Potential effect of antidepressants on remission from cocaine use disorder - A nationwide matched retrospective cohort study.

BACKGROUND: Cocaine use disorder (CUD) is a significant public health issue for which there is no Food and Drug Administration-approved pharmacotherapy. Depressive disorders are common psychiatric comorbidity amongst individuals with CUD. METHODS: A retrospective cohort study was conducted among 161,544 patients diagnosed with CUD and depression to evaluate the effectiveness of 13 antidepressants on CUD remission. For any antidepressant found to be associated with CUD remission that had an additional indication, we conducted an additional analysis to evaluate the effectiveness of the candidate drug in patients with CUD with that indication. We then analyzed publicly genomic and functional databases to identify potential explanatory mechanisms of action of the candidate drug in the treatment of CUD. RESULTS: Among these antidepressants, bupropion was associated with higher rates of CUD remission compared to propensity-score matched patients prescribed other antidepressants: hazard ratio (HR) and 95% confidence interval (CI) 1.57 (95% CI: 1.27-1.94). Bupropion is also approved for smoking cessation. We identified CUD patients with co-occurring nicotine dependence and observed that patients prescribed bupropion displayed a higher rate of CUD remission compared to matched individuals prescribed other drugs for nicotine dependence: 1.38 (95% CI: 1.11-1.71). Genetic and functional analyses revealed that bupropion interacts with four protein-encoding genes (COMT, DRD2, SLC6A3, and SLC6A4) which are also associated with CUD and targets CUD-associated pathways including serotonergic synapses, cocaine addiction, and dopaminergic synapses. CONCLUSIONS: Our findings suggest that bupropion might be considered a treatment for improving CUD remission in patients with CUD and co-occurring depression or nicotine dependence.

Inpatient Low-dose Transitions From Full Agonist Opioids Including Methadone Onto Long-acting Depot Buprenorphine: Case Series From a Multicenter Clinical Trial.

OBJECTIVES: Persons with opioid use disorder (OUD) suffer disproportionately from morbidity and mortality related to serious addiction-related infections requiring hospitalization. Long-acting buprenorphine (LAB) is an underused medication for OUD that may facilitate linkage to care and treatment retention when administered before hospital discharge. Transition onto buprenorphine in the inpatient setting is often complicated by pain, active infection management, potential surgical interventions, and risk of opioid withdrawal in transition from full agonists to a partial agonist. METHODS: The COMMIT Trial is a randomized controlled trial evaluating LAB administered by infectious disease physicians and hospitalists compared with treatment as usual for persons with OUD hospitalized with infections. We report a case series of participants on full agonist opioids including methadone who were transitioned to sublingual buprenorphine using low-dose ( microdosing ) strategies followed by LAB injection. RESULTS: Seven participants with current opioid use disorder and life-threatening infections, all with significant concurrent pain and many requiring surgical intervention, underwent low-dose transitions starting at buccal buprenorphine doses ranging from 225 µg to 300 µg 3 times a day on the first day. All were well tolerated with average time to LAB injection of 7.5 days (range, 5-10 days). CONCLUSIONS: Inpatient low-dose buprenorphine transition from full agonist opioids including methadone onto LAB is feasible even in those with complex hospitalizations for concurrent infections and/or surgery. This strategy facilitates dosing of LAB before hospital discharge when risk of opioid relapse and overdose are significant.

Sexual orientation differences among men in a randomized clinical trial of extended-release naltrexone and bupropion for methamphetamine use disorder.

BACKGROUND: Methamphetamine use disorder (MethUD) disproportionately affects men who have sex exclusively with men or with men and women (collectively MSM/W), compared to men who have sex with women (MSW). This study is the first MethUD medication trial to compare treatment effect for these groups, hypothesizing that extended-release injectable naltrexone 380mg every 3 weeks plus oral extended-release bupropion 450mg daily would be less effective for MSM/W than MSW. METHODS: Data come from men (N = 246) in a multi-site, double-blind, randomized, placebo-controlled trial with sequential parallel comparison design. In Stage 1 (6-weeks), participants were randomized to active treatment or placebo. In Stage 2 (6-weeks), Stage 1 placebo non-responders were rerandomized. Treatment response was ≥3 methamphetamine-negative urine samples, out of four obtained at the end of Stages 1 and 2. Treatment effect was the active-versus-placebo between-group difference in the weighted average Stages 1 and 2 responses. RESULTS: MSM/W (n = 151) were more likely than MSW (n = 95) to be Hispanic, college-educated, and living with HIV. Adjusting for demographics, among MSM/W, response rates were 13.95 % (active treatment) and 2.78 % (placebo) in Stage 1; 23.26 % (active treatment) and 4.26 % (placebo) in Stage 2. Among MSW, response rates were 7.69 % (active treatment) and 5.80 % (placebo) in Stage 1; 3.57 % (active treatment) and 0 % (placebo) in Stage 2. Treatment effect was significantly larger for MSM/W (h = 0.1479) than MSW (h = 0.0227) (p = 0.04). CONCLUSIONS: Findings suggest efficacy of extended-release naltrexone plus bupropion for MSM/W, a population heavily burdened by MethUD. While a secondary outcome, this intriguing finding merits testing in prospective trials.

Repetitive transcranial magnetic stimulation for smoking cessation: a pivotal multicenter double-blind randomized controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method increasingly used to treat psychiatric disorders, primarily depression. Initial studies suggest that rTMS may help to treat addictions, but evaluation in multicenter randomized controlled trials (RCTs) is needed. We conducted a multicenter double-blind RCT in 262 chronic smokers meeting DSM-5 criteria for tobacco use disorder, who had made at least one prior failed attempt to quit, with 68% having made at least three failed attempts. They received three weeks of daily bilat-eral active or sham rTMS to the lateral prefrontal and insular cortices, followed by once weekly rTMS for three weeks. Each rTMS session was administered following a cue-induced craving procedure, and participants were monitored for a total of six weeks. Those in abstinence were monitored for additional 12 weeks. The primary outcome measure was the four-week continuous quit rate (CQR) until Week 18 in the intent-to-treat efficacy set, as determined by daily smoking diaries and verified by urine cotinine measures. The trial was registered at ClinicalTrials.gov (NCT02126124). In the intent-to-treat analysis set (N=234), the CQR until Week 18 was 19.4% following active and 8.7% following sham rTMS (X2 =5.655, p=0.017). Among completers (N=169), the CQR until Week 18 was 28.0% and 11.7%, respectively (X2 =7.219, p=0.007). The reduction in cigarette consumption and craving was significantly greater in the active than the sham group as early as two weeks into treatment. This study establishes a safe treatment protocol that promotes smoking cessation by stimulating relevant brain circuits. It represents the first large multicenter RCT of brain stimulation in addiction medicine, and has led to the first clearance by the US Food and Drug Administration for rTMS as an aid in smok-ing cessation for adults.

Examination of Correlates of OUD Outcomes in Young Adults: Secondary Analysis From the XBOT Trial.

BACKGROUND AND OBJECTIVES: Opioid use disorder (OUD) treatment outcomes are poorer for young adults than older adults. Developmental differences are broadly implicated, but particular vulnerability factor interactions are poorly understood. This study sought to identify moderators of OUD relapse between age groups. METHODS: This secondary analysis compared young adults (18-25) to older adults (26+) from a comparative effectiveness trial ("XBOT") that randomized (N = 570) participants to extended-release naltrexone or sublingual buprenorphine-naloxone. We explored the relationship between 25 prespecified patient baseline characteristics and relapse to regular opioid use by age group and treatment condition, using logistic regression. RESULTS: Young adults (n = 111) had higher rates of 24-week relapse than older adults (n = 459) (70.3% vs 58.8%) and differed on a number of specific characteristics, including more smokers, more intravenous opioid use, and more cannabis use. No significant moderators predicted relapse, in either three-way or two-way interactions. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: No baseline factors were identified as moderating the relationship between age group and opioid relapse, nor any interactions between baseline characteristics, age group, and treatment condition to predict opioid relapse. Poorer treatment outcomes for young adults are likely associated with multiple developmental vulnerabilities rather than any single predominant factor. Although not reaching significance, several characteristics (using heroin, smoking tobacco, high levels of depression/anxiety, or treatment because of family/friends) showed higher odds ratio point estimates for relapse in young adults than older adults. This is the first study to explore moderators of worse OUD treatment outcomes in young adults, highlighting the need to identify predictor variables that could inform treatment enhancements. (Am J Addict 2021;00:1-12).

Reductions in tobacco use in naltrexone, relative to buprenorphine-maintained individuals with opioid use disorder: Secondary analysis from the National Drug Abuse Treatment Clinical Trials Network.

BACKGROUND: Smoking prevalence in individuals with opioid use disorder (OUD) is over 80%. Research suggests that opioid use significantly increases smoking, which could account for the strikingly low smoking-cessation rates observed in both methadone- and buprenorphine-maintained patients, even with the use of first-line smoking-cessation interventions. If opioids present a barrier to smoking-cessation, then better smoking outcomes should be observed in OUD patients treated with extended-release naltrexone (XR-NTX, an opioid antagonist) compared to those receiving buprenorphine (BUP-NX, a partial opioid agonist). METHODS: The current study is a secondary analysis of a 24-week, multi-site, open-label, randomized clinical trial conducted within the National Drug Abuse Treatment Clinical Trials Network comparing the effectiveness of XR-NTX vs. BUP-NX for adults with OUD. Longitudinal mixed effects models were used to determine if there was a significant reduction in cigarette use among daily smokers successfully inducted to treatment (n = 373) and a subset of those who completed treatment (n = 169). RESULTS: Among daily smokers inducted onto OUD medication, those in the XR-NTX group smoked fewer cigarettes per day (M = 11.36, SE = 0.62) relative to smokers in the BUP-NX group (M = 13.33, SE = 0.58) across all study visits, (b (SE) = -1.97 (0.55), p < .01). Results were similar for the treatment completers. CONCLUSIONS: OUD patients treated with XR-NTX reduced cigarette use more than those treated with BUP-NX, suggesting that XR-NTX in combination with other smoking cessation interventions might be a better choice for OUD smokers interested in reducing their tobacco use.

Design and methods of a multi-site randomized controlled trial of an integrated care model of long-acting injectable buprenorphine with infectious disease treatment among persons hospitalized with infections and opioid use disorder.

BACKGROUND: Hospitalization with co-occurring opioid use disorder (OUD) and infections presents a critical time to intervene to improve outcomes for these intertwined epidemics that are typically managed separately. A surge in life-threatening infectious diseases associated with injection drug use, including bacterial and fungal infections, HIV, and HCV accounts for substantial healthcare utilization, morbidity, and mortality. Infectious Disease (ID) specialists manage severe infections that require hospitalization and are a logical resource to engage patients in medication treatment for OUD (MOUD). An injectable long-acting monthly formulation of buprenorphine (LAB) has a potential advantage for initiating MOUD within hospital settings and bridging to treatment after discharge. METHODS: A randomized multi-site trial tests a new model of care (ID/LAB) in which OUD and infections are managed by ID specialists and hospitalists using LAB coupled with referrals to community resources for long-term MOUD. A sample of 200 adults admitted to three U.S. hospitals for OUD and infections are randomly assigned 1:1 to ID/LAB or treatment as usual (TAU). The primary outcome measure is the proportion of patients enrolled in effective MOUD at 12 weeks after randomization. Secondary outcomes include relapse to opioid use, adherence to infectious disease treatment, infection morbidity and mortality, and drug overdose. RESULTS: We describe the design, procedures, statistical analysis, and early implementation issues of this randomized trial. CONCLUSIONS: Study findings will provide insight into the feasibility and effectiveness of integrated treatment of OUD and serious infections and have the potential to reduce morbidity and mortality in this vulnerable population.

Bupropion and Naltrexone in Methamphetamine Use Disorder.

BACKGROUND: The use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied. METHODS: We conducted this multisite, double-blind, two-stage, placebo-controlled trial with the use of a sequential parallel comparison design to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg per day) in adults with moderate or severe methamphetamine use disorder. In the first stage of the trial, participants were randomly assigned in a 0.26:0.74 ratio to receive naltrexone-bupropion or matching injectable and oral placebo for 6 weeks. Those in the placebo group who did not have a response in stage 1 underwent rerandomization in stage 2 and were assigned in a 1:1 ratio to receive naltrexone-bupropion or placebo for an additional 6 weeks. Urine samples were obtained from participants twice weekly. The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of stage 1 or stage 2, and the weighted average of the responses in the two stages is reported. The treatment effect was defined as the between-group difference in the overall weighted responses. RESULTS: A total of 403 participants were enrolled in stage 1, and 225 in stage 2. In the first stage, 18 of 109 participants (16.5%) in the naltrexone-bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone-bupropion group and 2 of 111 (1.8%) in the placebo group had a response. The weighted average response across the two stages was 13.6% with naltrexone-bupropion and 2.5% with placebo, for an overall treatment effect of 11.1 percentage points (Wald z-test statistic, 4.53; P<0.001). Adverse events with naltrexone-bupropion included gastrointestinal disorders, tremor, malaise, hyperhidrosis, and anorexia. Serious adverse events occurred in 8 of 223 participants (3.6%) who received naltrexone-bupropion during the trial. CONCLUSIONS: Among adults with methamphetamine use disorder, the response over a period of 12 weeks among participants who received extended-release injectable naltrexone plus oral extended-release bupropion was low but was higher than that among participants who received placebo. (Funded by the National Institute on Drug Abuse and others; ADAPT-2 ClinicalTrials.gov number, NCT03078075.).

Quetiapine treatment for cannabis use disorder.

BACKROUND: Pharmacotherapy for cannabis use disorder (CUD) is an important unmet public health need. METHODS: In a 12-week randomized double-blind placebo-controlled trial, the efficacy of quetiapine (300 mg nightly) for the treatment of CUD was tested in 130 outpatients. Weekly cannabis use was categorized into three groups: heavy use (5-7 days), moderate use (2-4 days) and light use (0-1 days). RESULTS: At baseline both groups were considered heavy users (using days per week: median = 7.0; interquartile range (IQR): 6.5-7.0; daily dollar value: median = $121.4; IQR: 73.8-206.3). The week-by-treatment interaction was marginally significant (χ2(2) = 5.56, P = .06). With each week, the odds of moderate compared to heavy use significantly increased in the quetiapine group (OR=1.17, P < .0001), but not significantly in the placebo group (OR=1.05, P = .16). The odds of light versus heavy use did not significantly differ over time (P = .12). Treatment was also associated with reduced cannabis withdrawal symptoms by 10.4% each week (95% CI: 8.9-11.8). No serious adverse events occurred during the study and no evidence of development of a movement disorder was detected. Adverse effects were not significantly different between the quetiapine and placebo treatment arms. CONCLUSIONS: The use of quetiapine to treat CUD was associated with an increased likelihood of heavy frequency use transitioning to moderate use, but not light use. The clinical significance of reductions in cannabis use, short of abstinence warrants further study.

A week-long outpatient induction onto XR-naltrexone in patients with opioid use disorder.

BACKGROUND: Extended-release (XR) naltrexone can prevent relapse to opioid use disorder following detoxification. However, one of the barriers to initiating XR-naltrexone is the recommendation for a 7-10-day period of abstinence from opioids prior to the first dose. OBJECTIVES: The current study evaluated the feasibility of an XR-naltrexone induction protocol that can be implemented over 1 week in the outpatient clinic. METHODS: Participants (N = 44) were seen in the clinic daily. On Day 1, after abstaining from opioids for at least 12 h, they received buprenorphine 6-8 mg. Adjunctive medications (clonidine, clonazepam, zolpidem, trazodone, and prochlorperazine) were dispensed on Days 2-5, while ascending oral doses of naltrexone were given on Days 3-5 starting with 1 mg dose. An injection of XR-naltrexone was given on Day 5, 1 h after receiving and tolerating naltrexone 24 mg. RESULTS: Of the 44 participants (38 males), 35 (80%) were heroin users and 9 (20%) used prescription opioids. A total of 26 participants (59%) completed the induction and received their first injection of XR-naltrexone. XR-naltrexone was initiated in 54% (19/35) of heroin users and 78% (7/9) of prescription opioid users. CONCLUSION: The results support the feasibility of a week-long outpatient induction onto XR-naltrexone with ascending doses of naltrexone and standing doses of adjunctive medications. By circumventing the need for a protracted period of abstinence and mitigating the severity of withdrawal symptoms experienced during naltrexone titration, this strategy has the potential to increase patient acceptability and access to relapse prevention treatment with XR-naltrexone.

A randomized, double-blind, placebo-controlled study of the kappa opioid receptor antagonist, CERC-501, in a human laboratory model of smoking behavior.

Preclinical data indicate that selective kappa opioid receptor antagonists reduce nicotine self-administration and withdrawal symptoms. The aim of the current study was to determine whether treatment with CERC-501, an orally available, potent, and selective kappa opioid receptor antagonist, could alleviate nicotine withdrawal and craving and mitigate mood alterations associated with nicotine withdrawal in humans. Healthy, adult cigarette smokers were enrolled into this randomized, multisite, double-blind, placebo-controlled, crossover study. Participants completed two 8-day treatment phases during which they received either CERC-501 (15 mg, p.o., once daily) or placebo. On the seventh day of each dosing phase, participants were admitted as inpatients for an 18-hour cigarette abstinence period followed by experimental testing. The primary outcome measures were (a) performance on the McKee Smoking Lapse test (ie, latency to smoke in exchange for money) and (b) number of cigarettes self-administered during a 60-minute ad lib smoking period. Other outcomes included measures of craving, mood, anxiety, nicotine withdrawal, and subjective effects of cigarette smoking. A total of 71 participants who smoked an average of approximately 23 cigarettes per day were enrolled, and 56 subjects completed the study. CERC-501 was well tolerated, but it did not significantly alter the latency to start smoking (CERC-501: 16.5 min vs placebo: 17.7 min) or the number of cigarettes smoked (CERC-501: 3.3 cigarettes vs placebo: 3.1 cigarettes). Compared with placebo, CERC-501 also did not affect cigarette craving, mood, anxiety, nicotine withdrawal, or subjective effects of smoking. These findings do not support a role for CERC-501 in the treatment of nicotine use disorder.

Differential Posttreatment Outcomes of Methylphenidate for Smoking Cessation for Individuals With ADHD.

BACKGROUND AND OBJECTIVES: In a multisite, randomized study (CTN-0029), a 3-month course of Osmotic-Release Oral System Methylphenidate (OROS-MPH) improved smoking cessation in a group of patients with higher baseline severity in Attention-Deficit/Hyperactivity Disorder (ADHD). This treatment, however, worsened smoking cessation outcome in the group with lower baseline ADHD severity. We want to examine whether this differential treatment effect persisted after OROS-MPH was discontinued. METHODS: We conducted a secondary analysis of the 1-month follow-up data from CTN-0029 after the discontinuation of OROS-MPH (N = 134). Nicotine patch was tapered during this month. We tested whether OROS-MPH had an effect on self-reported 7-day abstinence by week, as well as possible treatment by baseline ADHD severity interactions. RESULTS: Abstinence diminished overall in time after the end of the treatment. In the high baseline severity group, patients who received OROS-MPH had an advantage in 7-day abstinence at week 15 (40% for OROS-MPH vs 20% for placebo, odds ratio = 2.63, P = .028). In the lower severity group (n = 121), no difference was detected (29% for OROS-MPH vs 32% for placebo, P = 1.00) between the two treatment groups. There was also a significant treatment by baseline ADHD severity interaction (P = .03). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: OROS-MPH promotes abstinence beyond the course of treatment for patients with more severe ADHD, while the paradoxical effects in the lower baseline severity group is not persistent after medication discontinuation. Targeting ADHD in smoking cessation as a comorbidity therefore can have broader impact with more precise patient selection. (Am J Addict).

Exploring longitudinal course and treatment-baseline severity interactions in secondary outcomes of smoking cessation treatment in individuals with attention-deficit hyperactivity disorder.

BACKGROUND: A double blind, placebo-controlled randomized trial (NCT00253747) evaluating osmotic-release oral system methylphenidate (OROS-MPH) for smoking-cessation revealed a significant interaction effect in which participants with higher baseline ADHD severity had better abstinence outcomes with OROS-MPH while participants with lower baseline ADHD severity had worse outcomes. OBJECTIVES: This current report examines secondary outcomes that might bear on the mechanism for this differential treatment effect. METHODS: Longitudinal analyses were conducted to evaluate the effect of OROS-MPH on three secondary outcomes (ADHD symptom severity, nicotine craving, and withdrawal) in the total sample (N = 255, 56% Male), and in the high (N = 134) and low (N = 121) baseline ADHD severity groups. RESULTS: OROS-MPH significantly improved ADHD symptoms and nicotine withdrawal symptoms in the total sample, and exploratory analyses showed that in both higher and lower baseline severity groups, OROS-MPH statistically significantly improved these two outcomes. No effect on craving overall was detected, though exploratory analyses showed statistically significantly decreased craving in the high ADHD severity participants on OROS-MPH. No treatment by ADHD baseline severity interaction was detected for the outcomes. CONCLUSIONS: Methylphenidate improved secondary outcomes during smoking cessation independent of baseline ADHD severity, with no evident treatment-baseline severity interaction. Our results suggest divergent responses to smoking cessation treatment in the higher and lower severity groups cannot be explained by concordant divergence in craving, withdrawal and ADHD symptom severity, and alternative hypotheses may need to be identified.

NIDA Clinical Trials Network CTN-0051, Extended-Release Naltrexone vs. Buprenorphine for Opioid Treatment (X:BOT): Study design and rationale.

INTRODUCTION: For opioid-dependent patients in the US and elsewhere, detoxification and counseling-only aftercare are treatment mainstays. Long-term abstinence is rarely achieved; many patients relapse and overdose after detoxification. Methadone, buprenorphine-naloxone (BUP-NX) and extended-release naltrexone (XR-NTX) can prevent opioid relapse but are underutilized. This study is intended to develop an evidence-base to help patients and providers make informed choices and to foster wider adoption of relapse-prevention pharmacotherapies. METHODS: The National Institute on Drug Abuse's Clinical Trials Network (CTN) study CTN-0051, X:BOT, is a comparative effectiveness study of treatment for 24weeks with XR-NTX, an opioid antagonist, versus BUP-NX, a high affinity partial opioid agonist, for opioid dependent patients initiating treatment at 8 short-term residential (detoxification) units and continuing care as outpatients. Up to 600 participants are randomized (1:1) to XR-NTX or BUP-NX. RESULTS: The primary outcome is time to opioid relapse (i.e., loss of persistent abstinence) across the 24-week treatment phase. Differences between arms in the distribution of time-to-relapse will be compared (construction of the asymptotic 95% CI for the hazard ratio of the difference between arms). Secondary outcomes include proportions retained in treatment, rates of opioid abstinence, adverse events, cigarette, alcohol, and other drug use, and HIV risk behaviors; opioid cravings, quality of life, cognitive function, genetic moderators, and cost effectiveness. CONCLUSIONS: XR-NTX and BUP-NX differ considerably in their characteristics and clinical management; no studies to date have compared XR-NTX with buprenorphine maintenance. Study design choices and compromises inherent to a comparative effectiveness trial of distinct treatment regimens are reviewed. CLINICAL TRIAL REGISTRATION: NCT02032433.

Mobile Phone Messaging During Unobserved "Home" Induction to Buprenorphine.

The deployment of health information technologies promises to optimize clinical outcomes for populations with substance use disorders. Electronic health records, web-based counseling interventions, and mobile phone applications enhance the delivery of evidence-based behavioral and pharmacological treatments, with minimal burden to clinical personnel, infrastructure, and work flows. This clinical case shares a recent experience utilizing mobile phone text messaging between an office-based buprenorphine provider in a safety net ambulatory clinic and a patient seeking buprenorphine treatment for opioid use disorder. The case highlights the use of text message-based physician-patient communication to facilitate unobserved "home" induction onto buprenorphine.

Anxiety and Depressed Mood Decline Following Smoking Abstinence in Adult Smokers with Attention Deficit Hyperactivity Disorder.

INTRODUCTION: A preponderance of relevant research has indicated reduction in anxiety and depressive symptoms following smoking abstinence. This secondary analysis investigated whether the phenomenon extends to smokers with attention deficit hyperactivity disorder (ADHD). METHODS: The study setting was an 11-Week double-blind placebo-controlled randomized trial of osmotic release oral system methylphenidate (OROS-MPH) as a cessation aid when added to nicotine patch and counseling. Participants were 255 adult smokers with ADHD. The study outcomes are: anxiety (Beck Anxiety Inventory (BAI)) and depressed mood (Beck Depression Inventory II (BDI)) measured one Week and six Weeks after a target quit day (TQD). The main predictor is point-prevalence abstinence measured at Weeks 1 and 6 after TQD. Covariates are treatment (OROS-MPH vs placebo), past major depression, past anxiety disorder, number of cigarettes smoked daily, demographics (age, gender, education, marital status) and baseline scores on the BAI, BDI, and the DSM-IV ADHD Rating Scale. RESULTS: Abstinence was significantly associated with lower anxiety ratings throughout the post-quit period (p<0.001). Depressed mood was lower for abstainers than non-abstainers at Week 1 (p<0.05), but no longer at Week 6 (p=0.83). Treatment with OROS-MPH relative to placebo showed significant reductions at Week 6 after TQD for both anxiety (p<0.05) and depressed mood (p<0.001), but not at Week 1. Differential abstinence effects of gender were observed. Anxiety and depression ratings at baseline predicted increased ratings of corresponding measures during the post-quit period. CONCLUSION: Stopping smoking yielded reductions in anxiety and depressed mood in smokers with ADHD treated with nicotine patch and counseling. Treatment with OROS-MPH yielded mood reductions in delayed manner.

Baseline characteristics of patients predicting suitability for rapid naltrexone induction.

BACKGROUND AND OBJECTIVES: Extended-release (XR) injection naltrexone has proved promising in the treatment of opioid dependence. Induction onto naltrexone is often accomplished with a procedure known as rapid naltrexone induction. The purpose of this study was to evaluate pre-treatment patient characteristics as predictors of successful completion of a rapid naltrexone induction procedure prior to XR naltrexone treatment. METHODS: A chart review of 150 consecutive research participants (N = 84 completers and N = 66 non-completers) undergoing a rapid naltrexone induction with the buprenorphone-clonidine procedure were compared on a number of baseline demographic, clinical and psychosocial factors. Logistic regression was used to identify client characteristics that may predict successful initiation of naltrexone after a rapid induction-detoxification. RESULTS: Patients who failed to successfully initiate naltrexone were younger (AOR: 1.040, CI: 1.006, 1.075), and using 10 or more bags of heroin (or equivalent) per day (AOR: 0.881, CI: 0.820, 0.946). Drug use other than opioids was also predictive of failure to initiate naltrexone in simple bivariate analyses, but was no longer significant when controlling for age and opioid use level. CONCLUSIONS: Younger age, and indicators of greater substance dependence severity (more current opioid use, other substance use) predict difficulty completing a rapid naltrexone induction procedure. Such patients might require a longer period of stabilization and/or more gradual detoxification prior to initiating naltrexone. SCIENTIFIC SIGNIFICANCE: Our study findings identify specific characteristics of patients who responded positively to rapid naltrexone induction.

Toward personalized smoking-cessation treatment: Using a predictive modeling approach to guide decisions regarding stimulant medication treatment of attention-deficit/hyperactivity disorder (ADHD) in smokers.

BACKGROUND AND OBJECTIVES: Osmotic-release oral system methylphenidate (OROS-MPH) did not show overall benefit as an adjunct smoking cessation treatment for adult smokers with ADHD in a randomized, placebo-controlled, multicenter clinical trial. A secondary analysis revealed a significant interaction between ADHD symptom severity and treatment-response to OROS-MPH, but did not account for other baseline covariates or estimate the magnitude of improvement in outcome if treatment were optimized. This present study addressed the gaps in how this relationship should inform clinical practice. METHODS: Using data from the Adult Smokers with ADHD Trial (N = 255, six sites in five US States), we build predictive models to calculate the probability of achieving prolonged abstinence, verified by self-report, and expired carbon monoxide measurement. We evaluate the potential improvement in achieving prolonged abstinence with and without stratification on baseline ADHD severity. RESULTS: Predictive modeling demonstrates that the interaction between baseline ADHD severity and treatment group is not affected by adjusting for other baseline covariates. A clinical trial simulation shows that giving OROS-MPH to patients with baseline Adult ADHD Symptom Rating Scale (ADHD-RS) >35 and placebo to those with ADHD-RS ≤35 would significantly improve the prolonged abstinence rate (52 ± 8% vs. 42 ± 5%, p < .001). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: In smokers with ADHD, utilization of a simple decision rule that stratifies patients based on baseline ADHD severity can enhance overall achievement of prolonged smoking abstinence. Similar analysis methods should be considered for future clinical trials for other substance use disorders.

Cigarette Smoking During Substance Use Disorder Treatment: Secondary Outcomes from a National Drug Abuse Treatment Clinical Trials Network study.

INTRODUCTION: The majority of patients enrolled in treatment for substance use disorders (SUDs) also use tobacco. Many will continue to use tobacco even during abstinence from other drugs and alcohol, often leading to smoking-related illnesses. Despite this, little research has been conducted to assess the influence of being a smoker on SUD treatment outcomes and changes in smoking during a treatment episode. METHODS: In this secondary analysis, cigarette smoking was evaluated in participants completing outpatient SUD treatment as part of a multi-site study conducted by the National Drug Abuse Treatment Clinical Trials Network. Analyses included the assessment of changes in smoking and nicotine dependence via the Fagerström Test for Nicotine Dependence during the 12-week study among all smokers (aim #1), specifically among those in the experimental treatment group (aim #2), and the moderating effect of being a smoker on treatment outcomes (aim #3). RESULTS: Participants generally did not reduce or quit smoking throughout the course of the study. Among a sub-set of participants with higher baseline nicotine dependence scores randomized to the control arm, scores at the end of treatment were lower compared to the experimental arm, though measures of smoking quantity did not appear to decrease. Further, being a smoker was associated with poorer treatment outcomes compared to non-smokers enrolled in the trial. CONCLUSIONS: This study provides evidence that patients enrolled in community-based SUD treatment continue to smoke, even when abstaining from drugs and alcohol. These results add to the growing literature encouraging the implementation of targeted, evidence-based interventions to promote abstinence from tobacco among SUD treatment patients.

Do withdrawal-like symptoms mediate increased marijuana smoking in individuals treated with venlafaxine-XR?

BACKGROUND AND AIMS: Cannabis-dependent participants with depressive disorder are less likely to achieve abstinence with venlafaxine-XR (VEN-XR) treatment. Individuals on VEN-XR reported more severe withdrawal, despite not reducing their smoking behavior. We hypothesized that withdrawal-like symptoms, likely medication side effects, led to continued marijuana smoking in this group. METHODS: We conducted a secondary analysis using Marijuana Withdrawal Checklist (MWC) scores and urine THC to test whether severity of withdrawal-like symptoms mediates the relationship between VEN-XR treatment and continued marijuana smoking. We included 103 participants (VEN-XR=51, Placebo=52). Marijuana use was dichotomized into smoking (THC>100 ng/ml) and non-smoking (THC ≤ 100 ng/ml) weeks. MWC scores were obtained weekly. We used three models in a regression based mediation analysis. RESULTS: The estimated risk of smoking marijuana was greater for individuals on VEN-XR in weeks 7-9, even when controlling for MWC scores (week 7 Risk Difference (RD)=0.11, p=0.034; week 8 RD=0.20, p=0.014), and higher scores mediated this effect. In weeks 10 and 11, the estimated effect was stronger (week 10 RD=0.03, p=0.380; week 11 RD=0.07, p=0.504), and worse withdrawal-like symptoms more fully accounted for continued marijuana smoking in the VEN-XR group, according to the models. CONCLUSIONS: Individuals treated with VEN-XR had more severe withdrawal-like symptoms, which mediated their continued marijuana smoking. Noradrenergic agents, such as VEN-XR, may negatively impact treatment outcomes in cannabis-dependent patients attempting to reduce or stop their use.