One of the main challenges in contemporary medicinal chemistry is the development of safer
analgesics, used in the treatment of
pain. Currently, moderate to severe
pain is still treated with the "gold standard"
opioids whose long-term often leads to severe side effects. With the discovery of biased agonism, the importance of this area of pharmacology has grown exponentially over the past decade. Of these side effects, tolerance,
opioid misuse, physical dependence and
substance use disorder (SUD) stand out, since these have led to many deaths over the past decades in both USA and Europe. New therapeutic molecules that induce a biased response at the
opioid receptors (MOR, DOR, KOR and NOP receptor) are able to circumvent these side effects and, consequently, serve as more advantageous
therapies with great promise. The concept of biased signaling extends far beyond the already sizeable field of GPCR pharmacology and covering everything would be vastly outside the scope of this review which consequently covers the biased
ligands acting at the
opioid family of receptors. The limitation of quantifying bias, however, makes this a controversial subject, where it is dependent on the reference
ligand, the equation or the assay used for the quantification. Hence, the major issue in the field of biased
ligands remains the translation of the in vitro profiles of biased signaling, with corresponding bias factors to in vivo profiles showing the presence or the lack of specific side effects. This review comprises a comprehensive overview of biased
ligands in addition to their bias factors at individual members of the
opioid family of receptors, as well as bifunctional
ligands.