Ziconotide


Article Author:
Christopher Wie


Article Editor:
Armen Derian


Editors In Chief:
James Beauchamp
Mark Pellegrini
Nicole Hale-Crutch


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
2/18/2019 11:27:24 PM

Indications

Ziconotide is a newer, intrathecal analgesic medication used for the treatment of chronic pain. Its FDA indication is for the treatment of chronic severe pain in patients that are intolerant or refractory to systemic analgesics or intrathecal morphine. Ziconotide can only be administered intrathecally as it does not cross the blood-brain barrier well. It shows efficacy in the treatment of intractable, severe, chronic pain secondary to cancer and also in non-malignant pain.[1][2][3][4]

Mechanism of Action

Ziconotide is a synthetic version of a peptide that is found in the venom of a marine snail, Conus magus. Specifically, it is a 25 amino acid polybasic peptide. Ziconotide blocks N-type voltage-gated calcium channels that are found in the A-delta and C afferent pain fibers in the dorsal horn of the spinal cord. Blockade of this calcium channel inhibits neurotransmitter release from nociceptive afferents and subsequent pain transmission. Ziconotide does not bind to opioid receptors. It is a central nervous system (CNS) depressant.[5][6][7][8]

Administration

Intrathecal thecal therapy was introduced in the 1980s as a means to treat chronic refractory pain. More commonly used medications include opioid analgesics such as morphine and local anesthetics such as bupivacaine. The medication is delivered by an implantable intrathecal drug-delivery system that consists of a drug reservoir and electronic system to deliver medication through a connected catheter that ultimately delivers medication into the intrathecal space. Medication is delivered directly to the dorsal horn of the spinal cord enhancing the potency and efficacy of analgesic medications. Since lower doses of medication are necessary, patients tend to have decreased side effects with this therapy.

Ziconotide can only be administered intrathecally by an intrathecal drug-delivery system. Common systems include Medtronic Synchromed II pump and the Flowonix Prometra II pump. It is recommended to trial ziconotide first by single shot bolus into the intrathecal space prior to implantation of an intrathecal pain pump. The patient should be monitored in a clinical setting for at least 8 hours. The initial single-shot bolus should be between 1 mcg to 2 mcg. Boluses of up to 8 mcg have been reported. It is not recommended to increase the ziconotide dose by more than 1.2 mcg per day if it is administered by continuous infusion. Recommended starting doses range between 1.2 mcg and 2.4 mcg/day. The maximum recommended dose of ziconotide is 19.2 mcg/day. Ziconotide can be coadministered with other intrathecal medications.

Ziconotide is formulated as a preservative-free isotonic solution in 1 mL, 2 mL, or 5 mL vials as a 100 mcg/mL concentration. There is also a 20 mL formulation at 25 mcg/mL.

Adverse Effects

Ziconotide is first cleaved by endopeptidases and exopeptidases. After systemic absorption ziconotide also undergoes proteolytic cleavage by a multitude of peptidases and proteases found in most organs.  Although there are no formal studies regarding medication administration in patients with hepatic or renal dysfunction, ziconotide is a peptide that does not undergo phase I biotransformation or phase II conjugation reactions. Also, there are likely no significant drug-drug interactions. Ziconotide shows linear kinetics with a half-life of 4.5 hours. No development of tolerance has been seen with intrathecal ziconotide infusion.

Contraindications

There is an FDA black-box warning that severe psychiatric symptoms and neurological impairment may occur during treatment with ziconotide. Specifically, patients with a preexisting history of psychosis should not be treated with this medication. Patients should, therefore, be monitored for evidence of cognitive impairment, hallucinations, or changes in mood or consciousness. There is no evidence of withdrawal effects from ziconotide, and therefore, in the event of severe side effects, this medication can be discontinued without tapering.

Since ziconotide must be administered intrathecally, contraindications to intrathecal drug administration apply, for example, infection at the injection site, bleeding disorders, and spinal canal obstruction.

Monitoring

Common side effects include peripheral edema, constipation, diarrhea, nausea, dizziness, blurred vision, somnolence, ataxia, headache, vertigo, dysarthria, and urinary retention. Creatine kinase (CK) levels have also been shown to be elevated in patients treated with ziconotide. These elevations of CK were not associated with muscle weakness. Serum CK levels must be checked monthly. Hypotension is another possible side effect that can be worsened with coadministration of clonidine or bupivacaine in the intrathecal space. More serious reactions may include hallucinations, delirium, paranoia, psychosis, rhabdomyolysis, meningitis, cognitive or memory impairment, and acute renal failure. Patients that are also on oral antidepressants and anticonvulsants might have increased risk of these side effects. Patients should frequently be monitored for cognitive impairment and changes in mood or consciousness.[9][10]

Toxicity

Toxicity

Although there is no antidote or treatment for an overdose of Ziconotide, if there are adverse side effects this medication can be discontinued without concerns for serious withdrawal symptoms.

Clinical Studies

Three randomized, double-blind, placebo-controlled trials have studied the safety and efficacy of intrathecal ziconotide. Ziconotide was associated with statistically significant pain relief, both for malignant and nonmalignant pain. Additional studies revealed that a low-dose, slow titration regimen had a lower incidence of adverse events, although its degree of pain relief was slightly less.  Long-term multicenter trials of intrathecal ziconotide have shown its efficacy, tolerability, and safety in the treatment of severe refractory chronic pain. Most adverse events experienced were mild or moderate in severity, the most common being nausea, dizziness, headache, confusion, and somnolence. The most common adverse events leading to discontinuation of ziconotide were psychiatric in nature. No related drug deaths, intrathecal granulomas, cardiovascular or permanent adverse events occurred with ziconotide therapy. There were no cases of respiratory depression, anaphylaxis, dependence, tolerance, or withdrawal. Most adverse events reported (58.6%) were unrelated to ziconotide.

Clinically significant elevations in CK above three times the upper limit of normal occurred in 5.7% of patients at one month. 33.7% of patients had >30% improvement in their pain scores from baseline.

Conclusion

Intrathecal ziconotide is an option for patients with severe, refractory chronic pain. It is a safe and effective medication not only for reducing pain, but also for improving function. Ziconotide is a non-opioid analgesic that provides another approach to the treatment of severe chronic pain. Adverse events are generally not life-threatening and resolve upon discontinuation of the medication. If serious adverse events occur, ziconotide may be stopped immediately without any concern for the development of withdrawal symptoms.

Enhancing Healthcare Team Outcomes

Ziconitide is a relatively new drug approved for the treatment of severe refractory chronic pain. The drug can only be administered intrathecally as it does not penetrate the BBB. The drug is chiefly used by the pain specialist and anesthesiologist. However, monitoring of the patient is done by ICU nurses.  Ziconotide is a non-opioid analgesic that provides another approach to the treatment of severe chronic pain. Adverse events are generally not life-threatening and resolve upon discontinuation of the medication. If serious adverse events occur, ziconotide may be stopped immediately without any concern for the development of withdrawal symptoms. All healthcare workers including nurses must be familiar with the drug and its indications. The drug can cause severe hypotension and hence a periperal intraveous line must be inserted incase the patient required fluid. [11]


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Ziconotide - Questions

Take a quiz of the questions on this article.

Take Quiz
On what type of ion channel does ziconotide act?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
From which of the following is ziconotide derived?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Ziconotide is known to block what type of ion channels?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is not caused by ziconotide?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Ziconotide acts on which type of calcium channel?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is the mechanism of action of ziconotide?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is the FDA black box warning for ziconotide?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
How is ziconotide metabolized?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
How is ziconotide administered?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is the FDA indication for ziconotide?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
At this time, what is the only FDA approved medicinal use of cone snail toxin?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Ziconotide - References

References

Di Stefano V,Valdesi C,Zilli M,Peri M, Pancoast's syndrome caused by lymph node metastasis from breast cancer. BMJ case reports. 2018 Nov 28;     [PubMed]
Schneider J,Kreutz R,Bolbrinker J, [Pharmacology of non-opioid analgesics]. Schmerz (Berlin, Germany). 2018 Dec 7;     [PubMed]
Burdge G,Leach H,Walsh K, Ziconotide-induced psychosis: A case report and literature review. The mental health clinician. 2018 Sep;     [PubMed]
Deer TR,Pope JE,Hanes MC,McDowell GC 2nd, Intrathecal Therapy for Chronic Pain: A Review of Morphine and Ziconotide as Firstline Options. Pain medicine (Malden, Mass.). 2018 Aug 22;     [PubMed]
Herring EZ,Frizon LA,Hogue O,Mejia JU,Rosenquist R,Bolash RB,Machado AG,Nagel SJ, Long-term Outcomes Using Intrathecal Drug Delivery Systems in Complex Regional Pain Syndrome. Pain medicine (Malden, Mass.). 2018 Jun 7;     [PubMed]
Bäckryd E, Do the potential benefits outweigh the risks? An update on the use of ziconotide in clinical practice. European journal of pain (London, England). 2018 Aug;     [PubMed]
Goga JK,Keshishian A,Kutzer D,Walters JK, Chronic Pain Management With Ziconotide Induces Suicidal and Homicidal Ideations. The Annals of pharmacotherapy. 2018 Jul;     [PubMed]
McDowell GC 2nd,Winchell J, Role of primary care physicians in intrathecal pain management: a narrative review of the literature. Postgraduate medicine. 2018 May;     [PubMed]
Nair AS,Poornachand A,Kodisharapu PK, Ziconotide: Indications, Adverse Effects, and Limitations in Managing Refractory Chronic Pain. Indian journal of palliative care. 2018 Jan-Mar;     [PubMed]
Comparison table: Some nonopioid analgesics for pain. The Medical letter on drugs and therapeutics. 2018 Feb 12;     [PubMed]
Smith HS,Deer TR, Safety and efficacy of intrathecal ziconotide in the management of severe chronic pain. Therapeutics and clinical risk management. 2009 Jun;     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Pharmacy-Technician (PTCB). The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Pharmacy-Technician (PTCB), it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Pharmacy-Technician (PTCB), you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Pharmacy-Technician (PTCB). When it is time for the Pharmacy-Technician (PTCB) board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Pharmacy-Technician (PTCB).