The incorporation of the 4-phenylpiperidine pharmacophore found in morphine into 4-anilidopiperidines related to fentanyl (1) led to a novel class of potent opioid analgesic and anesthetic agents with a favorable pharmacological profile. The synthesis, analgesic activity, and anesthetic properties of a series of 4-phenyl-4-anilidopiperidines (13-29) are discussed. Isosteric replacement of the phenyl by various heteroaryl substituents extended the series to include 4-heteroaryl-4-anilidopiperidines (30-53). Within this group, 1-[2-(1H-pyrazol-1-yl)ethyl]-4-(4-methylthiazol-2-yl)-4-(N- phenylpropionamido)piperidine (48), exhibited high analgesic potency, short duration of action, rapid recovery of motor coordination following anesthetic doses, and greater cardiovascular and respiratory safety during anesthesia as compared with opioids fentanyl (1) and alfentanil (2) currently in clinical use. Such analgesics could be of great utility to clinicians in the expanding outpatient surgical arena and for patient-controlled analgesia and computer assisted continuous infusion pain control techniques.