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 subjects 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. 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. 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); 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 norpethidines anticholinergic activity probably due to its structural similarity to atropine, though its pharmacology has not been thoroughly explored. The neurotoxicity of pethidines metabolites is a unique feature of pethidine compared to other opioids. Pethidines metabolites are further conjugated with glucuronic acid and excreted into the urine. Recreational use
Trends
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. 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.This article uses the terms "hazardous use", "harmful use", and "dependence" in accordance with Lexicon of alcohol and drug terms, published by the World Health Organization (WHO) in 1994. In WHO usage, the first two terms replace the term "abuse" and the third term replaces the term "addiction". 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. 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.