||The use of propofol and propofol in combination with remifentanil by nonanesthesiologists is a controversial topic. Much of the concern centers on adverse respiratory effects: loss of responsiveness, respiratory depression, and airway obstruction. The aim of this study was to investigate these adverse drug effects at propofol-remifentanil combinations commonly used in procedures requiring esophageal instrumentation and build response surface models of drug effects. A second aim was to investigate published dosing regimens through simulation with these models. A third aim was to develop an optimization algorithm to identify an ideal propofol-remifentanil dosing regimen for upper endoscopy procedures. Twenty-four volunteers received escalating target controlled remifentanil and propofol infusions. Responses to insertion of a bougie (40 cm), responsiveness, respiratory rate, and tidal volume were recorded at 384 targeted concentration pairs. Four published dosing regimens of propofol alone or in combination with opioids were simulated for a 10-min procedure. An optimization algorithm was developed to identify an optimal propofol-remifentanil dosing regimen from a set of possibilities. Models for loss of response to esophageal instrumentation, intolerable ventilatory depression, and respiratory compromise were built. Simulations of published dosing regimens showed that once drug administration ended, loss of responsiveness, and respiratory depression effects dissipated quickly. Respiratory compromise dissipated more quickly in propofol only techniques compared to propofol-opioid techniques. An optimal dosing recommendation was identified for a simulated 55 year-old, 75 kg, 175 cm male undergoing an anticipated 10-min upper endoscopy and consisted of a propofol bolus of 0.8 mg/kg and infusion rate of 40 mcg/kg/min and a remifentanil bolus of 0.2 mcg/kg and an infusion rate of 0.05 mcg/kg/min. High propofol-low remifentanil concentration pairs can block the response to esophageal instrumentation while avoiding intolerable ventilatory depression in spontaneously breathing volunteers. Propofol combined with remifentanil or fentanyl improved conditions for esophageal instrumentation and had a rapid return to responsiveness. Optimization techniques identified a remifentanil propofol dosing regimen that minimizes the duration of loss of responsiveness, respiratory depression, and airway obstruction and, according to expert opinion and models of drug effect, provides conditions that will permit upper endoscopy procedures. This dosing regimen merits clinical validation in patients undergoing brief endoscopic procedures.