Skeletal muscle relaxants are frequently used in patients with both acute and chronic pain when a component of muscle spasm is thought to be contributing to pain symptomatology. They are also used in the management of disorders in which spasticity is a prominent feature, such as multiple sclerosis, cerebral palsy, and after spinal cord injury or stroke with paresis. A wide variety of muscle relaxants are available, and selection of an agent for use may be influenced by factors such as cost, perceived potency, side effect profile, chronicity of pain, and addictive potential (or lack thereof). Commonly used muscle relaxants in the United States include baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, diazepam, metaxalone, methocarbamol, orphenadrine, and tizanidine.

The α₂ agonists are well known historically for their use in the management of hypertension, but more recently, these agents have been found effective in a variety of pain management, anesthesia, and critical care applications. These applications include use in perioperative sedation and as adjuncts to regional and neuraxial anesthesia for pain management, including the treatment of refractory cancer pain. α₂ Agonists have also been used in the palliative care setting to reduce pain and the distress of the dying and to facilitate withdrawal of ventilatory support. Additionally, they may be useful in the management of opioid-induced hyperalgesia and opioid and nicotine withdrawal. α₂ Agonists currently in clinical use include clonidine, tizanidine, and dexmedetomidine.

Muscle relaxants are most often used in the management of acute musculoskeletal pain but are also commonly combined with other analgesic agents in some chronic pain management regimens. These agents should be distinguished from the nondepolarizing and depolarizing muscle relaxants that are used to provide paralysis of skeletal and respiratory muscles during general anesthesia and act by production of blockade of neuromuscular conduction. The mechanism of action of the “muscle relaxant” agents used for managing muscle spasm is not fully understood, but in general, most of these drugs act centrally by suppressing polysynaptic reflexes in the spinal cord and via depressant effects on the central nervous system (CNS). This section describes the pharmacologic profile of the currently available skeletal muscle relaxants.

BACLOFEN

Baclofen is marketed in the United States under the brand name Lioresal. It is labeled for use in the management of disorders in which spasticity is present, such as multiple sclerosis and spinal cord injury. Unlabeled indications for the use of baclofen include intractable hiccups and trigeminal neuralgia and for the relief of intractable pain.¹ Baclofen is available for oral and intrathecal use. Baclofen is thought to act by inhibition of monosynaptic and polysynaptic reflex transmission at the level of the spinal cord, possibly through hyperpolarization of primary afferent nerve terminals.¹ It is derived from γ-aminobutyric acid (GABA), an inhibitory neurotransmitter thought to play an important role in pain transmission.² This may explain why baclofen seems to have analgesic properties that make it useful in the treatment of conditions such as trigeminal neuralgia.³ The usual dosing of baclofen is 5 to 10 mg orally three times daily, which may be titrated to 80 mg/day if needed for the management of spasticity. Caution should be used in prescribing baclofen to patients who are elderly, who have severe renal impairment, and who have a history of seizures.¹ The most frequently observed side effects of baclofen include drowsiness, ataxia, hypotonia, vertigo, insomnia, psychiatric disturbances, and weakness. Less commonly, patients may experience hypotension, confusion, fatigue, headache, rash, nausea, constipation, or polyuria with baclofen use. Withdrawal, which may be life threatening, can occur with abrupt discontinuation of baclofen, particularly if it is being administered intrathecally.¹ Baclofen is rapidly absorbed after oral administration has a half-life of 3.5 hours. It undergoes hepatic metabolism (15%) and renal and fecal excretion (85% as unchanged drug).¹

CARISOPRODOL

Carisoprodol is marketed in the United States under the brand name Soma. It is indicated for short-term use (2–3 weeks) in the treatment of acute musculoskeletal pain.⁴ The mechanism of action of carisoprodol is not completely understood, but it appears to have central depressant actions and anxiolytic and sedative effects related to its metabolism to meprobamate.⁴ Metabolism to meprobamate may explain the abuse potential associated with carisoprodol.^5,6 In the past few years, increasing concerns about the abuse of carisoprodol and a growing number of reports of emergency department visits and deaths associated with carisoprodol use led to an effort for it to be classified as a controlled substance. After a review of data regarding carisoprodol abuse, the Drug Enforcement Administration ruled on December 12, 2011, that carisoprodol be placed into schedule IV of the Controlled Substances Act, effective January 11, 2012.⁷ Caution is warranted when carisoprodol is used in patients with a history of drug abuse.⁸ Carisoprodol is dosed from 250 mg to 350 mg three times per day and at bedtime. As with other muscle relaxants, carisoprodol should be used with caution in elderly patients. Side effects seen in more than 1% of users of carisoprodol include drowsiness, dizziness, and headache.⁴ After ingestion, carisoprodol takes effect within 30 minutes and has a duration of action of 4 to 6 hours. It is hepatically metabolized and has an active metabolite (meprobamate), which is renally excreted. Whereas the half-life of carisoprodol is 2 hours, that of meprobamate is 10 hours.⁴

CHLORZOXAZONE

Chlorzoxazone is marketed in the United States under the brand name Parafon Forte It is indicated for use in the management of muscle spasm and pain caused by acute musculoskeletal conditions.^9,10 It is thought to act by depressing polysynaptic reflexes in the spinal cord and subcortical areas of the brain. The dosing of chlorzoxazone is 250 to 750 mg three to four times daily. It should be used with caution among elderly patients, with lower dosing regimens suggested. Some adverse effects associated with the use of chlorzoxazone are drowsiness, dizziness, lightheadedness, malaise, nausea, rash, paradoxical stimulation, and liver toxicity (sometimes fatal).^9,10 Chlorzoxazone has an onset within 1 hour after ingestion and a duration of action of 6 to 12 hours. It is hepatically metabolized via glucuronidation, and the conjugates are renally excreted.⁹

CYCLOBENZAPRINE

Cyclobenzaprine is marketed in the United States under the trade names Flexeril, Fexmid, and Amrix (an extended-release version). Cyclobenzaprine is indicated for short-term use (2–3 weeks) in the relief of muscle spasm. It is thought to reduce tonic somatic motor activity in both α and γ motor neurons and is chemically related to the tricyclic antidepressants (TCAs).¹¹ It is dosed at 5 to 10 mg three times a day (immediate release) or 15 to 30 mg/day (extended release). Use of the extended-release version is not recommended in elderly adults or patients with any significant hepatic impairment.¹¹ Cyclobenzaprine is structurally related to TCAs and should not be used within 14 days of monoamine oxidase inhibitors. It is also contraindicated for use in individuals with hyperthyroidism, a recent history of myocardial infarction, congestive heart failure, cardiac arrhythmias, or conduction block.¹¹ Side effects observed in more than 1% of users are drowsiness, dizziness, dry mouth, fatigue, headache, confusion, irritability, decreased mental acuity, nervousness, dyspepsia, nausea, constipation, diarrhea, abdominal pain, unpleasant taste, weakness, blurred vision, pharyngitis, and acute respiratory infection.¹¹ Cyclobenzaprine is hepatically metabolized and renally and fecally excreted. Its elimination half-life is approximately 18 hours (immediate release) to 33 hours (extended release).¹¹

DANTROLENE

Dantrolene is marketed in the United States under the trade names Dantrium and Revonto. It is well known for its use in the prevention and management of malignant hyperthermia. It is also used in the treatment of spasticity caused by upper motor neuron disorders such as spinal cord injury, stroke, cerebral palsy, and multiple sclerosis.¹² It is not indicated for the management of muscle spasm caused by rheumatic disorders.¹³ Dantrolene works by preventing release of calcium from the sarcoplasmic reticulum in skeletal muscle, preventing excitation-contraction coupling. Dosing of oral dantrolene is initiated at 25 mg/day and may be titrated up to a maximum of 400 mg/day over several weeks if needed to treat spasticity. Dantrolene has a black box warning because of the potential for hepatotoxicity with its use.¹⁴ It is recommended that dantrolene be discontinued after 45 days of therapy if no benefit is observed with its use because the onset of hepatitis is most common between 3 and 12 months of therapy.^12,13 Periodic monitoring of liver function tests is recommended when dantrolene is used in the management of spasticity, and its use is contraindicated in patients with preexisting liver disease.¹³ Caution should be used when prescribing dantrolene to women older than 35 years of age because hepatotoxicity occurs most frequently among this population.¹³ The most commonly observed side effects of dantrolene are dizziness, drowsiness, weakness, general malaise, fatigue, and diarrhea.¹³ Photosensitivity has also been reported with the use of dantrolene.^12,13 Dantrolene is hepatically metabolized, has an elimination half-life of 4 to 8 hours, and is eliminated fecally (45%–50%) and renally (25 % unchanged drug and metabolites).¹²

DIAZEPAM (BENZODIAZEPINES)

Diazepam (Valium) is the prototypical benzodiazepine used in the management of muscle spasm and spasticity. Clonazepam (Klonopin) and Lorazepam (Ativan) have also been used in the treatment of these conditions. These agents are also known for their use in the management of seizures, anxiety and panic disorders, ethanol withdrawal, and sedation in critically ill or perioperative patients. Benzodiazepines are thought to act by enhancing GABA inhibition of neuronal excitability. This effect occurs as a result of increased neuronal membrane permeability to chloride ions, which causes hyperpolarization of the neuronal membrane and thereby reduces the likelihood of action potential propagation.¹⁵ Benzodiazepines are schedule IV controlled substances. Diazepam is dosed at 2 to 10 mg orally three to four times daily when used as a skeletal muscle relaxant. Diazepam must be dose reduced (by 50%) in the setting of hepatic impairment because its half-life may be prolonged significantly in this setting. Significant renal impairment may also result in prolonged effects from diazepam and its metabolites. Long-acting benzodiazepines such as diazepam are not recommended for use in elderly adults because of an increased risk of falls.¹⁵ The benzodiazepines are associated with teratogenic effects, and they are category D medications for use in pregnancy. Side effects that may be observed with the use of benzodiazepines include anterograde amnesia, somnolence, paradoxical psychiatric reactions (e.g., agitation, hallucinations, or psychosis), and hypotension and in large doses, respiratory depression.¹⁵ With prolonged use, abrupt discontinuation may result in a withdrawal syndrome that, if severe, could involve seizures and be life threatening. Diazepam plasma concentrations peak 30 to 90 minutes after administration, and it has a terminal half-life of 1 to 2 days. It is hepatically metabolized to several active metabolites, which are renally excreted.¹⁶

METAXALONE

Metaxalone is marketed in the United States under the trade name Skelaxin. It is indicated for use in the relief of pain from acute musculoskeletal conditions.¹⁷ It is thought to act through CNS depressant effects and does not have a direct effect on skeletal muscle.¹⁷ Metaxalone is dosed at 800 mg three to four times daily. Its use is contraindicated in patients with significant hepatic or renal impairment. As with other muscle relaxants, it should be used with caution in elderly adults. Side effects associated with the use of metaxalone include dizziness, drowsiness, headache, irritability or nervousness, nausea, vomiting, and gastrointestinal (GI) upset.^17,18 Hemolytic anemia, leukopenia, and jaundice have also been reported with its use.¹⁷ Metaxalone is hepatically metabolized and renally excreted. Metaxalone has an onset of action of approximately 1 hour and a duration of action of 4 to 6 hours. Its elimination half-life is 4 to 14 hours.¹⁷

METHOCARBAMOL

Methocarbamol is marketed in the United States under the trade name Robaxin. It is indicated for use in the treatment of muscle spasm related to acute musculoskeletal conditions and in the management of tetanus.¹⁹ It is a derivative of guaifenesin that is thought to act through CNS depressant effects and has no action directly on skeletal muscle.²⁰ It is dosed at 1500 mg four times daily initially (the first 48–72 hours of treatment) with a maintenance dose of 1000 mg four times a day.²⁰ Because of its short half-life, it may be preferred over other muscle relaxants when used in elderly adults, although caution in this population is still warranted.¹⁹ Side effects that may be associated with the use of methocarbamol include hypotension, bradycardia, flushing, syncope, amnesia, confusion, diplopia, dizziness, drowsiness, insomnia, nystagmus, vertigo, seizures, headache, rash, urticaria, fever, pruritus, angioneurotic edema, leukopenia, jaundice, metallic taste, dyspepsia, nausea, and vomiting.^19,20 The onset of action of methocarbamol is approximately 30 minutes after ingestion. It has an elimination half-life of 1 to 2 hours and is hepatically metabolized and renally excreted. Its half-life may be significantly extended in the presence of hepatic or renal impairment.²⁰

ORPHENADRINE

Orphenadrine is marketed in the United States under the trade name Norflex. It is indicated for the treatment of muscle spasms caused by acute musculoskeletal conditions. It is thought to exert its effects centrally by atropine-like action on cerebral motor centers or on the medulla.^21,22 It has anticholinergic, antihistaminic, analgesic, and euphorigenic properties with associated potential for abuse.^21–23 Dosing of orphenadrine is 100 mg twice daily. Its use is contraindicated in patients with glaucoma, obstruction of the GI tract, stenosing peptic ulcers, myasthenia gravis, cardiospasm, prostatic hypertrophy, and bladder neck obstruction.^21,22 Caution is warranted when orphenadrine is used in elderly adults and in patients with significant cardiac disease. It is advised that patients receiving long-term orphenadrine therapy undergo periodic monitoring of blood cell counts and hepatic and renal functions.²² Adverse effects associated with the use of orphenadrine include tachycardia, palpitations, dizziness, drowsiness, hallucinations, euphoria, agitation, headache, confusion, urticaria, pruritus, nausea, vomiting, dry mouth, constipation, stomach upset, urinary retention, blurry vision, increased intraocular pressure, papillary dilation, nystagmus, and (rarely) aplastic anemia.^21,22 Orphenadrine undergoes extensive hepatic metabolism, and its metabolites are renally excreted.^21,22 Its effects peak 2 to 4 hours after ingestion, its duration of action is 4 to 6 hours, and its elimination half-life is 14 to 16 hours.^21,22

TIZANIDINE

Tizanidine is marketed in the United States under the trade name Zanaflex. It is an α₂-adrenergic agonist that is labeled for use in the management of spasticity. Unlabeled indications include management of tension headaches, low back pain (LBP), and trigeminal neuralgia.²⁴ It acts centrally with effects on the spinal cord to decrease excitatory input to α motor neurons.²⁴ Dosing is usually started at 4 mg at bedtime and gradually titrated to relief of symptoms in 2- to 4-mg increments to a maximum daily dose of 36 mg in divided doses. Use of tizanidine should be avoided in patients with hepatic impairment, and it should be dose reduced in patients with creatinine clearances less than 25 mL/min because its clearance is decreased by more than 50% in this setting.²⁴ Caution should be used when tizanidine is administered to elderly patients because of the potential for orthostatic hypotension and reduced renal clearance in this population.²⁴ Because use of tizanidine has been associated with visual hallucinations, its use in patients with a history of significant psychiatric disorders should be carefully considered. Adverse effects reported in more than 1% of patients taking tizanidine include hypotension, somnolence, dizziness, dry mouth, weakness, bradycardia (with large doses), nervousness, speech disorder, visual hallucinations, constipation, vomiting, urinary tract infection, increased urinary frequency, dyskinesia, blurred vision, pharyngitis, rhinitis, infection, flulike syndrome, and elevated liver enzymes.²⁴ Liver enzyme elevations to greater than three times the upper limit of normal have been reported in approximately 5% of patients taking tizanidine.²⁵ Because of the rare risk of fulminant hepatic failure during tizanidine administration, it is recommended by the manufacturer that liver enzymes be measured at baseline and then 1, 3, and 6 months after it is initiated with further periodic monitoring as needed.²⁵ If discontinuation of tizanidine is desired in patients who have received prolonged therapy, it is recommended that gradual tapering be undertaken to minimize the potential risk of withdrawal symptoms, which could include rebound hypertension, tachycardia, and hypertonia.²⁴ Tizanidine is hepatically metabolized with extensive first-pass effect and undergoes fecal (60%) and renal (20%) excretion.²⁴ It has a duration of action of 3 to 6 hours and an elimination half-life of 2.5 hours. Tizanidine is available in both capsule and tablet forms, which are bioequivalent in the fasted state but differ in their pharmacokinetic profiles when ingested with food. Because of the variation in pharmacokinetics that occurs with being fasted or fed, it is recommended that patients using tizanidine always consume it consistently in either the fasting or fed state and that capsules and tablets not be interchanged.

Muscle relaxants have been widely used in the treatment of both acute and chronic back pain and other painful conditions. It is estimated that in primary care settings, 35% of patients presenting with symptoms of acute LBP are prescribed muscle relaxants.²⁶ Despite their long-standing, widespread use, however, good-quality studies evaluating the efficacy of these agents are relatively sparse in the medical literature. One systematic review concluded that there was fair evidence for the efficacy of cyclobenzaprine, carisoprodol, orphenadrine, and tizanidine in the treatment of patients with musculoskeletal conditions such as back or neck pain.²⁷ The same review found there to be limited or inconsistent data to support the use of baclofen, chlorzoxazone, dantrolene, metaxalone, or methocarbamol for these conditions.²⁷ A meta-analysis of cyclobenzaprine in the treatment of back pain indicated that patients receiving cyclobenzaprine for a period of 14 days were five times as likely to report improvement than subjects receiving placebo for their back pain.²⁸ In this study, one subject reported modest improvement in local pain, muscle spasm, tenderness to palpation, range of motion, and activities of daily living per every three subjects exposed to cyclobenzaprine.²⁸ This degree of improvement, however, was accompanied by a significant occurrence of side effects, the most frequently reported being drowsiness (20% incidence).²⁸ A Cochrane review of muscle relaxants for nonspecific LBP found that there is strong evidence of efficacy of nonbenzodiazepines for acute LBP and that this treatment may reduce discomfort and accelerate recovery in this patient population. The evidence to support the use of benzodiazepines for acute LBP and nonbenzodiazepines for chronic LBP was less robust in this review.²⁶ This review also found that although muscle relaxants are effective for short-term relief of acute and chronic LBP, their use is associated with a high incidence of side effects such as dizziness and drowsiness.²⁶ The authors of the review suggested that muscle relaxants might best be used as adjunctive therapy along with nonsteroidal anti-inflammatory drugs (NSAIDs) and other analgesics in the management of back pain.²⁶ They also indicated a need for large, high-quality trials to further evaluate muscle relaxants in comparison with other analgesic agents such as NSAIDs for this purpose.²⁶ Unfortunately, another Cochrane review of cyclobenzaprine in the management of myofascial pain concluded that evidence to support its use for this indication was insufficient.²⁹ This was attributable to a paucity of clinical studies in this area. The authors indicated a need for additional large, high-quality studies to further evaluate the use of cyclobenzaprine in the management of myofascial pain before any solid inferences can be made regarding its efficacy and safety in this condition.²⁹