Sodium Valproate

Sodium valproate is an antiepileptic compound with an unknown mechanism of action, although it is suggested that its antiepileptic action may be attributed to increased GABA levels in the brain.

Sodium valproate has been used for over 30 years for the treatment and prevention of alcohol withdrawal. A number of anecdotal and open-label studies indicate that the efficacy and safety of the anticonvulsant valproate (divalproex sodium) are similar to the effects of the anticonvulsant phenobarbital and the benzodiazepine lorazepam in reducing symptoms of alcohol withdrawal. For example, Reoux et al., in a study of individuals with moderate alcohol withdrawal characterized as a score of ≥10 on the revised CIWA-Ar scale, showed that sodium valproate treatment was well tolerated, reduced the need for benzodiazepine treatment, and led to a decreased likelihood of progression in severity of withdrawal symptoms compared with placebo.

An unblinded pilot study by Longo et al. used stringent inclusion and exclusion criteria to compare the safety and efficacy of valproate with those of standard benzodiazepines for detoxification in a small ( N = 16) inpatient population of individuals with mildly to moderately severe alcohol dependence and moderate alcohol withdrawal. Subjects received standard benzodiazepine detoxification (with lorazepam or chlordiazepoxide), 5-day detoxification with valproate, or detoxification with valproate plus 6-week maintenance. Valproate was administered using a loading-dose strategy (20 mg/kg/day in two doses 6–8 hours apart on day 1, then twice daily for 4 days or 6 weeks). Although the differences were not significant, perhaps due to small sample size, alcohol withdrawal symptom reduction tended to be more rapid in the valproate treatment group than in the benzodiazepine control group at 12- and 24-hour intervals. Four of five subjects (80%) in the valproate maintenance group were completely abstinent at the 6-week follow-up, compared with 5 of 11 (45%) in the combined detoxification-only groups. Furthermore, the participants receiving valproate showed lower liver transaminase levels than at baseline and no other hematological abnormalities at the 6-week follow-up. This study demonstrated the importance of using a loading dose to achieve rapid therapeutic anticonvulsant blood levels. Despite the small sample size of this pilot study, the finding of higher abstinence rates at the 6-week follow-up in the valproate group supports further investigation of anticonvulsants as post-detoxification relapse prevention agents. A more recent retrospective chart review of 827 patients compared carbamazepine and valproate as adjunctive agents to the sedative-hypnotic clomethiazole and clonidine for inpatient detoxification and showed benefits of valproate over carbamazepine, including shorter pharmacological treatment, fewer transfers to the intensive care unit (ICU), fewer side effects, and a trend toward better effectiveness for preventing withdrawal seizures. However, unlike the earlier pilot study, no comparator group was receiving an anticonvulsant agent without the sedative-hypnotic clomethiazole, thereby limiting generalizability of the utility of either carbamazepine or valproate.

Notably, most trials have been open-label; seizure rates were reported by only a few authors, and standardized multidimensional alcohol rating scales were seldom included. A notable limitation to the use of valproate for the prevention and treatment of alcohol withdrawal symptoms was its disadvantageous adverse events profile. Fatalities due to hepatic failure, life-threatening pancreatitis, and thrombocytopenia have all been reported among individuals who had received valproate or its derivatives. Its use is contraindicated in pregnancy due to teratogenic effects, and thus women of childbearing potential require a pregnancy test prior to initiation of valproate. Furthermore, because nonspecific gastrointestinal symptoms also have been reported following the ingestion of valproate, its clinical utility as an antiwithdrawal agent has been limited. In sum, however, it appears that it is at least as effective as benzodiazepines for treating alcohol withdrawal and has other advantages as a longer-term treatment for alcohol use disorders, particularly in individuals with comorbid bipolar disorder.

Carbamazepine and Oxcarbazepine

Placebo-controlled studies since the 1970s have supported the use of the potent anticonvulsant carbamazepine as a pharmacological agent for the treatment of acute alcohol withdrawal. Carbamazepine exerts its primary effects by blockade of voltage-sensitive sodium channels, as well as GABAergic and glutamatergic modulatory effects. Several double-blind studies have demonstrated that carbamazepine has efficacy at reducing alcohol withdrawal symptoms equal or superior to that of lorazepam, oxazepam, clomethiazole, tiapride, and placebo. It also has been reported that carbamazepine can reduce effectively some measures of alcohol consumption (drinks per drinking day, number of heavy drinking days, and time to the first drinking day) during the postwithdrawal phase.

Malcolm et al. examined the efficacy of carbamazepine versus lorazepam for the treatment of alcohol withdrawal symptoms as well as drinking behavior in the 7 days immediately following the treatment period. They hypothesized that although both carbamazepine and lorazepam would suppress alcohol withdrawal, carbamazepine would show the greater efficacy at ameliorating symptoms and reducing posttreatment drinking among those with a history of multiple episodes of previously treated alcohol withdrawal. In that double-blind trial ( N = 136), carbamazepine 600–800 mg on day 1, tapered to 200 mg on day 5, was compared with lorazepam 6–8 mg on day 1, reduced to 2 mg on day 5, in a group of individuals experiencing moderate alcohol withdrawal. Participants were randomized to receive the carbamazepine or lorazepam fixed-dose taper across two levels of detoxification histories (0–1 or ≥2 prior medicated detoxifications). In addition, participants were administered the 10-item CIWA-Ar scale, an aggregate measure of the severity of alcohol withdrawal that assessed individual symptoms such as nausea, tremor, sweating, anxiety, and agitation prior to medication treatment, daily for 5 days during the treatment phase, and on days 7 and 12 of the posttreatment period. The authors reported that carbamazepine and lorazepam were equally effective at decreasing the acute symptoms of alcohol withdrawal. There were no significant differences by treatment group in CIWA-Ar scale scores when all 12 study days were considered. There was, however, a significant treatment-group effect on posttreatment drinking. Participants who had zero or one previous detoxification episode showed no differences in posttreatment drinks per day based on treatment group. Among participants with multiple detoxifications, those who received carbamazepine drank an average of less than one drink/day compared with about five drinks/day among the lorazepam group ( P = 0.004). Furthermore, the relative risk of having a first drink during the posttreatment period was three times higher for the lorazepam-treated group than for the carbamazepine group. Potential limitations of the study were the reliance on subjects’ reports of previous medically treated withdrawal episodes, the fairly homogeneous demographic profile, and the low level of concomitant substance abuse by the participants. Nonetheless, the results of the study showed that carbamazepine was as efficacious as lorazepam at treating acute alcohol withdrawal, and had greater efficacy than lorazepam in preventing posttreatment relapse to drinking in participants with a history of multiple alcohol detoxifications.

Psychosocial domains such as anxiety, depression, sleep quality, and the ability to return to work might be equally important in mediating outcomes of outpatient treatment but are often given only limited attention in the outpatient setting. Malcolm et al., therefore, extended their findings by comparing the effects of previous withdrawal history and treatment with carbamazepine or lorazepam on psychosocial outcome measures. In that study, designed as a 2 × 2 factorial (carbamazepine vs. lorazepam, 0–1 vs. ≥2 prior detoxifications), subjects completed a variety of self-rated measures of psychosocial function during the study period. The authors reported a statistically significant effect for scores to be lower for carbamazepine compared with lorazepam on the Zung anxiety scale (34.8 vs. 38.9, respectively; P = 0.01) but to be higher on the visual analog scale of sleep quality (i.e., 62.1 vs. 51.2, respectively; P = 0.02). Neither the treatment group nor the number of previous withdrawals significantly affected the depression scores. Neither the carbamazepine or the lorazepam treatment groups produced a statistically significant effect on the ability to return to work.

The finding that carbamazepine was more efficacious than lorazepam at reducing anxiety and improving sleep is clinically important because the treatment of these psychiatric symptoms during acute detoxification could result in less distress and improved sleep during withdrawal—both of which could reduce the likelihood of relapse. Furthermore, these results have important implications for the subtle withdrawal symptoms, known as “protracted withdrawal syndrome,” which can persist for weeks to months following the 5- to 7-day acute detoxification. The symptoms that occur during the protracted withdrawal syndrome include anxiety, sleep disturbances, and mood instability. During the protracted withdrawal period, there is an increased risk of relapse to drinking. Thus the effective treatment of the symptoms of protracted withdrawal with carbamazepine during the acute detoxification period might improve long-term drinking outcomes. Although benzodiazepines have an indication for the 5- to 7-day acute detoxification period, they are not indicated for protracted withdrawal due to their addictive potential, synergistic effects with alcohol if patients relapse, and their own inherent potential to result in a protracted withdrawal syndrome similar to that of alcohol with long-term use.

Oxcarbazepine, an analog of carbamazepine, has also shown efficacy in alcohol withdrawal, with the advantage of causing less induction of the cytochrome P450 (CYP) system and lower risk of neurological side effects, hormonal effects, and blood dyscrasias. In addition to blockade of voltage-sensitive sodium channels, like its antecedent, it also reduces glutamatergic transmission via reduction of high voltage-activated calcium currents. A small ( N = 29), randomized, single-blinded comparison of oxcarbazepine and carbamazepine showed similar effectiveness for alcohol withdrawal and no difference in side effects between the groups, but significantly less alcohol cravings in the oxcarbazepine group. However, a larger ( N = 50), double-blind, placebo-controlled study showed no differences in the need for rescue sedative-hypnotic medications (clothemiazole), withdrawal symptoms, or cravings, which the authors concluded may have been attributable to study design. Although information could reasonably be extrapolated from the numerous studies of carbamazepine, and the newer analog has a favorable side effect profile, more research is needed to evaluate the efficacy of oxcarbazepine for alcohol withdrawal.

In sum, carbamazepine appears to be at least as effective as benzodiazepines in reducing the symptoms of mild-to-moderate alcohol withdrawal in relatively healthy individuals, although more evidence is needed for the newer oxcarbazepine. The doses given in these studies were generally lower than those that are used when the goal is to achieve anticonvulsant effects in patients with seizure disorders. In addition, carbamazepine appears to have efficacy that is superior or at least equal to that of other agents such as clomethiazole and tiapride in reducing withdrawal symptoms. Systematic reviews have further verified carbamazepine’s safety, tolerability, and effectiveness for the treatment of alcohol withdrawal in comparison to both placebo and benzodiazepines. Despite the potential advantages of carbamazepine, its use can be associated with hepatotoxicity. Therefore the use of carbamazepine is contraindicated for the treatment of alcohol withdrawal among those with clinically significant hepatic disease. Because carbamazepine can cause blood dyscrasias, it should not be prescribed to individuals with either a propensity toward or a preexisting hematological disorder. And like valproate, it too can cause fetal neural tube defects, and is thus contraindicated for use in pregnant women.

Gabapentin

Gabapentin has a structural relationship similar to that of GABA, and its mechanisms of action, although understood imperfectly, include the blockade of l -type calcium channels as well as facilitation of GABA synthesis. Preclinical studies show that gabapentin decreases ethanol withdrawal–induced hyperexcitability in isolated slices of hippocampus as well as convulsions and anxiety in alcohol-withdrawn mice. In addition to these pharmacological properties, gabapentin’s suitability as a promising candidate medication for treating alcohol withdrawal symptoms is aided by the fact that it does not induce hepatic enzymes and it is excreted unmetabolized in the urine. Hence, gabapentin will not exacerbate the hepatotoxic effects of alcohol.

Preliminary evidence supporting the potential of gabapentin to reduce alcohol withdrawal symptoms came from a case report and a few case series that investigated the open-label use of the medication. In a double-blind trial ( N = 101), gabapentin was more efficacious than lorazepam at reducing insomnia during alcohol withdrawal In addition, it has been proposed from a case series that gabapentin could be useful for a particular facet of a severe alcohol withdrawal syndrome—the reduction of tonic-clonic seizures.

In a controlled study by Bonnet et al. of gabapentin (400 mg four times daily) versus placebo for treating alcohol withdrawal symptoms in an inpatient setting, there was no significant difference between the two groups in the frequency and severity of their withdrawal symptoms or in the frequency with which the “rescue medication,” clomethiazole, was used in the first 24 hours. However, the author followed this trial with an open trial of gabapentin for alcohol withdrawal using a loading protocol. The protocol design effectively screened subjects to determine an early response, defined as symptom score reduction within 2 hours of administration of an 800 mg loading dose of gabapentin, and this group was treated for 2 days with gabapentin 600 mg, four times daily and then tapered. They treated 73% ( N = 27) of the population as early responders and reclassified three participants as nonresponders due to worsening withdrawal in the following 36 hours—two participants of whom developed an epileptic seizure. The authors concluded that the gabapentin loading protocol was only helpful in less severe and less complicated acute alcohol withdrawal syndrome. Another open-label inpatient study by Mariani et al. randomized participants ( N = 27) to either a standard phenobarbital taper or gabapentin (1200 mg loading dose, with 2400 mg total in the first 24 hours, followed by a 3-day taper). The proportion of completers and of participants requiring rescue phenobarbital was not statistically significant between the groups. They did, however, find that those receiving gabapentin who required rescue phenobarbital had higher baseline CIWA-Ar scores. The same was true of the phenobarbital group, but this did not show statistical significance, whereas the gabapentin group did. Similar to the aforementioned study, the authors hypothesized that either gabapentin was underdosed for those in more severe withdrawal, or that gabapentin is ineffective for more severe manifestations of alcohol withdrawal.

Two outpatient studies further supported the utility of gabapentin in milder withdrawal syndromes. In a double-blind trial of gabapentin versus lorazepam, Myrick et al. showed statistical superiority for higher-dose gabapentin (1200 mg tapering to 800 mg) in reduction of CIWA-Ar scores. The lorazepam group was also more likely to drink on the first day of dose decrease, the second day off medication, and in the follow-up posttreatment period. A similar study comparing gabapentin to chlordiazepoxide for outpatient detoxification in a veteran population by Stock et al. The gabapentin group started at 1200 mg for 3 days and then tapered down by 300 mg per day over the next 4 days, and showed a greater reduction in sedation ( P = 0.04) and a trend to reducing alcohol cravings ( P = 0.08), but no differences in reduction of CIWA-Ar scores.

Although large-scale controlled studies are needed to determine whether gabapentin can be useful in treating more severe manifestations of alcohol withdrawal, including tonic-clonic seizures, its utility may go well beyond its use in the acute withdrawal phase. Two smaller ( N = 21 and N = 60), randomized double-blind trials showed statistically significant improvements in various alcohol consumption measures in participants not in acute withdrawal. These results were followed by a larger ( N = 150), randomized, double-blind trial by Mason et al. that demonstrated a significant linear-dose effect for rates of abstinence and no heavy drinking, with the 1800 mg/day gabapentin group outperforming the 900 mg/day gabapentin and placebo groups. There were also significant benefits for sleep, mood, and cravings in the higher-dosed gabapentin group.

Thus the utility of gabapentin may extend well beyond acute alcohol withdrawal phase and potentially serve as a maintenance treatment for alcoholism, particularly in those who tolerate the medication well during acute withdrawal, but larger trials are needed in both acute withdrawal and long-term maintenance to fully evaluate its effectiveness. Although, unlike valproate and carbamazepine, the side effect profile is much more favorable due to the fact that it is renally excreted—the dose can be adjusted for renal impairment—and that it carries no black box warning.

Topiramate

Topiramate, a sulfamate-substituted derivative of fructopyranose, was identified originally as a potential antidiabetic agent. Due to its structural similarity to known anticonvulsants, it was tested and found to have activity in several animal-seizure models. The compound was subsequently developed as an anticonvulsant based on its potency, duration of action, and neuroprotective effect. The anticonvulsant effects of topiramate have been validated in the traditional rodent maximal-electroshock seizure test, as well as in several animal models of epilepsy. In the rat and mouse maximal-electroshock seizure test, topiramate showed potency similar to that of phenytoin and carbamazepine and greater than that of valproate.

Recent studies of topiramate suggest that its pharmacokinetic properties provide several advantages over other antiepileptic agents. These advantages include its rapid and complete absorption, minimal metabolism, and minimal interaction with other medications, such as oral contraceptives. Similar to most marketed anticonvulsant agents, topiramate exerts its anticonvulsant effects through blockade of voltage-dependent sodium and l -type high voltage-gated calcium channels and facilitation of GABAergic neurotransmission via GABA _A . In addition, topiramate inhibits the activity of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate subtypes of glutamate receptors, rather than the more traditional action at the N -methyl- d -aspartate (NMDA) subtype, and selectively inhibits carbonic anhydrase-II and carbonic anhydrase-IV. Topiramate also has been reported to activate potassium conductance due to its ability to inhibit carbonic anhydrase.

Titrating topiramate (over a range of 200–800 mg/day) produces a dose-proportional increase in its plasma concentration; both the maximal plasma concentration (C _max ) and the area under the plasma concentration-time curve are linear and increase in proportion to the dose of topiramate at doses from 200 to 800 mg/day. Due to its low binding to plasma proteins (9%–17%), topiramate is unlikely to be displaced by highly protein-bound medications, thus limiting the likelihood for its interaction with other agents. Furthermore, because topiramate is eliminated predominantly in the urine, with an elimination half-life of approximately 21 hours, and is not metabolized extensively in humans (∼20%), topiramate will not exacerbate the hepatic-enzyme–inducing effects of alcohol.

The pharmacokinetic properties of topiramate might be altered in some special populations. Although no specific age-related changes in topiramate clearance or elimination half-life have been reported, a decline in renal function might occur with normal aging. Thus renal function should be evaluated in all elderly individuals receiving topiramate, since decreased renal function can alter the pharmacokinetics of medications eliminated by the kidneys, and adjustments of topiramate dose might be necessary in individuals with impaired renal function as well as in those undergoing hemodialysis.

Topiramate’s pharmacodynamic profile would appear to make it an ideal treatment for alcohol withdrawal. Topiramate might reduce the overactivity of the sympathetic nervous system and neuronal hyperexcitability commonly seen in the early phase of alcohol withdrawal, through suppression of glutaminergic input, facilitation of GABA _A -mediated inhibitory impulse, blockade of sodium and calcium channels, and facilitation of potassium conductance.

Indeed, an open-label inpatient study by Choi et al. found that topiramate 50 mg/day ( N = 25) was as efficacious as lorazepam up to 4 mg/day ( N = 27) at treating alcohol withdrawal, while allowing the individual to transition into outpatient care on the same regimen without the potential for abuse or the increased risk of relapse commonly seen in alcoholics treated with benzodiazepines. Previously, Rustembegovic et al., in a pilot open-label study ( N = 12), found topiramate (50 mg twice daily) to be efficacious in the treatment of tonic-clonic seizures associated with alcohol withdrawal, with no side effects. Furthermore, Krupitsky and colleagues, in a placebo-controlled, randomized single-blind study comparing the safety and efficacy of three antiglutamatergic agents—including topiramate (25 mg four times daily), memantine (10 mg three times daily), and lamotrigine (25 mg four times daily) versus diazepam (10 mg three times daily) for the treatment of alcohol withdrawal and detoxification in moderately severe alcoholic male patients ( N = 127)—found that all active medications significantly reduced observer-rated and self-rated withdrawal severity, dysphoric mood, and supplementary use of diazepam compared with placebo. All medications were well tolerated. This study also provided suggestive evidence of subtle advantages of lamotrigine over memantine and topiramate in reducing observer-rated (CIWA-Ar ) and self-reported withdrawal severity. However, this study compared only single doses of each drug; the dose used for topiramate is not the one shown to be efficacious in outpatient trials, thereby rendering it difficult to extrapolate such conclusions from this study.

Because topiramate can be initiated while an individual with alcohol use disorder is still drinking, and has been shown to improve drinking outcomes in such individuals, it is reasonable to hypothesize that topiramate treatment might be a strategy that can be used to decrease alcohol withdrawal as well as initiate and maintain abstinence from alcohol. Although its utility as monotherapy in the treatment of alcohol use disorder is more clearly delineated, more randomized trials are needed to determine its effectiveness in alcohol withdrawal syndrome, compared to benzodiazepines or barbiturates. Furthermore, individuals who receive topiramate treatment do need to be monitored closely during dose escalation to avoid adverse events such as sedation, paresthesia, anorexia, and cognitive impairment, and at all times for the rarer adverse events of glaucoma, transient blindness, nephrolithiasis, depression, and suicidal ideation.