Ziconotide

Ziconotide is a non-opioid, non-NSAID, non-local anesthetic used for the amelioration of chronic pain. Derived from the cone snail Conus magus, it is the synthetic form of the cone snail peptide ω-conotoxin M-VII-A, an N-type calcium channel blocker.^[1]

The brand name for the drug is Prialt.

In December 2004 the Food and Drug Administration approved ziconotide when delivered as an infusion into the cerebrospinal fluid using an intrathecal pump system.

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Discovery

Ziconotide is derived from the toxin of the cone snail species Conus magus. Scientists have been intrigued by the effects of the thousands of chemicals in marine snail toxins since the initial investigations in the late 1960s by Baldomero Olivera, who remembered the deadly effects from his childhood in the Philippines. Ziconotide was discovered in the early 1980s by Michael McIntosh,^[2] at the time barely out of high school and working with Baldomero Olivera.^[3] It was developed into an artificially manufactured drug by Elan Corporation. It was approved for sale under the name Prialt by the U.S. Food and Drug Administration on December 28, 2004, and by the European Commission on February 22, 2005.

Mechanism of action

The mechanism of ziconotide has not yet been discovered in humans. Results in animal studies suggest that ziconotide blocks the N-Type calcium channels on the primary nociceptor (pain signal) nerves in the spinal cord.

Therapeutic use

Due to the profound side effects or lack of efficacy when delivered through more common routes, such as orally or intravenously, ziconotide must be administered intrathecally (directly into the spine). As this is by far the most expensive and invasive method of drug delivery and involves additional risks of its own,^[4] ziconotide therapy is generally considered appropriate (as evidenced by the range of use approved by the FDA in US) only for “management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies or IT morphine”.^[5]

However, this must be weighed against the high level of pain management, both in terms of degree and length, and the apparent lack of tolerance^[6] and other signs of dependence^[7] even after extended treatment along with the need for alternatives to other therapies that have not worked for the patient. Ziconotide is also contraindicated for patients with certain preexisting mental disorders (e.g. psychosis) due to evidence that they are more susceptible to certain severe side effects.^[8]

Adverse reactions

The most common side effects are dizziness, nausea, confusion, and headache. Others may include weakness, hypertonia, ataxia, abnormal vision, anorexia, somnolence, unsteadiness on feet, and memory problems. The most severe, but rare side effects are hallucinations, thoughts of suicide, new or worsening depression, meningitis and seizures. Therefore, it is contraindicated in people with a history of psychosis, schizophrenia, clinical depression, and bipolar disorder.

Patents

The drug was patented by Neurex Corp., a U.S. company purchased in 1998 by Élan Corporation, plc of Ireland. U.S. patents assigned to Elan include 5,859,186, 5,795,864, 5,770,690, 5,587,454, and 5,559,095.

References