Preclinical toxicity study of intrathecal administration of the pain relievers dextrorphan, dextromethorphan, and memantine in the sheep model

Objectives: To determine the toxicity window for the continuous intrathecal administration of dextrorphan, dextromethorphan, and memantine via an implanted delivery pump. Materials and Methods: Using 48 sheep with programmable continuous intrathecal infusion systems we determined the behavioral, motor, neurological, and histopathological changes produced by a 43-day continuous infusion study of dextrorphan, dextromethorphan, and memantine dissolved in 0.9% NaCl. Daily doses of each N-methyl-D, aspartate (NMDA) antagonist were 0.013, 0.051,0.203, 0.510, 0.811, and 2.533 mg/kg/day, flow rates ranged from 13.25 ml/day to 0.051 ml/day at a concentration of 10 mg/ml. Control animals received saline in the range of 7.9985 ml/day to 1 ml/day. Conclusions: Infusion of saline in the control animals produced no behavioral or motor changes. However, infusion of dextrorphan, dextromethorphan, and memantine at the higher doses (> 0.051 mg/kg/day) produced dose-dependent negative behavioral, motor, and histopathologic changes as indicated by a series of nonparametric statistical analyses. The minimal toxic doses were dextrorphan dose 3, dextromethorphan dose 1 and memantine dose 1. This study suggests that continuous intrathecal infusion of dextrorphan, dextromethorphan, and memantine via an implantable pump system can cause significant toxicities at the higher doses studied.