Role of α2-agonists in the Treatment of Acute Alcohol Withdrawal

Andrew J Muzyk PharmD; Jill A Fowler PharmD; Daryn K Norwood PharmD; Allison Chilipko PharmD


The Annals of Pharmacotherapy. 2011;45(5):649-657. 

In This Article


Manifestations of alcohol withdrawal include increased anxiety, agitation, tachycardia, elevated blood pressure, and insomnia.29,30 These symptoms may evolve into seizures due to prolonged neurotransmitter imbalance precipitated by increased neurotoxins. Drug therapy is targeted to correct the imbalance between γ-aminobutyric acid (GABA) and glutamate receptors.[29] While the use of benzodiazepines has been well documented in the treatment of alcohol withdrawal, adjunctive use of drug therapy targeting other neurotransmitters remains to be established.[29–36]

Further understanding of alcohol withdrawal requires examination of the kindling process and neurochemical adaptation. Large consumption of alcohol over short periods can be problematic, as the process is often followed by abrupt periods of alcohol cessation. Each period of cessation is associated with an intense excitatory process in the central nervous system called kindling.[30–33] The kindling hypothesis states that withdrawal symptoms gradually become more severe with repeated occurrences of alcohol withdrawal due to altered transmission of various neurotransmitters, including GABA, glutamate, and norepinephrine. Ultimately, these gradual and continual physiological changes alter the transmission of these neurotransmitters, increasing the risk for seizures and DTs.[30,37] Targeting these neurotransmitters may ameliorate symptoms associated with alcohol withdrawal and has the potential to minimize some of the resulting neurotoxic effects observed in alcohol withdrawal.[30]

While GABA is the primary target of benzodiazepines, the noradrenergic system is another pathway shown to play an important role in the alcohol withdrawal syndrome.[29,36] Animal models revealed a decrease in brain epinephrine concentrations during alcohol consumption, which is suspected to be associated with the reward process. Furthermore, these animal studies have illustrated an endocrine pathway by discovering a depletion of epinephrine in the hypothalamus during alcohol consumption. However, when alcohol was removed, epinephrine concentrations were shown to increase beyond pre-alcohol exposure levels.[35,37] This neurochemical imbalance of elevated noradrenergic activity in alcohol withdrawal was later validated in humans.[38]

Similar to the animal models, specific areas of the brain were assessed for noradrenergic activity in humans. The locus coeruleus portion of the brain contains the cells for brain noradrenergic activity. The sedative effects of alcohol are potentially explained by a decrease in noradrenergic activity noted in the locus coeruleus during alcohol consumption. Alcohol consumption also has an effect on norepinephrine turnover in the brain; low levels of consumption result in increased turnover, while higher levels result in decreased turnover.[31,33]

One of the primary receptors for noradrenergic transmission is the α2-receptor. Under normal circumstances the α2-receptor inhibits the firing of the presynaptic norepinephrine neuron. However, evidence suggests that during alcohol withdrawal, signaling at the α2-receptor may be less sensitive, resulting in an inability of the noradrenergic system to regulate its firing.[31,33] Therefore, a potent α2-agonist, such as clonidine, is capable of reversing abnormal neuronal firing and elevated norepinephrine levels.[31,33] Thus, α2-agonists may provide benefit in managing alcohol withdrawal, as these agents offer an additional mechanism for minimizing the kindling process.


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