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Treatment of alcohol withdrawal with gabapentin
Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 197 – 199
Treatment of alcohol withdrawal with gabapentin Vasilis Bozikas*, Petros Petrikis, Katerina Gamvrula, Ioanna Savvidou, Athanasios Karavatos First Department of Psychiatry, Aristotle University of Thessaloniki, Thessaloniki, Greece
Abstract Gabapentin is an anticonvulsant agent, also effective in the treatment of mood disorders and anxiety disorders. Three cases of alcohol withdrawal treated with gabapentin are presented. All patients received gabapentin 400 mg tid for 3 days, 400 mg bid for 1 day, and finally 400 mg for 1 day. Withdrawal symptoms subsided and no adverse effects were observed. The possible effectiveness of gabapentin in the treatment of alcohol withdrawal warrants further investigation by systematic and well-designed studies. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Alcohol withdrawal; Anticonvulsant; Gabapentin
1. Introduction Gabapentin is a second-generation anticonvulsant, which does not bind to GABAA or GABAB receptors and does not interact with those sites affected by benzodiazepines. This drug binds a2d-subunit of L-type calcium channels and increases the synthesis and nonsynaptic release of GABA in the brain (Kelly, 1998). In psychiatry, gabapentin is used mainly as an adjunctive to previous treatment-resistant patients suffering from bipolar disorder (Erfurth et al., 1998; Knoll et al., 1998; Cabras et al., 1999; Perugi et al., 1999; Young et al., 1999). There are reports that it has also anxiolytic effects and that it can be successfully applied in anxiety disorder, e.g., in social phobia and generalized anxiety disorder (Pollack et al., 1998; Pande et al., 1999). Gabapentin demonstrated a selective action in decreasing both convulsive and anxiety-related aspects of withdrawal behaviour in mice after chronic ethanol treatment in doses that had no sedative or ataxic effect on animals (Watson et al., 1997). Myrick et al. (1998) reported the effective use of gabapentin as monotherapy in the treatment of alcohol withdrawal in six outpatients. Also, the drug had beneficial effects in the treatment of moderate alcohol withdrawal in four inpatients in an add-on fashion to clomethiazole, although two of them did not need any adjunctive medica-
* Corresponding author. 19 Iatrou Magou Str., Giannitsa 58100, Greece. Tel.: +30-3199-2311, +30-3199-2312; fax: +30-3199-2319.
tion and in three of them gabapentin led to a radical reduction in clomethiazole administration compared with previous detoxifications (Bonnet et al., 1999). In this paper, three cases of alcohol withdrawal treated with gabapentin are presented.
2. Case reports 2.1. Case 1 Mr. A. is a 32-year-old, single, unemployed man with a type B alcohol dependence. He is described as introverted and emotionally restricted, has no close relationships, and avoids making a family. His history of alcohol consumption combined with occasional use of cannabis started when he was 14 years old. By the age of 23 and for the next 2 1/2 years, the patient showed only opioid dependence. Afterwards, he restarted the daily consumption of enormous quantities of alcohol, together with occasional use of heroin and cannabis. As a consequence of the combined heroin and alcohol use, Mr. A. experienced delusions of persecution and reference and he attempted suicide by violent means 2 years ago. Then, he was, for the first time in his life, hospitalized in our clinic. In the next years, he had four admissions to our clinic for alcohol detoxification. Unfortunately, the biggest interval that he remained free of alcohol was 3 1/2 months, meanwhile abusing benzodiazepines. He has a child history of repeated cruel physical abuse from his father. The two
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V. Bozikas et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 197–199
brothers of his father suffer also from alcoholism. The patient is an HCV carrier. Mr. A. was re-admitted to our clinic about 48 h after a cessation of alcohol consumption. He showed hand tremor, sweating, pulse rate of 110/min, nausea, anxiety, and insomnia. The patient received gabapentin 400 mg tid for 3 days, 400 mg bid for 1 day, and finally 400 mg for 1 day. Withdrawal symptoms subsided within 2 days, except of insomnia, which subsided in 5 days after the initiation of treatment. Lorazepam 2.5 mg was given to him only for one night. No adverse effects caused by gabapentin were noted. 2.2. Case 2 Mr. B. is a 58-year-old, single, unemployed man with alcohol dependence. He is described as introverted, has no family relationships and close friends, and his affairs lack of strong affective investment. The patient has reported high daily consumption of alcohol for the last 10 years. He has been hospitalized for delirium tremens almost annually for the last 7 years. Mr. B. was admitted to our clinic for the first time 24 h after a cessation of alcohol consumption. He showed hand tremor, sweating, nausea, anorexia, and anxiety. The patient received gabapentin 400 mg tid for 3 days, 400 mg bid for 1 day, and finally 400 mg for 1 day. Withdrawal symptoms subsided within 2 days after the initiation of treatment. No adjunctive medicine was given and no adverse effects caused by gabapentin were noted.
3. Discussion Chlordiazepoxide and diazepam are the standard therapy for alcohol withdrawal. The effectiveness of benzodiazepines is based on their pharmacologic cross-tolerance with ethanol for GABAA receptors (Hyman et al., 1995). Carbamazepine was found to be an effective and safe alternative to benzodiazepine treatment for alcohol withdrawal, probably through an antikindling effect (Malcolm et al., 1989). A study of valproate has also been performed, but without conclusive results (Rosenthal et al., 1998). The three cases that were reported above are consistent with the findings of Myrick et al. (1998) and Bonnet et al. (1999) about gabapentin effectiveness in the treatment of alcohol withdrawal. In our study, we used the same doses that Myrick et al. (1998) had proposed. Bonnet et al. (1999), in their study, administrated to the patients 400 mg gabapentin qid (400 mg every 6 h) during the first 48 h of detoxification and from the third day, the daily dose of gabapentin was reduced by 400 mg daily. Benzodiazepines may be maintained as agents of choice in the therapy of delirium tremens. Gabapentin lacks drug interactions due to absence of protein binding and hepatic metabolism (Ketter et al., 1999), so it is not affected by liver dysfunction (Letterman and Markovitz, 1999). Moreover, this agent lacks the side effects of the anxiolytic drugs (Heffner, 1999) and abuse potential (Myrick et al., 1998; Bonnet et al., 1999), making it useful in the management of alcohol withdrawal states in outpatient settings.
2.3. Case 3 4. Conclusion Mr. C. is a 39-year-old, married man with alcohol dependence. His history of alcohol abuse started 9 years ago and soon it escalated to dependence. The pattern of his alcohol consumption was characterized by binges lasting for about 20 – 30 days. As a result, during the periods of alcohol binge, he presented serious occupational and social impairment, verbal abuse of his wife, and neglect of his 1-year-old daughter. Mr. C. has no other history of substance abuse. The patient was admitted to our clinic after an episode of binge, which started 17 days ago. This time, except occupational and family problems, he showed mild depressive mood, paranoid ideation, and transient visual hallucinations. In the first 24 h after cessation of drinking, he presented hand tremor, anorexia, sweating, pulse rate of 105/min, hypertension (160/100 mm Hg), and insomnia. Mr. C. received gabapentin 400 mg tid for 3 days, 400 mg bid for 1 day, and finally 400 mg for 1 day. Withdrawal symptoms subsided within the second day of detoxification, except sweating, which subsided at the end of the next day, and hand tremor, which subsided 10 days after. No adjunctive medicine was given and no adverse effects caused by gabapentin were noted.
Taken together, these preliminary data suggest that the possible effectiveness of gabapentin in the treatment of alcohol withdrawal warrants further investigation by systematic and well-designed studies.
References Bonnet, U., Bauger, M., Leweke, F.M., Maschke, M., Kawalksi, T., Gastpar, M., 1999. Treatment of alcohol syndrome with gabapentin. Pharmacopsychiatry 32, 107 – 109. Cabras, P.L., Hardoy, M.J., Hardoy, M.C., Carta, M.G., 1999. Clinical experience with gabapentin in patients with bipolar or schizoaffective disorder: results of an open-label study. J. Clin. Psychiatry 60, 245 – 248. Erfurth, A., Krammerer, C., Grunze, H., Normann, C., Walden, J., 1998. An open label study of gabapentin in the treatment of acute mania. J. Psychiatr. Res. 32, 261 – 264. Heffner, T., 1999. Preclinical models of anxiety: profile of gabapentin. In: Sussman, N. (Ed.), Anticonvulsants in Psychiatry. Royal Society of Medicine Press, London, pp. 41 – 47. Hyman, S.E., Arana, G.W., Rosenbaum, J.F., 1995. Handbook of psychiatric Drug Therapy, 3rd ed. Little, Brown, and Company, Boston (Chapter 6). Kelly, K.M., 1998. Gabapentin: antiepileptic mechanism of action. Neuropsychobiology 38, 139 – 144.
V. Bozikas et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 197–199 Ketter, T.A., Frye, M.A., Cora-Locatelli, G., Kimbrell, T.A., Post, R.M., 1999. Metabolism and excretion of mood stabilizers and new anticonvulsants. Cell. Mol. Neurobiol. 19, 511 – 532. Knoll, J., Stegman, K., Suppes, T., 1998. Clinical experience using gabapentin adjunctively in patients with history of mania or hypomania. J. Affective Disord. 49, 229 – 233. Letterman, L., Markovitz, J.S., 1999. Gabapentin: a review of published experience in the treatment of bipolar disorder and other psychiatric conditions. Pharmacotherapy 19, 565 – 572. Malcolm, R., Ballenger, J.C., Sturgis, E.T., Anton, R., 1989. Double-blind controlled trial comparing carbamazepine to oxazepam treatment of alcohol withdrawal. Am. J. Psychiatry 146, 617 – 621. Myrick, H., Malcolm, R., Brady, K.T., 1998. Gabapentin treatment of alcohol withdrawal. Am. J. Psychiatry 155, 1626. Pande, A.C., Davidson, J.R.T., Jefferson, J.W., Janney, C.A., Katzelnick, D.J., Weisler, R.H., Greist, J.H., Sutherland, S.M., 1999. Treatment of
199
social phobia with gabapentin: a placebo-controlled study. J. Clin. Psychopharmacol. 19, 341 – 348. Perugi, G., Toni, C., Ruffolo, G., Sartini, S., Simonini, E., Akiskal, H., 1999. Clinical experience using adjunctive gabapentin in treatment-resistant bipolar mixed states. Pharmacopsychiatry 32, 136 – 141. Pollack, M.H., Matthews, J., Scott, E.L., 1998. Gabapentin as a potential treatment for anxiety disorders. Am. J. Psychiatry 155, 992 – 993. Rosenthal, R.N., Perkel, C., Singh, P., Anad, O., Miner, C.R., 1998. A pilot open randomized trial of valproate and phenobarbital in the treatment of acute alcohol withdrawal. Am. J. Addict. 7, 189 – 197. Watson, W.P., Robinson, E., Little, H.J., 1997. The novel anticonvulsant, gabapentin, protects against both convulsant and anxiogenic aspects of the ethanol withdrawal syndrome. Neuropharmacology 36, 1369 – 1375. Young, L.T., Robb, J.C., Hasey, G.M., MacQueen, G.M., Patelis-Siotis, I., Marriott, M., Joffe, R.T., 1999. Gabapentin as an adjunctive treatment in bipolar disorder. J. Affective Disord. 55, 73 – 77.
Treatment of alcohol withdrawal with gabapentin Vasilis Bozikas*, Petros Petrikis, Katerina Gamvrula, Ioanna Savvidou, Athanasios Karavatos First Department of Psychiatry, Aristotle University of Thessaloniki, Thessaloniki, Greece
Abstract Gabapentin is an anticonvulsant agent, also effective in the treatment of mood disorders and anxiety disorders. Three cases of alcohol withdrawal treated with gabapentin are presented. All patients received gabapentin 400 mg tid for 3 days, 400 mg bid for 1 day, and finally 400 mg for 1 day. Withdrawal symptoms subsided and no adverse effects were observed. The possible effectiveness of gabapentin in the treatment of alcohol withdrawal warrants further investigation by systematic and well-designed studies. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Alcohol withdrawal; Anticonvulsant; Gabapentin
1. Introduction Gabapentin is a second-generation anticonvulsant, which does not bind to GABAA or GABAB receptors and does not interact with those sites affected by benzodiazepines. This drug binds a2d-subunit of L-type calcium channels and increases the synthesis and nonsynaptic release of GABA in the brain (Kelly, 1998). In psychiatry, gabapentin is used mainly as an adjunctive to previous treatment-resistant patients suffering from bipolar disorder (Erfurth et al., 1998; Knoll et al., 1998; Cabras et al., 1999; Perugi et al., 1999; Young et al., 1999). There are reports that it has also anxiolytic effects and that it can be successfully applied in anxiety disorder, e.g., in social phobia and generalized anxiety disorder (Pollack et al., 1998; Pande et al., 1999). Gabapentin demonstrated a selective action in decreasing both convulsive and anxiety-related aspects of withdrawal behaviour in mice after chronic ethanol treatment in doses that had no sedative or ataxic effect on animals (Watson et al., 1997). Myrick et al. (1998) reported the effective use of gabapentin as monotherapy in the treatment of alcohol withdrawal in six outpatients. Also, the drug had beneficial effects in the treatment of moderate alcohol withdrawal in four inpatients in an add-on fashion to clomethiazole, although two of them did not need any adjunctive medica-
* Corresponding author. 19 Iatrou Magou Str., Giannitsa 58100, Greece. Tel.: +30-3199-2311, +30-3199-2312; fax: +30-3199-2319.
tion and in three of them gabapentin led to a radical reduction in clomethiazole administration compared with previous detoxifications (Bonnet et al., 1999). In this paper, three cases of alcohol withdrawal treated with gabapentin are presented.
2. Case reports 2.1. Case 1 Mr. A. is a 32-year-old, single, unemployed man with a type B alcohol dependence. He is described as introverted and emotionally restricted, has no close relationships, and avoids making a family. His history of alcohol consumption combined with occasional use of cannabis started when he was 14 years old. By the age of 23 and for the next 2 1/2 years, the patient showed only opioid dependence. Afterwards, he restarted the daily consumption of enormous quantities of alcohol, together with occasional use of heroin and cannabis. As a consequence of the combined heroin and alcohol use, Mr. A. experienced delusions of persecution and reference and he attempted suicide by violent means 2 years ago. Then, he was, for the first time in his life, hospitalized in our clinic. In the next years, he had four admissions to our clinic for alcohol detoxification. Unfortunately, the biggest interval that he remained free of alcohol was 3 1/2 months, meanwhile abusing benzodiazepines. He has a child history of repeated cruel physical abuse from his father. The two
0278-5846/02/$ – see front matter D 2001 Elsevier Science Inc. All rights reserved. PII: S 0 2 7 8 - 5 8 4 6 ( 0 1 ) 0 0 2 3 4 - 2
198
V. Bozikas et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 197–199
brothers of his father suffer also from alcoholism. The patient is an HCV carrier. Mr. A. was re-admitted to our clinic about 48 h after a cessation of alcohol consumption. He showed hand tremor, sweating, pulse rate of 110/min, nausea, anxiety, and insomnia. The patient received gabapentin 400 mg tid for 3 days, 400 mg bid for 1 day, and finally 400 mg for 1 day. Withdrawal symptoms subsided within 2 days, except of insomnia, which subsided in 5 days after the initiation of treatment. Lorazepam 2.5 mg was given to him only for one night. No adverse effects caused by gabapentin were noted. 2.2. Case 2 Mr. B. is a 58-year-old, single, unemployed man with alcohol dependence. He is described as introverted, has no family relationships and close friends, and his affairs lack of strong affective investment. The patient has reported high daily consumption of alcohol for the last 10 years. He has been hospitalized for delirium tremens almost annually for the last 7 years. Mr. B. was admitted to our clinic for the first time 24 h after a cessation of alcohol consumption. He showed hand tremor, sweating, nausea, anorexia, and anxiety. The patient received gabapentin 400 mg tid for 3 days, 400 mg bid for 1 day, and finally 400 mg for 1 day. Withdrawal symptoms subsided within 2 days after the initiation of treatment. No adjunctive medicine was given and no adverse effects caused by gabapentin were noted.
3. Discussion Chlordiazepoxide and diazepam are the standard therapy for alcohol withdrawal. The effectiveness of benzodiazepines is based on their pharmacologic cross-tolerance with ethanol for GABAA receptors (Hyman et al., 1995). Carbamazepine was found to be an effective and safe alternative to benzodiazepine treatment for alcohol withdrawal, probably through an antikindling effect (Malcolm et al., 1989). A study of valproate has also been performed, but without conclusive results (Rosenthal et al., 1998). The three cases that were reported above are consistent with the findings of Myrick et al. (1998) and Bonnet et al. (1999) about gabapentin effectiveness in the treatment of alcohol withdrawal. In our study, we used the same doses that Myrick et al. (1998) had proposed. Bonnet et al. (1999), in their study, administrated to the patients 400 mg gabapentin qid (400 mg every 6 h) during the first 48 h of detoxification and from the third day, the daily dose of gabapentin was reduced by 400 mg daily. Benzodiazepines may be maintained as agents of choice in the therapy of delirium tremens. Gabapentin lacks drug interactions due to absence of protein binding and hepatic metabolism (Ketter et al., 1999), so it is not affected by liver dysfunction (Letterman and Markovitz, 1999). Moreover, this agent lacks the side effects of the anxiolytic drugs (Heffner, 1999) and abuse potential (Myrick et al., 1998; Bonnet et al., 1999), making it useful in the management of alcohol withdrawal states in outpatient settings.
2.3. Case 3 4. Conclusion Mr. C. is a 39-year-old, married man with alcohol dependence. His history of alcohol abuse started 9 years ago and soon it escalated to dependence. The pattern of his alcohol consumption was characterized by binges lasting for about 20 – 30 days. As a result, during the periods of alcohol binge, he presented serious occupational and social impairment, verbal abuse of his wife, and neglect of his 1-year-old daughter. Mr. C. has no other history of substance abuse. The patient was admitted to our clinic after an episode of binge, which started 17 days ago. This time, except occupational and family problems, he showed mild depressive mood, paranoid ideation, and transient visual hallucinations. In the first 24 h after cessation of drinking, he presented hand tremor, anorexia, sweating, pulse rate of 105/min, hypertension (160/100 mm Hg), and insomnia. Mr. C. received gabapentin 400 mg tid for 3 days, 400 mg bid for 1 day, and finally 400 mg for 1 day. Withdrawal symptoms subsided within the second day of detoxification, except sweating, which subsided at the end of the next day, and hand tremor, which subsided 10 days after. No adjunctive medicine was given and no adverse effects caused by gabapentin were noted.
Taken together, these preliminary data suggest that the possible effectiveness of gabapentin in the treatment of alcohol withdrawal warrants further investigation by systematic and well-designed studies.
References Bonnet, U., Bauger, M., Leweke, F.M., Maschke, M., Kawalksi, T., Gastpar, M., 1999. Treatment of alcohol syndrome with gabapentin. Pharmacopsychiatry 32, 107 – 109. Cabras, P.L., Hardoy, M.J., Hardoy, M.C., Carta, M.G., 1999. Clinical experience with gabapentin in patients with bipolar or schizoaffective disorder: results of an open-label study. J. Clin. Psychiatry 60, 245 – 248. Erfurth, A., Krammerer, C., Grunze, H., Normann, C., Walden, J., 1998. An open label study of gabapentin in the treatment of acute mania. J. Psychiatr. Res. 32, 261 – 264. Heffner, T., 1999. Preclinical models of anxiety: profile of gabapentin. In: Sussman, N. (Ed.), Anticonvulsants in Psychiatry. Royal Society of Medicine Press, London, pp. 41 – 47. Hyman, S.E., Arana, G.W., Rosenbaum, J.F., 1995. Handbook of psychiatric Drug Therapy, 3rd ed. Little, Brown, and Company, Boston (Chapter 6). Kelly, K.M., 1998. Gabapentin: antiepileptic mechanism of action. Neuropsychobiology 38, 139 – 144.
V. Bozikas et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 197–199 Ketter, T.A., Frye, M.A., Cora-Locatelli, G., Kimbrell, T.A., Post, R.M., 1999. Metabolism and excretion of mood stabilizers and new anticonvulsants. Cell. Mol. Neurobiol. 19, 511 – 532. Knoll, J., Stegman, K., Suppes, T., 1998. Clinical experience using gabapentin adjunctively in patients with history of mania or hypomania. J. Affective Disord. 49, 229 – 233. Letterman, L., Markovitz, J.S., 1999. Gabapentin: a review of published experience in the treatment of bipolar disorder and other psychiatric conditions. Pharmacotherapy 19, 565 – 572. Malcolm, R., Ballenger, J.C., Sturgis, E.T., Anton, R., 1989. Double-blind controlled trial comparing carbamazepine to oxazepam treatment of alcohol withdrawal. Am. J. Psychiatry 146, 617 – 621. Myrick, H., Malcolm, R., Brady, K.T., 1998. Gabapentin treatment of alcohol withdrawal. Am. J. Psychiatry 155, 1626. Pande, A.C., Davidson, J.R.T., Jefferson, J.W., Janney, C.A., Katzelnick, D.J., Weisler, R.H., Greist, J.H., Sutherland, S.M., 1999. Treatment of
199
social phobia with gabapentin: a placebo-controlled study. J. Clin. Psychopharmacol. 19, 341 – 348. Perugi, G., Toni, C., Ruffolo, G., Sartini, S., Simonini, E., Akiskal, H., 1999. Clinical experience using adjunctive gabapentin in treatment-resistant bipolar mixed states. Pharmacopsychiatry 32, 136 – 141. Pollack, M.H., Matthews, J., Scott, E.L., 1998. Gabapentin as a potential treatment for anxiety disorders. Am. J. Psychiatry 155, 992 – 993. Rosenthal, R.N., Perkel, C., Singh, P., Anad, O., Miner, C.R., 1998. A pilot open randomized trial of valproate and phenobarbital in the treatment of acute alcohol withdrawal. Am. J. Addict. 7, 189 – 197. Watson, W.P., Robinson, E., Little, H.J., 1997. The novel anticonvulsant, gabapentin, protects against both convulsant and anxiogenic aspects of the ethanol withdrawal syndrome. Neuropharmacology 36, 1369 – 1375. Young, L.T., Robb, J.C., Hasey, G.M., MacQueen, G.M., Patelis-Siotis, I., Marriott, M., Joffe, R.T., 1999. Gabapentin as an adjunctive treatment in bipolar disorder. J. Affective Disord. 55, 73 – 77.