Drugs and Human Performance FACT SHEETS - Carisoprodol (and Meprobamate)

Synonyms:Carisoprodol: N-isopropyl-2-methyl-2-propyl-1,3-propanediol dicarbamate; Soma®, Sodol®, Soprodol®, Soridol®. Meprobamate: Miltown®, Equanil®, Equagesic®, Meprospan®.

Source: Carisoprodol and meprobamate are available by prescription only. Carisoprodol itself is not a federally scheduled compound, while meprobamate is a Schedule IV drug. Soma® is available as a 350 mg strength round, white tablet; Soma® Compound is a 250 mg strength two-layered, white and light orange round tablet (also contains aspirin); and Soma® Compound with Codeine is a 250 mg strength two-layered, white and yellow oval tablet (also contains aspirin and codeine phosphate) and is a schedule III controlled substance. Miltown® is available as a 200 mg and 400 mg strength white tablet; Equanil® is a 200 mg and 400 mg strength tablet; and Equagesic® is a 200 mg strength two-layered, pink and yellow, round tablet (also contains aspirin).

Drug Class:Carisoprodol: muscle relaxant, CNS depressant; Meprobamate: antianxiety, CNS depressant.

Medicinal and Recreational Uses: Carisoprodol is a centrally acting skeletal muscle relaxant prescribed for the treatment of acute, musculoskeletal pain. Meprobamate is a major metabolite of carisoprodol, and is a CNS depressant in its own right, indicated for the management of anxiety disorders or for short-term treatment of anxiety symptoms. Use of these drugs begins with prescription for muscular pain or anxiety, and abuse develops for their sedative-hypnotic effects, resulting in increased dosage without medical advice, or continued use after pain or anxiety has subsided.

Potency, Purity and Dose: Carisoprodol is present as a racemic mixture. During treatment, the recommended dose of carisoprodol is for one 350 mg tablet taken three times daily and at bedtime (1400 mg/day). The usual dose for meprobamate is one

400 mg taken four times daily, or daily divided doses of up to 2400 mg. To control chronic pain, carisoprodol is often taken concurrently with other drugs, particularly opiates, benzodiazepines, barbiturates, and other muscle relaxants.

Route of Administration: Oral.

Pharmacodynamics: The pharmacological effects of carisoprodol appear to be due to the combination of the effects of carisoprodol and its active metabolite, meprobamate. Meprobamate is equipotent to carisoprodol. There is some evidence suggesting carisoprodol is a GABA A receptor indirect agonist with CNS chloride ion channel conductance effects. In animals, carisoprodol produces muscle relaxation by blocking interneuronal activity and depressing transmission of polysynaptic neurons in the descending reticular formation and spinal cord. It is unknown if this mechanism of action is also present in humans. In addition to the desired skeletal muscle relaxing effects, carisoprodol and meprobamate produce weak anticholinergic, antipyretic and analgesic properties.

Pharmacokinetics: Carisoprodol is rapidly absorbed from the gastrointestinal tract and rapidly distributed throughout the CNS. Protein binding is approximately 60%. Carisoprodol is predominantly dealkylated to meprobamate in the liver, and to a lesser extent hydroxylated to hydroxycarisoprodol and hydroxymeprobamate, followed by conjugation and excretion. The half-life of carisoprodol is approximately 100 minutes. Some individuals have impaired metabolism of carisoprodol, and exhibit a half life of 2-3 times that in normal subjects. The half-life of meprobamate is many times longer, between 6 and 17 hours. As a result of the significantly longer half-life of meprobamate relative to carisoprodol, accumulation of meprobamate during chronic therapy may occur.

Molecular Interactions / Receptor Chemistry: The cytochrome P450 2C19 isoenzyme is responsible for the conversion of carisoprodol to meprobamate. Potential inhibitors of the 2C19 isoenzyme could decrease the rate of drug elimination if administered concurrently, while potential inducers of the 2C19 isoenzyme could increase the rate of elimination.

Blood to Plasma Concentration Ratio: Data not available for carisoprodol; 3.3 to 5.0 for meprobamate.

Interpretation of Blood Concentrations: Following therapeutic doses of carisoprodol, blood concentrations are typically between 1 and 5 mg/L for carisoprodol, and between 2 and 6 mg/L for meprobamate. A single oral dose of 350 mg carisoprodol produced average peak plasma concentrations of 2.1 mg/L carisoprodol at one hour, declining to 0.24 mg/L at 6 hours. Following a single oral dose of 700 mg, average peak plasma concentrations of carisoprodol were 3.5 mg/L at 45 minutes, and meprobamate concentrations of 4.0 mg/L were obtained in 220 minutes. A single oral dose of 700 mg carisoprodol has also produced peak plasma concentrations of 4.8 mg/L carisoprodol. Following administration of meprobamate in the treatment of anxiety, concentrations are typically around 10 mg/L, but can range between 3 and 26 mg/L. A single oral dose of 1200 mg meprobamate produced concentrations of 15.6 mg/L at 4 hours. Plasma meprobamate concentrations of greater than 100 mg/L have been associated with deep coma; light coma between 60 and 120 mg/L; and patients with levels below 50 mg/L are invariably conscious.

Interpretation of Urine Test Results: Both drugs are excreted into the urine and are likely be detectable for several days following cessation of use. Less than 1% of a single oral dose of carisoprodol is excreted unchanged in the 24 hour urine, with meprobamate accounting for 4.7% of the dose. Following administration of meprobamate, up to 11% of a single dose is excreted in the urine in 24 hours.

Effects:

Psychological: Dizziness, drowsiness, sedation, confusion, disorientation, slowed thinking, lack of comprehension, drunken behavior, obtunded, coma.

Physiological: CNS depression, nystagmus (becoming more evident as concentrations increase), loss of balance and coordination, sluggish movements, slurred speech, bloodshot eyes, ataxia, tremor, sleep disturbances.

Side Effect Profile: Agitation, tremor, paresthesia, irritability, depression, facial flushing, headache, vertigo, postural hypotension, fainting, weakness, loss of balance and coordination, impairment of visual accommodation, tachycardia, nausea, vomiting, and stomach upset. In abuse or overdose, subjects are consistently sedated and obtunded, frequently becoming comatose. Overdose symptoms may include shallow breathing, clammy skin, dilated pupils, weak and rapid pulse, paradoxical excitement and insomnia, convulsions, and possible death. Meprobamate overdose can produce drowsiness, ataxia, severe respiratory depression, severe hypotension, shock, heart failure, and death.

Duration of Effects: The effects of carisoprodol begin within 30 minutes of oral administration, and last for up to 4-6 hours. In overdose, coma may last from several hours to a day or more. Meprobamate has a much longer duration of effect than carisoprodol due to a much longer half-life.

Tolerance, Dependence and Withdrawal: Development of abuse and moderate physical and psychological dependence can occur with chronic use of both carisoprodol and meprobamate. Abrupt discontinuation of long-term use can be followed by mild withdrawal symptoms such as anxiety, abdominal cramps, insomnia, headache, nausea, vomiting, ataxia, tremor, muscle twitching, confusion, and occasionally chills, convulsions and hallucinations. Onset of withdrawal from meprobamate occurs within 12-48 hours following cessation of use, and can last a further 12-48 hours. Carisoprodol has been shown to produce cross-tolerance to barbiturates.

Drug Interactions: Alcohol enhances the impairment of physical abilities produced by carisoprodol, and increased sedation, extreme weakness, dizziness, agitation, euphoria and confusion may be observed. Alcohol also inhibits the metabolism of meprobamate and produces an additive depressant effect on the CNS that includes sleepiness, disorientation, incoherence and confusion. The concurrent administration of other centrally acting drugs such as opiates, benzodiazepines, barbiturates, and other muscle relaxants can contribute to impairment. Meprobamate may enhance the analgesic effects of other drugs.

Performance Effects: Very limited studies are available for carisoprodol, however, single oral doses of 700 mg have not been shown to affect psychomotor and cognitive tests within 3 hours of dosing, to a significant degree. In contrast, single doses of meprobamate are capable of causing significant performance impairment. Performance effects include impaired divided attention, impaired coordination and balance, slowed reflexes and increased reaction time. With chronic dosing of either drug, it is likely that decrements in psychomotor performance would be even more pronounced.

Effects on Driving: The drug manufacturer suggests patients should be warned that carisoprodol and meprobamate may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a motor vehicle. Reported signs of psychomotor and cognitive impairment in subjects found to be driving under the influence of carisoprodol/meprobamate include poor perception, impaired reaction time, slow driving, confusion, disorientation, inattentiveness, slurred or thick speech, slow responses, somnolence, lack of balance and coordination, unsteadiness, and difficulty standing, walking or exiting vehicles.

Logan et al., 2000 describes 21 driving under the influence cases where carisoprodol and/or meprobamate were the only drugs detected. The mean carisoprodol and meprobamate concentrations were 4.6 mg/L (range 0-15 mg/L) and 14.5 mg/L (range 1-36 mg/L), respectively. Signs of impairment were noted at blood concentrations as low as 1 mg/L of meprobamate, however, the most severe driving impairment and the most overt symptoms of intoxication occurred in drivers whose combined carisoprodol and meprobamate blood concentrations were greater than 10 mg/L. Signs consistent with CNS depression were typically observed, including poor balance and coordination, horizontal gaze nystagmus, slurred speech, dazed or groggy appearance, depressed reflexes, slow movements, disorientation to place and time, and a tendency to dose off or fall asleep. Many subjects were involved in accidents, and other observed driving behaviors included extreme lane travel and weaving, striking other vehicles and fixed objects, slow speed, and hit and run accidents where the subject appeared unaware they had hit another vehicle.

DEC Category: CNS depressant

DEC Profile: Horizontal gaze nystagmus present; vertical gaze nystagmus may be present in high doses; lack of convergence present; pupil size normal to dilated; reaction to light slow; pulse rate normal to down; blood pressure normal to down; body temperature normal to down. Other characteristic indicators may include slurred speech, drowsiness, disorientation, drunken behavior without the odor of alcohol, and poor performance on field sobriety tests.

Panel’s Assessment of Driving Risks: A single therapeutic dose of carisoprodol is unlikely to cause significant performance impairment. However, single therapeutic doses of meprobamate and chronic doses of carisoprodol may produce moderate to severe impairment of psychomotor skills associated with safe driving.

References and Recommended Reading:

Bailey DN, Shaw RF. Interpretation of blood glutethimide, meprobamate, and methyprylon concentrations in non-fatal and fatal intoxications. J Tox Clin Tox 1983;20:133-45.

Baselt RC. Drug effects on psychomotor performance. Biomedical Publications, Foster City, CA; pp 74-5, pp 238-40;2001.

Finkle BS. The identification, quantitative determination, and distribution of meprobamate and glutethimide in biological material. J Forensic Sci 1967;12(4):509-28.

Logan BK, Case GA, Gordon AM. Carisoprodol, meprobamate, and driving impairment. J Forens Sci 2000;45(3):619-23.

Maddock RK, Bloomer HA. Meprobamate overdosage: evaluation of its severity and methods of treatment. JAMA 1967;201:123-7.

Marinetti-Scheff L, Ludwig RA. Occurrence of carisoprodol in casework associated with driving under the influence violations by the forensic toxicology subunit of the Michigan state police crime laboratory. Presented at the annual meeting of the American Academy of Forensic Sciences, New York, NY, 1997.

Physicians’ Desk Reference, Medical Economics Company, Montvale, NJ, 2002.

Reeves RR, Pinkofsky HB, Carter OS. Carisoprodol: A drug of continuing abuse. JAMA 1997;97(12):723-4.

Rust GS, Hatch R, Gums JG. Carisoprodol as a drug of abuse. Arch Fam Med 1993;2:429-32.

Weatherman R, Crabb DW. Alcohol and medication interactions. Alc Res & Health 1999;23(1):40-53.