Is It Prime Time for Alpha2-Adrenocepter Agonists in the Treatment of Withdrawal Syndromes?

Abstract

The need to treat withdrawal syndromes is a common occurrence in outpatient, inpatient ward, and intensive care unit (ICU) settings. A PubMed and Google Scholar search using alpha2-adrenoreceptor agonist (A2AA), specific A2AA agents, withdrawal syndrome and nicotine, and alcohol and opioid withdrawal terms was performed. A2AA agents appear to be able to modulate many of the signs and symptoms of significant withdrawal syndromes but are also capable of significant side effects, which can limit clinical use. Non-opioid oral A2AA agent use for opioid withdrawal has been well established. Pharmacologic combination therapy that utilizes A2AA agents for withdrawal syndromes appears promising but requires further formal testing to better define which other agents, under what condition(s), and at what A2AA doses are needed. The A2AA dexmedetomidine may be useful as an adjunctive agent in treating severe alcohol withdrawal syndromes in the ICU. In general, the current data does not support the routine use of A2AA as the primary or sole agent to treat ethanol/alcohol or nicotine withdrawal syndromes. Specific A2AA agents such as lofexidine has been shown to have a primary role in non-opioid-based treatment of opioid withdrawal syndrome and dexmedetomidine in combination with benzodiazepines has been shown to have potential in the treatment of severe ICU-based alcohol withdrawal syndrome.

Palonosetron and hydroxyzine pre-treatment reduces the objective signs of experimentally-induced acute opioid withdrawal in humans: a double-blinded, randomized, placebo-controlled crossover study

“…Two other α2-adrenergic receptor agonists have shown promise in reducing opioid withdrawal–clonidine and lofexidine (32). Walsh et al evaluated the modulation effects on opioid withdrawal of clonidine and lofexidine, finding that both drugs reduced the objective sympathomimetic response to naloxone-precipitated withdrawal but with little effect on subjective measures of opioid withdrawal (33).…”

“…Walsh et al evaluated the modulation effects on opioid withdrawal of clonidine and lofexidine, finding that both drugs reduced the objective sympathomimetic response to naloxone-precipitated withdrawal but with little effect on subjective measures of opioid withdrawal (33). The prior findings are compounded in a 2014 review of several clinical trials by Albertson et al, where in addition, lofexidine was found to be more effective in reducing the symptoms of opioid withdrawal than placebo and reduced the number of days required for detoxification when compared to methadone (32). …”

Activation of serotonin 5-HT2C receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in heroin-treated mice

“…Based on our current results, it would seem that conducting clinical trials with lorcaserin in heroin addicts will be a promising venture. Clonidine is a prescription drug for opioid addicts [14]. Pre-clinical studies indicate that clonidine suppresses behavioral sensitization and withdrawal in heroin-treated subjects by acting on α2-adrenoceptor, a Gαi protein-coupled receptor that has an inhibitory effect on noradrenergic neurons in the central nervous system [16].…”

“…Pre-clinical studies indicate that clonidine suppresses behavioral sensitization and withdrawal in heroin-treated subjects by acting on α2-adrenoceptor, a Gαi protein-coupled receptor that has an inhibitory effect on noradrenergic neurons in the central nervous system [16]. However, clonidine induces a number of adverse effects, including bradycardia, hypotension, sedation and withdrawal syndrome [14], which limit its application.…”

“…Therefore, in the present study, we investigated the effect of 5-HT 2C R activation on behavioral sensitization and withdrawal symptoms in heroin-treated mice. Clonidine (trade name “Iporel” and others), a prescription drug for opioid addicts [14], was used as a positive control in this study.…”