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Effect of lofexidine on cardiac repolarization during treatment of opioid withdrawal.

ABSTRACT: Background:Lofexidine is a non-opioid treatment for opioid withdrawal syndrome. Its sympatholytic actions counteract the nor-adrenergic hyperactivity that occurs during abrupt opioid withdrawal.

Methods:The effect of lofexidine 2.16 and 2.88?mg/day on QTcF (QT interval, heart-rate corrected, Fridericia formula) was studied as part of a large, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT01863186). ECGs were time-matched to blood sampling for lofexidine concentration and were collected at prespecified timepoints over a 7-day inpatient period. Analyses included mean change-from-baseline QTcF and exposure-response modeling to predict QTcF at relevant lofexidine concentrations.

Results:A total of 681 adult men and women received at least 1 dose of study drug; 566 qualified for inclusion in the concentration-QTcF analysis. Most subjects were withdrawing from heroin. During the first 24?h (Days 1-2) post-baseline, small increases in QTcF were observed in all groups: 4.7?ms for lofexidine 2.16?mg, 7.4?ms for lofexidine 2.88?mg and 1.4?ms for placebo. These increases were transient; by Day 4, when lofexidine levels had reached steady-state, QTcF increases were not present. By Day 7, QTcF was decreased from baseline in all groups. Exposure-response modeling predicted <10?ms increases in QTcF at lofexidine concentrations 3 times those obtained at maximal recommended dose.

Conclusions:Lofexidine was associated with small, transient QTcF increases. Decreases in QTcF that occurred with higher lofexidine concentrations argue for an indirect QTcF effect, potentially from changes in autonomic tone. Both opioid withdrawal and lofexidine's sympatholytic actions would be expected to alter sympathetic outflow over the 7-day withdrawal.

SUBMITTER: Darpo B

PROVIDER: S-EPMC7153804 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Effect of lofexidine on cardiac repolarization during treatment of opioid withdrawal.

Darpö Börje B Pirner Mark M Longstreth James J Ferber Georg G

Drug and alcohol dependence 20190927

<h4>Background</h4>Lofexidine is a non-opioid treatment for opioid withdrawal syndrome. Its sympatholytic actions counteract the nor-adrenergic hyperactivity that occurs during abrupt opioid withdrawal.<h4>Methods</h4>The effect of lofexidine 2.16 and 2.88 mg/day on QTcF (QT interval, heart-rate corrected, Fridericia formula) was studied as part of a large, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT01863186). ECGs were time-matched to blood sampling for lofexidine ...[more]

PMID: 31606589

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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.

Dataset Information

Effect of lofexidine on cardiac repolarization during treatment of opioid withdrawal.

Publications

Effect of lofexidine on cardiac repolarization during treatment of opioid withdrawal.

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