparts, even when they are prescribed smoking cessation medication. One strategy for improving treatment outcomes in this subgroup of tobacco users may be to combine medication therapies to target both alcohol and tobacco use simultaneously. Adding naltrexone to frontline smoking cessation treatments may improve treatment outcomes in this group. METHOD: This double-blind, placebo-controlled human laboratory study examined the effects of varenicline (2 mg/d) and varenicline (2 mg/d), combined with a low dose of naltrexone (25 mg/d) on alcohol-primed smoking behavior in a laboratory model of smoking relapse in heavy-drinking tobacco users (n = 30). Participants attended a laboratory session and received an alcohol challenge (target breath alcohol concentration = 0.030 g/dL). They completed a smoking delay task that assessed their ability to resist smoking followed by an ad libitum smoking phase (primary outcomes). They also provided ratings of subjective drug effects and craving, and carbon monoxide levels were measured after smoking (secondary outcomes). RESULTS: Participants receiving varenicline monotherapy delayed smoking longer and smoked fewer cigarettes than those on placebo. Participants receiving varenicline + low-dose naltrexone did not delay smoking longer than those receiving varenicline alone. Participants in both active medication arms smoked fewer cigarettes ad libitum than those receiving placebo. CONCLUSIONS: Varenicline can improve smoking outcomes even after an alcohol prime, supporting its use in heavy drinkers who wish to quit smoking. Findings did not support increased efficacy of combined varenicline + low-dose naltrexone relative to varenicline monotherapy.

An investigation of an open-access model for scaling up methadone maintenance treatment.

AIMS: To examine retrospectively patient and programmatic outcomes following the development and implementation of an 'open-access' model in which prospective patients were enrolled rapidly in methadone maintenance treatment, irrespective of ability to pay, and provided real-time access to multiple voluntary treatment options. DESIGN: Medical and administrative records were abstracted to compare data for 1 year before and 9 years after initiating the implementation of an open-access treatment model in May 2007. SETTING: Methadone maintenance treatment center in Connecticut, USA. PARTICIPANTS: Individuals with opioid use disorder entering treatment between July 2006 and June 2015. In June 2015, 64% (n = 2594) of the sample were men and 80% (n = 3133) reported that they were white. INTERVENTION: The Network for the Improvement of Addiction Treatment-informed open-access treatment model uses process improvement strategies to improve treatment access and capacity. MEASUREMENTS: Census, waiting time, retention, non-medical opioid use, patient mortality and financial sustainability (net income and state-block grants as proportions of revenue). FINDINGS: In the 9 years following the initial implementation of the open-access model, patient census increased by 183% from 1431 to 4051, and average waiting-time days decreased from 21 to 0.3 (same day) without apparent deleterious effects on rates of retention, non-medical opioid use or mortality. Between fiscal years (FY) 06 and FY 15, net operating margin rose from 2 to 10%, while state-block grant revenues declined 14% and the proportion of total revenue from state-block grant revenue decreased from 49 to 24%. CONCLUSIONS: An open-access model for rapid enrolment of people with opioid use disorder in methadone treatment appears to improve treatment access, capacity, and financial sustainability without evidence of deleterious effects on treatment outcomes.

Galantamine and Computerized Cognitive Behavioral Therapy for Cocaine Dependence: A Randomized Clinical Trial.

OBJECTIVE: To examine whether galantamine, a cognitive-enhancing medication that is both acetylcholinesterase inhibitor and agonist at nicotinic acetylcholine receptors, is effective at improving cocaine use outcomes and cognitive functioning, alone and in combination with computerized cognitive behavioral therapy (CBT). METHOD: A 12-week, randomized 2 × 2, factorial trial was conducted to evaluate galantamine versus placebo (double-blind) and computerized CBT plus standard methadone treatment versus standard methadone treatment alone in a community-based methadone maintenance program (September 2009-April 2015). One hundred twenty individuals diagnosed with DSM-IV cocaine use disorder were randomly assigned to the following conditions: (1) galantamine (8 mg/d) plus standard methadone maintenance treatment (treatment as usual [TAU]), (2) placebo plus TAU, (3) galantamine plus computerized CBT plus TAU, or (4) placebo plus computerized CBT plus TAU; medication administration was supervised at the time of daily methadone dosing. The primary cocaine use outcome was change in percent days of abstinence over time. Number of cocaine-negative urine toxicology screens submitted and cognitive function were secondary outcomes. RESULTS: Random effect regression analysis indicated significant reductions in frequency of cocaine use over time, with significant treatment-by-time effects for both galantamine over placebo (F = 5.3, P = .02, d = 0.34) and computerized CBT over standard methadone treatment (F = 4.2, P = .04, d = 0.30) but no evidence of significant benefit of the combination over either treatment alone. Pretreatment to posttreatment comparisons of multiple indices of cognitive functioning, including sustained attention, indicated no benefit of galantamine over placebo. CONCLUSIONS: Findings suggest benefits of galantamine and computerized CBT for reducing cocaine use in this sample. Although galantamine did not improve measures of cognitive function in this sample, multiple measures of cognitive function were associated with cocaine use outcomes, underlining the significance of cognitive function in cocaine treatment outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00809835.

Effect of doxazosin on stress reactivity and the ability to resist smoking.

Preclinical findings support a role for α1-adrenergic antagonists in reducing nicotine-motivated behaviors, but these findings have yet to be translated to humans. The current study evaluated whether doxazosin would attenuate stress-precipitated smoking in the human laboratory. Using a well-validated laboratory analogue of smoking-lapse behavior, this pilot study evaluated whether doxazosin (4 and 8 mg/day) versus placebo attenuated the effect of stress (vs neutral imagery) on tobacco craving, the ability to resist smoking and subsequent ad-libitum smoking in nicotine-deprived smokers ( n=35). Cortisol, adrenocorticotropin, norepinephrine, epinephrine, and physiologic reactivity were assessed. Doxazosin (4 and 8 mg/day vs placebo) decreased cigarettes per day during the 21-day titration period. Following titration, doxazosin (4 and 8 mg/day vs placebo) decreased tobacco craving. During the laboratory session, doxazosin (8 mg/day vs placebo) further decreased tobacco craving following stress versus neutral imagery. Doxazosin increased the latency to start smoking following stress, and reduced the number of cigarettes smoked. Dosage of 8 mg/day doxazosin increased or normalized cortisol levels following stress imagery and decreased cortisol levels following neutral imagery. These preliminary findings support a role for the noradrenergic system in stress-precipitated smoking behavior, and support further development of doxazosin as a novel pharmacotherapeutic treatment strategy for smoking cessation.

Onsite treatment of HCV infection with direct acting antivirals within an opioid treatment program.

With the advent of the direct acting antivirals (DAA), or all oral HCV treatment regimens, there exists a great opportunity to provide HCV treatment to people who inject drugs (PWID) enrolled in an opioid treatment program (OTP). This retrospective study conducted in the context of routine clinical care explores the outcomes of HCV treatment with DAAs in PWID enrolled in an OTP. Our study showed treatment outcomes among our first 75 patients treated with DAAs were nearly equivalent to patients in the general population. Ninety-eight percent of patients completing treatment obtained a sustained virologic response, with 10 patients lost to follow-up. Ninety-nine percent of patients adhered to HCV treatment. Ongoing drug use occurred in 23% of patients, however this did not alter HCV treatment outcomes. Treating HCV infection with DAAs in PWID onsite in an OTP is feasible.

Effect of Varenicline Combined with High-Dose Alcohol on Craving, Subjective Intoxication, Perceptual Motor Response, and Executive Cognitive Function in Adults with Alcohol Use Disorders: Preliminary Findings.

BACKGROUND: Varenicline has been found to decrease alcohol-motivated behaviors. Recent warnings regarding aversive events associated with varenicline used in conjunction with alcohol warrant further investigation into the safety of the drug when combined with alcohol. The purpose of this preliminary investigation was to examine the effect of combining varenicline with a high, fixed dose of alcohol on subjective reactivity and cognitive function in adults with alcohol use disorders (AUDs). METHODS: This double-blind, placebo-controlled preliminary investigation examined the effects of varenicline (0, 1, 2 mg/d) on subjective reactivity, cognition, perceptual motor function, and physiologic reactivity to a fixed dose of alcohol (vs. nonalcohol control beverage) using an established laboratory paradigm in smokers and nonsmokers meeting criteria for AUDs (n = 44). All participants had completed a parent varenicline study evaluating alcohol self-administration. Each subject completed 2 fixed-dose laboratory sessions assessing reactivity to a high-dose alcohol (0.08 g/dl) or a nonalcoholic control beverage, order counterbalanced. RESULTS: Varenicline attenuated alcohol-related increases in subjective intoxication and alcohol-related decreases in executive cognitive function. At baseline, varenicline reduced alcohol craving and diastolic blood pressure, and increased associative learning, working memory, and perceptual motor function. Varenicline produced nonspecific effects on diastolic blood pressure and heart rate. Overall, there were few differences in effects between 1 and 2 mg/d varenicline versus placebo. CONCLUSIONS: These preliminary results continue to support the safety and use of varenicline in combination with alcohol in individuals meeting criteria for AUDs.

Effect of Lowering the Dose of Varenicline on Alcohol Self-administration in Drinkers With Alcohol Use Disorders.

OBJECTIVES: Varenicline (2 mg/d) has been shown to be efficacious in reducing alcohol consumption. A lower dose of varenicline may be effective in reducing alcohol use while minimizing the potential for side effects. METHODS: This double-blind, placebo-controlled investigation examined the effect of varenicline (0, 1, 2 mg/d) on alcohol consumption in nontreatment-seeking adults meeting the Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV) criteria for alcohol use disorders (N = 60). Following 7 days of medication pretreatment, participants were administered a low fixed dose of alcohol (0.3 g/dL), and subjective and physiologic responses were assessed. A 2-hour ad libitum alcohol self-administration period followed. We also explored relationships between plasma varenicline levels and consumption. RESULTS: Overall, frequency and severity of adverse events were minimal. The 1 mg/d dose reduced the frequency of insomnia compared with the 2 mg/d dose. The 2 mg/d varenicline dose versus placebo reduced alcohol craving and showed limited effect on reduced alcohol consumption. Alcohol craving and consumption did not differ between the 1 mg/d varenicline dose versus placebo. Trough varenicline plasma levels greater than or equal to 3 ng/mL were associated with reduced drinking and levels greater than or equal to 5 ng/mL were associated with reduced heavy drinking. CONCLUSIONS: Overall, we found no evidence supporting an effect of 1 mg/d varenicline on craving or consumption, suggesting that doses of varenicline less than 2 mg/d may not be effective in reducing alcohol-related outcomes. Importantly, results suggest that higher plasma levels of varenicline may be needed to maximize the effect of varenicline on alcohol consumption and should be investigated in drinkers meeting criteria for alcohol use disorders.

A randomized factorial trial of disulfiram and contingency management to enhance cognitive behavioral therapy for cocaine dependence.

BACKGROUND: This study evaluated the extent to which the addition of disulfiram and contingency management for adherence and abstinence (CM), alone and in combination, might enhance the effects of cognitive behavioral therapy (CBT) for cocaine use disorders. METHODS: Factorial randomized double blind (for medication condition) clinical trial where CBT served as the platform and was delivered in weekly individual sessions in a community-based outpatient clinic. 99 outpatients who met DSM-IV criteria for current cocaine dependence were assigned to receive either disulfiram or placebo, and either CM or no CM. Cocaine and other substance use was assessed via a daily calendar with thrice weekly urine sample testing for 12 weeks with a one-year follow-up (80% interviewed at one year). RESULTS: The primary hypothesis that CM and disulfiram would produce the best cocaine outcomes was not confirmed, nor was there a main effect for disulfiram. For the primary outcome (percent days of abstinence, self report), there was a significant interaction, with the best cocaine outcomes were seen for the combination of CM and placebo, with the two groups assigned to disulfiram associated with intermediate outcomes, and poorest cocaine outcome among those assigned to placebo and no CM. The secondary outcome (urinalysis) indicated a significant effect favoring CM over no CM but the interaction effect was not significant. One year follow-up data indicated sustained treatment effects across conditions. CONCLUSIONS: CM enhances outcomes for CBT treatment of cocaine dependence, but disulfiram provided no added benefit to the combination of CM and CBT.

Efficacy of disulfiram and Twelve Step Facilitation in cocaine-dependent individuals maintained on methadone: a randomized placebo-controlled trial.

BACKGROUND: Cocaine use remains a major problem within methadone maintenance programs. Disulfiram's efficacy in reducing cocaine use has been demonstrated in several trials, but its relative efficacy among individuals who use versus abstain from alcohol remains unclear. Treatment approaches which seek to enhance substance users' involvement in self-help activities (Twelve Step Facilitation, TSF) have been associated with better outcomes among alcohol and cocaine users, but have rarely been evaluated among methadone-maintained cocaine-opioid users. METHODS: We conducted a randomized, placebo-controlled, double blind (for medication condition), factorial (2×2) trial with 4 treatment conditions: Disulfiram plus TSF, disulfiram plus standard counseling only, placebo plus TSF, and placebo plus standard counseling in the context of a community-based methadone maintenance program. Participants (N=112) received either disulfiram (250 mg/d) or placebo in conjunction with daily methadone maintenance. RESULTS: Assignment to TSF was associated with less cocaine use throughout treatment and a higher number of cocaine-negative urines. While there were no significant main effects of disulfiram versus placebo, individuals without an alcohol use disorder demonstrated greater reductions in cocaine use over time when assigned to disulfiram. CONCLUSIONS: TSF appears feasible in this methadone maintenance program and was associated with modest reductions in cocaine use, an often intractable problem in this setting. Support for the efficacy of disulfiram was weaker, as it appeared effective only for those without a current alcohol use disorder for this sample.