WARNINGDANGER OF DEATH
High doses alone or ordinary doses in combination with other depressants can fatally stop breathing.
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Pethidine
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.
Duration
Subjective Effects
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.
Dangerous
Highest riskThese 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.
Caution
Use cautionThese 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.
Tolerance
Tolerance timelines are rules of thumb, not exact schedules, and vary widely between individuals and use patterns.
All other opioids
Harm Potential
Addiction & Dependence
Psychological
Extremely HighChronic pethidine use is described as extremely addictive with high abuse potential and capable of causing psychological dependence, cravings, and withdrawal symptoms.
Physical
HighProlonged pethidine use may lead to morphine-type dependence with withdrawal symptoms, and pethidine can cause physical dependence.
Toxicity
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.
High doses and overdose may cause respiratory depression, abnormal breathing, unconsciousness, coma, cold clammy skin, hypotension, obtundation, and death.
High doses may cause seizures, and chronic parenteral use has been associated with convulsive seizures.
Serotonin syndrome has occurred with antidepressants and MAOIs and can include agitation, hyperpyrexia, hypertension, tachycardia, seizures, coma, and death.
Meperidine can pass through the placenta and enter breast milk.
Psychosis Risk
Overdose can cause psychosis, and norpethidine is described as hallucinogenic and associated with delirium and dysphoria.
Seizure Risk
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
References
Source Pages
Citations
Further Reading
Article Status
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