Pethidine

{{Short description|Opioid analgesic}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{about|the analgesic drug also sold under the trade name Dolantin|the anticonvulsant sold under the trade name Dilantin|phenytoin}} {{Drugbox | Watchedfields = changed | class = Opioid | verifiedrevid = 464199592 | IUPAC_name = Ethyl 1-methyl-4-phenylpiperidine-4-carboxylate | USAN = Meperidine | image = Pethidine2DACS.svg | image_class = skin-invert-image | width = 120px | image2 = Pethidine-PM3-based-on-xtal-1974-3D-balls.png | image_class2 = bg-transparent | width2 = 200px | tradename = Demerol, others | pregnancy_AU = C | pregnancy_US = C | legal_AU = S8 | legal_BR = A1 | legal_BR_comment = <ref>{{cite web | author = Anvisa | date = 2023-03-31 | title = RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial | language = pt-BR | publisher = Diário Oficial da União | url = https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 | access-date = 2023-08-16 | archive-date = 2023-08-03 | archive-url = https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 | author-link = Brazilian Health Regulatory Agency | trans-title = Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control | url-status = live | publication-date = 2023-04-04 }}</ref> | legal_CA = Schedule I | legal_DE = Anlage III | legal_NZ = Class B | legal_UK = Class A | legal_US = Schedule II | legal_UN = N I | dependency_liability = High | addiction_liability = High<ref>{{cite book | vauthors = Bonewit-West K, Hunt SA, Applegate E | date = 2012 | title = Today's Medical Assistant: Clinical and Administrative Procedures | publisher = Elsevier Health Sciences | page = 571 | isbn = 978-1-4557-0150-6 | url = https://books.google.com/books?id=YalYPI1KqTQC&pg=PA571 | access-date = 20 August 2019 | archive-date = 10 January 2023 | archive-url = https://web.archive.org/web/20230110030031/https://books.google.com/books?id=YalYPI1KqTQC&pg=PA571 | url-status = live }}</ref> | routes_of_administration = By mouth, intravenous, intramuscular, intrathecal,<ref>{{cite journal | vauthors = Ngan Kee WD | title = Intrathecal pethidine: pharmacology and clinical applications | journal = Anaesthesia and Intensive Care | volume = 26 |issue = 2 | pages = 137–146 | date = April 1998 | pmid = 9564390 | doi = 10.1177/0310057X9802600202 | doi-access = free}}</ref> subcutaneous, epidural<ref>{{cite journal | vauthors = Ngan Kee WD | title = Epidural pethidine: pharmacology and clinical experience | journal = Anaesthesia and Intensive Care | volume = 26 | issue = 3 | pages = 247–255 | date = June 1998 | pmid = 9619217 | doi = 10.1177/0310057X9802600303 | doi-access = free}}</ref> | bioavailability = 50–60% (Oral), 80–90% (Oral, in cases of hepatic impairment) | protein_bound = 65–75% | metabolism = Liver: CYP2B6, CYP3A4, CYP2C19, Carboxylesterase 1 | metabolites = * Norpethidine * Pethidinic acid * others | elimination_half-life = 2.5–4 hours, 7–11 hours (liver disease) | excretion = Renal | IUPHAR_ligand = 7221 | ATC_prefix = N02 | ATC_suffix = AB02 | ChEBI = 6754 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 607 | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 57-42-1 | PubChem = 4058 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00454 | ChemSpiderID_Ref = | ChemSpiderID = 3918 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 9E338QE28F | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D08343 | C = 15 | H = 21 | N = 1 | O = 2 | smiles = CCOC(=O)C1(c2ccccc2)CCN(C)CC1 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C15H21NO2/c1-3-18-14(17)15(9-11-16(2)12-10-15)13-7-5-4-6-8-13/h4-8H,3,9-12H2,1-2H3 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = XADCESSVHJOZHK-UHFFFAOYSA-N }}

'''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.<ref>{{cite web|title=Demerol, Pethidine (meperidine) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=9 April 2014|url=http://reference.medscape.com/drug/demerol-meperidine-343315#showall}}</ref><ref name="NZ">{{cite journal | vauthors = Shipton E | date = March 2006 | title = Should New Zealand continue signing up to the Pethidine Protocol? | journal = The New Zealand Medical Journal | volume = 119 | issue = 1230 | page = U1875 | pmid = 16532042 | url = http://journal.nzma.org.nz/journal/119-1230/1875/content.pdf | archive-date = 2014-04-08 | archive-url = https://web.archive.org/web/20140408211938/http://journal.nzma.org.nz/journal/119-1230/1875/content.pdf | url-status = dead }}</ref><ref name="crit">{{cite journal | vauthors = Latta KS, Ginsberg B, Barkin RL | title = Meperidine: a critical review | journal = American Journal of Therapeutics | volume = 9 | issue = 1 | pages = 53–68 | date = January–February 2002 | pmid = 11782820 | doi = 10.1097/00045391-200201000-00010 | s2cid = 23410891 }}</ref><ref name="SHPA">{{cite journal |title=Strategy to Eliminate Pethidine Use in Hospitals |journal=Journal of Pharmacy Practice and Research |volume=38 |issue=2 |year=2008 |pages=88–89 |vauthors=MacPherson RD, Duguid MD |doi=10.1002/j.2055-2335.2008.tb00807.x |s2cid=71812645 |doi-access=free }}</ref><ref>{{cite journal | vauthors = Mather LE, Meffin PJ | title = Clinical pharmacokinetics of pethidine | journal = Clinical Pharmacokinetics | volume = 3 | issue = 5 | pages = 352–368 | date = September–October 1978 | pmid = 359212 | doi = 10.2165/00003088-197803050-00002 | s2cid = 35402662 }}</ref><ref name = AMH/> Synthesized in 1938<ref>US 2167351 Piperidine compounds and a process of preparing them</ref> 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.<ref name="Michaelis">{{cite journal | vauthors = Michaelis M, Schölkens B, Rudolphi K | title = An anthology from Naunyn-Schmiedeberg's archives of pharmacology | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 375 | issue = 2 | pages = 81–84 | date = April 2007 | pmid = 17310263 | doi = 10.1007/s00210-007-0136-z | s2cid = 27774155 }}</ref> 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.<ref name="Allied Drugs 1957, pp 273-319">{{cite book | vauthors = Reynolds AK, Randall LO | date = 1957 | title = Morphine and Allied Drugs | publisher = University of Toronto Press/Oxford University Press | pages = 273–319 | location = Toronto/London }}</ref>

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.<ref name="Kaiko">{{cite journal | vauthors = Kaiko RF, Foley KM, Grabinski PY, Heidrich G, Rogers AG, Inturrisi CE, Reidenberg MM | title = Central nervous system excitatory effects of meperidine in cancer patients | journal = Annals of Neurology | volume = 13 | issue = 2 | pages = 180–185 | date = February 1983 | pmid = 6187275 | doi = 10.1002/ana.410130213 | s2cid = 44353966 }}</ref>

<!-- Society and culture --> It was patented in 1937 and approved for medical use in 1943.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR | date = 2006 | title = Analogue-based Drug Discovery | publisher = John Wiley & Sons | page = 52X | isbn = 978-3-527-60749-5 | url = https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA52X }}</ref> 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.<ref name = crit/> 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.<ref name = crit/> The norpethidine metabolite was found to have serotonergic effects, so pethidine could, unlike most opioids, increase the risk of triggering serotonin syndrome.<ref name = crit/><ref name = SHPA/>

==Medical uses== Pethidine is the most widely used opioid in labour and delivery.<ref>{{cite journal | vauthors = Bricker L, Lavender T | date = May 2002 | title = Parenteral opioids for labor pain relief: a systematic review | journal = American Journal of Obstetrics and Gynecology | volume = 186 | issue = 5 Suppl Nature | pages = S94–109 | doi = 10.1016/S0002-9378(02)70185-3 | pmid = 12011876 }}</ref> It has fallen out of favour in some countries, such as the United States, in favour of other opioids, due to its potential drug interactions, especially with serotonergics, and its neurotoxic metabolite, norpethidine.<ref name="AMH">{{cite book | year = 2013 | veditors = Rossi S | title = Australian Medicines Handbook | publisher = The Australian Medicines Handbook Unit Trust | edition = 2013 | isbn = 978-0-9805790-9-3 | place = Adelaide }}</ref> It is still commonly used in the United Kingdom and New Zealand,<ref>{{Cite web|title = Parenteral opioids for maternal pain relief in labour|url = http://apps.who.int/rhl/archives/CD007396_olayemio_com/en/index.html|archive-url = https://web.archive.org/web/20150620184220/http://apps.who.int/rhl/archives/CD007396_olayemio_com/en/index.html|url-status = dead|archive-date = June 20, 2015|publisher = World Health Organization |access-date = 2015-06-20}}</ref> and was the preferred opioid in the United Kingdom for use during labour, but has been superseded somewhat by other strong semi-synthetic opioids (e.g. hydromorphone) to avoid serotonin interactions since the mid-2000s.<ref>{{Cite web|title = Pain relief in labour – Pregnancy and baby guide |website=NHS Choices|url = http://www.nhs.uk/conditions/pregnancy-and-baby/pages/pain-relief-labour.aspx|access-date = 2015-06-20|archive-date = 2015-06-12|archive-url = https://web.archive.org/web/20150612105823/http://www.nhs.uk/conditions/pregnancy-and-baby/pages/pain-relief-labour.aspx|url-status = dead}}</ref>

Pethidine is the preferred painkiller for diverticulitis, because it decreases intestinal intraluminal pressure.<ref>''Blueprints – Family Medicine'' (3rd edition)</ref>{{fcn|date=May 2026}} Pethidine is the preferred drug for the management of shivering during therapeutic hypothermia, as it provides the greatest reduction in the shivering threshold.<ref name="pmid22135340">{{cite journal | vauthors = Logan A, Sangkachand P, Funk M | title = Optimal management of shivering during therapeutic hypothermia after cardiac arrest | journal = Critical Care Nurse | volume = 31 | issue = 6 | pages = e18–30 | date = December 2011 | pmid = 22135340 | doi = 10.4037/ccn2011618 }}</ref>

Before 2003, it was on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.<ref>{{cite web |title=Essential Medicines WHO Model List (revised April 2002)|edition=12th|location=Geneva, Switzerland|publisher=World Health Organization |date=April 2002|access-date=6 September 2017|url=http://apps.who.int/iris/bitstream/10665/67335/1/a76618.pdf}}</ref><ref>{{cite web|title=Essential Medicines WHO Model List (revised April 2003)|location=Geneva, Switzerland|publisher=World Health Organization|date=April 2003|access-date=6 September 2017|url=http://apps.who.int/iris/bitstream/10665/68168/1/a80290.pdf|edition=13th}}</ref>

==Adverse effects== The adverse effects of pethidine administration are primarily those of the opioids as a class: nausea, vomiting, dizziness, diaphoresis, urinary retention, and constipation. Due to moderate stimulant effects mediated by pethidine's dopamine and norepinephrine reuptake inhibition, sedation is less likely compared to other opioids. Unlike other opioids, it does not cause miosis because of its anticholinergic properties. Overdose can cause muscle flaccidity, respiratory depression, obtundation, psychosis, cold and clammy skin, hypotension, and coma.<ref>{{cite book | vauthors = Baselt R | date = 2008 | title = Disposition of Toxic Drugs and Chemicals in Man | publisher = Biomedical Publications | edition = 8th | pages = 911–914 | location = Foster City, CA }}</ref><ref>{{cite web | title = Package insert for meperidine hydrochloride | publisher = Boehringer Ingelheim | location = Ridgefield, CT | date = 2005 | url = https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Roxane/Dolophine/Dolophine%20Tablets.pdf }}</ref>

A narcotic antagonist such as naloxone is indicated to reverse respiratory depression and other effects of pethidine. Serotonin syndrome has occurred in patients receiving concurrent antidepressant therapy with selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase inhibitors, or other medication types (see Interactions below). Convulsive seizures sometimes observed in patients receiving parenteral pethidine on a chronic basis have been attributed to accumulation in plasma of the metabolite norpethidine (normeperidine). Fatalities have occurred following either oral or intravenous pethidine overdose.<ref>{{cite book | vauthors = Baselt R | date = 2008 | title = Disposition of Toxic Drugs and Chemicals in Man | publisher = Biomedical Publications | edition = 8th | pages = 911–914 | location = Foster City, CA }}</ref><ref>{{cite web | title = Package insert for meperidine hydrochloride | publisher = Boehringer Ingelheim | location = Ridgefield, CT | date = 2005 | url = https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Roxane/Dolophine/Dolophine%20Tablets.pdf }}</ref>

== Interactions ==

Pethidine has serious interactions that can be dangerous with monoamine oxidase inhibitors (e.g., furazolidone, isocarboxazid, moclobemide, phenelzine, procarbazine, selegiline, tranylcypromine). Such patients may suffer agitation, delirium, headache, convulsions, and/or hyperthermia. Fatal interactions have been reported including the death of Libby Zion.<ref name=brody>{{cite news| vauthors = Brody J |author-link=Jane Brody|title=A Mix of Medicines That Can Be Lethal|url=https://www.nytimes.com/2007/02/27/health/27brody.html?n=Top/News/Health/Diseases,%20Conditions,%20and%20Health%20Topics/Antidepressants|work=New York Times |date=February 27, 2007 |access-date=2009-02-13 }}</ref>

Seizures may develop when tramadol is given intravenously following, or with, pethidine.<ref>{{cite web|title=Serious Reactions with Tramadol: Seizures and Serotonin Syndrome|location=New Zealand Pharmacovigilance Centre, Dunedin|publisher=New Zealand Medicines and Medical Devices Safety Authority|website=medsafe.govt.nz|date=October 2007|access-date=7 November 2019|url=https://www.medsafe.govt.nz/profs/PUArticles/TramSerious.htm|edition=Prescriber Update 28(1)}}</ref> It can interact as well with SSRIs and other antidepressants, antiparkinson agents, migraine therapy, stimulants and other agents causing serotonin syndrome. It is thought to be caused by an increase in cerebral serotonin concentrations. It is probable that pethidine can also interact with a number of other medications, including muscle relaxants, benzodiazepines, and ethanol.

==Mechanism of action== {{Main|Opioid}}

Like morphine, pethidine exerts its analgesic effects by acting as an agonist at the μ-opioid receptor.<ref>{{cite book | vauthors = Bryant B, Knights K | year = 2010 | title = Pharmacology for Health Professionals | publisher = Mosby Australia | edition = 3rd | isbn = 978-0-7295-3929-6 | location = Chatswood }}</ref>

Pethidine is often employed in the treatment of postanesthetic shivering. The pharmacologic mechanism of this antishivering effect is not fully understood,<ref name=ISMP2005>{{cite journal | vauthors = Koczmara C, Perri D, Hyland S, Rousseaux L | title = Meperidine (Demerol) safety issues | journal = Dynamics | volume = 16 | issue = 1 | pages = 8–12 | year = 2005 | pmid = 15835452 | url = http://www.ismp-canada.org/download/caccn/CACCN-Spring05.pdf | access-date = 2014-01-11 }}</ref> but it may involve the stimulation of κ-opioid receptors.<ref name="Goodman and Gilman">{{cite book | vauthors = Laurence B | year = 2010 | title = Goodman & Gilman's pharmacological basis of therapeutics | publisher = McGraw-Hill | edition = 12th | page = 549 | isbn = 978-0-07-162442-8 }}</ref>

Pethidine has structural similarities to atropine and other tropane alkaloids and may have some of their effects and side effects.<ref>{{Cite web|url=http://www.fass.se/LIF/produktfakta/artikel_produkt.jsp?NplID=19741206000040&DocTypeID=3&UserTypeID=0|title = Petidin Meda - FASS Vårdpersonal}}</ref> In addition to these opioidergic and anticholinergic effects, it has local anesthetic activity related to its interactions with sodium ion channels.

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''.<ref>{{cite journal | vauthors = Wagner LE, Eaton M, Sabnis SS, Gingrich KJ | title = Meperidine and lidocaine block of recombinant voltage-dependent Na+ channels: evidence that meperidine is a local anesthetic | journal = Anesthesiology | volume = 91 | issue = 5 | pages = 1481–1490 | date = November 1999 | pmid = 10551601 | doi = 10.1097/00000542-199911000-00042 | s2cid = 34806974 | doi-access = free }}</ref> 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.<ref name="izenwasser">{{cite journal | vauthors = Izenwasser S, Newman AH, Cox BM, Katz JL | title = The cocaine-like behavioral effects of meperidine are mediated by activity at the dopamine transporter | journal = European Journal of Pharmacology | volume = 297 | issue = 1–2 | pages = 9–17 | date = February 1996 | pmid = 8851160 | doi = 10.1016/0014-2999(95)00696-6 }}</ref>

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.<ref>{{cite journal | vauthors = Lomenzo SA, Rhoden JB, Izenwasser S, Wade D, Kopajtic T, Katz JL, Trudell ML | title = Synthesis and biological evaluation of meperidine analogues at monoamine transporters | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 5 | pages = 1336–1343 | date = March 2005 | pmid = 15743177 | doi = 10.1021/jm0401614 }}</ref><ref name="psrs">{{citation | title = Demerol: Is It the Best Analgesic? | journal = Pennsylvania Patient Safety Reporting Service Patient Safety Advisory | volume = 3 | issue = 2 | date = June 2006 | url = http://patientsafetyauthority.org/ADVISORIES/AdvisoryLibrary/2006/Jun3(2)/documents/18.pdf | access-date = 2013-04-15 | url-status = dead | archive-url = https://web.archive.org/web/20130620131908/http://patientsafetyauthority.org/ADVISORIES/AdvisoryLibrary/2006/Jun3(2)/documents/18.pdf | archive-date = 2013-06-20 }}</ref> It has also been associated with cases of serotonin syndrome, suggesting some interaction with serotonergic neurons, but the relationship has not been definitively demonstrated.<ref name="izenwasser"/><ref name="psrs"/><ref name="nsw">{{cite web|url=http://www.clininfo.health.nsw.gov.au/nswtag/publications/posstats/Pethidinefinal.pdf|title=Use of pethidine for pain management in the emergency department: a position statement of the NSW Therapeutic Advisory Group|access-date=2007-01-17| vauthors = Davis S |date=August 2004|publisher=New South Wales Therapeutic Advisory Group|url-status=dead|archive-url=https://web.archive.org/web/20061009172524/http://www.clininfo.health.nsw.gov.au/nswtag/publications/posstats/Pethidinefinal.pdf|archive-date=2006-10-09}}</ref><ref name = "Latta">{{cite journal | vauthors = Latta KS, Ginsberg B, Barkin RL | title = Meperidine: a critical review | journal = American Journal of Therapeutics | volume = 9 | issue = 1 | pages = 53–68 | date = January–February 2002 | pmid = 11782820 | doi = 10.1097/00045391-200201000-00010 | s2cid = 23410891 }}</ref>

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.<ref name="izenwasser"/><ref name="psrs"/><ref name="Latta"/>

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.<ref name="psrs"/><ref name="Latta"/>

==Pharmacology==

===Pharmacodynamics=== Pethidine has weak binding affinity for the mu-opioid receptor in humans at 450.1 nM (Morphine 1.168).<ref name="lamont">{{cite book|isbn=978-1-119-83027-6 | vauthors = Simon BT, Lizarraga I |chapter=Opioids | veditors = Lamont L, Grimm K, Robertson S, Love L, Schroeder C |title=Veterinary Anesthesia and Analgesia, The 6th Edition of Lumb and Jones | date = 11 September 2024 |pages=378–379|publisher=Wiley Blackwell}}</ref> ===Pharmacokinetics=== frame|right 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);<ref>{{cite journal|title=Does pethidine still have a place in therapy?|journal=Australian Prescriber|year=2002|volume=25|issue=1|pages=12–13| vauthors = Molloy A |doi=10.18773/austprescr.2002.008|doi-access=free}}</ref> accumulating with regular administration, or in kidney failure. Norpethidine is toxic and has convulsant and hallucinogenic effects.{{medrs|date=May 2026}}

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.{{medrs|date=May 2026}}

class=skin-invert-image|600px

==Recreational use==

===Trends=== In data from the U.S. Drug Abuse Warning Network, mentions of hazardous or harmful use of pethidine declined between 1997 and 2002, in contrast to increases for fentanyl, hydromorphone, morphine, and oxycodone.<ref>{{cite journal | vauthors = Gilson AM, Ryan KM, Joranson DE, Dahl JL | title = A reassessment of trends in the medical use and abuse of opioid analgesics and implications for diversion control: 1997-2002 | journal = Journal of Pain and Symptom Management | volume = 28 | issue = 2 | pages = 176–188 | date = August 2004 | pmid = 15276196 | doi = 10.1016/j.jpainsymman.2004.01.003 | citeseerx = 10.1.1.387.1900 }}</ref> The number of dosage units of pethidine reported lost or stolen in the U.S. increased 16.2% between 2000 and 2003, from 32,447 to 37,687.<ref>{{cite journal | vauthors = Joranson DE, Gilson AM | title = Drug crime is a source of abused pain medications in the United States | journal = Journal of Pain and Symptom Management | volume = 30 | issue = 4 | pages = 299–301 | date = October 2005 | pmid = 16256890 | doi = 10.1016/j.jpainsymman.2005.09.001 | doi-access = free }}</ref>

==Synthesis== Pethidine can be produced in a two-step synthesis. The first step is reaction of benzyl cyanide and chlormethine in the presence of sodium amide to form a piperidine ring. The nitrile is then converted to an ester.<ref>Patent Appl. DE 679 281 IG Farben 1937.</ref> :class=skin-invert-image|thumb|left|500px|Pethidine synthesis{{clear left}}

==Control== 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).<ref>{{Cite web |url=http://www.deadiversion.usdoj.gov/fed_regs/quotas/2014/fr0825.htm |title=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 |access-date=2016-02-26 |archive-date=2016-03-04 |archive-url=https://web.archive.org/web/20160304053357/http://www.deadiversion.usdoj.gov/fed_regs/quotas/2014/fr0825.htm |url-status=dead }}</ref> 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.{{cn|date=May 2026}}

==Veterinary use== Pethidine provides analgesia for 60 to 90 minutes in the cat and dog.<ref name="lamont"/> Pethidine is less effective in horses, with IV, SC, and IM administration failing to provide thermal antinociception.<ref name="lamont"/><ref>{{cite journal | vauthors = Hanafi AL, Reed RA, Trenholme HN, Sakai DM, Ryan CA, Barletta M, Quandt JE, Knych HK | title = Pharmacokinetics and pharmacodynamics of meperidine after intramuscular and subcutaneous administration in horses | journal = Veterinary Surgery | volume = 50 | issue = 2 | pages = 410–417 | date = February 2021 | pmid = 33242227 | doi = 10.1111/vsu.13545 }}</ref><ref>{{cite journal | vauthors = Hamamoto-Hardman BD, Steffey EP, McKemie DS, Kass PH, Knych HK | date = October 2020 | title = Meperidine pharmacokinetics and effects on physiologic parameters and thermal threshold following intravenous administration of three doses to horses | journal = BMC Veterinary Research | volume = 16 | issue = 1 | page = 368 | doi = 10.1186/s12917-020-02564-4 | doi-access = free | pmc = 7528573 | pmid = 32998730 }}</ref> Epidural administration of pethidine into the caudal area provided 4-5 hours of analgesia with no cardiovascular depression and only minor sedation.<ref>{{cite journal | vauthors = Skarda RT, Muir WW | title = Analgesic, hemodynamic, and respiratory effects induced by caudal epidural administration of meperidine hydrochloride in mares | journal = American Journal of Veterinary Research | volume = 62 | issue = 7 | pages = 1001–1007 | date = July 2001 | pmid = 11453471 | doi = 10.2460/ajvr.2001.62.1001 }}</ref><ref name="lamont"/> Due to the short duration of analgesia and side effects pethidine is not commonly used with other opioids being used instead.<ref name="saunders">{{cite book | vauthors = Papich M | date = 2016 | title = Saunders Handbook of Veterinary Drugs | publisher = Elsevier | edition = 4th | isbn = 978-0-323-24485-5 }}</ref>

Pethidine is vagolytic but high doses cause bradycardia due to cardiac depression. Pethidine is metabolised by the hepatic enzyme CYP450 via N-demethylation to produce normeperidine. Normeperidine is excitotoxic and can cause myoclonus when too much pethidine is administered. The treatment for these side effects are benzodiazepines. Histamine release following IV administration can cause flare reaction, pruritus, hypersalivation, urination, defaecation, and tachypnoea. IM injection can cause localised oedema and erythema.<ref name="lamont"/>

== See also == * Libby Zion Law (a case involving phenelzine and pethidine)

== References == {{Reflist|30em}}

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