Comparison of neurotoxicity of intrathecally administered fentanyl and bupivacaine in rats

Background: Fentanyl is intrathecally used as an adjuvant to bupivacaine in spinal anesthesia, as well as labor analgesia, and in day surgery. The aim of this study was to determine the separate neurotoxic effect of each drug using histological analysis. Methods: Rats (N = 39) received fentanyl at 0.12μl/g body weight (0.05, 0.5, and 1 mg/ml) or bupivacaine (5, 25, and 50 mg/ml) dissolved in saline via an intrathecal catheter. Saline was used as the control solution. Walking behavior and sensory threshold were used as neurofunctional tests. Seven days after the intrathecal injection, the L2 spinal cords, of each rat, with both anterior and posterior roots, including the dorsal ganglion and cauda equina, were examined histologically. Results: No histological abnormalities were observed in any of the rats treated with fentanyl (0.05, 0.5, or 1 mg/ml) or bupivacaine (5 or 25 mg/ml). However, axonal degeneration originating from the posterior root, extending to the posterior white matter, was observed in rats treated with 50-mg/ml bupivacaine. Significantly higher sensory thresholds were observed in rats with 1 mg/ml fentanyl, or 50-mg bupivacaine at 2 hours after the injection. The higher thresholds gradually disappeared in rats with fentanyl after 1 hour even at 1 mg/ml, but remained in rats with 50-mg/ml bupivacaine after 2 hours, and significantly decreased at 7 days after the injection. The rats could walk normally within 15 minutes, 1 hour before, and 1 hour after the injection of fentanyl (0.05, 0.5, and 1 mg/ml), respectively, and within 1, 2, and 4 hours of bupivacaine (5, 25, and 50 mg/ml), respectively. Transient apnea was only observed in 1 rat treated with 0.05-mg/ml fentanyl, while both transient apnea and muscle rigidity were observed in rats treated with 0.5and 1-mg/ml fentanyl. No rats treated with bupivacaine (5, 25, or 50 mg/ml) showed both side effects. Conclusions: Our results indicated that intrathecal fentanyl does not cause any neurotoxic changes even at more than 40 times the clinical concentration (1 mg/ml), whereas bupivacaine causes nerve damage even when applied at 10 times the clinical concentration (50 mg/ml) in the spinal rat model. Side effects such as respiratory depression and muscle rigidity were seen in rats in the fentanyl group, even at 0.05 mg/ml. These results suggested that intrathecal fentanyl has strong side effects but low neurotoxicity because of the absence of morphological neurotoxicity even at high concentrations, whereas intrathecal bupivacaine induced sensory disturbance associated with axonal degeneration.