Bupropion Slow Release vs Placebo With Adaptive Incentives for Cocaine Use Disorder in Persons Receiving Methadone for Opioid Use Disorder: A Randomized Clinical Trial.

Importance: Opioid-stimulant co-use is a common problem with few evidence-based treatments. Objective: To examine bupropion slow release (SR) enhancement of a tailored abstinence incentive program for stimulant use in persons with opioid use disorder. Design, Setting, and Participants: This 26-week, double-blind, placebo-controlled randomized clinical trial with a 4-week follow-up period was conducted at 4 methadone treatment programs in Baltimore, Maryland. Included participants were persons receiving methadone for the treatment of opioid use disorder with past 3-month cocaine use and current cocaine use disorder between March 2015 and September 2019. Data were analyzed from November 2020 through August 2022. Interventions: A 6-week incentive induction period with monetary incentives for evidence of cocaine abstinence during thrice-weekly urine testing was conducted. Persons achieving 2 weeks of consecutive abstinence during induction were assigned to the relapse prevention group (20 individuals); otherwise, individuals were assigned to the abstinence initiation group (60 individuals). Participants were randomized within incentive groups to bupropion SR (150 mg oral twice daily; 40 participants) or placebo (40 participants). Incentives were available until week 26, and study medication ended week 30. Main Outcomes and Measures: The mean percentage of participants with cocaine abstinence (by negative urinalysis or self-report) during weeks 7 to 26 (ie, the incentive intervention period) and 27 to 30 (ie, the follow-up period) and the percentage of participants testing negative for cocaine at weeks 26 and 30 were assessed. Main effects of medication collapsed across incentive conditions and sensitivity analyses of medications within incentive conditions were assessed. Analyses were conducted in the modified intention-to-treat sample (ie, 80 individuals who received ≥1 dose of study medication) and completers (ie, 52 individuals who completed ≥1 visit during week 30). Results: Among 80 participants (42 Black [52.5% ] and 35 White [43.8%]; mean [SD] age, 45.7 (9.4) years; 52 males [65.0%]) receiving methadone for opioid use disorder, 40 participants were randomized to receive bupropion SR and 40 participants to receive placebo. No significant difference on urinalysis or self-reported cocaine use was observed between medication groups. Sensitivity analyses revealed differential patterns for incentive subgroups. Participants in the relapse prevention group had high abstinence (>80%; eg, during weeks 7-26 in the modified intention-to-treat analysis, 410 of 456 samples [89.9%] from participants in the bupropion SR group tested negative for cocaine) throughout the trial regardless of whether they were randomized to bupropion SR or placebo. Participants in the abstinence initiation group had better outcomes with bupropion SR than placebo throughout the trial (mean [SD] total number of samples testing negative for cocaine, 30.3 [21.6] samples for bupropion SR vs 17.1 [14.9] samples for placebo; P = .05) and more participants receiving bupropion SR than placebo were abstinent at the end of the study (20 of 30 participants [66.7%] vs 9 of 30 participants [30.0%]; P = .04). Conclusions and Relevance: In this randomized clinical trial, an overall benefit for bupropion SR vs placebo when combined with a financial abstinence incentive program was not observed. Results among incentive subgroups suggest that continued evaluation of medications, including bupropion SR, for stimulant treatment using a tailored approach that factors early abstinence into study design and interpretation may be needed. Trial Registration: ClinicalTrials.gov Identifier: NCT02111798.

Suvorexant ameliorated sleep disturbance, opioid withdrawal, and craving during a buprenorphine taper.

Increased orexin/hypocretin signaling is implicated in opioid withdrawal, sleep disturbances, and drug-seeking behaviors. This study examined whether a dual-orexin receptor antagonist would improve sleep and withdrawal outcomes when compared with placebo during a buprenorphine/naloxone taper. Thirty-eight participants with opioid use disorder were recruited to a clinical research unit and maintained on 8/2 to 16/4 mg of buprenorphine/naloxone treatment for 3 days before being randomized to 20 mg of suvorexant (n = 14), 40 mg of suvorexant (n = 12), or placebo (n = 12); 26 individuals completed the study. After randomization, participants underwent a 4-day buprenorphine/naloxone taper and 4-day post-taper observation period. Total sleep time (TST) was collected nightly with a wireless electroencephalography device and wrist-worn actigraphy; opioid withdrawal symptoms were assessed via the Subjective Opiate Withdrawal Scale (SOWS); and abuse potential was assessed on a 0- to 100-point visual analog scale of "High" every morning. A priori outcomes included two-group (collapsing suvorexant doses versus placebo) and three-group comparisons of area-under-the-curve (AUC) scores for TST, SOWS, and High. In two-group comparisons, participants receiving suvorexant displayed increased TST during the buprenorphine/naloxone taper and decreased SOWS during the post-taper period. In three-group comparisons, participants receiving 20 mg of suvorexant versus placebo displayed increased AUC for TST during the buprenorphine/naloxone taper, but there was no difference in SOWS among groups. There was no evidence of abuse potential in two- or three-group analyses. The results suggest that suvorexant might be a promising treatment for sleep and opioid withdrawal in individuals undergoing a buprenorphine/naloxone taper.

Buprenorphine treatment retention and comorbidities among patients with opioid use disorder in a primary care setting.

BACKGROUND AND OBJECTIVES: More information is needed about comorbidities among patients receiving buprenorphine maintenance treatment and their relationship with retention. METHODS: Retrospective electronic health record data over a 5-year period from primary care patients receiving buprenorphine for the treatment of opioid use disorder were examined (N = 899). The present analysis determined the prevalence of comorbidities and examined associations with treatment retention as defined by cumulative duration of buprenorphine prescription. RESULTS: Tobacco use and comorbidities including hypertension were prevalent but did not predict retention according to survival analyses controlling for demographic characteristics. Retention was poorer among patients testing positive for cocaine (HR = 1.38, 95% CI: 1.09-1.74, p = .007) and patients with hepatitis C virus (HR = 1.17, 95% CI: 1.01-1.37, p = .04). CONCLUSION AND SCIENTIFIC SIGNIFICANCE: This study provides new knowledge of previously unexamined associations between comorbidities (e.g., hypertension) and buprenorphine treatment retention. The robust association between cocaine use and poorer buprenorphine retention serves to resolve prior conflicting data in the literature.

Brain imaging of cannabinoid type I (CB1 ) receptors in women with cannabis use disorder and male and female healthy controls.

Cannabis effects are predominantly mediated by pharmacological actions on cannabinoid type 1 (CB1 ) receptors. Prior positron emission tomography (PET) studies in individuals who use cannabis included almost exclusively males. PET studies in females are needed because there are sex differences in cannabis effects, progression to cannabis use disorder (CUD), and withdrawal symptom severity. Females with CUD (N = 10) completed two double-blind cannabis smoking sessions (Session 1: placebo; Session 2: active), and acute cannabis effects were assessed. After Session 2, participants underwent 3 days of monitored cannabis abstinence; mood, craving, and withdrawal symptoms were assessed and a PET scan (radiotracer: [11 C]OMAR) followed. [11 C]OMAR Distribution volume (VT ) from these participants was compared with VT of age/BMI-similar female non-users of cannabis ("healthy controls"; N = 10). VT was also compared between female and male healthy controls (N = 7). Females with CUD displayed significantly lower VT than female healthy controls in specific brain regions (hippocampus, amygdala, cingulate, and insula). Amygdala VT was negatively correlated with mood changes (anger/hostility) during abstinence, but VT was not correlated with other withdrawal symptoms or cannabis effects. Among healthy controls, females had significantly higher VT than males in all brain regions examined. Chronic cannabis use appears to foster downregulation of CB1 receptors in women, as observed previously in men, and there are inherent sex differences in CB1 availability. Future studies should elucidate the time course of CB1 downregulation among females who use cannabis and examine the relation between CB1 availability and cannabis effects among other populations (e.g., infrequent users; medicinal users).

Differences in Availability and Use of Medications for Opioid Use Disorder in Residential Treatment Settings in the United States.

Importance: While many individuals with opioid use disorder seek treatment at residential facilities to initiate long-term recovery, the availability and use of medications for opioid use disorder (MOUDs) in these facilities is unclear. Objective: To examine differences in MOUD availability and use in residential facilities as a function of Medicaid policy, facility-level factors associated with MOUD availability, and admissions-level factors associated with MOUD use. Design, Setting, and Participants: This cross-sectional study used deidentified facility-level and admissions-level data from 2863 residential treatment facilities and 232 414 admissions in the United States in 2017. Facility-level data were extracted from the 2017 National Survey of Substance Abuse Treatment Services, and admissions-level data were extracted from the 2017 Treatment Episode Data Set-Admissions. Statistical analyses were conducted from June to November 2019. Exposures: Admissions for opioid use disorder at residential treatment facilities in the United States that identified opioids as the patient's primary drug of choice. Main Outcomes and Measures: Availability and use of 3 MOUDs (ie, extended-release naltrexone, buprenorphine, and methadone). Results: Of 232 414 admissions, 205 612 (88.5%) contained complete demographic data (166 213 [80.8%] aged 25-54 years; 136 854 [66.6%] men; 151 867 [73.9%] white). Among all admissions, MOUDs were used in only 34 058 of 192 336 (17.7%) in states that expanded Medicaid and 775 of 40 078 (1.9%) in states that did not expand Medicaid (P < .001). A relatively low percentage of the 2863 residential treatment facilities in this study offered extended-release naltrexone (854 [29.8%]), buprenorphine (953 [33.3%]), or methadone (60 [2.1%]). Compared with residential facilities that offered at least 1 MOUD, those that offered no MOUDs had lower odds of also offering psychiatric medications (odds ratio [OR], 0.06; 95% CI, 0.05-0.08; Wald χ21 = 542.09; P < .001), being licensed by a state or hospital authority (OR, 0.39; 95% CI, 0.27-0.57; Wald χ21 = 24.28; P < .001), or being accredited by a health organization (OR, 0.28; 95% CI, 0.23-0.33; Wald χ21 = 180.91; P < .001). Residential facilities that did not offer any MOUDs had higher odds of accepting cash-only payments than those that offered at least 1 MOUD (OR, 4.80; 95% CI, 3.47-6.64; Wald χ21 = 89.65; P < .001). Conclusions and Relevance: In this cross-sectional study of residential addiction treatment facilities in the United States, MOUD availability and use were sparse. Public health and policy efforts to improve access to and use of MOUDs in residential treatment facilities could improve treatment outcomes for individuals with opioid use disorder who are initiating recovery.

Increases in body mass index and cardiovascular risk factors during methadone maintenance treatment.

OBJECTIVE: This study describes changes in weight and cardiovascular risk factors over time among individuals enrolled in methadone maintenance treatment for opioid use disorder. Demographic and clinical predictors of weight gain were also evaluated. DESIGN: This study was a retrospective chart review evaluating data over a period of 3 years. SETTING: Medical records of individuals enrolled in an academic research outpatient methadone maintenance treatment program were reviewed. PATIENTS: Seventy-four individuals who were admitted and retained in methadone maintenance treatment for at least 3 consecutive years were included. OUTCOME MEASURES: Annual weight was assessed by calculating body mass index (BMI). Changes over time in cardiovascular risk factors of hypertension, diabetes, and hypercholesterolemia were also assessed. RESULTS: The percentage of patients categorized as overweight, obese, or morbidly obese BMI increased from 42 percent (n = 31) at admission to 76 percent (n = 56), 82 percent (n = 61), and 88 percent (n = 65) at 1, 2, and 3 years post-admission, respectively. Hypertension, diabetes, and hypercholesterolemia also tended to increase following admission. BMI increases tended to be greater for those with a higher dose of methadone, as well as for females and Black/African American individuals. No other predictors of weight gain were identified. CONCLUSIONS: These data indicate that methadone maintenance treatment is associated with clinically meaningful weight gain and increases in cardiovascular risk factors. Given the importance of methadone maintenance for treatment of opioid use disorder, future research should examine additional predictors and potential mechanisms of weight gain among methadone patients and develop tailored interventions including nutritional knowledge and lifestyle recommendations.

The effects of extended-release injectable naltrexone and incentives for opiate abstinence in heroin-dependent adults in a model therapeutic workplace: A randomized trial.

AIM: To determine whether extended-release injectable naltrexone (XR-NTX), incentives for opiate abstinence, and their combination reduce opiate use compared to a usual care control and whether the combination reduces opiate use compared to either treatment alone. DESIGN: Randomized 2 × 2 single-site controlled trial conducted from November 2012 through May 2016. After a detoxification and oral naltrexone induction, participants were assigned to a Usual Care, Abstinence Incentives, XR-NTX, or XR-NTX plus Abstinence Incentives group for a six-month intervention period. SETTING: A model therapeutic workplace where participants could work on automated computer programs that targeted job-skills training for 4 h every weekday for 24 weeks and earn about $10 per hour. PARTICIPANTS: 84 heroin-dependent adults who were unemployed and medically approved for naltrexone. Most participants were male (71.4%), African American (80.1%), and cocaine dependent (71.4%). MEASUREMENTS: The primary outcome measure was the percentage of urine samples negative for opiates that were collected at once weekly assessments (24 per participant) that were not part of the intervention and for which participants were paid $10 for completing. INTERVENTION: Participants who attended the workplace provided thrice-weekly urine samples. Abstinence Incentives participants had to provide opiate-free urine samples to maintain maximum pay. XR-NTX participants received one injection every 4 weeks and were required to take injections in order to work and to maintain maximum pay. Usual Care participants were not offered XR-NTX and opiate urinalysis results did not affect pay. FINDINGS: A large percentage (65 of 149; 43.6%) of individuals failed the induction protocol required for randomization and to be eligible to receive XR-NTX. When missing urine samples were considered positive, there was no significant interaction between XR-NTX and Abstinence Incentives. XR-NTX plus Abstinence Incentives participants provided significantly more opiate-negative samples (81.3%, SD 39.0%) than XR-NTX participants (64.5%, SD 47.9%; aOR 10.4, 95% CI 1.3-85.5; P = .030). When urine samples were not replaced, there was a significant interaction between XR-NTX and Abstinence Incentives (aOR 77.0, 95% CI 1.3-4432;P = 0.036); XR-NTX plus Abstinence Incentives participants provided significantly more opiate-negative samples (99.6%, SD 0.1%) than XR-NTX participants (85.0%, SD 35.7%; aOR 147.6, 95% CI 6.3-3472; P = 0.002), Abstinence Incentives participants (91.9%, SD 27.3%; aOR 121.7, 95% CI 4.8-3067; P =0.004), and Usual Care participants (78.7%, SD 41.0%; aOR 233.4, 95% CI 9.4-5814; P <.001). No other group differences were significant. CONCLUSION: XR-NTX plus incentives for opiate abstinence increased opiate abstinence, but XR-NTX alone did not. XR-NTX can promote opiate abstinence when it is combined with incentives for opiate abstinence in a model therapeutic workplace.

Predictors of induction onto extended-release naltrexone among unemployed heroin-dependent adults.

BACKGROUND AND AIM: Extended-release naltrexone (XR-NTX) blocks the effects of opioids for 4weeks; however, starting treatment can be challenging because it requires 7 to 10days of abstinence from all opioids. In the present study we identified patient and treatment characteristics that were associated with successful induction onto XR-NTX. METHODS: 144 unemployed heroin-dependent adults who had recently undergone opioid detoxification completed self-report measures and behavioral tasks before starting an outpatient XR-NTX induction procedure. Employment-based reinforcement was used to promote opioid abstinence and adherence to oral naltrexone during the induction. Participants were invited to attend a therapeutic workplace where they earned wages for completing jobs skills training. Participants who had used opioids recently were initially invited to attend the workplace for a 7-day washout period. Then those participants were required to provide opioid-negative urine samples and then take scheduled doses of oral naltrexone to work and earn wages. Participants who had not recently used opioids could begin oral naltrexone immediately. After stabilization on oral naltrexone, participants were eligible to receive XR-NTX and were randomized into one of four treatment groups, two of which were offered XR-NTX. Binary and multiple logistic regressions were used to identify characteristics at intake that were associated with successfully completing the XR-NTX induction. RESULTS: 58.3% of participants completed the XR-NTX induction. Those who could begin oral naltrexone immediately were more likely to complete the induction than those who could not (79.5% vs. 25.0%). Of 15 characteristics, 2 were independently associated with XR-NTX induction success: legal status and recent opioid detoxification type. Participants who were not on parole or probation (vs. on parole or probation) were more likely to complete the induction (OR [95% CI]=2.5 [1.1-5.7], p=0.034), as were those who had come from a longer-term detoxification program (≥21days) (vs. a shorter-term [<21days]) (OR [95% CI]=7.0 [3.0-16.6], p<0.001). CONCLUSIONS: Our analyses suggest that individuals recently leaving longer-term opioid detoxification programs are more likely to complete XR-NTX induction. Individuals on parole or probation are less likely to complete XR-NTX induction and may need additional supports or modifications to induction procedures to be successful.

Factors associated with using opiates while under extended-release naltrexone blockade: A descriptive pilot study.

BACKGROUND AND AIM: Extended-release naltrexone (XR-NTX) blocks the effects of opioids for 4weeks, yet many patients continue to use them. To learn more about why this occurs, we collected self-reports on subjective effects and drug use factors from participants' most recent heroin/opiate use while under XR-NTX blockade. METHODS: Participants (n=38) were unemployed, heroin-dependent adults enrolled in a randomized controlled trial evaluating employment-based incentives to promote adherence to XR-NTX. A subset of participants (n=18) were asked to complete a survey about their most recent use of heroin/opiates when they provided an opiate-positive urine sample while under XR-NTX blockade. Surveys were administered weekly, and participants could complete multiple surveys throughout the trial. Participants reported how high they were (11-point scale; 0=not at all, 10=extremely), how much heroin/opiates they took (less, more, or about the same as usual before starting naltrexone), whether they used cocaine at the same time, and the routes of administration for heroin/opiates and cocaine (if used). All analyses were descriptive. RESULTS: Of the 107 surveys, 75.7% indicated being "not at all" high the last time heroin/opiates were used. 75.5% of surveys reported opiate amounts that were less than usual, and only 7.5% reported amounts larger than usual. Cocaine was used at the same time as heroin for 57.9% of surveys but typically through a different route (74.2%). DISCUSSION: Using heroin/opiates while under XR-NTX blockade is not strongly associated with self-reports of high, taking larger than normal amounts of opiates, or taking opiates and cocaine simultaneously via the same route. Future research should incorporate measures of naltrexone concentration and more comprehensive and frequent assessments using ecological momentary assessment.

Effects of incentives for naltrexone adherence on opiate abstinence in heroin-dependent adults.

AIM: To test whether an incentive-based intervention that increased adherence to naltrexone also increased opiate abstinence. DESIGN: Post-hoc combined analysis of three earlier randomized controlled trials that showed individually that incentives for adherence to oral and to extended-release injection naltrexone dosing schedules increased naltrexone adherence, but not opiate abstinence. SETTING: Out-patient therapeutic work-place in Baltimore, MD, USA. PARTICIPANTS: One hundred and forty unemployed heroin-dependent adults participating from 2006 to 2010. INTERVENTIONS: Participants were hired in a model work-place for 26 weeks and randomized to a contingency (n = 72) or prescription (n = 68) group. Both groups were offered naltrexone. Contingency participants were required to take scheduled doses of naltrexone in order to work and earn wages. Prescription participants could earn wages independent of naltrexone adherence. MEASURES: Thrice-weekly and monthly urine samples tested for opiates and cocaine and measures of naltrexone adherence (percentage of monthly urine samples positive for naltrexone or percentage of scheduled injections received). All analyses included pre-randomization attendance, opiate use and cocaine use as covariates. Additional analyses controlled for cocaine use and naltrexone adherence during the intervention. FINDINGS: Contingency participants had more opiate abstinence than prescription participants (68.1 versus 52.9% opiate-negative thrice-weekly urine samples, respectively; and 71.9 versus 61.7% opiate-negative monthly urine samples, respectively) based on initial analyses [thrice-weekly samples, odds ratio (OR) = 3.3, 95% confidence interval (CI) = 1.7-6.5, P < 0.01; monthly samples, OR = 2.6, 95% CI = 1.0-7.1, P = 0.06] and on analyses that controlled for cocaine use (thrice-weekly samples, OR = 3.9, 95% CI = 3.3-4.5, P < 0.01; monthly samples, OR = 3.4, 95% CI = 1.1-11.1, P = 0.04), which was high and associated with opiate use. The difference in opiate abstinence rates between contingency and prescription participants was reduced when controlling for naltrexone adherence (monthly samples, OR = 1.1, 95% CI = 0.7-1.7, P = 0.84). CONCLUSIONS: Incentives for naltrexone adherence increase opiate abstinence in heroin-dependent adults, an effect that appears to be due to increased naltrexone adherence produced by the incentives.

Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial.

Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00465595.

Zonisamide Reduces Withdrawal Symptoms But Does Not Enhance Varenicline-Induced Smoking Cessation.

INTRODUCTION: Varenicline (Chantix) is a first-line treatment for smoking cessation but does not produce cessation in many individuals. It may be possible to improve abstinence by co-administering varenicline with other medications. Zonisamide (Zonegran) has a similar pharmacologic profile to topiramate, which has been shown to reduce smoking, but is better tolerated. This study evaluated whether combined zonisamide and varenicline reduced tobacco withdrawal and increased abstinence among smokers trying to quit, relative to varenicline and placebo. METHODS: This was a double-blind, randomized, placebo-controlled pilot trial of zonisamide + varenicline versus placebo + varenicline for smoking cessation. Smokers received brief counseling and study medications, and completed weekly assessments for 10 consecutive weeks. The primary outcome was continuous abstinence rates (biochemically verified) during the final 4 weeks of treatment. RESULTS: Results are presented as intent-to-treat and completer analyses. Seventy-four individuals were enrolled; 45 completed the study. Overall, 14.9% (intent-to-treat) and 25.0% (completer) of participants maintained sustained abstinence during the final 4 weeks of treatment. There were no differences between groups for biochemically-verified smoking, but zonisamide + varenicline reduced self-reported smoking, nicotine withdrawal, and craving compared to placebo + varenicline. CONCLUSIONS: Zonisamide decreased nicotine withdrawal and craving, though not of sufficient magnitude to modify smoking behavior. The sample size was small and low rates of abstinence across groups suggest the study population was difficult to treat. Additional evaluation of zonisamide or other medications that increase GABA or decrease glutamate in larger or more diverse populations may yield positive clinical benefit for nicotine/tobacco cessation. IMPLICATIONS: This study provides support for layering novel medications with varenicline for smoking cessation, for investigating medications that target the GABA and glutamate system, and for assessing the contribution that reductions in nicotine withdrawal have on ultimate cessation outcomes.

Topiramate impairs cognitive function in methadone-maintained individuals with concurrent cocaine dependence.

Topiramate is being investigated as a potential pharmacotherapy for the treatment of addictive disorders. However, its cognitive side effects raise concerns about its use, especially in populations with cognitive impairment, such as persons with chronic substance use disorders. This study investigated topiramate's cognitive effects in individuals dually dependent on cocaine and opioids as part of a double-blind, randomized, controlled trial of topiramate for cocaine dependence treatment. After 5 weeks of stabilization on daily oral methadone (M = 96 mg), participants were randomized to topiramate (n = 18) or placebo (n = 22). Cognitive testing took place at 2 time points: study weeks 4 through 5 to assess baseline performance and 10 to 13 weeks later to assess performance during stable dosing (300 mg topiramate or placebo). All participants were maintained on methadone at both testing times, and testing occurred 2 hours after the daily methadone plus topiramate/placebo administration. The topiramate and placebo groups did not differ on sex, level of education, premorbid intelligence, methadone dose, or illicit drug use. Topiramate slowed psychomotor and information processing speed, worsened divided attention, reduced n-back working memory accuracy, and increased the false alarm rate in recognition memory. Topiramate had no effects on visual processing, other measures of psychomotor function, risk-taking, self-control, Sternberg working memory, free recall, and metamemory. These findings indicate that topiramate may cause cognitive impairment in this population. This effect may limit its acceptability and use as a treatment in individuals with chronic opioid and cocaine use disorders, among whom preexisting cognitive impairments are common. (PsycINFO Database Record

Employment-based reinforcement of adherence to oral naltrexone in unemployed injection drug users: 12-month outcomes.

Oral naltrexone could be a promising relapse-prevention pharmacotherapy for recently detoxified opioid-dependent patients; however, interventions are often needed to promote adherence with this treatment approach. We recently conducted a study to evaluate a 26-week employment-based reinforcement intervention of oral naltrexone in unemployed injection drug users (Dunn et al., 2013). Participants were randomly assigned into a contingency (n = 35) group required to ingest naltrexone under staff observation to gain entry into a therapeutic workplace or a prescription (n = 32) group given a take-home supply of oral naltrexone and access to the workplace without observed ingestion. Monthly urine samples were collected and analyzed for evidence for naltrexone adherence, opioid use, and cocaine use. As previously reported, contingency participants provided significantly more naltrexone-positive urine samples than prescription participants during the 26-week intervention period. The goal of this current study is to report the 12-month outcomes, which occurred 6 months after the intervention ended. Results at the 12-month visit showed no between-groups differences in naltrexone-positive, opioid-negative, or cocaine-negative urine samples and no participant self-reported using naltrexone at the follow-up visit. These results show that even after a period of successfully reinforced oral naltrexone adherence, longer-term naltrexone use is unlikely to be maintained after reinforcement contingencies are discontinued. (PsycINFO Database Record

Identifying Drug (Cocaine) Intake Events from Acute Physiological Response in the Presence of Free-living Physical Activity.

A variety of health and behavioral states can potentially be inferred from physiological measurements that can now be collected in the natural free-living environment. The major challenge, however, is to develop computational models for automated detection of health events that can work reliably in the natural field environment. In this paper, we develop a physiologically-informed model to automatically detect drug (cocaine) use events in the free-living environment of participants from their electrocardiogram (ECG) measurements. The key to reliably detecting drug use events in the field is to incorporate the knowledge of autonomic nervous system (ANS) behavior in the model development so as to decompose the activation effect of cocaine from the natural recovery behavior of the parasympathetic nervous system (after an episode of physical activity). We collect 89 days of data from 9 active drug users in two residential lab environments and 922 days of data from 42 active drug users in the field environment, for a total of 11,283 hours. We develop a model that tracks the natural recovery by the parasympathetic nervous system and then estimates the dampening caused to the recovery by the activation of the sympathetic nervous system due to cocaine. We develop efficient methods to screen and clean the ECG time series data and extract candidate windows to assess for potential drug use. We then apply our model on the recovery segments from these windows. Our model achieves 100% true positive rate while keeping the false positive rate to 0.87/day over (9+ hours/day of) lab data and to 1.13/day over (11+ hours/day of) field data.

Topiramate for cocaine dependence during methadone maintenance treatment: a randomized controlled trial.

BACKGROUND: Dual dependence on opiate and cocaine occurs in about 60% of patients admitted to methadone maintenance and negatively impacts prognosis (Kosten et al. 2003. Drug Alcohol Depend. 70, 315). Topiramate (TOP) is an antiepileptic drug that may have utility in the treatment of cocaine dependence because it enhances the GABAergic system, antagonizes the glutamatergic system, and has been identified by NIDA as one of only a few medications providing a "positive signal" warranting further clinical investigation. (Vocci and Ling, 2005. Pharmacol. Ther. 108, 94). METHOD: In this double-blind controlled clinical trial, cocaine dependent methadone maintenance patients (N=171) were randomly assigned to one of four groups. Under a factorial design, participants received either TOP or placebo, and monetary voucher incentives that were either contingent (CM) or non-contingent (Non-CM) on drug abstinence. TOP participants were inducted onto TOP over 7 weeks, stabilized for 8 weeks at 300 mg daily then tapered over 3 weeks. Voucher incentives were supplied for 12 weeks, starting during the fourth week of TOP induction. Primary outcome measures were cocaine abstinence (Y/N) as measured by thrice weekly urinalysis and analyzed using Generalized Estimating Equations (GEE) and treatment retention. All analyses were intent to treat and included the 12-week evaluation phase of combined TOP/P treatment and voucher intervention period. RESULTS: There was no significant difference in cocaine abstinence between the TOP vs. P conditions nor between the CM vs. Non-CM conditions. There was no significant TOP/CM interaction. Retention was not significantly different between the groups. CONCLUSION: Topiramate is not efficacious for increasing cocaine abstinence in methadone patients.

Employment-based reinforcement of adherence to oral naltrexone treatment in unemployed injection drug users.

Oral naltrexone has high potential for use as a relapse prevention pharmacotherapy for opiate dependence yet suffers from notoriously poor adherence. This study evaluated whether entry to a therapeutic workplace could reinforce adherence with oral naltrexone. Opiate-dependent and cocaine-using injection drug users were detoxified, inducted onto oral naltrexone, and randomly assigned to a contingency (n = 35) or prescription (n = 32) group for a 26-week period. Contingency participants were required to ingest naltrexone under staff observation to gain access to the therapeutic workplace. Prescription participants received a take-home supply of naltrexone and could access the workplace independent of naltrexone ingestion. Primary outcome measures were percent of urine samples positive for naltrexone at 30-day assessments and negative for opiates and cocaine at 30-day assessments. Contingency participants provided significantly more urine samples that were positive for naltrexone compared with prescription participants (72% vs. 21%, p < .01); however, no effect of experimental group was observed on percent opiate-negative (71% vs. 60%, p = .19.) or cocaine-negative (56% vs. 53%, p = .82) samples in the contingency and prescription groups, respectively. Opiate-positive samples were significantly more likely to occur in conjunction with cocaine (p < .001) and when not protected by naltrexone (p < .02), independent of experimental group. Overall, these results show that contingent access to a therapeutic workplace significantly promoted adherence to oral naltrexone, and that the majority of opiate use occurred in conjunction with cocaine use, suggesting that untreated cocaine use may limit the effectiveness of oral naltrexone in promoting opiate abstinence.

Risk-taking propensity as a predictor of induction onto naltrexone treatment for opioid dependence.

OBJECTIVE: Heroin addiction is a chronic relapsing disorder that has devastating social, medical, and economic consequences. Naltrexone is an antagonist that blocks opioid effects and could be an effective medication for the treatment of opioid dependence. However, its clinical utility has been limited partly because of poor adherence and acceptability. Given the importance of compliance to naltrexone treatment for opioid dependence, the goal of the current study was to examine predictors involved in successful induction onto naltrexone treatment. METHOD: Parametric and nonparametric statistical tests were performed on data from a sample of 64 individuals entering treatment who met DSM-IV criteria for opioid dependence. The relationship between naltrexone induction (ie, inducted vs not inducted onto naltrexone) and risk-taking propensity, as indexed by riskiness on the Balloon Analogue Risk Task (BART), was examined. Participants were recruited from local detoxification programs, inpatient drug treatment, and other Baltimore programs that provided services to opioid-dependent adults (eg, Baltimore Needle Exchange Program) during the period from August 2007 to September 2008. RESULTS: Positive association was shown between risk-taking propensity and odds of naltrexone induction. Specifically, each 5-point increase in the total BART score was associated with a 25% decrease in odds of naltrexone induction (OR = 0.76; 95% CI, 0.58-0.99; P = .041). This association remained statistically significant, even after adjusting for potential confounds, including injection drug use and cocaine positive urine results (P = .05). After adjusting for the covariates, each 5-point increase in BART score was associated with 28% decrease in the odds of achieving the maintenance dose (adjusted OR = 0.73; 95% CI, 0.54-0.99; P = .046). CONCLUSIONS: Risk-taking propensity was predictive of induction onto naltrexone treatment, above and beyond injection drug use and cocaine-positive urine samples.

Comparison of cognitive performance in methadone maintenance patients with and without current cocaine dependence.

BACKGROUND: There is evidence for psychomotor and cognitive performance impairment in methadone maintenance patients (MMP), as well as in individuals with current cocaine dependence. It is unknown whether MMP with concurrent cocaine dependence perform worse on tests of cognitive function than MMP without cocaine dependence. METHODS: Performance was compared between MMP with and without current cocaine dependence (MMP/CD+; N = 53 and MMP/CD-; N = 24) on a standard battery of tasks designed to measure psychomotor performance, attention, episodic and working memory, and executive function. RESULTS: Participant characteristics were mostly similar across groups. However, the MMP/CD+ group had a shorter duration of methadone treatment, and a larger percentage of participants with self-reported 30-day poly-substance abuse and positive urine drug tests on the day of cognitive testing. There were no differences between the groups on measures of balance, psychomotor coordination, divided attention, working memory, most measures of episodic memory, or executive function. Relative to MMP/CD-, MMP/CD+ showed significant impairment on select measures of psychomotor performance/attention (simple reaction time and trail-making test A) and episodic memory (higher false alarm rates on recognition memory). CONCLUSIONS: The absence of differences between MMP/CD+ and MMP/CD- on measures of higher order cognitive functions, and the relatively small magnitude between-group differences on other measures suggest that current cocaine dependence, in the absence of cocaine intoxication, is unlikely to be associated with clinically meaningful increases in performance impairment in MMP.

Employment-based reinforcement of adherence to an FDA approved extended release formulation of naltrexone in opioid-dependent adults: a randomized controlled trial.

BACKGROUND: Naltrexone provides excellent opioid blockade, but its clinical utility is limited because opioid-dependent patients typically refuse it. An injectable suspension of naltrexone for extended release (XR-NTX) was recently approved by the FDA for treatment of opioid dependence. XR-NTX treatment may require concurrent behavioral intervention to maximize adherence and effectiveness, thus we sought to evaluate employment-based reinforcement as a method of improving adherence to XR-NTX in opiate dependent adults. METHODS: Opioid-dependent adults (n=38) were detoxified and inducted onto oral naltrexone, then randomly assigned to contingency or prescription conditions. Participants received up to six doses of XR-NTX at four-week intervals. All participants could earn vouchers for attendance and performance at a therapeutic workplace. Contingency participants were required to accept XR-NTX injections to access the workplace and earn vouchers. Prescription participants could earn vouchers independent of their acceptance of XR-NTX injections. RESULTS: Contingency participants accepted significantly more naltrexone injections than prescription participants (87% versus 52%, p=.002), and were more likely to accept all injections (74% versus 26%, p=.004). Participants in the two conditions provided similar percentages of samples negative for opiates (72% versus 65%) and for cocaine (58% versus 54%). Opiate positivity was significantly more likely when samples were also cocaine positive, independent of naltrexone blockade (p=.002). CONCLUSIONS: Long-term adherence to XR-NTX in unemployed opiate dependent adults is low under usual care conditions. Employment-based reinforcement can maintain adherence to XR-NTX. Ongoing cocaine use appears to interfere with the clinical effectiveness of XR-NTX on opiate use.