Can nortriptyline be co‑prescribed with duloxetine?

Co-Administration of Nortriptyline and Duloxetine

Do not combine nortriptyline with duloxetine due to the significant risk of serotonin syndrome and pharmacokinetic interactions that elevate tricyclic antidepressant levels to potentially dangerous concentrations. 1, 2

Primary Safety Concerns

Serotonin Syndrome Risk

• Both nortriptyline (a tricyclic antidepressant) and duloxetine (an SNRI) are serotonergic agents; their combined use markedly increases the risk of serotonin syndrome, a potentially life-threatening condition characterized by altered mental status, neuromuscular hyperactivity, and autonomic instability 1.
• Guidelines from expert consensus specifically advise caution when prescribing two or more non-MAOI serotonergic drugs together—including TCAs with SNRIs—because of this heightened risk 1.

Pharmacokinetic Drug Interaction

• Duloxetine is a moderate inhibitor of CYP2D6, the enzyme responsible for metabolizing nortriptyline 2, 3, 4.
• The FDA label explicitly warns that "co-administration of duloxetine with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants such as nortriptyline, amitriptyline, and imipramine)... should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with duloxetine" 2.
• This interaction can increase nortriptyline plasma levels by approximately 60%, raising the risk of cardiac arrhythmias, anticholinergic toxicity, and other serious adverse effects 2, 4.

Absolute Contraindications to This Combination

• Patients with cardiovascular disease 1
• Patients with hepatic impairment 1
• Patients with a history of arrhythmias 1
• Patients concurrently using other serotonergic medications 1

Evidence-Based Alternative Strategies

For Neuropathic Pain Management

If inadequate pain relief from monotherapy, add an opioid agonist or gabapentinoid rather than combining two serotonergic antidepressants 1.

• Combine either nortriptyline or duloxetine (but not both) with pregabalin or gabapentin—this strategy has been shown to improve efficacy and tolerability compared with monotherapy 1, 5.
• Randomized trials demonstrate that nortriptyline plus gabapentin is more effective than either drug alone, offering a safer alternative to co-administering two serotonergic antidepressants 1, 5.

Optimize Monotherapy Before Switching

• Titrate nortriptyline to a maximum tolerated dose of 75–150 mg/day 1.
• Titrate duloxetine to 60–120 mg/day 1.
• Ensure each agent is optimized as monotherapy before considering any alternative strategy 1.

Sequential Monotherapy

• If nortriptyline fails at optimal doses, switch to duloxetine monotherapy (or vice versa) rather than combining them 1.
• Duloxetine at 60 mg daily is effective for painful diabetic peripheral neuropathy (NNTB 5) and fibromyalgia (NNTB 8) 6.
• Nortriptyline has limited high-quality evidence but is recommended in guidelines as a first-line agent for neuropathic pain 7.

Recommended First-Line Combinations (Avoiding Dual Serotonergic Agents)

Gabapentin or Pregabalin Plus Either Nortriptyline OR Duloxetine

• Nortriptyline 25 mg at bedtime, titrate by 25 mg every 3–7 days to maximum 150 mg/day 7

  • Plus gabapentin starting 100–300 mg at bedtime, titrate to 1800–3600 mg/day in three divided doses 7, 5
  • Or pregabalin starting 75 mg twice daily, titrate to 300 mg/day within one week 7, 5

• Duloxetine 30 mg once daily for 1 week, then 60 mg once daily 7

  • Plus gabapentin or pregabalin at doses above 7, 5

Opioid Agonist Plus Either Nortriptyline OR Duloxetine

• For patients with inadequate pain relief from a first-line agent (TCA, SNRI, or α-δ agonist), guidelines recommend adding an opioid agonist rather than combining two serotonergic antidepressants 1.
• Tramadol 50 mg once or twice daily, titrate by 50–100 mg/day every 3–7 days to maximum 400 mg/day 7.

Critical Clinical Pitfalls to Avoid

• Never assume the combination is safe with "careful monitoring"—the pharmacokinetic interaction is predictable and substantial, and serotonin syndrome can develop rapidly 1, 2.
• Do not rely on therapeutic drug monitoring alone—even with TCA level monitoring, the risk of serotonin syndrome remains due to the pharmacodynamic interaction 1, 2.
• Avoid this combination in elderly patients (≥65 years)—TCAs are potentially inappropriate for older adults due to anticholinergic effects, and the combination substantially increases fall risk 8.
• Do not combine if the patient is on any other serotonergic medication (SSRIs, other SNRIs, tramadol, triptans, etc.) 1.

If Combination Is Absolutely Unavoidable (Rare Circumstances)

• Start with the lowest possible doses of both medications 8.
• Reduce nortriptyline dose by at least 50% when initiating duloxetine 2.
• Monitor plasma TCA concentrations and adjust dose accordingly 2.
• Assess for serotonin syndrome symptoms at every visit, particularly during the first 48 hours and after any dose adjustments 8.
• Watch for anticholinergic toxicity: urinary retention, constipation, dry mouth, blurred vision, and confusion 8.
• Discontinue immediately if any signs of serotonin syndrome develop: mental status changes, agitation, tremor, hyperreflexia, diaphoresis, tachycardia, or hyperthermia 1, 8.