ICONOTIDE (FORMERLY SNX-111, Neurex Pharmaceuticals, Menlo Park, Calif) is the synthetic equivalent of-conopeptide MVIIA, a 25-amino-acid polybasic peptide present in the venom of Conus magus, a marine snail. 1 Ziconotide produces potent antinociceptive effects 2 by selectively binding to N-type voltage-sensitive calcium channels 3,4 on neuronal somata, dendrites, dendritic shafts, and axon terminals, thus blocking neurotransmission from primary nociceptive afferents. Ziconotide is the first selective Ntype voltage-sensitive calcium channel blocking agent to be tested in clinical trials. There is no evidence of tolerance to ziconotide 5 or of addictive behavior in animals (Elan Pharmaceuticals Inc, unpublished data), and the drug must be administered intrathecally to maximize antinociceptive effectiveness and minimize sympatholysis. 6

Safety and efficacy data from a study of slow intrathecal (IT) ziconotide titration for the management of severe chronic pain are presented. Patients randomized to ziconotide (n = 112) or placebo (n = 108) started IT infusion at 0.1 microg/hour (2.4 microg/day), increasing gradually (0.05-0.1 microg/hour increments) over 3 weeks. The ziconotide mean dose at termination was 0.29 microg/hour (6.96 microg/day). Patients' baseline Visual Analogue Scale of Pain Intensity (VASPI) score was 80.7 (SD 15). Statistical significance was noted for VASPI mean percentage improvement, baseline to Week 3 (ziconotide [14.7%] vs. placebo [7.2%; P = 0.036]) and many of the secondary efficacy outcomes measures. Significant adverse events (AEs) reported in the ziconotide group were dizziness, confusion, ataxia, abnormal gait, and memory impairment. Discontinuation rates for AEs and serious AEs were comparable for both groups. Slow titration of ziconotide, a nonopioid analgesic, to a low maximum dose resulted in significant improvement in pain and was better tolerated than in two previous controlled trials that used a faster titration to a higher mean dose.

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