Managing Adverse Drug Effects in Pain: Focus on Muscle Relaxants
Last month, we reviewed the adverse drug effects (ADEs) that often can develop when providers prescribe triptans and non-steroidal anti-inflammatory drugs (NSAIDs) for pain management. (Read that article "Managing Adverse Druge Effects in Pain: Focus on Triptans and NSAIDs.") The third drug class commonly used for chronic pain conditions is muscle relaxants.
The skeletal muscle relaxants are a diverse class of drugs that are used for treating painful muscle spasticity or spasms, which can substantially affect a patient’s ability to function (Table 1). About 2 million people annually report using muscle relaxants, with about 15% being elderly.1 The muscle relaxant class is a heterogeneous group of agents, with individual differences in drug interactions, comorbidity considerations, and ADEs. These agents are categorized as either antispasmodics or antispasticity agents. The antispasmodics are either benzodiazepines (eg, diazepam) or nonbenzodiazepines (eg, cyclobenzaprine) and are used for muscular pain and spasms associated with peripheral musculoskeletal conditions. The antispasticity agents reduce hypertonicity associated with upper motor neuron disorders like multiple sclerosis and cerebral palsy. Chou et al performed a systematic review of trials to compare efficacy and safety of skeletal muscle relaxants.2 Although the evidence was considered to be of fair quality, they concluded that for the treatment of musculoskeletal pain, tizanidine, orphenadrine, carisoprodol, and cyclobenzaprine were more effective than placebo. There were not sufficient data of good quality to determine whether metaxalone, methocarbamol, chlorzoxazone, baclofen, or dantrolene were better than placebo for this indication.2 A Cochrane systematic review found that all agents were better than placebo for short-term relief of acute low back pain, and all were equally effective; however, they were associated with more adverse effects than placebo.3 At this time, guidelines do not recommend chronic use of muscle relaxants for musculoskeletal pain.
Agents that fall into this category act at the spinal cord or supraspinal level. Well-controlled clinical studies have not conclusively demonstrated whether relief of musculoskeletal pain by cyclobenzaprine, carisoprodol, chlorzoxazone, metaxalone, or methocarbamol results from skeletal muscle relaxant effects, sedative effects, or a placebo effect of the drug.2
In contrast to cyclobenzaprine, chlorzoxazone works primarily in the spinal cord and subcortical areas of the brain. As mentioned previously, there is little data supporting the effectiveness of this agent for musculoskeletal pain and spasm.2 As with all central nervous system (CNS) depressants, it must be used with caution in patients taking other CNS depressants, such as opioids. Adverse effects are also as expected with sedation and dizziness. There are also reports of liver toxicity.4 Chlorzoxazone should be avoided in patients with pre-existing liver disease.
Metaxalone and Methocarbamol
The mechanism of action of both metaxalone and methocarbamol are unknown but are likely due to their general CNS depressant effects. Despite this, metaxalone seems to have less sedation than other muscle relaxants, and little abuse potential.5 It has been shown to cause anemia so it is contraindicated in patients with any type of anemia, as well as any patient with liver or kidney compromise. It is metabolized via several hepatocellular cytochrome P450 (CYP450) enzyme families; however, it has not been shown to be an inducer or an inhibitor. Most of its drug interactions are pharmacodynamic in nature. Due to its CNS depressant effects, it should be used cautiously with other CNS depressants.6 Methocarbamol elimination is significantly reduced in patients with hepatic or renal impairment, and has been shown to interfere with the effects of pyridostigmine bromide and should not be used in patients with myasthenia gravis.7
Orphenadrine is similar in structure to diphenhydramine and its effects are thought to be due to its anticholinergic properties. This is also the mechanism of its adverse effects, including sedation, urinary retention, dry mouth, and constipation. It is contraindicated in patients with glaucoma, gastrointestinal obstruction, and cardiac spasm. It potentiates the anticholinergic effects when used with other similar agents such as phenothiazines or tricyclic antidepressants (TCAs).
Carisoprodol and Soma Compound (containing carisoprodol and aspirin) have been prescribed for many years for acute back pain. Carisoprodol’s pharmacologic activity is γ-aminobutyric acid (GABA)ergic, with activity at the GABAA receptor. However, because it is metabolized to meprobamate, a sedative/hypnotic similar to barbiturates, there is concern about misuse and abuse. In fact, The Substance Abuse and Mental Health Services Administration has reported that the number of emergency room visits involving misuse or abuse doubled from 2004 to 2009, more so in patients over the age of 50 years and those using other CNS depressants.8 The FDA recommends only short-term use (2 to 3 weeks after an acute injury). Zacny and colleagues found that at therapeutic doses, subjects noted little efficacy but had psychomotor impairment.9 Due to its lack of efficacy and potential for abuse, many institutions do not have it available on their formularies. In some states, carisoprodol is considered a controlled substance, and several European countries have withdrawn the product.
Cyclobenzaprine’s therapeutic effect is centrally mediated, and it has no direct peripheral action on the affected muscles. It functions primarily at supraspinal levels and not in the spinal cord. It has the greatest amount of literature support for its short-term use. It is structurally related to TCAs, and it has a similar ADE profile, including sedation, constipation, urinary retention, and dry mouth. It also has a similar drug interaction profile. Concomitant use of cyclobenzaprine with mono-amine oxidase inhibitors (MAOIs) may increase the potential for serotonin syndrome—fever/hypertensive crisis, seizures, and death. Therefore, this medication is contraindicated in patients receiving MAOIs and should not be used within 14 days following discontinuance of these drugs. Caution should be used in the elderly due to cyclobenzaprine’s TCA-like effects.10