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.