Combination therapy with flupirtine and opioid: studies in rat pain models

Flupirtine is an established clinical analgesic for mild to moderate musculoskeletal pain states. It has recently been shown to be a KCNQ2-3 potassium channel opener. These experiments were performed to see if this property could be useful in treating pain states characterized by central sensitization with the drug either given alone or in combination with morphine.

Experiments were performed in rats in an observer-blinded fashion with vehicle controls. Nonsedating doses of flupirtine, morphine, and combinations containing both drugs were defined using the rotarod test and open-field activity monitoring. Dose-response relationships were determined for nonsedating doses of both drugs given alone and together in combination in causing antinociception in two nociception paradigms: carrageenan paw inflammation and streptozotocin-induced diabetic neuropathy.

Flupirtine and morphine, when given alone at the highest nonsedating doses, caused slight to moderate antinociception in both paradigms. Flupirtine also caused significant increases in morphine antinociception in both models. In carrageenan paw inflammation, complete reversal of carrageenan-induced hyperalgesia was caused by 10 mg/kg flupirtine in combination with 0.4 mg/kg morphine. These doses of the two drugs were ineffective when given alone, but the combination caused complete antinociception in this model of inflammatory pain. In the diabetic neuropathy model, morphine 3.2 mg/kg given alone caused no significant antinociception. However, a lower dose of morphine (1.6 mg/kg shown to be ineffective when it was given alone) given in combination with flupirtine 10 mg/kg caused highly significant antinociceptive effects causing complete reversal of hyperalgesia caused by diabetic neuropathy (P < 0.001, one-way analysis of variance). This combination of drugs was not sedating.

Flupirtine increases morphine antinociception without causing an increase in sedation. Flupirtine should be investigated as an adjunct analgesic with opioids for the management of patients with pain states involving central sensitization.