Worldwide a large number of patients suffer from severe chronic pain even after 
treatment with opioids following the 3-step analgesic ladder developed by the 
WHO. Intraspinal agents, including morphine, have been tried as a fourth step. 
However, approximately 20% of cases remain refractory. Ziconotide, an 
intrathecal analgesic with orphan drug status, is a novel alternative for the 
management of chronic intractable pain. Ziconotide is a synthetic peptide based 
on the toxin of the fish-hunting marine snail, Conus magus. It is the first 
therapeutic agent in a new pharmacological class of "topically" active 
analgesics that selectively target neuron-specific (N-type), voltage-gated 
calcium channels. Ziconotide produces potent analgesia by interruption of 
Ca-dependent primary afferent transmission of pain signals in the spinal cord. 
Ziconotide was significantly more effective than placebo in the treatment of 
chronic malignant (p < 0.001) and non-malignant pain (p < 0.001). In several 
clinical studies morphine dosages could be substituted by ziconotide. The drug 
has a lag-time for the onset and offset of analgesia and adverse effects. 
Initial doses should therefore be low (2.4 microg/day) and titrated slowly 
(increasing up to a maximum of 21.6 microg/day in increases of 2.4 microg/day no 
more than twice weekly). The gradual increase in dose helps to reduce the 
incidence and severity of adverse events which affect primarily the central 
nervous system (e.g. dizziness, nausea, confusion). Ziconotide maintains its 
analgesic efficacy over months and does not cause tolerance, dependence or 
respiratory depression. Following intrathecal infusion ziconotide is distributed 
within the cerebral spinal fluid (CSF) where its clearance (0.38 ml/min) 
corresponds to the rate of turnover of the CSF. Negligible amounts of ziconotide 
are present in the systemic circulation where it is rapidly degraded by 
proteolysis. In conclusion, ziconotide is a new and valuable alternative 
analgesic for the acute and long-term treatment of severe pain, especially in 
patients refractory to opioids.