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