Objective Naltrexone, an efficacious medication for alcohol dependence, does not work for everyone. Symptoms (e.g. insomnia, mood instability), most evident during early abstinence, might respond better to a different pharmacotherapy. Gabapentin may reduce these symptoms and early relapse. This clinical trial evaluated whether gabapentin, in conjunction with naltrexone, was better than naltrexone alone and/or placebo during the early drinking cessation phase (first six weeks) and whether this effect persisted. Method A total of 150 alcohol-dependent individuals randomly received sixteen weeks of naltrexone alone (50 mg/day [N= 50]), with gabapentin (up to 1200 mg/day [N=50] for the first six weeks), or double placebo (N= 50) while receiving medical management. Results During the first six weeks, the naltrexone/gabapentin group had 1) a longer delay to heavy drinking than the naltrexone-alone group (p =0.04) which was similar to the placebo group, 2) had less heavy drinking days than the naltrexone-alone group (p= 0.0002) which did worse than placebo, and 3) had less drinks/drinking day than the naltrexone-alone group (p=0.02) and the placebo group (p=0.01). These differences faded over the remaining study weeks. Poor sleep was associated with more drinking in the naltrexone-alone group, but not in the combined group, while an alcohol withdrawal history was associated with better response in the combined group. Conclusion The addition of gabapentin to naltrexone improved drinking outcomes over naltrexone alone during the first six weeks after cessation of drinking. This effect did not endure once gabapentin was discontinued. Future studies should evaluate gabapentin alone and over longer durations of treatment.

Improved treatment of alcohol dependence is a high priority, including defining subtypes that might respond differently. We evaluated a medication combination of intravenous flumazenil (FMZ) and oral gabapentin (GBP) in alcoholics who did and did not exhibit pretreatment alcohol withdrawal (AW) symptoms. Sixty alcohol-dependent individuals (44 with low AW and 16 with high AW) were randomized to receive FMZ (2 mg of incremental bolus for 20 minutes for 2 consecutive days) and GBP (up to 1200 mg nightly for 39 days) or their inactive placebos. Alcohol withdrawal was measured for the first 2 days, and drinking, sleep parameters, and adverse events were monitored during weekly evaluations, along with behavioral counseling sessions. Percent days abstinent (PDA) during treatment and time to first heavy drinking (TFHD) day were primary outcome variables. There was an interaction between the pretreatment AW status and the medication group on PDA (P = 0.0006) and TFHD (P = 0.06). Those in the high AW group had more PDA and more TFHD if treated with active medications, whereas those in the low AW group had more PDA and more TFHD if treated with placebo. This interaction remained for those totally abstinent (P = 0.03) and was confirmed by percent carbohydrate-deficient transferrin values. In addition, the pattern of response remained up to 8 weeks after treatment. In addition, in those with high AW, greater improvement in AW symptoms was observed in the active medication group compared with the placebo group. These results suggest a differential response to FMZ/GBP treatment, depending on pretreatment AW status that should be taken into account during future treatment trials.

Compliance measurement does appear to influence the evaluation of the efficacy of naltrexone within the context of CBT. Treatment effect sizes approximately doubled in the most compliant individuals. Measuring compliance by either of 2 distinct methods provides approximately similar results. As compliance with naltrexone within the context of CBT has such a large impact of treatment outcome, methods of enhancing compliance during treatment should be given the utmost attention.

The relationship between the ability of repeated desipramine treatment to cause downregulation of the norepinephrine transporter (NET) and produce antidepressant-like effects on behavior was determined. Treatment of rats with 15 mg/kg per day desipramine reduced NET expression, measured by 3 H-nisoxetine binding and SDS-PAGE/immunoblotting, in cerebral cortex and hippocampus and reduced the time of immobility in the forced-swim test. The antidepressant-like effect on forced-swim behavior was evident 2 days following discontinuation of desipramine treatment when plasma and brain levels of desipramine and its major metabolite desmethyldesipramine were not detectable. Reduced NET expression resulted in reduced norepinephrine uptake, measured in vitro, and increased noradrenergic neurotransmission, measured in vivo using microdialysis. Overall, the dose-response and time-of-recovery relationships for altered NET expression matched those for production of antidepressant-like effects on behavior. The importance of increased noradrenergic neurotransmission in the persistent antidepressant-like effect on behavior was confirmed by demonstrating that it was blocked by inhibition of catecholamine synthesis with a-methyl-p-tyrosine. The present results suggest an important role for NET regulation in the long-term behavioral effects of desipramine and are consistent with clinical data suggesting that enhanced noradrenergic neurotransmission is necessary, but not sufficient, for its antidepressant actions. Understanding the mechanisms underlying NET regulation in vivo may suggest novel targets for therapeutic intervention in the treatment of depression.

This study was conducted to examine whether amount and/or pattern (intermittent or continuous) of chronic ethanol exposure subsequently alters sensitivity to the discriminative stimulus effects of ethanol. Adult male C57BL/6J mice were trained to discriminate between 1.5 g/kg ethanol and saline in a two-lever food-reinforced operant procedure. Once ethanol discrimination was successfully acquired, generalization testing was conducted using a cumulative dosing procedure to generate a baseline dose-response function (0 -2.5 g/kg ethanol). Discrimination training was then suspended while mice received chronic ethanol vapor or air exposure in inhalation chambers. The total amount of ethanol exposure was systematically increased, but it was delivered in an intermittent or continuous manner. At 24 or 16 h after inhalation treatment, ethanol discriminability was reassessed using the same generalization testing procedures. Results indicated that discrimination performance in control (air-exposed) mice was similar to baseline. However, sensitivity to the discriminative cue of ethanol following chronic ethanol treatment was reduced (as evidenced by rightward shifts in the dose-response functions and increased ED 50 values). The magnitude of this tolerance effect increased as a function of the number of chronic ethanol exposures as well as the total duration of ethanol exposure. In addition, tolerance was more robust when generalization testing was conducted earlier (16 versus 24 h) after chronic ethanol treatment was halted (2-to 3-fold increase in ED 50 values). These results may have important clinical implications, because blunted sensitivity to the discriminative cue of ethanol may contribute to enhanced ethanol self-administration behavior observed in these mice following similar chronic ethanol treatment.