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Pethidine
Pethidine
Pethidine
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Pethidine
Clinical data
Trade namesDemerol, others
Other namesMeperidine (USAN US)
Pregnancy
category
  • AU: C
Dependence
liability		High
Addiction
liability		High[1]
Routes of
administration		By mouth, intravenous, intramuscular, intrathecal,[2] subcutaneous, epidural[3]
Drug classOpioid
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability50–60% (Oral), 80–90% (Oral, in cases of hepatic impairment)
Protein binding65–75%
MetabolismLiver: CYP2B6, CYP3A4, CYP2C19, Carboxylesterase 1
Metabolites• Norpethidine
• Pethidinic Acid
• others
Elimination half-life2.5–4 hours, 7–11 hours (liver disease)
ExcretionRenal
Identifiers
  • 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 Edit this at Wikidata
Chemical and physical data
FormulaC15H21NO2
Molar mass247.338 g·mol−1
3D model (JSmol)
  • CCOC(=O)C1(c2ccccc2)CCN(C)CC1
  • 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 checkY
  • Key:XADCESSVHJOZHK-UHFFFAOYSA-N checkY
  (verify)

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.[5][6][7][8][9][10] Synthesized in 1938[11] 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.[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, including diphenoxylate and analogues.[13]

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.[14]

It was patented in 1937 and approved for medical use in 1943.[15] 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.[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 the neurotoxicity of its metabolite, norpethidine, it is more toxic than other opioids—especially during long-term use.[7] The norpethidine metabolite was found to have serotonergic effects, so pethidine could, unlike most opioids, increase the risk of triggering serotonin syndrome.[7][8]

Medical uses

[edit]

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 for diverticulitis, because it decreases intestinal intraluminal pressure.[19] Pethidine is the preferred drug for the management of shivering during therapeutic hypothermia, as it provides the greatest reduction in the shivering threshold.[20]

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.[21][22]

Adverse effects

[edit]

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.[23][24]

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.[25][26]

Interactions

[edit]

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.[27]

Seizures may develop when tramadol is given intravenously following, or with, pethidine.[28] 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

[edit]
Main article: Opioid

Like morphine, pethidine exerts its analgesic effects by acting as an agonist at the μ-opioid receptor.[29]

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 of κ-opioid receptors.[31]

Pethidine has structural similarities to atropine and other tropane alkaloids and may have some of their effects and side effects.[32] 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.[33] 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.[34]

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.[35][36] It has also been associated with cases of serotonin syndrome, suggesting some interaction with serotonergic neurons, but the relationship has not been definitively demonstrated.[34][36][37][38]

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.[34][36][38]

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.[36][38]

Pharmacokinetics

[edit]

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);[39] 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

[edit]
[edit]

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.[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 the Lexicon of alcohol and drug terms,[42] published by the World 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]

Synthesis

[edit]

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.[44]

Pethidine synthesis

Control

[edit]

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).[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.

Society and culture

[edit]

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.[46][47]

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.[48]

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.[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 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.[51]

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.'[52]

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.[53]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Pethidine

View on Grokipedia
from Grokipedia
Pethidine, also known as meperidine and marketed under the brand name Demerol, is a synthetic belonging to the phenylpiperidine class, primarily indicated for the relief of moderate to severe acute when alternative treatments are inadequate. It exerts its effects through agonism at μ- receptors in the , providing , , and antitussive properties, while also exhibiting , , and local anesthetic activities via blockade. As a Schedule II controlled substance under the U.S. , pethidine carries a high potential for , , and overdose, necessitating careful monitoring and limited use. Developed in in the late initially for its effects, pethidine's potent properties were soon recognized, leading to its widespread adoption in the mid-20th century as an alternative to for perioperative and postoperative . It is available in oral, intramuscular, subcutaneous, and intravenous formulations, with typical adult dosing ranging from 50 to 150 mg every 3 to 4 hours, not exceeding 600 mg per day to minimize toxicity risks. Pharmacokinetically, pethidine has an oral of approximately 50%, a of 3 to 8 hours, and is metabolized primarily by and enzymes in the liver to its normeperidine, which has a longer of about 15 to 30 hours and is excreted renally. Off-label uses include the treatment of postoperative due to its κ-opioid receptor activity and as an adjunct in labor analgesia, though evidence supports or other opioids as superior alternatives in many cases. Despite its efficacy, pethidine's clinical utility has declined due to significant adverse effects, including respiratory depression, , , , and pruritus, which occur at rates comparable to or higher than other . A major concern is from normeperidine accumulation, particularly in patients with renal impairment, leading to seizures, , and ; this risk prompted its removal from the World Health Organization's List of in 2003 and restrictions in many guidelines against its use for or in the elderly. Contraindications include , acute , gastrointestinal obstruction, and concurrent use of inhibitors (MAOIs) within 14 days, due to the potential for severe or . In overdose, symptoms such as , , and are managed with , supportive ventilation, and, in cases of normeperidine toxicity, . Overall, while pethidine remains available for short-term acute pain relief in controlled settings, safer opioid alternatives are preferred in contemporary practice to mitigate its unique toxicity profile.

Medical Uses

Pain Relief Applications

Pethidine, a synthetic , is primarily indicated for the management of moderate to severe acute , including postoperative following surgical procedures, labor during , and associated with traumatic injuries. It provides effective relief by acting on mu-opioid receptors in the , offering an alternative when non-opioid analgesics are insufficient. Clinical guidelines recommend its use in settings requiring short-term analgesia, such as emergency departments or recovery rooms, where rapid onset is beneficial. Pethidine can be administered via multiple routes to suit clinical needs, including intramuscular (IM), intravenous (IV), subcutaneous (SC), and oral, with IM and IV being the most common for acute pain scenarios due to faster absorption. For adults, the typical dosing regimen is 50-150 mg every 3-4 hours as needed, adjusted based on pain severity, patient response, and renal function to avoid accumulation of its metabolite normeperidine. Lower doses, such as 25-50 mg IV, may be used initially in elderly or debilitated patients to minimize risks. Historically, pethidine has been a preferred agent for labor analgesia in countries like the and , where intramuscular administration is routinely offered in over 95% of surveyed hospitals for intrapartum relief. Studies indicate that pethidine provides comparable short-term reduction to during labor, though women report lower satisfaction with analgesia three days postpartum when using pethidine compared to (relative risk 0.87, 95% CI 0.78-0.98). This preference stems from its rapid onset and perceived lower risk of respiratory depression in neonates at standard doses, despite concerns over fetal . Historically, pethidine was favored for in due to its properties, which help reduce intestinal intraluminal pressure and alleviate bowel s associated with colonic inflammation. Early clinical recommendations highlighted its dual and spasmolytic effects, making it suitable for acute exacerbations where hypermotility exacerbates discomfort. However, contemporary guidelines do not preferentially recommend pethidine over other opioids, as evidence indicates no significant risk of with alternatives like . This application leverages pethidine's ability to relax , providing targeted relief without solely relying on opioid-mediated analgesia.

Other Therapeutic Indications

Pethidine is employed to prevent and treat during therapeutic after , as it effectively depresses the shivering threshold through stimulation of kappa-opioid receptors. Among opioids, it demonstrates superior , reducing the shivering threshold nearly twice as much as the vasoconstriction threshold, making it a key agent in protocols. In labor and delivery, pethidine functions as an adjunct , particularly in regions where epidural access is limited, helping to alleviate pain and provide sedation that may reduce maternal anxiety while augmenting other forms of analgesia. Low doses (up to 50 mg intramuscularly or intravenously) are associated with minimal neonatal respiratory depression or low Apgar scores, though higher doses can lead to infant respiratory issues and decreased alertness; it remains favored in parts of , , and due to its low cost and ease of administration. Pethidine has limited veterinary applications for in animals, primarily due to its short duration of action and potential for adverse effects like excitation. In species such as horses, a dose of 0.5 mg/kg intravenously may offer brief analgesia for up to 45 minutes, but higher doses (1.0 mg/kg) are not recommended owing to inconsistent efficacy and side effects; dosing must be adjusted based on species, with lower ranges (e.g., 2-10 mg/kg intramuscularly or subcutaneously in dogs and cats) used cautiously where longer-acting opioids are unavailable. Pethidine was removed from the World Health Organization's Model List of Essential Medicines in 2003 because of its inferior safety profile compared to alternatives like , primarily due to the neurotoxic normeperidine that risks seizures and . As of 2025, it is not included on the list and is not recommended for routine use, with safer opioids preferred globally.

Pharmacology

Mechanism of Action

Pethidine, also known as meperidine, primarily exerts its analgesic effects by acting as an at the μ-opioid receptors in the , where it binds to these G-protein-coupled receptors to inhibit the release of neurotransmitters involved in pain transmission, such as and glutamate, thereby reducing the perception of pain. This μ-opioid receptor activation mimics the action of endogenous opioids like , leading to hyperpolarization of neurons through decreased cyclic AMP levels and increased conductance. In addition to its opioid activity, pethidine exhibits effects by antagonizing muscarinic receptors, which contributes to relaxation in the gastrointestinal and respiratory tracts, potentially aiding in the relief of associated spasms or secretions. It also possesses local anesthetic properties through blockade of voltage-gated sodium channels, preventing the propagation of action potentials in fibers, a mechanism shared with other phenylpiperidine derivatives like . Pethidine demonstrates some at κ-opioid receptors, which is thought to underlie its antishivering effects by modulating thermoregulatory pathways in the , distinct from its primary μ-mediated analgesia. Its activity at δ-opioid receptors is weaker and contributes minimally to its overall pharmacological profile. Uniquely among opioids, pethidine inhibits the reuptake of serotonin by blocking the (SERT), thereby increasing synaptic serotonin levels, which can enhance analgesia but also predisposes to risks such as when combined with other serotonergic agents. Its , norpethidine, further amplifies serotonergic effects.

Pharmacokinetics

Pethidine exhibits rapid absorption following , with a of 50-60% in individuals with normal hepatic function, reaching peak plasma concentrations within 1-2 hours. Intravenous administration provides an immediate , with peak effects occurring within minutes. The drug is moderately bound to plasma proteins at approximately 65-75%, primarily to and α1-acid , and distributes widely throughout the body with a of 3-4 L/kg. The elimination of pethidine itself ranges from 3-5 hours in healthy adults. Pethidine is primarily metabolized in the liver through N-demethylation to the norpethidine, catalyzed mainly by the enzymes , , and to a lesser extent ; norpethidine has an elimination half-life of approximately 15 to 30 hours and possesses neurotoxic properties at higher concentrations. Excretion occurs predominantly via the kidneys, with only about 5% of the parent drug eliminated unchanged and the majority as metabolites; renal impairment can lead to accumulation of norpethidine, increasing the risk of toxicity. Pharmacokinetic parameters are influenced by several factors, including age—where elimination is slower in the elderly due to increased and higher free fraction—hepatic function, which in cases of impairment like raises bioavailability to 80-90% and extends the , and repeated dosing, which promotes norpethidine accumulation due to its longer .

Adverse Effects

Common Side Effects

Pethidine, an analgesic, frequently induces gastrointestinal side effects primarily through its inhibition of gastrointestinal motility. and are among the most common, occurring in approximately 22% of patients in clinical settings. is also prevalent due to the same opioid-mediated reduction in gut . effects are similarly frequent, arising from pethidine's activation of opioid receptors as well as its activity. These include , , and , which can impair alertness and coordination. Dry mouth, another manifestation, affects many users and contributes to discomfort during treatment. Additional common reactions encompass sweating, urinary retention, and pruritus (itching), which are generally mild and transient. Sweating and pruritus occur as frequent autonomic responses to opioid administration, while urinary retention results from opioid effects on bladder function. In specific contexts, such as spinal anesthesia, pruritus has been noted in up to 20% of cases. Management of these side effects focuses on symptomatic relief and preventive measures. Antiemetics, such as metoclopramide or , are often employed to alleviate and vomiting. For , laxatives or stool softeners are recommended to promote bowel regularity. Patients experiencing or should rise slowly from sitting or lying positions to minimize fall risk, and adequate hydration can help mitigate dry mouth.

Serious Adverse Reactions

Overdose of pethidine can lead to severe respiratory depression, , and progression to , circulatory collapse, , apnea, and potentially death. These effects stem from the opioid's potent mu-receptor agonism, which suppresses central respiratory drive and cardiovascular function at high doses. Prolonged use of pethidine risks neuroexcitation due to accumulation of its metabolite normeperidine, which can cause seizures, , tremors, , and hallucinations. This toxicity arises particularly after repeated dosing, as normeperidine exhibits properties distinct from the parent drug's analgesia. Pethidine also inhibits , increasing the risk of , characterized by , muscle rigidity, autonomic instability, and seizures, especially when combined with other serotonergic agents. In elderly patients or those with renal impairment, pethidine and normeperidine accumulate due to reduced clearance, heightening the risk of and other adverse events. These concerns contributed to a decline in pethidine use over the late , as safer alternatives gained preference amid recognition of its unfavorable risk-benefit profile. Maternal administration during labor can cross the , causing neonatal respiratory depression, low Apgar scores, and in the newborn. As of 2025, regulatory warnings emphasize pethidine's potential for , misuse, and , akin to other opioids, with risks of overdose and ; it carries a for these hazards and is recommended only when benefits outweigh dangers.

Drug Interactions

Interactions with Other Drugs

Pethidine, also known as meperidine, exhibits significant pharmacodynamic and pharmacokinetic interactions with various classes of drugs, potentially leading to enhanced or reduced . One of the most critical interactions occurs with inhibitors (MAOIs), such as and tranylcypromine. Concomitant administration or use within 14 days of discontinuing an MAOI can precipitate a severe excitatory reaction characterized by hyperpyrexia, convulsions, , severe respiratory depression, , and . This interaction is contraindicated due to its life-threatening nature, as exemplified by the 1984 Libby Zion case, where an 18-year-old patient on developed fatal following intramuscular pethidine administration for chills. Pethidine also increases the risk of when combined with serotonergic agents, owing to its metabolite normeperidine's weak inhibition of . This manifests as agitation, , tremors, and potentially seizures or . Specific examples include selective inhibitors (SSRIs) like , inhibitors (SNRIs) such as , and other agents like , which can synergistically elevate serotonin levels. Clinicians must monitor for symptoms and discontinue therapy if is suspected, as the interaction can be fatal in severe cases. Interactions with central nervous system (CNS) depressants further compound pethidine's risks by potentiating sedation and respiratory depression. Drugs such as benzodiazepines (e.g., diazepam), other opioids, and alcohol amplify these effects, potentially leading to profound sedation, coma, or death. To mitigate this, concurrent use should be limited to the lowest effective doses and durations, with close patient monitoring for signs of respiratory compromise. Pharmacokinetically, pethidine is metabolized primarily by , making it susceptible to interactions with inhibitors of this enzyme. Agents like or erythromycin can reduce pethidine clearance, elevating plasma levels and increasing the risk of toxicity, including fatal respiratory depression or overdose. Conversely, CYP3A4 inducers such as rifampin may decrease pethidine concentrations, potentially leading to reduced analgesia or withdrawal symptoms upon discontinuation of the inducer. Dosage adjustments and vigilant monitoring are essential in these scenarios to prevent adverse outcomes.

Contraindications and Precautions

Pethidine is contraindicated in patients with known to the drug or any of its components, as this may lead to severe allergic reactions including . It is also absolutely contraindicated in individuals with significant respiratory depression, due to the risk of life-threatening exacerbation. Acute or severe bronchial in an unmonitored setting or without access to resuscitative equipment represents another contraindication, as pethidine can worsen respiratory compromise. Additionally, known or suspected gastrointestinal obstruction, including paralytic , prohibits its use, given the potential for delayed gastric emptying and further obstruction. Caution is advised in patients with renal or hepatic impairment, where the normeperidine can accumulate, increasing the risk of such as seizures and ; dosage should be titrated slowly with close monitoring. Elderly patients exhibit heightened sensitivity to pethidine's effects, including respiratory depression and , necessitating initiation at the lowest effective dose and vigilant observation. In , potential risks to the exist; it should be avoided during the third trimester and labor to prevent neonatal opioid withdrawal syndrome (NOWS) and prolonged normeperidine exposure in the newborn. Monitoring of , including and level, is essential during pethidine administration to detect early signs of depression or overdose. Particular attention to risk is required in patients with , where normeperidine accumulation may precipitate convulsions even with normal renal function. For breastfeeding individuals, pethidine and its metabolite are excreted into , potentially causing infant and respiratory depression; monitoring of the infant for drowsiness and feeding difficulties is recommended, with use limited to short durations if necessary. As of 2025, the FDA has issued a warning for pethidine highlighting its high potential for , , and misuse, which can result in overdose and death; healthcare providers must assess patients for risk prior to prescribing.

Non-Medical and Recreational Use

Patterns of Abuse

Non-medical use of pethidine is primarily driven by its euphoric and effects, which stem from its inhibition of and norepinephrine transporters, producing a rapid sense of pleasure and relaxation similar to cocaine-like mechanisms. Users often seek these effects to alleviate stress, , or emotional distress, leading to diversion from medical supplies such as hospital stocks or personal prescriptions. Injection of oral formulations, including crushed tablets or syrups, is a common method to enhance these effects, despite risks of vascular damage and emboli. Historical patterns of abuse are particularly prevalent among healthcare workers, such as nurses and midwives, who self-administer pethidine due to easy access in clinical settings. For instance, cases document escalation from legitimate postoperative use to frequent self-injection, often procuring vials through professional channels for personal use at work or home. Although pethidine has lower potency than —requiring higher doses for comparable effects—its availability in medical environments facilitates misuse over street drugs. Pethidine carries a high potential, classified as a Schedule II due to risks of rapid tolerance development from its short duration of action, necessitating escalating doses for sustained effects. Withdrawal symptoms upon cessation include anxiety, , , and restlessness, mirroring general dependence syndromes. As of 2025, reviews highlight ongoing misuse challenges, including difficulties in distinguishing therapeutic intent from abuse in healthcare contexts. Common routes for non-medical use include intravenous administration for a rapid, intense high, often via diverted injectable forms or modified oral preparations, while oral ingestion provides milder sedative effects over longer periods. is frequently associated with polydrug use, where pethidine is combined with other substances like benzodiazepines or alcohol to potentiate or mitigate withdrawal. In the United States, pethidine (also known as meperidine) was a commonly prescribed and abused during the , but recreational use declined sharply by the primarily due to growing awareness of its , including neurotoxic effects from its normeperidine, which can cause seizures and . Data from the Drug Abuse Warning Network (DAWN) indicated a 39% decrease in mentions of meperidine abuse from 1,335 in 1990 to 806 in 1996, reflecting reduced overall abuse reports relative to other drugs. This downward trend persisted into the late 1990s and early , with DAWN reports from 1997 to 2002 showing continued low and stable mentions amid rising abuse of other like . Diversion of pethidine remained relatively low compared to other , but reported thefts and losses in the increased by 16.2% between 2000 and 2003, rising from 32,447 dosage units to 37,687, primarily from pharmacies. Globally, patterns of vary by region, with higher risks in areas of continued widespread and less stringent controls, where opioid consumption remains elevated compared to Western countries. Demographically, pethidine abuse is disproportionately common among medical professionals, including physicians and nurses, who have greater access to the ; for instance, 65% of 280 pethidine-dependent individuals admitted to a were healthcare workers. This pattern holds internationally, with often linked to occupational exposure rather than broad recreational seeking. As of 2025, pethidine continues to raise concerns within the broader crisis, particularly due to challenges in distinguishing legitimate therapeutic use from misuse, especially in healthcare settings where hundreds of cases have been reported in regions like . Recent data indicate no major resurgence in recreational use, and it remains under monitoring by authorities as part of efforts to address diversion and .

Chemistry and Production

Chemical Structure and Properties

Pethidine, chemically known as meperidine, possesses the molecular formula C15H21NO2C_{15}H_{21}NO_{2}. Its systematic IUPAC name is ethyl 1-methyl-4-phenylpiperidine-4-carboxylate. As a member of the phenylpiperidine class of compounds, pethidine features a central piperidine ring substituted at the 1-position with a methyl group, and at the 4-position with both a phenyl ring and an ethoxycarbonyl ester group; this ester moiety is essential for conferring its characteristic opioid receptor affinity and analgesic properties. Unlike naturally derived opioid alkaloids such as morphine, which originate from opium poppy extracts, pethidine is entirely synthetic in origin, marking it as one of the first fully artificial opioids developed for clinical use. In its form, pethidine appears as a white crystalline powder with a of 270 °C. The compound exhibits moderate in (approximately 6 g/L at 25 °C) due to its lipophilic nature (logP ≈ 2.7), though the salt form—commonly used in pharmaceutical preparations—is freely soluble in aqueous media. The pKa of the salt is 8.7, reflecting the weakly basic character of the nitrogen, which influences its ionization and profile at physiological pH. Pethidine demonstrates certain stability challenges in solution, particularly in intravenous admixtures, where degradation can occur over time depending on storage conditions such as , light exposure, and diluent composition; studies indicate that concentrated solutions may require to maintain potency beyond short-term use.

Synthesis Methods

Pethidine was first synthesized in 1937 by German chemist Otto Eisleb at the laboratories of IG Farbenindustrie as part of efforts to develop agents. The original synthesis involved condensation of with β,β'-dichloroethyl ether in the presence of , followed by ring opening with halogen acid, treatment with for ring closure, to the , and esterification with using to yield ethyl 1-methyl-4-phenylpiperidine-4-carboxylate (pethidine). A simplified variant condenses directly with bis(2-chloroethyl)methylamine to form the key intermediate 1-methyl-4-cyano-4-phenylpiperidine, followed by and esterification. This method was patented by IG Farbenindustrie under German Patent 679,281 in 1937 and corresponding US Patent No. 2,242,575 in 1941, enabling scalable pharmaceutical production due to the availability of starting materials and straightforward reaction conditions. Modern industrial synthesis largely follows variations of Eisleb's approach to improve yield and safety, such as the 1944 method by Bergel et al., which utilizes β-chloroethyl vinyl ether and , followed by acid , treatment with to form the acid chloride, reaction with for ring closure, , and final esterification. Another variant, developed by Miescher and Kaegi in 1949 (US Patent No. 2,486,793), begins with α-phenyl-γ-(methyl-benzylamino) and ethylene dibromide using acid-binding agents, followed by heating to cyclize, , and esterification; this route offers flexibility for large-scale operations by avoiding certain hazardous intermediates. These processes prioritize efficiency and precursor accessibility while maintaining high purity for medicinal use. Illicit synthesis of pethidine presents significant challenges due to the need for controlled or hazardous precursors, such as bis(2-chloroethyl)methylamine, a potent vesicant that risks severe skin and respiratory damage to handlers without proper equipment. Intermediates like normeperidine (1-phenyl-4-carbethoxypiperidine) or the 4-cyano-4-phenylpiperidine nitrile are also regulated under international conventions, complicating clandestine production and often resulting in low yields or impure product unsuitable for distribution.

International Controls

Pethidine, also known as meperidine, is classified under Schedule I of the 1961 , subjecting it to the most stringent international controls on production, manufacture, distribution, and use, limited exclusively to medical and scientific purposes. The (INCB) oversees global compliance and establishes annual manufacturing quotas to balance legitimate needs with diversion prevention; for instance, the global quota for pethidine was set at 7,500 kg in 2014, with continued declines in subsequent years, including reduced consumption as of 2023. The (WHO) removed pethidine from its Model List of in 2003, citing its inferior safety and efficacy compared to alternatives like , particularly due to risks of from metabolite accumulation. As of 2025, WHO continues to monitor pethidine within the broader context of the , promoting rational prescribing practices and strategies to minimize misuse, dependence, and overdose risks associated with all opioids. Under the 1961 Convention, international export and import of pethidine require separate authorizations from competent national authorities for each shipment, including import certificates from the receiving country and verification of medical necessity to prevent illicit trafficking. Additionally, the 1988 Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances controls precursor chemicals essential to pethidine synthesis, such as , listed in Table II, mandating record-keeping, licensing, and reporting for their international trade. These treaties establish a harmonized global framework, though parties may adopt stricter controls in response to pethidine's abuse potential, including its euphoric effects and risk of dependence akin to other synthetic opioids.

National and Regional Regulations

, pethidine (also known as meperidine) is classified as a Schedule II controlled substance under the , indicating a high potential for with accepted medical use under strict regulation. It is available only by prescription, with the (DEA) imposing quotas on its production to limit supply; for instance, the aggregate production quota decreased by 91.6% from 10,168 kg in 2001 to 856.7 kg in 2020, with further reductions to 30 kg proposed for 2025, reflecting a broader decline in clinical use. is monitored through the DEA's monitoring programs and reporting requirements for manufacturers and prescribers. In the United Kingdom, pethidine is designated as a Class A drug under the Misuse of Drugs Act 1971, subjecting it to the strictest controls on possession, supply, and production due to its potential for harm. Within the National Health Service (NHS), its use for labor pain relief is restricted, as National Institute for Health and Care Excellence (NICE) guidelines highlight limited efficacy and potential adverse effects on mother and baby, favoring safer alternatives like epidurals or remifentanil. In , pethidine is categorized as a Schedule 8 controlled drug under the Poisons Standard, requiring special authorization for prescribing and dispensing to prevent misuse, with availability limited to acute in settings. Its use has declined significantly due to concerns over and inferior compared to alternatives like , though it remains accessible for short-term relief. Similarly, in , pethidine is a Class B3 controlled drug, with prescriptions monitored through real-time reporting systems and declining utilization for acute pain amid preferences for other opioids. As of 2025, the has implemented enhanced monitoring and reporting mechanisms for opioids like pethidine to curb diversion, including mandatory electronic prescription systems and annual consumption data submissions to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), aligning with broader efforts to address opioid-related harms. In some Asian countries, such as and , pethidine is subject to strict controls as a Category 2 in (as updated in 2025) and monitored clinical use in due to high abuse potential and associated health risks, with guidelines limiting its availability to specialized settings.

History and Societal Impact

Development and Early Use

Pethidine, also known as meperidine, was developed in the late 1930s by German chemist Otto Eisleb at the IG Farben laboratories in Frankfurt as a potential anticholinergic agent intended as a synthetic alternative to morphine. Its analgesic properties were soon identified by pharmacologist Otto Schaumann, leading to a German patent in 1937 (DE 659943) and synthesis of the compound in 1938. This marked pethidine as the first fully synthetic opioid, distinct from natural opium derivatives, and it was initially pursued for its promise of effective pain relief with reduced side effects compared to morphine. The drug entered medical use in in 1939, with early applications in noted by 1940. In the United States, it received approval from the in 1942 under the trade name Demerol for the management of moderate to severe , marketed as a safer option with lower potential and fewer respiratory effects than . Initial adoption focused on surgical and postoperative settings, where its rapid onset and shorter duration of action were advantageous. Pethidine reached peak popularity from the through the , becoming the preferred for labor analgesia and routine surgical pain control due to its versatility and perceived safety profile. However, recognition of risks associated with its metabolite norpethidine, which can accumulate and cause including seizures, led to a decline in use as safer alternatives like gained favor. Key milestones include its initial inclusion on the Health Organization's Model List of in the , followed by removal in 2003 due to inferior efficacy and toxicity compared to other s. As of 2025, pethidine's legacy endures as the pioneering synthetic that paved the way for subsequent phenylpiperidine derivatives.

Cultural and Social References

Pethidine, marketed under brand names such as Demerol in the and Dolantin in various international markets, has appeared in popular media as a symbol of dependency and the allure of prescription painkillers. In Michael Jackson's 1997 song "Morphine" from the album Blood on the Dance Floor: HIStory in the Mix, the lyrics repeatedly reference Demerol, portraying the singer's descent into addiction with lines like "Demerol, Demerol / Oh God, he's taking Demerol," drawing from Jackson's own documented struggles with the drug. Similarly, Irvine Welsh's 1993 Trainspotting and its 1996 film adaptation include pethidine in a famous monologue listing abused substances, underscoring its role in the underground drug culture of 1980s alongside and other . High-profile cases have further embedded pethidine in public consciousness regarding and drug safety. In the UK, general practitioner admitted in 1976 to forging more than 70 prescriptions for pethidine to sustain his personal , marking an early that highlighted vulnerabilities in healthcare professionals' access to controlled substances and foreshadowing his later convictions for patient murders. Across the Atlantic, the 1984 death of 18-year-old Libby Zion in New York Hospital resulted from a severe interaction between intramuscular pethidine and her prescribed MAOI antidepressant , causing ; this tragedy spurred the , mandating reforms in resident physician training, supervision, and work-hour limits to enhance . These events have influenced societal attitudes toward , elevating pethidine's profile in awareness initiatives focused on abuse prevention and risks. Its generic formulations, widely available since the mid-20th century, have amplified concerns about diversion and misuse, prompting inclusion in educational resources that emphasize safer alternatives for . By 2025, pethidine features in broader opioid prevention campaigns as a cautionary example of synthetic analgesics' addictive potential and clinical hazards.

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