Can you take amitriptyline with Cymbalta (duloxetine)?

Amitriptyline and Duloxetine Combination: Safety Concerns and Recommendations

Taking amitriptyline with duloxetine (Cymbalta) is not recommended due to increased risk of serotonin syndrome, drug interactions, and potential for serious adverse effects. 1

Drug Interaction Mechanism

The combination of these medications poses several significant risks:

• Pharmacokinetic interaction: Duloxetine inhibits CYP2D6, which metabolizes tricyclic antidepressants like amitriptyline, potentially leading to elevated plasma concentrations of amitriptyline 1
• Pharmacodynamic interaction: Both medications affect serotonin and norepinephrine neurotransmission, creating additive effects that increase risk of adverse reactions

Specific Risks of Combination Therapy

Serotonin Syndrome

• Combined serotonergic effects can lead to potentially life-threatening serotonin syndrome
• Symptoms include agitation, hallucinations, rapid heart rate, fever, excessive sweating, shivering, tremor, muscle stiffness, coordination problems, and nausea/vomiting/diarrhea

Cardiovascular Effects

• Both medications can affect heart rate and blood pressure
• Increased risk of orthostatic hypotension and cardiac conduction abnormalities 2
• Potential for QT interval prolongation and arrhythmias

Anticholinergic Effects

• Additive anticholinergic burden leading to dry mouth, blurred vision, urinary retention, constipation
• Particularly problematic in elderly patients 2

Autonomic Dysreflexia

• Case reports suggest this combination may trigger autonomic dysreflexia in susceptible individuals 3

Alternative Approaches for Neuropathic Pain

If you're considering this combination for neuropathic pain, consider these safer alternatives:

1. Optimize monotherapy first:

   • Duloxetine monotherapy (30-60 mg daily) 2, 1
   • Amitriptyline monotherapy (10-150 mg daily) 2

2. Alternative combinations with better safety profiles:

   • Pregabalin with either duloxetine or amitriptyline 4
   • Gabapentin with either medication 2

3. For refractory cases:

   • Consider referral to pain management specialist
   • Topical agents may be added (lidocaine patches) 2

Special Situations

In the rare case where a clinician determines the benefits outweigh the risks:

• Start with lowest possible doses
• Monitor closely for signs of serotonin syndrome
• Check plasma levels of amitriptyline to avoid toxicity 2
• Implement ECG monitoring for QT prolongation
• Consider gradual discontinuation of one agent before starting the other

Conclusion

While there are isolated case reports of successful combination use 5, the significant risks of this combination outweigh potential benefits for most patients. The FDA drug labeling for duloxetine specifically cautions against co-administration with tricyclic antidepressants like amitriptyline due to the risk of serious adverse effects 1.