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Although clinicians have traditionally used the Finnegan Neonatal Abstinence Scoring Tool to assess the severity of neonatal opioid withdrawal, a newer function-based approach - the Eat, Sleep, Console care approach - is increasing in use. Whether the new approach can safely reduce the time until infants are medically ready for discharge when it is applied broadly across diverse sites is unknown. In this cluster-randomized, controlled trial at 26 U.S. hospitals, we enrolled infants with neonatal opioid withdrawal syndrome who had been born at 36 weeks' gestation or more. At a randomly assigned time, hospitals transitioned from usual care that used the Finnegan tool to the Eat, Sleep, Console approach. During a 3-month transition period, staff members at each hospital were trained to use the new approach. The primary outcome was the time from birth until medical readiness for discharge as defined by the trial. Composite safety outcomes that were assessed during the first 3 months of postnatal age included in-hospital safety, unscheduled health care visits, and nonaccidental trauma or death. A total of 1305 infants were enrolled. In an intention-to-treat analysis that included 837 infants who met the trial definition for medical readiness for discharge, the number of days from birth until readiness for hospital discharge was 8.2 in the Eat, Sleep, Console group and 14.9 in the usual-care group (adjusted mean difference, 6.7 days; 95% confidence interval [CI], 4.7 to 8.8), for a rate ratio of 0.55 (95% CI, 0.46 to 0.65; P<0.001). The incidence of adverse outcomes was similar in the two groups. As compared with usual care, use of the Eat, Sleep, Console care approach significantly decreased the number of days until infants with neonatal opioid withdrawal syndrome were medically ready for discharge, without increasing specified adverse outcomes. (Funded by the Helping End Addiction Long-term (HEAL) Initiative of the National Institutes of Health; ESC-NOW ClinicalTrials.gov number, NCT04057820.).

There are no FDA-approved pharmacotherapies for cannabis dependence. Cannabis is the most widely used illicit drug in the world, and patients seeking treatment for primary cannabis dependence represent 25% of all substance use admissions. We conducted a phase IIa proof-of-concept pilot study to examine the safety and efficacy of a calcium channel/GABA modulating drug, gabapentin, for the treatment of cannabis dependence. A 12-week, randomized, double-blind, placebo-controlled clinical trial was conducted in 50 unpaid treatment-seeking male and female outpatients, aged 18-65 years, diagnosed with current cannabis dependence. Subjects received either gabapentin (1200 mg/day) or matched placebo. Manual-guided, abstinence-oriented individual counseling was provided weekly to all participants. Cannabis use was measured by weekly urine toxicology and by self-report using the Timeline Followback Interview. Cannabis withdrawal symptoms were assessed using the Marijuana Withdrawal Checklist. Executive function was measured using subtests from the Delis-Kaplan Executive Function System. Relative to placebo, gabapentin significantly reduced cannabis use as measured both by urine toxicology (p=0.001) and by the Timeline Followback Interview (p=0.004), and significantly decreased withdrawal symptoms as measured by the Marijuana Withdrawal Checklist (p<0.001). Gabapentin was also associated with significantly greater improvement in overall performance on tests of executive function (p=0.029). This POC pilot study provides preliminary support for the safety and efficacy of gabapentin for treatment of cannabis dependence that merits further study, and provides an alternative conceptual framework for treatment of addiction aimed at restoring homeostasis in brain stress systems that are dysregulated in drug dependence and withdrawal.

Symptoms of cognitive impairment during smoking withdrawal can be ameliorated by nicotine replacement. To define brain mechanisms contributing to this therapeutic effect, we conducted a functional connectivity analysis of resting-state fMRI in 17 abstinent smokers following nicotine replacement in a double-blind, placebo-controlled, crossover design. We found that individual differences in cognitive withdrawal symptom improvements after nicotine replacement were associated with increased inverse coupling between executive control and default mode brain networks. Furthermore, improvements in withdrawal symptoms were negatively correlated with altered functional connectivity within the default mode network, and with connectivity between the executive control network and regions implicated in reward processing. These findings demonstrate that nicotine administration in abstinent smokers modulates dynamic interactions between large-scale cognitive brain networks in the resting state. We specifically highlight the role of midline and prefrontal network regions in the neurocognitive response to nicotine pharmacotherapy and suggest that altered functional connectivity patterns of these networks reflect their engagement in reward and salience processing during smoking withdrawal. Individual differences in resting brain functional connectivity may predict therapeutic outcomes in nicotine addiction and other conditions associated with cognitive impairments.

Rationale Each year, over 300,000 individuals in the USA enter treatment for cannabis use disorder (CUD). The development of effective pharmacotherapy for CUD is a priority. Objective This placebo-controlled study examined the effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory measure of relapse. Methods Eleven daily, non-treatment-seeking cannabis users completed three, 8-day inpatient phases; each phase tested a different medication condition in counter-balanced order. On the first day of each phase, participants were administered placebo capsules t.i.d. and smoked experimenter-administered active cannabis (5.6 % Δ 9 -tetrahydrocannabinol (THC)). On days 2–8, the participants were administered capsules containing either placebo (0 mg at 0900, 1800, and 2300 hours), zolpidem (0 mg at 0900 and 1800, and 12.5 mg at 2300), or zolpidem (12.5 mg at 2300) and nabilone (3 mg at 0900 and 1800). Cannabis withdrawal, subjective capsule effects, and cognitive performance were examined on days 3–4, when only inactive cannabis (0.0 % THC) was available for self-administration. “Relapse” was measured on days 5–8, when participants could self-administer active cannabis. Results Both medication conditions decreased withdrawal-related disruptions in sleep, but only zolpidem in combination with nabilone decreased withdrawal-related disruptions in mood and food intake relative to placebo. Zolpidem in combination with nabilone, but not zolpidem alone, decreased self-administration of active cannabis. Zolpidem in combination with nabilone also produced small increases in certain abuse-related subjective capsule ratings, while zolpidem alone did not. Neither medication condition altered cognitive performance. Conclusions Clinical testing of nabilone, either alone, or in combination with zolpidem is warranted.

Background Buprenorphine is usually administered to treat opioid use disorder and pain syndromes. This research presents the first study regarding the effectiveness of different singly administered high doses of buprenorphine (a partial opioid agonist (of μ-opioid receptors), a potent opioid antagonist (of κ-receptors) and a partial agonist of nociception receptors) in reducing suicidal ideation in acutely depressed people with co-morbid opiate dependence. It follows small studies that suggest that ultra-low-dose buprenorphine may be useful in reducing suicidal ideation. The goal of this study was to describe the outcome of different doses of buprenorphine on suicidal opioid-dependent patients over a 3-day interval, by conducting a randomized clinical trial. Methods Fifty-one suicidal male inpatients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for both opioid dependence and major depressive disorder were randomized to three groups ( n = 17 per group) to receive a single, sublingual dose of buprenorphine (32 mg, 64 mg, or 96 mg). Out of 51 participants, there were 47 patients; 16 (34.04%) received 32 mg, 17 (36.17%) received 64 mg, and 14 (29.78%) received 96 mg of sublingual buprenorphine. They were evaluated by using psychometric assessment of the Beck Scale for Suicidal Ideation (BSSI) and interviews based on DSM-5 criteria. A placebo group was not included because of the high probability of severe withdrawal without active pharmacological treatment. The study was conducted with appropriate precautions and monitoring of respiratory and cardiovascular measures. The medication was administered while the patients were in moderate opiate withdrawal, as indicated by the presence of four to five withdrawal symptoms. A structured clinical interview was conducted, and urine toxicology testing was performed. Results Patients completed the 3-day trial course. The outcomes illustrated a significant reduction in BSSI scores within each of the three groups, p  < 0.01., but no difference in results between the groups, p  = 0.408. Conclusions The results suggest that a single high dose of buprenorphine could rapidly treat suicidal ideations. A single high dose of buprenorphine may be a main-mechanism medication that gives a rapid treatment for suicidal opioid-dependent patients. Placebo-controlled trials are required to measure the safety and the physiological and psychological effects of this medication.

Alcohol withdrawal syndrome, if untreated, can lead to potentially life-threatening complications. Benzodiazepines are the drugs of choice for the treatment of alcohol withdrawal syndrome. We aimed to compare the symptoms-triggered approach and fixed-dose approach of benzodiazepine administration for treatment of alcohol withdrawal syndrome in regard to the health care utilization measured by the total dose of benzodiazepines, length of hospital stays, and 90-day readmissions rate. A single-center prospective non-randomized controlled trial included all patients diagnosed with alcohol withdrawal syndrome. The group of patients admitted between October 1, 2019, and September 30, 2020, were treated with the fixed-scheduled approach (n = 150), while all patients admitted between November 1, 2020, to October 31, 2021, were treated with the symptoms-trigger approach (n = 50). The fixed-dose approach group showed a significant higher 90-day readmissions rate (HR: 2.61; 95% CI = 1.18, 6.84; p = 0.01). Kaplan–Meier survival analysis showed a significantly shorter duration to the first readmission in the fixed-scheduled approach group (HR: 2.3; 95% CI = 5.6, 1.16; p = 0.02). The symptoms-triggered approach group required a significantly lower dose of diazepam (40 mg vs. 10 mg; p < 0.01) and a higher dose of thiamine (800 mg vs. 600 mg; p < 0.01). Length of hospital stay was significantly increased in the symptoms-triggered approach group (3.9 vs. 2.2 days; p < 0.01). The use of a symptoms-triggered approach to treat alcohol withdrawal syndrome was associated with a lower 90-day readmission rate, prolonged period to the first readmission, and reduced total dose of benzodiazepines, but longer length of hospital stays. The symptoms-triggered approach is safe, cost-effective, and associated with reduced alcohol dependence relapse. •The use of the symptoms-triggered approach for treatment of alcohol withdrawal syndrome was associated with reduction of 90-day readmissions, increased duration to the first readmission, and reduced the total dose of benzodiazepines.•Compared to fixed doses of benzodiazepam, the symptoms-triggered approach for treatment of alcohol withdrawal syndrome may increase length of hospital stay.•The use of the symptoms-triggered approach for treatment of alcohol withdrawal syndrome is safe and was not associated with increased in-hospital adverse events.

Discontinuing long‐term pharmacotherapy for insomnia can result in rebound insomnia or withdrawal symptoms and suboptimal treatment. Post hoc analyses evaluated rebound insomnia and withdrawal symptoms among the subset of subjects from a phase III, 12‐month, global, multicenter, randomized, double‐blind, parallel‐group study who completed 12 or 6 months of active treatment and follow‐up period. Study E2006‐G000‐303 (Study 303) included adults (N = 655) with subjective sleep‐onset latency ≥30 min and/or subjective wake‐after‐sleep onset ≥60 min at least three times weekly during the 4 weeks before enrollment. Subjects were randomized 1:1:1 to lemborexant 5 mg (LEM5) or 10 mg (LEM10) or placebo for 6 months. Thereafter, for an additional 6 months, LEM5‐ and LEM10‐treated subjects continued lemborexant and the placebo group was rerandomized 1:1 to LEM5 or LEM10. Month 12 was followed by abrupt discontinuation and a 2‐week end‐of‐study follow‐up. Using daily electronic sleep diaries, patients reported (subjective) sleep end points (sleep‐onset latency, wake‐after‐sleep onset, sleep efficiency, and total sleep time). Withdrawal symptoms were assessed using the Tyrer Benzodiazepine Withdrawal Symptoms Questionnaire (T‐BWSQ). Sleep outcome improvements with lemborexant at month 12 were generally maintained throughout the 2‐week off‐treatment period wherein <20% of subjects experienced significant worsening of insomnia symptoms versus screening. There was no evidence of withdrawal symptoms by T‐BWSQ following lemborexant discontinuation. This analysis demonstrates rebound insomnia is unlikely to occur with lemborexant, and its effectiveness is maintained after abrupt discontinuation without placebo replacement following 6–12 months of treatment.

RationaleGiven that tetrahydrocannabinol (THC) and nicotine have similar effects on negative affect (NA), we hypothesized that a 7-mg nicotine patch (NP) would reduce NA-related cannabis (CAN) withdrawal symptoms in cannabis-dependent (CD) individuals who were not nicotine dependent.ObjectiveWe sought to determine whether NP reduces NA across 15 days of CAN abstinence in two groups: non-tobacco smokers (NTS) and light tobacco smokers (LTS).MethodsCD participants (N = 127; aged 18–35) who used CAN at least 5 times/week for the past 12 + months were randomized to (1) NP or (2) a placebo patch (PP) and received $300 for sustained biochemically verified CAN abstinence. Of those randomly assigned, 52 of 63 NP, and 56 of 64 PP maintained biochemically verified CAN abstinence and 51 NP and 50 PP participants complied with all aspects of the study. Affect and other withdrawal symptoms were measured every 48 h across 15 days of CAN abstinence.ResultsAfter controlling for age, tobacco use, baseline THC concentration, and baseline measurements of the dependent variable, NP reduced NA symptoms across the 15-day treatment relative to PP. Differences in NA and CAN withdrawal symptoms were not moderated by tobacco user status.ConclusionsThe findings provide the first evidence that NP may be able to attenuate NA-related withdrawal symptoms in individuals with cannabis use disorder who are not heavy users of tobacco or nicotine.Clinical trials registryNCT01400243 http://www.clinicaltrials.gov

Background The purpose of this study was to compare the effect of 300 mg of bupropion and 8 mg of buprenorphine per day on the treatment of methamphetamine withdrawal cravings over a 2-week treatment interval. Method Sixty-five methamphetamine-dependent men who met the DSM-IV-TR ( Diagnostic and Statistical Manual of Mental Disorders , 4th edition, text revision) criteria for methamphetamine dependence and withdrawal were randomly divided into two groups. Subjects randomly received 300 mg of bupropion or 8 mg of buprenorphine per day in a psychiatric ward. Of the 65 subjects, 35 (53.8%) received buprenorphine and 30 (46.2%) received bupropion. The subjects were assessed by using methamphetamine craving score, interview, and negative urine drug test. Findings There were no statistically significant differences between the two groups in regard to age, education, duration of methamphetamine dependency, marital status, employment, and income. The mean ages were 32.8 years (standard deviation (SD) = 7.26, range = 22 to 59) for the buprenorphine group and 32.21 years (SD = 8.45, range = 17 to 51) for the bupropion group. All 65 patients completed the 2-week study. Both medications were effective in the reduction of methamphetamine cravings. Reduction of craving in the buprenorphine group was significantly more than the bupropion group ( P = 0.011). Overall, a significant main effect of day ( P <0.001) and group ( P = 0.011) and a non-significant group-by-day interaction ( P >0.05) were detected. Conclusions The results support the safety and effectiveness of buprenorphine and bupropion in the treatment of methamphetamine withdrawal craving. Administration of 8 mg of buprenorphine per day can be recommended for the treatment of methamphetamine withdrawal cravings. We should note that it is to be expected that craving decreases over time without any medication. So the conclusion may not be that bupropion and buprenorphine both lower the craving. As the buprenorphine is superior to bupropion, only buprenorphine does so for sure. Trial registration Iranian Registry of Clinical Trials (IRCT) registration number: IRCT2015010320540N1 . Date registered: April 10, 2015.

Research shows that abstinence from tobacco leads to a withdrawal-related decrement in responsivity to nondrug rewards (ie, anhedonia). However, it remains unclear how anhedonia relates to other key withdrawal symptoms and withdrawal-related constructs over time. We analyzed ecological momentary assessment data to examine whether a decrement in response to rewards during a 10-day period following quitting shows a pattern of associations with other variables (ie, treatment, tobacco dependence, negative affect, and craving) that is consistent with anhedonia being a tobacco withdrawal symptom. As part of a randomized controlled trial of smoking cessation therapies, 1122 adults (58% female) were assigned to: placebo (n = 131), bupropion (alone or with nicotine lozenge; n = 401), or nicotine replacement therapy (NRT; lozenge, patch, both; n = 590). Participants completed 4 ecological momentary assessments per day for 10 days postquit, resulting in 22 575 assessments. Time-varying effect modeling showed that anhedonia was significantly greater among those high in dependence relative to lower dependent smokers out to day 9 postquit. The placebo group showed elevated anhedonia immediately postquit, which fell to levels similar to the treatment groups by day 7. NRT effectively reduced anhedonia and its time-varying association with craving early in the quit attempt. The positive association between negative affect and anhedonia was moderate and stable over time for both active treatment groups. These results provide additional support that anhedonia following quitting smoking is a manifestation of the tobacco withdrawal syndrome. This study supported the hypothesis that diminished responsivity to nondrug rewards (ie, anhedonia) is a symptom of the tobacco withdrawal syndrome. Results showed that anhedonia: (1) was significantly associated with dependence, especially during the early postquit period when withdrawal was at its peak intensity; (2) showed significant time-varying associations with other withdrawal symptoms, especially craving; and (3) was significantly suppressed by agonist administration as was its association with craving over time.