Is it safe to prescribe nefopam to a patient taking sertraline (selective serotonin reuptake inhibitor) for pain management?

Nefopam and Sertraline: Significant Serotonin Syndrome Risk

Nefopam should be used with extreme caution—or avoided entirely—in patients taking sertraline due to the significant risk of serotonin syndrome from their pharmacodynamic interaction.

Mechanism of Concern

Nefopam inhibits serotonin reuptake in both spinal and supraspinal spaces, creating a direct pharmacodynamic interaction with sertraline (an SSRI) 1. This dual serotonergic activity substantially increases the risk of serotonin syndrome, a potentially life-threatening condition characterized by:

• Neuromuscular excitation (tremor, myoclonus, rigidity)
• Autonomic instability (diaphoresis, tachycardia, fever, labile blood pressure)
• Altered mental status (agitation, confusion, decreased sensorium) 2, 3

Evidence for Serotonin Syndrome with SSRIs

Multiple case reports demonstrate serotonin syndrome when sertraline is combined with other serotonergic agents:

• Sertraline + metoclopramide: Resulted in agitation, dysarthria, diaphoresis, and movement disorders within 2 hours, requiring benzodiazepine treatment 3
• Sertraline + tramadol: Caused chest pain, tachycardia, confusion, psychosis, and tremor 4
• Rapid SSRI titration: Even with therapeutic agents, rapid dose escalation precipitated severe serotonin syndrome requiring 4-day hospitalization 2

Clinical Decision Algorithm

If nefopam is being considered:

1. Assess pain type and severity: Nefopam provides analgesia comparable to 6 mg IV morphine per 20 mg dose 1

2. Consider safer alternatives first:

   • For musculoskeletal/inflammatory pain: Acetaminophen (though monitor blood pressure if >4g daily), topical lidocaine, topical diclofenac, or less-sedating muscle relaxants like methocarbamol 1
   • For neuropathic pain: The patient is already on sertraline, which is appropriate for neuropathic pain in cardiovascular disease 1. Consider adding gabapentin or pregabalin if renal function permits 1
   • For persistent pain: Low-dose oral opioids (immediate-release formulations) are generally well-tolerated and safer than the nefopam-sertraline combination 1

3. If nefopam is absolutely necessary:

   • Temporarily discontinue sertraline with appropriate washout period (typically 5 half-lives = ~5-7 days for sertraline)
   • Monitor closely for serotonin syndrome symptoms during any overlap
   • Have benzodiazepines readily available for treatment 3

Critical Pitfalls to Avoid

• Do not assume "low doses are safe": Serotonin syndrome has occurred with single conventional doses of serotonergic agents when combined with SSRIs 3
• Do not miss early signs: Symptoms can develop within 2-3 hours of drug administration 3, 4
• Do not delay treatment: If serotonin syndrome develops, immediate discontinuation of offending agents and benzodiazepine administration is essential; symptoms typically resolve within 6-48 hours with appropriate management 3, 5

Additional Nefopam Considerations

Beyond serotonin syndrome risk, nefopam carries other safety concerns that may be problematic:

• Tachycardia (particularly concerning if patient has cardiovascular disease)
• Seizure risk
• Delirium
• Glaucoma exacerbation 1

The combination of nefopam's serotonergic activity with sertraline creates an unacceptable risk-benefit ratio when safer analgesic alternatives exist 1.