Compared to placebo, alpha2-adrenergic agonists (e.g., clonidine, lofexidine, guanfacine, tizanidine) have been found to be effective for reducing the severity of opioid withdrawal symptoms and increasing the probability of completing withdrawal management; however, the majority of patients will relapse to opioid use if only a withdrawal management strategy is used.299,302 Signs and symptoms of withdrawal appear to resolve earlier with alpha2-adrenergic agonists in comparison to tapered methadone doses. The chances of completing withdrawal management are similar between alpha2-adrenergic agonists and methadone, but alpha2-adrenergic agonists tend to require shorter treatment durations. 

However, compared to methadone tapers, alpha2-adrenergic agonists are somewhat less effective in mitigating withdrawal symptoms, and are more likely to present adverse effects such as hypotension.299 Compared to buprenorphine/naloxone, alpha2-adrenergic agonists are less effective at mitigating withdrawal symptoms, as they take a greater amount of time to reduce symptoms and reduce significantly fewer symptoms in that time. The likelihood of treatment success, treatment completion, and abstinence from unregulated opioids and other drugs during withdrawal management is also significantly lower for alpha2-adrenergic agonists tapers when compared to buprenorphine/naloxone tapers.303 

Prescribed in the United Kingdom and United States, lofexidine has been shown to have equivalent efficacy to clonidine for mitigation of opioid withdrawal symptoms and completion of opioid detoxification. Compared to clonidine, individuals prescribed lofexidine appear to have a lower incidence of alpha2-adrenergic agonist-related hypotension.304 Lofexidine could be considered as an alternative treatment for patients who do not respond to clonidine should it become available in Canada.