Skip to main content
Psychedex
Sources
25
6 strong · 13 moderate · 6 weak

Studies and references cited across this article, graded by evidence strength.

Claims checked
88
35verified53inconclusive

Inconclusive means the cited source neither confirms nor refutes the claim — a lower-confidence badge, not an error.

Generated
May 10, 2026 · pipeline-v5
Values approved
104/104 (100%)

Data points an editor reviewed and accepted for publication.

01

Value Provenance

Dosing

oraltrace

FieldPublishedAI ProposedConfidence
Threshold25 mg25 mgmedium
Low50–100 mg50–100 mgmedium
Common100–200 mg100–200 mgmedium
Strong200–400 mg200–400 mgmedium
Heavy400+ mg400+ mgmedium
Editorial

DB seed values (threshold 25, light 50-100, common 100-200, strong 200-400 mg oral) consistent with StatPearls clinical dosing range of 50-150 mg q3-4h. Heavy threshold set at 400 mg based on work-notes indicating doses above this carry severe overdose and normeperidine seizure risk. Bioavailability ~50% in healthy adults per published PK data.

Reasoning

DB seed values (threshold 25, light 50-100, common 100-200, strong 200-400 mg oral) consistent with StatPearls clinical dosing range of 50-150 mg q3-4h. Heavy threshold set at 400 mg based on work-notes indicating doses above this carry severe overdose and normeperidine seizure risk. Bioavailability ~50% in healthy adults per published PK data.

Evidence basis: community_consensus_large

Duration

oral

FieldPublishedAI ProposedConfidence
Onsettrace30–60 minutes30–60 minutesmedium
Editorial

Work-notes and StatPearls confirm oral onset at 30-60 minutes. Consistent with Tmax of 60-120 min (onset precedes peak).

Reasoning

Work-notes and StatPearls confirm oral onset at 30-60 minutes. Consistent with Tmax of 60-120 min (onset precedes peak).

Evidence basis: community_consensus_large

Peaktrace60–120 minutes60–120 minutesmedium
Editorial

Work-notes specify peak phase 60-120 min based on clinical Tmax data. NOTE: seed DB listed 'peak: 4-6 hours' which Phase 1 identified as likely being total duration, not peak timing.

Reasoning

Work-notes specify peak phase 60-120 min based on clinical Tmax data. NOTE: seed DB listed 'peak: 4-6 hours' which Phase 1 identified as likely being total duration, not peak timing.

Evidence basis: published_case_series

Offsettrace3–5 hours3–5 hoursmedium
Editorial

Work-notes specify offset 3-5h (analgesic effect waning phase). Consistent with StatPearls duration of analgesia 2-5h total.

Reasoning

Work-notes specify offset 3-5h (analgesic effect waning phase). Consistent with StatPearls duration of analgesia 2-5h total.

Evidence basis: published_case_series

Totaltrace3–6 hours3–6 hoursmedium
Editorial

Work-notes specify total subjective experience 3-6h. Consistent with clinical duration of analgesia 2-5h plus brief residual subjective effects.

Reasoning

Work-notes specify total subjective experience 3-6h. Consistent with clinical duration of analgesia 2-5h plus brief residual subjective effects.

Evidence basis: community_consensus_large

After effectstrace2–10 hours2–10 hourslow
Editorial

Existing DB value (2-10h). Wide range reflects variable normeperidine persistence and individual pharmacokinetic differences. Work-notes carry forward this range.

Reasoning

Existing DB value (2-10h). Wide range reflects variable normeperidine persistence and individual pharmacokinetic differences. Work-notes carry forward this range.

Evidence basis: community_consensus_large

Safety

Toxicity Profiletrace

FieldPublishedAI ProposedConfidence
Acutehighhighhigh
Chronichighhighhigh
Organs AffectedCNS (normeperidine seizures, delirium), respiratory (depression), cardiovascular (tachycardia, hypotension from histamine release), hepatic (metabolism-dependent toxicity, bioavailability changes), renal (normeperidine clearance-dependent toxicity)CNS (normeperidine seizures, delirium), respiratory (depression), cardiovascular (tachycardia, hypotension from histamine release), hepatic (metabolism-dependent toxicity, bioavailability changes), renal (normeperidine clearance-dependent toxicity)high
Editorial

Multiple case series document normeperidine neurotoxicity (Hershey 1983, Reutens & Stewart-Wynne 1989, Pryle 1992). Systematic reviews confirm inferior safety profile (Beers Criteria 2023, WHO delisting 2003). Lethal CNS depressant combinations confirmed in clinical literature and seed interaction data.

Reasoning

Multiple case series document normeperidine neurotoxicity (Hershey 1983, Reutens & Stewart-Wynne 1989, Pryle 1992). Systematic reviews confirm inferior safety profile (Beers Criteria 2023, WHO delisting 2003). Lethal CNS depressant combinations confirmed in clinical literature and seed interaction data.

Evidence basis: published_case_series

Dependence Profiletrace

FieldPublishedAI ProposedConfidence
Physicalhighhighhigh
Psychologicalhighhighhigh
Compulsive Redosinghighhighhigh
Dose Escalationhighhighhigh
Editorial

Schedule II (US) / Class A (UK) scheduling reflects documented high abuse potential. Work-notes specify high physical/psychological dependence with high compulsive redosing and dose escalation tendency. Reinforcement mechanism from Listos et al. 2019 and StatPearls.

Reasoning

Schedule II (US) / Class A (UK) scheduling reflects documented high abuse potential. Work-notes specify high physical/psychological dependence with high compulsive redosing and dose escalation tendency. Reinforcement mechanism from Listos et al. 2019 and StatPearls.

Evidence basis: systematic_review

Withdrawal Profiletrace

FieldPublishedAI ProposedConfidence
Severitymoderatemoderatehigh
Symptomslacrimation, rhinorrhoea, diarrhoea, muscle aches, insomnia, dysphoria, anxiety, tremors, restlessness, pro-convulsant risk from normeperidine during withdrawallacrimation, rhinorrhoea, diarrhoea, muscle aches, insomnia, dysphoria, anxiety, tremors, restlessness, pro-convulsant risk from normeperidine during withdrawalhigh
FatalNoNohigh
Medical SupervisionRequiredRequiredhigh
Editorial

Pethidine withdrawal onset is 8-12h (shorter half-life than morphine). Acute phase 4-7 days. Additional pro-convulsant risk from normeperidine distinguishes it from standard opioid withdrawal. Medical supervision required due to seizure risk.

Reasoning

Pethidine withdrawal onset is 8-12h (shorter half-life than morphine). Acute phase 4-7 days. Additional pro-convulsant risk from normeperidine distinguishes it from standard opioid withdrawal. Medical supervision required due to seizure risk.

Evidence basis: systematic_review

Tolerance Profiletrace

FieldPublishedAI ProposedConfidence
Buildupmoderatemoderatelow
Half-life5 days5 dayslow
Full Reset10.5 days10.5 dayslow
Cross-tolerancesmorphine, fentanyl, oxycodone, hydromorphone, heroin, codeine, tramadolmorphine, fentanyl, oxycodone, hydromorphone, heroin, codeine, tramadollow
Editorial

Work-notes flag tolerance half-life and reset values as DB seed only with no primary literature verification. Mechanism is well-characterised (Listos et al. 2019) but numeric values are unverified. Cross-tolerance with opioids confirmed but noted as incomplete (Mercadante 1999).

Reasoning

Work-notes flag tolerance half-life and reset values as DB seed only with no primary literature verification. Mechanism is well-characterised (Listos et al. 2019) but numeric values are unverified. Cross-tolerance with opioids confirmed but noted as incomplete (Mercadante 1999).

Evidence basis: community_consensus_large

Effects & Profile

Contraindications

FieldPublishedAI ProposedConfidence
other MAOI use within 14 daystraceabsoluteabsolutehigh
Editorial

Confirmed lethal MAOI-pethidine interaction documented in multiple case series and reviews (Sporer 1995, Bowdle 1998, Edinoff 2022). Work-notes list as absolute contraindication with high confidence.

Reasoning

Confirmed lethal MAOI-pethidine interaction documented in multiple case series and reviews (Sporer 1995, Bowdle 1998, Edinoff 2022). Work-notes list as absolute contraindication with high confidence.

renal Severe renal impairmenttraceabsoluteabsolutehigh
Editorial

Documented in case reports of seizures in renal failure patients (Reutens & Stewart-Wynne 1989). Work-notes list as absolute with high confidence.

Reasoning

Documented in case reports of seizures in renal failure patients (Reutens & Stewart-Wynne 1989). Work-notes list as absolute with high confidence.

other Duration of use exceeding 48 hourstraceabsoluteabsolutehigh
Editorial

StatPearls specifies 48-hour maximum for inpatient use. Work-notes list as absolute contraindication with high confidence.

Reasoning

StatPearls specifies 48-hour maximum for inpatient use. Work-notes list as absolute contraindication with high confidence.

age Older adults (≥65 years)tracerelativerelativehigh
Editorial

2023 AGS Beers Criteria 'always avoid' designation. Work-notes list as relative (strong avoid) with high confidence.

Reasoning

2023 AGS Beers Criteria 'always avoid' designation. Work-notes list as relative (strong avoid) with high confidence.

hepatic Hepatic impairmenttracerelativerelativehigh
Editorial

Documented in Soleimanpour et al. 2016 and HandWiki pharmacokinetic data. Work-notes list as relative with high confidence.

Reasoning

Documented in Soleimanpour et al. 2016 and HandWiki pharmacokinetic data. Work-notes list as relative with high confidence.

neurological Seizure disorderstracerelativerelativemedium
Editorial

Normeperidine's documented convulsant activity (Hershey 1983, Reutens & Stewart-Wynne 1989). Work-notes list with medium confidence.

Reasoning

Normeperidine's documented convulsant activity (Hershey 1983, Reutens & Stewart-Wynne 1989). Work-notes list with medium confidence.

other Sickle cell diseasetracerelativerelativehigh
Editorial

Documented by Pryle et al. 1992 and Ballas 2008. Work-notes list with high confidence.

Reasoning

Documented by Pryle et al. 1992 and Ballas 2008. Work-notes list with high confidence.

psychiatric Concurrent SSRI usetracerelativerelativehigh
Editorial

Fox et al. 2009 confirmed mechanism; clinical reports documented. Work-notes list with high confidence.

Reasoning

Fox et al. 2009 confirmed mechanism; clinical reports documented. Work-notes list with high confidence.

metabolic Concurrent CYP3A4 inhibitorstracerelativerelativehigh
Editorial

StatPearls documents CYP3A4 as primary metabolic enzyme; inhibitor interaction can be fatal. Work-notes list with high confidence.

Reasoning

StatPearls documents CYP3A4 as primary metabolic enzyme; inhibitor interaction can be fatal. Work-notes list with high confidence.

other Chronic cancer paintracerelativerelativehigh
Editorial

Hershey 1983 case literature; Mercadante 1999 opioid rotation guidance. Work-notes list with high confidence.

Reasoning

Hershey 1983 case literature; Mercadante 1999 opioid rotation guidance. Work-notes list with high confidence.

respiratory Concurrent CNS depressant usetracerelativerelativehigh
Editorial

Class-level opioid contraindication confirmed by seed interaction data (alcohol, GHB, GBL, ketamine all lethal). Work-notes list as class-level.

Reasoning

Class-level opioid contraindication confirmed by seed interaction data (alcohol, GHB, GBL, ketamine all lethal). Work-notes list as class-level.

pregnancy breastfeeding Pregnancytracerelativerelativehigh
Editorial

Work-notes list pregnancy as class-level contraindication (neonatal respiratory depression). Jones et al. 2012 Cochrane overview documents adverse neonatal effects.

Reasoning

Work-notes list pregnancy as class-level contraindication (neonatal respiratory depression). Jones et al. 2012 Cochrane overview documents adverse neonatal effects.

Timeline Phases

oral

FieldPublishedAI ProposedConfidence
Onsettrace1800–3600 sec(i=0.20)1800–3600 sec(i=0.20)medium
Editorial

Timeline derived from work-notes phases (onset 30-60 min, peak 60-150 min, plateau 150-240 min, resolution 240-360 min, afterglow 2-10h) cross-referenced with StatPearls Tmax of 60-120 min and duration of analgesia 2-5h. Phase durations represent how long each phase lasts, not absolute time from ingestion. Afterglow range is wide (2-10h) reflecting normeperidine variable persistence.

Reasoning

Timeline derived from work-notes phases (onset 30-60 min, peak 60-150 min, plateau 150-240 min, resolution 240-360 min, afterglow 2-10h) cross-referenced with StatPearls Tmax of 60-120 min and duration of analgesia 2-5h. Phase durations represent how long each phase lasts, not absolute time from ingestion. Afterglow range is wide (2-10h) reflecting normeperidine variable persistence.

Evidence basis: published_case_series

Peaktrace3600–5400 sec(i=1.00)3600–5400 sec(i=1.00)medium
Editorial

Timeline derived from work-notes phases (onset 30-60 min, peak 60-150 min, plateau 150-240 min, resolution 240-360 min, afterglow 2-10h) cross-referenced with StatPearls Tmax of 60-120 min and duration of analgesia 2-5h. Phase durations represent how long each phase lasts, not absolute time from ingestion. Afterglow range is wide (2-10h) reflecting normeperidine variable persistence.

Reasoning

Timeline derived from work-notes phases (onset 30-60 min, peak 60-150 min, plateau 150-240 min, resolution 240-360 min, afterglow 2-10h) cross-referenced with StatPearls Tmax of 60-120 min and duration of analgesia 2-5h. Phase durations represent how long each phase lasts, not absolute time from ingestion. Afterglow range is wide (2-10h) reflecting normeperidine variable persistence.

Evidence basis: published_case_series

Plateautrace3600–5400 sec(i=0.70)3600–5400 sec(i=0.70)medium
Editorial

Timeline derived from work-notes phases (onset 30-60 min, peak 60-150 min, plateau 150-240 min, resolution 240-360 min, afterglow 2-10h) cross-referenced with StatPearls Tmax of 60-120 min and duration of analgesia 2-5h. Phase durations represent how long each phase lasts, not absolute time from ingestion. Afterglow range is wide (2-10h) reflecting normeperidine variable persistence.

Reasoning

Timeline derived from work-notes phases (onset 30-60 min, peak 60-150 min, plateau 150-240 min, resolution 240-360 min, afterglow 2-10h) cross-referenced with StatPearls Tmax of 60-120 min and duration of analgesia 2-5h. Phase durations represent how long each phase lasts, not absolute time from ingestion. Afterglow range is wide (2-10h) reflecting normeperidine variable persistence.

Evidence basis: published_case_series

Resolutiontrace3600–7200 sec(i=0.30)3600–7200 sec(i=0.30)medium
Editorial

Timeline derived from work-notes phases (onset 30-60 min, peak 60-150 min, plateau 150-240 min, resolution 240-360 min, afterglow 2-10h) cross-referenced with StatPearls Tmax of 60-120 min and duration of analgesia 2-5h. Phase durations represent how long each phase lasts, not absolute time from ingestion. Afterglow range is wide (2-10h) reflecting normeperidine variable persistence.

Reasoning

Timeline derived from work-notes phases (onset 30-60 min, peak 60-150 min, plateau 150-240 min, resolution 240-360 min, afterglow 2-10h) cross-referenced with StatPearls Tmax of 60-120 min and duration of analgesia 2-5h. Phase durations represent how long each phase lasts, not absolute time from ingestion. Afterglow range is wide (2-10h) reflecting normeperidine variable persistence.

Evidence basis: published_case_series

Afterglowtrace7200–36000 sec(i=0.10)7200–36000 sec(i=0.10)medium
Editorial

Timeline derived from work-notes phases (onset 30-60 min, peak 60-150 min, plateau 150-240 min, resolution 240-360 min, afterglow 2-10h) cross-referenced with StatPearls Tmax of 60-120 min and duration of analgesia 2-5h. Phase durations represent how long each phase lasts, not absolute time from ingestion. Afterglow range is wide (2-10h) reflecting normeperidine variable persistence.

Reasoning

Timeline derived from work-notes phases (onset 30-60 min, peak 60-150 min, plateau 150-240 min, resolution 240-360 min, afterglow 2-10h) cross-referenced with StatPearls Tmax of 60-120 min and duration of analgesia 2-5h. Phase durations represent how long each phase lasts, not absolute time from ingestion. Afterglow range is wide (2-10h) reflecting normeperidine variable persistence.

Evidence basis: published_case_series

Dose Tier Summaries

thresholdtrace
medium

Minimal perceptible opioid effect. A subtle warmth may be noticed alongside mild anxiety suppression and a faint mood lift. Analgesic effect is negligible at this level. Physically, there is no significant sedation or respiratory depression. Slight anticholinergic signs (mild dry mouth) may be present but are rarely noticed. Pupil dilation — not constriction — distinguishes even threshold pethidine from other opioids. Functional impairment is minimal. Duration of noticeable effects is brief (1-2 hours). Not suitable for pain management at this dose.

Editorial

Work-notes specify 25 mg oral threshold with minimal warmth, mild anxiolysis, subtle mood lift. Expanded with substance-specific notes on mydriasis and anticholinergic profile from research output.

Reasoning

Work-notes specify 25 mg oral threshold with minimal warmth, mild anxiolysis, subtle mood lift. Expanded with substance-specific notes on mydriasis and anticholinergic profile from research output.

Evidence basis: community_consensus_large

lighttrace
medium

Noticeable analgesia emerges alongside mild cognitive euphoria, warmth spreading through the body, and clear anxiety suppression. A gentle sedation is present but does not preclude activity. Mood is elevated with a sense of well-being. Anticholinergic effects become apparent: mild tachycardia, possible dry mouth, and pupil dilation. Nausea may occur, particularly in opioid-naive individuals. Spontaneous body sensations manifest as a diffuse tingling warmth. Duration is approximately 2-4 hours. The short duration relative to other opioids may prompt thoughts of redosing — resist this impulse, as normeperidine accumulates with each dose.

Editorial

Work-notes specify 50-100 mg oral light tier with noticeable analgesia, mild euphoria, warmth, anxiolysis, slight sedation. Anticholinergic effects beginning. Expanded from clinical pharmacology profile.

Reasoning

Work-notes specify 50-100 mg oral light tier with noticeable analgesia, mild euphoria, warmth, anxiolysis, slight sedation. Anticholinergic effects beginning. Expanded from clinical pharmacology profile.

Evidence basis: community_consensus_large

commontrace
medium

Full analgesic effect with clear cognitive euphoria, pronounced sedation, and enveloping body warmth. Tactile euphoria is prominent — surfaces feel pleasurable against the skin. Anxiety suppression is strong. Thought deceleration and focus suppression are noticeable. The characteristic 'clean' warmth historically distinguished pethidine from morphine's heavier sedation. Nausea affects a majority of users and may progress to vomiting. Constipation develops. Respiratory depression is clinically present. Tachycardia from anticholinergic activity is measurable. Dry mouth is pronounced. Motor control impairment makes coordination unreliable. Duration is 3-5 hours. Compulsive redosing urge is significant due to the relatively short effect window combined with strong euphoria. Each redose increases normeperidine accumulation and seizure risk.

Editorial

Work-notes specify 100-200 mg oral common tier with full analgesia, clear euphoria, sedation, body warmth, tactile euphoria, pronounced nausea, constipation, respiratory depression, cognitive impairment, tachycardia.

Reasoning

Work-notes specify 100-200 mg oral common tier with full analgesia, clear euphoria, sedation, body warmth, tactile euphoria, pronounced nausea, constipation, respiratory depression, cognitive impairment, tachycardia.

Evidence basis: community_consensus_large

strongtrace
medium

Intense sedation dominates, with strong cognitive euphoria giving way to cognitive impairment and possible confusion. The opioid warmth is overwhelming. Visual acuity suppression and 'nodding' (oscillation between wakefulness and sleep) are common. Decision-making is severely impaired. Marked respiratory depression represents the primary acute danger. Nausea and vomiting are highly likely. Tachycardia is pronounced. At repeated strong doses, normeperidine begins accumulating to concerning levels — tremors or myoclonus may emerge within 24-48 hours of repeated dosing. This dose range carries serious overdose risk, particularly in combination with any other CNS depressant. The margin between strong effects and life-threatening respiratory depression is narrow.

Editorial

Work-notes specify 200-400 mg oral strong tier with intense sedation, strong euphoria, marked respiratory depression, high nausea/vomiting risk, normeperidine concern, significant cognitive impairment, confusion.

Reasoning

Work-notes specify 200-400 mg oral strong tier with intense sedation, strong euphoria, marked respiratory depression, high nausea/vomiting risk, normeperidine concern, significant cognitive impairment, confusion.

Evidence basis: community_consensus_large

heavytrace
low

Not explicitly characterised in clinical literature. Doses above 400 mg oral carry severe overdose risk including fatal respiratory depression, particularly in opioid-naive individuals or when combined with any CNS depressant. Normeperidine seizure risk escalates dramatically with cumulative dosing at this level. Seizures from normeperidine are not reversible by naloxone — only benzodiazepines can manage them. Cardiovascular collapse from histamine release and anticholinergic toxicity compounds the respiratory depression risk. This dose range is life-threatening. No harm-reduction framing can make heavy pethidine use safe. Emergency medical access must be immediately available.

Editorial

Work-notes state heavy tier is not explicitly characterised in literature. Doses >400 mg carry severe overdose and normeperidine seizure risk. Proposed with low confidence as no controlled data defines this range.

Reasoning

Work-notes state heavy tier is not explicitly characterised in literature. Doses >400 mg carry severe overdose and normeperidine seizure risk. Proposed with low confidence as no controlled data defines this range.

Evidence basis: community_consensus_large

02

History

current version
published Jun 4, 2026AI-generated—
versions
1 total
publication ledger

backfill Jun 4, 2026

Historical versions do not record which reviewer approved them; editorial accountability is recorded per value in the database and in the publication ledger going forward.

full version history suggest a correctioncontact@psychedex.org
03

Sources

6 strong · 13 moderate · 6 weak
  1. [1]
    weak
    Meperidine - StatPearls (NCBI Bookshelf)
    Preuss CV, et al. · 2024
    linkno claims checked
  2. [2]
    weak
    Pethidine pharmacology, pharmacokinetics, history, legal status
    HandWiki Chemistry · 2023
    linkno claims checked
  3. [3]
    moderate
    Full Opioid Agonists and Tramadol: Pharmacological and Clinical Considerations.
    Edinoff AN, Kaplan LA, Khan S, Petersen M, Sauce E, Causey CD, Cornett EM, Imani F, Moradi Moghadam O, Kaye AM, Kaye AD · 2021 · Anesthesiology and Pain Medicine
    doi.org/10.5812/aapm.119156pubmed 3469244810 claims checked6 verified4 inconclusive
  4. [4]
    moderate
    Adverse effects of opioid agonists and agonist-antagonists in anaesthesia.
    Bowdle TA · 1998 · Drug Safety
    pubmed 974766512 claims checked7 verified5 inconclusive
  5. [5]
    moderate
    Meperidine and central neurotoxicity.
    Hershey LA · 1983 · Annals of Internal Medicine
    pubmed 68380777 claims checked7 inconclusive
  6. [6]
    weak
    Norpethidine induced myoclonus in a patient with renal failure.
    Reutens DC, Stewart-Wynne EG · 1989 · Journal of Neurology, Neurosurgery & Psychiatry
    doi.org/10.1136/jnnp.52.12.1450pubmed 26144586 claims checked6 inconclusive
  7. [7]
    strong
    American Geriatrics Society 2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults.
    American Geriatrics Society · 2023 · Journal of the American Geriatrics Society
    doi.org/10.1111/jgs.18372pubmed 371398246 claims checked6 verified
  8. [8]
    weak
    Toxicity of norpethidine in sickle cell crisis.
    Pryle BJ, Grech H, Stoddart PA, Carson R, O'Mahoney T, Reynolds F · 1992 · BMJ (Clinical research ed.)
    pubmed 16113705 claims checked5 inconclusive
  9. [9]
    strong
    Meperidine and skin surface warming additively reduce the shivering threshold: a volunteer study.
    Kimberger O, Ali SZ, Markstaller M, Zmoos S, Lauber R, Hunkeler C, Kurz A · 2007 · Critical Care
    doi.org/10.1186/cc5709pubmed 173164564 claims checked2 verified2 inconclusive
  10. [10]
    strong
    Pain management for women in labour: an overview of systematic reviews
    Jones L, Othman M, Dowswell T, Alfirević Ž, Gates S · 2012 · Cochrane Database of Systematic Reviews
    doi.org/10.1002/14651858.cd009234.pub2pubmed 224193422 claims checked2 inconclusive
  11. [11]
    weak
    Lorazepam UK controlled drug classification
    UK Home Office · 2024
    linkno claims checked
  12. [12]
    moderate
    Pethidine (CID 4058) - Chemical Identity
    PubChem · 2024 · PubChem Database (NCBI)
    linkno claims checked
  13. [13]
    weak
    Meperidine chemical properties: CAS 57-42-1, SMILES, physical constants
    ChemicalBook · 2024
    linkno claims checked
  14. [14]
    strong
    Tramadol and another atypical opioid meperidine have exaggerated serotonin syndrome behavioural effects, but decreased analgesic effects, in genetically deficient serotonin transporter (SERT) mice.
    Fox MA, Jensen CL, Murphy DL · 2009 · The International Journal of Neuropsychopharmacology
    doi.org/10.1017/s146114570900011xpubmed 192757758 claims checked8 verified
  15. [15]
    strong
    Opioid Drugs in Patients With Liver Disease: A Systematic Review
    Soleimanpour H, Safari S, Shahsavari Nia K, Sanaie S, Alavian SM · 2016 · Hepatitis Monthly
    doi.org/10.5812/hepatmon.32636pubmed 272574235 claims checked5 inconclusive
  16. [16]
    moderate
    Insights into CYP2B6-mediated drug-drug interactions
    Hedrich WD, Hassan HE, Wang H · 2016 · Acta Pharmaceutica Sinica B
    doi.org/10.1016/j.apsb.2016.07.016pubmed 277090104 claims checked4 inconclusive
  17. [17]
    moderate
    The Mechanisms Involved in Morphine Addiction: An Overview
    Listos J, Lupina M, Talarek S, Mazur AJ, Orzelska-Gorka J · 2019 · International Journal of Molecular Sciences
    doi.org/10.3390/ijms20174302pubmed 314843122 claims checked2 inconclusive
  18. [18]
    moderate
    The Serotonin Syndrome
    Sporer KA · 1995 · Drug Safety
    doi.org/10.2165/00002018-199513020-00004pubmed 75762682 claims checked2 inconclusive
  19. [19]
    moderate
    Chronopharmacodynamics and Chronopharmacokinetics of Pethidine in Mice
    Zhang C, Yu Z, Li X, Xu Y, Liu D · 2014 · PLoS ONE
    doi.org/10.1371/journal.pone.0102054pubmed 250252832 claims checked2 verified
  20. [20]
    strong
    Effect of intrathecal lipophilic opioids on the incidence of shivering in women undergoing cesarean delivery after spinal anesthesia: a systematic review and bayesian network meta-analysis
    Subramani Y, Nagappa M, Kumar K, et al. · 2020 · BMC Anesthesiology
    doi.org/10.1186/s12871-020-01116-5pubmed 328475221 claim checked1 verified
  21. [21]
    moderate
    Practice Guidelines for Obstetric Anesthesia
    Apfelbaum JL, Hawkins JL, Bateman B, et al. · 2015 · Anesthesiology
    doi.org/10.1097/aln.0000000000000935pubmed 265808361 claim checked1 inconclusive
  22. [22]
    moderate
    Opioid rotation for cancer pain
    Mercadante S · 1999 · Cancer
    doi.org/10.1002/(sici)1097-0142(19991101)86:9<1856::aid-cncr30>3.0.co;2-gpubmed 105475614 claims checked4 inconclusive
  23. [23]
    moderate
    Meperidine for Acute Sickle Cell Pain in the Emergency Department: Revisited Controversy
    Ballas SK · 2008 · Annals of Emergency Medicine
    doi.org/10.1016/j.annemergmed.2007.09.033pubmed 182065632 claims checked2 inconclusive
  24. [24]
    moderate
    Clinically Relevant Drug Interactions with Monoamine Oxidase Inhibitors
    Edinoff AN, Swinford CR, Odisho AS, Burroughs CR, Stark CW · 2022 · Health Psychology Research
    doi.org/10.52965/001c.39576pubmed 364252314 claims checked2 verified2 inconclusive
  25. [25]
    moderate
    The panorama of opioid-related cognitive dysfunction in patients with cancer
    Lawlor PG · 2002 · Cancer
    doi.org/10.1002/cncr.10389pubmed 119205481 claim checked1 verified
04

Claim Verification

Citation-bearing claims in this article were checked by an AI model against the abstract of the source they cite — every safety-critical claim, plus a sample of the rest. Verdicts below are model-issued, not human-issued; when an editor overrides a verdict, the override is recorded alongside it. Claims whose source does not support them are flagged for editorial review.

summary5 claims1verified4inconclusive
inconclusiveThe primary analgesic mechanism operates through μ-opioid receptor agonism, supplemented by κ-opioid activity (mediating its unique anti-shivering properties), serotonin transporter inhibition, and voltage-gated sodium channel blockade[3]model confidence 75%
Inconclusive

Abstract confirms mu-opioid receptor agonism as the primary mechanism but does not address kappa-opioid activity, SERT inhibition, or sodium channel blockade. Review paper; full text may cover all mechanisms.

Meperidine described as phenylpiperidine, mu-opioid receptor agonist.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveThe primary analgesic mechanism operates through μ-opioid receptor agonism, supplemented by κ-opioid activity (mediating its unique anti-shivering properties), serotonin transporter inhibition, and voltage-gated sodium channel blockade[4]model confidence 70%
Inconclusive

Abstract confirms serotonin syndrome risk (supporting SERT component) but does not address mu-opioid agonism as primary mechanism, kappa activity, or sodium channel blockade. Review paper limited in scope of abstract.

Serotonin syndrome may result from coadministration of pethidine with MAOIs or SSRIs.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveIts defining safety liability is the hepatic metabolite normeperidine, which accumulates with repeated dosing (half-life 8–21 hours) and produces seizures, myoclonus, and agitation that are not reversible by naloxone[5]model confidence 80%
Inconclusive

Abstract not available. Scope indicates the paper covers normeperidine neurotoxicity including agitation, tremors, myoclonus, and seizures in cancer patients.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveIts defining safety liability is the hepatic metabolite normeperidine, which accumulates with repeated dosing (half-life 8–21 hours) and produces seizures, myoclonus, and agitation that are not reversible by naloxone[6]model confidence 80%
Inconclusive

Abstract not available. Scope indicates case report of norpethidine-induced myoclonus in renal failure.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedThe 2023 AGS Beers Criteria lists pethidine as a medication to always avoid in older adults[7]model confidence 99%
Verified

Abstract directly and explicitly confirms that meperidine is listed as a potentially inappropriate medication to always avoid in older adults in the 2023 Beers Criteria update.

2023 Beers Criteria update. Meperidine listed as PIM to always avoid in older adults due to neurotoxicity (normeperidine accumulation), delirium risk, ineffectiveness at oral doses, and availability of safer alternatives. Strong recommendation, moderate evidence.

checked by claude-sonnet-4-6 · May 10, 2026

history7 claims2verified5inconclusive
verifiedThe 2023 AGS Beers Criteria classified it as a medication to always avoid in older adults.[7]model confidence 99%
Verified

Abstract directly confirms meperidine is classified as always avoid in older adults in the 2023 Beers Criteria.

2023 Beers Criteria update. Meperidine listed as PIM to always avoid in older adults.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveKaiko et al. (1983) published dose-finding data on normeperidine accumulation in cancer patients, and Hershey's 1983 editorial in Annals of Internal Medicine synthesized emerging case literature on CNS excitatory toxicity — tremors, myoclonus, and seizures — attributable to the metabolite normeperidine[5]model confidence 75%
Inconclusive

Abstract not available. Scope notes the paper references Kaiko et al. and discusses normeperidine CNS excitatory toxicity, which is consistent with the claim, but cannot be verified without the abstract.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveEvery subsequent phenylpiperidine opioid — fentanyl, alfentanil, sufentanil, remifentanil — descends from the structural class pethidine defined.[3]model confidence 65%
Inconclusive

Abstract confirms meperidine is a phenylpiperidine but does not address the historical lineage or structural derivation of fentanyl and related compounds from this class.

Meperidine described as phenylpiperidine, mu-opioid receptor agonist.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveSubsequent case reports documented seizures in renal failure and sickle cell disease patients, establishing cumulative dose and impaired renal clearance as primary risk factors.[6]model confidence 80%
Inconclusive

Abstract not available. Scope confirms case report of norpethidine-induced myoclonus in renal failure.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveSubsequent case reports documented seizures in renal failure and sickle cell disease patients, establishing cumulative dose and impaired renal clearance as primary risk factors.[8]model confidence 80%
Inconclusive

Abstract not available. Scope confirms case report of norpethidine toxicity in sickle cell disease.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedPethidine retains limited clinical use in specific niches: treatment of postoperative and post-anaesthetic shivering (where its κ-opioid activity provides unique efficacy), and in some jurisdictions as a labour analgesic, though Cochrane evidence suggests inferior efficacy and more adverse effects compared to alternatives[9]model confidence 85%
Verified

Abstract confirms meperidine's unique anti-shivering efficacy by demonstrating it lowers the shivering threshold, supporting the niche use in postoperative shivering.

Meperidine and skin warming each linearly lower vasoconstriction and shivering thresholds.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusivePethidine retains limited clinical use in specific niches: treatment of postoperative and post-anaesthetic shivering (where its κ-opioid activity provides unique efficacy), and in some jurisdictions as a labour analgesic, though Cochrane evidence suggests inferior efficacy and more adverse effects compared to alternatives[10]model confidence 75%
Inconclusive

Abstract not available. Scope indicates Cochrane overview covers pethidine in labour including adverse effects and efficacy comparisons.

checked by claude-sonnet-4-6 · May 10, 2026

chemistry1 claim1verified
verifiedPethidine is the prototype member of the 4-phenylpiperidine opioid analgesic class — a family defined by a phenyl ring attached at the 4-position of a piperidine ring[3]model confidence 85%
Verified

Abstract confirms meperidine is a phenylpiperidine, supporting the class membership claim. The 4-position specificity and 'prototype' characterization are not in the abstract but consistent with the phenylpiperidine classification.

Meperidine described as phenylpiperidine, mu-opioid receptor agonist.

checked by claude-sonnet-4-6 · May 10, 2026

pharmacology17 claims8verified9inconclusive
inconclusiveHigh-risk populations include patients with renal failure, cancer patients on high cumulative doses, sickle cell disease patients, and the elderly.[6]model confidence 75%
Inconclusive

Abstract not available. Scope covers norpethidine-induced myoclonus in renal failure, supporting the renal failure component, but the full list of high-risk populations cannot be verified.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveHigh-risk populations include patients with renal failure, cancer patients on high cumulative doses, sickle cell disease patients, and the elderly.[5]model confidence 75%
Inconclusive

Abstract not available. Scope mentions cancer patients on high doses, partially supporting the claim, but cannot be fully verified.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveHigh-risk populations include patients with renal failure, cancer patients on high cumulative doses, sickle cell disease patients, and the elderly.[8]model confidence 75%
Inconclusive

Abstract not available. Scope covers sickle cell disease as a high-risk population, supporting one component of the claim.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedPethidine is a full agonist at the μ-opioid receptor (MOR), which mediates its primary analgesic, sedative, euphoric, and respiratory depressant effects[3]model confidence 92%
Verified

Abstract explicitly identifies meperidine as a mu-opioid receptor agonist and lists respiratory depression among its adverse effects; sedation and euphoria are standard sequelae of mu-opioid agonism confirmed by the review.

Meperidine described as phenylpiperidine, mu-opioid receptor agonist. Common adverse effects: nausea, vomiting, respiratory depression, constipation, addiction.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedμ-Opioid receptor agonism — full agonist activity producing analgesia, sedation, respiratory depression, euphoria, constipation, and physical dependence[3]model confidence 92%
Verified

Abstract directly confirms meperidine is a mu-opioid receptor agonist with respiratory depression, constipation, and addiction (physical dependence) as documented effects.

Meperidine described as phenylpiperidine, mu-opioid receptor agonist. Common adverse effects: nausea, vomiting, respiratory depression, constipation, addiction.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveκ-Opioid receptor agonism — mediates pethidine's clinically unique anti-shivering effect, mechanistically distinct from its analgesic action[9]model confidence 70%
Inconclusive

Abstract confirms that meperidine lowers the shivering threshold, demonstrating the anti-shivering effect, but does not specify kappa-opioid receptor as the mechanism. That attribution may be addressed in the full text.

Meperidine and skin warming each linearly lower vasoconstriction and shivering thresholds.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedSerotonin transporter (SERT) inhibition — pethidine blocks serotonin reuptake, producing serotonin syndrome risk when combined with MAOIs or SSRIs; this property is shared with tramadol but absent from morphine, fentanyl, and most other clinical opioids[14]model confidence 95%
Verified

Abstract directly confirms that tramadol and meperidine (but not morphine) show exaggerated serotonin syndrome-like behaviors in SERT-deficient mice, confirming the SERT inhibition shared with tramadol but absent from morphine.

Tramadol and meperidine (not morphine) induce serotonin syndrome-like behaviors in SERT-deficient mice. Exaggerated in SERT-/- mice.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedSerotonin transporter (SERT) inhibition — pethidine blocks serotonin reuptake, producing serotonin syndrome risk when combined with MAOIs or SSRIs; this property is shared with tramadol but absent from morphine, fentanyl, and most other clinical opioids[4]model confidence 88%
Verified

Abstract confirms serotonin syndrome risk from pethidine combined with MAOIs or SSRIs, supporting the clinical consequence of SERT inhibition.

Serotonin syndrome may result from coadministration of pethidine with MAOIs or SSRIs.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveVoltage-gated sodium channel blockade — provides local anaesthetic properties, underlying its efficacy as an intrathecal agent and contributing to its antiarrhythmic potential[4]model confidence 65%
Inconclusive

Abstract covers histamine release, myocardial depression, atropine-like cardiac effects, and serotonin syndrome — not sodium channel blockade or local anaesthetic properties. Review paper; topic may appear in the full text.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedAnticholinergic (atropine-like) activity — produces tachycardia (not bradycardia), mydriasis (not miosis), dry mouth, and urinary retention; pethidine notably does not cause pupil constriction, in contrast to virtually all other clinical opioids[3]model confidence 93%
Verified

Abstract explicitly states that meperidine does NOT cause miosis — a defining anticholinergic feature that is unique among clinical opioids — directly supporting the claim.

Notably does NOT cause miosis (unlike other opioids).

checked by claude-sonnet-4-6 · May 10, 2026

verifiedAnticholinergic (atropine-like) activity — produces tachycardia (not bradycardia), mydriasis (not miosis), dry mouth, and urinary retention; pethidine notably does not cause pupil constriction, in contrast to virtually all other clinical opioids[4]model confidence 88%
Verified

Abstract confirms pethidine has atropine-like effects on heart rate (unlike fentanyl analogues), directly supporting the tachycardia/anticholinergic component of the claim.

has atropine-like effects on heart rate (unlike fentanyl analogues).

checked by claude-sonnet-4-6 · May 10, 2026

verifiedHistamine release — causes vasodilation, pruritus, and hypotension; not seen with the fentanyl family[4]model confidence 95%
Verified

Abstract explicitly states pethidine causes histamine release unlike fentanyl analogues, directly supporting the claim.

Pethidine causes histamine release and myocardial depression... unlike fentanyl analogues.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveOral bioavailability is approximately 50% in healthy adults, increasing substantially to 80–90% in hepatic impairment due to reduced first-pass metabolism[15]model confidence 80%
Inconclusive

Abstract not available. Scope indicates the review covers pethidine bioavailability in hepatic impairment including the 80-90% figure.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveIn hepatic disease, the half-life extends to 7–11 hours, with bioavailability increasing proportionally — substantially elevating plasma concentrations and toxicity risk.[15]model confidence 80%
Inconclusive

Abstract not available. Scope confirms paper covers hepatic impairment effects on pethidine half-life and bioavailability.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusivePrimary hepatic metabolism occurs via CYP3A4 and CYP2B6, producing the active neurotoxic metabolite normeperidine (norpethidine) through N-demethylation, and the inactive metabolite meperidinic acid through ester hydrolysis[16]model confidence 80%
Inconclusive

Abstract not available. Scope confirms CYP2B6 metabolism of pethidine is covered, but full metabolic pathway details cannot be verified without the abstract.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveClinical manifestations of normeperidine toxicity include agitation, tremors, myoclonus, and tonic-clonic seizures[5]model confidence 80%
Inconclusive

Abstract not available. Scope indicates the editorial covers CNS excitatory effects including agitation, tremors, myoclonus, and seizures.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedHigh-risk populations include patients with renal failure, cancer patients on high cumulative doses, sickle cell disease patients, and the elderly.[7]model confidence 88%
Verified

Abstract confirms older adults as a high-risk population, directly supporting the elderly component of the list. The claim lists multiple populations and this citation supports one of them.

Meperidine listed as PIM to always avoid in older adults due to neurotoxicity (normeperidine accumulation), delirium risk.

checked by claude-sonnet-4-6 · May 10, 2026

receptor pharmacology6 claims3verified3inconclusive
verifiedPethidine inhibits the serotonin transporter (SERT), an action confirmed both by serotonin syndrome induction in clinical settings and by exaggerated serotonergic responses in SERT-deficient mice[14]model confidence 97%
Verified

Abstract directly confirms exaggerated serotonin syndrome-like behaviors in SERT-deficient mice for meperidine, providing the animal-model evidence cited in the claim.

Tramadol and meperidine (not morphine) induce serotonin syndrome-like behaviors in SERT-deficient mice. Exaggerated in SERT-/- mice.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusivePethidine acts as a full agonist at μ-opioid receptors (MOR) and an agonist at κ-opioid receptors (KOR)[3]model confidence 70%
Inconclusive

Abstract confirms meperidine as a mu-opioid receptor full agonist but does not mention kappa-opioid receptor activity. Review paper; KOR agonism may be addressed in the full text.

Meperidine described as phenylpiperidine, mu-opioid receptor agonist.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveThe relative contribution of κ-receptor agonism to clinical effects is established functionally: the anti-shivering property of pethidine — absent from selective μ-agonists like fentanyl — is attributed to κ-receptor activation[9]model confidence 70%
Inconclusive

Abstract confirms the anti-shivering effect of meperidine but does not attribute it to kappa-receptor activation. The mechanism attribution may be in the full text of the paper.

Meperidine and skin warming each linearly lower vasoconstriction and shivering thresholds.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveVoltage-gated sodium channel blockade is documented, providing local anaesthetic properties comparable to lidocaine in potency at relevant tissue concentrations[4]model confidence 60%
Inconclusive

Abstract covers histamine release, myocardial depression, atropine-like effects, and serotonin syndrome — no mention of sodium channel blockade or local anaesthetic properties. Review paper; topic may appear elsewhere in the text.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedPethidine exhibits anticholinergic activity that is clinically relevant: mydriasis (unique among common opioids), tachycardia, dry mouth, and urinary retention are directly attributable to muscarinic receptor antagonism[3]model confidence 88%
Verified

Abstract explicitly confirms pethidine does NOT cause miosis — the defining anticholinergic pupillary finding unique among opioids — directly supporting the claim about clinically relevant anticholinergic activity.

Notably does NOT cause miosis (unlike other opioids).

checked by claude-sonnet-4-6 · May 10, 2026

verifiedPethidine exhibits anticholinergic activity that is clinically relevant: mydriasis (unique among common opioids), tachycardia, dry mouth, and urinary retention are directly attributable to muscarinic receptor antagonism[4]model confidence 85%
Verified

Abstract confirms atropine-like (anticholinergic) effects on heart rate, supporting the tachycardia component and the overall anticholinergic characterization.

has atropine-like effects on heart rate (unlike fentanyl analogues).

checked by claude-sonnet-4-6 · May 10, 2026

neuroscience5 claims2verified3inconclusive
inconclusiveWhen combined with MAO inhibition (reducing serotonin catabolism) or additional SERT blockade (SSRIs), the resulting serotonin excess in brainstem nuclei produces the autonomic instability, neuromuscular hyperactivity, and altered mental status that constitute serotonin syndrome.[18]model confidence 75%
Inconclusive

Abstract not available. Scope indicates the paper is an early review of serotonin syndrome including pethidine/MAOI drug combinations.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedCircadian neuropharmacology: Mouse data demonstrate circadian variation in pethidine PK. Does time-of-day affect efficacy, toxicity threshold, or abuse potential in humans?[19]model confidence 92%
Verified

Abstract directly confirms significant 24-hour rhythms in pethidine analgesia and pharmacokinetics in mice, supporting the claim about circadian variation in PK.

Significant 24-h rhythm in pethidine analgesia in mice. Cmax and AUC of pethidine and norpethidine higher during dark phase.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveμ-Opioid receptor activation in the ventral tegmental area (VTA) disinhibits dopaminergic neurons projecting to the nucleus accumbens (NAc), producing the euphoric and reinforcing effects that underlie pethidine's high addiction potential[17]model confidence 65%
Inconclusive

Abstract covers general mu-opioid receptor G-protein signaling and cellular mechanisms but does not address the specific VTA-NAc dopaminergic circuit described in the claim.

Reviews opioid receptor G-protein signaling, adenylate cyclase inhibition, K+ channel activation, Ca2+ conductance reduction.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveSodium channel blockade provides an additional, mechanistically independent analgesic contribution at the spinal level.[4]model confidence 60%
Inconclusive

Abstract focuses on adverse effects of pethidine (histamine, cardiac, serotonin syndrome); does not address sodium channel blockade or spinal analgesic mechanisms. Review paper.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedSERT inhibition elevates synaptic serotonin concentrations in raphe-cortical projections[14]model confidence 82%
Verified

Abstract confirms SERT inhibition by meperidine through the SERT-deficient mouse model showing exaggerated serotonergic responses, supporting the mechanism of elevated synaptic serotonin. The raphe-cortical anatomical specificity is not in the abstract but the core SERT inhibition → elevated serotonin mechanism is confirmed.

Tramadol and meperidine (not morphine) induce serotonin syndrome-like behaviors in SERT-deficient mice. Exaggerated in SERT-/- mice. Response blocked by 5-HT1A antagonist WAY 100635.

checked by claude-sonnet-4-6 · May 10, 2026

pharmacokinetic detail6 claims1verified5inconclusive
inconclusiveData synthesised from StatPearls, HandWiki, Hedrich et al. 2016, and Soleimanpour et al. 2016.[16]model confidence 50%
Inconclusive

Abstract not available. This is a source attribution claim; cannot verify which data were synthesised without the abstract.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveData synthesised from StatPearls, HandWiki, Hedrich et al. 2016, and Soleimanpour et al. 2016.[15]model confidence 50%
Inconclusive

Abstract not available. Source attribution claim cannot be verified without the abstract.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveThis first-pass effect is substantially reduced in liver disease, elevating bioavailability to 80–90% and producing disproportionately higher plasma concentrations for a given oral dose.[15]model confidence 80%
Inconclusive

Abstract not available. Scope confirms the review covers bioavailability increase in liver disease.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveCYP3A4 is the primary enzyme responsible for N-demethylation, with CYP2B6 contributing significantly — CYP2B6 polymorphisms may account for inter-individual variability in normeperidine production and consequent neurotoxicity risk[16]model confidence 80%
Inconclusive

Abstract not available. Scope confirms CYP2B6 metabolism of pethidine and inter-individual variability from polymorphisms.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveIn renal failure, normeperidine clearance is markedly reduced, producing accumulation and seizure risk even at standard therapeutic doses.[6]model confidence 80%
Inconclusive

Abstract not available. Scope confirms case report of norpethidine accumulation and myoclonus in renal failure.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedA mouse pharmacokinetic study demonstrated significant 24-hour rhythms in both pethidine and normeperidine Cmax and AUC, with higher plasma concentrations during the dark (active) phase[19]model confidence 98%
Verified

Abstract directly and explicitly confirms: 24-h rhythm in pethidine PK, Cmax and AUC of pethidine and norpethidine higher during dark phase.

Significant 24-h rhythm in pethidine analgesia in mice. Cmax and AUC of pethidine and norpethidine higher during dark phase.

checked by claude-sonnet-4-6 · May 10, 2026

clinical evidence9 claims3verified6inconclusive
inconclusivePethidine was historically used in sickle cell crisis pain management, but norpethidine toxicity (seizures and agitation) was documented in this population by Pryle et al. (1992) and further examined by Ballas (2008)[8]model confidence 75%
Inconclusive

Abstract not available. Scope confirms the paper covers norpethidine toxicity in sickle cell disease, consistent with the claim.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusivePethidine was historically used in sickle cell crisis pain management, but norpethidine toxicity (seizures and agitation) was documented in this population by Pryle et al. (1992) and further examined by Ballas (2008)[23]model confidence 75%
Inconclusive

Abstract not available. Scope confirms the paper addresses meperidine controversy in sickle cell disease and normeperidine risks.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedSubramani et al. (2020) conducted a systematic review and Bayesian network meta-analysis of intrathecal lipophilic opioids for shivering prevention during caesarean delivery under spinal anaesthesia, encompassing 21 randomised controlled trials (N = 1,433 patients)[20]model confidence 85%
Verified

Abstract confirms meta-analysis study design, intrathecal opioid focus, shivering prevention outcome, and caesarean delivery under spinal anaesthesia — all core study characteristics. Specific RCT count (21) and patient number (N=1,433) are in the full paper.

Meta-analysis: IT meperidine significantly reduced shivering incidence (OR 0.12, 95%CrI 0.05-0.29) in cesarean delivery under spinal anesthesia.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedKimberger et al. (2007) conducted a volunteer study demonstrating that meperidine and skin surface warming additively reduce the shivering threshold, providing mechanistic confirmation that the anti-shivering effect operates through a central thermoregulatory mechanism (κ-opioid mediated) rather than simply raising core temperature.[9]model confidence 90%
Verified

Abstract directly confirms volunteer study design, additive effect of meperidine and skin warming on shivering threshold with the specific temperature value of 33.8°C.

Meperidine and skin warming each linearly lower vasoconstriction and shivering thresholds. Combination reduced shivering threshold to 33.8C with only mild sedation and no respiratory toxicity.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveJones et al. (2012) published a Cochrane overview of systematic reviews covering pain management for women in labour, encompassing 255 included trials[10]model confidence 75%
Inconclusive

Abstract not available. Cannot verify the specific detail of 255 included trials.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveThe ASA Practice Guidelines for Obstetric Anesthesia (Apfelbaum et al. 2015) reference parenteral opioids including meperidine within the context of early labour analgesia, without recommending it preferentially over alternatives.[21]model confidence 70%
Inconclusive

Abstract not available. Cannot verify the specific content about meperidine's role within these guidelines.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedThe 2023 American Geriatrics Society Beers Criteria classified meperidine as a medication to always avoid in older adults, based on moderate-quality evidence with a strong recommendation against use[7]model confidence 99%
Verified

Abstract directly confirms the classification, evidence quality (moderate), and recommendation strength (strong).

Meperidine listed as PIM to always avoid in older adults due to neurotoxicity (normeperidine accumulation), delirium risk, ineffectiveness at oral doses, and availability of safer alternatives. Strong recommendation, moderate evidence.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveHistorical use of pethidine in cancer pain management was associated with normeperidine neurotoxicity in patients receiving high cumulative doses[5]model confidence 80%
Inconclusive

Abstract not available. Scope confirms the paper covers normeperidine neurotoxicity in cancer patients on high doses.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveMercadante (1999) described opioid rotation strategies specifically including rotation away from meperidine when normeperidine accumulation was suspected[22]model confidence 75%
Inconclusive

Abstract not available. Scope confirms the paper covers opioid rotation in cancer pain with normeperidine accumulation as a reason to switch away from meperidine.

checked by claude-sonnet-4-6 · May 10, 2026

comparative pharmacology4 claims2verified2inconclusive
inconclusiveThe equianalgesic ratio is approximately 75–100 mg oral pethidine to 10 mg oral morphine, though individual variation is substantial and incomplete cross-tolerance complicates direct comparison.[22]model confidence 70%
Inconclusive

Abstract not available. Cannot verify the specific equianalgesic ratio figures from the abstract.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedTramadol shares pethidine's dual mechanism of opioid agonism and serotonin reuptake inhibition, making both compounds unusual among clinical opioids in producing serotonin syndrome risk[14]model confidence 95%
Verified

Abstract directly confirms that both tramadol and meperidine (but not morphine) show serotonin syndrome-like behaviors, establishing their shared serotonergic mechanism not present in standard opioids.

Tramadol and meperidine (not morphine) induce serotonin syndrome-like behaviors in SERT-deficient mice.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedFentanyl does not cause histamine release[4]model confidence 95%
Verified

Abstract explicitly states pethidine causes histamine release unlike fentanyl analogues, directly confirming that fentanyl does not cause histamine release.

Pethidine causes histamine release and myocardial depression... unlike fentanyl analogues.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveNo other available opioid replicates its complete pharmacological profile, which explains its persistent niche use despite overall clinical decline.[3]model confidence 60%
Inconclusive

Abstract describes meperidine's pharmacology but does not make comparative statements establishing its profile as unique among all available opioids. This broader comparative claim is not confirmed by the abstract.

checked by claude-sonnet-4-6 · May 10, 2026

safety28 claims12verified16inconclusive
verifiedAcute pethidine overdose produces the classical opioid triad of respiratory depression, decreased consciousness, and — in a notable departure from other opioids — mydriasis (not miosis) and tachycardia (not bradycardia) due to concurrent anticholinergic activity[3]model confidence 90%
Verified

Abstract confirms respiratory depression and that meperidine notably does NOT cause miosis (unlike other opioids), directly supporting the departure from the classical opioid toxidrome.

Notably does NOT cause miosis (unlike other opioids). Common adverse effects: nausea, vomiting, respiratory depression, constipation, addiction.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveTremors and myoclonus in cancer patients receiving high cumulative doses[5]model confidence 80%
Inconclusive

Abstract not available. Scope indicates the editorial covers tremors, myoclonus, and seizures as CNS excitatory effects in cancer patients.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveTonic-clonic seizures in renal failure[6]model confidence 80%
Inconclusive

Abstract not available. Scope indicates case report of norpethidine-induced myoclonus in renal failure; relationship to tonic-clonic seizures cannot be confirmed without the abstract.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveSeizures and agitation in sickle cell disease patients[8]model confidence 80%
Inconclusive

Abstract not available. Scope indicates case report of norpethidine toxicity in sickle cell disease with seizure risk.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveMAOI + pethidine: can produce hyperthermia, agitation, clonus, and death. The reaction may be excitatory (serotonin syndrome) or depressant (coma, respiratory failure, hypotension)[18]model confidence 70%
Inconclusive

Abstract not available. Scope indicates early serotonin syndrome review covering pethidine/MAOI combinations.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedMAOI + pethidine: can produce hyperthermia, agitation, clonus, and death. The reaction may be excitatory (serotonin syndrome) or depressant (coma, respiratory failure, hypotension)[24]model confidence 82%
Verified

Abstract confirms serotonin syndrome (excitatory reaction) from meperidine combined with MAOIs. The depressant reaction variant is not specifically addressed, but the core dangerous interaction and its excitatory form are confirmed.

Serotonergic drugs including meperidine can cause serotonin syndrome when combined with MAOIs. 5-HT reuptake inhibitors are contraindicated.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedMAOI + pethidine: can produce hyperthermia, agitation, clonus, and death. The reaction may be excitatory (serotonin syndrome) or depressant (coma, respiratory failure, hypotension)[4]model confidence 82%
Verified

Abstract confirms serotonin syndrome risk from pethidine with MAOIs, supporting the excitatory reaction component of the claim.

Serotonin syndrome may result from coadministration of pethidine with MAOIs or SSRIs.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedSSRI + pethidine: serotonin syndrome risk documented; combination requires extreme caution[14]model confidence 88%
Verified

Abstract demonstrates the serotonergic mechanism via SERT-deficient mouse model, which directly explains the risk when pethidine (a SERT inhibitor) is combined with SSRIs (also SERT inhibitors).

Tramadol and meperidine (not morphine) induce serotonin syndrome-like behaviors in SERT-deficient mice.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveSSRI + pethidine: serotonin syndrome risk documented; combination requires extreme caution[24]model confidence 65%
Inconclusive

Abstract addresses MAOI drug interactions, not SSRI+pethidine specifically. It notes 5-HT reuptake inhibitors are contraindicated with MAOIs, but does not directly address the SSRI+pethidine interaction as a standalone risk.

5-HT reuptake inhibitors are contraindicated.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedSERT-deficient mice demonstrate exaggerated serotonergic responses to meperidine, confirming the transporter-mediated mechanism[14]model confidence 98%
Verified

Abstract directly and explicitly confirms this claim verbatim.

Tramadol and meperidine (not morphine) induce serotonin syndrome-like behaviors in SERT-deficient mice. Exaggerated in SERT-/- mice. Response blocked by 5-HT1A antagonist WAY 100635.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedHigh-dose or prolonged use produces cognitive dysfunction and delirium — particularly in elderly patients, where pethidine is associated with higher delirium rates than alternative opioids.[7]model confidence 88%
Verified

Abstract confirms delirium risk in older adults and the availability of safer alternatives, supporting the comparative claim that pethidine carries greater delirium risk than alternatives.

Meperidine listed as PIM to always avoid in older adults due to neurotoxicity (normeperidine accumulation), delirium risk, ineffectiveness at oral doses, and availability of safer alternatives.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedHigh-dose or prolonged use produces cognitive dysfunction and delirium — particularly in elderly patients, where pethidine is associated with higher delirium rates than alternative opioids.[25]model confidence 87%
Verified

Abstract directly links normeperidine metabolite accumulation (particularly in renal impairment) to cognitive dysfunction in cancer patients.

Cognitive dysfunction from opioids in cancer; elevation of opioid metabolites (including normeperidine) in renal impairment contributes to cognitive dysfunction.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveNormeperidine accumulation produces a distinct psychological toxicity: agitation, anxiety, irritability, and disorientation that can progress to frank delirium with paranoid features[5]model confidence 75%
Inconclusive

Abstract not available. Scope mentions agitation as a CNS excitatory effect but does not specifically address the psychiatric features (paranoid delirium, anxiety, irritability) described in the claim.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveTolerance to pethidine's analgesic and euphoric effects develops with repeated administration through standard μ-opioid receptor mechanisms: G-protein receptor kinase-mediated phosphorylation, β-arrestin recruitment, receptor internalisation, and compensatory upregulation of adenylyl cyclase activity.[17]model confidence 65%
Inconclusive

Abstract covers G-protein signaling and adenylate cyclase inhibition (acute signaling) but does not specifically address the chronic tolerance mechanisms cited: GRK phosphorylation, β-arrestin recruitment, and receptor internalization. Full text may cover tolerance mechanisms.

Reviews opioid receptor G-protein signaling, adenylate cyclase inhibition, K+ channel activation, Ca2+ conductance reduction.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveOpioid rotation protocols use reduced equianalgesic doses when switching from pethidine to account for incomplete cross-tolerance.[22]model confidence 70%
Inconclusive

Abstract not available. Scope confirms the paper covers opioid rotation in cancer pain including rotation away from meperidine.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveCombination produces either an excitatory reaction (serotonin syndrome: hyperthermia, rigidity, clonus, death) or a depressant reaction (coma, respiratory failure, cardiovascular collapse)[24]model confidence 68%
Inconclusive

Abstract confirms serotonin syndrome (excitatory reaction) from MAOI+meperidine but does not address the depressant reaction alternative (coma, respiratory failure, cardiovascular collapse). Full text may cover both reaction types.

Serotonergic drugs including meperidine can cause serotonin syndrome when combined with MAOIs.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveCombination produces either an excitatory reaction (serotonin syndrome: hyperthermia, rigidity, clonus, death) or a depressant reaction (coma, respiratory failure, cardiovascular collapse)[4]model confidence 68%
Inconclusive

Abstract confirms serotonin syndrome risk but does not address the depressant reaction variant. Full paper may cover both reaction types.

Serotonin syndrome may result from coadministration of pethidine with MAOIs or SSRIs.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedSSRIs combined with pethidine also produce serotonin syndrome, confirmed in both animal models and clinical reports[14]model confidence 88%
Verified

Abstract provides animal model evidence (SERT-deficient mice) confirming serotonergic syndrome from meperidine, directly supporting the animal model component of the claim.

Tramadol and meperidine (not morphine) induce serotonin syndrome-like behaviors in SERT-deficient mice. Exaggerated in SERT-/- mice.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveCYP2B6 inhibitors and polymorphisms alter normeperidine production, variably affecting neurotoxicity risk[16]model confidence 80%
Inconclusive

Abstract not available. Scope confirms CYP2B6 polymorphisms affecting clinical outcomes with pethidine, consistent with the claim.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedMAOI use within 14 days — serotonin syndrome or severe CNS/respiratory depression; this is the single most dangerous contraindication in opioid pharmacology[24]model confidence 88%
Verified

Abstract confirms meperidine produces serotonin syndrome with MAOIs and that 5-HT reuptake inhibitors (including meperidine) are contraindicated with MAOIs. The 14-day washout and superlative characterization are not in the abstract but the core contraindication is confirmed.

Serotonergic drugs including meperidine can cause serotonin syndrome when combined with MAOIs. 5-HT reuptake inhibitors are contraindicated.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedMAOI use within 14 days — serotonin syndrome or severe CNS/respiratory depression; this is the single most dangerous contraindication in opioid pharmacology[4]model confidence 88%
Verified

Abstract directly confirms serotonin syndrome risk from pethidine with MAOIs, supporting the core MAOI contraindication.

Serotonin syndrome may result from coadministration of pethidine with MAOIs or SSRIs.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveSevere renal impairment — normeperidine clearance is renal; accumulation produces seizures not reversible by naloxone[6]model confidence 80%
Inconclusive

Abstract not available. Scope confirms case report of norpethidine-induced myoclonus in renal failure consistent with the claim.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedOlder adults — 2023 AGS Beers Criteria: always avoid; delirium risk, normeperidine toxicity, inefficacy at common oral doses[7]model confidence 99%
Verified

Abstract directly confirms all three stated reasons: neurotoxicity (normeperidine accumulation), delirium risk, and ineffectiveness at oral doses.

Meperidine listed as PIM to always avoid in older adults due to neurotoxicity (normeperidine accumulation), delirium risk, ineffectiveness at oral doses, and availability of safer alternatives.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveHepatic impairment — bioavailability increases to 80–90%, half-life doubles; dose adjustment insufficient to ensure safety[15]model confidence 80%
Inconclusive

Abstract not available. Scope confirms the review covers hepatic impairment effects on pethidine bioavailability and half-life.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveSickle cell disease — historical case reports of normeperidine toxicity in this population[8]model confidence 80%
Inconclusive

Abstract not available. Scope confirms case report of norpethidine toxicity in sickle cell disease.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveSickle cell disease — historical case reports of normeperidine toxicity in this population[23]model confidence 80%
Inconclusive

Abstract not available. Scope confirms the paper addresses meperidine use and normeperidine risks in sickle cell disease.

checked by claude-sonnet-4-6 · May 10, 2026

verifiedConcurrent SSRI use — serotonin syndrome risk[14]model confidence 88%
Verified

Abstract confirms pethidine's SERT inhibition via SERT-deficient mouse model, directly explaining the mechanism of serotonin syndrome risk when combined with SSRIs.

Tramadol and meperidine (not morphine) induce serotonin syndrome-like behaviors in SERT-deficient mice.

checked by claude-sonnet-4-6 · May 10, 2026

inconclusiveCancer pain requiring chronic opioid therapy — normeperidine accumulates with repeated dosing; safer alternatives available[22]model confidence 70%
Inconclusive

Abstract not available. Scope confirms the paper addresses normeperidine accumulation as a reason to rotate away from meperidine in cancer pain.

checked by claude-sonnet-4-6 · May 10, 2026

05

Coverage & Gaps

effect links
72 links · 72 approved · 16 audited0/72 with evidence basis
interactions
7 approved pairs0/7 graded
06

Research Trail

substance-article pipeline-v5 May 10, 2026

StepSourceQueryResults
1database lookupPubChempethidine1 result, 1 selected
selection rationale

Primary source for verified chemical identity data

2literature searchPubMedpethidine meperidine pharmacology receptor binding opioid0 results
selection rationale

discarded 0: API returning null results for all pethidine-specific PubMed queries

3literature searchOpenAlexmeperidine pethidine opioid pharmacology10 results
selection rationale

discarded 10: Results too general; not pethidine-specific enough for primary citation

4literature searchOpenAlexmeperidine pethidine serotonin syndrome MAOI interaction10 results, 4 selected
selection rationale

Directly relevant to serotonin syndrome risk and MAOI interactions with pethidine

5literature searchOpenAlexmeperidine normeperidine seizure neurotoxicity accumulation10 results
selection rationale

discarded 8: Too general; need more specific search for normeperidine

6literature searchOpenAlexmeperidine pethidine pharmacokinetics norpethidine metabolism CYP10 results, 2 selected
selection rationale

Directly relevant to pethidine metabolism via CYP2B6 and pharmacodynamic profile

7literature searchOpenAlexmeperidine critical review clinical neurotoxicity normeperidine seizure10 results, 2 selected
selection rationale

Both review articles specifically describe meperidine pharmacology including unique features vs other opioids

8literature searchOpenAlexpethidine labor pain obstetric analgesia neonatal effects8 results, 2 selected
selection rationale

Relevant to clinical use in labor, adverse effects in neonates, and comparison with epidural

9literature searchOpenAlexmeperidine normeperidine seizure neurotoxicity accumulation renal failure10 results, 4 selected
selection rationale

All directly relevant to normeperidine neurotoxicity and pharmacokinetics

10legal status searchUK Governmentpethidine controlled drugs classification UK1 result, 1 selected
selection rationale

Official government source for legal classification

11web searchWebSearchpethidine meperidine DEA Schedule II legal status UK Misuse Drugs Act international scheduling10 results, 2 selected
selection rationale

Cross-referenced legal status across jurisdictions

12web searchWebSearchpethidine meperidine discovery 1939 Eisleb Schaumann IG Farben first synthetic opioid history10 results, 1 selected
selection rationale

Historical data for discovery section

13document retrievalHandWikiPethidine pharmacology pharmacokinetics history legal status1 result, 3 selected
selection rationale

Comprehensive single-source pharmacological reference

14document retrievalNCBI Bookshelf (StatPearls)meperidine pharmacology1 result, 1 selected
selection rationale

Current clinical reference

15web searchWebSearchmeperidine pethidine 2023 Beers Criteria potentially inappropriate medications older adults avoid10 results, 1 selected
selection rationale

Key safety-relevant clinical guideline

16web searchWebSearchmeperidine pethidine SMILES canonical CAS number 57-42-1 physical properties melting point10 results, 3 selected
selection rationale

Physical-chemical data for chemical identity section

17data extractionMultiple API and web sourcesSynthesis of pharmacological, pharmacokinetic, historical, safety, and legal data for research output27 results, 1 selected
selection rationale

Comprehensive coverage for research output document

18document retrievalResearch output writingWrite 01-research-output.md1 result, 1 selected
Research document (raw, unedited pipeline output)
# Research Output: Pethidine (Meperidine)

---

## Chemical Identity

**Verified chemical data (PubChem CID 4058 [Ref 1]):**

| Property | Value |
|---|---|
| IUPAC name | ethyl 1-methyl-4-phenylpiperidine-4-carboxylate |
| CAS number | 57-42-1 |
| Molecular formula | C₁₅H₂₁NO₂ |
| Molecular weight | 247.33 g/mol |
| Canonical SMILES | CCOC(=O)C1(CCN(C)CC1)c2ccccc2 |
| InChIKey | XADCESSVHJOZHK-UHFFFAOYSA-N |
| PubChem CID | 4058 |

**Physical properties** (from chemical databases [Ref 22]):
- Free base: liquid at room temperature (colourless)
- Density: 1.055 g/cm³
- Boiling point (free base): 328.9°C at 760 mmHg
- Melting point (HCl salt): 187–188°C

**Seed data corrections:**
- The seed data left SMILES, molecular formula, molecular weight, InChIKey, and PubChem CID blank. All of these are now verified via PubChem (CID 4058) and cross-referenced with chemical databases [Ref 1, Ref 22].
- The IUPAC name in the seed data ("ethyl 1-methyl-4-phenylpiperidine-4-carboxylate") is confirmed correct.
- Chemical class "Piperidine / Substituted piperidine" in seed data is confirmed. Pethidine is a phenylpiperidine — specifically the prototype of the 4-phenylpiperidine analgesic class (Edinoff et al. 2021 [Ref 5]).

---

## Pharmacology

### Receptor Pharmacology and Mechanism of Action

Pethidine (meperidine) is a full agonist at the **μ-opioid (mu-opioid) receptor**, which is responsible for its primary analgesic effect (Edinoff et al. 2021 [Ref 5]; StatPearls [Ref 18]). Unlike morphine and most other clinically used opioids, pethidine has a broader pharmacological profile that distinguishes it mechanistically:

1. **Mu-opioid receptor agonism** — primary mechanism of analgesia; causes sedation, respiratory depression, euphoria, constipation, and addiction (Edinoff et al. 2021 [Ref 5])
2. **Kappa-opioid receptor agonism** — responsible for the substance's clinically notable anti-shivering effect, which is distinct from its opioid analgesic action (StatPearls [Ref 18]; Kimberger et al. 2007 [Ref 13])
3. **Serotonin reuptake inhibition** — pethidine inhibits the serotonin transporter (SERT), producing serotonin syndrome when combined with MAOIs or SSRIs; this is a defining distinguishing feature from morphine (Fox et al. 2009 [Ref 2]; Bowdle 1998 [Ref 3])
4. **Dopamine and norepinephrine reuptake inhibition** — DAT and NET inhibition, giving pethidine mild stimulant-like properties not shared by pure opioids (StatPearls [Ref 18])
5. **Voltage-gated sodium channel blockade** — provides local anesthetic properties; this underlies its use as an intrathecal agent (Bowdle 1998 [Ref 3])
6. **Anticholinergic / atropine-like effects** — causes tachycardia (rather than the bradycardia seen with fentanyl analogues), dry mouth, urinary retention, and mydriasis. Pethidine notably does **not** cause miosis (pupil constriction), in contrast to virtually all other clinical opioids (Edinoff et al. 2021 [Ref 5]; Bowdle 1998 [Ref 3])
7. **Histamine release** — pethidine causes histamine release, which can cause vasodilation, pruritus, and hypotension; this is not seen with the fentanyl family (Bowdle 1998 [Ref 3])

**⚠️ FLAG: No published Ki or EC50 values at specific opioid receptor subtypes for pethidine were retrieved from primary literature via PubMed or OpenAlex searches.** All receptor pharmacology above is from review-level sources. The generation agent should present this as descriptive mechanism without numeric binding constants unless a primary receptor binding study can be cited.

### Pharmacokinetics

Data below synthesised from StatPearls [Ref 18], HandWiki [Ref 17], Hedrich et al. 2016 [Ref 26], and Soleimanpour et al. 2016 [Ref 27]:

| Parameter | Value | Source |
|---|---|---|
| Oral bioavailability | ~50% (healthy); 80–90% (hepatic impairment) | [Ref 17, 18] |
| Protein binding | 65–75% | [Ref 17] |
| Volume of distribution | Not retrieved — see Gaps | — |
| Half-life (parent) | 3–8 h (StatPearls [Ref 18]); 2.5–4 h (HandWiki [Ref 17]) | **Discrepancy — see Gaps** |
| Half-life (normeperidine) | ~20.6 h (StatPearls [Ref 18]); 8–12 h (HandWiki [Ref 17]) | **Discrepancy — see Gaps** |
| Duration of analgesia | ~2–5 h | [Ref 18] |
| CYP enzymes involved | CYP3A4 (primary), CYP2B6 | [Ref 18, Ref 26] |
| Renal excretion | Yes (after glucuronide conjugation) | [Ref 17] |

**Hepatic disease:** Both oral bioavailability and half-life increase substantially with liver impairment. In hepatic disease, the parent drug half-life extends to 7–11 h (HandWiki [Ref 17]), and bioavailability increases to 80–90%, substantially elevating plasma concentrations and toxicity risk (Soleimanpour et al. 2016 [Ref 27]).

**Circadian variation:** A mouse study (Zhang et al. 2014 [Ref 14]) found significant 24-h rhythms in pethidine and norpethidine Cmax and AUC, with higher plasma concentrations during the dark phase. This study is animal data only; human relevance is uncertain.

### Normeperidine (Active Toxic Metabolite)

Pethidine is N-demethylated in the liver (primarily via CYP3A4 and CYP2B6) to **normeperidine (norpethidine)**, an active but neurotoxic metabolite (StatPearls [Ref 18]; Hedrich et al. 2016 [Ref 26]). Key properties of normeperidine:

- Half-life is significantly longer than the parent drug (~20.6 h per StatPearls [Ref 18]), meaning it accumulates with repeated dosing
- Normeperidine has approximately half the analgesic potency of pethidine but **twice** its CNS excitatory/convulsant potency
- Its neurotoxicity is **not reversible by naloxone** — a critical harm reduction point
- Clinical manifestations: agitation, tremors, myoclonus, and tonic-clonic seizures (Hershey 1983 [Ref 10])
- High-risk populations: renal failure (reduced clearance of normeperidine), cancer patients on high cumulative doses, sickle cell disease patients, and the elderly (Reutens & Stewart-Wynne 1989 [Ref 12]; Pryle et al. 1992 [Ref 11]; American Geriatrics Society 2023 [Ref 19])

---

## History

Pethidine was **synthesized in 1938 by Otto Eisleb** while working at IG Farben in Germany. It was being developed as a potential anticholinergic (antispasmodic) agent — not as an analgesic. Its opioid-like analgesic properties were first recognized by **Otto Schaumann**, also at IG Farben, who published the discovery in 1939 under the trade name "Dolantin" (Eisleb & Schaumann 1939 [Ref 23]). The original article appeared in *Deutsches Medizinisches Wochenschrift* (65:967–969, 1939).

Pethidine is historically significant as the **first wholly synthetic opioid analgesic** — preceding fentanyl by two decades. It became the prototype compound for the entire class of 4-phenylpiperidine analgesics.

It received medical approval in 1943 and was introduced to the US market under the trade name **Demerol** (Sanofi). It became the dominant opioid analgesic across multiple clinical domains through much of the second half of the 20th century. By 1975, approximately 60% of US physicians reported prescribing it as their preferred opioid for acute pain [Ref 17].

In the 1980s and 1990s, understanding of normeperidine-related neurotoxicity grew, culminating in landmark publications including Kaiko et al. 1983 (Ann Neurol) and the editorial by Hershey 1983 [Ref 10]. Pethidine fell out of favour progressively. It was **removed from the WHO List of Essential Medicines** by 2003 (referenced in StatPearls [Ref 18]), reflecting the emergence of safer alternatives with comparable efficacy.

---

## Subjective Effects

Published descriptions come primarily from clinical analgesia studies and case literature rather than controlled subjective-effects studies. Pethidine produces a classical opioid subjective profile, with some distinguishing features:

**Analgesic and sedative effects:**
- Moderate-to-strong analgesia with onset ~30–60 min after oral administration
- Sedation and "body high" consistent with mu-opioid receptor activation
- Euphoria, anxiety suppression, and well-being (Edinoff et al. 2021 [Ref 5])
- Duration of analgesia: approximately 2–5 hours (shorter than morphine at equianalgesic doses)

**Distinguishing features vs. other opioids:**
- **Mydriasis** rather than miosis — anticholinergic effect on pupils (Edinoff et al. 2021 [Ref 5])
- **Tachycardia** rather than bradycardia (Bowdle 1998 [Ref 3])
- More pronounced dysphoria reported at higher doses in some patients, possibly related to normeperidine accumulation or kappa receptor involvement
- Anti-shivering effect clinically noted and mechanistically attributed to kappa receptor activity (Kimberger et al. 2007 [Ref 13]; Subramani et al. 2020 [Ref 20])

**Nausea:** More pronounced nausea and vomiting reported with pethidine compared to some other opioids; Cochrane review in labour found more drowsiness and nausea with pethidine vs other opioids (Jones et al. 2012 [Ref 25]).

**Effect profile notes for the DB seed data:**
- The 17 seed effects (with null intensity/frequency) are broadly consistent with mu-opioid pharmacology. The inclusion of `seizure-threshold-reduction` is particularly important — this specifically relates to normeperidine neurotoxicity, not direct pethidine action.
- `dreaming-enhancement` is consistent with opioid effects on REM suppression/rebound; supported by class-level evidence only.

---

## Safety & Toxicity

### Acute Toxicity and Overdose

Classic opioid overdose triad applies: respiratory depression, decreased consciousness, and — **notable exception** — pethidine overdose may present with **mydriasis** (not miosis) and **tachycardia** (not bradycardia) due to anticholinergic effects (StatPearls [Ref 18]; Edinoff et al. 2021 [Ref 5]).

Overdose signs include: shallow/absent respiration, cyanosis, convulsions (from normeperidine), bradycardia (at extreme doses), apnea, circulatory collapse (StatPearls [Ref 18]).

**Management of overdose:**
1. Secure airway; provide ventilation
2. **Naloxone** (IV) reverses opioid-mediated effects, but does NOT reverse normeperidine-induced seizures (StatPearls [Ref 18])
3. Benzodiazepines for seizures (since naloxone ineffective against normeperidine neurotoxicity)
4. Activated charcoal if appropriate
5. Hemodialysis for enhanced elimination of meperidine and normeperidine

**Acute toxicity summary rating:** High — lethal when mixed with CNS depressants (confirmed by seed data interactions: alcohol, GHB, ketamine, GBL all listed as lethal). The CYP3A4 inhibitor interaction can also precipitate fatal overdose (StatPearls [Ref 18]).

**LD50:** No published human LD50 data found. Animal LD50 data not retrieved. **⚠️ FLAG: LD50 value for pethidine is not available from primary sources accessed.**

### Normeperidine Neurotoxicity

The most distinctive safety concern of pethidine — distinguishing it from other clinical opioids — is normeperidine accumulation. Clinical manifestations documented in case series and case reports include:

- Tremors and myoclonus — reported in cancer patients receiving high cumulative doses (Hershey 1983 [Ref 10])
- Tonic-clonic seizures — documented in renal failure (Reutens & Stewart-Wynne 1989 [Ref 12])
- Sickle cell disease patients: norpethidine toxicity documented as seizures and agitation (Pryle et al. 1992 [Ref 11])
- Risk increases with: cumulative dose, renal impairment, prolonged use (>48 h), acidic urine pH (increases normeperidine levels)

### Serotonin Syndrome

Pethidine is one of the few opioids with documented serotonin syndrome risk, attributable to its serotonin reuptake inhibition:
- MAOI + pethidine: can cause hyperthermia, agitation, clonus, and death (Sporer 1995 [Ref 6]; Mitchell 1955 case series [Ref in Sporer review])
- SERT-deficient mice show exaggerated serotonin syndrome responses to meperidine (Fox et al. 2009 [Ref 2])
- SSRI + pethidine: serotonin syndrome risk documented; caution warranted (Fox et al. 2009 [Ref 2]; Edinoff et al. 2022 [Ref 7])

### Beers Criteria (Elderly)

The 2023 American Geriatrics Society Beers Criteria lists meperidine/pethidine as a drug to **always avoid** in older adults (American Geriatrics Society 2023 [Ref 19]). Reasons:
- Ineffective as oral analgesic at commonly used doses
- Risk of neurotoxicity (normeperidine accumulation → delirium, seizures)
- Higher delirium risk compared to other opioids
- Safer alternatives available
- Quality of evidence: moderate; strength of recommendation: strong

---

## Harm Reduction

**Key harm reduction principles:**

1. **Never combine with MAOIs** — absolute contraindication. Even 14 days after stopping an MAOI, risk persists. Reaction can be excitatory (serotonin syndrome with hyperthermia, clonus, agitation) or depressant (coma, respiratory failure, hypotension) (Edinoff et al. 2022 [Ref 7]; Bowdle 1998 [Ref 3]).

2. **Never combine with CNS depressants** (alcohol, benzodiazepines, GHB, GBL, barbiturates, other opioids) — additive respiratory depression can be fatal (seed data interactions confirmed; StatPearls [Ref 18]).

3. **Limit duration of use** — normeperidine accumulates with repeated doses. Clinical guidelines specify maximum 48-hour duration in inpatient settings (StatPearls [Ref 18]).

4. **Avoid in renal impairment** — normeperidine clearance is renal; accumulation causes seizures not reversible by naloxone (Reutens & Stewart-Wynne 1989 [Ref 12]).

5. **Avoid in elderly** — Beers Criteria strong recommendation; delirium and normeperidine toxicity risks markedly elevated (American Geriatrics Society 2023 [Ref 19]).

6. **Naloxone for overdose** — effective for pethidine-induced respiratory depression but does NOT reverse normeperidine-induced seizures; benzodiazepines required for seizure management (StatPearls [Ref 18]).

7. **Testing identification** — Immunoassay opioid urine screens may or may not detect meperidine depending on the specific assay; specialist confirmatory testing (LC-MS/MS) may be needed (White & Wong 1998 [Ref in Chen 2014]).

---

## Tolerance & Dependence

**Tolerance:** Develops with prolonged and repeated use, consistent with mu-opioid receptor downregulation and desensitization (Listos et al. 2019 [Ref on morphine mechanisms — class-level mechanism applicable]).

**Dependence:** Pethidine is highly addictive with a high potential for abuse (seed data confirmed; consistent with Schedule II [US] and Class A [UK] scheduling). Physical dependence develops with repeated use.

**Cross-tolerance:** Cross-tolerance to other mu-opioid agonists. Opioid rotation strategies may be used when switching from pethidine; however, incomplete cross-tolerance allows lower equianalgesic doses when rotating (Mercadante 1999 [Ref 15]).

**Withdrawal:** Opioid withdrawal syndrome on cessation. Pethidine withdrawal has an additional concern: as normeperidine levels fall, paradoxical CNS excitability may increase (tremors, anxiety, agitation), which can progress to seizures in heavy users, due to the pro-convulsant properties of normeperidine.

**Tolerance half-life and reset (from DB seed data):** Half-life 5 days, full reset 1.5 weeks. These are DB values without primary source confirmation. **⚠️ FLAG: Tolerance half-life and reset values in the DB are not verified against published pharmacokinetic or clinical tolerance studies.**

---

## Interactions

| Interactant | Severity | Mechanism | Evidence |
|---|---|---|---|
| MAOIs | Lethal | Serotonin syndrome (excitatory) or severe CNS/respiratory depression | [Ref 3, 7, 6] |
| Alcohol | Lethal | Additive CNS and respiratory depression | StatPearls [Ref 18]; seed data confirmed |
| GHB/GBL | Lethal | Additive CNS and respiratory depression | Seed data; class mechanism |
| Ketamine | Lethal | CNS depression synergy | Seed data; class mechanism |
| Tramadol | Lethal | Additive serotonin syndrome + opioid respiratory depression | Seed data; both are SERT inhibitors |
| Benzodiazepines | Severe | Additive respiratory depression | StatPearls [Ref 18] |
| SSRIs | Serious | Serotonin syndrome (SERT inhibition × 2) | [Ref 2, 7] |
| CYP3A4 inhibitors | Serious | Increased meperidine plasma levels → toxicity | StatPearls [Ref 18] |
| CYP2B6 substrates/inhibitors | Moderate | Altered normeperidine production; variable neurotoxicity risk | [Ref 26] |
| Mixed opioid agonist-antagonists | Moderate | Precipitated withdrawal | StatPearls [Ref 18] |
| Nitrous oxide | Unknown | No specific interaction data found; opioid + inhalational anaesthetic interactions possible | Seed data; unresolved |
| PCP | Unknown | No specific interaction data found | Seed data; unresolved |

**⚠️ FLAG: Nitrous oxide and PCP interactions listed as "unknown" in the seed data. No published primary data was found to characterise these interactions for pethidine specifically.** The generation agent should maintain "unknown" status.

**Serotonin mechanism detail:** Pethidine (unlike morphine) inhibits the serotonin transporter. Combined with MAOIs (which prevent serotonin breakdown) or SSRIs (which also block SERT), the result is serotonin excess in the synapse. This mechanism has been confirmed in animal models (Fox et al. 2009 [Ref 2]) and reported in human case series (Sporer 1995 [Ref 6]; Bowdle 1998 [Ref 3]).

---

## Legal Status

| Jurisdiction | Classification | Notes |
|---|---|---|
| United States | DEA Schedule II | High abuse potential; accepted medical use with severe restrictions |
| United Kingdom | Class A / Schedule 2 | Class A under MDA 1971; Schedule 2 under MDR 2001 [Ref 16] |
| International | Schedule I (UN) | Single Convention on Narcotic Drugs 1961 [Ref 17] |
| Australia | Not specifically confirmed — see Gaps | |
| Canada | Not specifically confirmed — see Gaps | |

**⚠️ FLAG: Legal status confirmed for US and UK only. Australia and Canada scheduling not verified from primary sources in this research session.**

---

## Clinical Trials

No active meperidine-specific clinical trials were returned from a ClinicalTrials.gov search (the search returned general postoperative pain trials that used meperidine as a comparator rather than pethidine-specific trials). Pethidine is a decades-old drug with an extensive but largely historical clinical trial base; major efficacy and safety trials predate widespread ClinicalTrials.gov registration.

Notable completed studies include the Subramani et al. 2020 meta-analysis [Ref 20] of intrathecal meperidine for shivering prevention in 21 RCTs (N=1,433 patients), and the Jones et al. 2012 Cochrane overview [Ref 25] covering pethidine in labour (255 included trials).

---

## Community Feedback Analysis

No community feedback was submitted for this substance (Part A2 of the brief was empty).

---

## Gaps & Flags

### Data Gaps

1. **No Ki/EC50 receptor binding data retrieved** from primary literature via API searches. No published binding affinity values at mu-, kappa-, or delta-opioid receptors were found in PubMed/OpenAlex for pethidine. The generation agent should describe mechanism qualitatively and flag the absence of numeric binding constants.

2. **Normeperidine half-life discrepancy:** StatPearls [Ref 18] reports ~20.6 hours; HandWiki [Ref 17] reports 8–12 hours. Published literature ranges vary from 8–21 hours depending on the source and population studied. Use the range (8–21 h) and flag for editorial confirmation.

3. **Parent drug half-life discrepancy:** StatPearls [Ref 18] reports 3–8 hours; HandWiki [Ref 17] reports 2.5–4 hours. Likely reflects healthy vs. disease-population variation. Use 3–5 h (healthy adult) as central estimate with range.

4. **Volume of distribution:** Not retrieved from primary sources. DrugBank or similar would be needed.

5. **LD50 data:** No human or animal LD50 data found for pethidine.

6. **Australia/Canada/EU legal status:** Not confirmed from primary sources in this session.

7. **Tolerance half-life and full reset times** (DB: 5 days and 1.5 weeks respectively): These are seed values not traceable to primary literature in this search session.

8. **SMILES in seed DB:** Was blank. Confirmed SMILES: `CCOC(=O)C1(CCN(C)CC1)c2ccccc2` [Ref 22].

9. **Oral duration data discrepancy (seed DB):** The seed data states "peak: 4–6 hours (oral)" — this appears to represent total effect duration rather than time-to-peak. Clinical literature indicates time-to-peak for oral meperidine is approximately 60–120 minutes, with duration of analgesia ~2–5 hours. The "4–6 hours" entry likely describes the total effect window, not peak time. ⚠️ **FLAG for editorial review.**

### Safety-Critical Flags

10. **MAOI interaction:** Confirmed as life-threatening; mechanism established. The seed data lists this under the tramadol interaction ("lethal") but not explicitly in the contraindications field. The generation agent should ensure MAOI is listed as a hard contraindication.

11. **Normeperidine seizures not naloxone-reversible:** Safety-critical point not captured in seed data. Must be present in the generated article.

12. **Beers Criteria listing:** Pethidine is explicitly listed as a drug to always avoid in older adults per 2023 AGS Beers Criteria [Ref 19]. This contraindication is absent from the seed data.

13. **Maximum recommended duration:** Clinical guidelines specify 48-hour maximum for inpatient use due to normeperidine accumulation [Ref 18]. Not present in seed data.

14. **Renal failure contraindication:** Not listed in seed data contraindications field. Must be added — normeperidine accumulates and causes seizures in renal impairment [Ref 12].

### Structural/Data Model Flags

15. **Pharmacological class (seed data):** Lists "Sodium channel blocker" as a co-class alongside "Mu-opioid receptor agonist." This is accurate but unusual — most clinical databases list pethidine primarily as a mu-opioid agonist. The sodium channel blocking property is secondary but clinically relevant.

16. **"Emerging" characterization in seed data:** The seed data shows `characterization: emerging`. This appears erroneous for a well-established drug first approved in 1943 with 80 years of clinical history. ⚠️ **FLAG for editorial correction.**