Gabapentin Augments the Antihyperalgesic Effects of Diclofenac Sodium Through Spinal Action in a Rat Postoperative Pain Model

Abstract

Gabapentin and nonsteroidal antiinflammatory drugs (NSAIDs) attenuate postoperative pain and neuropathic pain in humans. The combination of gabapentin and NSAIDs is effective for postoperative pain and enhances functional recovery after surgery. Intrathecal administration of gabapentin or NSAIDs inhibits hyperalgesia in a rat postoperative pain model. However, there is no information on the effects of intrathecal administration of a combination of gabapentin and NSAIDs. We therefore investigated the effects of intrathecal administration of gabapentin and NSAIDs in a rat model of postoperative pain. Rats were prepared for intrathecal catheters under halothane anesthesia. Two days after catheterization, gabapentin (4, 40, or 400 μg per 20 μL of saline), diclofenac sodium, a nonselective cyclooxygenase inhibitor (2, 20, or 200 μg per 20 μL of 6% glucose), 20 μL saline, 20 μL 6% glucose, and a combination of gabapentin and diclofenac (40 μg gabapentin + 20 μg diclofenac and 4 μg gabapentin + 2 μg diclofenac per 20 μL 6% glucose) were injected intrathecally. We performed a hindpaw incision 30 minutes after injection. Each group consisted of 6 rats. The mechanical threshold was measured to evaluate secondary hyperalgesia using von Frey filaments before intrathecal catheterization and at 2 hours, and 1, 3, 5, and 7 days after paw incision. Gabapentin 400 μg attenuated mechanical hyperalgesia for 7 days compared with the control group. Diclofenac 200 μg inhibited hyperalgesia for 5 days compared with the control group. The 40 μg gabapentin + 20 μg diclofenac group had a significantly reduced secondary hyperalgesic response in 2 hours and 1 day compared with 40 μg gabapentin and 20 μg diclofenac, respectively. The 4 μg gabapentin + 2 μg diclofenac group had a significantly reduced secondary hyperalgesic response in 2 hours and 1 day compared with 2 μg diclofenac. The withdrawal threshold on the contralateral paw did not change compared with the preincision threshold. Intrathecal administration of gabapentin and diclofenac in combination reduced secondary hyperalgesia at doses having no antihyperalgesic effects when given individually. Our results suggest that gabapentin and diclofenac have an important role in postoperative pain reduction at the spinal level, and that gabapentin augments the antihyperalgesic effects of diclofenac through action in the spinal cord.