generation run 2026-04-24
55 min completedmodel pipeline-v5plan not recordedrun/eac98b44…Selection
Verification
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The model's own caveats
- sparse_evidence
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Reproduce
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- 41 source keys (listed under Sources)
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26 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | tramadol CYP2D6 polymorphism poor extensive metabolizer O-desmethyltramadol | 8 | 5 | CYP2D6 metabolism and pharmacogenomics |
| 2 | PubMed | tramadol seizure threshold lowering mechanism epilepsy | 1 | 1 | Seizure risk data |
| 3 | PubMed | tramadol receptor binding affinity Ki mu opioid serotonin norepinephrine | 1 | 1 | Core receptor binding data |
| 4 | PubMed | tramadol pharmacology mechanism action opioid serotonin norepinephrine | 10 | 5 | Core pharmacology references |
| 5 | OpenAlex | tramadol pharmacology mechanism opioid receptor | 10 | 0 | Results too general; selected no tramadol-specific papers |
| 6 | PubMed | tramadol pharmacokinetics bioavailability half-life metabolism CYP2D6 humans | 3 | 2 | Bioavailability and PK data |
| 7 | PubMed | tramadol overdose fatality death respiratory depression seizure | 2 | 2 | Toxicity and overdose data |
| 8 | ClinicalTrials.gov | tramadol pain management | 10 | 1 | Relevant tramadol-specific trial |
| 9 | PubChem | tramadol | 1 | 1 | Primary chemical identity data for tramadol |
| 10 | PubMed | tramadol serotonin syndrome drug interaction MAOI antidepressant | 1 | 1 | Serotonin syndrome mechanism |
| 11 | WebSearch | tramadol history development Grünenthal 1977 | 10 | 2 | Historical development data |
| 12 | WebSearch | tramadol legal status UK USA Canada Australia scheduling 2014 | 10 | 2 | Legal status across major jurisdictions |
| 13 | PubMed | tramadol CYP2D6 genotype therapy pharmacogenomics | 5 | 1 | Pharmacogenomics of tramadol - clinical implications of CYP2D6 status |
| 14 | WebSearch | tramadol legal status European Union Germany France controlled drug | 10 | 2 | European legal status context |
| 15 | PubMed | tramadol cardiovascular risk codeine comparison cohort study | 1 | 1 | Cardiovascular safety of tramadol |
| 16 | PubMed | PMID 37791819 atypical withdrawal | 1 | 1 | Tramadol atypical withdrawal characterization |
| 17 | PubMed | tramadol premature ejaculation treatment efficacy | 4 | 3 | Off-label use of tramadol for premature ejaculation |
| 18 | PubMed | tramadol European non-medical use | 1 | 1 | European tramadol misuse epidemiology |
| 19 | WebSearch | tramadol natural occurrence Nauclea latifolia Africa 2013 | 10 | 2 | Natural occurrence controversy - notable historical/scientific context |
| 20 | PubMed | tramadol serotonin syndrome case reports clinical presentations | 6 | 5 | SS case reports documenting interaction risks |
| 21 | PubMed | O-desmethyltramadol metabolite M1 pharmacology binding opioid active | 5 | 3 | M1 pharmacology and potency data |
| 22 | Multiple API sources | Final data compilation and handoff file writing | 49 | 0 | Final compilation step |
| 23 | WebSearch | tramadol Australia Schedule 8 rescheduled 2020 legal status EU | 10 | 0 | Legal status verification |
| 24 | PubMed · absence | tramadol atypical withdrawal hallucinations anxiety serotonergic discontinuation | 0 | 0 | Search unsuccessful; withdrawal data obtained from prior search |
| 25 | PubMed · absence | tramadol NMDA receptor antagonism local anesthetic sodium channel blocking | 0 | 0 | NMDA mechanism claim in brief unverified - flagged for correction |
| 26 | PubChem REST API | CID 33741 SMILES InChIKey MolecularFormula | 1 | 4 | Chemical identity verification for brief - all fields were blank |
104 claims by section — every cited sentence, checked against its source
safety42 · 33 ok
Serotonin syndrome. Life-threatening serotonergic toxicity is well-documented in multiple clinical contexts: tramadol combined with SNRIs, gabapentin, MAOIs, tricyclic antidepressants, and ziprasidonesupported
58-year-old woman on venlafaxine + tramadol developed SS (tremor, hyperreflexia, diarrhea, tachycardia, hypertension, fever). cureus.76968
Claim in safety — inconclusiveinconclusiveworking →
In rat kindling models, generalized seizures emerge at doses above the analgesic range (≥30 mg/kg i.p.)supported
Tramadol: anticonvulsant within analgesic dose range in kindled rats; generalized seizures at 30 mg/kg. pmid:10991912
Tramadol-induced seizures are independent of brain serotonin levels — neither cyproheptadine nor 5-HT precursor loading prevented seizures in rat models.supported
Tramadol-induced seizures independent of brain serotonin. j.taap.2016.09.013
Claim in safety — inconclusiveinconclusiveworking →
Combination with benzodiazepines abolishes seizures but significantly worsens respiratory depression by reducing tidal volume — a critical pharmacodynamic interaction in which the seizure "protective" response is eliminated while respiratory risk intensifies.supported
Diazepam abolishes seizures but enhances respiratory depression. j.taap.2016.09.013
Serotonin syndrome. Life-threatening serotonergic toxicity is well-documented in multiple clinical contexts: tramadol combined with SNRIs, gabapentin, MAOIs, tricyclic antidepressants, and ziprasidonesupported
Case of SS after IV tramadol + oral gabapentin post-spine surgery. j.wneu.2019.03.092
Serotonin syndrome. Life-threatening serotonergic toxicity is well-documented in multiple clinical contexts: tramadol combined with SNRIs, gabapentin, MAOIs, tricyclic antidepressants, and ziprasidonesupported
SS despite DBS in subthalamic nucleus which decreases central serotonin; tramadol widely prescribed but significant potential for SS through serotonin reuptake inhibition. mjt.0b013e3182456d88
Serotonin syndrome has also occurred from tramadol intoxication alone in a pediatric patient without concurrent serotonergic drugssupported
8-month-old girl: accidental ingestion of 200mg tramadol. Developed moderate SS (agitation, tachycardia, hyperreflexia, hyperthermia). j.pediatrneurol.2010.08.005
Tramadol and meperidine are the two opioids that induce serotonin syndrome-like behaviors in SERT-deficient mice; morphine does not.supported
Tramadol and meperidine (not morphine) induce serotonin syndrome-like behaviors in mice; exaggerated in SERT-/- mice. s146114570900011x
Retrospective analysis of over 12 million FDA FAERS reports identified a significantly increased hypoglycemia propensity with tramadol compared to other opioids, SNRIs, and NMDAR-active drugssupported
Analysis of 12M+ FDA FAERS reports: tramadol and methadone show increased propensity for hypoglycemia compared to other opioids, SNRIs, and NMDAR-active drugs. s41598-019-48955-y
The mechanism is unknown.supported
Hypoglycemia as unusual complication of tramadol use/poisoning; exact mechanism unknown. bm.2020.010802
Tramadol's serotonin- and norepinephrine-raising mechanism raises theoretical concerns for arterial ischemia and cardiovascular eventssupported
Concern that tramadol's mechanism (increasing 5-HT and NE) could increase arterial ischemia and cardiovascular event risk. bcp.15099
Claim in safety — inconclusiveinconclusiveworking →
Life-threatening respiratory depression and death have occurred in pediatric patients.supported
CYP2D6 UM: life-threatening respiratory depression risk... Pediatric contraindications post-tonsillectomy. journal.pone.0247546
Lagard et al. determined the median lethal dose experimentally in rats using the Dixon-Bruce up-and-down method, but the specific value was not reported in the available abstract.supported
LD50 data in rats. j.taap.2016.09.013
Claim in safety — inconclusiveinconclusiveworking →
Dependence and craving: Psychological dependence is moderate. Misuse is well-documented in specific regions, particularly Iran, Egypt, and sub-Saharan Africa, where tramadol is the primary drug of misuse.supported
Misuse prevalent in Iran and Africa. cureus.26000
Dependence and craving: Psychological dependence is moderate. Misuse is well-documented in specific regions, particularly Iran, Egypt, and sub-Saharan Africa, where tramadol is the primary drug of misuse.supported
Tramadol dependence studied after large-scale exposure in Egypt since 2004. 10826084.2014.991406
Claim in safety — inconclusiveinconclusiveworking →
Adolescent vulnerability: Case reports document undetected tramadol dependence in adolescents with non-malignant pain, highlighting underrecognition of abuse risk in younger populations.supported
18-year-old with scoliosis and chronic back pain: covert Ultracet (tramadol+acetaminophen) dependence. Severe withdrawal symptoms on disclosure. Warning signs missed by clinical team. jom.2013.0163
Claim in safety — inconclusiveinconclusiveworking →
Physical dependence occurs with prolonged and repeated usesupported
Tramadol dependence studied after large-scale exposure in Egypt since 2004. Evaluated medical and psychiatric effects of high dose long-term dependence. 10826084.2014.991406
Claim in safety — inconclusiveinconclusiveworking →
European data confirm lower drug liking, though significant misuse exists in regions where tramadol is a primary drug of abuse.supported
Tramadol misuse compared to conventional opioids in Germany, Italy, Spain, UK; tramadol has low drug liking compared to conventional opioids. j.drugalcdep.2020.108367
Documented combinations include SNRIs (duloxetine, venlafaxine), gabapentin, ziprasidone, MAOIs, TCAs, SSRIs, and serotonin precursors (5-HTP, tryptophan)supported
58-year-old woman on venlafaxine + tramadol developed SS. cureus.76968
Documented combinations include SNRIs (duloxetine, venlafaxine), gabapentin, ziprasidone, MAOIs, TCAs, SSRIs, and serotonin precursors (5-HTP, tryptophan)supported
Patient on high-dose tramadol + duloxetine developed serotonin syndrome. 15360288.2014.911798
Documented combinations include SNRIs (duloxetine, venlafaxine), gabapentin, ziprasidone, MAOIs, TCAs, SSRIs, and serotonin precursors (5-HTP, tryptophan)supported
Case of SS after IV tramadol + oral gabapentin post-spine surgery. j.wneu.2019.03.092
Documented combinations include SNRIs (duloxetine, venlafaxine), gabapentin, ziprasidone, MAOIs, TCAs, SSRIs, and serotonin precursors (5-HTP, tryptophan)supported
Serotonin syndrome after the use of tramadol and ziprasidone. mjt.0b013e3182456d88
Tramadol and meperidine are uniquely susceptible among opioids — they produce exaggerated serotonin syndrome behaviors in SERT-deficient mice, while morphine does not.supported
Tramadol and meperidine (not morphine) induce serotonin syndrome-like behaviors in mice; exaggerated in SERT-/- mice. s146114570900011x
The tramadol-benzodiazepine combination carries a specific paradox: diazepam abolishes tramadol-induced seizures but significantly worsens respiratory depression by reducing tidal volume.supported
Diazepam abolishes seizures but enhances respiratory depression. j.taap.2016.09.013
CYP2D6 inhibition. Potent CYP2D6 inhibitors (paroxetine, fluoxetine, duloxetine) reduce M1 formation — diminishing opioid analgesia — while simultaneously increasing tramadol plasma levels and serotonergic exposure.supported
DDI prediction with duloxetine and paroxetine (CYP2D6 inhibitors). phar.2494
Claim in safety — inconclusiveinconclusiveworking →
CYP2D6 ultrarapid metabolizer status: Excess M1 production causes opioid toxicity at standard doses.supported
CYP2D6 UM: life-threatening respiratory depression risk. journal.pone.0247546
Claim in safety — inconclusiveinconclusiveworking →
Post-tonsillectomy/adenoidectomy in patients under 18 years: Specific FDA contraindication.supported
Pediatric contraindications post-tonsillectomy. journal.pone.0247546
Epilepsy or lowered seizure threshold: Tramadol's proconvulsant activity at supratherapeutic doses makes it inappropriate for patients with seizure disorders.supported
Lowered seizure threshold increases risk. Kindling enhances susceptibility to tramadol-induced seizures. pmid:10991912
Concurrent serotonergic medication: SSRIs, SNRIs, TCAs, triptans, and serotonin precursors increase serotonin syndrome risk.supported
58-year-old woman on venlafaxine + tramadol developed SS. cureus.76968
Concurrent serotonergic medication: SSRIs, SNRIs, TCAs, triptans, and serotonin precursors increase serotonin syndrome risk.supported
Case of SS after IV tramadol + oral gabapentin post-spine surgery. SS can occur even without classic serotonergic combinations. j.wneu.2019.03.092
Pregnancy: Tramadol misuse in pregnancy is associated with neonatal abstinence syndrome.supported
Tramadol misuse during pregnancy: obstetric complications, teratogenicity, neonatal abstinence syndrome reviewed. j.siny.2019.01.010
Lactation in CYP2D6 UM mothers: Excess M1 in breast milk poses risk to nursing infants.supported
ultrarapid metabolizer mothers may cause neonatal toxicity via high M1 in breast milk. jcph.1113
Concurrent CNS depressants: Alcohol, benzodiazepines, other opioids — enhanced respiratory depression.supported
Diazepam abolishes seizures but enhances respiratory depression. j.taap.2016.09.013
pharmacology15 · 12 ok
Tramadol is a centrally acting analgesic with a dual mechanism of action confirmed across multiple independent studies:supported
It is a central analgesic with a low affinity for opioid receptors. Its selectivity for mu receptors has recently been demonstrated... Monoaminergic activity inhibits NA and 5-HT reuptake. pmid:9190321
Tramadol is a centrally acting analgesic with a dual mechanism of action confirmed across multiple independent studies:supported
(+)-enantiomer specific for mu-opioid and 5-HT carrier; (-)-enantiomer higher affinity for NA transporter. pmid:8955860
Tramadol is a centrally acting analgesic with a dual mechanism of action confirmed across multiple independent studies:supported
Tramadol prodrug: metabolites active in inhibiting 5-HT and NE reuptake. cureus.26000
Claim in pharmacology — inconclusiveinconclusiveworking →
The primary opioid activity derives from the active metabolite O-desmethyltramadol (M1), produced by hepatic CYP2D6 O-demethylation. (+)-M1 has MOR affinity more than 100-fold higher than (+)-tramadol and approximately one-tenth that of morphinesupported
M1 (O-demethyltramadol) shows pronounced mu-selectivity >100x higher than (+)-tramadol, ~1/10 of morphine. pmid:8955860
M1 is estimated to be up to 6-fold more potent than tramadol for producing analgesia.supported
M1 metabolite is up to 6x more potent than tramadol for analgesia. journal.pone.0247546
Serotonin-norepinephrine reuptake inhibition. Tramadol inhibits both the serotonin transporter (SERT) and the norepinephrine transporter (NET), contributing substantially to analgesia by blocking nociceptive impulse transmission at the spinal levelsupported
Monoaminergic activity inhibits NA and 5-HT reuptake. pmid:9190321
This monoaminergic component is responsible for tramadol's atypical properties — including its off-label efficacy in premature ejaculation and its capacity to produce serotonin syndrome.supported
Tramadol inhibits ejaculation primarily via 5-HT reuptake inhibition; naloxone only partially reverses this. j.neuropharm.2016.11.020
The enantiomers have complementary, synergistic pharmacological profiles:supported
(+)-enantiomer specific for mu-opioid and 5-HT carrier; (-)-enantiomer higher affinity for NA transporter. pmid:8955860
Claim in pharmacology — inconclusiveinconclusiveworking →
M1 inhibits muscarinic M1 receptors (IC50 ≈ 2 µM) but not M3 receptorssupported
O-desmethyl tramadol inhibits M1 muscarinic receptor function (IC50 = 2 uM); does not affect M3 receptors. pmid:15976229
Claim in pharmacology — inconclusiveinconclusiveworking →
Identified metabolites include O-desmethyltramadol (M1, primary active), N-desmethyltramadol (NDT), and N,O-didesmethyltramadol, with enantiomers of eachsupported
enantioselective PK of tramadol and metabolites (ODT, NDT, N,O-didesmethyltramadol); CYP2D6 PM show different metabolic profile with higher NDT and lower ODT AUC. prp2.419
A once-daily 200 mg extended-release formulation achieves bioequivalent AUC to immediate-release with lower C,,max,,, reaching steady state within 48 hours while maintaining the analgesic threshold throughout the dosing intervalsupported
Tramadol OAD 200mg vs IR 50mg: AUC bioequivalent; Cmax lower with OAD; steady state within 48h; analgesic threshold (>100 ng/mL) maintained throughout dosing interval. 0091270009347673
Rifampicin, a CYP2D6/3A4 inducer, markedly decreases tramadol exposure.supported
Rifampicin enzyme induction markedly reduces tramadol exposure. s00228-012-1460-x
pharmacokinetic-detail10 · 8 ok
In mothers who are CYP2D6 ultrarapid metabolizers, excess M1 in breast milk poses a risk of opioid toxicity in the nursing infant.supported
ultrarapid metabolizer mothers may cause neonatal toxicity via high M1 in breast milk. jcph.1113
Oral bioavailability of tramadol is 68–70.6%, reflecting moderate first-pass metabolismsupported
Oral bioavailability 68%. pmid:9190321
Oral bioavailability of tramadol is 68–70.6%, reflecting moderate first-pass metabolismsupported
Absolute bioavailability of oral tramadol drops: 70.6%. pmid:10719611
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Enantiomers of each metabolite are produced and may have distinct pharmacological profiles.supported
enantioselective PK of tramadol and metabolites (ODT, NDT, N,O-didesmethyltramadol). prp2.419
CYP2D6 genotype is the single most important determinant of tramadol's clinical pharmacology, substantially impacting M1 exposure and clinical outcomes:supported
CYP2D6 gene polymorphism influence; DDI prediction with duloxetine and paroxetine (CYP2D6 inhibitors). phar.2494
CYP2D6 genotype is the single most important determinant of tramadol's clinical pharmacology, substantially impacting M1 exposure and clinical outcomes:supported
CYP2D6 UM: life-threatening respiratory depression risk. CYP2D6 PM: inadequate pain relief. journal.pone.0247546
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
CYP2D6 inhibitors (paroxetine, fluoxetine, duloxetine) increase tramadol exposure but reduce M1 formation — reducing opioid-mediated analgesia while potentially increasing serotonergic side effects.supported
DDI prediction with duloxetine and paroxetine (CYP2D6 inhibitors). phar.2494
Plasma concentrations remain above the analgesic threshold (>100 ng/mL) throughout the 24-hour dosing interval.supported
analgesic threshold (>100 ng/mL) maintained throughout dosing interval. 0091270009347673
summary9 · 7 ok
Claim in summary — inconclusiveinconclusiveworking →
A 2025 review of 58 clinical trials confirmed efficacy for chronic pain across multiple conditions, though not consistently superior to comparators.supported
Review of 58 clinical trials; tramadol effective as analgesic with reasonable safety profile; not enough long-term evidence. 15360288.2024.2411239
Tramadol's analgesic effect arises from two complementary mechanisms distributed across its enantiomers: (+)-tramadol preferentially inhibits serotonin reuptake and acts as a weak MOR agonist, while (−)-tramadol preferentially inhibits norepinephrine reuptakesupported
(+)-enantiomer specific for mu-opioid and 5-HT carrier; (-)-enantiomer higher affinity for NA transporter. pmid:8955860
Hepatic CYP2D6 O-demethylation produces the active metabolite O-desmethyltramadol (M1), which has MOR affinity more than 100-fold greater than the parent compound and approximately one-tenth that of morphinesupported
M1 (O-demethyltramadol) shows pronounced mu-selectivity >100x higher than (+)-tramadol, ~1/10 of morphine. pmid:8955860
This prodrug-like dependency on CYP2D6 makes tramadol's clinical effects highly sensitive to genetic polymorphism.supported
CYP2D6 UM: life-threatening respiratory depression risk. CYP2D6 PM: inadequate pain relief. journal.pone.0247546
The dominant safety concerns are seizure threshold reduction at supratherapeutic doses, serotonin syndrome when combined with serotonergic agents, and life-threatening respiratory depression in CYP2D6 ultrarapid metabolizers who produce excessive M1supported
Tramadol: anticonvulsant within analgesic dose range in kindled rats; generalized seizures at 30 mg/kg. Lowered seizure threshold increases risk. pmid:10991912
The dominant safety concerns are seizure threshold reduction at supratherapeutic doses, serotonin syndrome when combined with serotonergic agents, and life-threatening respiratory depression in CYP2D6 ultrarapid metabolizers who produce excessive M1supported
Tramadol induces dose-dependent sedation, early-onset seizures, respiratory depression. j.taap.2016.09.013
The dominant safety concerns are seizure threshold reduction at supratherapeutic doses, serotonin syndrome when combined with serotonergic agents, and life-threatening respiratory depression in CYP2D6 ultrarapid metabolizers who produce excessive M1supported
CYP2D6 UM: life-threatening respiratory depression risk. journal.pone.0247546
Claim in summary — inconclusiveinconclusiveworking →
neuroscience7 · 4 ok
Serotonergic withdrawal neurobiology: Tramadol withdrawal includes atypical features (hallucinations, unusual sensory phenomena, mucus production) not seen with classical opioid cessation. The neural substrate of this dual withdrawal syndrome — reflecting simultaneous opioid and SNRI discontinuation — is not characterized.partially supported
Atypical withdrawal after abrupt discontinuation including mucus production, chest fullness, neck soreness - not classic opioid withdrawal. 15360288.2023.2261913
At slightly higher doses, generalized seizures emergesupported
Tramadol: anticonvulsant within analgesic dose range in kindled rats; generalized seizures at 30 mg/kg. pmid:10991912
Claim in neuroscience — inconclusiveinconclusiveworking →
Claim in neuroscience — inconclusiveinconclusiveworking →
Claim in neuroscience — inconclusiveinconclusiveworking →
Tramadol exemplifies how CYP2D6 pharmacogenomics transform a single administered dose into radically different pharmacological exposures across individualssupported
CYP2D6 UM: life-threatening respiratory depression risk. CYP2D6 PM: inadequate pain relief. journal.pone.0247546
Hypoglycemia mechanism: FDA adverse event analysis shows significantly increased hypoglycemia with tramadol compared to other opioids. The mechanism is unknown — no receptor-level explanation has been proposed.supported
Analysis of 12M+ FDA FAERS reports: tramadol and methadone show increased propensity for hypoglycemia compared to other opioids, SNRIs, and NMDAR-active drugs. s41598-019-48955-y
comparative-pharmacology6 · 2 ok
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Both produce serotonin syndrome-like behaviors in SERT-deficient mice, while morphine does notsupported
Tramadol and meperidine (not morphine) induce serotonin syndrome-like behaviors in mice; exaggerated in SERT-/- mice. s146114570900011x
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Receptor potency: Tramadol's MOR affinity is approximately 6,000-fold lower than morphine. Even its active metabolite M1 has only one-tenth the MOR affinity of morphine.supported
M1 (O-demethyltramadol) shows pronounced mu-selectivity >100x higher than (+)-tramadol, ~1/10 of morphine. pmid:8955860
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
clinical-evidence5 · 5 ok
A Phase 4 trial (NCT01116531) at Turku University Hospital examining tramadol combined with duloxetine or pregabalin for diabetic polyneuropathy and postherpetic neuralgia was withdrawn — potentially reflecting safety concerns about the tramadol-duloxetine combination given documented serotonin syndrome risk.supported
Patient on high-dose tramadol + duloxetine developed serotonin syndrome. Risks for this clinically important drug interaction and management discussed. 15360288.2014.911798
Preclinical evidence suggests sustained-release tramadol formulations may palliate heroin-conditioned place preference and withdrawal in animal models, with lower abuse potential than conventional opioid formulationssupported
Tramadol implants reduce heroin CPP and naloxone-induced withdrawal in rats. Low abuse potential of implant formulation. fbp.0000000000000778
A 2025 systematic review by Seidmohammadi et al. evaluated 58 clinical trials of tramadol across multiple chronic pain conditionssupported
Review of 58 clinical trials; tramadol effective as analgesic with reasonable safety profile. 15360288.2024.2411239
A systematic review by Da Rocha et al. assessed tramadol for fibromyalgia pain managementsupported
Systematic review of tramadol for fibromyalgia; SNRI properties; safety and efficacy not established. ijcp.13455
A 2025 umbrella review of meta-analyses found evidence supporting tramadol's efficacy in this indication, and a randomized placebo-controlled trial demonstrated the effectiveness of on-demand tramadol combined with sildenafil.partially supported
Umbrella review: tramadol as off-label option for premature ejaculation; methodological heterogeneity in trials limits conclusions. qdaf094
receptor-pharmacology5 · 1 ok
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Although some review literature attributes NMDA receptor antagonism to tramadol, primary in vitro binding data do not support this mechanism at therapeutic concentrationssupported
No affinity for 5-HT1A, 5-HT2, 5-HT3, NMDA, DA-D1/D2, benzodiazepine, muscarinic. pmid:8955860
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
chemistry3 · 1 ok
Claim in chemistry — not_supportednot supportedworking →
Tramadol is a synthetic aminocyclohexanol — structurally a 4-phenylpiperidine analogue of codeinesupported
(+/-)-Tramadol is a synthetic 4-phenyl-piperidine analogue of codeine. pmid:9190321
Claim in chemistry — inconclusiveinconclusiveworking →
history2 · 2 ok
In 2013, tramadol was detected in the roots of Nauclea latifolia (the African peach or pincushion tree) in Cameroon at concentrations of 0.4–3.9% in dried bark, described at the time as the first synthetic drug found in a natural sourcesupported
First detection of tramadol in roots of Nauclea latifolia... Concentrations 0.4–3.9% in dried bark extracts. anie.201305697
Misuse is documented at scale in Iran, Egypt, and parts of sub-Saharan Africa, where tramadol is reportedly taken for its combined stimulant and euphoric effects, often at doses far exceeding therapeutic rangessupported
Tramadol dependence studied after large-scale exposure in Egypt since 2004. Evaluated medical and psychiatric effects of high dose long-term dependence. 10826084.2014.991406