Results of this study indicate that the anticonvulsaant gabapentin, as measured by CIWA-Ar scores, was as at least as effective as the benzodiazepine lorazepam in the outpatient treatment of alcohol withdrawal at the doses used in this study. The high dose gabapentin (1200 mg) was found to be of marginal clinical but of statistical superiority to both lorazepam and low dose gabapentin (900 mg) in decreasing alcohol withdrawal symptoms.
Participants treated with either high dose (1200 mg) or low dose (900 mg) of the anticonvulsant gabapentin had lower odds of drinking alcohol both during treatment and in the week post treatment. Those treated with high dose gabapentin had less anxiety and rated their ability to perform work higher than lorazepam-treated subjects. During the medication treatment phase of the study, participants treated with high dose gabapentin had less craving for alcohol, less anxiety, and less daytime sedation as compared to participants treated with lorazepam. During the same treatment phase, participants treated with low dose gabapentin had less craving for alcohol and less anxiety, but also less depressive symptoms.
Although it is unclear how gabapentin exerts its pharmacological effects, it has been shown to bind with high affinity to auxiliary alpha(2)delta subunits (specifically the alpha(2)delta-1 and alpha(2)delta-2 subtypes) of voltage-gated calcium channels (Davies et al., 2007
; Gee et al., 1996
), which results in a plethora of down-stream neurochemical alterations. Nevertheless, from a mechanistic point of view, there is rationale to support the use of gabapentin during acute alcohol withdrawal. Gabapentin has been found to potentiate CNS GABA in humans (Petroff et al., 1996
), inhibit glutamate synthesis, modulate calcium current, inhibit sodium channels, and reduce norepinephrine and dopamine release (Cho et al., 1998
; Taylor, 1998
). Gabapentin’s unique pharmacology of increasing GABAergic tone and reducing glutamatergic tone in the brain should reverse the low GABA/high glutamate state found after cessation of drinking (Littleton, 1998
). This implies that gabapentin should be a useful therapeutic agent in normalizing the hyperactive state of the brain that is characteristic of alcohol withdrawal. In addition, the potential neuroprotective actions of gabapentin may decrease the neurotoxic effects associated with alcohol withdrawal (Baydas et al., 2005
There are several possible reasons why gabapentin decreased drinking during alcohol withdrawal treatment as compared to placebo. It is established that 30-50% of alcoholics relapse during the first three months after stopping drinking (Mann et al., 2004
; Kyrstal et al., 2001
). This vulnerable period to relapse is associated with impaired sleep, mood instability, and anxiety. These symptoms are suggested to play a role in relapse to alcohol use (Littleton, 1998
). In the current study, gabapentin reduced craving, anxiety/depressive symptoms and individuals complained of less subjective discomfort as compared to the individuals treated with lorazepam. As such, gabapentin may have blocked these important triggers to continue alcohol consumption. Whether gabapentin has an effect on reinforcement mechanisms separate from reducing neurotransmitter abnormalities associated with alcohol withdrawal is not known. However, individuals treated with gabapentin did endorse less craving for alcohol during treatment than did lorazepam-treated individuals, but this craving may have been related to early abstinence or alcohol withdrawal effects leading to an urge for relief drinking. It has been postulated that agents that affect GABA/glutamate balance might also be useful in relapse prevention, especially during the early stages of abstinence where perturbations in these systems might underlie craving and relapse (Littleton, 1998
; Anton, 1999
). In fact, other studies have been suggested gabapentin to be useful in preventing relapse and reducing drinking (Bisaga et al., 2006 Furieri et al., 2007
; Brower et al., 2008
). Gabapentin has been found to decrease stimulated dopamine release in striatal and limbic areas thought to be associated with drug-induced relapse (Pugsley et al., 1998
). As such, gabapentin may have an effect on reinforcement mechanisms which is independent of its effects on acute or protracted withdrawal symptoms.
From a safety and tolerability standpoint, both drugs were similar. While several anticonvulsant agents have been found effective in the treatment of alcohol withdrawal, some of these agents have side effects or complications that may cause concern when used in alcoholics. These complications include liver toxicity, thrombocytopenia, pancreatitis and bone marrow toxicity. Gabapentin is free of such side effects and may be safer than carbamazepine or valproic acid, but no comparison trials have been made. In addition, due to a saturable transport mechanism in the gut, gabapentin has been found to be safe in overdose. Of the six reported overdose cases in the literature, two have documented elevated gabapentin concentrations and lack of serious clinical toxicity (Fernandez et al., 1996
; Garofalo et al., 1993
). Of importance to the use of gabapentin in alcoholism, one case report documented an ingestion of 91 grams of gabapentin with large amounts of beer and whiskey without serious side effects (Fernandez et al., 1996
). Recent work by our group suggested that gabapentin did not interact negatively with alcohol under controlled conditions (Myrick et al., 2007
Initially, the intent of the study was to compare three doses of gabapentin to lorazepam: 600mg, 900mg, and 1200mg. The gabapentin 600mg dose was discontinued after three significant adverse events occurred. As noted above, two individuals experienced seizure-like activity during treatment, and one individual had a syncopal episode requiring emergency room assessment, indicating that this dose was ineffectively low. None of these events were observed in the two higher dose groups in this study. Nevertheless, the fact that all three occurred in the lowest gabapentin group suggests that the population under treatment was indeed vulnerable to more severe alcohol withdrawal symptoms and that the medications used in the other groups likely inhibited the more severe alcohol withdrawal symptoms from being expressed.
There are several limitations in the current study. Participants that were selected had extensive drinking histories, but with only mild to moderate withdrawal severity. Many of our participants were in better general health than patients in alcohol withdrawal presenting to emergency departments or hospitals. Although we had a benzodiazepine index group, we did not have a placebo group for ethical reasons. Thus, it is not possible to make absolute comparisons between drugs and the natural course of untreated withdrawal. Gabapentin and many other anticonvulsants are not available for parenteral administration and are inappropriate in vomiting or uncooperative delirious patients. Our sample size was relatively small and conclusions about side effects of uncommon frequency cannot be made. One can argue that a different dosing schedule of lorazepam or a different benzodiazepine might have yielded different results. The resources to evaluate such questions are however substantial and can only be definitely determined in a large multi-dosing multi-center trial.
In conclusion, the current study adds to a growing literature on the use of gabapentin in alcoholism. Specifically, gabapentin was found to be superior to the benzodiazepine lorazepam in the treatment of outpatients in moderate alcohol withdrawal as measured by lower probability of drinking and by superior but clinically similar alcohol withdrawal symptom reduction. Rarely has drinking during detoxification been examined in alcohol withdrawal treatment trials, so our data provide important new information on this important issue. Studies enrolling individuals with more severe alcohol withdrawal symptoms and medical comorbidities are needed to provide further evidence of the utility of gabapentin in the treatment of more complicated withdrawal symptoms.