1. 2012;15;395-403Ziconotide Adverse Events in Patients with Cancer Pain: A Multicenter Observational Study of a Slow Titration, Multidrug Protocol
   Observational Study
   Dominique Monnin, MD, Nathalie Lebrec, MD, Florence Dixmerias, MD, Nadia Buisset, MD, Sabine de Bourmont, MD, Olivier Brenet, MD, Danièle Lefebvre-Kuntz, MD, François Bore, MD, and Denis Dupoiron, MD.

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.