No evidence for the development of acute tolerance to analgesic, respiratory depressant and sedative opioid effects in humans

It is widely accepted that chronic opioid therapy is associated with the development of pharmacological tolerance. More controversial is the question as to whether acute opioid administration can result in “acute tolerance.” The aim of this double-blind, placebo-controlled study in thirty-six healthy human volunteers was to examine whether a 3-h intravenous infusion delivering two different but clinically relevant doses of the μ-opioid receptor agonist remifentanil would result in tolerance to analgesic, respiratory depressant and/or sedative opioid effects. The blood remifentanil concentration versus opioid effect relationship was determined before and after the 3-h infusion. Tolerance was inferred if the potency of remifentanil was significantly lower after the 3-h infusion. Opioid analgesia was assessed with the aid of the cold pressor test and models of electrical and heat pain. Respiratory depression was assessed by measuring arterial pCO2 and minute ventilation. Subjective sedation scores were assessed on a visual analogue scale. Mixed effects modeling was used to relate the steady-state blood remifentanil concentration to each pharmacodynamic assessment. Neither dose of remifentanil produced detectable tolerance to any of the measured opioid effects following a 3-h infusion. The study was adequately powered to detect a decrease in potency of 5-24% for analgesia, 20-48% for respiratory depression, and 32% for sedative effects. These results suggest that short-term administration of clinically useful doses of remifentanil is not associated with the development of significant tolerance to analgesic, respiratory depressant, or sedative opioid effects.