Pethidine

Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a synthetic opioid pain medication of the phenylpiperidine class.[3][4][5][6][7][8] Synthesized in 1938[9] 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, Germany.[10] Pethidine is the prototype of a large family of analgesics including the pethidine 4-phenylpiperidines (piminodine, anileridine and others), the prodines (alphaprodine, MPPP, etc.), bemidones (ketobemidone, etc.) and others more distant, including diphenoxylate and analogues.[11]

This article is about the analgesic drug also sold under the trade name Dolantin. For the anticonvulsant sold under the trade name Dilantin, see phenytoin.
Pethidine
Clinical data
Trade namesDemerol
Other namesMeperidine (USAN US)
Pregnancy
category
  • AU: C
Dependence
liability		High
Routes of
administration		By mouth, IV, IM, IT,[1] SC, epidural[2]
ATC code
Legal status
Legal status
  • AU: S8 (Controlled drug)
  • CA: Schedule I
  • DE: Anlage III (Special prescription form required)
  • NZ: Class B
  • UK: Class A
  • US: Schedule II
  • UN: Narcotic Schedule I
Pharmacokinetic data
Bioavailability50–60% (Oral), 80–90% (Oral, in cases of hepatic impairment)
Protein binding65–75%
MetabolismLiver
Elimination half-life2.5–4 hours, 7–11 hours (liver disease)
ExcretionRenal
Identifiers
IUPAC name
  • Ethyl 1-methyl-4-phenylpiperidine-4-carboxylate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.299
Chemical and physical data
FormulaC15H21NO2
Molar mass247.338 g·mol−1
3D model (JSmol)
  • O=C(C1(CCN(CC1)C)C2=CC=CC=C2)OCC
  • InChI=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 Y
  • Key:XADCESSVHJOZHK-UHFFFAOYSA-N Y
  (verify)

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.[12]

It was patented in 1937 and approved for medical use in 1943.[13] Compared with morphine, pethidine was thought 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 putative anticholinergic effects.[5] 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, and due to its toxic metabolite, norpethidine, it is more toxic than other opioids—especially during long-term use.[5] The norpethidine metabolite was found to have serotonergic effects, so pethidine could, unlike most opioids, contribute to serotonin syndrome.[5][6]

Medical uses

Pethidine is the most widely used opioid in labour and delivery[14] but 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.[8] It is still commonly used in the United Kingdom and New Zealand,[15] and was the preferred opioid in the United Kingdom for use during labour, but has been superseded somewhat by diamorphine and other strong semi-synthetic opioids (e.g. hydromorphone) to avoid serotonin interactions since the mid-2000s.[16] Pethidine is the preferred painkiller for diverticulitis, because it decreases intestinal intraluminal pressure.[17]

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.[18][19]

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 dopamine and norepinephrine, 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. 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.[20][21]

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.[22] Seizures may develop when tramadol is given intravenously following, or with, pethidine.[23] 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 article: Opioid

Like morphine, pethidine exerts its analgesic effects by acting as an agonist at the μ-opioid receptor.[24]

Pethidine is often employed in the treatment of postanesthetic shivering. The pharmacologic mechanism of this antishivering effect is not fully understood,[25] but it may involve the stimulation of κ-opioid receptors.[26]

Pethidine has structural similarities to atropine and other tropane alkaloids and may have some of their effects and side effects.[27] 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.[28] Pethidine also has stimulant effects mediated by its inhibition of the dopamine transporter (DAT) and norepinephrine transporter (NET). Because of its DAT inhibitory action, pethidine will substitute for cocaine in animals trained to discriminate cocaine from saline.[29]

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.[30][31] It has also been associated with cases of serotonin syndrome, suggesting some interaction with serotonergic neurons, but the relationship has not been definitively demonstrated.[29][31][32][33]

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.[29][31][33]

Like other opioid drugs, pethidine has the potential to cause physical dependence or addiction. It may be more likely to be abused than other prescription opioids, perhaps because of its rapid onset of action.[34] A study which compared 75 mg pethidine administered via intravenous injection (IV) and 100 mg administered orally (PO) to 10 mg oxycodone (IV) and 10 mg (PO), 10 mg morphine (IV) and 20 mg (PO), 2 mg hydromorphone (IV) and 4 mg (PO), and placebo (C) in the subject's self-reported subjective effects such as 'drug-liking' (how many of the subjects enjoyed or not, the experience; if yes, what was the most enjoyable part and why?, etc.) and how eagerly did subject 'want to re-experience it', and after IV doses were administered, pethidine 75 mg second-highest rates of 'drug-liking', after morphine 10 mg. Descriptive adjectives for morphine by subjects were: “more sedating”, “more relaxing” and in comparison to the others, many subjects described that the experience was “more intense”. Pethidine followed, then hydromorphone, oxycodone and last was placebo. Upon oral administration, preference went from (greatest>least): oxycodone 10 mg>morphine 20 mg>hydromorphone 4 mg>pethidine 100 mg>placebo.[35] 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.[31][33]

Pharmacokinetics

Pethidine is quickly hydrolysed in the liver to pethidinic acid and is also demethylated to norpethidine, which has half the analgesic activity of pethidine but a longer elimination half-life (8–12 hours);[36] 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.

Recreational use

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.[37] 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.[38]

This article uses the terms "hazardous use", "harmful use", and "dependence" in accordance with Lexicon of alcohol and drug[39] terms, published by the World Health Organization (WHO) in 1994.[40] In WHO usage, the first two terms replace the term "abuse" and the third term replaces the term "addiction".[40][29]

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.[41]

Pethidine synthesis

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).[42] 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

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 once got addicted to pethidine.[43][44]

Danish writer Tove Ditlevsen suffered a lifelong addiction to pethidine since her husband, a dodgy doctor, had injected her a dose as a painkiller.[45]

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.[46] 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".[47]

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 injects pethidine in himself and gets addicted to it.

A doctor in the TV show Call the Midwife becomes addicted to pethidine.[48]

In William Gibson's book Neuromancer, one of the characters say '"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.'[49]

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

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.

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

References
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