Mixed mu-nociceptin/orphanin FQ opioid receptor agonists and the search for the analgesic holy grail

Is the search for more highly selective MOP (mu; µ) receptor ligands over ? Do we need more morphine like molecules; fentanyl, oxycodone and the like ? These molecules produce analgesia and are the gold standard against which all analgesics are compared. Sadly, these clinically essential drugs are now better known for their adverse events; on the patient, the misuser and on society. The adverse events associated with opioid use (and misuse) are significant and many. These include respiratory depression, nausea and vomiting, pruritis, gastro intestinal (GI) immobility, immune suppression, tolerance and abuse potential. In some settings, such as palliative care, the adverse events driven by a vicious cycle of dose escalation to titrate effective analgesia begin to outweigh the benefits e.g. when considering GI-immobility; constipation. Designing out these side effects whilst maintaining analgesic efficacy is the challenge for modern experimental pharmacology in alliance with clinical pharmacology (anaesthesia); our Holy Grail.