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Flumazenil reversal of carisoprodol (Soma) intoxication
The Journal of Emergency Medicine, Vol. 18, No. 1, pp. 61– 64, 2000 Copyright © 2000 Elsevier Science Inc. Printed in the USA. All rights reserved 0736-4679/00 $–see front matter
PII S0736-4679(99)00177-8
Selected Topics: Toxicology
FLUMAZENIL REVERSAL OF CARISOPRODOL (SOMA) INTOXICATION Raymond J. Roberge,
MD, MPH, FAAEM, ACMT,*
Esson Lin,
MD,†
and Edward P. Krenzelok,
PharmD, DABAT‡
*Department of Emergency Medicine, Western Pennsylvania Hospital; †Affiliated Residency in Emergency Medicine, University of Pittsburgh School of Medicine; ‡Pittsburgh Poison Center, Pittsburgh, Pennsylvania Reprint Address: Raymond J. Roberge, MD, MPH, FAAEM, ACMT, Department of Emergency Medicine, Western Pennsylvania Hospital, 4800 Friendship Avenue, Pittsburgh, PA 15224
e Abstract—A 52-year-old woman presented with central nervous system depression and a Glasgow Coma Score of 9 secondary to ingestion of carisoprodol, a centrally acting muscle relaxant analgesic. After administration of i.v. flumazenil, the patient’s neurologic status normalized and she required no further therapy. Carisoprodol and its active sedative-hypnotic metabolite, meprobamate, are gamma aminobutyric acid receptor indirect agonists with central nervous system chloride ion channel conduction effects similar to the benzodiazepines, thus making flumazenil a potentially useful antidote in toxic presentations. © 2000 Elsevier Science Inc.
CASE REPORT A 51-year-old woman was transported to our emergency department (ED) via ambulance with lethargy, abnormal speech, and earlier robot-like movements. According to family members, the patient was supposed to take two tablets of carisoprodol (350 mg each) qid for back discomfort but was depressed and was thought to be taking her medication in an erratic fashion. A prescription bottle of 100 carisoprodol tablets filled 13 days before admission contained 13 tablets. Prior medical history included low back pain, hypertension, and depression. Current medications were carisoprodol, clonidine, and buspirone; compliance was questionable. In the ED, the patient was stuporous but could be aroused by forceful tactile stimuli. She was confused, varying from unintelligible sounds to slow, garbled speech. The initial Glasgow Coma Score was 9 (E3, T2, M4); the remainder of the physical examination was significant only for reactive small (2-mm) pupils. Vital signs were: blood pressure 152/98 mmHg, heart rate 84 beats/min and regular, respirations 18 breaths/min but somewhat shallow, rectal temperature 36.4°C, and pulse oximetry 96% on ambient oxygen. The 12-lead electrocardiogram (EKG) was normal, as was a chest radiograph. A prehospital glucose check was reported as 80 –120 mg/dL. Two i.v. naloxone boluses (2 mg each) were administered 5 minutes apart in the ED with no discernible effect and no change in pupillary size. Flumazenil (0.2 mg i.v. over 2 min) was administered 10 min after the last naloxone dose, and the
e Keywords— carisoprodol; meprobamate; flumazenil; intoxication; reversal.
INTRODUCTION Carisoprodol is a centrally acting skeletal muscle relaxant analgesic that has been used for several decades in the treatment of spastic muscle disorders. Carisoprodol’s active metabolite, meprobamate, is a sedative-hypnotic (1). We present a case of carisoprodol intoxication associated with elevated meprobamate levels, that was reversed after administration of the benzodiazepine antidote flumazenil. Carisoprodol and meprobamate toxicity are reviewed, and the role of flumazenil in toxic presentations is discussed.
RECEIVED: 5 February 1999; FINAL ACCEPTED: 7 July 1999
SUBMISSION RECEIVED:
9 June 1999; 61
62
R. J. Roberge et al.
patient became more alert and conversant within 2 min, though her speech remained somewhat thick and she was mildly somnolent. A second, equal dose of flumazenil 5 min later reversed all signs of intoxication within 2 min. The patient denied suicidal or homicidal ideation and admitted that she had been taking her carisoprodol in an irregular pattern over the past week with increased use over the previous 2 days, though she could not estimate the actual amount ingested in the prior 48 h. The patient’s status remained normal during an observation period of 4 h in the ED, and she was discharged after follow-up arrangements were made with her private physician. A comprehensive drug screen performed on blood and urine obtained at the time of presentation, using gas chromatography/mass spectrometry (GC/MS) confirmation, was subsequently reported positive only for carisoprodol (serum levels of 7.4 mcg/mL) and heprobamate (serum level 30.7 mcg/mL).
DISCUSSION Carisoprodol (isopropylmeprobamate) is a commonly prescribed, noncontrolled, centrally acting muscle relaxant analgesic (Soma, others) developed in 1956 for the treatment of spastic muscle disorders (1). Early animal studies indicated that carisoprodol produces muscle relaxation by blocking interneuronal activity and depressing transmission of polysynaptic neurons in the spinal cord and descending reticular system of the brain (2). Well-designed human studies demonstrating muscle relaxation are lacking, and sedation is thought to account for most of carisoprodol’s clinical effects (1,3). Rapid gastrointestinal absorption results in peak carisoprodol plasma concentrations of 4 g/mL to 7 g/mL within 2– 4 h, and onset of action is within 30 min of ingestion (1). Carisoprodol undergoes hepatic biotransformation to hydroxycarisoprodol, hydroxymeprobamate, and an active sedative-hypnotic metabolite, meprobamate, all of which are primarily eliminated by the kidneys (1,4). Liver metabolism is catalyzed by P-450 enzyme, CYP2C19, with a mean carisoprodol half-life (t1/2) of 99 min ⫹/⫺ 46 min (5). Genetically determined hepatic metabolic polymorphism may influence drug elimination. Poor metabolizers of mephytoin clear carisoprodol four times more slowly than extensive metabolizers, placing these individuals at increased risk of developing concentration-dependent side effects even at normal therapeutic doses of carisoprodol (4). The rate of meprobamate formation exceeds the absorption rate of carisoprodol after normal doses (6). Meprobamate levels exceeded those of carisoprodol 2–1/2 h after oral administration of 700 mg of carisoprodol to healthy volunteers (5). The elimination t1/2 of meprobamate averages 12 h
but may be decreased via hepatic enzyme induction with chronic exposure or prolonged in overdose states (7). Carisoprodol toxicity may present as two distinctly different syndromes, depending on whether carisoprodol or meprobamate effects supervene. Carisoprodol toxicity is noted with serum carisoprodol levels ⬎ 25 mcg/mL and commonly manifests as agitation and bizarre movement disorders (myoclonus, choreiform movements, myoclonic encephalopathy) (8,9). Such findings are described in association with elevated carisoprodol levels early in the course of overdose before significant liver metabolism to meprobamate (8). Massive acute ingestions, or overdose in those individuals who are slow metabolizers of carisoprodol, can result in significantly elevated serum levels and predominantly carisoprodol manifestations of toxicity (4,7). Seizures with acute overdose have been reported, and drug-induced agitation can lead to myoglobinuria with the possibility of associated renal failure (7,10,11). Agitation and muscular rigidity have been observed for 2 days after significant overdose, and convulsions were noted for 17 h in one patient after carisoprodol poisoning (8,11). Our patient’s “robotic movements” before presentation, as described by family members, could have represented a movement disorder early in the course of her intoxication when carisoprodol levels may have been higher. Although most clinical findings after overdose are central nervous system (CNS)-depressant in nature and ostensibly related to meprobamate, Roth et al. report that 16% of carisoprodol overdoses in their regional poison center had findings consistent with agitation and bizarre movement disorders (8). Treatment is mainly supportive, and, although seemingly counterintuitive, the use of muscle relaxants or neuromuscular blocking agents to treat prolonged muscular rigidity after carisoprodol overdose may be warranted, though this has not been subjected to clinical scrutiny. Meprobamate, structurally a carbamate and pharmacologically similar to barbiturates, was synthesized in the 1940s as a muscle relaxant and marketed in this country in 1955 as an anxiolytic agent (1,7). Toxicity generally manifests as CNS depression and may be associated with respiratory depression and cardiac failure (6). Therapeutic serum levels range from 5–20 g/mL, and stupor and lethargy are noted with levels of 30 –100 g/mL (12). Serum levels do not necessarily correlate with clinical effects, in part because tolerance develops after prolonged use (13). Our patient used carisoprodol only on a sporadic basis and probably was not acclimated to the drug, thus experiencing toxic effects at serum meprobamate levels only 50% above the therapeutic range (12). Flumazenil is an imidazobenzodiazepine that acts as a competitive antagonist of CNS benzodiazepine receptors (14). Benzodiazepines are thought to exert their anxio-
Flumazenil Reversal of Carisoprodol Intoxication Table 1. Non-Benzodiazepine Drugs Reported to be Reversed by Flumazenil* Baclofen (16) Carbamazepine (17) Chloral hydrate (18) Chlorzoxazone (19) Ethanol (20) Promethazine (14) Phenothiazines (21) Meprobamate (22) Tetrahydrocannabinol (23) Zolpidem (24–26) *Efficacy has not been established. Numbers in parentheses are references.
lytic, depressant, and anticonvulsive effects through an interaction with the inhibitory neurotransmitter, ␥-aminobutyric acid (GABA), of which there are two subtypes of receptors (GABAA and GABAB) (15). GABAA receptors are a structural component of the chloride ion (Cl⫺) channels and mediate neuroinhibition by facilitating Cl⫺ conductance with resultant hyperpolarization of the postsynaptic neuronal membrane (14,15). Drugs such as benzodiazepines, barbiturates, and ethanol have receptor sites in close proximity to the GABAA receptor and are direct-acting GABAA agonists (15). Flumazenil, originally considered a specific benzodiazepine antagonist, has been reported to reverse CNS depressant effects of a number of other nonbenzodiazepine drugs (Table 1), the implication being that these drugs interact with GABAA receptors (14,16 –25). Carisoprodol and meprobamate are known to be indirect GABAA agonists, thereby lending a plausible explanation for the efficacy of flumazenil in the present case (15). Previously, one report documented that flumazenil was successful in reversing some toxic manifestations of a combined benzodiazepine/meprobamate overdose confirmed by toxicologic testing (22). Unfortunately, significant overlap in the toxic manifestations of overdose for both drugs, and the lack of quantitative serum drug levels, precludes accurate apportionment of flumazenil antidotal activity in that case. Our patient’s drug screen and GC/MS confirmation only demonstrated the presence of a low serum level of carisoprodol and elevated serum meprobamate, thus suggesting that flumazenil reversed the meprobamate effects. Although the dose of flumazenil we used was small, it is similar to that reported for reversal of coma after overdose of another nonbenzodiazepine muscle relaxant, chlorzoxazone (19). It may be that certain drugs have affinities of different degree for the GABAA receptor and may require smaller doses of flumazenil for reversal of effects, though this assumption requires verification. Caution is advised when using flumazenil in patients on long-term carisoprodol or meprobamate therapy, as withdrawal can be precipitated (1). Similarly, although cari-
63
soprodol is considered a Cl⫺ channel indirect agonist, flumazenil probably should not be used as an antidote for toxicity presenting as agitation, movement abnormalities, or muscular rigidity pending further clinical experience and research. Our patient experienced CNS depression associated with an elevated meprobamate level secondary to subacute ingestion of an unknown amount of carisoprodol. Meprobamate and carisoprodol share some benzodiazepine-like CNS effects due, in part, to indirect agonism of the GABAA receptor with resultant hyperpolarization of postsynaptic neurons. The benzodiazepine antagonist flumazenil reversed all manifestations of CNS toxicity, and the patient required no further therapy.
REFERENCES 1. Littrell RA, Hayes LR, Stillner V. Carisoprodol (Soma): a new and cautious perspective on an old agent. South Med J 1993;86:753– 6. 2. del Castillo J, Nelson T. The mode of action of carisoprodol. Ann N Y Acad Sci 1960;86:108 – 42. 3. Elenbaas JK. Centrally acting oral skeletal muscle relaxants. Am J Hosp Pharm 1980;37:1313–23. 4. Dalen P, Alvan G, Wakelkamp M, Olsen H. Formation of meprobamate from carisoprodol is catalyzed by CYP2C19. Pharmacogenetics 1996;6:387–94. 5. Olsen H, Koppang E, Alvan G, Morland J. Carisoprodol elimination in humans. Ther Drug Monit 1994;16:337– 40. 6. Ellenhorn MJ, Barceloux DG. Medical toxicology: diagnosis and treatment of human poisoning, New York: Elsevier Science Publishing; 1988. 7. Henretig FM, Vuignier BI. Other sedative-hypnotics. In: HarwoodNuss A, Linden C, Luten RC, Sternback G, Wolfson AB, eds. The Clinical Practice of Emergency Medicine. Philadelphia: JB Lippincott; 1991:576 –9. 8. Roth BA, Vinson DR, Kim S. Carisoprodol-induced myoclonic encephalopathy. J Toxicol Clin Toxicol 1998;36:609 –12. 9. Goldberg D. Carisoprodol toxicity. Mil Med 1969;134:597– 601. 10. Elder NC. Abuse of skeletal muscle relaxants. Am Fam Physician 1991;44:1223– 6. 11. Brandslund I. Et tilfaelde af akut karisoprodolforgiftning. Symptomkompleks og metabolisering. (Danish) [A case of acute carisoprodol poisoning. Symptoms and metabolism]. Ugeskr Laeger 1976;138:281–3. 12. Physicians’ Desk Reference: 49th edn. Montvale, NJ: Medical Economics; 1995. 13. Bailey DN. The present status of meprobamate ingestion. A fiveyear review of cases with serum concentrations and clinical findings. Am J Clin Pathol 1981;75:102– 6. 14. Plant JR, MacLeod DB. Response of a promethazine-induced coma to flumazenil. Ann Emer Med 1994;24:979 – 82. 15. Osborn H, Goldfrank LR. Sedative-hypnotic agents. In: Goldfrank LR, Flomenbaum NE, Lewin NA, Weisman RS, Howland MA, Hoffman RS, eds. Goldfrank’s Toxicologic Emergencies, 5th edn. Norwalk, CT: Appleton Lange; 1996:787– 804. 16. Saissy JM, Vitris M, Demaziere J, et al. Flumazenil counteracts intrathecal baclofen-induced central nervous system depression in tetanus. Anesthesiology 1992;76:1051–3. 17. Zuber M, Elsasser S, Ritz R, Scollo-Lanizzari G. Flumazenil (Anexate) in severe intoxication with carbamazepine (Tegretol). Eur Neurol 1988;28:161–3. 18. Donovan KL, Fisher DJ. Reversal of chloral hydrate overdose with flumazenil. Br Med J 1989;298:1253. 19. Roberge RJ, Atchley B, Ryan K, Krenzelok EP. Two chlorzoxa-
64 zone (Parafon forte) overdoses and coma in one patient: reversal with flumazenil. Am J Emer Med 1998;16:393–5. 20. Linowiecki K, Paloucek F, Donnelly A, Leikin JB. Reversal of ethanol-induced respiratory depression by flumazenil. Vet Hum Toxicol 1992;34:417–9. 21. O’Sullivan GF, Wade DN. Flumazenil in the management of acute drug overdose with benzodiazepines and other agents. Clin Pharmacol Ther 1987;42:254 –9. 22. Pollard BJ, Masters AP, Bunting P. The use of flumazenil (Anexate, Ro 15–1788) in the management of drug overdose. Anaesthesia 1989;44:137– 8.
R. J. Roberge et al. 23. Rubio F, Quintero S, Hernandez A, et al. Flumazenil for coma reversal in children after cannabis. (Letter) Lancet 1993:1028 –9. 24. Wyss PA, Radovanovic D, Meier-Abt PJ. Akute uberdosierungen mit Zolpidem (Stilnox). (German) [Acute overdose of Zolpidem (Stilnox)]. Schweiz Med Wochenschr 1996;126:750 – 6. 25. Carbajal R, Blanc P, Paupe A, et al. Flumazenil dans les intoxications au zolpidem chez l’enfant. (French) Flumazenil in zolpidem poisoning in children. (Letter) Arch de Pediatrie 1996;3:191–2. 26. Burton JH, Lyon L, Dorfman T, Tomassoni AJ. Continuous flumazenil infusion in the treatment of zolpidem (Ambien) and ethanol ingestion. (Letter) J Toxicol Clin Toxicol 1998;36:743– 4.
PII S0736-4679(99)00177-8
Selected Topics: Toxicology
FLUMAZENIL REVERSAL OF CARISOPRODOL (SOMA) INTOXICATION Raymond J. Roberge,
MD, MPH, FAAEM, ACMT,*
Esson Lin,
MD,†
and Edward P. Krenzelok,
PharmD, DABAT‡
*Department of Emergency Medicine, Western Pennsylvania Hospital; †Affiliated Residency in Emergency Medicine, University of Pittsburgh School of Medicine; ‡Pittsburgh Poison Center, Pittsburgh, Pennsylvania Reprint Address: Raymond J. Roberge, MD, MPH, FAAEM, ACMT, Department of Emergency Medicine, Western Pennsylvania Hospital, 4800 Friendship Avenue, Pittsburgh, PA 15224
e Abstract—A 52-year-old woman presented with central nervous system depression and a Glasgow Coma Score of 9 secondary to ingestion of carisoprodol, a centrally acting muscle relaxant analgesic. After administration of i.v. flumazenil, the patient’s neurologic status normalized and she required no further therapy. Carisoprodol and its active sedative-hypnotic metabolite, meprobamate, are gamma aminobutyric acid receptor indirect agonists with central nervous system chloride ion channel conduction effects similar to the benzodiazepines, thus making flumazenil a potentially useful antidote in toxic presentations. © 2000 Elsevier Science Inc.
CASE REPORT A 51-year-old woman was transported to our emergency department (ED) via ambulance with lethargy, abnormal speech, and earlier robot-like movements. According to family members, the patient was supposed to take two tablets of carisoprodol (350 mg each) qid for back discomfort but was depressed and was thought to be taking her medication in an erratic fashion. A prescription bottle of 100 carisoprodol tablets filled 13 days before admission contained 13 tablets. Prior medical history included low back pain, hypertension, and depression. Current medications were carisoprodol, clonidine, and buspirone; compliance was questionable. In the ED, the patient was stuporous but could be aroused by forceful tactile stimuli. She was confused, varying from unintelligible sounds to slow, garbled speech. The initial Glasgow Coma Score was 9 (E3, T2, M4); the remainder of the physical examination was significant only for reactive small (2-mm) pupils. Vital signs were: blood pressure 152/98 mmHg, heart rate 84 beats/min and regular, respirations 18 breaths/min but somewhat shallow, rectal temperature 36.4°C, and pulse oximetry 96% on ambient oxygen. The 12-lead electrocardiogram (EKG) was normal, as was a chest radiograph. A prehospital glucose check was reported as 80 –120 mg/dL. Two i.v. naloxone boluses (2 mg each) were administered 5 minutes apart in the ED with no discernible effect and no change in pupillary size. Flumazenil (0.2 mg i.v. over 2 min) was administered 10 min after the last naloxone dose, and the
e Keywords— carisoprodol; meprobamate; flumazenil; intoxication; reversal.
INTRODUCTION Carisoprodol is a centrally acting skeletal muscle relaxant analgesic that has been used for several decades in the treatment of spastic muscle disorders. Carisoprodol’s active metabolite, meprobamate, is a sedative-hypnotic (1). We present a case of carisoprodol intoxication associated with elevated meprobamate levels, that was reversed after administration of the benzodiazepine antidote flumazenil. Carisoprodol and meprobamate toxicity are reviewed, and the role of flumazenil in toxic presentations is discussed.
RECEIVED: 5 February 1999; FINAL ACCEPTED: 7 July 1999
SUBMISSION RECEIVED:
9 June 1999; 61
62
R. J. Roberge et al.
patient became more alert and conversant within 2 min, though her speech remained somewhat thick and she was mildly somnolent. A second, equal dose of flumazenil 5 min later reversed all signs of intoxication within 2 min. The patient denied suicidal or homicidal ideation and admitted that she had been taking her carisoprodol in an irregular pattern over the past week with increased use over the previous 2 days, though she could not estimate the actual amount ingested in the prior 48 h. The patient’s status remained normal during an observation period of 4 h in the ED, and she was discharged after follow-up arrangements were made with her private physician. A comprehensive drug screen performed on blood and urine obtained at the time of presentation, using gas chromatography/mass spectrometry (GC/MS) confirmation, was subsequently reported positive only for carisoprodol (serum levels of 7.4 mcg/mL) and heprobamate (serum level 30.7 mcg/mL).
DISCUSSION Carisoprodol (isopropylmeprobamate) is a commonly prescribed, noncontrolled, centrally acting muscle relaxant analgesic (Soma, others) developed in 1956 for the treatment of spastic muscle disorders (1). Early animal studies indicated that carisoprodol produces muscle relaxation by blocking interneuronal activity and depressing transmission of polysynaptic neurons in the spinal cord and descending reticular system of the brain (2). Well-designed human studies demonstrating muscle relaxation are lacking, and sedation is thought to account for most of carisoprodol’s clinical effects (1,3). Rapid gastrointestinal absorption results in peak carisoprodol plasma concentrations of 4 g/mL to 7 g/mL within 2– 4 h, and onset of action is within 30 min of ingestion (1). Carisoprodol undergoes hepatic biotransformation to hydroxycarisoprodol, hydroxymeprobamate, and an active sedative-hypnotic metabolite, meprobamate, all of which are primarily eliminated by the kidneys (1,4). Liver metabolism is catalyzed by P-450 enzyme, CYP2C19, with a mean carisoprodol half-life (t1/2) of 99 min ⫹/⫺ 46 min (5). Genetically determined hepatic metabolic polymorphism may influence drug elimination. Poor metabolizers of mephytoin clear carisoprodol four times more slowly than extensive metabolizers, placing these individuals at increased risk of developing concentration-dependent side effects even at normal therapeutic doses of carisoprodol (4). The rate of meprobamate formation exceeds the absorption rate of carisoprodol after normal doses (6). Meprobamate levels exceeded those of carisoprodol 2–1/2 h after oral administration of 700 mg of carisoprodol to healthy volunteers (5). The elimination t1/2 of meprobamate averages 12 h
but may be decreased via hepatic enzyme induction with chronic exposure or prolonged in overdose states (7). Carisoprodol toxicity may present as two distinctly different syndromes, depending on whether carisoprodol or meprobamate effects supervene. Carisoprodol toxicity is noted with serum carisoprodol levels ⬎ 25 mcg/mL and commonly manifests as agitation and bizarre movement disorders (myoclonus, choreiform movements, myoclonic encephalopathy) (8,9). Such findings are described in association with elevated carisoprodol levels early in the course of overdose before significant liver metabolism to meprobamate (8). Massive acute ingestions, or overdose in those individuals who are slow metabolizers of carisoprodol, can result in significantly elevated serum levels and predominantly carisoprodol manifestations of toxicity (4,7). Seizures with acute overdose have been reported, and drug-induced agitation can lead to myoglobinuria with the possibility of associated renal failure (7,10,11). Agitation and muscular rigidity have been observed for 2 days after significant overdose, and convulsions were noted for 17 h in one patient after carisoprodol poisoning (8,11). Our patient’s “robotic movements” before presentation, as described by family members, could have represented a movement disorder early in the course of her intoxication when carisoprodol levels may have been higher. Although most clinical findings after overdose are central nervous system (CNS)-depressant in nature and ostensibly related to meprobamate, Roth et al. report that 16% of carisoprodol overdoses in their regional poison center had findings consistent with agitation and bizarre movement disorders (8). Treatment is mainly supportive, and, although seemingly counterintuitive, the use of muscle relaxants or neuromuscular blocking agents to treat prolonged muscular rigidity after carisoprodol overdose may be warranted, though this has not been subjected to clinical scrutiny. Meprobamate, structurally a carbamate and pharmacologically similar to barbiturates, was synthesized in the 1940s as a muscle relaxant and marketed in this country in 1955 as an anxiolytic agent (1,7). Toxicity generally manifests as CNS depression and may be associated with respiratory depression and cardiac failure (6). Therapeutic serum levels range from 5–20 g/mL, and stupor and lethargy are noted with levels of 30 –100 g/mL (12). Serum levels do not necessarily correlate with clinical effects, in part because tolerance develops after prolonged use (13). Our patient used carisoprodol only on a sporadic basis and probably was not acclimated to the drug, thus experiencing toxic effects at serum meprobamate levels only 50% above the therapeutic range (12). Flumazenil is an imidazobenzodiazepine that acts as a competitive antagonist of CNS benzodiazepine receptors (14). Benzodiazepines are thought to exert their anxio-
Flumazenil Reversal of Carisoprodol Intoxication Table 1. Non-Benzodiazepine Drugs Reported to be Reversed by Flumazenil* Baclofen (16) Carbamazepine (17) Chloral hydrate (18) Chlorzoxazone (19) Ethanol (20) Promethazine (14) Phenothiazines (21) Meprobamate (22) Tetrahydrocannabinol (23) Zolpidem (24–26) *Efficacy has not been established. Numbers in parentheses are references.
lytic, depressant, and anticonvulsive effects through an interaction with the inhibitory neurotransmitter, ␥-aminobutyric acid (GABA), of which there are two subtypes of receptors (GABAA and GABAB) (15). GABAA receptors are a structural component of the chloride ion (Cl⫺) channels and mediate neuroinhibition by facilitating Cl⫺ conductance with resultant hyperpolarization of the postsynaptic neuronal membrane (14,15). Drugs such as benzodiazepines, barbiturates, and ethanol have receptor sites in close proximity to the GABAA receptor and are direct-acting GABAA agonists (15). Flumazenil, originally considered a specific benzodiazepine antagonist, has been reported to reverse CNS depressant effects of a number of other nonbenzodiazepine drugs (Table 1), the implication being that these drugs interact with GABAA receptors (14,16 –25). Carisoprodol and meprobamate are known to be indirect GABAA agonists, thereby lending a plausible explanation for the efficacy of flumazenil in the present case (15). Previously, one report documented that flumazenil was successful in reversing some toxic manifestations of a combined benzodiazepine/meprobamate overdose confirmed by toxicologic testing (22). Unfortunately, significant overlap in the toxic manifestations of overdose for both drugs, and the lack of quantitative serum drug levels, precludes accurate apportionment of flumazenil antidotal activity in that case. Our patient’s drug screen and GC/MS confirmation only demonstrated the presence of a low serum level of carisoprodol and elevated serum meprobamate, thus suggesting that flumazenil reversed the meprobamate effects. Although the dose of flumazenil we used was small, it is similar to that reported for reversal of coma after overdose of another nonbenzodiazepine muscle relaxant, chlorzoxazone (19). It may be that certain drugs have affinities of different degree for the GABAA receptor and may require smaller doses of flumazenil for reversal of effects, though this assumption requires verification. Caution is advised when using flumazenil in patients on long-term carisoprodol or meprobamate therapy, as withdrawal can be precipitated (1). Similarly, although cari-
63
soprodol is considered a Cl⫺ channel indirect agonist, flumazenil probably should not be used as an antidote for toxicity presenting as agitation, movement abnormalities, or muscular rigidity pending further clinical experience and research. Our patient experienced CNS depression associated with an elevated meprobamate level secondary to subacute ingestion of an unknown amount of carisoprodol. Meprobamate and carisoprodol share some benzodiazepine-like CNS effects due, in part, to indirect agonism of the GABAA receptor with resultant hyperpolarization of postsynaptic neurons. The benzodiazepine antagonist flumazenil reversed all manifestations of CNS toxicity, and the patient required no further therapy.
REFERENCES 1. Littrell RA, Hayes LR, Stillner V. Carisoprodol (Soma): a new and cautious perspective on an old agent. South Med J 1993;86:753– 6. 2. del Castillo J, Nelson T. The mode of action of carisoprodol. Ann N Y Acad Sci 1960;86:108 – 42. 3. Elenbaas JK. Centrally acting oral skeletal muscle relaxants. Am J Hosp Pharm 1980;37:1313–23. 4. Dalen P, Alvan G, Wakelkamp M, Olsen H. Formation of meprobamate from carisoprodol is catalyzed by CYP2C19. Pharmacogenetics 1996;6:387–94. 5. Olsen H, Koppang E, Alvan G, Morland J. Carisoprodol elimination in humans. Ther Drug Monit 1994;16:337– 40. 6. Ellenhorn MJ, Barceloux DG. Medical toxicology: diagnosis and treatment of human poisoning, New York: Elsevier Science Publishing; 1988. 7. Henretig FM, Vuignier BI. Other sedative-hypnotics. In: HarwoodNuss A, Linden C, Luten RC, Sternback G, Wolfson AB, eds. The Clinical Practice of Emergency Medicine. Philadelphia: JB Lippincott; 1991:576 –9. 8. Roth BA, Vinson DR, Kim S. Carisoprodol-induced myoclonic encephalopathy. J Toxicol Clin Toxicol 1998;36:609 –12. 9. Goldberg D. Carisoprodol toxicity. Mil Med 1969;134:597– 601. 10. Elder NC. Abuse of skeletal muscle relaxants. Am Fam Physician 1991;44:1223– 6. 11. Brandslund I. Et tilfaelde af akut karisoprodolforgiftning. Symptomkompleks og metabolisering. (Danish) [A case of acute carisoprodol poisoning. Symptoms and metabolism]. Ugeskr Laeger 1976;138:281–3. 12. Physicians’ Desk Reference: 49th edn. Montvale, NJ: Medical Economics; 1995. 13. Bailey DN. The present status of meprobamate ingestion. A fiveyear review of cases with serum concentrations and clinical findings. Am J Clin Pathol 1981;75:102– 6. 14. Plant JR, MacLeod DB. Response of a promethazine-induced coma to flumazenil. Ann Emer Med 1994;24:979 – 82. 15. Osborn H, Goldfrank LR. Sedative-hypnotic agents. In: Goldfrank LR, Flomenbaum NE, Lewin NA, Weisman RS, Howland MA, Hoffman RS, eds. Goldfrank’s Toxicologic Emergencies, 5th edn. Norwalk, CT: Appleton Lange; 1996:787– 804. 16. Saissy JM, Vitris M, Demaziere J, et al. Flumazenil counteracts intrathecal baclofen-induced central nervous system depression in tetanus. Anesthesiology 1992;76:1051–3. 17. Zuber M, Elsasser S, Ritz R, Scollo-Lanizzari G. Flumazenil (Anexate) in severe intoxication with carbamazepine (Tegretol). Eur Neurol 1988;28:161–3. 18. Donovan KL, Fisher DJ. Reversal of chloral hydrate overdose with flumazenil. Br Med J 1989;298:1253. 19. Roberge RJ, Atchley B, Ryan K, Krenzelok EP. Two chlorzoxa-
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