Venlafaxine compromises the antinociceptive actions of gabapentin in rat models of neuropathic and persistent pain

Rationale Neuropathic pain is associated with a number of disease states of diverse aetiology that can share common pathophysiological mechanisms. Antiepileptic drugs modulate ion channel function and antidepressants increase extracellular monoamine levels, and both drug classes variously attenuate signs and symptoms of neuropathic pain. Thus, coadministration of the antiepileptic gabapentin and the antidepressant venlafaxine may provide superior pain relief to administration of either drug alone.Objectives To systematically establish the pain relieving efficacies of venlafaxine and gabapentin alone and in combination.Materials and methods Gabapentin (50 and 100 mg/kg, s.c.) and venlafaxine (10, 25, 50 mg/kg, s.c.) were tested alone or in combination in the rat spared nerve injury (SNI) model of neuropathic pain and the rat formalin test of persistent pain. Diuresis was measured in a separate experiment after administration of venlafaxine.Results Hindpaw mechanical allodynia was dose-dependently reversed by gabapentin (50 and 100 mg/kg, s.c.), whereas venlafaxine was ineffective (10 and 50 mg/kg, s.c.). Both gabapentin and venlafaxine also attenuated hindpaw mechanical hyperalgesia. Surprisingly, coadministration of venlafaxine (50 mg/kg) significantly lowered the antiallodynic effect of both doses of gabapentin by up to 60% in spared-nerve-injury rats and a negative antinociceptive interaction between gabapentin and venlafaxine was also observed in the rat formalin test. We demonstrated that venlafaxine administration was associated with a dose-dependent increase in urine output over the time course of the nociceptive experiments.Conclusion Venlafaxine compromises the antiallodynic effects of coadministered gabapentin most probably as consequence-increased diuresis.