Opioid-hypnotic synergy - A response surface analysis of propofol-Remifentanil pharmacodynamic interaction in volunteers

Background Characterizing drug interactions using a response surface allows for the determination of the interaction over a complete range of clinically relevant concentrations. Gathering the data necessary to create this surface is difficult to do in a clinical setting and requires the use of volunteer experiments with surrogate noxious stimuli to adequately control the process for data collection. The pharmacodynamic synergy of opioids and hypnotics was investigated using a volunteer study paradigm. Methods: Twenty-four volunteer subjects (12 male, 12 female) were studied using computer-controlled infusions of propofol and remifentanil to create an increasing staircase drug concentration profile in each subject. Three different drug delivery profiles were administered to subjects, one with a single agent and two with combinations of propofol and remifentanil. At each plateau of the staircase profile, drug effect was assessed using four surrogate measures: Observer Assessment of Alertness/Sedation score, tibial pressure algometry, electrical tetany, and response to laryngoscopy. Response surfaces were developed that mapped the interaction of propofol and remifentanil to these surrogate effect measures in all subjects. An interaction parameter was used to assess whether these two drugs behave synergistically to blunt response to noxious stimuli. Results: The response surfaces showed considerable synergy between remifentanil and propofol for blunting response to the noxious stimuli. The interaction index, a measure of synergy, was 8.2 and 14.7 for response to algometry and tetany, respectively (P < 0.001), and 5.1 and 33.2 for sedation and laryngoscopy, respectively (P < 0.001), using the Greco interaction model. The surrogate stimuli mapped to clinically relevant concentrations for these agents in combination. Conclusions: The response surface models reveal the tremendous synergy between remifentanil and propofol. The surface morphologic features give some indication of the relative contribution of sedation and analgesia to blunting subject response. Further, the results of this investigation validate the volunteer study paradigm and use of surrogate effect measures for its clinical relevance.