Methocarbamol

Mechanism of Action

The precise mechanism of action of methocarbamol remains unknown. In theory, involuntary muscle spasms may result from a protective reflex preventing movement that would otherwise cause injury. However, in some cases, muscle spasms themselves may become painful and debilitating. This phenomenon, known as the "pain-spasm-pain cycle," has not been confirmed in rigorous clinical and electrophysiologic studies.[9] Along with other muscle relaxants, the discovery and development of methocarbamol were based on animal studies that observed decreased muscle tone without concurrent depression of motor activity.[15] Theoretically, the relief skeletal muscle relaxants (SMR) provide results from global central nervous system depression. The other proposed mechanism is anticholinergic inhibition of the midbrain reticular activating system, which results in depressed polysynaptic reflexes and reduced muscle tone. This is also characterized as an indirect inhibition of the interneuronal junction of the spinal cord. Methocarbamol does not directly affect the skeletal muscle contractility, motor nerve fiber, or motor end plate.[4]

Pharmacokinetics

Absorption: The onset of action of oral methocarbamol is 30 minutes. Methocarbamol is well absorbed in the gastrointestinal tract and attains peak plasma concentrations at 2 hours.[16]

Distribution: Methocarbamol demonstrates moderate binding to plasma proteins, typically ranging from 46% to 50%.

Metabolism: Methocarbamol undergoes metabolic processes predominantly via dealkylation and hydroxylation pathways, potentially followed by conjugation.

Elimination: In healthy volunteers, methocarbamol exhibits plasma clearance rates ranging from 0.20 to 0.80 L/h/kg and an average plasma elimination half-life spanning 1 to 2 hours. Methocarbamol is primarily excreted as an inactive metabolite in the urine. Methocarbamol is typically dosed every 6 hours based on observed clinical pharmacokinetics. One study of methocarbamol in hemodialysis patients demonstrated no alteration in elimination time compared to control patients; however, renal clearance was reduced.[17] Clearance is also reduced in patients with cirrhosis; however, no specific dose adjustment is suggested. In one study, a dosage of 500 mg given twice daily was well tolerated by patients with cirrhosis.[12]

Administration

Available Dosage Forms and Strengths

Methocarbamol is commonly administered via the oral route. Methocarbamol is commercially available in 500 mg and 750 mg tablets. Intravenous (IV) and intramuscular (IM) formulations may also be used commonly in the post-operative setting.

Adult Dosage

The daily recommended dosing ranges from 4 to 6 grams orally in divided doses every 6 hours. The maximum recommended dosage is 6 grams daily, and up to 8 grams daily have been utilized. However, lower doses are more common in clinical practice. For example, in a retrospective cohort study, the typical dose of methocarbamol for a hospitalized patient was 500 mg orally every 8 hours.[10] Intravenous (IV) and intramuscular (IM) formulations may also be used commonly in the post-operative setting. One gram can be injected every 8 hours by IM or IV route. The dosage should not exceed 3 grams daily, and methocarbamol should not be used for more than 3 consecutive days.[18][19]

Specific Patient Population

Renal impairment: All major metabolites of methocarbamol are excreted in the urine. Similarly, small amounts of unchanged methocarbamol are excreted in the urine. The intravenous formulation of methocarbamol is contraindicated in renal impairment due to the presence of polyethylene glycol excipient. The oral methocarbamol should be cautiously used for patients with mild to moderate renal impairment. Healthcare providers should be cautious when giving methocarbamol to patients who are undergoing dialysis.[17]

Hepatic impairment: Methocarbamol is metabolized via liver dealkylation, hydroxylation, and conjugation. However, manufacturer labels do not provide dose recommendations.

Pregnancy considerations: Methocarbamol is considered a pregnancy category C medicine. Case reports have documented fetal and congenital abnormalities in pregnant women exposed to methocarbamol. As a result, this medication should not be used by women who are pregnant or may become pregnant, especially in the early stages of pregnancy, unless the potential benefits significantly outweigh the risks.[20]

Breastfeeding considerations: No studies have been conducted to evaluate methocarbamol use in breastfeeding women. The manufacturer recommends using caution when administering methocarbamol to a nursing woman. Methocarbamol is known to cross the placental barrier and is excreted in breast milk, according to animal studies. Therefore, it is not recommended for use in women who may become pregnant or who are breastfeeding.

Pediatric patients: The efficacy and safety of methocarbamol in patients younger than 16 have not been established.

Older patients: SMRs, including methocarbamol, are included in the Beers Criteria as medications that should be avoided in adults older than 65. They have been associated with a small but statistically significant increase in injury for older patients. This theoretical "injury" is based on retrospective case-control analyses evaluating patients who present to urgent care facilities, emergency rooms, and hospitals. The primary diagnoses of concern include falls, non-vertebral fractures, soft-tissue injuries, and other cognitive or psycho-motor disruptions. The absolute risk increase from methocarbamol calculated from the extant data is approximately 0.2%. All SMRs share anticholinergic properties that may contribute to sedation, falls, confusion, and polypharmacy in older patients, and methocarbamol is no exception.[21][22]

Adverse Effects

Severe adverse effects noted in the methocarbamol package insert include seizures, leukopenia, and cholestatic jaundice. According to the LiverTox resource governed by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), methocarbamol has not been linked to liver or kidney injury.[1] According to drug monographs, there have been reports of seizures in patients with a history of epilepsy after IV administration and cases of polysubstance toxicity. The product labeling indicates that neurologic adverse drug reactions are more common, with sedation being the most prevalent, followed by dizziness and headache. Other reported neurologic adverse drug reactions include confusion, amnesia, falls, syncope, and diplopia. Gastrointestinal adverse effects include dyspepsia, nausea, emesis, metallic taste, and cholestatic jaundice. IV administration of methocarbamol has been associated with thrombophlebitis and injection site pain related to the extravasation of hypertonic solution. Methocarbamol may cause urine discoloration, but this is not clinically significant.[23]

Drug-Drug Interactions

There have been multiple studies assessing the abuse potential of methocarbamol. Animal studies have demonstrated low abuse potential when methocarbamol is compared to barbiturates and benzodiazepines.[24] However, multiple human studies have reported abuse potential.[25][26] Despite abuse concerns, a recent review of German pharmacovigilance data did not indicate abuse potential for methocarbamol. However, the authors noted that under-reporting of adverse effects was a limitation of the study, so the concern for abuse should remain. Exercise caution when prescribing methocarbamol to patients who are also prescribed multiple central nervous system depressants, such as opioids and benzodiazepines, or who have known substance use disorders.[27]

Contraindications

According to the FDA, methocarbamol is contraindicated in patients with a history of drug hypersensitivity to methocarbamol or excipient. In addition, IV-administered methocarbamol is contraindicated in renal impairment due to the presence of excipient polyethylene glycol, which is independently associated with metabolic acidosis, renal injury, and hyperosmolarity.[28] There have been multiple studies assessing the abuse potential of methocarbamol. Animal studies have demonstrated low abuse potential when methocarbamol is compared to benzodiazepines and barbiturates.[24] However, considerable human studies have reported abuse potential.[25][26] Despite abuse concerns, a recent review of German pharmacovigilance data did not indicate abuse potential for methocarbamol; however, the authors noted that under-reporting of adverse effects was a limitation of the study, so the concern for abuse should remain. Methocarbamol should be used with caution on multiple central nervous system (CNS) depressants, including benzodiazepines, opioids, and known substance use disorders.

Warning and Precautions

Myasthenia gravis: Methocarbamol should not be prescribed in patients with myasthenia gravis who are taking acetylcholinesterase inhibitors. This recommendation is in the package insert and based on a case report of an exacerbation of muscle weakness and fatigue associated with methocarbamol's anticholinergic effects.[29] 

Beers criteria: As stated earlier, methocarbamol is included in the Beers Criteria and should be avoided in the geriatric population due to the risk of falls, fractures, soft-tissue injuries, and other cognitive or psychomotor impairments.[21]

Drug-laboratory interference: Methocarbamol can interfere with urine screening of vanillyl mandelic acid (VMA) and 5-hydroxy indole acetic acid (5-HIAA).[30]

Monitoring

Recommended monitoring of methocarbamol involves evaluating the clinical response and mitigating the risk of the emergence of adverse effects. There is no requirement to check blood chemistry in follow-up or therapeutic drug monitoring. Specific populations at risk for toxicity include cirrhosis, use of multiple CNS depressants, renal impairment, substance use disorders, and older patients.[22]

Toxicity

Signs and Symptoms of Overdose

Isolated methocarbamol overdose is rare and unlikely to be life-threatening in the absence of multiple drug exposures.[31] Based on limited data, toxicity symptoms may include nausea, sedation, seizures, coma, and death.

Management of Overdose

There is no antidote for methocarbamol overdose. Treatment is supportive. One retrospective study utilizing National Poison Data System data aimed to characterize poisoning exposures to skeletal muscle relaxants in pediatric and adolescent populations. From 2010 to 2020, a study identified 2605 cases of single-agent exposures to carisoprodol, meprobamate, methocarbamol, or metaxalone in patients aged 6 to 19. Findings revealed that the majority of cases (75.74%) were intentional exposures, with suicide attempts accounting for over half of these incidents. Clinical effects commonly observed included drowsiness, tachycardia, vomiting, and slurred speech. Most exposures (81.04%) resulted in referral or management at healthcare facilities, with intravenous fluids and activated charcoal commonly administered interventions. The study underscores the importance of understanding skeletal muscle relaxant toxicity in adolescents to inform effective management strategies.[32]

Enhancing Healthcare Team Outcomes

SMRs, including methocarbamol, are commonly prescribed for non-specific musculoskeletal pain. In 2004, an estimated 2 million American adults took a muscle relaxant, the most common indication being low back pain.[33] Low back pain was among the leading causes of years lived with disability globally in 2016.[34] A specific nociceptive etiology of low back pain is often elusive. In such cases, symptoms result from multiple factors, including biomechanical pain generators, central and peripheral nociceptive processing, medical comorbidity, and psychosocial factors.[35] A biopsychosocial approach is encouraged when a specific etiology cannot be identified due to the complexity of factors contributing to low back pain. First-line recommendations are non-pharmacologic, including patient education, maintaining activity, and using heat and ice.[36] Pharmacologic treatments are an option for those with persistent symptoms but should be part of a multi-modal treatment plan that may include psychological and biomechanically oriented therapies.

Despite more than 3 million methocarbamol prescriptions annually in the United States, limited high-quality data is available to demonstrate clinical efficacy.[1] Methocarbamol is superior to placebo for acute musculoskeletal pain and similar to other muscle relaxants. However, this conclusion is based mostly on dated, small case series and small randomized clinical trials (RCT).[37] There is conflicting evidence regarding whether methocarbamol is superior to or provides any additional benefit compared to NSAIDs. In a randomized controlled trial conducted in 2018, Friedman et al found that adding methocarbamol to naproxen did not improve outcomes at 1 week; however, their study was small. The same group also reported a similar lack of effect when methocarbamol was added to oxycodone-acetaminophen, cyclobenzaprine, corticosteroids, and diazepam.[38]

However, a retrospective cohort study published in 2024 examined injury risks linked to combining SMRs with commonly prescribed opioids in a US Medicaid population. The study results highlighted variations in injury rates based on specific SMR-opioid combinations and the order of initiation. Specifically focusing on methocarbamol, it demonstrated consistently lower injury rates compared to other SMRs like carisoprodol and tizanidine when used alongside oxycodone or tramadol. These results offer crucial insights into optimizing pain management strategies and underscore the necessity for further research to validate these findings and guide evidence-based clinical practice.[39]

Clinicians should be vigilant while prescribing methocarbamol to older patients, those at risk of polypharmacy. Clinicians should keep in mind that there is no high-quality evidence to suggest methocarbamol is more effective than NSAIDs for acute musculoskeletal pain. Nurses and pharmacists should verify that methocarbamol is used only in select patients as part of multi-modal treatment with close monitoring of efficacy, adverse effects, and polypharmacy. Additionally, extensive randomized controlled trials are warranted to guide the clinical decision-making for a drug that appears to be a popular clinical tool for prescribers without solid evidence. Interprofessional collaborative work and open communication between physicians, nurse practitioners, physician assistants, nurses, and pharmacists could enhance patient outcomes related to methocarbamol.