Nociceptin/orphanin FQ receptor ligands and translational challenges: focus on cebranopadol as an innovative analgesic.

Opioids are characterized as classical (mu, delta, and kappa) along with the non-classical nociceptin/orphanin FQ (N/OFQ) receptor or NOP. Targeting NOP has therapeutic indications in control of the cardiovascular and respiratory system along with control of micturition and a profile as an antidepressant; in all of these indications there is translational human data. Opioids such as morphine and fentanyl (activating the mu receptor) are the mainstay of pain treatment in the perioperative period, despite a challenging side effect profile. Opioids in general have poor efficacy in neuropathic pains. Moreover, longer term use is associated with tolerance. There is good evidence for an interaction between opioid receptors and co-activation can reduce side effects without compromising analgesia; this is particularly true for mu and NOP co-activation. Recent pharmaceutical development has produced a mixed opioid/NOP agonist cebranopadol. This new chemical entity is effective in animal models of nociceptive and neuropathic pain with greater efficacy in the latter. In these animal models there is little evidence for respiratory depression and tolerance (compared to morphine) only develops after substantial treatment periods. There is now early phase clinical development in diabetic neuropathy, cancer pain and low back pain where cebranopadol displays significant efficacy. In 1996 N/OFQ was formally identified with an innovative analgesic profile, ~20 years later, cebranopadol as a clinical ligand is advancing through the human trials process.