What are the interactions between Selective Serotonin Reuptake Inhibitors (SSRIs) and cyclobenzaprine?

From the Guidelines

Combining SSRIs with cyclobenzaprine should be avoided due to the risk of serotonin syndrome, a potentially life-threatening condition. Both medications increase serotonin levels in the brain, and when taken together, they can cause excessive serotonin accumulation. If you are currently taking an SSRI such as fluoxetine (Prozac), sertraline (Zoloft), escitalopram (Lexapro), or others, consult your healthcare provider before using cyclobenzaprine (Flexeril) 1.

Key Considerations

• The interaction between SSRIs and cyclobenzaprine can lead to serotonin syndrome, characterized by symptoms such as agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, tremor, excessive sweating, diarrhea, and in severe cases, seizures or loss of consciousness 1.
• SSRIs inhibit the CYP450 liver enzymes that metabolize cyclobenzaprine, potentially increasing cyclobenzaprine levels in the bloodstream, while both medications independently increase serotonin activity.
• If both medications are deemed necessary, your doctor may prescribe lower doses and monitor you closely for symptoms of serotonin syndrome.

Recommendations

• Consult your healthcare provider before using cyclobenzaprine if you are currently taking an SSRI.
• Monitor for symptoms of serotonin syndrome, especially in the first 24 to 48 hours after dosage changes 1.
• If you experience any concerning symptoms while taking these medications together, seek immediate medical attention.
• Consider alternative treatments or adjust the dosage of one or both medications to minimize the risk of serotonin syndrome.

Important Notes

• Cyclobenzaprine has the potential to interact with sedatives and anesthetic agents and can cause adverse anticholinergic effects, including hallucinations, confusion, drowsiness, constipation, urinary retention, and dry mouth 1.
• Concomitant use of cyclobenzaprine with monoamine oxidase inhibitors may increase the potential for serotonin syndrome 1.

From the FDA Drug Label

The development of a potentially life-threatening serotonin syndrome has been reported with Cyclobenzaprine Hydrochloride when used in combination with other drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase (MAO) inhibitors. Postmarketing cases of serotonin syndrome have been reported during combined use of Cyclobenzaprine Hydrochloride and other drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase (MAO) inhibitors If concomitant treatment with Cyclobenzaprine Hydrochloride and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases

The interaction between Selective Serotonin Reuptake Inhibitors (SSRIs) and cyclobenzaprine is a potentially life-threatening serotonin syndrome.

• Symptoms of serotonin syndrome may include:
  • Mental status changes (e.g., confusion, agitation, hallucinations)
  • Autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia)
  • Neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity)
  • Gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea)
• Treatment with cyclobenzaprine and any concomitant serotonergic agents should be discontinued immediately if the above reactions occur and supportive symptomatic treatment should be initiated.
• If concomitant treatment with cyclobenzaprine and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases 2 2

From the Research

Interactions between Selective Serotonin Reuptake Inhibitors (SSRIs) and Cyclobenzaprine

• The interaction between SSRIs and cyclobenzaprine can lead to serotonin syndrome, a potentially life-threatening condition 3, 4.
• Serotonin syndrome is characterized by alterations in cognition, behavior, autonomic nervous system function, and neuromuscular activity 5.
• Cyclobenzaprine can block serotonin and norepinephrine transporters and bind to serotonin receptors, increasing the risk of serotonin syndrome when combined with SSRIs 4.
• The concurrent use of two or more drugs that enhance central nervous system serotonin activity, such as SSRIs and cyclobenzaprine, can produce serotonin syndrome 5.
• Patients taking SSRIs and cyclobenzaprine should be closely monitored for manifestations of serotonin syndrome, including autonomic instability, agitation, and neuromuscular symptoms 3, 5.
• Discontinuation of the offending drugs and supportive care are usually sufficient to treat serotonin syndrome, but antiserotonergic agents may also be required in some cases 5, 6.