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/
Highlights
Opioid withdrawal syndrome (OWS) is a significant, incapacitating complication of abrupt opioid discontinuation in opioid-dependent individuals
Study 1 had a lower proportion of Hispanic participants and a higher proportion of subjects using heroin as their primary opioid compared with Study 2 but in general the study populations were similar
As we deal with the impact of the opioid crisis in this country, lofexidine provides an important addition to pharmacotherapy options and is the only non-narcotic approved for the initial opioid discontinuation period, more commonly considered “detox.”
Summary
Opioid withdrawal syndrome (OWS) is a significant, incapacitating complication of abrupt opioid discontinuation in opioid-dependent individuals. Distress caused by OWS is especially severe during the first several days after withdrawal of short-acting opioids[3,4] and fear of OWS is a substantial barrier to opioid discontinuation[5,6]. A major physiologic driver of OWS is central noradrenergic hyperactivity that results when opioids are abruptly discontinued in opioid-tolerant individuals[7]. Lofexidine is a non-opioid medication that acts as an agonist at central alpha2-adrenergic presynaptic receptors and thereby suppresses noradrenergic hyperactivity[8]. Lofexidine has been approved in the UK for OWS since the 1990s and was approved by the FDA in May of 2018 for mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults
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