Pethidine

ethyl 1-methyl-4-phenylpiperidine-4-carboxylate

Overview

Pethidine belongs to Opioids.

Key safety note: Like all strong opioids, pethidine can cause dose-dependent respiratory depression, the usual mechanism of opioid death, greatly worsened by alcohol, benzodiazepines and other CNS depressants, and reversible (for the opioid effect) by naloxone.[2]
Effects
Subjective effects vary. What a substance feels like depends on dose, individual physiology, mindset, and setting. The points below describe commonly reported effects, not guaranteed, uniform, or desirable outcomes.
  • Opioid analgesia with relaxation, warmth and, especially at higher or injected doses, euphoria. Drowsiness and clouded thinking. Onset is quick but the effect is short (≈2–2.5 h).
  • Because of its atropine-like action it often does NOT produce the classic pinpoint pupils, and may cause a dry mouth and a faster heart rate. Nausea, sweating and dizziness are common.
  • With accumulation of norpethidine (repeated dosing, kidney impairment): tremor, muscle twitching, agitation and seizures: a stimulant toxicity distinct from opioid overdose.
Dosing & duration
Harm-reduction note: These are commonly cited reference ranges, not a recommendation or a “safe” dose. Potency, purity, body chemistry, tolerance, and drug combinations vary widely. Start low, go slow, wait for full effects before redosing, and never assume an unknown product matches these figures. Missing data is not evidence of safety.

Oral, and by injection (IM/IV/subcutaneous): clinician-prescribed and titrated. Figures below are clinical context, NOT a recreational guide.. Pethidine is dosed to effect by clinicians. There is no safe recreational dose: opioid respiratory depression overlaps the euphoric range and is worsened by any other depressant, and repeated dosing risks norpethidine seizures (which naloxone will not reverse). It is short-acting and a poor choice for ongoing pain. Avoid entirely within 14 days of an MAOI.

Dose ranges

Analgesia (adult, IM/SC, clinical)

≈25–100 mg every 3–4 h, titrated

Anti-shivering (clinical)

≈25–50 mg IV

Equianalgesic reference

≈75–100 mg pethidine IM ≈ 10 mg morphine IM (~1/10 as potent)

Duration

onset

IM ≈10–15 min, IV within minutes

total

Analgesia ≈2–2.5 h

after effects

Sedation, with accumulation, norpethidine tremor/seizure risk. Withdrawal after regular use

Chemical & Physical Properties
FormulaC15H21NO2
Molar mass247.33 g/mol
StateSolid
Melting point270 °C
Boiling pointNot reported
DensityNot reported
Vapor pressureNot reported
pKa8.7
LogP2.72
Solubility3220 mg/L (at 30 °C), In water, 3.22×10³ mg/L at 30 °C, 1.11×10⁰ g/L
Refractive indexnα 1.545, nβ 1.581, nγ 1.618
Identifiers & Synonyms
CAS57-42-1
CAS (enantiomer)
PubChem CID4058
InChIKeyXADCESSVHJOZHK-UHFFFAOYSA-N
InChIInChI=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
SMILESCCOC(=O)C1(CCN(CC1)C)C2=CC=CC=C2

Synonyms

  • Meperidine
  • Demerol
Pharmacodynamics & Biochemistry

Pethidine (meperidine, Demerol) was the first fully synthetic opioid: a phenylpiperidine made in 1939 and the structural ancestor of the fentanyls. It is an agonist at the μ-opioid receptor (MOR), acting like other opioids through Gi/Go signalling to produce analgesia, sedation, euphoria, respiratory depression and constipation, but it is comparatively weak: its human μ affinity (IC50 ≈316 nM, a separate compilation lists Kᵢ ≈450 nM) is only about a tenth of morphine's, with weaker κ and negligible δ activity. Unusually for an opioid, pethidine has several 'off-target' actions that shape its clinical profile: a local-anaesthetic effect on sodium channels, atropine-like antimuscarinic activity (so it tends NOT to cause the pinpoint pupils typical of opioids, and can raise the heart rate), and inhibition of monoamine reuptake including serotonin. The serotonergic action is clinically important. It underlies a dangerous interaction with MAOIs and other serotonergic drugs (serotonin syndrome). Its defining liability is its metabolism. Pethidine is demethylated in the liver (CYP2B6/CYP3A4/CYP2C19) to norpethidine (normeperidine), an active metabolite with a much longer half-life (≈8–12 h) that is NOT an opioid but a CNS stimulant and convulsant. Norpethidine accumulates with repeated dosing and in renal impairment, causing tremor, twitching (myoclonus) and seizures, and because it is not an opioid, this neurotoxicity is not reversed by naloxone (which can even unmask it). Pethidine itself is short-acting (half-life ≈2.5–4 h), so it is a poor choice for ongoing pain.

Biological targets

  • MOR

Binding & functional measurements

TargetMeasurementSpecies
μ-opioid receptorKi 450 nMHuman
Pharmacokinetics
BioavailabilityOral ≈50–60% (≈80–90% in hepatic impairment)
TmaxNot reported
Half-life≈2.5–4 h (norpethidine ≈8–12 h)
VdNot reported
Protein bindingNot reported
MetabolismHepatic (CYP2B6/CYP3A4/CYP2C19 + carboxylesterase) → norpethidine + pethidinic acid
ExcretionRenal (glucuronide conjugates)
Toxicology & Safety
Harm-reduction note: Toxicity and risk depend on dose, route, purity, combinations, setting, and individual health factors. Missing harms should never be interpreted as evidence of safety.

Not reported

Like all strong opioids, pethidine can cause dose-dependent respiratory depression, the usual mechanism of opioid death, greatly worsened by alcohol, benzodiazepines and other CNS depressants, and reversible (for the opioid effect) by naloxone. But pethidine carries two distinctive extra dangers. First, its metabolite norpethidine is a long-lived CNS stimulant and convulsant that accumulates with repeated or high dosing and in kidney impairment, causing tremor, myoclonus, agitation and seizures that naloxone does NOT reverse: the main reason pethidine is discouraged for anything beyond brief use. Second, it inhibits serotonin reuptake, so combining it with an MAOI (or, less severely, SSRIs/SNRIs, tramadol or other serotonergic drugs) can trigger a potentially fatal serotonin syndrome or an excitatory MAOI reaction. Pethidine is contraindicated within 14 days of an MAOI. It also has abuse and dependence potential, with an opioid withdrawal syndrome on stopping. There is no safe recreational dose. Have naloxone available for the opioid effects, but note it will not treat the metabolite-driven seizures.[2]

Legal Status
Legal note: Legal status can change over time and may vary by country, region, formulation, analogue status, prescription context, and enforcement practice. Always confirm with current official sources before relying on this section.
Interactions & Contraindications

Drug interactions

MAOIs Contraindicated: pethidine's serotonin-reuptake inhibition can cause a severe, sometimes fatal reaction (serotonin syndrome or excitatory crisis). Avoid within 14 days of an MAOI.[2]
SSRIs, SNRIs, Tramadol, Triptans Added risk of serotonin syndrome.[2]
Alcohol, Benzodiazepines Additive, potentially fatal respiratory depression.[2]

Contraindications

Concurrent MAOI, SSRI/SNRI or other serotonergic medication concurrent or recent (within 14 days) MAOI use.[2]
Significant respiratory depression or acute severe asthma significant respiratory depression.[2]
Kidney or liver impairment renal impairment causes norpethidine accumulation and seizures, so avoid or use with great caution.[2]
Current or prior seizure disorder[2]
Combining with alcohol or other CNS depressants and caution with other serotonergic drugs.[2]
Usage & Context
  • A synthetic opioid analgesic (Demerol/pethidine) for moderate-to-severe acute pain, historically very common in labour and delivery and still used to control shivering (e.g. during therapeutic hypothermia or drug-induced rigors).
  • Its use has declined markedly: the neurotoxic norpethidine metabolite, the serotonergic/MAOI interaction and its inferior, short-lived analgesia have led many guidelines to prefer morphine or hydromorphone.
  • Encountered in misuse and diversion, though less commonly than other strong opioids.
Sources & Evidence

Further Information