OVERDOSE

Overdosage of carisoprodol produces CNS depression, and in severe cases coma. Shock, respiratory depression, seizures and death have also been reported rarely. The following signs and symptoms may be associated with carisoprodol overdosage: horizontal and vertical nystagmus, blurred vision, mydriasis, mild tachycardia and hypotension, respiratory depression, euphoria, CNS stimulation, muscular incoordination, and/or rigidity, confusion, headache, hallucinations, and dystonic reactions. The effects of an overdosage of carisoprodol and alcohol or other CNS depressants or psychotropic agents can be additive even when one of the drugs has been taken in the usual recommended dosage. Fatal accidental and non-accidental overdoses have been reported alone or in combination with alcohol or psychotropic drugs.

Treatment of Overdosage: Basic life support measures should be instituted as dictated by the clinical presentation. Induced emesis is not recommended due to the risk of CNS and respiratory depression. Gastric lavage should be considered soon after ingestion (usually within 1 hour.) In cases of severe CNS depression, airway protective reflexes may be compromised. In such cases, tracheal intubation should be considered for airway protection and respiratory support. Circulatory support should be administered with volume infusion and pressor agents as indicated. Seizures should be treated with a benzodiazepine IV and may be followed with phenobarbital if seizures recur.

Carisoprodol is metabolized in the liver and excreted by the kidney. The following types of treatment have been used successfully with the related drug meprobamate: activated charcoal (oral or via nasogastric tube), forced diuresis, peritoneal dialysis, and hemodialysis (carisoprodol is dialyzable). Careful monitoring of urinary output is necessary and caution should be taken to avoid overhydration. Observe for possible relapse due to incomplete gastric emptying and delayed absorption. Carisoprodol can be measured in biological fluids by gas chromatography

Usage in Pregnancy and Lactation

Usage in Pregnancy and Lactation -The safety of this drug in pregnancy or lactation has not been established. Therefore, use of this drug in pregnancy, in nursing mothers, or in women of childbearing potential requires that the potential benefits of the drug be weighed against the potential hazards to mother and child. Carisoprodol is present in breast milk of lactating mothers at concentrations two to four times that of maternal plasma. This factor should be taken into account when use of the drug is contemplated in breast-feeding patients.

Usage in Children --The efficacy and safety of carisoprodol in patients under 12 years of age has not been determined.
PRECAUTIONS

Seizure Disorders: There have been rare reports of seizures in postmarketing surveillance in temporal association with carisoprodol. These events have involved patients with and without previous medical histories of seizures and have occurred during therapeutic use, with overdose and during withdrawal from prolonged use. The role of carisoprodol in the causality of these seizures has not been established.

Carisoprodol is metabolized in the liver and excreted by the kidney; to avoid its excess accumulation, caution should be exercised in administration to patients with compromised liver or kidney function.

Additive Effects

Additive Effects --Since the effects of carisoprodol and alcohol or carisoprodol and other CNS depressants or psychotropic drugs may be additive, appropriate caution should be exercised with patients who take more than one of these agents simultaneously. Concomitant use of carisoprodol and meprobamate is not recommended.

Idiosyncratic Reactions --On very rare occasions, the first dose of carisoprodol has been followed by idiosyncratic symptoms appearing within minutes or hours. Symptoms reported include: extreme weakness, transient quadriplegia, dizziness, ataxia, temporary loss of vision, diplopia, mydriasis, dysarthria, agitation, euphoria, confusion, and disorientation. Symptoms usually subside over the course of the next several hours. Supportive and symptomatic therapy, including hospitalization, may be necessary.

Allergic Reactions -- Occasionally, within the period of the first to fourth dose of carisoprodol allergic reactions have occurred in patients who have had no previous contact with the drug. Skin rash, erythema multiforme, pruritus, eosinophilia, and fixed drug eruption have been reported with carisoprodol with cross reaction to meprobamate. Severe reactions have been manifested by asthmatic episodes, fever, weakness, dizziness, angioneurotic edema, smarting eyes, hypotension, and anaphylactoid shock. (See also Idiosyncratic Reactions under "Warnings." )

In case of allergic or idiosyncratic reactions to carisoprodol, discontinue the drug and initiate appropriate symptomatic therapy, which may include epinephrine, antihistamines, and in severe cases corticosteroids.

WARNINGS

Potentially Hazardous Tasks -- Patients should be warned that carisoprodol may have sedative properties and may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a motor vehicle or operating machinery.

Drug Dependence, Withdrawal and Abuse - In postmarketing experience, cases of drug abuse, dependence and withdrawal have been reported. Carisoprodol should be used with caution in addiction-prone individuals. (See DRUG ABUSE AND DEPENDENCE).

Carisoprodol: Reproductive Assessment by Continuous Breeding in Swiss Mice1
THOMAS B. GRIZZLE*, JULIA D. GEORGE*, PATRICIA A. FAIL* and JERROLD J. HEINDEL

*Center for Life Sciences and Toxicology. Chemistry and Life Sciences Division, Research Triangle Institute P.O Box 12194, Research Triangle Park, North Carolina 27709 Developmental and Reproductive Toxicology Group, National Toxicology Program, National Institute of Environmental Health Sciences P.O. Box 12233, Research Triangle Park, North Carolina 27709

Received August 26, 1993; accepted June 28, 1994

Carisoprodol (CARI), a commonly prescribed neuromuscular relaxant, was evaluated for reproductive toxicity in Swiss CD-1 mice using the Reproductive Assessment by Continuous Breeding (RACB) protocol. Male and female mice were given CARI in corn oil suspension by daily gavage at doses of 0, 300, 750, and 1200 mg/kg body wt/day. Clinical signs of general toxicity in Fo animals included sedation, primarily in the high-dose group during the first week of exposure, and reduced body weight in high-dose females. CARI administration for 14 weeks did not affect the ability of the F0 animals to produce litters. However, decreases in proportion of pups born alive (4%) and absolute (5%) and adjusted live pup weight (7%) were observed at 1200 mg/kg CARI when compared to controls. In a crossover mating trial to determine the affected sex, there were no significant differences in the measured reproductive parameters. CARI at the high dose increased the proportion of time spent in proestrus and estrus, but cycle length was unaffected. At F0 necropsy (Week 27 of treatment), all sperm parameters were normal. Right epididymis and liver weights, relative to body weight, were increased (12 and 23%, respectively) over the control group for high-dose males. A mating trial to determine the fertility and reproductive competence of the F1 generation showed no effect of CARI on indices of mating, pregnancy, or fertility, the proportion of F2 pups born alive, the sex ratio of live F2 pups, live F2 pup weight, or gestation length. However, decreases in the number of F2 pups per litter (22%) and adjusted live F2 pup weight (8%) were observed in the high-dose group. Indications of generalized toxicity in the F1 generation included decreased survival through Postnatal Day 21 at 750 (5%) and 1200 (9%) mg/kg CARI, and transiently decreased body weights during postnatal development and as adults for males and females at all dose levels. At necropsy, there was no effect of treatment on the relative weight of any male or female reproductive organs; testicular spermatid concentration was reduced at all levels of CARI. Relative liver weight was increased for females at 300 mg/kg and for males and females at both 750 and 1200 mg/kg. In summary, CARI produced generalized toxicity and moderate effects on the reproductive processes of F0 and F1 generation Swiss mice during chronic exposures of up to 1200 mg/kg/day.

SIDE EFFECTS

Cardiovascular --Tachycardia, postural hypotension, and facial flushing.

Central Nervous System --Drowsiness and other CNS effects may require dosage reduction. Also observed: dizziness, vertigo, ataxia, tremor, agitation, irritability, headache, depressive reactions, syncope, seizures, and insomnia. (See also Idiosyncratic Reactions under "Warnings." )

Gastrointestinal --Nausea, vomiting, hiccup, and epigastric distress.

Hematologic --Leukopenia, in which other drugs or viral infection may have been responsible, and pancytopenia, attributed to phenylbutazone, have been reported. No serious blood dyscrasias have been attributed to carisoprodol.

DRUG ABUSE AND DEPENDENCE

In post-marketing experience, drug abuse and dependence have been reported. The majority of cases of drug abuse, dependence and withdrawal have been reported with prolonged use of carisoprodol (beyond several months of treatment) or in combination with other CNS depressant or psychotropic drugs. However, there have been cases reported with carisoprodol alone. Withdrawal symptoms including abdominal cramps, insomnia, headache, nausea, and seizure, have been reported following abrupt cessation after prolonged use. One of the metabolites of carisoprodol, meprobamate, may be habit forming. (See Pharmacokinetics).

Carisoprodol should be used with caution in addiction-prone individuals, and its use should generally be limited to the acute treatment setting and not for more than 2 - 3 weeks.

Metabolism

Carisoprodol is metabolized in the liver via cytochrome P450 enzyme, CYP2C19. This enzyme exhibits genetic polymorphism . For example, 15-20% of Asian populations may be expected to be poor metabolizers. For Caucasians and Blacks, the prevalence of poor metabolizers is 3-5%. Following a single 350 mg dose of carisoprodol, the corresponding normalized peak concentration of meprobamate, which is a metabolite of carisoprodol, was 2.08 ± 0.48 ug/mL. These levels are approximately ¼ of those seen following a single 400 mg dose of meprobamate.

Elimination

Carisoprodol is eliminated by both renal and non-renal routes with a terminal elimination half-life of 2.44 ± 0.93 hours. It is dialyzable by peritoneal and hemodialysis.

Special Populations

The pharmacokinetic profile of carisoprodol in patients with renal impairment or hepatic impairment has not been evaluated. Because carisoprodol is metabolized by the liver and excreted by the kidneys, possible increased exposure of carisoprodol is expected if hepatic and/or renal function is impaired. The drug should be used with caution in patients with impaired hepatic or renal function.

The pharmacokinetic profile of carisoprodol in elderly patients has not been evaluated.

Soma Online

Carisoprodol is a centrally acting skeletal muscle relaxant that does not directly relax tense skeletal muscles in man. The mode of action of carisoprodol in relieving acute muscle spasm of local origin has not been clearly identified, but may be related to its sedative properties. In animals, carisoprodol has been shown to produce muscle relaxation by blocking interneuronal activity and depressing transmission of polysynaptic neurons in the spinal cord and in the descending reticular formation of the brain. The onset of action is rapid and lasts four to six hours.

Carisoprodol is metabolized in the liver and is excreted by the kidneys. One of the products of metabolism, meprobamate, is active as an anxiolytic. The degree to which it contributes to the efficacy of carisoprodol is unknown. Carisoprodol is dialyzable by peritoneal and hemodialysis.

Absorption, Distribution, Metabolism, Excretion

Following a single oral dose of carisoprodol, the time to maximum concentration (Tmax) was 1.98 ± 1.16 hours and the terminal elimination half-life was 2.44 ± 0.93 hours. By normalizing to a single 350 mg carisoprodol tablet, the mean peak plasma concentration (Cmax) was 2.29 ±- 0.68 ug/mL, the area under the plasma level time curve (AUC 0-∞ ) was 10.33 ± 3.87 ug/mL* hour, and the oral clearance (Cl/F) was 39.52 ± 16.83 L/hour. The mean Cmax of metabolite, meprobamate, was 2.08 ± 0.48 ug/mL, a subtherapeutic concentration when compared to a plasma concentration of a single oral meprobamate 400 mg tablet which would yield a meprobamate concentration of approximately 8.0 ug/mL.

Pharmacokinetics

Absorption

The pharmacokinetics of carisoprodol was determined in a small in vivo biostudy of 5 men and 5 women. When the dose was normalized to 350 mg, the mean peak plasma concentration (Cmax) achieved was 2.29 ± 0.68 ug/mL. Women tended to reach peak plasma concentrations earlier than men (1.45 vs. 2.5 hours) and had a faster apparent oral clearance (0.772 vs. 0.38 L/hour/kg). The clinical significance of these findings is unknown and they may in part be due to the small number of subjects present in the trial.

SEPTEMBER NEWS

Carisoprodol (Soma, others), a nonscheduled prescription medication, is a centrally acting synthetic skeletal muscle relaxant structurally and pharmacologically related to meprobamate (Miltown, Equinil), a potentially addictive agent. Carisoprodol undergoes hepatic biotransformation to three primary metabolites: hydroxycarisoprodol, hydroxymeprobamate, and meprobamate. The significant serum levels of meprobamate after chronic use of carisoprodol may lead to meprobarnate dependency: Withdrawal from meprobamate may result in severe reactions including seizures and coma.
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Ms. A, a 37-year-old White female, was admitted to the University of Kentucky Medical Center on June 16, 1990, following a motor vehicle accident in which she sustained Cl, T6, right ankle, and multiple rib fractures. A routine urine drug screen revealed the presence of meprobamate and phenothiazine metabolites. A quantitative serum analysis revealed a meprobamate level of 19.8 [mu]g/L which is equivalent to peak levels observed after ingestion of 400 mg oral meprobamate in normal volunteers. Ms. A denied recent use of meprobamate. Despite the use of greater than 100 mg intravenous morphine for 3 days postoperatively, the patient continued to complain of pain. A psychiatry consult uncovered a history of multiple drug abuse including sleeping pills, muscle relaxants, and marijuana. The patient had been hospitalized once in 1987 for detoxification. Ms. A admitted to taking carisoprodol (Soma) for lower back pain and that she had taken some just prior to her motor vehicle accident. She continued, however, to deny recent use of meprobamate. She required higher than normal doses of narcotics throughout her hospital stay. Ms. A was discharged in stable condition on hospital day 11 with prescriptions for methadone 12.5 mg orally every 8 hours and ibuprofen 600 mg orally every 6 hours. She also was given an appointment with a substance abuse counselor and instructed that all prescriptions for methadone would be written only by physicians in the Pain Management Clinic. It was agreed that die patient would remain carisoprodol-free. Following discharge, the patient did not consistently attend appointments with her counselor but was successfully weaned from methadone by Pain Management physicians. Recently it was learned that the patient is under legal investigation for passing forged carisoprodol prescriptions at numerous pharmacies in the area of her residence.

Meprobamate dependence is a possible complication of chronic carisoprodol use due to hepatic conversion of carisoprodol to meprobamate. Two previous reports[1, 2] have described such dependence and we report an additional case. Carisoprodol (Soma) is prescribed frequently by family physicians, internists, orthopedic surgeons, neurologists, neurosurgeons, anesthesiologists, and psychiatrists as well as other healthcare professionals. Carisoprodol prescribers need to be made aware of its abuse potential. Stricter controls may be necessary in the future to properly control the prescribing and distribution of this potentially addictive agent.

REFERENCES

[1] Morse, R. M., and Chua, L., Carisoprodol dependence: A case report, Am. J. Drug Alcohol Abuse 5:527-530 (1978). [2] Luehr, J. G., Meyerle, K. A., and Larson, E. W., Mail-order (veterinary) drug dependence, JAMA 263:657 (1990).

Letters

Methadone Maintenance and Recovery

In their recent article, Maddux and Desmond[1] reviewed follow-up studies of patients who had been treated with methadone maintenance and of others who received drug-free treatment.

Comparisons of different addiction treatment modalities are always difficult. The difficulty is compounded, however, when comparing posttreatment outcomes. Many methadone programs discontinue treatment primarily as a result of what is deemed therapeutic failure, e.g., continued use of illicit drugs, noncompliance with program rules, etc. On the other hand, most drug-free programs plan from the day of admission for "graduation" of patients after a prescribed course of treatment is completed, and those discharged in this fashion are defined as successful clients. Analysis of follow-up studies when programs have such disparate goals inevitably will yield data which are difficult to interpret. Nevertheless, one can hardly quarrel with the cautions conclusion of the authors that the articles they reviewed "... do not suggest that methadone maintenance impedes eventual recovery from opioid dependence, but they do not clearly exclude such an effect."

A more fundamental question raised by this article, however, is whether "recovery from opioid dependence" is a meaningful concept. To date, no one knows what "opioid dependence" is, let alone how to define, identify, or help patients achieve "recovery. " The authors whose studies are quoted by Maddux and Desmond merely determined whether or not there was a state of abstinence from heroin (and, in some instances, from other drugs and alcohol as well) at some arbitrary interval after treatment ended. This can hardly be deemed synonymous with "recovery" from such a notoriously recidivist condition as "addiction."

It is not unreasonable to postulate today, as Dole and Nyswander did a quarter-century ago[2], that "opioid dependence" reflects a physiological perturbation that is neither resolved nor even mitigated by any of the therapeutic modalities which are employed in the treatment of narcotic addicts. Should the possibility that this hypothesis is correct be the cause for gloom? Not at all! Unlike so many other diseases whose nature and etiology are unknown, and/or which defy "cure," heroin addiction is a condition which can be treated successfully - as measured by cessation of heroin use, sharply reduced morbidity and mortality, and restoration of the ability to lead a productive and self-fulfilling life. Not a bad set of objectives - objectives which, as Desmond and Maddux acknowledge, are achievable with methadone maintenance and, presumably, with other modalities as well.

We do a disservice to methadone maintenance programs and their patients by suggesting that "completion" of treatment and subsequent abstinence are the sine qua non of therapeutic success in the treatment of opioid dependence. Research efforts certainly should focus on understanding the factors which cause or contribute to addiction, and identifying potential "cures" of addictive disease(s). At the same time, our public policy should be focused on making effective treatment available promptly to all those who want it and need it.

[1] Maddux, J. F., and Desmond, D. P., Methadone maintenance and recovery from opioid dependence, Am. J. Drug Alcohol Abuse 18(1):63-74 (1992). [2] Dole, V.P., and Nyswander, M.E., Heroin addiction - A metabolic disease, Arch. Intern. Med. 120:19-24 (1967).

Response. Our review did not attempt to compare the treatment success or failure of methadone maintenance programs with those of drug-free treatment programs. As Dr. Newman points out, the disparate goals make such comparison difficult. Our inquiry focused narrowly on the long-term outcomes with respect to recovery from opioid dependence.

Dr. Newman questions the concept of "recovery from opioid dependence." We used "recovery" in the usual dictionary sense of "regaining or returning toward a normal or usual state"[1]. We used abstinence not as a synonym for recovery but as an indicator of some degree of recovery. Similarly, a return to a normal temperature may serve as an indicator of recovery from an infection. The National Institute on Drug Abuse apparently considers recovery from substance abuse (including opioid dependence) to be a useful concept. The agency sponsored a conference which focused on this topic and published a research monograph entitled Relapse and Recovery in Substance Abuse[2]. Of course, "recovery" is an abstract term, and it can be limited by specific criteria. If we limit "recovery" to mean total and complete return to a premorbid state, then recovery from opioid dependence (and from many other disorders) seems unlikely.

The studies of the acute and protracted abstinence syndromes which we cited in our article support the concept of a "physiological perturbation," but they do not provide evidence of irreversible neural change. The evidence, in our interpretation, suggests a slow recovery after cessation of opioid use.

We do not know if the authors of the article are included in the "We" who "do a disservice to methadone maintenance programs and their patients by suggesting that |completion' of treatment and subsequent abstinence are the sine qua non of therapeutic success in the treatment of opioid dependence." We cannot find an assertion resembling this one in our article. As we mentioned earlier, our review was not focused on treatment success or failure. We wish to assure Dr. Newman that we do not oppose methadone maintenance. He may not be aware that the senior author reported one of the early studies which supported the effectiveness of methadone maintenance[3]. Currently we are conducting a five-year NIDA-supported project entitled "Improving Retention on Methadone Maintenance." We advocate both methadone maintenance and drug-free modes of treatment. We also advocate research into all aspects of treatment of drug abuse.

REFERENCES

[1] Webster's Third New International Dictionary, Unabridged. G. and C. Merriam, Springfield, Massachusetts, 1971. [2] Tims, F. M., and Leukefeld, C. G. (Eds.), Relapse and Recovery in Drug Abuse [National Institute on Drug Abuse Research Monograph 72, DHHS Publication (ADM) 86-14731, U.S. Department of Health and Human Services, Rockville, Maryland, 1986. [3] Maddux, J. F., and McDonald, L. K., Status of 100 San Antonio addicts one year after admission to methadone maintenance, Drug Forum 2:239-252 (1973).

COPYRIGHT 1993 Taylor & Francis Ltd.
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