Consistent Efficacy of Lofexidine Across Primary and Secondary Efficacy Outcomes in a Large, Placebo-Controlled Trial

Introduction: Abrupt opioid withdrawal after chronic use results in central noradrenergic hyperactivity that is expressed clinically as opioid withdrawal syndrome (OWS). Patients with opioid use disorder (OUD) frequently continue opioids to avoid OWS. Lofexidine is an alpha2-adrenergic receptor agonist approved for mitigation of OWS symptoms.

Methods: This was a double-blind, placebo-controlled study evaluating lofexidine 2.16 and 2.88 mg/day. Adults with opioid dependence were abruptly withdrawn from short-acting opioids prior to entering a 7-day treatment period. Overall treatment effect and 95% confidence interval was calculated for the primary outcome (Short Opiate Withdrawal Scale of Gossop) and 5 secondary outcomes [Objective Opiate Withdrawal Scale-Handelsman, Modified Clinical Global Impressions Scale (for Subject and Rater), Visual Analog Scale for Efficacy, and Clinical Opiate Withdrawal Scale]. Outcomes were assessed daily at 3.5 hours after the 8am dose.

Results: A total of 602 subjects received study drug: lofexidine 2.16 mg, n=229; lofexidine 2.88 mg, n=222; and placebo, n=151. The majority of subjects was male (71%), white (74%), and used heroin as their primary opioid (83%). The treatment effect was significant (P < 0.05) across all 6 efficacy outcomes in both lofexidine treatment groups.

Discussion: Lofexidine 2.16 and 2.88 mg/day demonstrated consistent, statistically significant efficacy for OWS across a variety of subject- and clinician-reported outcomes during early opioid withdrawal. Treatment of OWS during this period may be critical for successful opioid cessation and subsequent transition to OUD treatment.