What are the risks of taking Flexeril (cyclobenzaprine) with another medication?

Risks of Taking Flexeril (Cyclobenzaprine) with Other Medications

Flexeril (cyclobenzaprine) should not be combined with MAO inhibitors, serotonergic medications (SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil), or CNS depressants due to potentially life-threatening interactions including serotonin syndrome and enhanced sedative effects. 1

Major Drug Interaction Risks

Serotonin Syndrome Risk

• Potentially life-threatening serotonin syndrome can occur when cyclobenzaprine is combined with:

  • Selective serotonin reuptake inhibitors (SSRIs)
  • Serotonin norepinephrine reuptake inhibitors (SNRIs)
  • Tricyclic antidepressants (TCAs)
  • Tramadol
  • Bupropion
  • Meperidine
  • Verapamil
  • MAO inhibitors 1

• Signs and symptoms of serotonin syndrome include:

  • Mental status changes (confusion, agitation, hallucinations)
  • Autonomic instability (sweating, tachycardia, labile blood pressure, hyperthermia)
  • Neuromuscular abnormalities (tremor, ataxia, hyperreflexia, clonus, muscle rigidity)
  • Gastrointestinal symptoms (nausea, vomiting, diarrhea) 1, 2

Enhanced CNS Depression

• Cyclobenzaprine may enhance the effects of:

  • Alcohol
  • Barbiturates
  • Benzodiazepines
  • Opioids
  • Other CNS depressants 1, 3

• The FDA has issued a black box warning about the combination of opioids with medications having sedating effects (like cyclobenzaprine), which can lead to:

  • Slowed or difficult breathing
  • Death 3

Absolute Contraindications

• MAO inhibitors: Concomitant use or use within 14 days after MAO inhibitor discontinuation is contraindicated due to risk of hyperpyretic crisis, seizures, and death 1

• Cardiovascular conditions:

  • Acute recovery phase of myocardial infarction
  • Arrhythmias
  • Heart block or conduction disturbances
  • Congestive heart failure 1

• Hyperthyroidism 1

Specific Medication Interactions

Opioid Combinations

• Combining cyclobenzaprine with hydrocodone has been reported to cause serotonin syndrome 4
• The FDA warns specifically about the risk of respiratory depression when combining opioids with medications having sedating effects like cyclobenzaprine 3

Anticholinergic Effects

• Due to its atropine-like action, cyclobenzaprine should be used with caution in patients taking other anticholinergic medications, which can lead to:
  • Urinary retention
  • Increased intraocular pressure
  • Exacerbation of angle-closure glaucoma 1

Other Significant Interactions

• Cyclobenzaprine may block the antihypertensive action of guanethidine and similar compounds 1
• May enhance seizure risk in patients taking tramadol 1

Adverse Effects When Used Alone or in Combination

Neurologic Adverse Events

• Cyclobenzaprine can cause neurologic adverse events including:

  • Drowsiness/sedation (most common)
  • Dizziness
  • Fatigue
  • Headache 3, 5

• Low-dose cyclobenzaprine (5mg TID) has been shown to be as effective as 10mg TID with a lower incidence of sedation 5

Gastrointestinal Adverse Events

• GI adverse events include:
  • Dry mouth
  • Nausea
  • Constipation 3

Special Populations and Considerations

Hepatic Impairment

• Plasma concentration of cyclobenzaprine is increased in patients with hepatic impairment
• Use with caution in mild hepatic impairment, starting with 5mg and titrating slowly
• Not recommended for moderate to severe hepatic impairment 1

Elderly Patients

• Increased frequency and severity of adverse events in elderly patients
• Should initiate with 5mg and titrate slowly 1

Clinical Decision-Making Algorithm

1. First, assess for absolute contraindications:

   • MAO inhibitor use (current or within past 14 days)
   • Cardiac conditions (arrhythmias, heart block, recent MI, CHF)
   • Hyperthyroidism

2. Review current medications for high-risk interactions:

   • Serotonergic medications (SSRIs, SNRIs, TCAs, tramadol, etc.)
   • CNS depressants (opioids, benzodiazepines, alcohol)
   • Anticholinergic medications

3. Consider patient-specific factors:

   • Hepatic function
   • Age (elderly patients at higher risk)
   • History of urinary retention or glaucoma

4. If no contraindications exist but interactions are present:

   • Consider alternative muscle relaxants
   • If cyclobenzaprine must be used, start with lowest effective dose (5mg)
   • Monitor closely for signs of serotonin syndrome or excessive sedation

5. Patient education:

   • Avoid alcohol and other CNS depressants
   • Do not drive or operate machinery until response to medication is known
   • Report any unusual symptoms immediately

Common Pitfalls and Caveats

• Assuming cyclobenzaprine is safe to combine with SSRIs or SNRIs due to their common use - this combination can lead to serotonin syndrome 2
• Failing to recognize early signs of serotonin syndrome, which can rapidly progress to a life-threatening condition
• Prescribing standard doses in elderly patients or those with hepatic impairment
• Using for longer than 2-3 weeks (recommended maximum duration) 3
• Combining with benzodiazepines, which is specifically contraindicated by the FDA due to respiratory depression risk 6