Ziconotide

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 10.16.2021
Released 08.08.2000
Expires For CME 10.16.2024

Ziconotide

Author: K K Jain MD†

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Ziconotide

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Introduction

Historical note and terminology

Ziconotide, the synthetic form of cone snail peptide pi (variant) conotoxin MVIIA, is a neuron-specific N-type calcium channel blocker that has been under development for the treatment of severe chronic pain and ischemia. The snail has been used in medicine since antiquity and prepared according to several formulations. Pliny considered the snail to be "a sovereign remedy to treat pain related to burns, abscesses and other wounds” (05).

Pi (variant) peptides that block voltage-sensitive calcium channels were isolated from a species of conus snails in 1991 (15). Development of SNX-111 (now ziconotide) for cerebral ischemia and traumatic brain injury began in 1993, and clinical trials for chronic pain started in 1995. Intrathecal ziconotide for pain was approved by the FDA in 2004 and by the European Medicines Agency in 2005.

Pharmacology

Ziconotide is a 25-amino acid polycationic peptide containing 6 cysteine residues linked by 3 disulfide bridges and is the synthetic form of a conotoxin peptide found in the venom of the snail Conus magus.

Ziconotide (chemical structure)

(Contributed by Dr. K K Jain.)

Because of the problems associated with delivery and bioavailability of peptides, small molecule, nonpeptidic mimics of conotoxins have been modified to improve their drug-like properties and are in development (08). One of these, leconotide, is the most selective conotoxin for the N-type calcium channel and has a wider therapeutic window than ziconotide, with fewer cardiovascular side effects.

Pharmacodynamics. The therapeutic potential of ziconotide is based on its property as a specific and selective blocker of N-type voltage-specific calcium channel, with no significant affinity for other ion channels. The N-type channel is found exclusively in neurons and regulates depolarization-induced calcium influx. It controls a variety of calcium-dependent processes including the modulation of neuronal excitability and the release of neurotransmitters. Direct blockade of N-type channel inhibits the activity of a subset of neurons, including pain-sensing primary nociceptors. This mechanism of action distinguishes ziconotide from all other analgesics, including opioid analgesics. Ziconotide also acts as a neuroprotective agent by its ability to inhibit the release of excitotoxic neurotransmitters and to prevent pathologic calcium entry into neurons after traumatic and vascular insults to the brain. Spinally administered ziconotide produces analgesia by blocking the neurotransmitter release from primary nociceptive afferents and preventing the proliferation of pain signals to the brain. It is 50 times more potent than morphine but does not cause the adverse effects of opiates.

Pharmacokinetics. In healthy volunteers, a 2-compartment model with linear elimination and dose-proportional plasma concentration characterizes the pharmacokinetics of ziconotide. After a continuous infusion, ziconotide had a half-life of 1.3h and a tMAX of 5.3h.

In CSF, the median half-life of ziconotide is 4.5 hours. The pharmacokinetics of ziconotide are linear, based on cumulative exposure and peak CSF concentrations. Following intrathecal bolus injection or infusion in the dog, ziconotide is cleared slightly more rapidly than inulin from the lumbar CSF (24).

An open-label, nonrandomized clinical trial of ziconotide by trial intrathecal bolus injection showed that predictive power of efficacy of further doses was unclear (04). In view of the slow tissue penetration of ziconotide due to high hydrophilicity, the rationale for trial bolus injection of the drug is questionable.

Methods of delivery of ziconotide. Ziconotide is administered intrathecally as systemically administered drugs do not cross the blood-brain barrier. Virus-like nanoparticles containing ziconotide have been successfully transported in several blood-brain barrier models of rat and human brain microvascular endothelial cells, opening the possibility of an alternative to intrathecal injection of ziconotide using a tailored drug delivery nanocontainer to cross the blood-brain barrier (02).

Goals and duration of treatment

Ziconotide is a non-opioid therapeutic option for treatment of severe chronic pain in patients who have exhausted all other agents, including intrathecal morphine, and for whom the potential benefit outweighs the risks of adverse effects and of having an implanted device. However, ziconotide has a narrow therapeutic window because of significant neurologic adverse effects that restrict its use to a small subset of patients with severe chronic pain (21). If intrathecal analgesia is considered necessary, ziconotide has obvious advantages over opioids in neuropathic and chronic noncancer pain, but lack of adverse effects of opioids should be weighed against severe neuropsychiatric adverse effects of ziconotide when making a decision (03). Combination of low doses of intrathecal ziconotide and morphine enables safe and rapid control of oral opioid-refractory malignant pain (01). A retrospective analysis of patients treated with low-dose intrathecal ziconotide as the first-line monotherapy showed no side effects that resulted in discontinuation of the treatment at 3-month follow-up, and treatment was effective in 53% of the patients (17).

A study on patients who had undergone a successful ziconotide trial and were scheduled for standard-of-care placement of a pump for intrathecal drug therapy showed that intrathecal ziconotide relieves neuropathic pain and improves its emotional components (ie, disability, emotional well-being, and catastrophizing of pain) (22).

A pilot study has shown that after an initial bolus dose of 2.5 mcg ziconotide, pain perception on visual analog scale was reduced by approximately 25% at the group level and it was generally well tolerated (14). Further studies are needed to determine if bolus dosing with ziconotide is a good predictor of continued response to long-term ziconotide administration via an implanted intrathecal drug delivery pump. It is important to remember that although ziconotide is effective, it has a narrow therapeutic window and should be titrated slowly and carefully to achieve maximal effect without adverse events (23).

The treatment is continuous depending on the duration of the pain. The analgesic effect can last for months. Ziconotide is a non-narcotic agent and does not have the problems associated with the use of narcotic medications such as morphine and morphine substitutes. There is no evidence that tolerance develops with prolonged use of the drug. Accumulated evidence from clinical trials and case studies suggests that ziconotide is a potential therapeutic option for patients with refractory neuropathic pain, but further studies are required to establish the long-term efficacy and safety (19). The Italian registry of long-term intrathecal ziconotide treatment has conducted a retrospective study of 104 patients treated at 17 centers in Italy and observed sustained relief of pain in 45 patients who received uninterrupted treatment for over 6 months (18).

Final analysis of “Patient Registry of Intrathecal Ziconotide Management” showed that intrathecal ziconotide provided clinically meaningful pain relief in 17.4% and 38.5% of patients at week 12 and month 18, respectively; at these same time points, patient-rated improvement was reported in at least two thirds of patients (13).

According to the European perspective, there is a need for consensus as ziconotide is underused in Europe, but it has potential to be a first-line alternative to morphine; both are already first-line options in the United States. Intrathecal ziconotide, when initiated using a low-dose, slow-titration approach, is suitable for many patients with noncancer- or cancer-related chronic refractory pain and no history of psychosis (12). Polyanalgesic Consensus Conference treatment algorithms for intrathecal ziconotide provide useful guidance, but recommendations tailored specifically for European settings are required.

References

01: Alicino I, Giglio M, Manca F, Bruno F, Puntillo F. Intrathecal combination of ziconotide and morphine for refractory cancer pain: a rapidly acting and effective choice. Pain 2012;153(1):245-9. PMID 22082570
02: Anand P, O'Neil A, Lin E, Douglas T, Holford M. Tailored delivery of analgesic ziconotide across a blood brain barrier model using viral nanocontainers. Sci Rep 2015;5:12497. PMID 26234920
03: Backryd E. Do the potential benefits outweigh the risks? An update on the use of ziconotide in clinical practice. Eur J Pain 2018;22(7):1193-202.** PMID 29635804
04: Backryd E, Sörensen J, Gerdle B. Ziconotide trialing by intrathecal bolus injections: an open-label non-randomized clinical trial in postoperative/posttraumatic neuropathic pain patients refractory to conventional treatment. Neuromodulation 2015;18(5):404-13. PMID 25879804
05: Bonnemain B. Helix and Drugs: Snails for Western Health Care From Antiquity to the Present. Evid Based Complement Alternat Med 2005;2(1):25-8. PMID 15841274
06: Brookes ME, Eldabe S, Batterham A. Ziconotide monotherapy: a systematic review of randomised controlled trials. Curr Neuropharmacol 2017;15(2):217-31.** PMID 26861472
07: Deer T, Rauck RL, Kim P, et al. Effectiveness and safety of intrathecal ziconotide: interim analysis of the Patient Registry of Intrathecal Ziconotide Management (PRIZM). Pain Pract 2018;18(2):230-8. PMID 28449352
08: Duggan PJ, Tuck KL. Bioactive mimetics of conotoxins and other venom peptides. Toxins (Basel) 2015;7(10):4175-98. PMID 26501323
09: Dupoiron D, Bore F, Lefebvre-Kuntz D, et al. Ziconotide adverse events in patients with cancer pain: a multicenter observational study of a slow titration, multidrug protocol. Pain Physician 2012;15(5):395-403. PMID 22996851
10: Klotz U. Ziconotide--a novel neuron-specific calcium channel blocker for the intrathecal treatment of severe chronic pain--a short review. Int J Clin Pharmacol Ther 2006;44(10):478-83. PMID 17063978
11: Maier C, Gockel HH, Gruhn K, Krumova EK, Edel MA. Increased risk of suicide under intrathecal ziconotide treatment. - a warning. Pain 2011;152(1):235-7. PMID 21041028
12: Matis G, De Negri P, Dupoiron D, Likar R, Zuidema X, Rasche D. Intrathecal pain management with ziconotide: time for consensus? Brain Behav 2021;11 Suppl 1(Suppl 1):e02055.** PMID 33690987
13: McDowell GC, Saulino MF, Wallace M, et al. Effectiveness and safety of intrathecal ziconotide: final results of the Patient Registry of Intrathecal Ziconotide Management (PRIZM). Pain Med 2020:21(11):2935-8.** PMID 32472137
14: Mohammed SI, Eldabe S, Simpson KH, et al. Bolus intrathecal injection of ziconotide (Prialt®) to evaluate the option of continuous administration via an implanted intrathecal drug delivery (ITDD) system: a pilot study. Neuromodulation 2013;16(6):576-81; discussion 582. PMID 23205907
15: Olivera BM, Rivier J, Scott JK, Hillyard DR, Cruz LJ. Conotoxins. J Biol Chem 1991;266(33):22067-70. PMID 1939227
16: Phan SV, Waldfogel JM. Ziconotide-induced psychosis: a case report. Gen Hosp Psychiatry 2015;37(1):97.e11-2. PMID 25459190
17: Prusik J, Argoff C, Peng S, Pilitsis JG. Use of low dose ziconotide as first-line intrathecal monotherapy. Neuromodulation 2017;20(4):386-91.** PMID 27492135
18: Raffaeli W, Sarti D, Demartini L, Sotgiu A, Bonezzi C; Italian Ziconotide Group. Italian registry on long-term intrathecal ziconotide treatment. Pain Physician 2011;14(1):15-24. PMID 21267038
19: Rauck RL, Wallace MS, Burton AW, Kapural L, North JM. Intrathecal ziconotide for neuropathic pain: a review. Pain Pract 2009;9(5):327-37. PMID 19682321
20: Sanford M. Intrathecal ziconotide: a review of its use in patients with chronic pain refractory to other systemic or intrathecal analgesics. CNS Drugs 2013;27(11):989-1002. PMID 25054405
21: Schmidtko A, Lötsch J, Freynhagen R, Geisslinger G. Ziconotide for treatment of severe chronic pain. Lancet 2010;375:1569-77. PMID 20413151
22: Shao MM, Khazen O, Hellman A, et al. Effect of first-line ziconotide intrathecal drug therapy for neuropathic pain on disability, emotional well-being and pain catastrophizing. World Neurosurg 2021;145:e340-7. PMID 33096281
23: Sukul VV. Intrathecal pain therapy for the management of chronic noncancer pain. Neurosurg Clin N Am 2019;30(2):195-201.** PMID 30898270
24: Yaksh TL, de Kater A, Dean R, Best BM, Miljanich GP. Pharmacokinetic analysis of ziconotide (SNX-111), an intrathecal N-type calcium channel blocking analgesic, delivered by bolus and infusion in the dog. Neuromodulation 2012;15(6):508-19; discussion 519. PMID 22748108

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Ziconotide

Other Pertinent Drugs

Analgesics
Calcium channel blockers

Also Relevant

Cancer pain
Central neuropathic pain
Chronic pain
Drug-induced delirium
Intrathecal administration of drugs
- Ion channels and neurologic disorders
- Neuropharmacology
- Neuroprotection for CNS disorders

	• Cardiovascular: bradycardia and orthostatic hypotension may occur and are dose-dependent.
	• Central nervous system: dizziness, nystagmus, dysmetria, ataxia, agitation, hallucinations, sedation, and coma have been reported. Some of these adverse effects required days or weeks to clear after stopping or reducing the dose of the drug.
	• There are 2 case reports of suspected ziconotide-induced suicidality in patients who had no depressive symptoms at the time of initiation of intrathecal ziconotide treatment (11).
	• Gastrointestinal: nausea, vomiting, and diarrhea.
	• Other events: skin rash, conjunctival hyperemia, nasal congestion, abnormal values of liver function tests, and urinary retention.
	• Psychosis: auditory hallucinations and paranoid ideation were reported in a patient after implantation of an intrathecal ziconotide infusion pump for chronic pain (16).

Ziconotide

Ziconotide

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

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	• The combination of intrathecal ziconotide and hydromorphone can provide significant pain relief for patients with neuropathic pain associated with spinal cord injury.
	• Chronic neuropathic pain in the distribution of the second branch of the trigeminal nerve.

Ziconotide

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

NF2-related schwannomatosis

Familial dysautonomia

Primary headache associated with sexual activity

Peripheral nerve complications of HIV-1 infection

Neuropathies associated with cytomegalovirus infection

Primary cough headache

Medications and substances causing headache

Headache in children: overview and treatment approaches

This is an article preview.
Start a Free Account
to access the full version.