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Background Reducing opioid use is challenging due to limited evidence-based weaning methods and a lack of interventions to mitigate withdrawal symptoms. An emerging intervention using transcutaneous auricular neurostimulation (tAN) is being developed to reduce opioid withdrawal symptoms, but its mechanisms of action are not yet well understood. This is a clinical trial performed to investigate the mechanisms of tAN in managing pain and opioid withdrawal during opioid taper in adults with chronic pain. Methods This is a single-site, randomized, double-blind, and sham-controlled superiority framework trial during an inpatient opioid taper for participants on long-term opioid therapy for chronic pain. Participants are recruited for an inpatient stay at a large, academic medical center in the United States. Included participants are adults between 18 and 75 years of age who have the presence of pain more than half of the days in the past 6 months, are prescribed opioid medication, have a willingness to taper the opioid dose by at least 10%, and have a urine drug screen positive for the prescribed opioid but negative for illicit drugs and nonprescribed opioids. Participants are excluded with a condition affecting their safety of participation (e.g., epileptic seizures, current suicidal ideation, current abuse of illicit drugs or alcohol, pregnancy), a condition that precludes fMRI assessment (implanted medical device, claustrophobia), or a status affecting pain medication intake (e.g., surgery in the past month, opioid prescription dose > 200 morphine milligram equivalents per day, history of neurological diseases or traumatic brain injury, active treatment for cancer). Participants are randomized to receive either active tAN ( n  = 20) or sham tAN ( n  = 20). Both groups undergo a mild-to-moderate opioid taper on day 1 and are maintained at the reduced level for 4 days under inpatient medical supervision. The primary outcome measure, brain functional magnetic resonance imaging (fMRI), is used to measure BOLD signals and resting functional connectivity ( z -value) of pain networks. Secondary outcome measures are self- and clinician-observed opioid withdrawal scales, behavioral assessment questionnaires, and quantitative sensory testing (QST) data. The first subject enrollment was completed from July 25 to 28, 2023. The total enrollment count was set to 40 with two arms of equal ratios. Randomization stratification by gender at birth was performed. The study physician, intervention-providing staff member, and outcome-assessing study coordinator each perform recruitment, and each is blinded to treatment group assignment. Safety and harm measures of opioid withdrawal will be assessed with the Clinical and Subject-reported Opiate Withdrawal Scores. Vital signs will be assessed three times per day, and adverse events will be recorded and reported as necessary. Discussion Understanding the mechanisms of action of tAN will lead to the development of more effective future non-pharmacologic treatments in mitigating withdrawal while gradually tapering participants off prescription opioid management. Trial registration Clinicaltrials.gov, NCT05555485. Registered on 15 September 2022.

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.

Background:Varenicline, a new treatment for smoking cessation, has demonstrated significantly greater efficacy over placebo and sustained release bupropion (bupropion SR). A study was undertaken to compare a 12-week standard regimen of varenicline with a 10-week standard regimen of transdermal nicotine replacement therapy (NRT) for smoking cessation.Methods:In this 52-week, open-label, randomised, multicentre, phase 3 trial conducted in Belgium, France, the Netherlands, UK and USA, participants were randomly assigned (1:1) to receive varenicline uptitrated to 1 mg twice daily for 12 weeks or transdermal NRT (21 mg/day reducing to 7 mg/day) for 10 weeks. Non-treatment follow-up continued to week 52. The primary outcome was the biochemically confirmed (exhaled carbon monoxide ⩽10 ppm) self-reported continuous abstinence rate (CAR) for the last 4 weeks of the treatment period in participants who had taken at least one dose of treatment. Secondary outcomes included CAR from the last 4 weeks of treatment through weeks 24 and 52, and measures of craving, withdrawal and smoking satisfaction.Results:A total of 376 and 370 participants assigned to varenicline and NRT, respectively, were eligible for analysis. The CAR for the last 4 weeks of treatment was significantly greater for varenicline (55.9%) than NRT (43.2%; OR 1.70, 95% CI 1.26 to 2.28, p<0.001). The week 52 CAR (NRT, weeks 8–52; varenicline, weeks 9–52) was 26.1% for varenicline and 20.3% for NRT (OR 1.40, 95% CI 0.99 to 1.99, p = 0.056). Varenicline significantly reduced craving (p<0.001), withdrawal symptoms (p<0.001) and smoking satisfaction (p<0.001) compared with NRT. The most frequent adverse event was nausea (varenicline, 37.2%; NRT, 9.7%).Conclusions:The outcomes of this trial established that abstinence from smoking was greater and craving, withdrawal symptoms and smoking satisfaction were less at the end of treatment with varenicline than with transdermal NRT.Trial registration number:NCT00143325.

Objective This study aimed to examine the associations of individual trajectories of three types of negative affect (NA: anxiety, depression, and anger) and craving during a 44-day period of incentivized smoking abstinence period with cessation outcome at 3 months and at 1 year. Methods Adult smokers ( N  = 140) completed questionnaire assessments of NA and craving during pre-quit baseline sessions and 15 postquit sessions over the 45 days of biochemically verified abstinence while on nicotine or placebo patch treatment. Growth curve and logistic regression analyses were used to examine the associations of trajectory parameters of the individual NA states and craving with the abstinence outcomes at 3 months and 1 year postquit. Results Greater declines in anxiety, depression, and anger symptoms over the first 44 days of smoking cessation were predictive of higher odds of abstinence at both 3 months and 1 year. Moreover, the greater declines in anxiety and anger remained as significant predictors of abstinence at both time points, independent of the predictive ability of the trajectory profiles of craving. Conclusions The findings suggest that slower dissipation of NA, especially anxiety and anger, represents a greater risk for relapse to smoking beyond that predicted by craving during early abstinence. Thus, temporal profiles of the affective symptoms convey unique motivational significance in relapse. Reduction in NA during early abstinence may be a valid target for interventions to increase long-term cessation success rates particularly among individuals with refractory affective symptoms.

The aim of this study was to assess cognitive effects of anticonvulsants in a way that would yield results that are most directly applicable to epilepsy populations. This was done with a placebo-controlled, prospective, randomized, double-blind, parallel group study of anticonvulsant withdrawal in a population of subjects taking a single anticonvulsant with completely controlled seizures. Outcomes of this study on cognitive measures from the California Computerized Assessment Package have recently been reported. To aid comparison with results of prior studies, we report outcomes here on several more standard measures of neuropsychological function. The major findings were that, in subjects with therapeutic drug levels at baseline, drug withdrawal was associated with significant improvement in performance on the Controlled Oral Word Association Test and the Stroop Color–Word Interference Test. Comparable results were achieved in the subgroup taking carbamazepine. (JINS, 2007, 13, 393–400.)

Inhaled longacting β 2 agonists improve lung function and health status in symptomatic chronic obstructive pulmonary disease (COPD), whereas inhaled corticosteroids reduce the frequency of acute episodes of symptom exacerbation and delay deterioration in health status. We postulated that a combination of these treatments would be better than each component used alone. 1465 patients with COPD were recruited from outpatient departments in 25 countries. They were treated in a randomised, double-blind, parallel-group, placebo-controlled study with either 50 μg salmeterol twice daily (n=372), 500 μg fluticasone twice daily (n=374), 50 μg salmeterol and 500 μg fluticasone twice daily (n=358), or placebo (n=361) for 12 months. The primary outcome was the pretreatment forced expiratory volume in 1 s (FEV 1) after 12 months treatment' and after patients had abstained from all bronchodilators for at least 6 h and from study medication for at least 12 h. Secondary outcomes were other lung function measurements, symptoms and rescue treatment use, the number of exacerbations, patient withdrawals, and disease-specific health status. We assessed adverse events, serum cortisol concentrations, skin bruising, and electrocardiograms. Analysis was as predefined in the study protocol. All active treatments improved lung function, symptoms, and health status and reduced use of rescue medication and frequency of exacerbations. Combination therapy improved pretreatment FEV 1 significantly more than did placebo (treatment difference 133 mL, 95% CI 105–161, p<0·0001), salmeterol (73 mL, 46–101, p<0·0001), or fluticasone alone (95 mL, 67–122, p<0·0001). Combination treatment produced a clinically significant improvement in health status and the greatest reduction in daily symptoms. All treatments were well tolerated with no difference in the frequency of adverse events, bruising, or clinically significant falls in serum cortisol concentration. Because inhaled long-acting β 2 agonists and corticosteroid combination treatment produces better control of symptoms and lung function, with no greater risk of side-effects than that with use of either component alone, this combination treatment should be considered for patients with COPD. Published online Jan 28, 2003 http://image.thelancet.com/extras/02art5284web.pdf

Background Benzodiazepines (BDZs) are the gold standard in the treatment of alcohol withdrawal syndrome (AWS). Sodium oxybate (SMO) has been tested as a treatment for AWS with encouraging results. The aim of this phase IV, multicenter, randomized, double-blind, double-dummy study was to evaluate the efficacy of SMO in comparison with oxazepam in the treatment of uncomplicated AWS. Methods Alcohol-dependent outpatients ( n = 126) affected by uncomplicated AWS according to the Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-Ar) scale were enrolled in the study and randomized in two groups: 61 patients received SMO and 65 patients received oxazepam for 10 days. The primary endpoint was the reduction of symptoms of AWS measured by the change in the total CIWA-Ar score from baseline (day 1) to the end of the study (day 10). This study is registered with ClinicalTrials.gov, number: NCT02090504 Results A significant decrease of the mean total CIWA-Ar score from baseline to the end of the study was found in both the SMO ( p  < 0.0001) and the oxazepam group ( p  < 0.0001), with no significant differences between the two treatments ( p = 0.21). Treatment with SMO and oxazepam resulted in a marked decrease in the severity of the mean CIWA subscales, i.e. sweating, tremor, and anxiety, with no significant differences between the two treatments. Both drugs were well tolerated and no severe side effects were reported. Conclusion SMO is as effective as oxazepam, one of the gold standard BDZs, in the treatment of uncomplicated AWS. Due to its tolerability and absence of significant side effects, SMO may be considered a valid alternative choice in the treatment of AWS.

This was a 6-month, randomized, flexible-dose study comparing the effects of methadone (Meth) and buprenorphine (Bup) on retention rate and substance use in a sample of 140 opioid-dependent, primarily heroin-addicted, patients who had been without opioid substitution therapy in the 4 weeks prior to the study. The major aims were to compare the efficacy of Bup and Meth in a flexible dosing regimen and to identify possible predictors of outcome. There were no major inhomogeneities between treatment groups. All patients also received standardized psychosocial interventions. Mean daily dosages after the induction phase were 44–50 mg for Meth and 9–12 mg for Bup. Results from this study indicate a favourable outcome, with an overall retention rate of 52.1% and no significant differences between treatment groups (55.3% vs. 48.4%). Substance use decreased significantly over time in both groups and was non-significantly lower in the Bup group. Predictors of outcome were length of continuous opioid use and age at onset of opioid use, although these were only significant in the Bup group. Mean dosage and other parameters were not significant predictors of outcome. Overall, the results of this study give further evidence that substitution treatment is a safe and effective treatment for drug dependence. Meth and Bup are equally effective. Duration of continuous opioid use and age at onset were found to have predictive value for negative outcome. The intensity of withdrawal symptoms showed the strongest correlation with drop-out. Future studies are warranted to further address patient profiles and outcome under different substitution regimens.