Differences between and combinations of opioids re-visited.

PURPOSE OF REVIEW Recent studies highlighting between-opioid differences in patient outcomes, opioid receptor interactions and animal study findings implicating a 'fine control' mechanism underpinning potential diversity in opioid receptor signalling that could potentially be exploited to develop novel opioid analgesics with improved tolerability are reviewed. RECENT FINDINGS Recent clinical trials confirm the success of 'opioid rotation' for improving opioid tolerability and restoring analgesia in most patients who would otherwise experience intolerable side effects and poor pain relief. These findings suggest that individual strong opioids may interact, at least in part, with different opioid receptor sub-populations or modulate mu opioid receptor signalling in subtly different ways. Identification of novel mu opioid splice variants with different intron 1 sizes that heterodimerize with, and modulate the function of, native mu opioid receptors provide insight into potential diversity in opioid signalling. Oxycodone, unlike other strong opioids, does not cause potassium current desensitization nor does it displace [3H]-morphine binding, consistent with its different in-vivo pharmacological profile to morphine. Opioid analgesic combinations administered as tethered bivalent ligands or admixture demonstrate good pain relief with improved side effect profiles. SUMMARY Enhanced understanding of diversity in opioid signalling has the potential to produce novel strong opioid analgesics with improved tolerability.