Pethidine

Effects

EuphoriaDry MouthMood liftItchinessRelaxantConstipationPupil constrictionAnalgesia TS

Overview

Pethidine, known as meperidine in the United States (sold under the brand name Demerol), is a synthetic opioid analgesic used for the treatment of moderate to severe pain. Compared to traditional opioids such as morphine, pethidine was originially thought to be much safer and have less potential for abuse. It was later discovered that pethidine is significantly less safe than morphine and its metabolite norpethidine can be extremely toxic. PW

A phenylpiperidine opioid first synthesised by Otto Eisleb in 1939, better known by the names meperidine and pethidine. An analgesic, once widely prescribed it has since declined in usage due to the discovery of a toxic metabolite - norpethidine. Also reacts dangerously with many drugs. TS

Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a fully synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1938 as a potential anticholinergic agent by the German chemist Otto Eisleb, its analgesic properties were first recognized by Otto Schaumann while working for IG Farben, in Germany. Pethidine is the prototype of a large family of analgesics including the pethidine 4-phenylpiperidines (e.g., piminodine, anileridine), the prodines (e.g., alphaprodine, MPPP), bemidones (e.g., ketobemidone), and others more distant, including diphenoxylate and analogues.[1–9] WP

Pethidine is indicated for the treatment of moderate to severe pain, and is delivered as a hydrochloride salt in tablets, as a syrup, or by intramuscular, subcutaneous, or intravenous injection. For much of the 20th century, pethidine was the opioid of choice for many physicians; in 1975, 60% of doctors prescribed it for acute pain and 22% for chronic severe pain.[10] WP

It was patented in 1937 and approved for medical use in 1943. Compared with morphine, pethidine was considered to be safer, carry a lower risk of addiction, and to be superior in treating the pain associated with biliary spasm or renal colic due to its assumed anticholinergic effects. These were later discovered to be inaccurate assumptions, as it carries an equal risk of addiction and possesses no advantageous effects on biliary spasm or renal colic compared to other opioids. Due to the neurotoxicity of its metabolite, norpethidine, it is more toxic than other opioids—especially during long-term use. The norpethidine metabolite was found to have serotonergic effects, so pethidine could, unlike most opioids, increase the risk of triggering serotonin syndrome.[3][4][11] WP

History

Legal status

• Germany: Pethidine is a controlled substance under Anlage III of the BtMG. It can only be prescribed on a narcotic prescription form.[15] PW
• Russia: Pethidine is a Schedule I controlled substance.[16] PW
• Switzerland: Pethidine is a controlled substance specifically named under Verzeichnis A. Medicinal use is permitted.[17] PW
• Turkey: Pethidine is a 'red prescription' only substance and illegal when sold or possessed without a prescription.[18] PW⚠ PsychonautWiki itself has flagged this text: citation needed.
• United Kingdom: Pethidine is a Class A, Schedule 2 drug in the United Kingdom.[19] PW
• United States: Pethidine is a Schedule II Controlled Substance.[20] PW

Legal status

Pethidine is in Schedule II of the Controlled Substances Act 1970 of the United States as a Narcotic with ACSCN 9230 with a 6250 kilo aggregate manufacturing quota as of 2014. The free base conversion ratio for salts includes 0.87 for the hydrochloride and 0.84 for the hydrobromide. The A, B, and C intermediates in production of pethidine are also controlled, with ACSCN being 9232 for A (with a 6 gram quota) and 9233 being B (quota of 11 grams) and 9234 being C (6 gram quota). It is listed under the Single Convention for the Control of Narcotic Substances 1961 and is controlled in most countries in the same fashion as is morphine.[21] WP⚠ Wikipedia itself has flagged this text: citation needed.

Pharmacology

Mechanism of action

Like morphine, pethidine exerts its analgesic effects by acting as an agonist at the μ-opioid receptor.[22] WP

Pethidine is often employed in the treatment of postanesthetic shivering. The pharmacologic mechanism of this antishivering effect is not fully understood, but it may involve the stimulation of κ-opioid receptors.[23][24] WP

Pethidine has structural similarities to atropine and other tropane alkaloids and may have some of their effects and side effects. In addition to these opioidergic and anticholinergic effects, it has local anesthetic activity related to its interactions with sodium ion channels.[25] WP

Pethidine's apparent in vitro efficacy as an antispasmodic agent is due to its local anesthetic effects. It does not have antispasmodic effects in vivo. Pethidine also has stimulant effects mediated by its inhibition of the dopamine transporter (DAT) and norepinephrine transporter (NET). Pethidine will substitute for cocaine in animals trained to discriminate cocaine from saline, probably as a result of its inhibitory actions on DAT and NET.[26][27] WP

Several analogs of pethidine such as 4-fluoropethidine have been synthesized that are potent inhibitors of the reuptake of the monoamine neurotransmitters dopamine and norepinephrine via DAT and NET. It has also been associated with cases of serotonin syndrome, suggesting some interaction with serotonergic neurons, but the relationship has not been definitively demonstrated.[3][27–30] WP

It is more lipid-soluble than morphine, resulting in a faster onset of action. Its duration of clinical effect is 120–150 minutes, although it is typically administered at 4– to 6-hour intervals. Pethidine has been shown to be less effective than morphine, diamorphine, or hydromorphone at easing severe pain, or pain associated with movement or coughing.[3][27][29] WP

Like other opioid drugs, pethidine has the potential to cause physical dependence or addiction. The especially severe side effects unique to pethidine among opioids—serotonin syndrome, seizures, delirium, dysphoria, tremor—are primarily or entirely due to the action of its metabolite, norpethidine.[3][29] WP

Pharmacodynamics

Pethidine has weak binding affinity for the mu-opioid receptor in humans at 450.1 nM (Morphine 1.168).[31] WP

Pharmacokinetics

Pethidine is quickly hydrolysed in the liver to pethidinic acid and is also demethylated to norpethidine, which has half the analgesic activity of pethidine but a longer elimination half-life (8–12 hours); accumulating with regular administration, or in kidney failure. Norpethidine is toxic and has convulsant and hallucinogenic effects.[32] WP⚠ Part of this sentence could not be copied from the source. Open the source to read it in full.

The toxic effects mediated by the metabolites cannot be countered with opioid receptor antagonists such as naloxone or naltrexone, and are probably primarily due to norpethidine's anticholinergic activity probably due to its structural similarity to atropine, though its pharmacology has not been thoroughly explored. The neurotoxicity of pethidine's metabolites is a unique feature of pethidine compared to other opioids. Pethidine's metabolites are further conjugated with glucuronic acid and excreted into the urine. WP⚠ Part of this sentence could not be copied from the source. Open the source to read it in full.

Chemistry

Formula

C15H21NO2 PC

CAS number

57-42-1 PC

Molar mass (g/mol)

247.33 PC

IUPAC name (computed by PubChem)

ethyl 1-methyl-4-phenylpiperidine-4-carboxylate PC

SMILES

CCOC(=O)C1(CCN(CC1)C)C2=CC=CC=C2 PC

InChIKey

XADCESSVHJOZHK-UHFFFAOYSA-N PC

PubChem CID

4058

Pop culture

No references added yet.

References

1. Other Demerol, Pethidine (meperidine) dosing, indications, interactions, adverse effects, and more
2. Journal / agency Shipton E. Should New Zealand continue signing up to the Pethidine Protocol?. The New Zealand Medical Journal. March 2006. PMID 16532042
3. Journal / agency Latta KS, Ginsberg B, Barkin RL. Meperidine: a critical review. American Journal of Therapeutics. January–February 2002. doi:10.1097/00045391-200201000-00010 · PMID 11782820
4. Journal / agency MacPherson RD, Duguid MD. Strategy to Eliminate Pethidine Use in Hospitals. Journal of Pharmacy Practice and Research. 2008. doi:10.1002/j.2055-2335.2008.tb00807.x
5. Journal / agency Mather LE, Meffin PJ. Clinical pharmacokinetics of pethidine. Clinical Pharmacokinetics. September–October 1978. doi:10.2165/00003088-197803050-00002 · PMID 359212
6. Other Australian Medicines Handbook. 2013
7. Other US 2167351 Piperidine compounds and a process of preparing them
8. Journal / agency Michaelis M, Schölkens B, Rudolphi K. An anthology from Naunyn-Schmiedeberg's archives of pharmacology. Naunyn-Schmiedeberg's Archives of Pharmacology. April 2007. doi:10.1007/s00210-007-0136-z · PMID 17310263
9. Other Reynolds AK, Randall LO. Morphine and Allied Drugs. 1957
10. Journal / agency Kaiko RF, Foley KM, Grabinski PY, Heidrich G, Rogers AG, Inturrisi CE, Reidenberg MM. Central nervous system excitatory effects of meperidine in cancer patients. Annals of Neurology. February 1983. doi:10.1002/ana.410130213 · PMID 6187275
11. Other Fischer J, Ganellin CR. Analogue-based Drug Discovery. 2006
12. Other Serotonin Syndrome and the Libby Zion Affair. 2011
13. Other Why Heroin Relapse Often Ends In Death - Lauren F Friedman (Business Insider)
14. Journal / agency Siegel, S., Hinson, R. E., Krank, M. D., McCully, J. Heroin “Overdose” Death: Contribution of Drug-Associated Environmental Cues. Science. 23 April 1982. doi:10.1126/science.7200260
15. Other Anlage III BtMG - Einzelnorm
16. Other Постановление Правительства РФ от 01.10.2012 N 1002 (ред. от 09.08.2019)
17. Other Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien
18. Other KIRMIZI REÇETEYE TABİ İLAÇLAR
19. Other List of most commonly encountered drugs currently controlled under the misuse of drugs legislation
20. Other DEA Controlled Substances
21. Other Final Adjusted Aggregate Production Quotas for Schedule I and II Controlled Substances and Assessment of Annual Needs for the List I Chemicals Ephedrine, Pseudoephedrine, and Phenylpropanolamine for 2014
22. Other Bryant B, Knights K. Pharmacology for Health Professionals. 2010
23. Journal / agency Koczmara C, Perri D, Hyland S, Rousseaux L. Meperidine (Demerol) safety issues. Dynamics. 2005. PMID 15835452
24. Other Laurence B. Goodman & Gilman's pharmacological basis of therapeutics. 2010
25. Other Petidin Meda - FASS Vårdpersonal
26. Journal / agency Wagner LE, Eaton M, Sabnis SS, Gingrich KJ. Meperidine and lidocaine block of recombinant voltage-dependent Na+ channels: evidence that meperidine is a local anesthetic. Anesthesiology. November 1999. doi:10.1097/00000542-199911000-00042 · PMID 10551601
27. Journal / agency Izenwasser S, Newman AH, Cox BM, Katz JL. The cocaine-like behavioral effects of meperidine are mediated by activity at the dopamine transporter. European Journal of Pharmacology. February 1996. doi:10.1016/0014-2999(95)00696-6 · PMID 8851160
28. Journal / agency Lomenzo SA, Rhoden JB, Izenwasser S, Wade D, Kopajtic T, Katz JL, Trudell ML. Synthesis and biological evaluation of meperidine analogues at monoamine transporters. Journal of Medicinal Chemistry. March 2005. doi:10.1021/jm0401614 · PMID 15743177
29. Journal / agency Demerol: Is It the Best Analgesic?. Pennsylvania Patient Safety Reporting Service Patient Safety Advisory. June 2006
30. Other Davis S. Use of pethidine for pain management in the emergency department: a position statement of the NSW Therapeutic Advisory Group. August 2004
31. Other Simon BT, Lizarraga I. Veterinary Anesthesia and Analgesia, The 6th Edition of Lumb and Jones. 11 September 2024
32. Journal / agency Molloy A. Does pethidine still have a place in therapy?. Australian Prescriber. 2002. doi:10.18773/austprescr.2002.008

Text and values on this page are quoted from PsychonautWiki (CC BY-SA 4.0), Wikipedia (CC BY-SA 4.0), TripSit factsheets, PubChem (public domain). Each value links to the exact revision it came from.