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Chronic CED appears to be a potentially useful method for significantly circumventing the BBB and increasing delivery of water-soluble drugs to the brain.

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The antinociceptive actions of morphine and tizanidine (an alpha 2-adrenergic agonist) administered intrathecally in a rat model of mononeuropathic pain were investigated. Tizanidine increased to normal levels the intensity of a noxious pressure stimulus required to induce paw withdrawal (p < 0.01) and decreased the duration of limb withdrawal from both normal-temperature and cooled floors in a dose-dependent manner (p < 0.01). Tizanidine had virtually no effect on the latency of paw withdrawal from a noxious heat stimulus. In comparison, morphine significantly decreased, in a dose-dependent manner, limb withdrawal from the normal-temperature and cooled floors and increased to cutoff values the withdrawal latencies of both noxious heat and pressure stimuli (p < 0.01). The effect of tizanidine was limited to the hyperalgesic limb and served to normalize reactive latencies, whereas morphine affected both hindlimbs and increased latencies to supranormal cutoff values. These data suggest that intrathecal tizanidine may be more specific than morphine in reversing the allodynia and hyperpathia associated with neuropathic pain states and may be of value in the management of patients with these clinical syndromes.

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 α₂-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 µg IT MS or 10, 25 or 50 µg 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 ≤ 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 µg/day MS, or 75 or 150 µg/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 µg tizanidine or 30 µg 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. IT MS is more potent in that it acutely increased measures to cutoff whereas TZ only increased measures to their normal values. IT TZ more specifically blocked those processes underlying neuropathic pain, inhibiting spontaneous pain and pressure hyperalgesia without affecting normal pain transmission. While both IT MS and TZ may be of value, the increased specificity of TZ suggests that it may be of particular clinical utility in human neuropathic pain states. Mor...