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Gabapentin for alcohol use disorder: A good option, or cause for concern?

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References

ALCOHOL’S ACTIONS

The actions of alcohol on the brain are also complex.18 Alpha-2-delta type 1 subunits of calcium channels are upregulated in the reward centers of the brain by addictive substances, including alcohol.16 Alcohol interacts with corticotropin-releasing factor and several neurotransmitters,18 and specifically affects neuropathways involving norepinephrine, GABA, and glutamate.19 Alcohol has reinforcing effects mediated by the release of dopamine in the nucleus accumbens.20

Acutely, alcohol promotes GABA release and may also reduce GABA degradation, producing sedative and anxiolytic effects.21 Chronic alcohol use leads to a decrease in the number of GABAA receptors. Clinically, this downregulation manifests as tolerance to alcohol’s sedating effects.21

Alcohol affects the signaling of glutamatergic interaction with the N-methyl-d-aspartate (NMDA) receptor.22 Glutamate activates this receptor as well as the voltage-gated ion channels, modifying calcium influx and increasing neuronal excitability.22,23 Acutely, alcohol has an antagonistic effect on the NMDA receptor, while chronic drinking upregulates (increases) the number of NMDA receptors and voltage-gated calcium channels.22,23

Alcohol withdrawal increases excitatory effects

Patients experiencing alcohol withdrawal have decreased GABA-ergic functioning and increased glutamatergic action throughout the central nervous system.19,24

Withdrawal can be subdivided into an acute phase (lasting up to about 5 days) and a protracted phase (of undetermined duration). During withdrawal, the brain activates its “stress system,” leading to overexpression of corticotropin-releasing factor in the amygdala. Protracted withdrawal dysregulates the prefrontal cortex, increasing cravings and worsening negative emotional states and sleep.16

GABAPENTIN FOR ALCOHOL WITHDRAWAL

Benzodiazepines are the standard treatment for alcohol withdrawal.3,24 They relieve symptoms and can prevent seizures and delirium tremens,24 but they are sedating and cause psychomotor impairments.3 Because of the potential for addiction, benzodiazepine use is limited to acute alcohol withdrawal.3

Gabapentin shows promise as an agent that can be used in withdrawal and continued through early abstinence without the highly addictive potential of benzodiazepines.16 It is thought to affect drinking behaviors during early abstinence by normalizing GABA and glutamate activity.2,16

Early preclinical studies in mouse models found that gabapentin decreases anxiogenic and epileptic effects of alcohol withdrawal. Compared with other antidrinking medications, gabapentin has the benefits of lacking elimination via hepatic metabolism, few pharmacokinetic interactions, and good reported tolerability in this population.

Inpatient trials show no benefit over standard treatments

Bonnet et al25 conducted a double-blind placebo-controlled trial in Germany in inpatients experiencing acute alcohol withdrawal to determine whether gabapentin might be an effective adjunct to clomethiazole, a GABAA modulator commonly used in Europe for alcohol withdrawal. Participants (N = 61) were randomized to receive placebo or gabapentin (400 mg every 6 hours) for 72 hours, with tapering over the next 3 days. All patients could receive rescue doses of clomethiazole, using a symptom-triggered protocol.

The study revealed no differences in the amount of clomethiazole administered between the 2 groups, suggesting that gabapentin had no adjunctive effect. Side effects (vertigo, nausea, dizziness, and ataxia) were mild and comparable between groups.

Nichols et al26 conducted a retrospective cohort study in a South Carolina academic psychiatric hospital to assess the adjunctive effect of gabapentin on the as-needed use of benzodiazepines for alcohol withdrawal. The active group (n = 40) received gabapentin as well as a symptom-triggered alcohol withdrawal protocol of benzodiazepine. The control group (n = 43) received only the symptom-triggered alcohol withdrawal protocol without gabapentin.

No effect was found of gabapentin use for benzodiazepine treatment of alcohol withdrawal. It is notable that Bonnet et al and Nichols et al had similar findings despite their studies being conducted in different countries using distinct comparators and methods.

Bonnet et al,27 in another study, tried a different design to investigate a possible role for gabapentin in inpatient alcohol withdrawal. The study included 37 patients with severe alcohol withdrawal (Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised [CIWA-Ar] > 15).

All participants received gabapentin 800 mg. Those whose CIWA-Ar score improved within 2 hours were considered “early responders” (n = 27) and next received 2 days of gabapentin 600 mg 4 times a day before starting a taper. The nonresponders whose CIWA-Ar score worsened (associated with greater anxiety and depressive symptoms; n = 10) were switched to standard treatment with clomethiazole (n = 4) or clonazepam (n = 6). Scores of 3 early responders subsequently worsened; 2 of these participants developed seizures and were switched to standard treatment.

The authors concluded that gabapentin in a dose of 3,200 mg in the first 24 hours is useful only for milder forms of alcohol withdrawal. Hence, subsequent efforts on the use of gabapentin for alcohol withdrawal have focused on outpatients.

Outpatient trials reveal benefits over benzodiazepines

Myrick et al3 compared gabapentin vs lorazepam in 100 outpatients seeking treatment for alcohol withdrawal. Participants were randomized to 1 of 4 groups: gabapentin 600 mg, 900 mg, or 1,200 mg, or lorazepam 6 mg, each tapering over 4 days. Alcohol withdrawal was measured by the CIWA-Ar score. Only 68 patients completed all follow-up appointments to day 12.

Gabapentin 600 mg was discontinued because of seizures in 2 patients, but it was generally well tolerated and was associated with diminished symptoms of alcohol withdrawal, especially at the 1,200 mg dose. The gabapentin groups experienced less anxiety and sedation and fewer cravings than the lorazepam group. Those treated with lorazepam fared worse for achieving early abstinence and were more likely to return to drinking when the intervention was discontinued. However, significant relapse by day 12 occurred in both groups.

The authors concluded that gabapentin was at least as effective as lorazepam in the outpatient treatment of alcohol withdrawal, with the 1,200-mg gabapentin dosage being more effective than 900 mg. At 1,200 mg, gabapentin was associated with better sleep, less anxiety, and better self-reported ability to work than lorazepam, and at the 900-mg dose it was associated with less depression than lorazepam.

Stock et al28 conducted a randomized, double-blind study of gabapentin in acute alcohol withdrawal in 26 military veterans in an outpatient setting. Patients were ran­domized to one of the following:

  • Gabapentin 1,200 mg orally for 3 days, followed by 900 mg, 600 mg, and 300 mg for 1 day each (n = 17)
  • Chlordiazepoxide 100 mg orally for 3 days, followed by 75 mg, 50 mg, and 25 mg for 1 day each (n = 9).

Withdrawal scores improved similarly in both groups. Early on (days 1–4), neither cravings nor sleep differed significantly between groups; but later (days 5–7), the gabapentin group had superior scores for these measures. Gabapentin was also associated with significantly less sedation than chlordiazepoxide and trended to less alcohol craving.

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