Which muscle relaxant is safer to prescribe for a patient on a selective serotonin reuptake inhibitor (SSRI)?

Muscle Relaxant Selection for Patients on SSRIs

For patients taking SSRIs, methocarbamol or metaxalone are the safest muscle relaxant choices, as they have the lowest risk of precipitating serotonin syndrome. 1

Preferred Agents

First-Line: Methocarbamol or Metaxalone

• Methocarbamol and metaxalone are specifically recommended as "less-sedating muscle relaxants" for patients with cardiovascular disease on SSRIs, indicating their superior safety profile in this population 1
• Metaxalone has the fewest reported side effects among commonly prescribed muscle relaxants and no reports of major safety issues 2
• While metaxalone has been associated with serotonin syndrome at supratherapeutic concentrations (58 mcg/mL versus therapeutic peak of 0.9 mcg/mL), this occurs only with overdose or abuse, not at prescribed doses 3
• Standard dosing: Methocarbamol 1500 mg four times daily; Metaxalone 800 mg three to four times daily 1, 2

Agents to Avoid

Cyclobenzaprine (Flexeril) - High Risk

• Cyclobenzaprine should be avoided in patients on SSRIs due to documented cases of serotonin syndrome at therapeutic doses 4
• Cyclobenzaprine has anticholinergic properties similar to tricyclic antidepressants (amitriptyline), which increases serotonin syndrome risk when combined with SSRIs 1, 4
• A case report documented serotonin syndrome in a patient taking escitalopram (Lexapro) and cyclobenzaprine (Flexeril) at prescribed doses, confirming this drug-drug interaction 4

Carisoprodol - Avoid

• Carisoprodol should be avoided entirely due to high risk of sedation, falls, and significant potential for physical and psychological dependence 5, 2
• Has the greatest toxicity profile among muscle relaxants 2

Benzodiazepines (Diazepam) - Use with Extreme Caution

• The FDA issued a black box warning in 2016 against co-prescribing benzodiazepines with serotonergic agents 1
• Co-prescribing increases mortality risk 3- to 10-fold compared to either agent alone 1, 5
• If benzodiazepines must be used, avoid co-prescribing at discharge; use only for acute in-hospital management with close monitoring 1

Clinical Pitfalls

Serotonin Syndrome Recognition

• Monitor for: altered mental status, hyperthermia, rigidity (especially lower extremities), myoclonus, hyperreflexia, and seizure-like activity 3
• Serotonin syndrome can occur even with therapeutic SSRI levels when combined with serotonergic muscle relaxants 3, 4
• The syndrome is dose-dependent and more likely with higher doses or drug combinations 6

Avoid Polypharmacy

• Never combine muscle relaxants with opioids or benzodiazepines at discharge, as combination therapy does not outperform monotherapy with NSAIDs for acute pain conditions 1
• Recent meta-analyses show combination pharmacotherapy (opioid with muscle relaxant or muscle relaxant with NSAID) provides no clinically significant additional pain relief over NSAID monotherapy for acute low back pain 1

Special Populations

Elderly Patients

• The American Geriatrics Society lists muscle relaxants as potentially inappropriate medications for older adults due to anticholinergic effects, sedation, and increased fall risk 5
• If muscle relaxation is essential in elderly patients on SSRIs, use methocarbamol at reduced doses with close monitoring 1

Duration of Therapy

• All muscle relaxant trials demonstrating efficacy were 2 weeks or less in duration (except one 3-week trial) 1
• Prescribe for the shortest duration necessary, typically no more than 2 weeks 1