Lofexidine versus clonidine for mitigation of opioid withdrawal symptoms: a systematic review

Abstract Objective The U.S. Food and Drug Administration recently approved lofexidine, an alpha-2-adrenergic agonist, as the first non-opioid medication for mitigation of opioid withdrawal symptoms. Clonidine, an alpha-2-adrenergic agonist, historically was used off-label for this indication. This review aimed to evaluate the effectiveness of lofexidine versus clonidine for mitigation of opioid withdrawal symptoms, and to discuss the current role of lofexidine in management of patients at risk of experiencing opioid withdrawal. Data sources MEDLINE/PubMed, EBSCO, and CENTRAL were searched using the terms: "lofexidine," "clonidine," and "opioid withdrawal." Study selection The literature search included English-language literature administering/prescribing lofexidine and clonidine for management of opioid withdrawal symptoms in adults. Data sources were searched to include articles published from October 1993 to May 2019. Data extraction Three independent reviewers analyzed studies via title and abstract to identify studies including comparisons of lofexidine to clonidine for mitigation of opioid withdrawal symptoms. Reviewers were initially blinded to the individual determinations. Results were then unblinded and discussed amongst reviewers. Results Of the 110 citations screened, five articles were included. One study demonstrated a statistically significant reduction in opioid withdrawal symptom severity with lofexidine compared to clonidine, whereas the other four studies showed no significant difference. Three studies reported on completion of opioid detoxification treatment, with no significant differences seen. In one study additionally comparing lofexidine to placebo, lofexidine caused significant hypotension, bradycardia, and pupillary constriction. Three studies showed significant adverse effects of hypotension and symptoms of feeling unwell with clonidine compared to lofexidine. Conclusions Lofexidine appears to be equivalent in efficacy to clonidine with fewer adverse effects and may have a limited role in management of opioid withdrawal symptoms. However, cost, venue of detoxification, and value of other preferred treatment modalities may also impact the comparative efficacy of lofexidine to other agents.