What are the potential drug interactions to consider when prescribing Flexeril (cyclobenzaprine) to an adult patient with acute musculoskeletal conditions?

Drug Interactions with Cyclobenzaprine (Flexeril)

Life-Threatening Interactions: Absolute Contraindications

Cyclobenzaprine is absolutely contraindicated with monoamine oxidase (MAO) inhibitors due to life-threatening interactions, and must not be used within 14 days of MAO inhibitor discontinuation. 1

Serotonin Syndrome Risk

• Cyclobenzaprine can cause serotonin syndrome when combined with serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, and verapamil. 1
• Case reports document serotonin syndrome occurring with the combination of cyclobenzaprine (Flexeril) and escitalopram (Lexapro), demonstrating this is a clinically significant risk. 2
• Patients must be counseled to immediately seek medical care if they develop signs of serotonin syndrome: agitation, hallucinations, rapid heart rate, fever, excessive sweating, tremor, rigidity, or incoordination. 1

High-Risk Drug-Drug Interactions to Avoid

Central Nervous System Depressants

• The American College of Emergency Physicians explicitly recommends against co-prescribing cyclobenzaprine with other muscle relaxants or sedative-hypnotics due to increased toxicity from additive central nervous system depression. 3
• Cyclobenzaprine enhances the effects of alcohol, barbiturates, and other CNS depressants, increasing risk of sedation, falls, and injury. 1
• The 2019 AGS Beers Criteria warns against concurrent use of three or more CNS agents (including muscle relaxants, antidepressants, antipsychotics, benzodiazepines, antiepileptics, and opioids) due to increased fall risk. 4

Opioid Combinations

• Avoid concurrent use of cyclobenzaprine with opioids and benzodiazepines, as the 2019 AGS Beers Criteria specifically identifies this three-drug combination as potentially clinically important to avoid in older adults. 4
• The combination of opioids with gabapentinoids should also be avoided when cyclobenzaprine is prescribed, given the cumulative CNS depressant effects. 4

Anticholinergic Medications

• Cyclobenzaprine has atropine-like (anticholinergic) action and should be used with caution in patients taking other anticholinergic medications due to cumulative anticholinergic burden. 1
• The cumulative anticholinergic effect may be associated with decline in cognition, functional status, and activities of daily living. 5
• Specific caution is warranted in patients with urinary retention, angle-closure glaucoma, or increased intraocular pressure. 1

Cardiovascular Drug Interactions

Antihypertensive Agents

• Tricyclic compounds (cyclobenzaprine is structurally related to tricyclic antidepressants) may block the antihypertensive action of guanethidine and similarly acting compounds. 1

Anticoagulants and Antiplatelet Agents

• While not a direct cyclobenzaprine interaction, the 2019 AGS Beers Criteria notes that concurrent use of SSRIs (which interact with cyclobenzaprine) and clopidogrel can increase bleeding risk. 4
• Proton pump inhibitors may decrease the effectiveness of clopidogrel, which is relevant when managing patients on multiple medications. 4

Metabolic and Pharmacokinetic Considerations

Hepatic Metabolism

• Cyclobenzaprine is extensively metabolized by cytochromes P-450 3A4, 1A2, and to a lesser extent 2D6. 1
• Plasma concentrations are approximately doubled in patients with hepatic impairment, requiring dose reduction starting at 5 mg and slow upward titration in mild hepatic impairment. 1
• Moderate to severe hepatic impairment is a contraindication to cyclobenzaprine use. 1

Drug Metabolism Interactions

• Drugs that inhibit CYP3A4, CYP1A2, or CYP2D6 may increase cyclobenzaprine plasma concentrations, though specific interactions are not well-characterized in the FDA label. 1
• The 2019 AGS Beers Criteria notes that macrolide antibiotics (excluding azithromycin) and ciprofloxacin have multiple drug-drug interactions, though specific interactions with cyclobenzaprine are not detailed. 4

Analgesic Combinations

NSAIDs and Acetaminophen

• No significant effect on plasma levels or bioavailability occurs when cyclobenzaprine is administered concomitantly with aspirin, naproxen, or diflunisal. 1
• However, combination therapy with naproxen was associated with more side effects than naproxen alone, primarily drowsiness. 1
• The 2020 ACP/AAFP guideline found that cyclobenzaprine alone did not show statistically significant increase in GI adverse events compared to placebo (low-certainty evidence), but ibuprofen plus cyclobenzaprine increased neurologic adverse events (OR 4.91). 4

Tramadol

• Tramadol should be avoided with cyclobenzaprine due to both serotonin syndrome risk and enhanced seizure risk. 1
• Tricyclic compounds may enhance the seizure risk in patients taking tramadol. 1

Special Population Considerations

Older Adults

• The American Geriatrics Society identifies cyclobenzaprine as a potentially inappropriate medication for older adults due to increased risk of anticholinergic effects, sedation, and falls. 5
• Elderly patients have approximately 1.7-fold higher steady-state AUC values compared to younger adults, with elderly males showing 2.4-fold increases. 1
• Initiate therapy in elderly patients at 5 mg and titrate slowly upward, as frequency and severity of adverse events are increased in this population. 1

Perioperative Management

• Cyclobenzaprine may enhance the effects of anesthetic agents, increasing sedation risk during surgery. 5
• Topical cyclobenzaprine should be held on the day of surgery due to potential interactions with anesthetics and sedatives. 5

Monitoring and Management Strategies

Duration of Therapy

• All muscle relaxant trials were 2 weeks or less in duration; do not continue cyclobenzaprine beyond 2-3 weeks even if symptoms persist. 6, 3
• Prolonged use increases risk of CNS adverse events (RR 2.04 compared to placebo). 6

Discontinuation Protocol

• When discontinuing cyclobenzaprine after long-term use, taper gradually over 2-3 weeks to prevent withdrawal symptoms including malaise, nausea, and headache. 6, 5

Alternative Approaches

• If cyclobenzaprine is ineffective or poorly tolerated, switch to tizanidine rather than adding another muscle relaxant, as tizanidine has the strongest evidence base as an alternative and works through a different mechanism (alpha-2 adrenergic agonism). 6, 3
• Avoid carisoprodol due to controlled substance status and significant abuse potential. 6

Common Pitfalls to Avoid

• Do not assume sedation is required for efficacy: Analysis shows cyclobenzaprine produces clinical improvement whether or not sedation occurs, and efficacy is independent of sedative effects. 7
• Do not combine multiple sedating agents: The cumulative effect dramatically increases fall risk, particularly in older adults. 4, 3
• Do not overlook anticholinergic burden: Cyclobenzaprine's atropine-like effects add to total anticholinergic load from other medications. 1
• Do not use standard dosing in hepatic impairment or elderly patients: Both populations require 5 mg starting doses with slow titration. 1