Department of Psychiatry, Division of Alcohol and Drug Addiction, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284-7953, USA
Received 11 November 1999; in revised form 7 February 2000; accepted 22 February 2000
ABSTRACT
In the human central nervous system, the gamma-aminobutyric acid (GABA) type A receptor complex undergoes changes with both acute and chronic exposure to sedativehypnotic drugs. These changes contribute to both the acute effects of these drugs as well as the chronic effects of sedativehypnotic dependence, withdrawal, and drug craving. Clinically these chronic effects are difficult to treat in patients dependent on ethanol or benzodiazepines. Valproate may return the GABA type A receptor function to a state more closely resembling its normal function. By this mechanism, it is possible to reduce the symptoms of sedativehypnotic withdrawal and relapse.
INTRODUCTION: ROLE OF THE GAMMA-AMINOBUTYRIC ACID TYPE A RECEPTOR COMPLEX IN SEDATIVEHYPNOTIC DEPENDENCE AND WITHDRAWAL
Benzodiazepines are commonly used in the detoxification treatment of ethanol dependence and withdrawal (Lejoyeux, 1998). Benzodiazepines decrease ethanol withdrawal symptoms because of cross-dependence between benzodiazepines and ethanol (Mihic et al., 1991
; Allen et al., 1992
). This presumably arises from the fact that both agents facilitate the actions of the gamma-aminobutyric acid type A (GABAA) receptor (Grobin et al., 1998
; Lejoyeux, 1998
). The GABAA receptor is a ligand-gated chloride ion channel modulated by its endogenous ligand, GABA. When GABA binds to the GABAA receptor, the chloride channel opens to allow chloride influx into the neuron resulting in neuronal inhibition (Klein et al., 1995
; Hevers and Luddens, 1998
). Chronic exposure to ethanol, benzodiazepines, or other GABAA receptor positive modulators results in sedativehypnotic tolerance by decreasing chloride influx (Hoffman and Tabakoff, 1996
) and down-regulating GABAA receptor numbers (Abi-Dargham et al., 1998
; Lingford-Huges et al., 1998
). Decreased GABAA receptor function results in reduced inhibitory input, which persists for days to weeks after sedativehypnotic or ethanol discontinuation (Barnes, 1996
; Crews et al., 1996
; Faingold et al., 1998
; Grobin et al., 1998
). This decrease of inhibitory input may contribute to the anxiety, motor excitability, and other central nervous system and peripheral nervous system stimulatory symptoms associated with ethanol and other sedative hypnotic withdrawal.
VALPROATE'S RELATION TO GABA AND THE GABAA RECEPTOR COMPLEX
Valproate is a broad-spectrum anticonvulsant which is quite effective in the treatment of grand mal seizures and of petit mal seizures (absence seizures) (MacDonald and Kelly, 1995; Perucca, 1996
; Feely, 1999
). It also has proven efficacy as a mood stabilizer for bipolar mood disorder (Post et al., 1983
; Bowden et al., 1994
; Bowden, 1995
, 1998
) and as an anxiolytic (Keck et al., 1992
; Viola et al., 1997
). Despite more than two decades of research, valproate's therapeutic mechanism of action is still unclear. It appears to have diverse neuropharmacological effects. For example, this anticonvulsant has been shown to suppress N-methyl-d-aspartate (NMDA)-evoked, transient depolarizations in the rat neocortex in vitro (Zeise et al., 1991
). Valproate also has effects on second messenger systems, such as protein kinase C (Chen et al., 1994
, 1996
; Manji et al., 1996
) and it may indirectly inhibit serotonergic cells in the dorsal raphe nuclei (Nishikawa and Scatton, 1985a
,b
; Scatton et al., 1985
). In addition to these diverse actions, valproate may indirectly increase GABAA receptor activation by increasing brain GABA levels (Loescher and Vetter, 1985
; Lee et al., 1995
; Cutrer and Moskowitz, 1996
; Cutrer et al., 1997
). In the brain, valproate activates the GABA synthetic enzyme, glutamic acid decarboxylase (Loescher, 1981
), and inhibits the GABA degradative enzymes, GABA aminotransferase (Maitre et al., 1978
; Loescher, 1981
) and succinate semialdehyde dehydrogenase (van der Laan et al., 1979
). In addition to increasing brain GABA levels, valproate increases GABA release from rat cortical slices (Ekwuru and Cunningham, 1990
) and, in the presence of GABA, may positively modulate brain GABAA receptors (Ogden et al., 1994
). Thus, valproate appears to facilitate GABAergic neural inhibition through multiple mechanisms. Given valproate's GABA-facilitating effects and the presumptive role of GABA in sedativehypnotic dependence and withdrawal, valproate may offer an alternative or adjunct to benzodiazepines for ethanol and other sedativehypnotic withdrawal.
THE NEED FOR ALTERNATIVE TREATMENTS
Long-acting benzodiazepines are the most commonly used treatment for ethanol withdrawal in the USA, with chlordiazepoxide being the single most commonly used agent (Saitz et al., 1994; Mayo-Smith, 1997
). The rationale for this trend is that longer-acting benzodiazepines have slower elimination rates and therefore provide more continuous coverage and produce a lower risk of seizures (Mayo-Smith and Bernard, 1995
; Mayo-Smith, 1997
). For the vast majority of ethanol detoxification patients, long-acting benzodiazepines are very effective. However, elderly patients are more susceptible to benzodiazepines' central nervous system side-effects including confusion, delirium, ataxia, and obtundation (Morgan, 1990
; Ladner, 1991
; Aston, 1994
). Benzodiazepine over-medication itself can cause delirium in the elderly. Finally, even when elderly and liver failure patients are treated optimally with benzodiazepines, they still suffer a longer, more severe course of ethanol withdrawal and have a higher risk of withdrawal-induced delirium (Elton, 1983
; Liskow et al., 1989
; Egbert, 1993
; Brower et al., 1994
; Peppers, 1996
).
Patients with withdrawal-induced delirium are considered the most difficult and dangerous group of detoxification patients to treat. Despite the tremendous effectiveness of benzodiazepines in reducing the course and severity of ethanol withdrawal-induced delirium, often this delirium is extremely severe and protracted, even when treated with very high doses of benzodiazepines (Miller, 1995; Kunkel et al., 1997
).
Because some anticonvulsant drugs decrease ethanol withdrawal symptoms (Roy-Byrne et al., 1989; Keck et al., 1992
; Rosenthal et al., 1998
), anticonvulsant treatments may reduce the length of hospital stay for ethanol withdrawal, reduce the need for benzodiazepines in subgroups sensitive to benzodiazepines' side-effects, and add to the effectiveness of benzodiazepines when given in combination. Phenytoin has been widely studied and found to have minimal utility for alcohol withdrawal (Saitz et al., 1995
; Knoll et al., 1997
). It is not effective in preventing ethanol withdrawal-induced seizures (Rathlev et al., 1994
). On the other hand, carbamazepine has shown promise as a treatment for ethanol withdrawal (Malcolm et al., 1989
; Keck et al., 1992
; Litten et al., 1996
). It also has the advantage of not interacting with alcohol and not being contraindicated in cirrhosis (Williams and McBride, 1998
). It also is less sedating and less subject to abuse than benzodiazepines (Butler and Messiha, 1986
; Gallant, 1992
). Its lower sedation may be of particular benefit to the elderly and to those with decreased liver function, where over-sedation is a concern. Also, the anticonvulsant action of carbamazepine may prevent withdrawal seizures (Miller, 1995
).
Certain patient subgroups seem to have more protracted and severe benzodiazepine withdrawal. For example, patients with anxiety disorders may have rebound anxiety symptoms during benzodiazepine discontinuation and, therefore, these patients may require slower tapering (Rickels and Schweizer, 1998; Schweizer and Rickels, 1998
). As another example, elderly patients may be at increased risk for delirium when tapered off benzodiazepines (Moss and Lanctot, 1995
; Rosebush and Mazurek, 1996
; Zalsman et al., 1998
). Another subgroup who experience difficulties during benzodiazepine tapering are polysubstance abusers. Often, these patients are using high doses of short-acting benzodiazepines and are not compliant with outpatient medication tapers (Seivewright and Dougal, 1993
; Pages and Ries, 1998
). This population's lack of compliance, as well as their severe withdrawal course, may necessitate inpatient detoxification (Pages and Ries, 1998
). Unfortunately, benzodiazepine tapers can last weeks and, therefore, require long hospital stays. Clearly an adjunctive treatment that could shorten the taper's course would be valuable. Anticonvulsant medications may allow more rapid and safer benzodiazepine tapering (Pages and Ries, 1998
). Adjunctive carbamazepine reduces iatrogenic benzodiazepine withdrawal severity in placebo-controlled studies (Schweizer et al., 1991
; Roy-Byrne et al., 1993
). Similarly, two studies found that carbamazepine reduced benzodiazepine withdrawal in benzodiazepine-abusing populations (Ries et al., 1989
; Lichtigfeld and Gillman, 1991
).
A POSSIBLE ROLE FOR VALPROATE IN SEDATIVEHYPNOTIC WITHDRAWAL
There have been four controlled studies suggesting valproate's efficacy for ethanol withdrawal. One study compared valproate with phenobarbital (Rosenthal et al., 1998). The two treatments did not differ significantly on subjective withdrawal symptoms or the physiological withdrawal measures of pulse and blood pressure increases. This strengthens the study's results, as increased pulse and blood pressure are reliable indicators of withdrawal severity (King et al., 1991
; Sellers et al., 1991
) and prognostic indicators of progression to withdrawal-induced delirium (Wetterling et al., 1994
; Ferguson et al., 1996
). This study also demonstrated that valproate was well tolerated and safe when used for ethanol withdrawal. The study's weaknesses were that it was not placebo-controlled or blinded. Another study compared valproate to a standard withdrawal treatment, chlormethiazole, and found both drugs to have a similar effectiveness (Lambie et al., 1980
). However, the study is weakened by the fact that some valproate group patients also received unspecified amounts of chlormethiazole. Another weakness was the lack of consistent reporting of physiological withdrawal symptoms. For example, the study did not include pulse in its withdrawal measurements and did not report blood pressure data consistently. Although the two aforementioned studies reported no adverse side-effects from valproate, a double-blind comparison of placebo with valproate for ethanol withdrawal concluded that valproate had limited utility for ethanol withdrawal due to the high incidence of gastric distress, nausea and vomiting (Hillbom et al., 1989
). This study used the valproic acid form of valproate, which has a much higher incidence of gastric side-effects than the currently used form of valproate, Divalproex (Zarate et al., 1999
). More recently, a study compared valproate to lorazepam, a benzodiazepine, in the treatment of ethanol withdrawal in an open label study and concluded that valproate was a well-tolerated, safe, and effective treatment for ethanol withdrawal (H. Myrick et al., in preparation). In this latter study, lorazepam was administered on an as-needed basis to the control group and the experimental group received a scheduled dose of valproate. There were no differences between the two groups in the severity of withdrawal, which suggests that valproate may be a useful adjunct to benzodiazepines for alcohol withdrawal. In conclusion, valproate may hold promise as an ethanol withdrawal treatment, but its role needs further support from placebo-controlled trials. Placebo-controlled trials are also needed to test valproate's efficacy for benzodiazepine withdrawal.
Furthermore, there are three case-based reports suggest-ing that valproate may be effective for the treatment of sedativehypnotic withdrawal. Valproate loading in two manic schizoaffective patients withdrawing from ethanol resulted in rapid reduction of both mania and withdrawal within 72 h (Hammer and Brady, 1996). Both patients received lorazepam 4 mg total for withdrawal in addition to valproate 20 mg/kg/ day. This is a low lorazepam dose, given the severity of the ethanol withdrawal syndromes described, thus the cases imply that valproate decreased withdrawal symptoms. In a single case report of a 23-year-old male with panic disorder treated with clonazepam 12 mg/day and tranylcypromine 130 mg/day, repeated attempts to taper the clonazepam dose were unsuccessful, due to extreme rebound anxiety and panic (i.e. withdrawal-like symptoms) (McElroy et al., 1991
). Then the patient received valproate doses increased gradually over an unspecified number of days to 2000 mg/day (serum level 89 µg/ml). On this dose of valproate, the patient tolerated a clonazepam taper without anxiety or withdrawal symptoms. The authors concluded that valproate treated both anxiety and benzodiazepine withdrawal. The third report treated four cases of protracted withdrawal symptoms from benzodiazepines with valproate (Apelt and Emrich, 1990
). The symptoms included psychosis, anxiety, panic, vomiting, insomnia, ataxia, and paraesthesia. These symptoms occurred after benzodiazepine tapers lasting between 11 and 21 days, which were relatively rapid tapers considering that the four benzodiazepine use histories ranged from 1 to 18 years. All symptoms ended after valproate administration. Considering that valproate was begun 6 days to 5 weeks after the benzodiazepine taper was completed, it is difficult to conclude whether the symptoms' resolution was a consequence of valproate or spontaneous resolution. If it was due to the valproate, it cannot be stated whether this represented treatment of withdrawal or of reappearing anxiety disorder.
Despite these encouraging case reports of valproate in the treatment of benzodiazepine withdrawal, one double-blind placebo-controlled trial failed to confirm that valproate treatment decreased benzodiazepine withdrawal severity (Rickels et al., 1999).
VALPROATE FOR SEDATIVEHYPNOTIC RELAPSE PREVENTION
Valproate's effect on GABAA receptors suggests that it may reduce relapse to ethanol and sedative use. Abstinent alcoholics and sedative abusers may have reduced GABAA receptor activity, even after withdrawal (Crews et al., 1996; Faingold et al., 1998
). Additionally, chronic sedative exposure might produce long-term down-regulation of GABAA receptor function or number lasting weeks to months after drug termination. If this long-term GABAA receptor down-regulation persisted even after the sedative withdrawal phase, it might explain ethanol and sedative craving and relapse. One study showed that administration of valproate to rats reduced alcohol intake (Gardell et al., 1998
). However, the dose of valproate used in this study enhanced the intoxicating effect of alcohol. Therefore, valproate may have reduced ethanol intake in rats by reducing the amount of ethanol needed to produce a satiating level of intoxication. Nevertheless, two case reports concerning ethanol relapse prevention (Brady et al., 1994
) and benzodiazepine relapse prevention (Roberts et al., 1994
) suggest that valproate may reduce sedativehypnotic relapse. In each of these reports, patients had relapsed to sedative abuse many times prior to a trial of valproate and then ceased to relapse after initiation of valproate treatment.
One small (n = 13), outpatient, single-blind study compared two doses of valproate and placebo in a crossover design with ethanol-dependent patients (Minuk et al., 1995). Although this study demonstrated that there were no hepatic side-effects associated with valproate use in ethanol-dependent patients, it did not find a decreased desire to use ethanol on a visual analogue rating scale. However, the conclusions are limited by the small number of patients, the lack of an investigator blind for the placebo dose, lack of data on the alcohol intake of subjects, and the short period of time (1 month) that the subjects took the study medication. Moreover, because of the small size of this study, it may not have been adequate to fully evaluate the dangers of heavy chronic ethanol intake combined with valproate. Unfortunately, there are no large trials evaluating the safety of valproate in subjects concurrently consuming ethanol.
CONCLUSION
There is evidence that valproate may have a role to play for the treatment of sedativehypnotic withdrawal and relapse prevention. However, no well-controlled trials have tested valproate for either of these uses. Theoretically, efficacy for sedativehypnotic withdrawal and relapse would be predicted by valproate's facilitating actions on GABA levels and GABAA receptor function. Therefore valproate is a promising candidate for treating a spectrum of sedativehypnotic related disorders, but more investigation is needed. Placebo-controlled trials with valproate are especially warranted.
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