Hot Topics in Opioid Pharmacology: Mixed and Biased Opioids.

Analgesic design and evaluation has been driven by the desire to create high affinity, high selectivity MOP (mu;µ) agonists. Such ligands are the mainstay of current clinical practice and include morphine and fentanyl. Advances in this sphere have come from designing pharmacokinetic advantage; rapid metabolism for remifentanil. These produce analgesia but also the adverse effect profile that currently defines this drug class; namely ventilatory depression, tolerance and abuse liability. The MOP receptor is part of a family and there are significant functional interactions between other members of the family (DOP;delta;δ, KOP;kappa;κ and NOP;nociceptin/orphanin FQ). Experimentally MOP agonism and DOP antagonism produced antinociception (animals) with no tolerance and low doses of MOP and NOP ligands synergize to antinociceptive advantage. In this latter context lack of effect of NOP agonists on ventilation is an additional advantage. Recent development has been to move towards low selectivity multifunctional ‘mixed ligands’ (e.g., Cebranopadol) or ligand mixtures (e.g., Targinact). Moreover, the observation that β-arrestin coupling underlies the side effect profile for MOP ligands (from knockout animal studies) led to the discovery of biased (to G-protein and away from β-arrestin) MOP ligands (e.g., oliceridine). There is sufficient excitement in the opioid field to suggest that opioid analgesics without significant side effects may be on the horizon and the ‘opioid holy grail’ might be in reach.