Continuing Education Activity

Methocarbamol is a medication used in the management and treatment of acute musculoskeletal pain. It is in the skeletal muscle relaxant class of medications. This activity reviews the indications, mechanism of action, and contraindications for methocarbamol as an option in the multimodal treatment of acute musculoskeletal pain. This activity will also underscore critical factors to consider when prescribing methocarbamol: adverse event profile, evidence of efficacy, pharmacodynamic and pharmacokinetic considerations, and recommendations for monitoring in managing patients with musculoskeletal pain and related conditions.

Objectives:

• Review the indications for the use of methocarbamol in the treatment of musculoskeletal pain.
• Identify populations at risk for adverse effects of methocarbamol.
• Summarize different approaches for the use of anti-spastic and anti-spasmodic classes of skeletal muscle relaxants.
• Describe common adverse effects of skeletal muscle relaxants, and review methods of educating patients on how to avoid harm.

Indications

Methocarbamol is a centrally-acting skeletal muscle relaxant (SMR) approved for the treatment of acute musculoskeletal pain. Specific FDA indications for use are vague and have not been recently reviewed. Methocarbamol has been approved for muscle spasms since 1957.[1] The clinical efficacy of methocarbamol is recognized within the larger class of muscle relaxants.[2] As a treatment for involuntary skeletal muscle spasm, methocarbamol is considered an anti-spasmodic agent compared to anti-spastic agents like dantrolene and baclofen, which treat spasticity resulting from upper motor neuron disorders.  Other commonly prescribed anti-spasmodic agents include cyclobenzaprine and carisoprodol.  Tizanidine and diazepam have anti-spastic and anti-spasmodic properties.[3] These anti-spastic and anti-spasmodic medications have different mechanisms of action; for the scope of this review, we shall focus on methocarbamol.

Methocarbamol was discovered in the early 1950s and was approved for use in 1957.[1] In 1958, O'Doherty and Shields described methocarbamol as an effective treatment for muscle spasms observed in individuals with pyramidal spine lesions, such as those caused by herniated intervertebral discs.[4] Concurrent with the work of O'Doherty and Shields, Forsyth described methocarbamol's efficacy in a case series of one hundred patients with orthopedic conditions, including acute and chronic disc herniation and post-operative muscle spasm. In the published study, all but six patients had either a "moderate" or "pronounced" response in subjective relief of pain or spasm. No significant adverse effects were noted, and only nine patients reported "minor" adverse effects, including dizziness and nausea.[5] 

Despite its common use today, there are few high-quality studies and no meta-analyses comparing methocarbamol to placebo or alternative agents for muscle spasms.[6] Today, clinical use is typically limited to the adjunctive treatment of acute pain of musculoskeletal origin; however, off-label use has been investigated for a range of painful conditions, including acute and chronic non-specific low-back pain, inflammatory arthritides, fibromyalgia, and myofascial pain, rib fractures, perioperative care of hip and knee replacements, and abdominal muscle cramps in patients with cirrhosis.[7][8][9][10][11] Historically, methocarbamol had also been used to treat tetanus, a practice which today has been replaced by benzodiazepines.[12] Methocarbamol is not effective for treating contracture, rigidity, or spasticity that is believed to originate from upper motor neuron injury.

Mechanism of Action

The exact mechanism of action of methocarbamol remains unknown; similarly unknown is the relationship between musculoskeletal pain and muscle spasm.[8] In theory, involuntary muscle spasm may result from a protective reflex preventing movement that would otherwise cause injury. In some cases, muscle spasms themselves may become painful and debilitating.[4] This phenomenon, known as the “pain-spasm-pain cycle,” has not been confirmed in rigorous clinical and electrophysiologic studies.[8] 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.[13] It is thought that the relief provided by SMRs is the result of global central nervous system depression. One proposed mechanism is anticholinergic inhibition of the midbrain reticular activating system resulting in depressed polysynaptic reflexes and decreased muscle tone. This is also described as an indirect inhibition of the interneuronal junction of the spinal cord. Methocarbamol has no direct action at the motor nerve fiber, motor nerve end plate, or skeletal muscle contractility.[4]

Administration

Methocarbamol is administered commonly via the oral route. Oral methocarbamol is available in 500 mg and 750 mg tablets. Recommended daily dosing ranges from four to six grams daily in divided doses every six hours. The maximum recommended dose is six grams daily, and up to eight grams daily have been used. However, lower doses are often used in practice. For example, in a recent retrospective study of a reasonably sized cohort, the typical dose for a hospitalized patient was 500 mg orally every eight hours.[9]

Intravenous (IV) and intramuscular (IM) formulations may also be used commonly in the postoperative setting.[14][15] one gram can be injected every eight hours by IM or IV route. The dose should not exceed three grams daily and should not be used for more than three consecutive days.

Pharmacokinetics

The onset of action of oral methocarbamol is 30 minutes. The drug is completely absorbed by the gastrointestinal tract and reaches peak plasma concentrations at two hours.[16] It has a variable half-life of one to two hours and is metabolized in the liver by dealkylation, hydroxylation, and glucuronidation. Methocarbamol is primarily excreted as an inactive metabolite in the urine. It is typically dosed every six hours based on observed pharmacokinetics. One study in hemodialysis patients observed no change 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.[11]

Specific Population

Renal Impairment: All major metabolites of methocarbamol are excreted in the urine. Similarly, some small amounts of unchanged methocarbamol are also excreted in the urine. IV dose is contraindicated in patients with renal impairment due to the presence of polyethylene glycol excipient. The oral dose should be used with caution for patients with mild to moderate kidney conditions. Patients who are on dialysis should also be using methocarbamol with caution.[17]

Hepatic Impairment: Methocarbamol is mainly metabolized via dealkylation, hydroxylation, and conjugation in the liver. However, there are no dose recommendations available in manufacturer labels.

Pregnant Women: It is considered pregnancy category C medicine. Some reports exist of fetal and congenital abnormalities following exposure to methocarbamol in pregnant women. Therefore, it should not be used in women who may become pregnant or are pregnant, particularly in early pregnancy, until potential benefits outweigh the risk.[18]

Breastfeeding Women: There are no studies conducted to evaluate methocarbamol use in breastfeeding women. The manufacturer recommends exercising caution when methocarbamol is administered to a nursing woman.

Pediatric: Effectiveness and safety of methocarbamol in pediatric patients below the age of 16 have not been studied.

Adverse Effects

Severe adverse effects documented in the methocarbamol package insert include seizure, leukopenia, and cholestatic jaundice. The incidence of these severe effects is unknown, and no case reports appear on a literature review. 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 individuals with a history of epilepsy after IV administration and cases of polysubstance toxicity; however, no published cases were available for review.

Drug monographs report neurologic adverse effects as more common, including sedation, followed by dizziness and headache. Other reported neurologic adverse effects include confusion, amnesia, falls, syncope, and diplopia. 

Gastrointestinal side effects include dyspepsia, nausea, emesis, metallic taste, and cholestatic jaundice.

Methocarbamol may cause urine discoloration, which is not clinically significant; however, it may interfere with urine screening of  5-hydroxy indole acetic acid (5-HIAA) and vanillyl mandelic acid (VMA).

IV administration has been associated with phlebitis and injection site pain related to the extravasation of hypertonic solution.

Contraindications

According to the FDA, methocarbamol is contraindicated in individuals with a history of drug hypersensitivity to methocarbamol or component products.

Importantly, IV methocarbamol is contraindicated in renal impairment due to the presence of polyethylene glycol, which independently is associated with metabolic acidosis, renal injury, and hyperosmolarity.[19]

There have been multiple studies evaluating the abuse potential of methocarbamol. Animal studies have shown low abuse potential when methocarbamol is compared to benzodiazepines and barbiturates.[20] However, multiple human studies have reported abuse potential.[21][22] 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 in those prescribed multiple central nervous system (CNS) depressants, benzodiazepines, opioids, and those who have known substance use disorders.

Methocarbamol should not be used in patients with myasthenia gravis 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.[23]

SMRs, including methocarbamol, are included in the Beers Criteria as medications that should be avoided in adults older than 65 years of age. They have been associated with a small but statistically significant increase in injury for elderly 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 fall, non-vertebral fracture, soft-tissue injury, and other cognitive or psycho-motor disruption. 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 elderly patients, and methocarbamol is no exception.[24]

Methocarbamol is classified as Pregnancy Category C, as it has not been systematically studied in pregnant women. In addition, based on animal studies, methocarbamol is known to cross the placenta and is excreted in breast milk. Therefore, it is not recommended for use in women who may become pregnant or who are breastfeeding.

Monitoring

The recommended monitoring of methocarbamol is to evaluate the clinical response and mitigate risk for the emergence of adverse effects. There is no need to check blood chemistry in follow-up, nor blood levels of the drug. Specific populations at risk for toxicity include those on multiple CNS depressants, patients with cirrhosis, renal impairment, substance use disorders, and, most importantly, the elderly.

Toxicity

Isolated methocarbamol overdose is rare and unlikely to be life-threatening in the absence of multiple drug exposures.[25] Based on limited data, toxicity symptoms may include nausea, sedation, seizures, coma, and death. Treatment is supportive.

Enhancing Healthcare Team Outcomes

SMRs, including methocarbamol, are commonly prescribed for non-specific musculoskeletal pain. In 2004, an estimated two million American adults took a muscle relaxant, the most common indication being low back pain.[26] Low back pain was the leading cause of years lived with disability worldwide in 2016.[27] 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.[28] A biopsychosocial approach is encouraged when a specific etiology is not readily identified due to the complexity of factors contributing to low back pain. First-line recommendations are non-pharmacologic, including patient education, maintaining activity, and the use of heat and ice.[29] 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 three million methocarbamol prescriptions yearly in the United States, there is limited high-quality data describing clinical efficacy.[1] Based mostly on dated, small case series and small randomized clinical trials (RCT), methocarbamol is superior to placebo for acute musculoskeletal pain and similar to other muscle relaxants.[30] There is conflicting evidence as to whether methocarbamol is superior or provides any additive benefit to NSAIDs alone. In a 2018 RCT, Friedman et al. found that adding methocarbamol to naproxen did not improve outcomes at one 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.[31]  

MDs, DOs, PAs, NPs, and physical therapists should be vigilant while prescribing methocarbamol in older patients, those at risk of polypharmacy, and those with a history of addiction. 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 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. Integrated and collaborative work of the healthcare team could bring the best possible outcomes for patients using methocarbamol. [Level 5]