Original Articles
Preclinical Toxicity Study of Intrathecal Administration of the Pain Relievers Dextrorphan, Dextromethorphan, and Memantine in the Sheep Model

https://doi.org/10.1046/j.1525-1403.1999.00230.xGet rights and content

ABSTRACT

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.

Section snippets

MATERIALS AND METHODS

After approval by the Institutional Animal Care and Use Committee at The University of Texas M.D. Anderson Cancer Center; this study was conducted at M.D. Anderson Cancer Center-Science Park’s Department of Veterinary Sciences (Bastrop, TX) in strict accordance to the Guide for the Care and Use of Laboratory Animals published by National Research Council (42). The 48, one- and two-year-old Rambouillet/Suffolk-cross sheep used in this study weighed between 22 and 58 kg. The male sheep (N = 39)

RESULTS

All 48 sheep randomly received continuous intrathecal administration of dextrorphan, dextromethorphan, or memantine via subcutaneous, programmable continuous-infusion pumps (Medtronic Synchromed, pump models 8615 and 8617). Of these 48 animals, 41 were actually used in the study groups. Of the seven animals excluded from the study, three animals had questionable patency of the intrathecal catheters; one animal had a neurologic deficit caused by intraoperative trauma; another animal developed a

DISCUSSION

The administration of intrathecal or epidural morphine for chronic pain states is widespread and well-established (15,18). However, unpredicted side effects such as ventilatory depression, itching, and urinary retention have been reported (16) and the use of spinally administered morphine has been accompanied by reports of tolerance (43). Common clinical practice including our experience and that of others (44) found that morphine tolerance could develop to a point where intrathecal doses of 50

ACKNOWLEDGMENTS

We would like to thank Richard Terrell, Kyle Voelker, Rodney Helgren and Gerald Costello for their valuable assistance in conducting this study. We would also like to thank Medtronic, Inc. (Minneapolis, MN) for the use of the implantable infusion devices. Quanyun Xu, Ph.D. was instrumental in preparing the antagonists.

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