Continuing Education Activity

Carisoprodol is an FDA-approved drug indicated for the relief of discomfort associated with acute, painful musculoskeletal conditions. Although marketed as a muscle relaxant, the parent compound is actually in the tranquilizer class of medications, with its primary metabolite meprobamate considered actually to be a benzodiazepine. This activity discusses the indications, mechanism of action, and contraindications for carisoprodol as a valuable agent to relax muscles after strains, sprains, and muscle injuries. This medication is intended to be used together with rest, physical therapy, and other measures. This activity highlights the mechanism of action, the potential benefits, the side effect profile, and other key factors (e.g., dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for healthcare professionals in managing patients with myofascial pain symptoms and related conditions.

Objectives:

• Identify the mechanism of action of carisoprodol and its primary metabolite, meprobamate.
• Describe the common potential adverse events or side effects associated with carisoprodol therapy.
• Review the potential toxicity of carisoprodol and its appropriate management.
• Explain why it is essential for the healthcare team to be aware of and up to date on the indications, interactions, adverse effects, and other pharmacodynamic and pharmacokinetic factors that can affect successful carisoprodol use in clinical care and lead to improved patient outcomes.

Indications

Carisoprodol is an FDA-approved drug indicated for the relief of discomfort associated with acute, painful musculoskeletal conditions.  It has approval for up to three weeks of use only. Carisoprodol is not recommended for use in patients under the age of 16 since this medication has not been evaluated in the pediatric population. In the United States, it is a schedule IV controlled substance. First approved for medical use in the United States in 1959, carisoprodol is available as a generic medication. It comes in tablet form and can be taken by mouth up to three times a day and once before bed. According to the package insert, carisoprodol is intended to be used together with rest, physical therapy, and other measures to relax muscles after strains, sprains, and muscle injuries.

Mechanism of Action

Per the package insert, the exact mechanism of action of carisoprodol in relieving discomfort associated with acute painful musculoskeletal conditions has not been clearly identified. It is believed to be a centrally acting skeletal muscle relaxant that does not directly relax skeletal muscles. The muscle relaxation effects induced by carisoprodol in animal studies are associated with altered interneuronal activity in the spinal cord and the descending reticular formation of the brain. Its primary metabolite, meprobamate, is believed to work at the GABA receptors similar to benzodiazepines and is believed to be responsible for carisoprodol’s therapeutic effects as well as its abuse potential.[1] Meprobamate is a benzodiazepine-type anxiolytic that also has sedative properties.    

Carisoprodol is metabolized in the liver primarily by the cytochrome P450 oxidase isozyme CYP2C19, and is excreted by the kidneys. The absolute bioavailability of carisoprodol remains undetermined. Carisoprodol’s primary metabolite is meprobamate, a known drug of abuse and dependence.[2][3][4] Meprobamate was classified as a schedule IV controlled substance in 1970 and is in the tranquilizer medication class, and its marketing was under several names. Per the package insert, carisoprodol, after oral ingestion, has a quick onset of action with the time to maximum plasma concentration being approximately 1.5 to 1.7 hours for the 250-milligram strength and the 350-milligram strength, respectively. The elimination half-life for carisoprodol is 1.7 to 2 hours, whereas the half-life for the meprobamate metabolite is approximately 10 hours.  The time to maximum plasma concentration for the meprobamate metabolite is approximately 3.6 to 4.5 hours.    

Given the significantly prolonged half-life of meprobamate compared to the carisoprodol, there is a risk of meprobamate bio-accumulation following extended periods of carisoprodol administration.  Also, patients with reduced CYP2C19 activity are poor metabolizers of the carisoprodol resulting in up to a 4-fold increase in exposure to carisoprodol and a 50% reduced exposure to meprobamate.[5][6]

Carisoprodol is a racemic mixture, only slightly soluble in water but freely soluble in alcohol. The solubility of carisoprodol is practically independent of pH.  Furthermore, as per the package insert, taking this medication with fatty food did not appear to affect its pharmacokinetics.[7]

Administration

Carisoprodol is available in 250 mg and 350 mg tablet dosages taken by the mouth up to three times a day and once before bed. This medication is also available in various co-formulated forms: carisoprodol combined with acetaminophen and caffeine, carisoprodol combined with gamma-aminobutyric acid, and carisoprodol with acetylsalicylic acid and codeine.

Although the safety and pharmacokinetics of carisoprodol in patients with renal impairment have not undergone evaluation, caution is recommended since this medication's metabolite is excreted renally.  Of note, carisoprodol is dialyzable by hemodialysis and peritoneal dialysis.[8] Carisoprodol gets metabolized by CYP2C19 in the liver. As per the package insert, caution is necessary if administered to patients with impaired hepatic function or reduced CYP2C19 activity since this could result in higher exposure to carisoprodol. Co-administration of CYP2C19 inhibitors could result in increased levels of carisoprodol and decreased levels of the meprobamate metabolite. Common CYP2C19-inhibitors include omeprazole, ticlopidine, fluoxetine, fluvoxamine, topiramate, sertraline, and tricyclic antidepressants. Conversely, co-administration of CYP2C19-inducers could result in decreased levels of carisoprodol and increased levels of meprobamate. Common CYP2C19-inducers include rifampin, carbamazepine, phenobarbital, aspirin, and St. John's Wort.

Carisoprodol is pregnancy category C. However, animal studies indicate that carisoprodol adversely affected fetal growth and postnatal survival. Based on the limited post-marketing data, the primary metabolite meprobamate did not demonstrate any increased risk for particular congenital malformations.[1]  

Although carisoprodol prescribing appears to be declining to number 214 of the previous year down from number 181 of the top 300 commonly prescribed medications, it is still a commonly prescribed medication in the U.S., with over 3.4 million prescriptions in 2017. 

The efficacy, safety, and pharmacokinetics of carisoprodol have not been established in patients under the age of 16 or patients over the age of 65.

Adverse Effects

The most common side effects of carisoprodol include drowsiness, dizziness, and headache. According to the package insert, up to 17% of patients experienced sedation after taking carisoprodol compared to 6% of patients who received a placebo. This side effect can potentially impair the mental and physical abilities necessary to perform potentially hazardous work such as driving a vehicle or operating heavy machinery. There are post-marketing reports of motor vehicle accidents correlated with the use of carisoprodol. Since the sedative effects of CNS depressants may be additive, patients should be cautioned to avoid or minimize taking other CNS depressants such as alcohol, opioids, or benzodiazepines simultaneously and to take necessary precautions not to drive or engage in other potentially dangerous activities if experiencing sedation. 

Significant hypotension can also occur with carisoprodol overdose and is usually treated with supportive care and possibly dialysis.[8][9][10]

Dependence, withdrawal, and carisoprodol misuse have been reported with prolonged use, especially in patients with a history of addiction or when used in combination with other drugs with misuse potential.[1][11] Furthermore, withdrawal symptoms have been reported after abrupt discontinuation after prolonged use.  Therefore as per the package insert and labeling, it is recommended that carisoprodol not be used for more than two to three weeks to relieve acute musculoskeletal discomfort. The belief is that carisoprodol elicits barbiturate-like effects, where animal studies show that this medication can produce rewarding effects, like other drugs of abuse.[1] In addition to the potential for somnolence, a normal prescribed dosage of carisoprodol may result in short-lived mild to moderate euphoria or dysphoria due to carisoprodol's potent anxiolytic effects. Carisoprodol, more so than meprobamate, may be responsible for the euphoria. Tolerance to the side effects of carisoprodol can develop and lessen over time.

The active metabolite meprobamate itself was a frequently misused drug in the 1950s and 1960s, and there have been reported overdoses.[3][6] With prolonged usage, carisoprodol and meprobamate can produce physical dependence of the barbiturate type and withdrawal symptoms similar to those of alcohol withdrawal. Like benzodiazepines, potential psychological dependence can result in withdrawal symptoms that persist for significantly longer periods, lasting months or even years. These symptoms may include anxiety and depression, long-term memory loss, chronic insomnia, social withdrawal, agitation and aggression, and other potential symptoms.[1][6][7] The severity of the symptoms appears to be magnified in patients with a history of substance misuse and patients concomitantly on other drugs with sedatives or benzodiazepine or opioid-like effects. The combination of carisoprodol with opioids and benzodiazepines has been referred to as "the Holy Trinity," reportedly to increase the power of the "high."[11] Because of its significant abuse potential due to its sedating, relaxant, and anxiolytic effects, in December of 2011, the drug enforcement agency classified carisoprodol as a schedule IV medication according to the Controlled Substance Act.

In March of 2007, Norwegian medical regulatory authorities conducted a review of carisoprodol, and the European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use (CHMP) concluded that the benefits of medicines containing carisoprodol no longer outweigh their risks and that all marketing authorizations for carisoprodol be suspended throughout Europe.

Another potential significant reported adverse effect is seizures. In Indonesia, in September 2017, close to 100 people suffered seizures with at least one fatality when PCC, standing for "paracetamol-caffeine-carisoprodol," was mixed into student's drinks. 

Contraindications

Important contraindications listed in the package insert are acute intermittent porphyria as well as hypersensitivity reactions to a carbamate such as meprobamate. Patients with a sulfa allergy can develop a reaction after the carisoprodol is converted into meprobamate.[12]

Monitoring

No specific monitoring is necessary per the package insert. However, considering that this medication is metabolized in the liver and excluded through the kidney, the levels of carisoprodol and meprobamate can potentially increase if the patient has decreased liver function or renal insufficiency. Therefore dose or frequency adjustments may be indicated. Also, given the significant abuse potential of this medication and given that it is a controlled medication, performing appropriate monitoring such as periodic urine drug tests and pill counts should be considered.[13]

Toxicity

Since carisoprodol itself likely acts at the barbiturate site, a carisoprodol overdose itself is not directly reversible with flumazenil, a GABA-A receptor antagonist. However, the primary metabolite meprobamate, similar to benzodiazepines, does work on the GABA A receptor.[1] Therefore later in the course of an overdose, when there is potentially a significant amount of meprobamate, flumazenil can help reverse the effects of an overdose. Supportive care, including possibly charcoal,  gastric lavage, and dialysis, should be considered in overdose situations.[8]

Several case reports indicate that in overdose situations, there is direct cardiac toxicity.[5][9] Due to limited redistribution, maximum concentrations of carisoprodol appear in cardiac tissue.[9]

Enhancing Healthcare Team Outcomes

A good understanding of muscle relaxants in conjunction with the proper management of myofascial pain and muscle spasm can favorably impact a patient's mobility, quality of life, safety,  and outcome after an acute painful muscular injury or strain. Carisoprodol indications include the relief of discomfort associated with acute, painful musculoskeletal conditions. This medication is recommended to be used together with rest, physical therapy, and other measures to relax muscles after strains, sprains, and muscle injuries.  It is also important for healthcare team members to be aware that this medication is a schedule IV controlled substance with abuse potential and, therefore, to assess a patient's risk factors for substance abuse. Risk factors for substance abuse include a personal history of substance abuse, a first-degree relative with substance abuse problems, and environmental factors. To minimize the potential risks of drug dependence and abuse, it is not recommended to use carisoprodol for more than three weeks and is therefore approved for only up to three weeks of use.  In addition, due to potentially serious side effects such as sedation, seizures, and falls, this medication is not recommended to be used in pediatric patients under 16 years of age nor in elderly patients over the age of 65. 

In summary, healthcare professionals need to work together as an interprofessional team to thoroughly evaluate a patient and consider a patient's risk factors, including a history of substance abuse and a history of medication noncompliance, to make informed decisions about the potential role of carisoprodol in their treatment. It is also essential for healthcare providers to be cognizant of the duration of treatment with this medication. The pharmacist should perform medication reconciliation and verify there are no interactions and that dosing is within proper limits, and let the prescriber know of any concerns. Nursing should counsel patients on possible adverse effects and monitor the patient's usage to ensure there is no misuse and that therapy is effective, reporting any concerns to the prescribing clinician. Carisoprodol has been a commonly prescribed muscle relaxant for many years. To help improve patient outcomes when considering utilizing carisoprodol in a patient's care, the interprofessional health care team members should be aware of the indications, potential interactions, potential adverse effects, pharmacodynamic variables, and pharmacokinetic factors that can affect the successful implementation and use of this medication. [Level 5]