Dosing protocol and analgesic efficacy determine opioid tolerance in the mouse

Analgesic efficacy of opioids and dosing protocol have been shown to influence analgesic tolerance. This study tested the hypothesis that there is an inverse relationship between analgesic efficacy and tolerance following continuous infusion of opioid analgesics. Furthermore, it was hypothesized that analgesic efficacy plays a minor role in determining the magnitude of tolerance following intermittent or acute administration, and that acute and intermittent administration of opioid agonists produces less tolerance than continuous infusion. Analgesic (tailflick) efficacy (tau) of etorphine, methadone, oxycodone, and hydrocodone was determined using the operational model of agonism. To induce tolerance, mice were injected with opioid agonists once (acute), once per day for 7 days (intermittent) or continuously infused for 7 days. Dose-response studies were conducted using morphine following treatment. The order of analgesic efficacy was etorphine > methadone > oxycodone a parts per thousand... hydrocodone. Infusion of the higher analgesic efficacy drug etorphine produced significantly less tolerance than the lower analgesic efficacy drugs oxycodone, methadone, and hydrocodone at equi-effective doses. In general, intermittent and acute treatment produced less tolerance compared to continuous infusion even at similar daily doses. Taken together, intermittent and acute opioid agonist administration produces minimal tolerance compared to continuous infusion. Furthermore, there is an inverse relationship between analgesic efficacy and tolerance following continuous infusion. These results suggest that opioid analgesic tolerance may be increased when sustained release dosing formulations or continuous infusions are employed clinically.