Access to the PPM Journal and newsletters is FREE for clinicians.
12 Articles in Volume 12, Issue #5
A-Delta Pain Fiber Nerve Conduction Study Benefits Patients With Spinal Pain
Chronic Pain Management of the Noncompliant Patient
Clinical Applications of Radiofrequency Lesioning for Back and Neck Pain
Current Understanding and Management Of Medication-overuse Headache
Fibromyalgia: An Overview of Etiology and Non-pharmaceutical Treatment Options
June 2012 Pain Research Updates
Junk The Term Narcotics—Call Them Opioids
Managing Adverse Drug Effects in Pain: Focus on Muscle Relaxants
Music Therapy for Pain Management
Perioperative Pain Management in the Opioid-tolerant Elderly Patient: Case Challenge
Practical Tips in the Treatment Of Osteoarthritis of the Knee
Sudden, Unexpected Death in Chronic Pain Patients

Managing Adverse Drug Effects in Pain: Focus on Muscle Relaxants

Part 2 of a two-part series reviews the adverse effects, drug–drug, and drug–disease state interactions of 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.

Antispasmodic Agents
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

Table: Adverse Drug Effects of Muscle Relaxants

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.

Table: Adverse Drug Effects Muscle Relaxants (continued)

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

Antispasticity Agents
Tizanidine is a centrally acting α2-agonist and is thought to act by increasing presynaptic inhibition of neuronal activity. Several studies have shown the effectiveness of tizanidine as monotherapy and in conjunction with NSAIDs in the treatment of acute low back pain with associated muscle spasm, as well as myofascial pain.11 Additionally, tizanidine has been found to be equally effective as baclofen in the treatment of spasticity related to multiple sclerosis.2 Tizanidine is pharmacologically similar to clonidine, but it has less potent hypotensive effects.11 Postmarketing surveillance has also shown liver transaminases as high as 3 times the upper limit of normal in 5% of patients.12 This is usually asymptomatic and reversible when the agent is stopped. The manufacturer suggests transaminase monitoring for the first 6 months of therapy.13 Other adverse effects include sedation in up to 48% of patients and hallucinations.13 Since elderly patients are at risk for hypotension and are sensitive to sedation, this agent should be used with caution in this population. This agent should also be used with caution in patients with low baseline blood pressure. Tizanidine clearance is significantly reduced when used in combination with oral contraceptives, ciprofloxacin, fluvoxamine, and other CYP450 1A2 inhibitors. Caution should also be exercised in patients taking antihypertensives or other CNS depressants as well as those with pre-existing liver disease.14

Baclofen is an analog of GABA and is an agonist at the GABAB receptor. Several studies have compared baclofen with tizanidine and other agents for spasticity in multiple sclerosis, and they were found to be equally effective, with various rates of adverse effects and study withdrawal.2 Baclofen is a versatile agent, and may be used intrathecally in patients with extensive spasticity, as with cerebral palsy. However, when used in high doses, baclofen can cause seizures, ataxia, and hallucinations. Abrupt withdrawal of baclofen should be avoided because it can precipitate seizures and hallucinations. It should be used with caution in patients with renal impairment and in those patients taking other CNS depressants.

Although benzodiazepines are not FDA approved for spasms or spasticity, this class of medications is effective in treating both muscle spasms and spasticity. Diazepam has been studied the most, but others have been used for muscle spasms as well. Benzodiazepines primarily work on the benzodiazepine receptors on the postsynaptic GABAA receptors in the spinal cord and higher motor centers in the brain.2 Several benzodiazepines have been utilized for the short-term relief (1 to 2 weeks) of muscular flare-ups due to chronic musculoskeletal pain. Benzodiazepines without active metabolites (lorazepam, clonazepam, temazepam, and oxazepam) may be considered for short-term use in the elderly and in patients with liver or kidney insufficiency. Some of the common ADEs associated with benzodiazepines include drowsiness, confusion, ataxia, cognitive impairment, and agitation. The greatest risk with these agents is that of respiratory depression, particularly when used with opioids or alcohol. Withdrawal symptoms may occur after abruptly stopping benzodiazepines.

Dantrolene (Dantrium), which inhibits the release of calcium from the sarcoplasmic reticulum, does not directly affect the CNS. Though dantrolene has been found to be equally effective as the antispasticity agents, there are some significant safety concerns with this agent.2 The FDA has required a black-box warning for this agent due to the risk of sometimes fatal hepatic toxicity. Women and patients older than 35 years of age are at increased risk of this toxicity. Regular monitoring of transaminases is recommended. Slow titration can help minimize the development of some of the common adverse events: drowsiness, weakness, dizziness, and diarrhea.15 Some other serious but relatively rare adverse effects are seizure, heart failure, aplastic anemia, leukopenia, thrombocytopenia, respiratory depression, pleural effusion, and pericarditis. Caution should be taken in patients with heart failure, chronic obstructive pulmonary disease, and liver disease.15 Coadministration of dantrolene with estrogen may cause hepatotoxicity. Myocardial depression has also been reported in patients given IV dantrolene with verapamil.15

Muscle relaxants are a class of drugs that contain individual differences in ADEs, drug interactions, and comorbidity considerations. The antispasmodics and antispasticity agents in this drug class have the potential to cause various undesired effects, which providers need to understand in order to effectively manage the patient’s pain and minimize complications.

Last updated on: September 25, 2012
close X