Ziconotide Adverse Events in Patients with Cancer Pain: A Multicenter Observational Study of a Slow Titration, Multidrug Protocol

Abstract

Background: Ziconotide is a new analgesic agent administered intrathecally. It is challenging to use and can induce several and sometimes serious adverse events. A low initial dosage followed by slow titration may reduce serious adverse events. Objective: To determine whether a low starting dosage of ziconotide, followed by slow titration, decreases the incidence of major adverse events associated with ziconotide when used for intractable cancer pain. Study Design: Observational cohort study. Setting: Three French cancer centers. Methods: Patients with incurable cancer causing chronic pain rated above 6/10 on a numerical scale while receiving high-dose opioid therapy (more than 200 mg/d of oral morphine equivalent) and/or exhibiting severe opioid-related adverse events received intrathecal infusions of ziconotide combined with morphine, ropivacaine, and clonidine. Results: Seventy-seven patients were included. Adverse events were recorded in 57% of them; moderate adverse events occurred in 51%. Adverse events required treatment discontinuation in 7 (9%) including 5 (6%) for whom a causal role for ziconotide was highly likely; among them 4 (5%) were serious. All patients experienced a significant and lasting decrease in pain intensity (by 48%) in response to intrathecal analgesic therapy that included ziconotide. Limitations: Limitations include the nonrandomized, observational nature of the study. Determining the relative contributions of each drug to adverse events was difficult, and some of the adverse events manifested as clinical symptoms of a subjective nature. Conclusions: The rates of minor and moderate adverse events were consistent with previous reports. However, the rate of serious adverse events was substantially lower. Our study confirms the efficacy of intrathecal analgesia with ziconotide for relieving refractory cancer pain. These results indicate that multimodal intrathecal analgesia in patients with cancer pain should include ziconotide from the outset in order to provide time for subsequent slow titration. Key words: Ziconotide, adverse events, intrathecal therapy, cancer pain, morphine, ropivacaine, clonidine.

Pancreatic Cancer Related Pain: Review of Pathophysiology and Intrathecal Drug Delivery Systems for Pain Management

“…IDDS are an invasive pain treatment technique that implies implantation of an infusion system with a catheter placed accurately in the posterior subarachnoid space. This allows treatment of pain with precise dosage of analgesics to spinal dorsal horn fibers, bypassing the cerebrospinal blood brain barrier with minimal systemic levels of opioids (87)(88)(89)(90). The first intrathecal use of bolus morphine for cancer pain analgesia was described by Wang in 1979 and in 1980 intrathecal analgesia for pancreatic cancer pain was described by Tung (91,92).…”

“…www.painphysicianjournal.com ment guidelines now have IDDS as an alternative for complex cases (96)(97)(98). Multidrug regimens including morphine, ropivacaine, and ziconotide allow for reduction of individual intrathecal drug doses (90,99). According to a study, standard placement for precise drug delivery to the posterior spine, close to T6, allowed for better pain control in 90% of patients with IDDS (100).…”

“…Optimal IT drug regimen for PCRP is not as yet known. Combination strategies using an opioid, a local anesthetic, and N-type voltage-gated calcium channel blocker have been shown to be stable and have been used with success (100,119,121,122).…”

Narrative review of intrathecal drug delivery (IDD): indications, devices and potential complications

“…However, ziconotide is difficult to manage, especially at higher doses, because of a narrow therapeutic window and requires careful and targeted dosage. Moreover, severe side effects can be reduced by starting with low doses of ziconotide followed by slow titration (29). Rapid titration is associated with cognitive and neuropsychiatric alterations (psychosis, suicide).…”

Intrathecal pain management with ziconotide: Time for consensus?

“…However, in Europe, ITA is practiced in few specialist centers, and most regimens involve morphine rather than ziconotide, although where ziconotide is used the experiences are positive (McDowell et al., 2020). The low adoption of ziconotide ITA in Europe can be traced to key, inter‐related differences between the United States and European practices, in particular: European concerns regarding ziconotide dose selection and tolerability (high starting dose; poor tolerability): these concerns relate to the ziconotide dosing regimen listed in the EU Summary of Product Characteristics (SmPC) (Table 1) Limited recent European‐specific clinical data and formal guidance on ziconotide ITA (Alicino et al., 2012; Dupoiron et al., 2012; Dupoiron et al., 2019; Raffaeli et al., 2011): this clinical literature does not align with the dosing regimen in the EU SmPC …”