Intrathecal pain management with ziconotide: Time for consensus?

Abstract

This article summarizes recommendations made by six pain specialists who discussed the rationale for ziconotide intrathecal analgesia (ITA) and the requirement for evidence-based guidance on its use, from a European perspective. Riemser Pharma GmbH (Greifswald, Germany), which holds the European marketing authorization for ziconotide, hosted the meeting. The group agreed that ITA is under-used in Europe, adding that ziconotide ITA has potential to be a first-line alternative to morphine; both are already first-line options in the USA. Ziconotide ITA (initiated using a low-dose, slow-titration approach) is suitable for many patients with noncancer- or cancer-related chronic refractory pain and no history of psychosis. Adopting ziconotide as first-line ITA could reduce opioid usage in these patient populations. The group advocated a risk-reduction strategy for all candidate patients, including compulsory prescreening for neuropsychosis, and requested US-European alignment of the licensed starting dose for ziconotide: the low-and-slow approach practiced in the USA has a better tolerability profile than the fixed high starting dose licensed in Europe. Of note, an update to the European Summary of Product Characteristics is anticipated in early 2021. The group acknowledged that the Polyanalgesic Consensus Conference (PACC) treatment algorithms for ziconotide ITA provide useful guidance, but recommendations tailored specifically for European settings are required. Before a consensus process can formally begin, the group called for additional European prospective studies to investigate ziconotide in low-and-slow dosing strategies, in different patient settings. Such data would enable European guidance to have the most appropriate evidence at its core.

Keywords: cancer pain; chronic pain; consensus; intrathecal therapy; pain management; ziconotide.

FIGURE 1

Intrathecal (IT) analgesia (ITA): central and peripheral sites related to the mechanisms of action of morphine and ziconotide ITA formulations, and common adverse effects. (a) Intrathecally administered drugs spread out of the IT space through the spinal cord into the epidural space, then enter systemic circulation, which might produce systemic adverse events. (b) ITA travels with the pulsatile motion of the cerebrospinal fluid (CSF) into the brain. (c) At high concentrations, ziconotide ITA might enter cortical regions, possibly leading to the development of neuropsychiatric events (e.g., cognitive impairment, psychosis). (d) Because morphine and ziconotide ITA travel with the pulsatile motion of the CSF, brainstem activity may be affected, causing systemic events (e.g., nausea, somnolence, headache); morphine ITA can also suppress respiratory centers in the brainstem, causing respiratory depression. (e) Morphine ITA spreads from the IT space into gastrointestinal and urinary systems and can act on opioid receptors involved with voiding urine and feces, leading to urinary retention and constipation. Reproduced from (Webster, 2015) with permission from Wiley Periodicals Inc

FIGURE 2

Mechanisms of action of ziconotide, a nonopioid analgesic administered intrathecally for chronic, refractory cancer‐ or noncancer‐related pain (modified from Klotz, 2006, with permission)

FIGURE 3

Infographic summarizing the key requirements for consideration in of any European Consensus Statement for initiation and long‐term management phases of ziconotide intrathecal analgesia (continuous infusion) (ITA). s.c., spinal catheter; NPRS, numeric pain rating scale; RAND‐SF36, Research and Development Corporation short‐form 36; EQ5D‐3L, EuroQol five‐dimension three‐level