What are the common side effects of muscle relaxants and the prescribing considerations for elderly patients or those with liver disease, hypotension, or substance‑use disorder?

Common Side Effects of Muscle Relaxants and Prescribing Considerations

Muscle relaxants cause sedation, dizziness, and falls as their most common and clinically significant side effects, and should be avoided in elderly patients, those with liver disease, hypotension, or substance-use disorder due to substantial safety concerns. 1, 2

Universal Side Effects Across All Muscle Relaxants

Central Nervous System Effects

• Sedation and drowsiness are the most consistently reported adverse effects across all muscle relaxants, occurring in up to 48% of patients with tizanidine and 92% at higher doses 3, 4
• Dizziness, ataxia, and confusion are common, particularly in elderly patients, contributing to increased fall risk 5, 6, 7
• Cognitive impairment including slowed comprehension and delirium can occur, especially with cyclobenzaprine which has tricyclic antidepressant-like properties 1, 8

Cardiovascular Effects

• Hypotension and orthostatic hypotension are particularly problematic with tizanidine, where two-thirds of patients experience 20% reductions in blood pressure within 1-3 hours of dosing 3
• Bradycardia can occur, especially with tizanidine and in combination with other cardiovascular medications 5, 3

Other Common Effects

• Muscle weakness and fatigue are frequently reported, particularly with benzodiazepines like diazepam 6
• Anticholinergic effects including dry mouth, constipation, urinary retention, and blurred vision occur with cyclobenzaprine and orphenadrine 5, 1, 6
• Gastrointestinal symptoms including nausea and constipation are common across agents 6, 3

Agent-Specific Serious Adverse Effects

Hepatotoxicity

• Tizanidine causes liver injury in approximately 5% of patients, with ALT/AST elevations >3 times upper limit of normal, and three deaths from fulminant hepatic failure have been reported 3
• Metaxalone is contraindicated in patients with significant hepatic dysfunction 5, 1
• Methocarbamol elimination is significantly impaired in liver disease, increasing toxicity risk 1

Psychiatric and Paradoxical Reactions

• Tizanidine causes hallucinations and psychotic-like symptoms in 3% of patients, typically within the first 6 weeks of treatment 3
• Benzodiazepines (diazepam) cause paradoxical reactions including agitation, aggression, rage, and inappropriate behavior, more commonly in elderly patients 6

Substance Abuse and Dependence

• Carisoprodol has substantial abuse potential and is classified as a controlled substance, with escalating abuse patterns in the United States and removal from European markets 5, 2, 8
• Withdrawal symptoms occur with carisoprodol (requiring 4-9 day taper), cyclobenzaprine (2-3 week taper), and baclofen (risk of seizures and delirium if stopped abruptly) 5, 1, 2

Increased Injury Risk

• All muscle relaxants increase fall and fracture risk in elderly patients, with overall injury risk increased 32% (OR 1.32) 7
• Specific agents show varying risk: carisoprodol (OR 1.73), methocarbamol (OR 1.42), and cyclobenzaprine (OR 1.22) 7

Critical Prescribing Considerations for Special Populations

Elderly Patients

• Muscle relaxants are listed in the American Geriatrics Society Beers Criteria as potentially inappropriate medications due to anticholinergic effects, sedation, and fall risk 1, 2
• If absolutely necessary, baclofen is preferred starting at 5 mg three times daily with gradual titration, maximum 30-40 mg/day, though a 2023 study found baclofen carries higher risk of injury (HR 1.54) and delirium (HR 3.33) compared to tizanidine 1, 2, 9
• Avoid cyclobenzaprine, carisoprodol, and orphenadrine entirely in elderly patients due to unacceptable risk profiles 1, 2
• Tizanidine should be avoided in elderly patients due to significant sedation and hypotension 5, 1

Liver Disease

• Tizanidine should be used only with extreme caution and requires monitoring of aminotransferases at baseline, 1,3, and 6 months, then periodically 3
• Metaxalone is absolutely contraindicated in significant hepatic dysfunction 5, 1
• Methocarbamol elimination is significantly impaired, requiring dose reduction or avoidance 1

Hypotension and Cardiovascular Disease

• Tizanidine is contraindicated in patients with baseline hypotension or orthostatic hypotension, as it causes dose-related blood pressure reductions in two-thirds of patients 3
• Carisoprodol causes postural hypotension and tachycardia, making it inappropriate for cardiovascular patients 5
• Orphenadrine should be used with extreme caution in cardiac patients due to cardiovascular instability risk 1

Renal Impairment

• Tizanidine requires dose adjustment and careful monitoring in renally impaired patients 1
• Methocarbamol elimination is significantly impaired in kidney disease 1

Substance-Use Disorder

• Carisoprodol is absolutely contraindicated due to high abuse potential, dependence risk, and controlled substance classification 5, 2, 8
• Benzodiazepines should be avoided despite potential efficacy, given abuse potential and lack of direct analgesic effect 1, 2

Drug-Drug Interactions of Critical Importance

Dangerous Combinations

• Co-prescribing opioids with muscle relaxants (especially benzodiazepines) increases mortality 3-10 fold due to potentiation of respiratory depression, and carries an FDA black box warning 5
• Tizanidine is contraindicated with ciprofloxacin and fluvoxamine due to significantly reduced clearance 5
• Tizanidine with CYP1A2 inhibitors (oral contraceptives, acyclovir, amiodarone, verapamil, cimetidine) causes significant hypotension, bradycardia, and sedation 5
• Cyclobenzaprine with monoamine oxidase inhibitors may precipitate serotonin syndrome 5

Key Clinical Pitfalls to Avoid

• Never discontinue baclofen abruptly after prolonged use—requires slow tapering to prevent withdrawal seizures, delirium, and CNS irritability 1, 2
• Do not prescribe muscle relaxants believing they directly relax skeletal muscle—most have nonspecific effects and lack evidence for chronic pain 1, 2
• Avoid combining with other anticholinergic medications to prevent additive cognitive and anticholinergic burden 2
• Do not use for chronic pain management—evidence supports only short-term use for acute musculoskeletal conditions when NSAIDs or acetaminophen fail 5, 4
• Monitor liver function with tizanidine at baseline, 1,3, and 6 months, then periodically 3