Dataset Information

Efficacy of lofexidine for mitigating opioid withdrawal symptoms: results from two randomized, placebo-controlled trials.

ABSTRACT: Objectives: Fear of opioid withdrawal syndrome (OWS) often dissuades opioid discontinuation. Lofexidine is an FDA-approved, alpha₂-adrenergic receptor agonist for treatment of OWS. Pivotal trial results from the per-protocol statistical analyses have been published. However, the FDA prescribing information presents these efficacy results using a different, standardized statistical approach that does not transform data or impute missing values. This analysis is easier to interpret and allows comparison across studies. This reanalysis is presented here. Methods: Studies were double-blind, placebo-controlled for 7 days in Study 1 and 5 days in Study 2. Opioid-dependent adults received placebo or lofexidine; efficacy was assessed using the Short Opioid Withdrawal Scale of Gossop (SOWS-G) daily. Results: Study 1 (N = 602) mean SOWS-G scores were 6.1 (SE: 0.35), 6.5 (SE: 0.34), and 8.8 (SE: 0.47) over Days 1-7 for lofexidine 2.88 mg/day, 2.16 mg/day, and placebo, respectively (for 2.88, p < .0001; for 2.16 mg, p < .0001). Study 2 (N = 264) mean SOWS-G scores were 7.0 (SE: 0.44) and 8.9 (SE: 0.48) over Days 1-5 for lofexidine 2.16 mg/day and placebo, respectively (p = .0037). Median time to treatment discontinuation was approximately 2 days later with lofexidine treatment than with placebo and significantly more lofexidine-treated subjects completed the studies. Hypotension and bradycardia were more common with lofexidine. More placebo subjects withdrew prematurely for lack of efficacy. Conclusion: This simplified analysis confirmed previous per-protocol results, that lofexidine better reduces OWS severity and increases retention compared with placebo in opioid-dependent adults. These results are robust and comparable across studies using various methods of analysis. ClinicalTrials.gov identifier: Study 1, NCT01863186; Study 2 NCT00235729. URL: https://clinicaltrials.gov/.

SUBMITTER: Alam D

PROVIDER: S-EPMC6968526 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:ObjectivesTo investigate the safety and efficacy of lofexidine for treating opioid withdrawal syndrome (OWS) and facilitating completion of opioid withdrawal.MethodsA multicenter, double-blind, placebo-controlled study was conducted at 18 US centers from June 2013 to December 2014. Participants (n = 603) aged ≥18 years, dependent on short-acting opioids, and seeking withdrawal treatment, randomized 3:3:2 to receive lofexidine 2.88 mg/d (n = 222), lofexidine 2.16 mg/d (n = 230), or placebo (n = 151) for 7 days. Primary outcome was the Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) scores rating withdrawal symptoms over days 1 to 7.ResultsParticipants were of mean age, 35 years; 71% male. Pairwise differences in overall SOWS-Gossop log-transformed least squares means were statistically significant for lofexidine 2.16 mg (difference, -0.21; 95% CI, -0.37 to -0.04; P = 0.02) and 2.88 mg (-0.26; 95% CI, -0.44 to -0.09; P = 0.003) compared with placebo. Fewer than half of participants in both groups completed the study. Completion rates for lofexidine 2.16 mg (41.5%; odds ratio [OR], 1.85; P = 0.007) and 2.88 mg (39.6%; OR, 1.71; P = 0.02) were significantly better compared with placebo (27.8%). Overall adverse event (AE) rates were similar across groups. Common AEs for lofexidine included orthostatic hypotension, hypotension, and bradycardia, but resulted in few study discontinuations.ConclusionsLofexidine 2.16 mg and 2.88 mg significantly reduced symptoms of OWS versus placebo, and increased absolute rates of completing the 7-day study by 14% and 12%, respectively (a relative increase of 85% and 71%). Data suggest that lofexidine is a generally safe and effective nonopioid treatment for opioid withdrawal. Lofexidine could serve as a withdrawal treatment option when a nonopioid agent is preferred or required, when agonist-assisted withdrawal is unavailable, when agonist discontinuation caused OWS, and during induction into maintenance treatment with opioid agonists or antagonists.Trial registrationClinicalTrials.gov identifier: NCT01863186.

Project description:BackgroundAs pharmacological treatments are the primary option for opioid use disorder, neuromodulation has recently demonstrated efficacy in managing opioid withdrawal syndrome (OWS). This study investigated the safety and effectiveness of transcutaneous auricular neurostimulation (tAN) for managing OWS.MethodsThis prospective inpatient trial included a 30-minute randomized, sham-controlled, double-blind period followed by a 5-day open-label period. Adults with physical dependence on opioids were randomized to receive active or sham tAN following abrupt opioid discontinuation. The Clinical Opiate Withdrawal Scale (COWS) was used to determine withdrawal level, and participants were required to have a baseline COWS score ≥ 13 before enrollment. The double-blind period of the study occurred during the first 30-minutes to assess the acute effects of tAN therapy compared to a sham control. Group 1 received active tAN during both the 30-minute double-blind period and the 5-day open-label period. Group 2 received passive sham tAN (no stimulation) during the double-blind period, followed by active tAN during the 5-day open-label period. The primary outcome was change in COWS from baseline to 60-minutes of active tAN (pooled across groups, accounting for 30-minute delay). Secondary outcomes included difference in change in COWS scores between groups after 30-minutes of active or sham tAN, change in COWS scores after 120-minutes of active tAN, and change in COWS scores on Days 2-5. Non-opioid comfort medications were administered during the trial.ResultsAcross all thirty-one participants, the mean (SD) COWS scores relative to baseline were reduced by 7.0 (4.7) points after 60-minutes of active tAN across both groups (p < 0.0001; Cohen's d = 2.0), demonstrating a significant and clinically meaningful reduction of 45.9%. After 30-minutes of active tAN (Group 1) or sham tAN (Group 2), the active tAN group demonstrated a significantly greater COWS score reduction than the sham tAN group (41.7% vs. 24.1%; p = 0.036). Participants across both groups achieved an average COWS reduction up to 74.7% on Days 2-5.ConclusionResults demonstrate tAN is a safe and effective non-opioid approach for reducing symptoms of OWS. This study supported an FDA clearance.Clinical trial registrationclinicaltrials.gov/ct2/show/NCT04075214 , Identifier: NCT04075214, Release Date: August 28, 2019.

Project description:ObjectiveAlcohol use disorder (AUD) is a leading cause of global disease burden. Chronic, heavy use increases the likelihood of alcohol withdrawal symptoms and associated secondary outcomes of alcohol craving and mood, anxiety, and sleep disturbances, which are predictive of poor treatment outcomes. The authors examined whether alcohol withdrawal symptoms moderate the efficacy of prazosin in reducing alcohol intake and associated secondary outcomes.MethodsA 12-week, double-blind, randomized, controlled proof-of-concept trial of prazosin (16 mg/day, with a 2-week titration) was conducted in community-recruited adults with current alcohol dependence (N=100) with varying levels of alcohol withdrawal symptoms assessed at treatment entry. Primary outcomes were daily self-reported drinking days and heavy drinking days, and secondary outcomes were average drinks/day and mood, anxiety, craving, and sleep quality ratings.ResultsModified intent-to-treat analyses indicated a significant interaction of alcohol withdrawal symptom score by treatment by full-dose treatment period (weeks 3-12) for drinking days, heavy drinking days, and average drinks/day. By week 12, participants with high alcohol withdrawal symptoms on prazosin reported 7.07% heavy drinking days and 27.46% drinking days, while those on placebo had 35.58% heavy drinking days and 58.47% drinking days (heavy drinking days: odds ratio=0.14, 95% CI=0.058, 0.333; drinking days: odds ratio=0.265, 95% CI=0.146, 0.481). No such benefit of prazosin was observed in those reporting low or no alcohol withdrawal symptoms. Individuals with high alcohol withdrawal symptoms on prazosin compared with placebo also showed significantly improved anxiety, depression, and alcohol craving over the course of the trial.ConclusionsThe findings indicate that alcohol withdrawal symptoms are a significant moderator of prazosin treatment response for alcohol use outcomes and for associated symptoms of alcohol craving, anxiety, and mood symptoms. These data support further evaluation of alcohol withdrawal symptoms as a prognostic indicator of prazosin's efficacy in the treatment of AUD.

Project description:Δ(9)-Tetrahydrocannbinol (THC), the primary active constituent of Cannabis sativa, has long been known to reduce opioid withdrawal symptoms. Although THC produces most of its pharmacological actions through the activation of CB(1) and CB(2) cannabinoid receptors, the role these receptors play in reducing the variety of opioid withdrawal symptoms remains unknown. The endogenous cannabinoids, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), activate both cannabinoid receptors but are rapidly metabolized by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The objective of this study was to test whether increasing AEA or 2-AG, via inhibition of their respective hydrolytic enzymes, reduces naloxone-precipitated morphine withdrawal symptoms in in vivo and in vitro models of opioid dependence. Morphine-dependent mice challenged with naloxone reliably displayed a profound withdrawal syndrome, consisting of jumping, paw tremors, diarrhea, and weight loss. THC and the MAGL inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) dose dependently reduced the intensity of most measures through the activation of CB(1) receptors. JZL184 also attenuated spontaneous withdrawal signs in morphine-dependent mice. The FAAH inhibitor N-(pyridin-3-yl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)benzyl)-piperdine-1-carboxamide (PF-3845) reduced the intensity of naloxone-precipitated jumps and paw flutters through the activation of CB(1) receptors but did not ameliorate incidence of diarrhea or weight loss. In the final series of experiments, we investigated whether JZL184 or PF-3845 would attenuate naloxone-precipitated contractions in morphine-dependent ilea. Both enzyme inhibitors attenuated the intensity of naloxone-induced contractions, although this model does not account mechanistically for the autonomic withdrawal responses (i.e., diarrhea) observed in vivo. These results indicate that endocannabinoid catabolic enzymes are promising targets to treat opioid dependence.

Dataset Information

Efficacy of lofexidine for mitigating opioid withdrawal symptoms: results from two randomized, placebo-controlled trials.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets