Efficacy and safety of the Cav2.2 blocker Ziconotide in pain: a meta-analysis and systematic review

Chronic pain remains a significant clinical challenge, especially in refractory cases. Ziconotide, a selective Ca_v2.2 channel blocker, offers an intrathecal approach, but concerns about its safety, potential biases, and impact on opioid consumption persist. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a systematic review and meta-analysis of 23 studies (1,531 participants) to evaluate the efficacy, safety, and secondary outcomes of Ziconotide. Key outcomes were pain intensity reduction, adverse events, and serious adverse events. As secondary outcomes, we assessed changes in opioid consumption. The risk of bias and the certainty of evidence were assessed using risk of bias 2 and Grading of Recommendations, Assessment, Development and Evaluation for randomized controlled trials, ROBINS-I and the Newcastle-Ottawa Scale for observational studies, and the Joanna Briggs Institute checklist for case reports. Publication bias was explored using funnel plot analysis. Ziconotide demonstrated significant pain reduction compared with placebo (mean difference: -22.54, 95% confidence interval [CI]: -36.70 to -8.38, <i>P</i> = 0.002), although heterogeneity was high. Adverse events were frequent (94.9% vs 76.9% in placebo; risk ratio 1.24, 95% CI: 1.09-1.41, <i>P</i> = 0.0008), with serious adverse events reported in 17.85% patients (risk ratio 2.63, 95% CI: 1.52-4.57, <i>P</i> = 0.0006). Secondary outcomes suggested potential reductions in opioid consumption in observational studies, with decreases ranging from 6.4% to 91.5%, though randomized trials showed inconsistent results. Certainty of the evidence was rated as low to moderate. Although Ziconotide shows promise as an intrathecal treatment for refractory pain, its frequent adverse effects, the availability of high-certainty evidence, and inconclusive impact on opioid consumption highlight the need for cautious use. This meta-analysis underscores the need for future research.