The acute effects of gabapentin in combination with alcohol in heavy drinkers

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Abstract

Background

Alcohol effects in humans involve gamma-amino butyric acid (GABA) neurotransmission. It has been proposed that GABAergic medications may be effective in the treatment of alcohol dependence. This study evaluated the acute effects of gabapentin, an anticonvulsant that increases extracellular GABA, on the subjective, physiological, and performance effects of alcohol in heavy (mean 34 drinks per week) alcohol drinkers.

Methods

Seventeen volunteers without alcohol dependence were tested using a double-blind design with three 3-day long inpatient phases, each separated by at least a 1-week wash-out period. Each phase, gabapentin (0, 1000, or 2000 mg) was administered 4 h before alcohol (0.75 g/kg), which was given in four divided doses every 20 min.

Results

Gabapentin impaired the ability to balance without producing changes in subjective, physiological or other performance measures. Pretreatment with gabapentin did not significantly alter subjective and performance effects of alcohol and did not alter alcohol craving. Gabapentin, dose-dependently enhanced alcohol-induced tachycardia.

Conclusions

Acute gabapentin administration was well tolerated in combination with alcohol, but did not alter the effects of alcohol.

Introduction

It is postulated that augmenting GABAergic neurotransmission may be effective in the treatment of alcohol use disorders (Johnson et al., 2005). Several pharmacological mechanisms have been proposed to account for the beneficial effects of these treatments. First, GABAergic medications and alcohol have a similar pharmacological profile. Alcohol increases GABA release (Carta et al., 2004, Roberto et al., 2003, Ziskind-Conhaim et al., 2003) and interacts with both GABA (A) and GABA (B) receptors (Besheer et al., 2004, Chester and Cunningham, 2002, Davies, 2003). Therefore, GABAergic agents may offer benefits as agonist-replacements, similar to agonist approaches to the treatment of nicotine and opioid-dependence. Second, GABAergic neurotransmission provides inhibitory control over the mesolimbic dopaminergic neurons, which are thought to be involved in the reinforcing effects of alcohol and other drugs of abuse (Gonzales et al., 2004, Koob, 2004). Third, GABAergic neurotransmission also provides inhibitory control on the release of excitatory amino acids, and inhibition of glutamatergic neurotransmission may have therapeutic potential in the treatment of drug- and alcohol-use disorders (Bisaga et al., 2000). Fourth, hypofunction of GABAergic neurotransmission is implicated in changes in reinforcing effects thought to accompany alcohol dependence and may contribute to relapse in newly abstinent alcoholics (Koob, 2003), and GABAergic agents may normalize neurotransmission in this system. Finally, GABAergic agents may provide anxiolytic effects and therefore be beneficial in the treatment of anxiety symptoms in alcoholics that are frequently linked to relapse.

One GABAergic medication that has an excellent safety-profile is gabapentin. While gabapentin increases brain GABA levels in humans (Petroff et al., 1996) it also may affect neurotransmission at other sites (Taylor et al., 1998). Gabapentin has been found to have beneficial effects in the treatment of alcohol withdrawal (Bozikas et al., 2002, Rustembegovic et al., 2004, Voris et al., 2003), although results of a controlled study were equivocal (Bonnet et al., 2003). It appears to be effective in treating alcohol-related insomnia (Karam-Hage and Brower, 2003) and anxiety symptoms (Perugi et al., 2002), as well as reducing alcohol craving (Chatterjee and Ringold, 1999).

The aim of the present study was to assess the safety and tolerability of gabapentin given in combination with intoxicating doses of alcohol to volunteers who were heavy alcohol drinkers. Alcohol was given using a cumulative dosing procedure (de Wit et al., 1989), which permits examination of participants’ responses to a range of alcohol doses and blood alcohol concentrations. The effects of acute pretreatment with two doses of gabapentin on the physiological performance and subjective effects of alcohol, as well as alcohol pharmacokinetics, were evaluated. We hypothesized that pretreatment with gabapentin would enhance the intoxicating effects of alcohol and decrease alcohol craving.

Section snippets

Participants

Research volunteers were recruited via advertisements in newspapers. Eligible volunteers received a detailed medical, psychological, and psychiatric evaluation. Laboratory testing included blood and urine analysis, urine drug toxicologies (opioids, cocaine, benzodiazepines, cannabinoids, and amphetamines), and an electrocardiogram. Participants were excluded from the study if they had any current physical disorder, body mass index lower than 19 or above 28 kg/m2, were taking any prescription

Effects of gabapentin alone

VAS cluster scores of ‘Physical Symptoms’ increased as a function of Time (F2,32 = 7.28, p < 0.01), but no effect of Dose was present. VAS cluster scores of ‘Elevated Mood’ increased as a function of Time (F2,32 = 8.17, p < 0.01) with gabapentin increasing scores at the level reaching statistical significance (p = 0.052). There was no effect of Time or Dose on any other VAS clusters. Gabapentin impaired the ability to balance (F2,32 = 3.3, p < 0.05), with the high dose significantly decreasing balance

Discussion

In this study, we evaluated the effects of acute doses of gabapentin on the pharmacokinetic and pharmacodynamic effects of alcohol in heavy drinkers. Gabapentin alone decreased the ability to balance, but otherwise had no discernible subjective or behavioral effects prior to alcohol administration. Administration of alcohol, using a cumulative dosing procedure, produced time-dependent changes on a broad range of subjective, physiological, and psychomotor performance measures. Pretreatment with

Conclusion

In conclusion, the present study suggests that acute doses of gabapentin are safe in combination with alcohol. Although gabapentin did not alter the intoxicating effects of alcohol or alcohol craving, this does not exclude the possibility that gabapentin may still be an effective treatment for alcohol-use disorders. Further human laboratory and clinical studies should seek to determine whether treatment with gabapentin may facilitate cessation of alcohol use or relapse to alcohol use in

Acknowledgements

This work was supported by research grants from the National Institute of Alcohol Abuse and Alcoholism (AA12599) to Dr. Evans, the National Institute of Drug Abuse to Dr. Bisaga (K23 DA00429), and the National Institute of Mental Health to Dr. Papp (MH 61274). Portions of the data contained in this manuscript were presented at the 65th Annual Meeting of the College on Problems of Drug Dependence, Bal Harbour, FL, 2003. The authors thank Dr. Richard Foltin and Fatima Garawi for help in data

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