Editing 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
| 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 |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |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 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |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 |title=Today's Medical Assistant: Clinical and Administrative Procedures |date=2012 |page=571 |publisher=Elsevier Health Sciences |isbn=9781455701506 |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 = [[Oral administration|By mouth]], [[intravenous]], [[intramuscular injection|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 injection|subcutaneous]], [[epidural administration|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]]<br /> • [[Pethidinic Acid]]<br /> • 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]] [[analgesic|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 | title = Should New Zealand continue signing up to the Pethidine Protocol? | journal = The New Zealand Medical Journal | volume = 119 | issue = 1230 | pages = U1875 | date = March 2006 | pmid = 16532042 | url = http://journal.nzma.org.nz/journal/119-1230/1875/content.pdf | url-status = dead | archive-url = https://web.archive.org/web/20140408211938/http://journal.nzma.org.nz/journal/119-1230/1875/content.pdf | archive-date = 2014-04-08 }}</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 | title = Morphine and Allied Drugs | vauthors = Reynolds AK, Randall LO | publisher =  University of Toronto Press/Oxford University Press | location = Toronto/London | date = 1957 | pages = 273–319 }}</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 injection|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>

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It was patented in 1937 and approved for medical use in 1943.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=52X |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA52X |language=en}}</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 [[Gallstone|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, 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 [[Serotonin|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 | 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 | date = May 2002 | pmid = 12011876 | doi = 10.1016/S0002-9378(02)70185-3 }}</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 | veditors = Rossi S | isbn = 978-0-9805790-9-3 | title = Australian Medicines Handbook | place = Adelaide | publisher = The Australian Medicines Handbook Unit Trust | year = 2013 | edition = 2013 }}</ref> It is still commonly used in the United Kingdom and New Zealand,<ref>{{Cite web|title = WHO {{!}} 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|website = apps.who.int|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 - NHS Choices|url = http://www.nhs.uk/conditions/pregnancy-and-baby/pages/pain-relief-labour.aspx|website = www.nhs.uk|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> 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 |website=apps.who.int |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|website=apps.who.int|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 | edition = 8th | location = Foster City, CA | publisher = Biomedical Publications | pages = 911–914 }}</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 | edition = 8th | location = Foster City, CA | publisher = Biomedical Publications | pages = 911–914 }}</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 [[selective serotonin reuptake inhibitors|SSRIs]] and other [[antidepressant]]s, antiparkinson agents, migraine therapy, [[amphetamines|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, [[benzodiazepine]]s, 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 |title=Pharmacology for Health Professionals | edition = 3rd |publisher=Mosby Australia|year=2010|location=Chatswood|isbn=978-0-7295-3929-6}}</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 receptor]]s.<ref name="Goodman and Gilman">{{cite book| vauthors = Laurence B |title=Goodman & Gilman's pharmacological basis of therapeutics|year=2010|publisher=McGraw-Hill|isbn=978-0071624428|edition=12th|page=549}}</ref>

Pethidine has structural similarities to [[atropine]] and other [[tropane alkaloid]]s 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 channel]]s.

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 [[structural analog|analogs]] of pethidine such as [[4-Fluoropethidine|4-fluoropethidine]] have been synthesized that are potent inhibitors of the reuptake of the [[monoamine neurotransmitter]]s 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 [[Serotonin|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 [[Substance dependence|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"/>

==Pharmacokinetics==
[[File:Pethidine DOJ.jpg|frame|right]]
Pethidine is quickly hydrolysed in the liver to [[Pethidinic Acid|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. 

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.

[[File:Metabolism of pethidine.png|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>

This article uses the terms "hazardous use", "harmful use", and "dependence" in accordance with ''Lexicon of alcohol and drug''<ref>{{Cite web|url=https://www.who.int/substance_abuse/terminology/who_lexicon/en/|archive-url=https://web.archive.org/web/20040704055537/http://www.who.int/substance_abuse/terminology/who_lexicon/en/|url-status=dead|archive-date=July 4, 2004|title=WHO &#124; Lexicon of alcohol and drug terms published by the World Health Organization|website=WHO}}</ref> terms, published by the [[World Health Organization]] (WHO) in 1994.<ref name=WHOLexicon>{{cite book |veditors=Babor T, Campbell R, Room R, Saunders J |title=Lexicon of alcohol and drug terms |publisher=World Health Organization |year=1994 |location=Geneva |isbn=978-92-4-154468-9 |url=https://archive.org/details/lexiconofalcohol0000unse |url-access=registration }}</ref> In WHO usage, the first two terms replace the term "abuse" and the third term replaces the term "addiction".<ref name=WHOLexicon/><ref name="izenwasser" />

==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>
:[[File:Pethidine synthesis.PNG|class=skin-invert-image|thumb|left|500px|Pethidine synthesis]]{{clear left}}

==Control==
Pethidine is in [[Schedule II Controlled Substance|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 [[Intermediate good|intermediate]]s in production of pethidine are also controlled, with ACSCN being [[Pethidine intermediate A|9232]] for A (with a 6 gram quota) and [[Pethidine intermediate B|9233]] being B (quota of 11 grams) and [[Pethidine intermediate C|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.

== Society and culture ==
[[Marcial Maciel]] (1920-2008), a Mexican Catholic priest, accused of sexually abusing children, founder of the Legionaries of Christ and Regnum Christi congregations, was repeatedly accused of being addicted to the substance Demerol as well as morphine.

In John D. MacDonalds 's book "Dress Her  in Indigo" (1969) one of the protagonists speaks of thinking of killing an immobilized enemy of hers by injecting him with meperedine which was left over from a husband who used it while terminally ill.

In [[Raymond Chandler]]'s novel ''[[The Long Goodbye (novel)|The Long Goodbye]]'' (1953), in response to "How is Mrs. Wade?", police Lieutenant Bernie Ohls answers, "Too relaxed. She must have grabbed some pills. There's a dozen kinds up there -- even demerol. That's bad stuff."

[[Harold Shipman]] was addicted to pethidine at one stage, convicted of forging prescriptions to obtain it, fined £500 and briefly attended a drug rehabilitation clinic.<ref name="bbc2002">{{cite news|title=Harold Shipman: Timeline|work=BBC News|date=18 July 2002|url=http://news.bbc.co.uk/2/hi/health/2136444.stm|access-date=1 April 2010}}</ref><ref name="telegraph2001">{{cite news| vauthors = Bunyan N |title=The Killing Fields of Harold Shipman|work=The Daily Telegraph|date=16 June 2001|url=https://www.telegraph.co.uk/culture/4724155/The-Killing-Fields-of-Harold-Shipman.html |archive-url=https://ghostarchive.org/archive/20220112/https://www.telegraph.co.uk/culture/4724155/The-Killing-Fields-of-Harold-Shipman.html |archive-date=2022-01-12 |url-access=subscription |url-status=live|access-date=1 April 2010 | location=London}}{{cbignore}}</ref>

Danish writer [[Tove Ditlevsen]] suffered a lifelong addiction to pethidine after her husband, a doctor, had injected her with Demerol as a painkiller for an illegal abortion in 1944.<ref>{{Cite web | vauthors = Grady C |date=2021-01-29 |title=This notorious poet is required reading in Denmark. Her masterpiece is now out in the US. |url=https://www.vox.com/culture/22249049/copenhagen-trilogy-review-tove-ditlevsen-childhood-youth-dependency |access-date=2023-01-18 |website=Vox |language=en}}</ref>

Pethidine is referenced by its brand name Demerol in the song "Morphine" by singer [[Michael Jackson]] on his 1997 album ''[[Blood on the Dance Floor: HIStory in the Mix]]''.<ref name="mjdemerol">{{Cite AV media notes |title=Blood on the Dance Floor: HIStory in the Mix |date=1997 | vauthors = Jackson M |type=booklet |publisher=Epic Records, Sony Music, MJJ}}</ref> Pethidine was one of several prescription drugs which Michael Jackson was addicted to at the time and the singer describes this in the lyrics of the song with phrases such as "Relax/This won't hurt you" and "Yesterday you had his trust/Today he's taking twice as much".<ref name=Donaldson>{{cite web | vauthors = James SD | url = https://abcnews.go.com/Health/MichaelJackson/story?id=7938918&page=1 | title = Friend Says Michael Jackson Battled Demerol Addiction | work = ABC News | date = 26 June 2009 }}</ref>

Pethidine is referenced in the television show ''[[Broadchurch]]'', season 2, episode 3, as it was given to the character Beth after she has her baby.

In the 1987 [[Malayalam]] movie, ''[[Amrutham Gamaya]]'', [[Mohanlal]]'s character, Dr. P.K. Haridas self-injects pethidine and gets addicted to it.

A doctor in the TV show ''[[Call the Midwife (TV series)|Call the Midwife]]'' becomes addicted to pethidine.<ref>{{cite web|url=https://www.radiotimes.com/tv/drama/what-is-pethidine-call-the-midwife/|title=What is pethidine – and why is Call the Midwife's Dr McNulty so desperate for a dose?|date=23 February 2020|work=Radio Times|access-date=27 February 2021}}</ref>

In [[William Gibson]]'s book ''[[Neuromancer]]'', one of the characters says '"A mixture of cocaine and meperidine, yes." The Armenian went back to the conversation he was having with the Sanyo. "Demerol, they used to call that," said the Finn.'<ref>{{Cite book| vauthors = Gibson W |title=Neuromancer|publisher=Ace|year=1984|isbn=0-441-56956-0|pages=105}}</ref>

South Carolina-based modern rock group [[Crossfade (American band)|Crossfade]] mentions Demerol in the lyrics of their 2004 song, "Dead Skin".

In Korean drama [[Punch (TV series)]], main character Park Jung-hwan is illegally given Demerol by his doctor in exchange for legal counseling.

In the episode "[[The Fight (Parks and Recreation)|The Fight]]" of the TV show ''[[Parks and Recreation]]'', some characters become intoxicated on a mixed drink called Snake Juice. The character Ann (Rashida Jones), who is a nurse, asks, "What the hell is in Snake Juice? Demerol?"

In [[David Foster Wallace]]'s book ''[[Infinite Jest]]'', one of the main characters, Don Gately, is a Demerol addict in recovery.

Demerol was mentioned in the 1988 film starring [[Sean Penn]] " [[Colors]] " by a sargeant walking past a group of cops right after a meeting about gang violence and he says comically, " what I need is a shot of Demerol and some clean sheets"

“Demerol” is mentioned in a 1990 version of the song, [[Pennyroyal Tea]] by [[Nirvana (band)|Nirvana]]. It is implies the painkiller is being used to combat pain caused by “bad posture”. However, this line was not included in the final 1993 version recorded on the [[In Utero]] album.<ref>{{Cite web |title=Pennyroyal Tea |url=https://www.livenirvana.com/songguide/pennyroyal-tea.html |access-date=2025-03-08 |website=www.livenirvana.com}}</ref>

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

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

{{Analgesics}}
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