On May 16, 2018, the FDA announced its approval of Lucemyra (lofexidine) as a drug to help patients withdraw from opioids. Like clonidine, lofexidine is an alpha-2 agonist, but it is touted as causing less orthostatic hypotension and therefore being somewhat safer to use.

To put this in perspective, it’s important to note that buprenorphine is the preferred agent for opioid detox because of its superior treatment retention and ability to be continued as maintenance therapy. But buprenorphine is not available in many settings, such as jails or any setting that doesn’t have buprenorphine-waivered physicians. Thus, clonidine remains the backbone of many opioid detox protocols. So why do we need another detox medication? The main reason seems to be lofexidine’s claimed decrease in orthostatic hypotension compared with clonidine.

FDA approval was based on 2 randomized, double-blind, placebo-controlled, non-inferiority trials of 866 adults who met DSM-IV criteria for opioid dependence. Participants were physically dependent on opioids and were undergoing abrupt opioid discontinuation. The primary outcome was withdrawal symptom severity on both a clinician-rated scale (the MHOWS) and a self-rated scale (the SOWS-G). In the first study, done in 2008 and lasting 11 days, lofexidine decreased day 5 MHOWS scores (19.5) compared to placebo (30.9), p = .0019 (Drug Alcohol Depend 2008;97(1–2):158–168). But scores on the self-reported SOWS-G scale did not separate from placebo.

In a second study of 264 patients, completed in 2017 over 8 days, lofexidine decreased SOWS-G scores (6.32) compared to placebo (8.67), p = .0212 (Gorodetzky CW et al, Drug Alcohol Depend 2017;176:79–88). Retention was better for lofexidine than placebo in both studies, but did not exceed 38.2% in either study. This means over 60% of participants quit before reaching the 11- or 8-day mark, respectively.

If you prescribe lofexidine, start with 3 0.18 mg tabs every 5–6 hours during peak withdrawal, then increase to 4 tabs/dose up to a maximum of 16 tabs daily. Lower dosing is recommended for patients over 65. Lofexidine’s most common adverse effects are very similar to clonidine—not surprising, since the two are close chemical relatives—and include bradycardia, hypotension, dizziness, and dry mouth. In addition, rebound hypertension can occur when the drug is withdrawn abruptly. The FDA has mandated 15 postmarketing studies, so we’re likely to learn more about the side effects of lofexidine over the next few years.

CATR’S TAKE
Will lofexidine change how US doctors treat opioid withdrawal? It’s hard to say. Lofexidine is not a new drug; it was developed more than 40 years ago and has been used for opioid withdrawal in the United Kingdom since 1992 (Vartak AP, Expert Opin Drug Discov 2014;9(11):1371–1377). It’s become especially popular in the UK for ultra-rapid detox, sometimes in combination with naltrexone.

However, clonidine is inexpensive, readily available, and effective for many patients. Moreover, buprenorphine works even better for relieving opioid withdrawal and retaining patients—and best of all, it can be continued as maintenance therapy. Whatever agent you chose, it’s important to remember that detox alone increases the risk of fatal overdose. Thus, treating opioid withdrawal should be followed by pharmacotherapy with buprenorphine, methadone, or extended release naltrexone.