generation run 2026-05-08
83 min completedmodel pipeline-v5plan not recordedrun/d536d622…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- sparse_evidence
- note
Reproduce
- inputs
- 41 source keys (listed under Sources)
- plan
- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
- model
- pipeline-v5
- streams
- none — agent transcripts are persisted from 2026-09 onward
24 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | OpenAlex | O-desmethyltramadol tramadol active metabolite opioid | 10 | 4 | High-citation landmark papers directly relevant to ODT metabolism and clinical use |
| 2 | PubMed | tramadol O-desmethyltramadol overdose death toxicology case report | 3 | 3 | Relevant overdose/toxicology data for ODT safety section |
| 3 | ClinicalTrials.gov | O-desmethyltramadol | 10 | 4 | NCT04683926 is critical - ODT being developed as standalone drug desmetramadol by Syntrix Biosystems |
| 4 | PubMed | O-desmethyltramadol pharmacology opioid receptor | 14 | 13 | All directly relevant to ODT pharmacology and mechanisms |
| 5 | PubChem | O-Desmethyltramadol | 1 | 1 | Primary chemical identity verification |
| 6 | PubMed | tramadol dependence abuse potential withdrawal opioid addiction | 7 | 4 | Relevant to ODT dependence and abuse potential |
| 7 | WebSearch | ACMD O-desmethyltramadol UK scheduling recommendation | 10 | 2 | Primary regulatory source for UK scheduling |
| 8 | WebSearch | O-desmethyltramadol legal status scheduling UK Germany Australia 2026 | 10 | 2 | Legal status research essential for harm reduction and context sections |
| 9 | WebSearch | O-desmethyltramadol SMILES structure PubChem CID 9838803 | 10 | 2 | SMILES not returned by PubChem API tool; obtained via web search |
| 10 | PubMed | Desmetramadol clinical trial safety analgesic randomized double-blind | 1 | 1 | Landmark clinical trial for ODT as standalone drug |
| 11 | WebSearch | Krypton legal high Sweden deaths O-desmethyltramadol kratom | 10 | 1 | Critical safety data - ODT directly implicated in fatal overdoses |
| 12 | PubMed | tramadol enantiomer opioid serotonin norepinephrine mechanism | 2 | 2 | Key papers on tramadol/ODT stereochemistry and mechanism |
| 13 | WebSearch | tramadol DEA Schedule IV 2014 | 10 | 2 | US scheduling history essential for legal status section |
| 14 | PubMed | fetch PMID 39291005 chiral switches tramadol ACS 2024 | 1 | 1 | Historical and stereochemistry context for ODT development |
| 15 | WebSearch | O-desmethyltramadol mu-opioid receptor Ki binding affinity nM morphine comparison | 10 | 2 | Quantitative binding affinity data for ODT vs morphine |
| 16 | WebSearch | O-desmethyltramadol Australia Canada legal status scheduling 2024 | 10 | 2 | Completing legal status research across major jurisdictions |
| 17 | WebSearch | desmetramadol NCT04683926 Syntrix Phase 1 oral dose proportionality | 10 | 1 | Details of Syntrix Phase 1 clinical program for standalone ODT |
| 18 | PubMed | fetch PMID 32116679 desmetramadol G-protein biased mu opioid receptor agonist | 1 | 1 | Critical mechanistic finding explaining ODT's relatively safer respiratory profile |
| 19 | PubMed | fetch PMID 8982709 tramadol M1 enantiomer affinities cloned human opioid receptors | 1 | 1 | Primary binding affinity source for ODT at human cloned opioid receptors |
| 20 | PubMed | fetch PMID 20589494 physical dependence tramadol humans | 1 | 1 | Primary human dependence data for tramadol/ODT |
| 21 | PubMed | fetch PMID 28225374 tramadol toxicity children | 1 | 1 | Pediatric vulnerability to ODT toxicity |
| 22 | WebSearch | tramadol Grunenthal history 1962 1977 synthesis development | 10 | 3 | Historical timeline for ODT/tramadol development section |
| 23 | PubChem/WebSearch cross-reference | ODT SMILES InChI canonical isomeric | 5 | 3 | Complete chemical identity data for brief |
| 24 | WebSearch | O-desmethyltramadol physical properties melting point | 10 | 2 | Physical chemistry data needed for chemistry section |
99 claims by section — every cited sentence, checked against its source
safety43 · 33 ok
Fatal outcomes have been documented at postmortem blood ODT concentrations of 0.4–4.3 µg/g in the presence of mitragynine co-administrationsupported
ODT blood concentrations 0.4-4.3 μg/g. Mitragynine 0.02-0.18 μg/g. Deaths attributed to respiratory depression. pmid:21513619
Claim in safety — inconclusiveinconclusiveworking →
In animal models, ODT — but not tramadol itself — induced emesis and tremor in ferrets, with ODT-induced retching inhibited by the dopamine D₂ antagonist prochlorperazine but not by olanzapine, indicating a receptor mechanism distinct from morphine-induced emesispartially supported
M1 (ODT) induced emesis and tremor in ferrets (not tramadol). M1-induced retching inhibited by D2 antagonist prochlorperazine. jat.4912
ODT suppressed gastrointestinal transit in mice, consistent with µOR-mediated constipation.supported
M1 suppressed GI transit in mice. jat.4912
The most direct human fatality data for ODT derives from the Swedish Krypton cases (2009–2010): nine deaths with postmortem blood ODT concentrations of 0.4–4.3 µg/g alongside mitragynine at 0.02–0.18 µg/gsupported
9 fatal cases in Sweden (Oct 2009-Oct 2010). ODT blood concentrations 0.4-4.3 μg/g. Mitragynine 0.02-0.18 μg/g. pmid:21513619
For context, tramadol therapeutic serum concentrations range from 0.28–0.61 mg/Lsupported
Therapeutic serum range 0.28-0.61 mg/L. pmid:15461118
Claim in safety — inconclusiveinconclusiveworking →
Tramadol-attributed deaths in a Washington State review (66 deaths, 1995–2000) consistently involved co-intoxicants, suggesting that tramadol/ODT alone has a relatively wider margin than classical opioids, though fatal single-substance tramadol intoxications have been documented: one case at blood tramadol 7.7 mg/L with ODT 1.33 mg/L, and another at tramadol 48.34 mg/L with ODT 2.43 mg/L (norfluoxetine co-detected in the latter)partially supported
Two fatal tramadol intoxication cases. ODT concentrations: 1.33 and 2.43 mg/L. Norfluoxetine detected in case 2. pmid:21073815
A confirmed suicidal tramadol poisoning produced femoral blood levels of 61.83 µg/mL with ODT detected in all tissues.supported
Fatal tramadol poisoning case. ODT detected in blood, bile, urine, viscera. Femoral blood tramadol 61.83 µg/mL (~30x lethal). j.jflm.2013.03.006
Claim in safety — not_supportednot supportedworking →
ODT itself demonstrates a biphasic seizure profile in kindled rats: anticonvulsant activity at analgesic doses transitioning to proconvulsant effects at supratherapeutic doses, with respiratory depression becoming the dose-limiting toxicity at convulsant concentrations.partially supported
(+/-)-tramadol anticonvulsant at analgesic doses but proconvulsant slightly higher. (+)-M1 limited by respiratory depression at convulsant doses. pmid:10991912
An epidemiological study in Egypt documented tramadol as a common cause of seizures in young men.supported
Tramadol-associated seizures emerged as common cause in Egypt, mainly young men. j.neuro.2020.05.002
Benzodiazepines abolish tramadol-induced seizures but significantly worsen respiratory depression — benzodiazepine co-administration is not protective against death in tramadol/ODT overdose.supported
Diazepam+tramadol combination abolished seizures but enhanced respiratory depression (reduced tidal volume). j.taap.2016.09.013
The SERT inhibitory component of ODT (primarily via the (-)-enantiomer) creates a serotonin syndrome risk absent from classical opioidssupported
Tramadol inhibits serotonin and norepinephrine reuptake. Increasing reports of tramadol-associated serotonin syndrome, especially with concurrent serotonergic drugs. pmid:26218943
The SERT inhibitory component of ODT (primarily via the (-)-enantiomer) creates a serotonin syndrome risk absent from classical opioidssupported
Tramadol inhibits SERT and NET; serotonin syndrome risk. bph.14105
Fatal serotonin syndrome has been documented with the combination of moclobemide (an MAO-A inhibitor), clomipramine, and tramadol.supported
Fatal case: moclobemide (MAO-A inhibitor) + clomipramine + tramadol + diazepam. Death from serotonin syndrome. pmid:7876795
Children demonstrate dose-related CNS depression, respiratory depression, and seizures with tramadol/ODT exposuresupported
Tramadol causes dose-related CNS and respiratory depression and seizures in children. pec.0000000000001084
Euphoria and reinforcement: Tramadol-dependent subjects demonstrate euphoric responses on the Morphine-Benzedrine Group (MBG) subscale comparable to heroin and methamphetamine users, indicating significant abuse potential. Standalone ODT, with higher µOR affinity and more direct opioid effects, may carry equal or greater euphoric potential at equivalent opioid receptor occupancy.supported
MBG euphoria scores comparable to heroin/MA groups. High abuse potential with long-term use at high doses. 283425
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — not_supportednot supportedworking →
Claim in safety — not_supportednot supportedworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
A case report of abrupt discontinuation after more than 10 years of daily tramadol use documented atypical withdrawal symptoms including excessive mucus production and chest fullness.supported
Case: 68-year-old female with fibromyalgia, 10+ years tramadol 50 mg q6h, abrupt discontinuation leading to atypical withdrawal (mucus production, chest fullness, neck soreness). 15360288.2023.2261913
Abuse potential: Euphoric effects in tramadol-dependent subjects are comparable to those of heroin and methamphetamine on standardized subjective drug effect measuressupported
MBG euphoria scores comparable to heroin/MA groups. High abuse potential with long-term use at high doses. 283425
Tramadol/ODT has been used in opioid withdrawal management with efficacy comparable to methadone, demonstrating pharmacological cross-tolerance with full agonists.supported
n=70 opioid-dependent patients. Tramadol 600 mg/day vs methadone 60 mg/day. Similar efficacy on OOWS scores. 10550887.2012.665728
Tramadol/ODT has been used in opioid withdrawal management with efficacy comparable to methadone, demonstrating pharmacological cross-tolerance with full agonists.supported
Tramadol compared to buprenorphine for opioid (heroin) withdrawal management. Confirms tramadol's mu-opioid activity sufficient for withdrawal management. jom.2013.0145
The (-)-enantiomer's SERT inhibition creates a risk of serotonin syndrome when ODT is combined with other serotonergic agentssupported
Tramadol inhibits serotonin and norepinephrine reuptake. Increasing reports of tramadol-associated serotonin syndrome, especially with concurrent serotonergic drugs. pmid:26218943
The (-)-enantiomer's SERT inhibition creates a risk of serotonin syndrome when ODT is combined with other serotonergic agentssupported
Tramadol inhibits SERT and NET; serotonin syndrome risk. bph.14105
Monoamine oxidase inhibitors (MAOIs) represent an absolute contraindication — fatal serotonin syndrome has occurred with the combination of tramadol, moclobemide, and clomipraminesupported
Fatal case: moclobemide (MAO-A inhibitor) + clomipramine + tramadol + diazepam. Death from serotonin syndrome. pmid:7876795
Claim in safety — inconclusiveinconclusiveworking →
The nine Swedish Krypton deaths demonstrate the lethality of combining ODT with mitragynine, even at moderate individual doses.supported
9 fatal cases in Sweden (Oct 2009-Oct 2010). Krypton = powdered kratom + O-desmethyltramadol. Deaths attributed to respiratory depression. pmid:21513619
The benzodiazepine interaction warrants specific attention: while benzodiazepines abolish tramadol-induced seizures, they significantly worsen respiratory depressionsupported
Diazepam+tramadol combination abolished seizures but enhanced respiratory depression (reduced tidal volume). j.taap.2016.09.013
CYP3A4 inducers (rifampicin) decrease exposure to both tramadol and ODTsupported
CYP enzyme induction by rifampicin markedly decreased tramadol and ODT plasma exposure. s00228-012-1460-x
For standalone ODT: CYP2D6 inhibitors do not affect pharmacokinetics, a clinically significant distinction.supported
CYP inhibition with paroxetine abolished tramadol analgesia but not desmetramadol analgesia. j.jpain.2019.04.005
ODT produces false-positive phencyclidine (PCP) results on EMIT II+ immunoassaysupported
Tramadol and ODT together caused false-positive PCP on EMIT II+ immunoassay. Confirmatory HPLC negative for PCP. ODT cross-reactivity: 27 mAU/min. pmid:17133040
Concurrent MAOI use: Fatal serotonin syndrome risk. Tramadol labeling includes MAOI contraindication; the same applies to standalone ODT.supported
Fatal case: moclobemide (MAO-A inhibitor) + clomipramine + tramadol + diazepam. Death from serotonin syndrome. pmid:7876795
Concurrent serotonergic medications (SSRIs, SNRIs, tricyclics, triptans, linezolid): elevated serotonin syndrome risk.supported
Increasing reports of tramadol-associated serotonin syndrome, especially with concurrent serotonergic drugs. pmid:26218943
Seizure disorders or lowered seizure threshold: ODT demonstrates proconvulsant effects at supratherapeutic doses in animal models.partially supported
(+/-)-tramadol anticonvulsant at analgesic doses but proconvulsant slightly higher. (+)-M1 limited by respiratory depression at convulsant doses. pmid:10991912
CYP2D6 ultrarapid metabolizer status (relevant when ODT is generated from tramadol): dangerously elevated ODT production.supported
CYP2D6 ultrarapid metabolizers have higher ODT exposure and risk of adverse effects. Recommends against tramadol in ultrarapid metabolizers. cpt.2149
Pediatric patients: Dose-related CNS depression, respiratory depression, and seizures; enhanced risk in CYP2D6 ultrarapid metabolizers.partially supported
Tramadol causes dose-related CNS and respiratory depression and seizures in children. Life-threatening toxicity in overdose. pec.0000000000001084
Elderly patients: Approximately 50% longer ODT elimination half-life requires dose adjustment.supported
Elderly subjects have significantly longer half-life (50% longer) than younger subjects. s40266-015-0315-4
Claim in safety — inconclusiveinconclusiveworking →
pharmacology15 · 12 ok
Claim in pharmacology — inconclusiveinconclusiveworking →
At the spinal cord level, ODT inhibits L-glutamate release from presynaptic terminals in substantia gelatinosa neurons through µOR activation, suppressing excitatory transmission (spontaneous excitatory postsynaptic currents, sEPSCs) while enhancing inhibitory transmission (spontaneous inhibitory postsynaptic currents, sIPSCs)partially supported
M1 reduces glutamate release frequency via µ-opioid receptor activation. Effects on Aδ and C fiber EPSCs comparable. Presynaptic mechanism. 1744806918824243
At the spinal cord level, ODT inhibits L-glutamate release from presynaptic terminals in substantia gelatinosa neurons through µOR activation, suppressing excitatory transmission (spontaneous excitatory postsynaptic currents, sEPSCs) while enhancing inhibitory transmission (spontaneous inhibitory postsynaptic currents, sIPSCs)supported
IV tramadol (>5mg/kg) decreased sEPSCs and increased sIPSCs in SG neurons. Effects naloxone-blocked. Both mediated primarily via mu-opioid receptors. journal.pone.0125147
In rats, ODT at 5 mg/kg intravenous produced spinal cord effects equivalent to tramadol at 15 mg/kg intravenous, consistent with a 3:1 potency ratio at the spinal levelsupported
M1 at 5mg/kg had similar effects to tramadol at 15mg/kg. journal.pone.0125147
All spinal effects were abolished by naloxone, confirming µOR dependence.supported
Effects naloxone-blocked. Both mediated primarily via mu-opioid receptors. journal.pone.0125147
The (-)-enantiomer inhibits serotonin (SERT) and norepinephrine (NET) transporters, contributing to descending pain inhibitory pathways and conferring serotonin syndrome risksupported
Tramadol inhibits SERT and NET; serotonin syndrome risk. bph.14105
Claim in pharmacology — inconclusiveinconclusiveworking →
ODT and tramadol both selectively suppress transient receptor potential ankyrin 1 (TRPA1) channels without affecting TRPV1, representing an additional non-opioid analgesic mechanism.supported
Tramadol and M1 selectively suppress TRPA1 (not TRPV1) — additional non-opioid analgesic mechanism. ane.0000000000000625
In preclinical oncology research, ODT induced endoplasmic reticulum stress proteins (p-eIF2α, ATF4, CHOP) in breast cancer cell lines through a µOR-independent mechanism (IC₅₀ ~64 µg/mL), well above any clinically relevant concentration.supported
ODT IC50: 64.2 µg/mL (MDA-MB-231). Non-opioid mechanism (alvimopan did not block). ER stress induction via p-eIF2α, ATF4, CHOP. ijms26094139
When generated from tramadol in vivo, ODT production depends on CYP2D6-mediated O-demethylation, with CYP3A4 and CYP2B6 providing minor contributionssupported
CYP2D6, CYP2B6, CYP3A4 all involved in tramadol metabolism. s00228-012-1460-x
When generated from tramadol in vivo, ODT production depends on CYP2D6-mediated O-demethylation, with CYP3A4 and CYP2B6 providing minor contributionssupported
CYP2D6 polymorphism correlated with tramadol clearance and conversion to M1. dddt.s199574
The elimination half-life of ODT is approximately 7.5 hours in young adults, increasing by approximately 50% in elderly subjectssupported
ODT half-life ~7.5 hours. Elderly subjects have significantly longer half-life (50% longer) than younger subjects. s40266-015-0315-4
The elimination half-life of ODT is approximately 7.5 hours in young adults, increasing by approximately 50% in elderly subjectssupported
ODT half-life ~7.5 hours. Elderly subjects have significantly longer half-life (50% longer) than younger subjects. s40266-015-0315-4
Claim in pharmacology — inconclusiveinconclusiveworking →
When administered directly as desmetramadol, pharmacokinetics are CYP2D6-independent, and 20 mg every 6 hours produces steady-state (+)-M1 plasma levels equivalent to 50 mg tramadol every 6 hourssupported
20 mg desmetramadol q6h = 50 mg tramadol q6h in analgesic effect. CYP inhibition with paroxetine abolished tramadol analgesia but not desmetramadol analgesia. j.jpain.2019.04.005
history7 · 4 ok
Forensic analysis confirmed ODT at blood concentrations of 0.4–4.3 µg/g alongside mitragynine (0.02–0.18 µg/g); critically, tramadol and its N-desmethyl metabolite were absent from all samples, confirming that the ODT had been added directly rather than generated from tramadol metabolism.supported
ODT blood concentrations 0.4-4.3 μg/g. Mitragynine 0.02-0.18 μg/g. No tramadol or NDT detected, confirming direct ODT ingestion. pmid:21513619
The company initiated a clinical program under the investigational name desmetramadol (brand name Omnitram), completing two consecutive randomized, double-blind Phase 1 trials: Trial A (NCT02205554, n = 43) established that 20 mg desmetramadol administered every 6 hours produces analgesia equivalent to 50 mg tramadol every 6 hours; Trial B (NCT03312777, n = 60) demonstrated that CYP2D6 inhibition by paroxetine abolished tramadol's analgesic efficacy but left desmetramadol's efficacy intactsupported
20 mg desmetramadol q6h = 50 mg tramadol q6h in analgesic effect in healthy subjects (n=103). CYP inhibition with paroxetine abolished tramadol analgesia but not desmetramadol analgesia. NCT02205554, NCT03312777. j.jpain.2019.04.005
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Between October 2009 and October 2010, nine young people died in Sweden after consuming Krypton productssupported
Nine deaths in Sweden October 2009 onward from Krypton (kratom + ODT). pmid:21294331
The identification of desmetramadol as a G-protein biased µ-opioid receptor agonist in 2019 added pharmacological significance to the clinical program, situating ODT alongside oliceridine in a class of opioids designed to separate analgesic efficacy from β-arrestin2-mediated adverse effectssupported
Desmetramadol as effective as morphine, oxycodone, fentanyl in G-protein coupling at human MOR. Supratherapeutic concentrations spare βarrestin2 recruitment. Biased agonism similar to oliceridine. fphar.2019.01680
pharmacokinetic-detail7 · 5 ok
A 5:2 dose ratio (50 mg tramadol to 20 mg desmetramadol) produces equivalent steady-state (+)-ODT plasma levels under controlled conditions.partially supported
20 mg desmetramadol q6h = 50 mg tramadol q6h in analgesic effect in healthy subjects (n=103). j.jpain.2019.04.005
When generated from tramadol in vivo, ODT production is governed primarily by CYP2D6, with minor contributions from CYP3A4 and CYP2B6supported
CYP2D6, CYP2B6, CYP3A4 all involved in tramadol metabolism. s00228-012-1460-x
When generated from tramadol in vivo, ODT production is governed primarily by CYP2D6, with minor contributions from CYP3A4 and CYP2B6supported
CYP2D6 polymorphism correlated with tramadol clearance and conversion to M1. dddt.s199574
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Intracerebroventricular administration of the CYP2D inhibitor propafenone increased oral tramadol analgesia by 1.5-fold in rats, suggesting that local brain metabolism modulates analgesic response beyond what peripheral plasma ODT levels predict.supported
CYP2D inhibition in brain increases tramadol analgesia. Propafenone intracerebroventricularly increased analgesic AUC 1.5-fold. j.brainresbull.2020.09.001
Dogs predominantly produce the pharmacologically inactive N-desmethyl metabolite (NDT) rather than ODT, explaining the poor analgesic efficacy of tramadol in caninessupported
Cats produce ODT rapidly with longer elimination half-life (analgesic). Dogs mainly produce inactive NDT. javar.2021.h529
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
comparative-pharmacology6 · 5 ok
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Sources: µOR Ki; dose equivalence; half-life; G-protein bias; seizure data.supported
Ki at mu sites: (+)-M1 153 nM, morphine 7.1 nM. pmid:8982709
Sources: µOR Ki; dose equivalence; half-life; G-protein bias; seizure data.supported
ODT half-life ~7.5 hours. Elderly subjects have significantly longer half-life (50% longer) than younger subjects. s40266-015-0315-4
Sources: µOR Ki; dose equivalence; half-life; G-protein bias; seizure data.supported
(+/-)-tramadol anticonvulsant at analgesic doses but proconvulsant slightly higher. (+)-M1 limited by respiratory depression at convulsant doses. pmid:10991912
Morphine remains the reference standard for µ-opioid pharmacology. (+)-ODT is 5–21× less potent than morphine at the µOR depending on assay conditions (Ki = 153 nM vs 7.1 nM in radioligand binding; Ki = 3.4 nM vs 0.62 nM in GTP-shift assay)supported
(+)-M1 153 nM, morphine 7.1 nM. pmid:8982709
ODT's G-protein bias distinguishes it mechanistically from morphine, which recruits β-arrestin2 robustlysupported
Desmetramadol as effective as morphine, oxycodone, fentanyl in G-protein coupling at human MOR. Supratherapeutic concentrations spare βarrestin2 recruitment. fphar.2019.01680
receptor-pharmacology6 · 5 ok
However, the bias is relative, not absolute — fatal respiratory depression occurs at sufficiently high ODT concentrations, as demonstrated by the Krypton fatalities.supported
ODT blood concentrations 0.4-4.3 μg/g. Deaths attributed to respiratory depression. pmid:21513619
The definitive binding affinity data for ODT and its enantiomers at cloned human opioid receptors were established using radioligand binding at transfected HN9.10 neuroblastoma cells:supported
Ki at mu sites: tramadol 17000 nM, (+)-tramadol 15700 nM, (-)-tramadol 28800 nM, M1 (racemic) 3190 nM, (+)-M1 153 nM, (-)-M1 9680 nM, morphine 7.1 nM. pmid:8982709
The (+)-enantiomer is the opioid-active species, with greater than 100-fold higher µOR affinity than (+)-tramadol and approximately 63-fold greater affinity than the (-)-enantiomersupported
(+)-tramadol 15700 nM, (+)-M1 153 nM, (-)-M1 9680 nM. pmid:8982709
Claim in receptor-pharmacology — not_supportednot supportedworking →
Desmetramadol is a G-protein biased µ-opioid receptor agonistsupported
Desmetramadol as effective as morphine, oxycodone, fentanyl in G-protein coupling at human MOR. Supratherapeutic concentrations spare βarrestin2 recruitment. fphar.2019.01680
CYP2D6-mediated O-demethylation converts this methyl ether to a free phenol, removing the steric block and enabling hydrogen bonding with receptor residues in the binding pocketsupported
Methoxy group at position 3 reduces binding (explaining tramadol vs ODT difference). pmid:1851921
summary6 · 5 ok
The (+)-enantiomer binds the human µ-opioid receptor with Ki = 153 nM — approximately 100-fold greater affinity than the parent compound — producing oral effects lasting 6–10 hours at a molecular weight of 249.35 g/mol.partially supported
Ki at mu sites: tramadol 17000 nM, (+)-tramadol 15700 nM, (-)-tramadol 28800 nM, M1 (racemic) 3190 nM, (+)-M1 153 nM, (-)-M1 9680 nM, morphine 7.1 nM. pmid:8982709
ODT entered public health discourse after nine fatalities in Sweden (2009–2010) linked to the compound as an adulterant in "Krypton," a kratom-based herbal productsupported
9 fatal cases in Sweden (Oct 2009-Oct 2010). Krypton = powdered kratom + O-desmethyltramadol. pmid:21513619
Syntrix Biosystems subsequently advanced desmetramadol through Phase 1 clinical trials, establishing 20 mg desmetramadol as dose-equivalent to 50 mg tramadol and characterizing it as a G-protein biased µ-opioid receptor agonist.partially supported
20 mg desmetramadol q6h = 50 mg tramadol q6h in analgesic effect in healthy subjects (n=103). First human study of standalone desmetramadol. j.jpain.2019.04.005
At supratherapeutic concentrations, desmetramadol preferentially activates Gαi/o signaling over β-arrestin2 recruitment, a bias comparable to oliceridine that may partially account for the wider therapeutic index observed with tramadol-class compounds relative to classical opioids.supported
Supratherapeutic concentrations spare βarrestin2 recruitment (associated with respiratory depression). Biased agonism similar to oliceridine. fphar.2019.01680
Respiratory depression is the established mechanism of death in ODT overdose, with postmortem blood concentrations of 0.4–4.3 µg/g documented in the Swedish Krypton fatalitiessupported
ODT blood concentrations 0.4-4.3 μg/g. Deaths attributed to respiratory depression. pmid:21513619
Claim in summary — inconclusiveinconclusiveworking →
neuroscience5 · 5 ok
ODT's preferential Gαi/o activation over β-arrestin2 recruitment may reduce the magnitude of respiratory depression per unit of analgesia, though the mechanism is concentration-dependent and does not confer safety at overdose levels.supported
Supratherapeutic concentrations spare βarrestin2 recruitment (associated with respiratory depression). Biased agonism similar to oliceridine. fphar.2019.01680
Tramadol-dependent subjects demonstrate euphoric responses (Morphine-Benzedrine Group subscale scores) comparable to heroin and methamphetamine users, confirming that the ODT-mediated opioid component drives significant reward pathway activation.supported
MBG euphoria scores comparable to heroin/MA groups. High abuse potential with long-term use at high doses. 283425
At the spinal level, ODT directly suppresses glutamatergic excitatory transmission and enhances GABAergic/glycinergic inhibitory transmission in substantia gelatinosa neurons, providing a dual mechanism of spinal antinociception.partially supported
M1 reduces glutamate release frequency via µ-opioid receptor activation. Presynaptic mechanism. 1744806918824243
The (-)-enantiomer's SERT/NET inhibition augments descending pain modulation through serotonergic and noradrenergic pathways independent of opioid receptors, contributing to the atypical analgesic profile of the tramadol/ODT class.supported
Tramadol inhibits SERT and NET; serotonin syndrome risk. bph.14105
The G-protein biased agonism framework posits that receptor ligands can differentially activate intracellular signaling cascades, and that separating G-protein signaling from β-arrestin2 recruitment at the µOR could yield analgesics with reduced respiratory depression, constipation, and tolerance liabilitysupported
Supratherapeutic concentrations spare βarrestin2 recruitment (associated with respiratory depression). Biased agonism similar to oliceridine. fphar.2019.01680
chemistry2 · 2 ok
The demethylation that converts tramadol to ODT — removal of the methyl group from the 3-methoxy position to yield a free phenol — is the structural modification responsible for the dramatic increase in µ-opioid receptor affinity.supported
Methoxy group at position 3 reduces binding (explaining tramadol vs ODT difference). pmid:1851921
The (1S,2S)-(-)-trans enantiomer has substantially lower µOR affinity (Ki = 9,680 nM) but contributes to serotonin and norepinephrine reuptake inhibitionsupported
(-)-M1 9680 nM. pmid:8982709
clinical-evidence2 · 1 ok
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Paroxetine abolished tramadol's analgesic effect — confirming that tramadol is a prodrug dependent on CYP2D6 conversion to ODT — but did not impair desmetramadol's analgesic efficacysupported
CYP inhibition with paroxetine abolished tramadol analgesia but not desmetramadol analgesia. j.jpain.2019.04.005