The invention relates to administration of clinical anesthesia. Particular embodiments provide systems and methods for controlled delivery of a combination of an analgesic agent and a hypnotic agent. More specifically, the invention relates to closed-loop control systems/methods for automatically controlling the administration of a combination of a hypnotic agent and an analgesic agent in a clinical anesthesia setting which incorporate feedback based on one or more indirect measures/indicia of analgesia. The invention further relates to such control systems/methods that account for limitations of such indirect measures/indicia of analgesia.