On pethidine: The 'accidental' opioid that became a 'model' analgesic agent

A 1939 German publication on a search for novel synthetic atropine substitutes reported that 'Substanz III', named Dolantin (now generically known as pethidine and meperidine), was found coincidentally to also have morphine-like, albeit markedly weaker, analgesic properties. With a chemical structure not obviously related to morphine, it was thus an 'accidental opioid' and was soon successfully marketed in many countries for pain relief. By the 1970s, continuing advances in analytical chemistry were enabling pharmacokinetic studies of countless drugs. Among opioid analgesic agents, pethidine's larger dosing requirements made it suitable for such research, which was performed in healthy volunteers and patients with various doses and routes of administration, with some reports also including pharmacological responses. Standard postoperative intramuscular pethidine administration revealed steep and unpredictable plasma concentration-analgesic response relationships characterised by marked variability between patients. Novel computer-designed intravenous infusions based on typical pethidine pharmacokinetic data were trialled to replace intramuscular injections. These infusions improved the reliability of postoperative pain management but could not overcome the variability in individual patient requirements. This limitation accelerated the development of empirical 'patient-controlled analgesia' techniques, initially with pethidine, and subsequently with other opioid analgesic agents, thereby enabling personalised pain management. The 1970s' discovery of spinal opioid receptors and mechanisms led to neuraxial pethidine administration being investigated and subsequently integrated into standard clinical practice. Although pethidine has now been superseded in many countries, it served as an important 'model' drug to investigate how to improve the use of opioid analgesic agents for the management of severe pain.