Ziconotide
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FDA-approved venom-derived peptide analgesic; selective N-type calcium channel blocker for severe chronic pain via intrathecal delivery. First non-opioid intrathecal analgesic.
Quick Facts
| Property | Value |
|---|---|
| Also Known As | Prialt, SNX-111, omega-conotoxin MVIIA |
| Category | Analgesic / Pain peptide (venom-derived) |
| Sequence | CKGKGAKCSRLMYDCCTGSCRSGKC (25 amino acids, 3 disulfide bonds) |
| Molecular Weight | ~2639 Da |
| Molecular Formula | C₁₀₂H₁₇₂N₃₆O₃₂S₇ |
| PubChem CID | 16135415 |
| Administration | Intrathecal only (via implanted or external pump) |
| Typical Dose Range | 0.1-19.2 mcg/day intrathecal; start at 2.4 mcg/day, titrate slowly |
| Half-Life | ~4.6 hours (in CSF) |
| Storage | Refrigerated (2-8 C); stable at room temperature for 14 days in pump |
| FDA Status | FDA Approved (2004) — Severe chronic pain refractory to other therapies (Prialt, Jazz Pharmaceuticals) |
| WADA Status | Not listed |
Mechanism of Action
Ziconotide is the synthetic equivalent of omega-conotoxin MVIIA, a 25-amino acid peptide naturally produced in the venom of the marine cone snail Conus magus. The peptide contains three intramolecular disulfide bonds (Cys1-Cys16, Cys8-Cys20, Cys15-Cys25) that create a compact, highly stable "inhibitor cystine knot" (ICK) structural motif characteristic of conotoxins (PMID-15578997).
Ziconotide selectively and reversibly blocks N-type voltage-gated calcium channels (CaV2.2) located presynaptically on primary afferent nociceptive neurons in the dorsal horn of the spinal cord. CaV2.2 channels are essential for neurotransmitter release from nociceptive C-fibers and A-delta fibers. By blocking these channels, ziconotide prevents the calcium influx required for vesicular release of pain signaling neurotransmitters including substance P, glutamate, and calcitonin gene-related peptide (CGRP) (PMID-15578997).
The selectivity for N-type over P/Q-type, L-type, and T-type calcium channels is a critical pharmacological property — it targets pain transmission specifically without broadly disrupting neuronal or cardiac calcium channel function. This selectivity is determined by the specific residues in the peptide's loop regions, particularly Tyr13 which is essential for N-type binding.
Unlike opioids, ziconotide does not bind mu, delta, or kappa opioid receptors. Therefore, it produces NO tolerance, NO physical dependence, NO respiratory depression, and NO addiction. This represents a fundamentally different mechanism for severe pain management. However, because it cannot cross the blood-brain barrier from systemic circulation, it must be delivered directly into the cerebrospinal fluid via intrathecal pump.
Key Research Areas
- Severe chronic cancer pain — Pivotal RCT showed 53.1% vs 18.1% pain reduction (P<0.001) (PMID-14709577)
- Chronic nonmalignant pain — RCT demonstrated 31.2% vs 6.0% pain reduction in refractory patients (PMID-22151630)
- N-type calcium channel pharmacology — Ziconotide as the definitive tool compound for CaV2.2 research (PMID-15578997)
- Venom-derived therapeutics — Proof-of-concept for cone snail venom as a source of novel analgesic peptides
- Opioid-sparing strategies — Non-addictive alternative for severe intractable pain
Evidence Level Summary
| Evidence Type | Count | Notes |
|---|---|---|
| Human RCTs | 3 | Two pivotal (cancer/AIDS, nonmalignant), one slow-titration |
| Human observational | Several | Long-term open-label extension studies |
| Animal in vivo | Many | Extensive preclinical pain models |
| In vitro | Many | CaV2.2 binding, structure-activity studies |
| Systematic reviews | 1+ | Intrathecal therapy review |
Clinical Applications
- Cancer Pain Management — FDA-approved for refractory cancer pain
- Neuroprotection — Related calcium channel mechanisms
Protocols Using This Peptide
Ziconotide is administered exclusively in specialized pain management settings via intrathecal pump. It is not used in outpatient peptide protocols.
Ageless Peps Products
Ziconotide is an FDA-approved prescription medication (Prialt) requiring intrathecal delivery and is NOT sold by Ageless Peps. It is included in this vault as a reference for venom-derived peptide science and non-opioid pain management education.
Dosing Reference
FDA-Approved Dosing
| Route | Dose | Frequency | Duration | Source |
|---|---|---|---|---|
| Intrathecal | Initial: 2.4 mcg/day (0.1 mcg/hr) | Continuous infusion | Chronic; titrate no more than 2-3x/week | FDA label |
| Intrathecal | Max: 19.2 mcg/day (0.8 mcg/hr) | Continuous infusion | Adjust to pain response and tolerability | FDA label |
Cycling
Not applicable — ziconotide is used as continuous intrathecal infusion. Dose is titrated upward slowly (increments of <=2.4 mcg/day, no more often than 2-3 times per week) to balance efficacy and CNS side effects.
Contraindications & Safety
- Contraindications: History of psychosis; infection at microinfusion site; uncontrolled bleeding; spinal canal obstruction impeding CSF flow
- Common side effects: Dizziness (47%), nausea (30%), confusion (33%), headache, somnolence, nystagmus, abnormal gait, memory impairment
- Serious adverse events: Psychosis, suicidal ideation (rare but documented — FDA black box warning), meningitis (pump-related), elevated creatine kinase
- Drug interactions: Additive CNS depression with opioids, sedatives, anticonvulsants (use caution, but can be combined)
- Pregnancy/nursing: Category C; limited data
- Special populations: Requires careful monitoring in elderly; contraindicated in patients with psychotic disorders
Synergistic Combinations
Ziconotide is often used in combination intrathecal therapy:
- Ziconotide + intrathecal morphine — Complementary mechanisms (calcium channel + opioid receptor)
- Ziconotide + baclofen — For patients with combined pain and spasticity
Related Research
| PMID | Title | Year | Study Type |
|---|---|---|---|
| 14709577 | Ziconotide for Refractory Cancer/AIDS Pain (pivotal JAMA trial) | 2004 | RCT |
| 15578997 | Ziconotide: Neuronal Calcium Channel Blocker Review | 2004 | Narrative Review |
| 22151630 | Ziconotide in Chronic Nonmalignant Pain | 2012 | RCT |
References
- PMID-14709577 — Staats et al., Ziconotide cancer pain RCT, JAMA 2004
- PMID-15578997 — Miljanich, Ziconotide mechanism review, Curr Med Chem 2004
- PMID-22151630 — Rauck et al., Nonmalignant pain RCT, J Pain 2012
Related
FDA Disclaimer: Ziconotide (Prialt) is an FDA-approved prescription medication requiring intrathecal delivery by specialized pain management providers. This vault entry is for educational reference only.
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