Ziconotide

Mechanism of Action

Ziconotide is the synthetic form of a 25 amino acid polybasic peptide found in the venom of the marine snail Conus magus. Ziconotide blocks N-type (neuronal) voltage-gated calcium channels found in the A-δ 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 is a central nervous system (CNS) depressant and does not bind to opioid receptors.[11][12][13]

Pharmacokinetics

Absorption: Ziconotide is administered intrathecally via 1-hour infusions ranging from 1 to 10 μg. The total exposure (AUC) and peak exposure (Cmax) values in the cerebrospinal fluid (CSF) are dose-dependent, showing variability but approximately dose-proportional increases. Plasma pharmacokinetics (PK) following intravenous infusion (0.3 to 10 μg/kg/d) have also been studied to gather systemic exposure data.

Distribution: Ziconotide is about 50% bound to human plasma proteins. After intrathecal administration, the mean CSF volume of distribution (Vd) of ziconotide is approximately 140 mL, similar to the estimated total CSF volume.

Metabolism: Ziconotide is cleaved by endopeptidases and exopeptidases at multiple sites along the peptide. Following its passage from the CSF into the systemic circulation during continuous intrathecal infusion, it is subject to proteolytic cleavage by various peptidases/proteases present in most organs (kidney, liver, lung, muscle), leading to its degradation into peptide fragments and individual free amino acids. In human and animal CSF and blood, there is minimal hydrolytic activity toward ziconotide in vitro. The biological activity of ziconotide's expected proteolytic degradation products has not been assessed. The literature review suggests that intranasal administration could be a noninvasive method of delivering ziconotide to CSF for chronic pain.[14]

Elimination: Minimal amounts of ziconotide (<1%) have been recovered in human urine after intravenous infusion. The terminal half-life of ziconotide in CSF following intrathecal administration is around 4.6 hours (range 2.9 to 6.5 hours). The mean CSF clearance is approximately 0.38 mL/min, similar to the adult human CSF turnover rate (0.3 to 0.4 mL/min).[8]

Administration

Available Dosage Forms and Strengths

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

Adult Dosage

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.[15] Medication is delivered directly to the dorsal horn of the spinal cord, enhancing the potency and efficacy of analgesic medications. Since this route allows for lower doses, patients tend to have fewer adverse 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. A trial of ziconotide therapy should be performed by administering a single intrathecal bolus before implanting an intrathecal pain pump. The patient should be monitored in a clinical setting for at least 8 hours. The trial bolus should be between 1 μg and 2 μg. Boluses of up to 8 μg have been reported. Increasing the ziconotide dose by more than 1.2 μg/d is not recommended if administered by continuous infusion. Recommended starting doses range between 1.2 μg and 2.4 μg/d. The maximum recommended dose of ziconotide is 19.2 μg/d. Ziconotide can be coadministered with other intrathecal medications.

Specific Patient Populations

Hepatic impairment: Due to the low systemic exposure of ziconotide following intrathecal administration, no formal studies have assessed the effect of demographic factors, renal or hepatic dysfunction, or concomitant drugs, so it should be used cautiously in hepatic impairment. 

Renal impairment: No dosage adjustments for renal impairment are provided in the product labeling; use with caution.

Pregnancy considerations: There is insufficient human data to determine a drug-associated risk of congenital disabilities or miscarriage with ziconotide use during pregnancy. Animal studies showed no malformations, but some fetal mortality and maternal toxicity were observed at high doses. The background risk of congenital disabilities and miscarriage in the general population is 2% to 4% and 15% to 20%, respectively. High-dose ziconotide did not affect pup development in rats, though maternal toxicity was noted. The risk to humans is unknown, and the drug should be used during pregnancy only if needed.

Breastfeeding considerations: There is no available data on using ziconotide during breastfeeding. Due to its low plasma levels after intrathecal administration and its large molecular size, the amount in breast milk is expected to be minimal. Ziconotide is also likely broken down in the infant’s digestive system, resulting in limited absorption. If ziconotide is necessary for the mother, breastfeeding does not need to be stopped. However, infants should be monitored for sedation, which may lead to respiratory issues or feeding difficulties.[16]

Pediatric patients: The safety and effectiveness of ziconotide in pediatric patients have not been established.[8]

Older patients: During clinical studies involving ziconotide, 22% of subjects were aged 65 or older, and a higher incidence of confusion was noted in this group. Dose selection for older patients should be cautious, starting at the lower end of the dosing range due to potential age-related declines in organ function and concurrent health conditions.

Adverse Effects

The most common adverse reactions (≥25%) associated with ziconotide therapy include dizziness, ataxia, confusion, and nystagmus.[17] Slowing the titration process may help reduce the rate or severity of adverse effects and the need to discontinue treatment. No development of tolerance has been observed in patients receiving intrathecal ziconotide infusion.

Drug-Drug Interactions

• No formal drug-drug interaction studies involving ziconotide have been conducted. Ziconotide is primarily degraded by endopeptidases and exopeptidases (phase I enzymes), not by the cytochrome P450 system or phase II conjugation reactions. Due to its peptide structure, intrathecal administration, low plasma concentrations, and peptidase metabolism, drug-drug metabolic interactions are unlikely. Ziconotide is not highly plasma protein-bound (~50%), and clinically significant protein displacement interactions with co-administered medications are unlikely.

• CNS depressants like antiepileptics, anxiolytics, neuroleptics, and sedatives commonly co-administered with ziconotide may increase the risk of CNS-related adverse effects, such as dizziness and confusion.

Contraindications

Ziconotide is contraindicated for patients with a known hypersensitivity to the drug or excipients. Since ziconotide must be administered intrathecally, contraindications to intrathecal drug administration apply (eg, injection site infections, bleeding disorders, and spinal canal obstruction). Additionally, ziconotide should not be administered to patients with a history of psychosis.

Box Warnings

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 adverse effects, this medication can be discontinued without tapering.[18]

Warnings and Precautions

• Meningitis and infections: The risk of meningitis increases with external microinfusion devices. Symptoms include fever, headache, and altered mental state. Aseptic techniques are essential to prevent infection. If meningitis is suspected, discontinue treatment, remove the infusion system, and initiate appropriate therapy.

• Reduced level of consciousness: Ziconotide can cause unresponsiveness or stupor. Treatment should be halted if this occurs, and other causes, such as meningitis, should be investigated. The risk is higher when used with other CNS depressants.

• Opioid withdrawal: Ziconotide does not alleviate opioid withdrawal symptoms. Opioids should be gradually tapered before starting ziconotide to avoid withdrawal.

• Driving and operating machinery: Ziconotide may impair cognitive function and alertness. Patients should avoid activities requiring full attention, such as driving or operating heavy machinery.

Monitoring

Common adverse effects include peripheral edema, constipation, diarrhea, nausea, dizziness, blurred vision, somnolence, ataxia, headache, vertigo, dysarthria, and urinary retention. Elevated creatine kinase (CK) levels have also been observed in patients treated with ziconotide. Serum CPK levels must be checked monthly. A case report of rhabdomyolysis due to long-term treatment with intrathecal ziconotide has been reported.[19] Hypotension is another possible adverse 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 who 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.[20][21]

Toxicity

Signs and Symptoms of Overdose

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 during the treatment of severe refractory chronic pain. Most adverse events experienced were mild or moderate, the most common being nausea, dizziness, headache, confusion, and somnolence. The most common adverse events leading to discontinuation of ziconotide were related to mental health. No related drug deaths, intrathecal granulomas, or 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 CPK more than 3x the upper limit of normal occurred in 5.7% of patients at 1 month. 33.7% of patients had >30% improvement in their pain scores from baseline.

Management of Overdose

There is no specific antidote for ziconotide overdose. Management involves general supportive care until the effects of the drug subside. Hospitalization may be necessary, and treatment should focus on symptom management. As ziconotide does not interact with opioid receptors, its effects cannot be reversed by opioid antagonists. In cases of accidental intravenous or epidural administration, severe hypotension may occur, which can be managed with positional adjustments and blood pressure support as needed.

Conclusion

Intrathecal ziconotide is an option for patients with severe, refractory chronic pain. This safe and effective medication reduces pain and improves function. Ziconotide is a non-opioid analgesic that provides another approach to treating severe chronic pain. Associated adverse events are generally not life-threatening and resolve upon discontinuation. 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 effectively penetrate the BBB. Pain specialists and anesthesiologists primarily prescribe this medication. MICU/SICU nurses should monitor patients receiving this drug. 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 know the drug and its indications. The drug can cause severe hypotension, and hence, a large bore peripheral intravenous line must be inserted in case the patient requires IV fluids.[22] An interprofessional team approach and communication among clinicians is crucial to decreasing potential adverse effects and improving patient outcomes related to ziconotide pharmacotherapy.