Cone-snail peptide · severe chronic pain
A non-opioid pain medicine that is a synthetic copy of a peptide found in Conus magus, a fish-hunting marine cone snail. It is infused into the fluid around the spinal cord (intrathecally) through a microinfusion pump, and is reserved for adults with severe chronic pain who have not done well on other treatments.
Ziconotide is a 25-amino-acid peptide held in shape by three disulfide bridges1. It binds N-type voltage-sensitive calcium channels on the pain-carrying A-delta and C nerve fibers where they enter the dorsal horn of the spinal cord1. Animal studies suggest that blocking these channels stops the nerve endings from releasing excitatory neurotransmitters, interrupting pain signals on their way to the brain; the label notes this mechanism has not been established in humans1. It does not work through opioid receptors, and the label states it can be stopped abruptly without evidence of withdrawal1. It is delivered intrathecally, close to these nerve endings. Reviewers describe it as potent but with a narrow therapeutic window5.
Three placebo-controlled trials in humans support its use. In 111 people with cancer- or AIDS-related pain, nearly all already taking opioids, pain scores improved 53.1% with ziconotide versus 18.1% with placebo after a rapid dose increase2. A similar fast-titration trial in 255 people with severe nonmalignant pain found a 31.2% versus 6.0% improvement, but side effects such as dizziness, abnormal gait, nausea and urinary retention were frequent3.
A later trial in 220 adults used slower titration to lower doses: pain improved 14.7% versus 7.2%, a smaller effect, and the drug was better tolerated4. Across trials, 1,254 adults received ziconotide, and the label notes that slower titration may lead to fewer serious adverse reactions1.
FDA-approved in December 2004 as Prialt for severe chronic pain in adults who need intrathecal therapy and cannot tolerate, or do not respond to, other treatments such as systemic pain medicines or intrathecal morphine.
Prialt's boxed warning states that "severe psychiatric symptoms and neurological impairment may occur during treatment", that people with a pre-existing history of psychosis must not be treated with it, and that patients should be monitored often for cognitive impairment, hallucinations and changes in mood or consciousness, with the drug stopped if serious signs appear1. Reported effects include hallucinations (12%), paranoia, confusion, memory problems and reduced consciousness, and it may cause or worsen depression with a risk of suicide. The most common effects in trials were dizziness, nausea, confusion and nystagmus (involuntary eye movements). Other warnings cover meningitis, raised creatine kinase, and the need to taper opioids gradually rather than stop them abruptly when switching.
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