Repeated Intrathecal Administration of Ropivacaine Causes Neurotoxicity in Rats

Abstract

Previous studies suggest that ropivacaine causes the least neurotoxicity among local anaesthetics. Most data derive from a single injection of ropivacaine into the subarachnoid space. The histological changes and behavioural effects of repeated intrathecal administration have yet to be studied. We examined the possible neurotoxicity of multiple doses of intrathecal ropivacaine in rats. Rats received 0.12 ml/kg body weight ropivacaine in normal saline at concentrations of 0.25%, 0.5%, 0.75% and 1.0% at 90-minute intervals via an implanted intrathecal catheter (ID 0.12 mm, OD 0.35 mm) for 48 hours. At L3, the spinal cord and posterior roots were examined by light and electron microscopy. We performed in situ TUNEL assay to evaluate apoptosis in the spinal cord. Sensory threshold to noxious stimulation along with behavioural change were also studied. Both 0.75% and 1.0% ropivacaine induced neuronal injury characterised by infiltration of inflammatory cells, vacuolation of myelin sheaths and axons, abnormal morphology of neurons and apoptosis in the spinal cord, mainly in posterior roots and the adjacent posterior white matter. Compared to controls, the percentage of maximum possible effect did not show any significant differences between the rats treated with variable concentrations of ropivacaine or tested with either heat or mechanical stimulation. As expected, the recovery time to normal ambulation was prolonged as the ropivacaine concentration was increased. Ropivacaine can induce neurotoxicity and trigger apoptosis in a dose-dependent manner after repeated intrathecal administration. Although the clinical safety profile of ropivacaine appears favourable compared with other local anaesthetics, it is possible our findings have clinical significance.