Ziconotide

Mechanism of Action

Ziconotide is a synthetic version of a peptide 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 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. There are several pump systems available on the market. It is recommended to trial ziconotide first by single-shot bolus into the intrathecal space prior to implanting 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.[2]

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 the 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 an 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, this medication can be discontinued without concerns for serious withdrawal symptoms if there are adverse side effects.

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

Ziconotide 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 pain specialists and anesthesiologists. 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 peripheral intravenous line must be inserted in case the patient required fluid.[11]