Cebranopadol: novel dual opioid/NOP receptor agonist analgesic

Abstract

SUMMARYWhat is known and objective: Chronic pain presents a difficult clinical challenge because of the limited efficacy, the limiting adverse-effect profile or the abuse potential of current analgesic options. Cebranopadol is a novel new agent in clinical trials that combines dual agonist action at opioid and nociceptin/orphanin FQ peptide (NOP) receptors. It is the first truly unique, centrally acting analgesic in several years. We here review the basic and clinical pharmacology of cebranopadol. Methods: Published literature and Internet sources were searched to identify information related to the basic science (pharmacology and medicinal chemistry) and development (clinical trial) information on the mechanism of dual opioid and NOP receptor pharmacologic action in general, and for cebranopadol in particular. The identified sources were reviewed and the information synthesized. Results: The preclinical testing of cebranopadol has characterized it as a dual opioid and NOP receptor agonist that displays antinociceptive and antihyperalgesic action in a variety of acute and chronic pain models in animals. Unlike most current traditional opioids, it is generally more potent against neuropathic than nociceptive pain. Several phase 2 clinical trials have been completed. What is new and conclusion: Despite the medical need, a truly novel centrally acting analgesic has not been developed in many years. Cebranopadol represents a truly novel mechanistic approach. Its actual place in pain pharmacotherapy awaits the results of phase 3 clinical trials.

Cancer‐related chronic pain: Investigation of the novel analgesic drug candidate cebranopadol in a randomized, double‐blind, noninferiority trial

“…Morphine PR was selected as the active comparator in this trial given that it is well accepted that oral morphine is as effective as other oral opioids, and there is no conclusive evidence that other strong opioids are superior in efficacy to morphine (Caraceni et al, 2012;Wiffen et al, 2016). In addition, given that cebranopadol besides NOP receptor agonism also acts on opioid receptors Raffa et al, 2017;Schunk et al, 2014), a comparison of its effects to pure MOP agonism was appropriate as well. The use of rescue medication (morphine IR) was selected as a primary endpoint in this trial, assuming that the used amounts of medication would reflect the efficacy of the IMP in the management of cancer pain.…”

“…Cebranopadol is a novel, first‐in‐class, strong small‐molecule analgesic, characterized by a high nociceptin/orphanin FQ peptide (NOP) receptor (encoded by the opioid receptor‐like 1 [OPRL1] gene) (Mollereau et al., ) and opioid receptor agonistic activity (Linz et al., ; Raffa et al., ; Schunk et al., ). As NOP and opioid receptor agonists modulate pain via distinct yet related targets, targeting both mechanisms may be particularly suited to provide potent analgesia and a better tolerability profile than classical opioids (Linz et al., ).…”

Usefulness of knockout mice to clarify the role of the opioid system in chronic pain

“…This drug has long‐term analgesic effects in acute and chronic pain models, and its side effects are less severe than those of standard opioid drugs. Indeed, motor coordination and respiratory function remains unaltered at high doses, and tolerance is delayed compared with morphine (Sukhtankar et al, ; Linz et al, ; Schunk et al, ; Raffa et al, ). According to ClinicalTrials.gov (National Institutes of Health, ), seven Phase II clinical trials have been completed with cebranopadol.…”

Toward an effective peripheral visceral analgesic: responding to the national opioid crisis

“…Cebranopadol is a novel new agent that combines dual, full agonist action at ORs and NOP receptors (53). It has demonstrated good efficacy and safety in a variety of preclinical models of acute pain and particularly potent efficacy in preclinical models of neuropathic pain (44).…”