Is there evidence for combining gabapentin with duloxetine (Cymbalta) for the treatment of peripheral neuropathic pain?

From the Guidelines

The combination of gabapentin and duloxetine can be considered for the treatment of peripheral neuropathic pain when either medication alone provides insufficient relief, as suggested by the most recent guidelines 1.

Treatment Approach

When using this combination, it is essential to start with one agent and add the second medication if pain control remains inadequate.

• Gabapentin can be initiated at 300mg daily, gradually titrated up to 1200-3600mg daily in divided doses.
• Duloxetine can be started at 30mg daily for one week, then increased to 60mg daily.

Mechanism of Action

The theoretical benefit of this combination stems from their complementary mechanisms of action:

• Gabapentin reduces pain by binding to calcium channels and decreasing excitatory neurotransmitter release.
• Duloxetine inhibits serotonin and norepinephrine reuptake, enhancing descending pain inhibitory pathways.

Monitoring and Dose Adjustments

Patients should be monitored for increased side effects when using this combination, including dizziness, somnolence, and dry mouth.

• Dose adjustments may be necessary for patients with renal impairment (particularly for gabapentin) or hepatic impairment (particularly for duloxetine).

Clinical Considerations

The most recent guidelines suggest that gabapentinoids, serotonin-norepinephrine reuptake inhibitors (SNRIs), and other pharmacologic therapies can be considered in the treatment of pain in diabetic peripheral neuropathy 1.

• The American Academy of Neurology update suggested that gabapentinoids, SNRIs, sodium channel blockers, tricyclic antidepressants (TCAs), and SNRI/opioid dual-mechanism agents could all be considered in the treatment of pain in DPN 1.

From the Research

Combination Therapy for Peripheral Neuropathic Pain

There is evidence to suggest that combining gabapentin with duloxetine may be effective for the treatment of peripheral neuropathic pain. The following points summarize the key findings:

• A study published in the European journal of pharmacology 2 found that the combination of gabapentin, duloxetine, and donepezil yielded a synergistic interaction to reduce hypersensitivity after nerve injury in rats.
• Another study published in the International journal of clinical practice 3 compared the safety and tolerability of duloxetine, pregabalin, and the combination of duloxetine plus gabapentin in patients with diabetic peripheral neuropathic pain, and found that the combination of duloxetine plus gabapentin was generally safe and tolerable.
• However, it is worth noting that the study published in the Lancet (London, England) 4 did not directly investigate the combination of gabapentin and duloxetine, but rather compared the efficacy of different combinations of first-line drugs, including duloxetine supplemented with pregabalin, for the treatment of diabetic peripheral neuropathic pain.
• The study published in Pain 5 found that combining duloxetine and pregabalin was not significantly superior to high-dose monotherapy, but was considered to be effective, safe, and well tolerated.

Key Findings

• The combination of gabapentin and duloxetine may be effective for the treatment of peripheral neuropathic pain, although more research is needed to confirm this.
• The safety and tolerability of the combination of duloxetine and gabapentin have been investigated, and found to be generally safe and tolerable.
• More research is needed to fully understand the efficacy and safety of combining gabapentin with duloxetine for the treatment of peripheral neuropathic pain.

Studies Investigated

• 4: Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain.
• 5: Duloxetine and pregabalin: high-dose monotherapy or their combination? The "COMBO-DN study"--a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain.
• 2: Multiplicative interactions to enhance gabapentin to treat neuropathic pain.
• 6: Amitriptyline, Pregabalin and Duloxetine for Treatment of Painful Diabetic Peripheral Neuropathy.
• 3: Comparative safety and tolerability of duloxetine vs. pregabalin vs. duloxetine plus gabapentin in patients with diabetic peripheral neuropathic pain.