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

Role in Chronic Pain Pharmacotherapy

Ziconotide blocks the entry of calcium into N-type, neuron-specific, voltage-sensitive calcium channels at presynaptic afferent nerve terminals. In rats, the drug binds to the superficial laminae of the dorsal horn of the spinal cord, where afferent pain fibers make their synapse in the CNS. Given the anatomic site of action and the profound sympatholytic properties of the drug when it is intravenously administered, systemic delivery to produce analgesia is not feasible. Direct intrathecal infusion into the CSF is necessary to deliver the drug to the site of action and to minimize untoward effects.

Opioids and local anesthetics are intrathecally delivered in patients with acute pain to provide postoperative analgesia. One group suggests that, with further dose-finding efficacy and safety research, ziconotide could be a useful adjunct in postoperative pain management.[33] Ziconotide might share some of the advantages of intrathecal opioids and local anesthetics in lowering the risk of CNS respiratory depression after surgery. The drug could be given as an infusion or as a single or intermittent injection, given its duration of action in some clinical studies. The clinical utility of ziconotide needs further definition, and direct comparisons with current practices are also necessary.

The likely primary use of intrathecal ziconotide is to provide an additional drug option for patients who have progressed through the recommended pain treatment guidelines and who still have significant and chronic pain.[9] Intrathecal delivery is one of the last drug delivery mechanisms described in the guidelines of pain treatment. This delivery method is clearly the most invasive route and produces its own risks of infection and device manipulation. Intrathecal delivery is also expensive, given the need for external infusion catheters and pumps for testing. If the test results are satisfactory, surgically implanted and computer-managed internalized infusion pumps are required, along with monthly injection-based pump refills.

Many patients progress through pain treatment paradigms and still have unrelieved pain and/or unacceptable toxicity. Intrathecal ziconotide gives patients with unrelieved, severe pain a novel treatment for pain relief in addition to that achieved with standard therapy.

Considerable research and patient exposures are needed for clinicians to fully understand the properties of ziconotide. This drug may change the paradigm for treating neuropathic pain. Given what is known about the natural history and progression of nerve-injury pain, providing a trial of ziconotide early in the treatment of patients with this pain could easily be justified. The rationale stems from that fact that neuropathic pain conditions often respond poorly to oral drugs and that patients also have significant drug-induced morbidity. Despite the recognized toxicities of ziconotide in some patients, others have had dramatic and unexpected results, including complete pain relief.[9,34] Additional research is needed to understand the relationship among the injuries, pathophysiologic processes, and mechanisms by which these outcomes occurred.

Because of its unique pharmacology and delivery mode, ziconotide plays an important role in understanding the function of neurons.[40] The cellular neuroplastic mechanisms that mediate pain persistence have been reviewed in detail.[18] The term "plasticity" is applied to the interplay of intracellular signaling that occurs in the CNS and peripheral nervous system. This theory of excitatory synaptic transmission has been applied to epilepsy, neurodegeneration, and nervous function of the spinal dorsal horn in the context of chronic neuropathic pain (characterized by a long-term signal sent to the dorsal horn).[40] Adaptive changes occur in the dorsal horn and in microglial cells of the spinal cord and CNS that enable persistent hypersensitivity to pain (Figure 8).[18] Voltage-sensitive calcium channels are present in afferent dorsal horn nerves and are recruited to amplify pain signaling. Nerve depolarization and influx of calcium into cells are mechanisms for activating N-methyl-D-aspartate and α amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors, calcium- and/or calmodulin-dependent kinase, and other modulators of nerve transmission.[18] Direct delivery of ziconotide to the nerve prevents calcium from entering it, blocking pain transmission.[3,4] An unresolved but important question remains: what role, if any, does ziconotide play in reversing the pathologic neuroadaption that occurs during injury? Perhaps the answer will explain why a few patients have complete pain relief even when they are no longer taking ziconotide.

Molecular mechanisms for maladaptive neuronal pain transmission. AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; CAK β = cell adhesion kinase β; Ca2+ = calcium ion; Glu = glutamate; KAI = kainate glutamate receptor; Na+ = sodium ion; NMDA = N-methyl D-aspartate; P = substance P; PKC = protein kinase C; Src = tyrosine kinase Src. (From reference 18.)

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