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Context: Ziconotide (formerly SNX-111) selectively blocks N-type voltage-sensitive calcium channels and may be effective in patients with pain that is refractory to opioid therapy or those with intolerable opioid-related adverse effects., Objective: To assess the safety and efficacy of intrathecal ziconotide in patients with pain that is refractory to conventional treatment., Design, Setting, and Patients: Double-blind, placebo-controlled, randomized trial conducted from March 12, 1996, to July 11, 1998, at 32 study centers in the United States, Australia, and the Netherlands. Patients were 111 individuals ages 24 to 85 years with cancer or AIDS and a mean Visual Analog Scale of Pain Intensity (VASPI) score of 50 mm or greater. Patients were randomly assigned in a 2:1 ratio to receive ziconotide or placebo treatment., Interventions: Intrathecal ziconotide was titrated over 5 to 6 days, followed by a 5-day maintenance phase for responders and crossover of nonresponders to the opposite treatment group., Main Outcome Measure: Mean percentage change in VASPI score from baseline to the end of the initial titration period., Results: Of the evaluable population, 67 (98.5%) of 68 patients receiving ziconotide and 38 (95%) of 40 patients receiving placebo were taking opioids at baseline (median morphine equivalent dosage of 300 mg/d for the ziconotide group and 600 mg/d for the placebo group; P =.63, based on mean values), and 36 had used intrathecal morphine. Mean (SD) VASPI scores were 73.6 (1.8) mm in the ziconotide group and 77.9 (2.3) mm in the placebo group (P =.18). Mean VASPI scores improved 53.1% (95% confidence interval [CI], 44.0%-62.2%) in the ziconotide group and 18.1% (95% CI, 4.8%-31.4%) in the placebo group (P<.001), with no loss of efficacy of ziconotide in the maintenance phase. Pain relief was moderate to complete in 52.9% of patients in the ziconotide group compared with 17.5% in the placebo group (P<.001). Five patients receiving ziconotide achieved complete pain relief, and 50.0% of patients receiving ziconotide responded to therapy compared with 17.5% of those receiving placebo (P =.001)., Conclusion: Intrathecal ziconotide provided clinically and statistically significant analgesia in patients with pain from cancer or AIDS.

In an earlier report, we demonstrated that subcutaneous injection of formalin in the rat hindpaw evokes a characteristic pattern of expression of the fos protein product of the c-fos protooncogene in spinal cord neurons, and that systemic morphine reversed the fos-like immunoreactivity in a dose-dependent, naloxone-reversible manner. The present study compared the effects of intracerebroventricular administration of the mu-selective opioid ligand [D-Ala2, NMe-Phe4, Gly-ol5] enkephalin, on the pain behavior and spinal cord fos-like immunoreactivity produced by subcutaneous formalin. Formalin injection produced a biphasic pain behavioral response which lasted about 1 h. There was a significant correlation between the formalin pain score and overall fos-like immunoreactivity in the lumbar enlargement. The greatest numbers of labeled cells and most intense fos-like immunoreactivity were found in laminae I, IIo and V of the L4-5 segments, ipsilateral to the formalin-injected paw. Considerable staining was also found in the ipsilateral ventral horn laminae VII and VIII. [D-Ala2, NMe-Phe4, Gly-ol5]enkephalin produced a dose-related, naloxone-reversible inhibition of both the formalin-evoked pain behavior and fos expression in the cord. The behavioral response to formalin, however, could be completely blocked without eliminating the expression of fos in spinal neurons. Moreover, subpopulations of neurons were differentially regulated. Thus, 100% inhibition of pain behavior was produced at a dose of [D-Ala2, NMe-Phe4, Gly-ol5]enkephalin which reduced fos-like immunoreactivity in the superficial laminae by only 64% and in the neck and ventral cord by 85%. Furthermore, the dose of [D-Ala2, NMe-Phe4, Gly-ol5]enkephalin which produced approximately 50% inhibition of fos-like immunoreactivity in the neck and ventral regions of the spinal cord was without effect in the superficial dorsal horn. Since the potencies for inhibition of pain behavior and fos-like immunoreactivity in the neck and ventral horn were comparable, these data suggest that the activity of neurons in these regions is directly related to the pain behavior produced by nociceptive inputs. Finally, we found that bilateral, midthoracic lesions of the dorsal part of the lateral funiculus blocked both the antinociception and fos suppression produced by intracerebroventricular [D-Ala2, NMe-Phe4, Gly-ol5]enkephalin. These results are consistent with the hypothesis that the analgesic action of supraspinally administered opiates results from an increase in descending inhibitory controls that regulate the firing of subpopulations of spinal cord nociresponsive neurons.