Analgesic Action of Acute and Chronic Intraspinally Administered Opiate and α<sub>2</sub>-Adrenergic Agonists in Chronic Neuropathic Pain

Abstract

Intrathecal (IT) administration of opiate analgesics has become a popular method of pain control in patients with pain of both malignant and nonmalignant origin. Therapeutic efficacy for nonmalignant pain states might be improved by having a broader range of available pharmacologic agents for intrathecal administration. Toward this aim, we have applied a new model of neuropathic pain in the rat to evaluate the relative analgesic efficacy and potential cross tolerance of both acutely and chronically administered IT morphine (MS) and tizanidine (TZ), an alpha 2-adrenergic agonist. Under anesthesia, 225 Sprague-Dawley male rats underwent unilateral multiple partial suture ligation of the sciatic nerve. This produces a syndrome similar to human neuropathic pain. Chronic lumbar IT cannulae were placed via the cisterna magna. Seven days after surgery, animals were tested for spontaneous ambulation and paw pinch tolerance. These tests correlate with human clinical observations of chronic pain and hyperpathia. For the acute drug administration, animals were then given saline, 10, 20, or 30 micrograms IT MS or 10, 25 or 50 micrograms IT TZ and testing was repeated. Preliminary results suggest that MS, in a dose-dependent manner, significantly decreased abnormal limb withdrawal from the floor while ambulating and increased paw pinch withdrawal latency to cutoff values (p < or = 0.01 in all tests). IT MS had significant effects on pain sensation in the operated and unoperated limbs, increasing latencies to cutoff and nonspecifically inhibiting pain transmission. IT TZ had a similar effect on decreasing limb withdrawal from the floor, but paw pinch withdrawal latency was increased only to the normal range, not to cutoff values. These effects were also dose-dependent. For chronic drug administration, after baseline testing, osmotic minipumps (Alza, Palo Alto, Calif.) delivering either saline, 60 or 120 micrograms/day MS, or 75 or 150 micrograms/day TZ were attached to the IT catheter. Testing was done on days 1, 4, 7 and 14 after pump attachment. On day 14, the animals were given an IT bolus of the noninfused drug (50 micrograms tizanidine or 30 micrograms morphine) and the tests were repeated to determine degree of cross tolerance. Initially, chronic MS and TZ administration produced a similar degree of analgesia seen with results obtained with acute administration. The animals rapidly became tolerant to these agents so that by day 4, neither drug had an analgesic effect. No significant cross tolerance between MS and TZ was observed. Thus, both IT MS and TZ are analgesic in experimental chronic neuropathic pain.(ABSTRACT TRUNCATED AT 400 WORDS)