Benefit versus Severe Side Effects of Opioid Analgesia: Novel Utility Functions of Probability of Analgesia and Respiratory Depression.

Abstract

Previous studies integrated opioid benefit and harm into one single function-the utility function-to determine the drug toxicity (respiratory depression) in light of its wanted effect (analgesia). This study further refined the concept of the utility function using the respiratory and analgesic effects of the opioid analgesic alfentanil as example. Data from three previous studies in 48 healthy volunteers were combined and reanalyzed using a population pharmacokinetic-pharmacodynamic analysis to create utility probability functions. Four specific conditions were defined: probability of adequate analgesia without severe respiratory depression, probability of adequate analgesia with severe respiratory depression, probability of inadequate analgesia without severe respiratory depression, and probability of inadequate analgesia with severe respiratory depression. The four conditions were successfully identified with probabilities varying depending on the opioid effect-site concentration. The optimum analgesia probability without serious respiratory depression is reached at an alfentanil effect-site concentration of 68 ng/ml, and exceeds the probability of the most unwanted effect, inadequate analgesia with severe respiratory depression (odds ratio, 4.0). At higher effect-site concentrations the probability of analgesia is reduced and exceeded by the probability of serious respiratory depression. The utility function was successfully further developed, allowing assessment of specific conditions in terms of wanted and unwanted effects. This approach can be used to compare the toxic effects of drugs relative to their intended effect and may be a useful tool in the development of new compounds to assess their advantage over existing drugs.