This article is about the analgesic drug also sold under the trade name Dolantin. For the anticonvulsant sold under the trade name Dilantin, seephenytoin.
Pethidine, also known asmeperidine and sold under the brand nameDemerol among others, is a fully syntheticopioidpain medication of thephenylpiperidine class.[5][6][7][8][9][10] Synthesized in 1938[11] as a potentialanticholinergic agent by the German chemist Otto Eisleb, its analgesic properties were first recognized by Otto Schaumann while working forIG Farben, in Germany.[12] 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, includingdiphenoxylate and analogues.[13]
Pethidine is indicated for the treatment of moderate to severe pain, and is delivered as ahydrochloride salt in tablets, as a syrup, or byintramuscular,subcutaneous, orintravenous 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.[14]
It was patented in 1937 and approved for medical use in 1943.[15] Compared withmorphine, pethidine was considered to be safer, carry a lower risk of addiction, and to be superior in treating the pain associated withbiliary spasm orrenal colic due to its assumedanticholinergic effects.[7] 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 theneurotoxicity of its metabolite,norpethidine, it is more toxic than other opioids—especially during long-term use.[7] The norpethidine metabolite was found to haveserotonergic effects, so pethidine could, unlike most opioids, increase the risk of triggeringserotonin syndrome.[7][8]
Pethidine is the most widely used opioid in labour and delivery.[16] 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.[10] It is still commonly used in the United Kingdom and New Zealand,[17] and was the preferred opioid in the United Kingdom for use during labour, but has been superseded somewhat by other strong semi-synthetic opioids (e.g.hydromorphone) to avoid serotonin interactions since the mid-2000s.[18]
Pethidine is the preferred painkiller fordiverticulitis, because it decreases intestinal intraluminal pressure.[19] Pethidine is the preferred drug for the management of shivering duringtherapeutic hypothermia, as it provides the greatest reduction in the shivering threshold.[20]
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 causemiosis because of its anticholinergic properties. Overdose can cause muscle flaccidity, respiratory depression,obtundation,psychosis, cold and clammy skin, hypotension, and coma.[23][24]
A narcotic antagonist such asnaloxone is indicated to reverse respiratory depression and other effects of pethidine.Serotonin syndrome has occurred in patients receiving concurrent antidepressant therapy withselective serotonin reuptake inhibitors (SSRIs) ormonoamine 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.[25][26]
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/orhyperthermia. Fatal interactions have been reported including the death ofLibby Zion.[27]
Seizures may develop whentramadol is given intravenously following, or with, pethidine.[28] It can interact as well withSSRIs and otherantidepressants, antiparkinson agents, migraine therapy,stimulants and other agents causingserotonin 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, andethanol.
Pethidine is often employed in the treatment of postanesthetic shivering. The pharmacologic mechanism of this antishivering effect is not fully understood,[30] but it may involve the stimulation ofκ-opioid receptors.[31]
Pethidine has structural similarities toatropine and othertropane alkaloids and may have some of their effects and side effects.[32] In addition to these opioidergic and anticholinergic effects, it haslocal anesthetic activity related to its interactions withsodium ion channels.
Pethidine's apparentin vitro efficacy as an antispasmodic agent is due to its local anesthetic effects. It does not have antispasmodic effectsin vivo.[33] Pethidine also has stimulant effects mediated by its inhibition of thedopamine transporter (DAT) andnorepinephrine 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.[34]
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, orhydromorphone at easing severe pain, or pain associated with movement or coughing.[34][36][38]
Like other opioid drugs, pethidine has the potential to causephysical dependence oraddiction. 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.[36][38]
Pethidine is quickly hydrolysed in the liver topethidinic acid and is also demethylated to norpethidine, which has half the analgesic activity of pethidine but a longer elimination half-life (8–12 hours);[39] accumulating with regular administration, or inkidney 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 withglucuronic acid and excreted into the urine.
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 forfentanyl, hydromorphone, morphine, and oxycodone.[40] 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.[41]
The terms "hazardous use", "harmful use", and "dependence" are used in accordance with theLexicon of alcohol and drug terms,[42] published by theWorld Health Organization (WHO) in 1994.[43] In WHO usage, the first two terms replace the term "abuse" and the third term replaces the term "addiction".[43][34]
Pethidine is inSchedule 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 Cintermediates in production of pethidine are also controlled, with ACSCN being9232 for A (with a 6 gram quota) and9233 being B (quota of 11 grams) and9234 being C (6 gram quota).[45] 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.
InJohn D. MacDonald's bookDress 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.
InRaymond Chandler's novelThe 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.[46][47]
Danish writerTove 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.[48]
Pethidine is referenced by its brand name Demerol in the song "Morphine" by singerMichael Jackson on his 1997 albumBlood on the Dance Floor: HIStory in the Mix.[49] 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".[50]
Pethidine is referenced in the television showBroadchurch, season 2, episode 3, as it was given to the character Beth after she has her baby.
In the 1987Malayalam movie,Amrutham Gamaya,Mohanlal's character, Dr. P.K. Haridas self-injects pethidine and gets addicted to it.
InWilliam Gibson's bookNeuromancer, 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.'[52]
South Carolina-based modern rock groupCrossfade mentions Demerol in the lyrics of their 2004 song, "Dead Skin".
In Korean dramaPunch, 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 showParks 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?"
Demerol was mentioned in the 1988 film starringSean PennColors 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" byNirvana. 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 theIn Utero album.[53]
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