Several alpha-2-adrenergic agonist medications have been investigated and found to facilitate positive opioid withdrawal outcomes. One process underlying opioid withdrawal is noradrenergic hyperactivity 79
. Alpha-2-adrenergic agonists moderate the symptoms of noradrenergic hyperactivity by acting centrally. Clonidine was the first alpha-2 agonist discovered to ameliorate some signs and symptoms of withdrawal. Because it is not a drug of abuse or dependence, clonidine has gained widespread use as a non-opioid alternative for managing withdrawal 80
. Unfortunately, clonidine is associated with significant hypotension which has limited its use. This finding led to a search for alternative alpha-2 agonist medications without significant side effects. Lofexidine, guanfacine, and guanabenz acetate have been investigated to varying extents 81
. Of these, lofexidine has been the most frequently studied 82–87
, and results indicate it does not appear to have the hypotension side effect that plagues clonidine. It is likely to replace clonidine as the leading opioid withdrawal treatment in this drug class.
Initial studies of clonidine reported reduction or elimination of lacrimation, rhinorrhea, muscle pain, joint pain, restlessness, and gastrointestinal symptoms 88, 89
, suggesting significant potential for managing opiate withdrawal. Clonidine is typically administered orally, in three or four doses per day up to a maximum of one milligram per day. Dizziness, sedation, and lethargy attributed to orthostatic hypotension and dry mouth were the primary adverse side effects.
Lofexidine can be prescribed up to about two milligrams per day and appears to be associated with fewer adverse effects. Completion rates of managed withdrawal assisted with clonidine and other alpha-2-adrenergic agents vs. methadone have been comparable 90–92
, with at least one study finding poorer outcomes for clonidine 93
. Withdrawal symptoms, while reasonably similar in intensity demonstrate a difference in time course. Symptoms occur much earlier in the withdrawal period for clonidine and lofexidine than for methadone, which perhaps has implications for length of time in treatment. In a few studies specifically reporting duration of treatment, subjects receiving reducing doses of methadone remained in treatment longer than those receiving alpha-2 agonists 92, 94
In the United Kingdom, lofexidine has had a product license for treatment of opiate detoxification since 1992, and the extent of use has increased steadily since that time. Lofexidine treatment is typically initiated at .2 mg twice daily, increasing daily by .2–.4 mg with a recommended final dose of 2.4 mg/day. Doses required to effectively manage withdrawal symptoms, however, vary for each patient depending on the amount, frequency, and duration of opioid used. Yu et al. 87
, in a phase 3 randomized, placebo-controlled trial, confirmed that lofexidine significantly decreases the signs and symptoms of opioid withdrawal. Retention was also higher in the lofexidine condition. Three studies comparing the efficacy and tolerability of lofexidine to clonidine suggested comparable efficacy in reducing withdrawal symptoms, with an advantage for lofexidine due to smaller hypotensive effect. Interestingly, Bearn et al. 90
reported that an accelerated 5-day lofexidine regimen resulted in faster attenuation of withdrawal symptoms relative to a more conventional 10-day lofexidine schedule.
As stated earlier, buprenorphine appears to be somewhat more effective in facilitating opioid withdrawal than clonidine 63, 95
. Of the two open-label trials comparing lofexidine and buprenorphine, one found the two treatments to be equivalent in effectiveness 84
, while the other found buprenorphine to result in less severe withdrawal symptoms in a large portion of subjects 86
. Thus, the alpha-2-adrenergic agonists are of significance given the paucity of medications approved for opioid detoxification and relapse prevention purposes, particularly non-opioid medications; arguably, however, alpha-2 agonists may not be the best “first-line” treatment for opioid detoxification. Further research is needed to determine optimal dose, duration and perhaps combinations of medications to improve upon the typically poor detoxification outcomes.