Ziconotide, an Intrathecally Administered N-Type Calcium Channel Antagonist for the Treatment of Chronic Pain

Daniel P. Wermeling, Pharm.D.

Disclosures

Pharmacotherapy. 2005;25(8):1084-1094. 

In This Article

Abstract and Introduction

Ziconotide is a novel peptide that blocks the entry of calcium into neuronal N-type voltage-sensitive calcium channels, preventing the conduction of nerve signals. N-type calcium channels are present in the superficial laminae of the dorsal horn of the spinal cord. In various animal models of pain, intrathecal administration of ziconotide blocked nerve transmission and nociception. The United States Food and Drug Administration recently approved ziconotide intrathecal infusion for the management of severe chronic pain in patients who require intrathecal therapy and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. The drug has a narrow therapeutic window and a lag time for the onset and offset of analgesia and adverse events. In early clinical trials, frequent and severe psychiatric and central nervous system adverse effects were associated with rapid intrathecal infusion (0.4 µg/hr) and frequent up-titration (every 12 hrs). Therefore, patients with psychiatric symptoms are not candidates for this drug. Drug trials of external intrathecal catheters and microinfusion devices demonstrated a 3% risk of meningitis. A low initial infusion rate of 0.1 µg/hour and limiting infusion rate increases to 2-3 times/week are now recommended. Patients responsive to intrathecal ziconotide require an implanted infusion system to receive long-term therapy.

Chronic malignant pain syndromes, such as those due to advanced cancer, acquired immunodeficiency syndrome (AIDS), and multiple sclerosis, and chronic neuropathy of various etiologies, are some of the most challenging clinical problems in medicine. Medical researchers continue to document the undertreatment or inappropriate treatment of pain.[1] These inadequacies have improved with education and with the publication of guidelines on the best use of drugs in the treatment of chronic pain. However, in certain circumstances, tolerance to drugs, such as opiates, develops. Moreover, drugs used in combination to relieve pain can create polypharmacy-type toxicity.[1]

Specialists in pain management have used creative pharmacology and drug delivery techniques to solve their patients' pain. To their benefit, research continues to advance our understanding of the pathophysiology of pain, and that knowledge creates the opportunity to develop new pharmacologic treatments. Still, few new molecules for treatment of pain are in development.

Ziconotide (Prialt; Elan Pharmaceuticals, Inc., San Diego, CA) intrathecal injection was recently approved by the United States Food and Drug Administration (FDA) for the management of severe chronic pain in patients who require intrathecal therapy and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. The drug is synthetically derived from a toxin produced by the piscivorous Conus magus cone snail.[2] The toxin contains, among other substances, a potent target of voltage-sensitive calcium channels.[3] Ziconotide is a potent and specific inhibitor of the N-type calcium channel. These channels are found throughout the peripheral nervous system and central nervous system (CNS).[4] Inhibiting the entry of calcium into cells is a central mechanism for modulating nerve transmission and action. Thus, the systemic or CNS administration of ziconotide may have broad applications in the mediation of cell death and/or ischemia in cardiovascular disease, CNS disease, and diseases involving pathologic nerve transmission, including those causing neuropathic pain. An implanted drug delivery pump is required for long-term therapy.

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