pethidine

Pethidine is the most widely used opioid in labour and delivery.{{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 }} 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.{{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 }} It is still commonly used in the United Kingdom and New Zealand,{{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= 2015-06-20}} and was the preferred opioid in the United Kingdom for use during labour, but has been superseded somewhat by other strong semi-synthetic opioids (e.g. hydromorphone) to avoid serotonin interactions since the mid-2000s.{{Cite web|title = Pain relief in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}}

Pethidine is the preferred painkiller for diverticulitis, because it decreases intestinal intraluminal pressure.Blueprints - Family Medicine (3rd edition) Pethidine is the preferred drug for the management of shivering during therapeutic hypothermia, as it provides the greatest reduction in the shivering threshold.{{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 }}

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.{{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}}{{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}}

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.{{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 }}{{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 }}

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.{{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 }}{{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 }}

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.{{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 }}

Seizures may develop when tramadol is given intravenously following, or with, pethidine.{{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)}} 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.

{{Main|Opioid}}

Like morphine, pethidine exerts its analgesic effects by acting as an agonist at the μ-opioid receptor.{{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}}

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

Pethidine has structural similarities to atropine and other tropane alkaloids and may have some of their effects and side effects.{{Cite web|url=http://www.fass.se/LIF/produktfakta/artikel_produkt.jsp?NplID=19741206000040&DocTypeID=3&UserTypeID=0|title = Petidin Meda - FASS Vårdpersonal}} 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.{{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 }} 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.{{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 }}

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.{{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 }}{{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 }} It has also been associated with cases of serotonin syndrome, suggesting some interaction with serotonergic neurons, but the relationship has not been definitively demonstrated.{{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}}{{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 }}

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.

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.

File:Pethidine DOJ.jpg

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);{{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}} 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

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.{{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 }} 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.{{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 }}

This article uses the terms "hazardous use", "harmful use", and "dependence" in accordance with Lexicon of alcohol and drug{{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 | Lexicon of alcohol and drug terms published by the World Health Organization|website=WHO}} terms, published by the World Health Organization (WHO) in 1994.{{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 }} In WHO usage, the first two terms replace the term "abuse" and the third term replaces the term "addiction".

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.Patent Appl. DE 679 281 IG Farben 1937.

:File:Pethidine synthesis.PNG{{clear left}}

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).{{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 }} 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.

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. MacDonald'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 (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.{{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}}{{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}}

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.{{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}}

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.{{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}} Pethidine was one of several prescription drugs which 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".{{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 }}

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 becomes addicted to pethidine.{{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}}

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.'{{Cite book| vauthors = Gibson W |title=Neuromancer|publisher=Ace|year=1984|isbn=0-441-56956-0|pages=105}}

South Carolina-based modern rock group Crossfade mentions Demerol in the lyrics of their 2004 song, "Dead Skin".

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

In the episode "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. It is implied 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.{{Cite web |title=Pennyroyal Tea |url=https://www.livenirvana.com/songguide/pennyroyal-tea.html |access-date=2025-03-08 |website=www.livenirvana.com}}

• Libby Zion Law (a case involving phenelzine and pethidine)

{{Reflist|30em}}

{{Analgesics}}

{{Navboxes

| title = Pharmacodynamics

| titlestyle = background:#ccccff

| list1 =

{{Glycine receptor modulators}}

{{Ion channel modulators}}

{{Ionotropic glutamate receptor modulators}}

{{Monoamine reuptake inhibitors}}

{{Muscarinic acetylcholine receptor modulators}}

{{Opioid receptor modulators}}

}}

Category:Analgesics

Category:Convulsants

Category:Ethyl esters

Category:Euphoriants

Category:Glycine receptor antagonists

Category:Kappa-opioid receptor agonists

Category:Local anesthetics

Category:Mu-opioid receptor agonists

Category:Muscarinic antagonists

Category:NMDA receptor antagonists

Category:4-Phenylpiperidines

Category:Serotonin–norepinephrine–dopamine reuptake inhibitors

Category:Sodium channel blockers

Category:Synthetic opioids

Category:German inventions of the Nazi period

Category:1938 in science

Category:1938 in Germany