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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Meprobamate

Last Update: February 12, 2014.

OVERVIEW

Introduction

Meprobamate is a sedative used for anxiety and insomnia, which infrequently causes liver enzyme elevations and which has not been linked to instances of clinically apparent liver injury.

Background

Meprobamate (me" proe bam' ate) is a bis-carbamate ester which was found to have antianxiety activity and was introduced into medical use in the 1950s. Meprobamate rapidly became one of the most widely used psychotropic agents, being considered a “tranquillizer”. Commonly known by its brand name Miltown, it was approved for use in anxiety, but was widely used as a sedative and for insomnia. The sedative effects of meprobamate resemble those of the benzodiazepines, and it is known to bind to the GABA-A receptor. However, the precise mechanism of action of meprobamate is unclear. Meprobamate also has major abuse potential and many cases of dependency, habituation and overdose have been described. Withdrawal can lead to hallucinations and seizures. Meprobamate was approved for use in generalized anxiety disorders in the United States in 1955, but it is currently rarely used and is classified as a Schedule IV controlled substance because of its potential for abuse and dependency. Nevertheless, meprobamate remains available in several generic forms as 200 and 400 mg tablets. In addition, the muscle relaxant carisoprodol is a prodrug of meprobamate and is clinically available, although now it is also classified as a Schedule IV controlled substance [January 2012]. The recommended dosage of meprobamate is 1200 to 1600 mg daily in three or four divided doses. Side effects may include drowsiness, ataxia, dizziness, headache, weakness, nervousness, euphoria, overstimulation and physical dependence.

Hepatotoxicity

Rates of serum enzyme elevations during meprobamate therapy have not been reported. While instances of clinically apparent liver injury due to meprobamate have been mentioned in review articles, no cases with specific information on clinical features have appeared in the published literature. Thus, meprobamate may be capable of causing clinically apparent liver injury, but it must be very rare. Meprobamate is metabolized in the liver via the cytochrome P450 system (predominantly CYP 3A4) and has major potential for drug-drug interactions. Meprobamate can exacerbate symptoms of porphyria. Serious allergic reactions to meprobamate have been reported including Stevens Johnson syndrome. In cases of meprobamate overdose, the cause of death has been respiratory suppression and not liver failure, although liver histology was not well defined.

Drug Class: Sedatives and Hypnotics, Miscellaneous

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Meprobamate – Generic

DRUG CLASS

Sedatives and Hypnotics

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Meprobamate57-53-4C9-H18-N2-O4
Meprobamate Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 12 February 2014

  • Zimmerman HJ. Psychotropic and anticonvulsant agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 483-516.
    (Expert review of hepatotoxicity published in 1999; mentions that there have been three reported instances of liver injury attributed to meprobamate, but clinical features are not specifically discussed).
  • Kanel GC. Histopathology of drug-induced liver disease. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 2nd ed. New York: Informa Healthcare USA, 2007, p. 284.
    (Meprobamate is listed as causing cholestasis with inflammation, but is not specifically discussed).
  • Mihic SJ, Harris RA. Hypnotics and sedatives. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 457-80.
    (Textbook of pharmacology and therapeutics).
  • Selling LS. Clinical study of a new tranquilizing drug; use of miltown(2-methyl-2-n-propyl-1,3-propanediol dicarbamate). J Am Med Assoc 1955; 157: 1594-6. [PubMed: 14367012]
    (Among 187 patients with anxiety treated with meprobamate in a private practice, 64 recovered, 88 were improved, 35 were not improved and 3 patients developed allergic reactions; states that meprobamate "is not habit forming", but does not mention liver complications).
  • Friedman HT, Marmelzat WL. Adverse reactions to meprobamate. J Am Med Assoc 1956; 162: 628-30. [PubMed: 13366645]
    (Description of 7 cases of severe adverse events due to meprobamate, including rash [n=5], ocular palsy and severe diarrhea; no mention of liver injury).
  • Ewing JA, Fullilove RE. Addiction to meprobamate. N Engl J Med 1957; 257: 76-7. [PubMed: 13452049]
    (32 year old man taking 4 to 8 g of meprobamate daily developed headaches, muscle twitching, anxiety and somatic complaints during withdrawal).
  • Haizlip TM, Ewing JA. Meprobamate habituation: a controlled clinical study. N Engl J Med 1958; 258: 1181-6. [PubMed: 13552940]
    (75 residents of a State mental hospital were given meprobamate [3.2 and 6.4 g daily] or placebo for 40 days and then "surreptitiously" switched to placebo; withdrawal symptoms included insomnia, anxiety, tremors, nausea, hallucinations, acute psychosis and convulsions; no hepatic complications mentioned).
  • Cowger ML, Labbe RF. Contraindications of biological-oxidation inhibitors in the treatment of porphyria. Lancet 1965; 1 (7376): 88-9. [PubMed: 14234213]
    (Mentions that clinical relapses of acute intermittent porphyria have occurred with drugs other than barbiturates, including chlordiazepoxide and meprobamate).
  • Ayd FJ Jr. Meprobamate: A decade of experience. Psychosomatics 1964; 5: 82-7. [PubMed: 14130886]
    (Review of the safety and efficacy of meprobamate after a decade of its wide scale clinical use; states "that meprobamate is free from hepatotoxicity is incontrovertible").
  • Maddock RK Jr, Bloomer HA. Meprobamate overdosage. Evaluation of its severity and methods of treatment. JAMA 1967; 201: 999-1003. [PubMed: 6072491]
    (10 patients with meprobamate overdose [1.6 to 30 g], ages 16 to 48 years, 7 women, 8 in coma, 1 died; plasma levels correlated with coma state and there was rapid renal clearance; no mention of liver injury).
  • Schwartz HS. Acute meprobamate poisoning with gastrotomy and removal of a drug-containing mass. N Engl J Med 1976; 295: 1177-8. [PubMed: 980021]
    (56 year old woman developed coma and respiratory failure after overdose of 36 g of meprobamate, with persistent high levels in serum, gastroscopy demonstrating a mass of undigested meprobamate tablets in the stomach, ultimately requiring surgical removal; no mention of liver injury).
  • Crome P, Higgenbottom T, Elliott JA. Severe meprobamate poisoning: successful treatment with haemoperfusion. Postgrad Med J 1977; 53: 698-9. [PMC free article: PMC2496842] [PubMed: 593997]
    (56 year old woman with meprobamate overdose developed coma and respiratory depression, improved by hemoperfusion with charcoal column; no mention of liver injury).
  • Kintz P, Tracqui A, Mangin P, Lugnier AA. Fatal meprobamate self-poisoning. Am J Forensic Med Pathol 1988; 9139-40. [PubMed: 3381792]
    (35 year old man found dead with lethal levels of meprobamate in blood; no description of liver histology).
  • Littrell RA, Sage T, Miller W. Meprobamate dependence secondary to carisoprodol (Soma) use. Am J Drug Alcohol Abuse 1993; 19: 133-4. [PubMed: 8438828]
    (37 year old woman was found to have meprobamate on urine screening after a motor vehicle accident, but denied taking meprobamate, but did admit to use of carisoprodol which she was later found to regularly abuse).
  • Bailey DN, Briggs JR. Carisoprodol: an unrecognized drug of abuse. Am J Clin Pathol 2002; 117: 396-400. [PubMed: 11888078]
    (Over a 6 month period, 19 patients were found to have carisoprodol in urine on comprehensive drug screens, 12 with decrease in level of consciousness; liver injury not mentioned).
  • Buire AC, Vitry F, Hoizey G, Lamiable D, Trenque T. Overdose of meprobamate: plasma concentration and Glasgow Coma Scale. Br J Clin Pharmacol 2009; 68: 126-7. [PMC free article: PMC2732949] [PubMed: 19660012]
    (Among 59 cases of meprobamate overdose, plasma levels correlated roughly with degree of coma; only one patient died).
  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]
    (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, none were attributed to meprobamate).
  • Fathallah N, Zamy M, Slim R, Fain O, Hmouda H, Bouraoui K, Ben Salem C, Biour M. Acute pancreatitis in the course of meprobamate poisoning. JOP 2011; 12: 404-6. [PubMed: 21737904]
    (43 year old woman took an overdose of meprobamate [60 g] and was admitted in stupor and found to have pancreatitis [bilirubin 1.0 mg/dL, ALT 65 U/L, Alk P 115 U/L, lipase 21.3 times ULN], resolving with temporary ventilator support and hydration).
  • Herzberg D. Blockbusters and controlled substances: Miltown, Quaalude, and consumer demand for drugs in postwar America. Stud Hist Philos Biol Biomed Sci 2011; 42: 415-26. [PubMed: 22035715]
    (History of discovery, approval, marketing and subsequent wide scale use and abuse of meprobamate).
  • Reeves RR, Burke RS, Kose S. Carisoprodol: update on abuse potential and legal status. South Med J 2012; 105: 619-23. [PubMed: 23128807]
    (Review of the clinical features and frequency of carisoprodol abuse which increased between 2001 and 2008 and decreased with the introduction of restrictions on its sale; carisoprodol was classified as a schedule IV controlled substance in the US starting in January 2012).

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