{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T11:25:58Z","timestamp":1793964358612,"version":"4.8.0"},"reference-count":116,"publisher":"SAGE Publications","issue":"3_suppl","license":[{"start":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T00:00:00Z","timestamp":1781395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T00:00:00Z","timestamp":1781395200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Anaesth Intensive Care"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:p>A 1939 German publication on a search for novel synthetic atropine substitutes reported that \u2018Substanz III\u2019, 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 \u2018accidental opioid\u2019 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\u2019s 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\u2013analgesic 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 \u2018patient-controlled analgesia\u2019 techniques, initially with pethidine, and subsequently with other opioid analgesic agents, thereby enabling personalised pain management. The 1970s\u2019 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 \u2018model\u2019 drug to investigate how to improve the use of opioid analgesic agents for the management of severe pain.<\/jats:p>","DOI":"10.1177\/0310057x261442548","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T06:02:20Z","timestamp":1781503340000},"page":"8-18","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["On pethidine: The \u2018accidental\u2019 opioid that became a \u2018model\u2019 analgesic agent"],"prefix":"10.1177","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8174-7752","authenticated-orcid":false,"given":"Laurence E","family":"Mather","sequence":"first","affiliation":[{"name":"Department of Anaesthesia, The University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6400-9333","authenticated-orcid":false,"given":"Geoffrey T","family":"Tucker","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, University of Sheffield, Sheffield, South Yorkshire, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,6,14]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0028-1120563"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-007-0136-z"},{"key":"e_1_3_2_4_2","first-page":"462","article-title":"Eine empfindliche biologische Reaktion auf Morphin","volume":"37","author":"Straub W.","year":"1911","unstructured":"Straub W. Eine empfindliche biologische Reaktion auf Morphin. Dtsch Med Wochenschr 1911; 37: 462.","journal-title":"Dtsch Med Wochenschr"},{"key":"e_1_3_2_5_2","unstructured":"Eisleb O. Patent DE 679281C. Process for the preparation of piperidine compounds. Germany 1937. https:\/\/patents.google.com\/patent\/DE679281C\/en?inventor=Dr+Otto+Eisleb&sort=old&page=1 (accessed 24 May 2025)."},{"key":"e_1_3_2_6_2","unstructured":"Eisleb O. Patent US2167351A. Process for the preparation of piperidine compounds. USA 1938. https:\/\/patents.google.com\/patent\/US2167351A\/en (accessed 24 May 2025)."},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/bf01861099"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/bf00248060"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.5001.1091"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0028-1120564"},{"key":"e_1_3_2_11_2","first-page":"318","article-title":"Pharmacological action of ethylmethylphenylpiperidinecarboxylate","volume":"13","author":"Duguid AME","year":"1940","unstructured":"Duguid AME, Heathcote RStA. Pharmacological action of ethylmethylphenylpiperidinecarboxylate. Quart J Pharm Pharmacol 1940; 13: 318\u2013331.","journal-title":"Quart J Pharm Pharmacol"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-194309000-00026"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.1943.00210030046004"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0002-9610(43)90663-4"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1213\/00000539-194301000-00050"},{"key":"e_1_3_2_16_2","first-page":"509","article-title":"Demerol in surgery and obstetrics","volume":"51","author":"Hori CG","year":"1944","unstructured":"Hori CG, Gold S. Demerol in surgery and obstetrics. Can Med Assoc J 1944; 51: 509\u2013517.","journal-title":"Can Med Assoc J"},{"key":"e_1_3_2_17_2","unstructured":"Walvood CA. Demerol: new substitute for morphine. MD Thesis University of Nebraska Medical Center USA 1944. https:\/\/digitalcommons.unmc.edu\/mdtheses\/1274 (Accessed 5 June 2025.)"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01775350"},{"key":"e_1_3_2_19_2","first-page":"17","article-title":"\u00dcber Dolantinsucht","volume":"35","author":"Schwarke R.","year":"1941","unstructured":"Schwarke R. \u00dcber Dolantinsucht. Dtsch Z Gesamte Gerichtl Med 1941; 35: 17\u201323.","journal-title":"Dtsch Z Gesamte Gerichtl Med"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-3565(25)09194-3"},{"key":"e_1_3_2_21_2","unstructured":"Amending federal narcotic laws to apply to a recently discovered synthetic drug-(isonipecaine). 78th Congress 2nd Session. Senate Report No.1004. June 21 1944. Report. https:\/\/www.finance.senate.gov\/download\/1944\/06\/21\/amending-federal-narcotic-laws-to-apply-to-a-recently-discovered-synthetic-drug-isonipecaine-report-78-1004&download=1 (accessed 5 June 2025)."},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/jps.3030350204"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/bf01863572"},{"key":"e_1_3_2_24_2","unstructured":"Full page advertisement for pethidine in the Advertising Supplement of the Postgrad Med J December 1944; i."},{"key":"e_1_3_2_25_2","first-page":"4","volume-title":"Milngavie and Bearsden Herald","author":"Anon. A pain-killer","year":"1943","unstructured":"Anon. A pain-killer. Milngavie and Bearsden Herald (Milngavie, Scotland), 20 March 1943, p.4."},{"key":"e_1_3_2_26_2","volume-title":"The Evening News","author":"Anon. German drug kills pain \u2013 becomes habit","year":"1943","unstructured":"Anon. German drug kills pain \u2013 becomes habit. The Evening News (London, England), 26 October 1943, p.4."},{"key":"e_1_3_2_27_2","first-page":"8","volume-title":"New York Herald Tribune","author":"Anon. Ilicit traffic reported in morphine substitute","year":"1944","unstructured":"Anon. Ilicit traffic reported in morphine substitute. New York Herald Tribune (New York, NY, USA), 14 May 1944, p.8."},{"key":"e_1_3_2_28_2","volume-title":"Smith\u2019s Weekly","author":"Anon. Patients and pain","year":"1944","unstructured":"Anon. Patients and pain. Smith\u2019s Weekly (Sydney, Australia), 6 May 1944, p.17."},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.2042-7158.1954.tb11033.x"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00232a015"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0165-6147(03)00066-x"},{"key":"e_1_3_2_32_2","first-page":"271","volume-title":"Goodman & Gilman\u2019s: the pharmacological basis of therapeutics","author":"Jutkiewicz EM","year":"2025","unstructured":"Jutkiewicz EM, Traynor JR. Opioid analgesics. In: Brunton LL and Knollmann BC (eds) Goodman & Gilman\u2019s: the pharmacological basis of therapeutics. 14th ed. New York: McGraw-Hill Education, 2025, pp.271\u2013305.","edition":"14"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/0163-7258(81)90097-8"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)35120-7"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-3565(25)03707-3"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(25)39916-7"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/b978-1-4831-9988-7.50010-x"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.2042-7158.1967.tb08089.x"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1080\/00032717308062889"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600630232"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0021-9673(01)99389-6"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1007\/bf00561790"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1002\/cpt1974164667"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1002\/cpt197517121"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1002\/cpt1978233288"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9378(79)90310-7"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1552-4604.1974.tb01370.x"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1975.tb02773.x"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/47.12.1269"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1552-4604.1976.tb02401.x"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1002\/cpt1976205535"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1007\/bf00561475"},{"key":"e_1_3_2_53_2","first-page":"188","article-title":"Compartmental models","volume":"2","author":"Hull CJ.","year":"1994","unstructured":"Hull CJ. Compartmental models. Anaesth Pharmacol Rev 1994; 2: 188\u2013203.","journal-title":"Anaesth Pharmacol Rev"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/58.8.888"},{"key":"e_1_3_2_55_2","first-page":"83","volume-title":"Mechanisms of action of drugs in anaesthetic practice","author":"Runciman WB","year":"1993","unstructured":"Runciman WB, Myburgh J, Upton RN, et al. Effects of anaesthesia on drug disposition. In: Feldman SA, Scurr CF, and Paton W (eds) Mechanisms of action of drugs in anaesthetic practice. 2nd ed. London: Edward Arnold, 1993, pp.83\u2013128.","edition":"2"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1552-4604.1975.tb01447.x"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0021-9673(00)85713-1"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1007\/bf00561790"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-86-6-738"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600670131"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9378(80)90281-1"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1213\/00000539-197903000-00006"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-197803050-00002"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3959(80)90089-5"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-198012000-00005"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-198207050-00003"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-3565(25)28956-x"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.174.4007.421"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/47.12.1265"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600671106"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600710313"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600720107"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-198207030-00006"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.3109\/03602539608994011"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0304-3959(97)00142-5"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1097\/00007691-199101000-00001"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-3565(25)30562-8"},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1007\/bf00645137"},{"key":"e_1_3_2_79_2","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/52.9.959-a"},{"key":"e_1_3_2_80_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2044.1986.tb13233.x"},{"key":"e_1_3_2_81_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0378-4347(97)88058-9"},{"key":"e_1_3_2_82_2","doi-asserted-by":"publisher","DOI":"10.1053\/eujp.2001.0280"},{"key":"e_1_3_2_83_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.6136.517"},{"key":"e_1_3_2_84_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2044.1979.tb04929.x"},{"key":"e_1_3_2_85_2","doi-asserted-by":"publisher","DOI":"10.1177\/0310057x7900700103"},{"key":"e_1_3_2_86_2","first-page":"1","volume-title":"The News","author":"Safe M. SA team smashes pain barrier","year":"1978","unstructured":"Safe M. SA team smashes pain barrier. The News [Adelaide, South Australia], 8 November 1978, pp.1\u20133."},{"key":"e_1_3_2_87_2","volume-title":"Pharmacokinetic and pharmacodynamic studies of selected therapeutic agents","author":"Austin KL.","year":"1980","unstructured":"Austin KL. Pharmacokinetic and pharmacodynamic studies of selected therapeutic agents. PhD Thesis, Flinders University of South Australia, 1980."},{"key":"e_1_3_2_88_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0002-9378(16)34084-4"},{"key":"e_1_3_2_89_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.bmb.a072255"},{"key":"e_1_3_2_90_2","doi-asserted-by":"publisher","DOI":"10.1177\/0310057x8801600409"},{"key":"e_1_3_2_91_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0889-8537(21)00223-6"},{"key":"e_1_3_2_92_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-6576.1979.tb01475.x"},{"key":"e_1_3_2_93_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-198207020-00004"},{"key":"e_1_3_2_94_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-198207020-00005"},{"key":"e_1_3_2_95_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199324020-00003"},{"key":"e_1_3_2_96_2","doi-asserted-by":"publisher","DOI":"10.3727\/107156997819566082"},{"key":"e_1_3_2_97_2","doi-asserted-by":"publisher","DOI":"10.2165\/00023210-199708030-00003"},{"key":"e_1_3_2_98_2","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/71.5.738"},{"key":"e_1_3_2_99_2","doi-asserted-by":"publisher","DOI":"10.1177\/0310057x9902700419"},{"key":"e_1_3_2_100_2","doi-asserted-by":"publisher","DOI":"10.1191\/0968130201pr184ra"},{"key":"e_1_3_2_101_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(78)91146-0"},{"key":"e_1_3_2_102_2","doi-asserted-by":"publisher","DOI":"10.1038\/scientificamerican0377-44"},{"key":"e_1_3_2_103_2","first-page":"3","article-title":"Analgesic effect of intrathecally administered morphine","volume":"2","author":"Wang JK.","year":"1977","unstructured":"Wang JK. Analgesic effect of intrathecally administered morphine. Reg Anesth Pain Med 1977; 2: 3\u20138.","journal-title":"Reg Anesth Pain Med"},{"key":"e_1_3_2_104_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(79)90947-4"},{"key":"e_1_3_2_105_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(79)91817-8"},{"key":"e_1_3_2_106_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(79)90365-9"},{"key":"e_1_3_2_107_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-198111000-00007"},{"key":"e_1_3_2_108_2","doi-asserted-by":"publisher","DOI":"10.1177\/0310057x8100900301"},{"key":"e_1_3_2_109_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-198409000-00008"},{"key":"e_1_3_2_110_2","doi-asserted-by":"publisher","DOI":"10.1177\/0310057x9802600202"},{"key":"e_1_3_2_111_2","doi-asserted-by":"publisher","DOI":"10.1177\/0310057x9802600303"},{"key":"e_1_3_2_112_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpa.2023.01.001"},{"key":"e_1_3_2_113_2","doi-asserted-by":"publisher","DOI":"10.5055\/jom.2012.0114"},{"key":"e_1_3_2_114_2","first-page":"17","volume-title":"Australasian anaesthesia","author":"Pattullo G","year":"2011","unstructured":"Pattullo G, MacPherson R. Pethidine: the case for its withdrawal. In: Riley R (ed), Australasian anaesthesia. Melbourne, VIC: Australian and New Zealand College of Anaesthetists, 2011, pp.17\u201325."},{"key":"e_1_3_2_115_2","doi-asserted-by":"publisher","DOI":"10.3390\/pharmacy10060154"},{"key":"e_1_3_2_116_2","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.809"},{"key":"e_1_3_2_117_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40140-023-00597-7"}],"container-title":["Anaesthesia and Intensive Care"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/0310057X261442548","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/0310057X261442548","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/0310057X261442548","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T10:46:26Z","timestamp":1793961986000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/0310057X261442548"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,14]]},"references-count":116,"journal-issue":{"issue":"3_suppl","published-print":{"date-parts":[[2026,11]]}},"alternative-id":["10.1177\/0310057X261442548"],"URL":"https:\/\/doi.org\/10.1177\/0310057x261442548","relation":{},"ISSN":["0310-057X","1448-0271"],"issn-type":[{"value":"0310-057X","type":"print"},{"value":"1448-0271","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,14]]}}}