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Pethidine

Pethidine molecule structurePethidine molecule structure
Ethyl 1-methyl-4-phenylpiperidine-4-carboxylate
Meperidine, Demerol, Dolantin, DolcontralOpen in Piru
Psychoactive Class
Chemical Class

Pethidine is a synthetic opioid1 depressant2 of the phenylpiperidine class3 that relieves moderate to severe pain2 and produces sedation.2 Otto Eisleb first synthesized it in 1938 as a potential anticholinergic agent. It also suppresses postoperative shivering4 and has a slightly shorter duration of action than morphine. Prolonged use can cause dependence,3 and its metabolite norpethidine can cause neurotoxicity,1 particularly during long-term use.5 Pethidine can also increase the risk of serotonin syndrome, especially when combined with serotonergic substances.6

Dosage & Duration

Dosage

Doses are population estimates that vary widely between individuals.

Threshold25-50 mg
Light50-100 mg
Moderate100-200 mg
Strong200-400 mg
Heavy400+ mg
Bioavailability
50-60%

Duration

Onset30-60 minutes
Peak4-6 hours
After Effects2-10 hours

Subjective Effects

Subjective Effects not written up yet

Reagent Testing

Expected colorimetric results for common reagent tests. Colors show reaction change over 1–2 minutes.

Froe(FR)
white → black2
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Pharmacology

Pharmacodynamics

Pethidine produces analgesia through μ-opioid receptor agonism in the central nervous system.7 Its opioid signaling reduces neuronal excitability and neurotransmitter release through inhibition of adenylate cyclase and changes in calcium and potassium channel activity. κ-Receptor stimulation may contribute to its antishivering action, although this mechanism is not fully understood. Pethidine also inhibits dopamine and norepinephrine reuptake, contributing to stimulant activity,8 and has anticholinergic effects.9 Its interactions with sodium channels produce local anesthetic activity and account for antispasmodic activity observed in vitro, which is not observed in vivo; it also antagonizes NMDA receptors.

Pharmacokinetics

Pethidine undergoes extensive first-pass metabolism, giving oral bioavailability of 50-60% with normal liver function and 80-90% with hepatic impairment. Hepatic metabolism involves hydrolysis and N-demethylation,3 followed by further hydrolysis and partial conjugation with glucuronic acid. It is listed as a substrate of CYP2B6, CYP2C19, CYP2D6, CYP3A and CYP3A4, and P-glycoprotein, and as an inducer of CYP1A2 and CYP3A4 with unspecified induction strength. Pethidine crosses the placenta, enters breast milk,2 and is 60-80% bound to plasma proteins,2 primarily albumin and α1-acid glycoprotein;10 cirrhosis and active viral hepatitis do not appear to change this binding. Its initial distribution half-life is 2-11 minutes and terminal elimination half-life is 3-5 hours, increasing to 7-11 hours with hepatic dysfunction. Its active N-demethylated metabolite has an elimination half-life of 8-12 hours and can accumulate with repeated administration or kidney failure. Elimination occurs through urine, with urinary acidity influencing the proportions recovered as unchanged drug and metabolites: approximately 5% is excreted unchanged and 5-30% as the N-demethylated metabolite when urine pH is uncontrolled. Acidic urine contains the parent drug and its N-demethylated metabolite, whereas alkaline urine contains free and conjugated acid metabolites. One study in healthy adults found that 80-85% of an intragluteal intramuscular dose was absorbed within 6 hours, with substantial variation between individuals. Food does not significantly affect absorption.

Interactions

Dangerous

Highest risk

These combinations are considered extremely harmful and should always be avoided. Reactions to these drugs taken in combination are highly unpredictable and have a potential to cause death.

5-HTPAlcoholBenzodiazepinesDXMGrapefruitKetamineMAOIsMXENitrous oxidePCPSNRIsSSRIsSerotonin releasersStimulantsTramadol

Caution

Use caution

These combinations are not usually physically harmful, but may produce undesirable effects, such as physical discomfort or overstimulation. Extreme use may cause physical health issues. Synergistic effects may be unpredictable. Care should be taken when choosing to use this combination.

1,2-BenzodiazepineAbacavirAbametapirAbataceptAbemaciclib
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Tolerance

Tolerance timelines are rules of thumb, not exact schedules, and vary widely between individuals and use patterns.

Full Tolerance
Prolonged, repeated pethidine use produces tolerance to many effects, with the rate of development varying by effect. Tolerance to constipation develops particularly slowly.
Baseline Reset
Tolerance returns to baseline after approximately 1–2 weeks without further use.
Half Tolerance
Tolerance falls to approximately half its previous level after 3–7 days without further use.
Cross Tolerance

All other opioids

Harm Potential

Addiction & Dependence

Psychological

Extremely High

Chronic pethidine use is described as extremely addictive with high abuse potential and capable of causing psychological dependence, cravings, and withdrawal symptoms.

Physical

High

Prolonged pethidine use may lead to morphine-type dependence with withdrawal symptoms, and pethidine can cause physical dependence.

Toxicity

Lethal Dosage

Pethidine has high toxicity relative to dose, can be fatal in overdose, and is potentially lethal with depressants such as alcohol or benzodiazepines. Severe overdose can cause coma or death without immediate medical attention.

respiratory and central nervous system

High doses and overdose may cause respiratory depression, abnormal breathing, unconsciousness, coma, cold clammy skin, hypotension, obtundation, and death.

neurologic

High doses may cause seizures, and chronic parenteral use has been associated with convulsive seizures.

serotonergic and autonomic

Serotonin syndrome has occurred with antidepressants and MAOIs and can include agitation, hyperpyrexia, hypertension, tachycardia, seizures, coma, and death.

pregnancy and lactation

Meperidine can pass through the placenta and enter breast milk.

Psychosis Risk

Moderate

Overdose can cause psychosis, and norpethidine is described as hallucinogenic and associated with delirium and dysphoria.

Seizure Risk

High

High doses may cause seizures through norpethidine accumulation, and serious interactions with MAOIs or tramadol can also produce convulsions.

History & Culture

Discovery and development

Pethidine was patented in 1937. In 1938, the German chemist Otto Eisleb synthesized it as a potential anticholinergic agent. Otto Schaumann subsequently recognized its analgesic properties while working for IG Farben in Germany.11 It was approved for medical use in 1943.…

Legality

International

1961 Single Convention (as amended): Pethidine (meperidine), chemically 1-methyl-4-phenylpiperidine-4-carboxylic acid ethyl ester (the same identity as ethyl 1-methyl-4-phenylpiperidine-4-carboxylate), is expressly in Schedule I; Schedule-I isomers, esters/ethers (unless in another Schedule), and their possible salts are also controlled. It is not in Schedule IV, and no pethidine preparation is listed in Schedule III.

1971 Convention on Psychotropic Substances: Pethidine/meperidine and its stated chemical identity are not listed in any of Schedules I, II, III or IV in the complete current Green List; therefore the Convention's salts and stereoisomer provisions do not transfer control to pethidine.

1988 Convention against Illicit Traffic: Pethidine/meperidine and its stated chemical identity are not listed in either Table I or Table II in the complete current official Tables (as at 3 December 2024); no applicable class, derivative, isomer, salt, ester or preparation entry was identified. The separately listed piperidone/fentanyl-precursor entries do not establish control of pethidine.

By Country

Illegal1
Israel flagIsraelIllegal
Controlled / restricted1
Japan flagJapanRestricted
Prescription23
Argentina flagArgentinaPrescription only
Brazil flagBrazilPrescription only
Canada flagCanadaPrescription only
China flagChinaPrescription only
Czech Republic flagCzech RepublicPrescription only
Denmark flagDenmarkPrescription only
Finland flagFinlandPrescription only
France flagFrancePrescription only
Indonesia flagIndonesiaPrescription only
Ireland flagIrelandPrescription only
Mexico flagMexicoPrescription only
Netherlands flagNetherlandsPrescription only
New Zealand flagNew ZealandPrescription only
Philippines flagPhilippinesPrescription only
Poland flagPolandPrescription only
Portugal flagPortugalPrescription only
Singapore flagSingaporePrescription only
South Africa flagSouth AfricaPrescription only
South Korea flagSouth KoreaPrescription only
Spain flagSpainPrescription only
Turkey flagTurkeyPrescription only
United Arab Emirates flagUnited Arab EmiratesPrescription only
United Kingdom flagUnited KingdomPrescription only
Legal / decriminalized4
United States flagUnited StatesLegal (regulated)
Belgium flagBelgiumLegal (regulated)
Colombia flagColombiaLegal (regulated)
Switzerland flagSwitzerlandLegal (regulated)

References

Source Pages

  1. DrugBank
  2. Erowid
  3. Erowid: Meperidine Vault
  4. Isomer Design (TiHKAL/PiHKAL)
  5. PsychonautWiki
  6. TripSit Factsheets
  7. Wikipedia

Citations

Further Reading

  1. Edwards et al. 1982 - Clinical Pharmacokinetics of Pethidine
  2. Gillman 2005 - MAOIs, Opioid Analgesics and Serotonin Toxicity
  3. Meperidine - StatPearls NCBI
  4. Siegel et al. 1982 - Heroin Overdose Death and Drug-Associated Environmental Cues
  5. Walker & Zacny 1999 - Subjective Effects of Cumulative Opioid μ Agonist Doses

Article Status

  • Josie Kins avatar
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    An autonomous workflow built by Josie Kins compiled this article's foundation from information published across the web.

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