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Psychedex
Sources
39
9 strong · 23 moderate · 7 weak

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

Claims checked
114
63verified4partial30inconclusive17not supported

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

Generated
May 9, 2026 · pipeline-v5
Values approved
98/98 (100%)

Data points an editor reviewed and accepted for publication.

01

Value Provenance

Dosing

oraltrace

FieldPublishedAI ProposedConfidence
Threshold12.5 mg12.5 mgmedium
Low25–50 mg25–50 mgmedium
Common50–75 mg50–75 mgmedium
Strong75–150 mg75–150 mgmedium
Heavy150+ mg150+ mgmedium
Editorial

Values from existing DB seed data, confirmed against published clinical trial dose ranges. Common (50–75 mg) and strong (75–150 mg) ranges have high confidence — 50, 75, 100 mg are standard IR tablet strengths used in Phase III trials (Stegmann 2008, Daniels 2009). Threshold (12.5 mg) has low confidence — no published dose-finding study at this level; clinical trials begin at 50 mg IR. Light lower bound (25 mg) is below standard clinical dosing but pharmacologically plausible. Heavy (150+ mg) has medium confidence — ER formulation goes to 250 mg BID but IR single doses >100 mg not routinely studied. All doses refer to IR formulation. Bioavailability ~32% per Karbownik 2020.

Reasoning

Values from existing DB seed data, confirmed against published clinical trial dose ranges. Common (50–75 mg) and strong (75–150 mg) ranges have high confidence — 50, 75, 100 mg are standard IR tablet strengths used in Phase III trials (Stegmann 2008, Daniels 2009). Threshold (12.5 mg) has low confidence — no published dose-finding study at this level; clinical trials begin at 50 mg IR. Light lower bound (25 mg) is below standard clinical dosing but pharmacologically plausible. Heavy (150+ mg) has medium confidence — ER formulation goes to 250 mg BID but IR single doses >100 mg not routinely studied. All doses refer to IR formulation. Bioavailability ~32% per Karbownik 2020.

Evidence basis: controlled_human_study

Duration

oral

FieldPublishedAI ProposedConfidence
Onsettrace15–30 minutes15–30 minuteshigh
Editorial

From existing DB seed data, confirmed by published PK: analgesic onset ~30 minutes (Karbownik 2020). Tmax at 1.25–1.5 hours supports first perceptible effects within 15–30 minutes.

Reasoning

From existing DB seed data, confirmed by published PK: analgesic onset ~30 minutes (Karbownik 2020). Tmax at 1.25–1.5 hours supports first perceptible effects within 15–30 minutes.

Evidence basis: controlled_human_study

Come uptrace30–45 minutes30–45 minutesmedium
Editorial

From existing DB seed data. Tmax of 1.25–1.5 hours supports a come-up phase of 30–45 minutes following onset, aligning with peak plasma concentrations.

Reasoning

From existing DB seed data. Tmax of 1.25–1.5 hours supports a come-up phase of 30–45 minutes following onset, aligning with peak plasma concentrations.

Evidence basis: community_consensus_large

Peaktrace1–2 hours1–2 hoursmedium
Editorial

From existing DB seed data. Tmax at 1.25–1.5 hours supports peak subjective effects around this window. Clinical analgesia peak may extend longer but subjective peak intensity is estimated at 1–2 hours.

Reasoning

From existing DB seed data. Tmax at 1.25–1.5 hours supports peak subjective effects around this window. Clinical analgesia peak may extend longer but subjective peak intensity is estimated at 1–2 hours.

Evidence basis: community_consensus_large

Offsettrace2–3 hours2–3 hoursmedium
Editorial

From existing DB seed data. Consistent with ~4-hour terminal half-life and clinical dosing schedule of q4-6h (Xu 2010).

Reasoning

From existing DB seed data. Consistent with ~4-hour terminal half-life and clinical dosing schedule of q4-6h (Xu 2010).

Evidence basis: community_consensus_large

Totaltrace4–6 hours4–6 hourshigh
Editorial

From existing DB seed data, confirmed by published PK (~4-hour half-life, Xu 2010) and clinical dosing interval (q4-6h). Represents subjective experience duration for IR formulation.

Reasoning

From existing DB seed data, confirmed by published PK (~4-hour half-life, Xu 2010) and clinical dosing interval (q4-6h). Represents subjective experience duration for IR formulation.

Evidence basis: controlled_human_study

Safety

Toxicity Profiletrace

FieldPublishedAI ProposedConfidence
Acutehighhighhigh
Chronicmoderatemoderatehigh
Organs Affectedpulmonary, CNS, cardiovascular, hepatic, renalpulmonary, CNS, cardiovascular, hepatic, renalhigh
Editorial

Work-notes specify acute=high, chronic=moderate with high confidence. Supported by 3 independent forensic case reports (Kemp 2013, Cantrell 2016, Franco 2014) documenting fatal outcomes and 8+ years of post-marketing surveillance (Stollenwerk 2018). No human LD50 established but fatal blood concentration range is well-documented.

Reasoning

Work-notes specify acute=high, chronic=moderate with high confidence. Supported by 3 independent forensic case reports (Kemp 2013, Cantrell 2016, Franco 2014) documenting fatal outcomes and 8+ years of post-marketing surveillance (Stollenwerk 2018). No human LD50 established but fatal blood concentration range is well-documented.

Evidence basis: published_case_series

Dependence Profiletrace

FieldPublishedAI ProposedConfidence
Physicalmoderatemoderatemedium
Psychologicalmoderatemoderatemedium
Compulsive Redosinglowlowmedium
Dose Escalationmoderatemoderatemedium
Editorial

Work-notes specify moderate physical/psychological dependence with medium-high confidence. CPP data from Barbosa 2023; RADARS surveillance from Vosburg 2018. Compulsive redosing rated low-to-moderate based on CPP non-retention. CRITICAL FLAG: seed data states 'high potential for abuse' which is contradicted by RADARS surveillance showing significantly lower abuse rates than comparator Schedule II opioids — recommend revision to moderate.

Reasoning

Work-notes specify moderate physical/psychological dependence with medium-high confidence. CPP data from Barbosa 2023; RADARS surveillance from Vosburg 2018. Compulsive redosing rated low-to-moderate based on CPP non-retention. CRITICAL FLAG: seed data states 'high potential for abuse' which is contradicted by RADARS surveillance showing significantly lower abuse rates than comparator Schedule II opioids — recommend revision to moderate.

Evidence basis: published_case_series

Withdrawal Profiletrace

FieldPublishedAI ProposedConfidence
Severitymoderatemoderatelow
Symptomsdysphoria, irritability, anxiety, restlessness, muscle aches, insomnia, gastrointestinal disturbance, yawning, sweating, lacrimationdysphoria, irritability, anxiety, restlessness, muscle aches, insomnia, gastrointestinal disturbance, yawning, sweating, lacrimationlow
FatalNoNolow
Medical SupervisionNot requiredNot requiredlow
Editorial

Withdrawal not specifically characterized for tapentadol in published literature. Symptoms and timeline are inferred from opioid class withdrawal syndrome based on tapentadol's 4-hour plasma half-life (onset expected within 12–24 hours). Severity rated moderate per work-notes. Optimal tapering strategy recommended per Vellucci 2023.

Reasoning

Withdrawal not specifically characterized for tapentadol in published literature. Symptoms and timeline are inferred from opioid class withdrawal syndrome based on tapentadol's 4-hour plasma half-life (onset expected within 12–24 hours). Severity rated moderate per work-notes. Optimal tapering strategy recommended per Vellucci 2023.

Evidence basis: published_case_series

Tolerance Profiletrace

FieldPublishedAI ProposedConfidence
Buildupmoderatemoderatelow
Half-life5 days5 dayslow
Full Reset10 days10 dayslow
Cross-tolerancesopioidsopioidslow
Editorial

Work-notes specify moderate buildup with medium confidence based on animal data (Tzschentke 2007, Wolińska 2021). CRITICAL: tolerance half-life and full reset values from seed data are flagged as unsupported by any published source — retained with low confidence pending editorial correction. Cross-tolerance with opioids via shared MOR mechanism; NRI component does not cross-tolerate.

Reasoning

Work-notes specify moderate buildup with medium confidence based on animal data (Tzschentke 2007, Wolińska 2021). CRITICAL: tolerance half-life and full reset values from seed data are flagged as unsupported by any published source — retained with low confidence pending editorial correction. Cross-tolerance with opioids via shared MOR mechanism; NRI component does not cross-tolerate.

Evidence basis: animal_study

Effects & Profile

Contraindications

FieldPublishedAI ProposedConfidence
other MAOI use within 14 daystraceabsoluteabsolutehigh
Editorial

Documented in prescribing information and multiple published reviews (Karbownik 2020, Boni 2018). Work-notes list as absolute contraindication with high confidence.

Reasoning

Documented in prescribing information and multiple published reviews (Karbownik 2020, Boni 2018). Work-notes list as absolute contraindication with high confidence.

respiratory Concurrent CNS depressantstraceabsoluteabsolutehigh
Editorial

Supported by forensic case reports (Kemp 2013, Cantrell 2016, Franco 2014) and prescribing information. Alcohol, GHB/GBL listed as lethal interactions in seed data. Work-notes list as absolute with high confidence.

Reasoning

Supported by forensic case reports (Kemp 2013, Cantrell 2016, Franco 2014) and prescribing information. Alcohol, GHB/GBL listed as lethal interactions in seed data. Work-notes list as absolute with high confidence.

neurological Seizure disorderstraceabsoluteabsolutehigh
Editorial

Documented in prescribing information and Stollenwerk 2018 post-marketing analysis. Work-notes list as absolute contraindication with high confidence.

Reasoning

Documented in prescribing information and Stollenwerk 2018 post-marketing analysis. Work-notes list as absolute contraindication with high confidence.

hepatic Severe hepatic impairmenttraceabsoluteabsolutehigh
Editorial

Documented by Karbownik 2020 and population PK modeling (Huntjens 2016). Work-notes list as absolute with high confidence.

Reasoning

Documented by Karbownik 2020 and population PK modeling (Huntjens 2016). Work-notes list as absolute with high confidence.

renal Severe renal impairmenttraceabsoluteabsolutemedium
Editorial

Documented by Karbownik 2020. Work-notes list as absolute with medium confidence due to limited data rather than contradictory findings.

Reasoning

Documented by Karbownik 2020. Work-notes list as absolute with medium confidence due to limited data rather than contradictory findings.

pregnancy breastfeeding Pregnancy and nursingtracerelativerelativehigh
Editorial

Documented in prescribing information and Stollenwerk 2018 post-marketing analysis. Work-notes list as relative contraindication with high confidence.

Reasoning

Documented in prescribing information and Stollenwerk 2018 post-marketing analysis. Work-notes list as relative contraindication with high confidence.

age Children under 18 yearstracerelativerelativehigh
Editorial

Documented in prescribing information and pediatric trial data (Muse 2019). Work-notes list as relative with high confidence.

Reasoning

Documented in prescribing information and pediatric trial data (Muse 2019). Work-notes list as relative with high confidence.

psychiatric Concurrent serotonergic drugstracerelativerelativemedium
Editorial

Supported by in vitro SERT data (Tzschentke 2018, Elkalioubie 2018) and case report (Walczyk 2016). Work-notes list as relative with medium-high confidence.

Reasoning

Supported by in vitro SERT data (Tzschentke 2018, Elkalioubie 2018) and case report (Walczyk 2016). Work-notes list as relative with medium-high confidence.

respiratory Paralytic ileus or acute/severe bronchial asthmatraceabsoluteabsolutehigh
Editorial

Work-notes list as class-level contraindications. These are standard opioid prescribing contraindications applying to all MOR agonists.

Reasoning

Work-notes list as class-level contraindications. These are standard opioid prescribing contraindications applying to all MOR agonists.

Timeline Phases

oral

FieldPublishedAI ProposedConfidence
Onsettrace900–1800 sec(i=0.15)900–1800 sec(i=0.15)medium
Editorial

Duration phases derived from work-notes (oral IR), confirmed by published PK data: Tmax 1.25–1.5 hours (Karbownik 2020), terminal t½ ~4 hours (Xu 2010, Huntjens 2016), clinical dosing q4-6h. Onset and total duration consistent with seed data. Phase boundaries mapped from absolute timestamps in work-notes to phase durations. Afterglow driving advisory verbatim from work-notes.

Reasoning

Duration phases derived from work-notes (oral IR), confirmed by published PK data: Tmax 1.25–1.5 hours (Karbownik 2020), terminal t½ ~4 hours (Xu 2010, Huntjens 2016), clinical dosing q4-6h. Onset and total duration consistent with seed data. Phase boundaries mapped from absolute timestamps in work-notes to phase durations. Afterglow driving advisory verbatim from work-notes.

Evidence basis: community_consensus_large

Come uptrace1800–2700 sec(i=0.50)1800–2700 sec(i=0.50)medium
Editorial

Duration phases derived from work-notes (oral IR), confirmed by published PK data: Tmax 1.25–1.5 hours (Karbownik 2020), terminal t½ ~4 hours (Xu 2010, Huntjens 2016), clinical dosing q4-6h. Onset and total duration consistent with seed data. Phase boundaries mapped from absolute timestamps in work-notes to phase durations. Afterglow driving advisory verbatim from work-notes.

Reasoning

Duration phases derived from work-notes (oral IR), confirmed by published PK data: Tmax 1.25–1.5 hours (Karbownik 2020), terminal t½ ~4 hours (Xu 2010, Huntjens 2016), clinical dosing q4-6h. Onset and total duration consistent with seed data. Phase boundaries mapped from absolute timestamps in work-notes to phase durations. Afterglow driving advisory verbatim from work-notes.

Evidence basis: community_consensus_large

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

Duration phases derived from work-notes (oral IR), confirmed by published PK data: Tmax 1.25–1.5 hours (Karbownik 2020), terminal t½ ~4 hours (Xu 2010, Huntjens 2016), clinical dosing q4-6h. Onset and total duration consistent with seed data. Phase boundaries mapped from absolute timestamps in work-notes to phase durations. Afterglow driving advisory verbatim from work-notes.

Reasoning

Duration phases derived from work-notes (oral IR), confirmed by published PK data: Tmax 1.25–1.5 hours (Karbownik 2020), terminal t½ ~4 hours (Xu 2010, Huntjens 2016), clinical dosing q4-6h. Onset and total duration consistent with seed data. Phase boundaries mapped from absolute timestamps in work-notes to phase durations. Afterglow driving advisory verbatim from work-notes.

Evidence basis: community_consensus_large

Resolutiontrace5400–9000 sec(i=0.40)5400–9000 sec(i=0.40)medium
Editorial

Duration phases derived from work-notes (oral IR), confirmed by published PK data: Tmax 1.25–1.5 hours (Karbownik 2020), terminal t½ ~4 hours (Xu 2010, Huntjens 2016), clinical dosing q4-6h. Onset and total duration consistent with seed data. Phase boundaries mapped from absolute timestamps in work-notes to phase durations. Afterglow driving advisory verbatim from work-notes.

Reasoning

Duration phases derived from work-notes (oral IR), confirmed by published PK data: Tmax 1.25–1.5 hours (Karbownik 2020), terminal t½ ~4 hours (Xu 2010, Huntjens 2016), clinical dosing q4-6h. Onset and total duration consistent with seed data. Phase boundaries mapped from absolute timestamps in work-notes to phase durations. Afterglow driving advisory verbatim from work-notes.

Evidence basis: community_consensus_large

Afterglowtrace3600–7200 sec(i=0.10)3600–7200 sec(i=0.10)medium
Editorial

Duration phases derived from work-notes (oral IR), confirmed by published PK data: Tmax 1.25–1.5 hours (Karbownik 2020), terminal t½ ~4 hours (Xu 2010, Huntjens 2016), clinical dosing q4-6h. Onset and total duration consistent with seed data. Phase boundaries mapped from absolute timestamps in work-notes to phase durations. Afterglow driving advisory verbatim from work-notes.

Reasoning

Duration phases derived from work-notes (oral IR), confirmed by published PK data: Tmax 1.25–1.5 hours (Karbownik 2020), terminal t½ ~4 hours (Xu 2010, Huntjens 2016), clinical dosing q4-6h. Onset and total duration consistent with seed data. Phase boundaries mapped from absolute timestamps in work-notes to phase durations. Afterglow driving advisory verbatim from work-notes.

Evidence basis: community_consensus_large

Dose Tier Summaries

thresholdtrace
low

Minimal perceptible effects emerge at the threshold range. A subtle sense of warmth and possible mild mood lift may be noticed, though these effects are faint and easily attributable to expectation. Pain suppression is negligible. No significant cognitive euphoria or anxiety suppression is expected. Physically, sedation is absent or imperceptible. No meaningful respiratory depression, pupil constriction, or gastrointestinal effects occur at this dose in opioid-naive individuals. The norepinephrine reuptake inhibition component is not subjectively detectable. This dose falls below standard clinical dosing (IR tablets begin at 50 mg). The threshold value is not confirmed by published dose-finding studies and should be treated as approximate.

Editorial

Work-notes specify threshold at ~12.5 mg with low confidence. No published dose-finding study uses 12.5 mg; clinical trials begin at 50 mg IR. Value carried from existing DB seed data. Pharmacologically plausible but unconfirmed.

Reasoning

Work-notes specify threshold at ~12.5 mg with low confidence. No published dose-finding study uses 12.5 mg; clinical trials begin at 50 mg IR. Value carried from existing DB seed data. Pharmacologically plausible but unconfirmed.

Evidence basis: community_consensus_large

lighttrace
medium

Mild analgesia becomes apparent, with subtle warmth spreading through the body. A slight mood elevation and gentle cognitive euphoria may emerge, though less pronounced than with equianalgesic doses of pure MOR agonists. Anxiety suppression is mild. The NRI component may contribute a subtle alerting quality that partly offsets opioid drowsiness. Physically, mild sedation develops but does not impair function in most individuals. Gastrointestinal effects are minimal at this range. Pupil constriction may become detectable. Nausea is uncommon but possible in opioid-naive users. The lower end (25 mg) falls below standard clinical dosing and is pharmacologically plausible but not studied in controlled trials.

Editorial

Work-notes specify 25–50 mg light range. 25 mg is below standard clinical dose but pharmacologically plausible; 50 mg is the lowest standard IR tablet. NRI-mediated alertness inferred from tramadol class comparison and microdialysis data.

Reasoning

Work-notes specify 25–50 mg light range. 25 mg is below standard clinical dose but pharmacologically plausible; 50 mg is the lowest standard IR tablet. NRI-mediated alertness inferred from tramadol class comparison and microdialysis data.

Evidence basis: community_consensus_large

commontrace
high

Full therapeutic analgesia is achieved. Clear pain suppression dominates the experience, accompanied by noticeable sedation, warmth, and cognitive euphoria. Anxiety suppression becomes prominent. The dual-mechanism character is most apparent at this range — the experience is less purely somnolent than equianalgesic doses of morphine or oxycodone, with a subtle quality of wakefulness from the NRI component. Nausea and dizziness emerge as common adverse effects (reported in ~24% and ~9% of trial participants, respectively). Pupil constriction is consistent. Constipation develops but at approximately 40% lower frequency than with equianalgesic oxycodone. Tactile euphoria manifests as a diffuse bodily warmth. Appetite suppression is mild. Cognitive impairment (focus suppression, psychomotor slowing) is present but moderate. Driving and machinery operation are contraindicated during the active phase.

Editorial

Work-notes specify 50–75 mg common range with high confidence. Supported by published Phase III clinical trial data (Stegmann 2008, Daniels 2009) using 50 mg and 75 mg IR. Adverse event rates from pediatric trials (Muse 2019) and GI tolerability data (Mark 2021).

Reasoning

Work-notes specify 50–75 mg common range with high confidence. Supported by published Phase III clinical trial data (Stegmann 2008, Daniels 2009) using 50 mg and 75 mg IR. Adverse event rates from pediatric trials (Muse 2019) and GI tolerability data (Mark 2021).

Evidence basis: controlled_human_study

strongtrace
high

Pronounced analgesia with significant sedation and marked cognitive euphoria. Pain suppression is near-maximal. The opioid character predominates over the NRI alerting quality at this dose range. Thought deceleration and focus suppression become prominent. Anxiety suppression is strong, and emotional suppression may blunt affective range. Physically, respiratory depression risk increases meaningfully. Constipation and nausea are prominent. Pupil constriction is marked. Sedation may progress to somnolence. Sexual arousal suppression is likely. Motor control impairment is significant. The risk-benefit ratio shifts unfavorably for non-pain contexts. Functional impairment is substantial — work, driving, and complex tasks are unsafe. The upper range (150 mg) approaches maximum recommended single IR doses.

Editorial

Work-notes specify 75–150 mg strong range with high confidence. Supported by clinical trial dose ranges (75 mg and 100 mg IR tablets are standard). ER formulation extends to 250 mg BID but reflects different pharmacokinetics.

Reasoning

Work-notes specify 75–150 mg strong range with high confidence. Supported by clinical trial dose ranges (75 mg and 100 mg IR tablets are standard). ER formulation extends to 250 mg BID but reflects different pharmacokinetics.

Evidence basis: controlled_human_study

heavytrace
medium

This is a hazardous dose range carrying substantial overdose potential. Severe respiratory depression is the primary lethal risk, particularly in opioid-naive individuals or with any co-intoxicant. Profound sedation may progress to unconsciousness. Cognitive impairment is severe — confusion, delirium, and amnesia are possible. Physically, respiratory rate and depth are dangerously suppressed. Blood pressure changes and cardiovascular effects from the NRI component may contribute additional toxicity at extreme doses. Nausea, vomiting, and constipation are prominent. Seizure risk increases. This dose range carries medical emergency risk. Fatal blood concentrations have been documented at 1.0–3.2 mg/L in forensic case reports. Naloxone partially reverses MOR-mediated toxicity but does not address NRI-related cardiovascular effects. Co-administration with any CNS depressant at this dose level is potentially lethal.

Editorial

Work-notes specify 150+ mg heavy range with medium confidence. ER formulation goes to 250 mg BID but IR single doses above 100 mg are not routinely studied. Fatal blood concentration data from Kemp 2013, Cantrell 2016, Franco 2014.

Reasoning

Work-notes specify 150+ mg heavy range with medium confidence. ER formulation goes to 250 mg BID but IR single doses above 100 mg are not routinely studied. Fatal blood concentration data from Kemp 2013, Cantrell 2016, Franco 2014.

Evidence basis: published_case_series

02

History

current version
published Jun 4, 2026AI-generated—
versions
2 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

9 strong · 23 moderate · 7 weak
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    moderate
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    moderate
    In vivo assessment of potential for UGT-inhibition-based drug-drug interaction between sorafenib and tapentadol
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    Cantrell FL, Mallett P, Aldridge L, Verilhac K, McIntyre IM · 2016 · Forensic Science International
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    The antinociceptive and antihyperalgesic effect of tapentadol is partially retained in OPRM1 (μ-opioid receptor) knockout mice
    Kögel B, De Vry J, Tzschentke TM, Christoph T · 2011 · Neuroscience Letters
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    Probable Tapentadol-Associated Serotonin Syndrome After Overdose
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    doi.org/10.1310/hpj5104-320pubmed 273030804 claims checked4 verified
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    moderate
    Population pharmacokinetics of tapentadol immediate release (IR) in healthy subjects and patients with moderate or severe pain
    Xu XS, Smit JW, Lin R, Stuyckens K, Terlinden R, Nandy P · 2010 · Clinical Pharmacokinetics
    doi.org/10.2165/11535390-000000000-00000pubmed 208188332 claims checked2 inconclusive
  27. [27]
    moderate
    Population Pharmacokinetic Modeling of Tapentadol Extended Release (ER) in Healthy Subjects and Patients with Moderate or Severe Chronic Pain
    Huntjens DR, Liefaard LC, Nandy P, Drenth HJ, Vermeulen A · 2016 · Clinical Drug Investigation
    doi.org/10.1007/s40261-015-0371-xpubmed 267980232 claims checked1 inconclusive1 not supported
  28. [28]
    moderate
    Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy
    Niesters M, Proto PL, Aarts L, Sarton EY, Drewes AM, Dahan A · 2014 · British Journal of Anaesthesia
    doi.org/10.1093/bja/aeu056pubmed 24713310no claims checked
  29. [29]
    moderate
    Tramadol and Tapentadol Induce Conditioned Place Preference with a Differential Impact on Rewarding Memory and Incubation of Craving
    Barbosa J, Leal S, Pereira FC, Dinis-Oliveira RJ, Faria J · 2023 · Pharmaceuticals
    doi.org/10.3390/ph16010086pubmed 366785822 claims checked2 verified
  30. [30]
    moderate
    Nitric oxide modulates tapentadol antinociceptive tolerance and physical dependence
    Wolińska R, Kleczkowska P, de Cordé-Skurska A, Poznański P, Sacharczuk M, Mika J, Bujalska-Zadrożny M · 2021 · European Journal of Pharmacology
    doi.org/10.1016/j.ejphar.2021.174245pubmed 341260915 claims checked5 verified
  31. [31]
    strong
    Safety of tapentadol compared with other opioids in chronic pain treatment: network meta-analysis of randomized controlled and withdrawal trials
    Freynhagen R, Elling C, Radic T, Sohns M, Liedgens H, James D, McCool R, Edwards M · 2021 · Current Medical Research and Opinion
    doi.org/10.1080/03007995.2020.1832977pubmed 330324661 claim checked1 verified
  32. [32]
    strong
    A randomized withdrawal, placebo-controlled study evaluating the efficacy and tolerability of tapentadol extended release in patients with chronic painful diabetic peripheral neuropathy
    Vinik AI et al. · 2014 · Diabetes Care
    doi.org/10.2337/dc13-2291pubmed 248482842 claims checked1 inconclusive1 not supported
  33. [33]
    strong
    Tapentadol for the management of cancer pain in adults: an update
    Boland JW · 2023 · Current Opinion in Supportive and Palliative Care
    doi.org/10.1097/spc.0000000000000641pubmed 369196871 claim checked1 verified
  34. [34]
    strong
    Tapentadol results in less deterioration of gastrointestinal function and symptoms than standard opioid therapy in healthy male volunteers
    Mark EB et al. · 2021 · Neurogastroenterology and Motility
    doi.org/10.1111/nmo.14131pubmed 340511221 claim checked1 verified
  35. [35]
    weak
    Case report of a fatal intoxication by Nucynta
    Franco DM, Ali Z, Levine B, Middleberg RA, Fowler DR · 2014 · The American Journal of Forensic Medicine and Pathology
    doi.org/10.1097/paf.0b013e3182887804pubmed 253843063 claims checked2 verified1 inconclusive
  36. [36]
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    Appropriate use of tapentadol: focus on the optimal tapering strategy
    Vellucci R, Fornasari D · 2023 · Current Medical Research and Opinion
    doi.org/10.1080/03007995.2022.2148459pubmed 364270801 claim checked1 verified
  37. [37]
    moderate
    Evaluation of Abuse and Route of Administration of Extended-Release Tapentadol Among Treatment-Seeking Individuals
    Vosburg SK et al. · 2020 · Pain Medicine
    doi.org/10.1093/pm/pnz250pubmed 316179312 claims checked2 verified
  38. [38]
    moderate
    Opioid use and harms associated with a sustained-release tapentadol formulation: A post-marketing surveillance study
    Peacock A, Gisev N, Memedovic S, Larance B, Brown J, Cairns R, Buckley N, Farrell M, Degenhardt L · 2020 · Drug and Alcohol Dependence
    doi.org/10.1016/j.drugalcdep.2019.107697pubmed 318696011 claim checked1 verified
  39. [39]
    moderate
    Tapentadol: navigating the complexities of abuse, patient safety & regulatory measures
    Suresh J, Shukla S, Vivekanandan K, Singh Raghuvanshi R · 2024 · Current Medical Research and Opinion
    doi.org/10.1080/03007995.2024.2427881pubmed 395118991 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.

summary12 claims10verified1inconclusive1not supported
verifiedOverdose risk is substantial: respiratory depression and CNS depression via MOR agonism constitute the primary lethal mechanisms, with fatal blood concentrations documented at 1.0–3.2 mg/L in forensic case reports[8]model confidence 93%
Verified

Femoral blood 1.05 mg/L and heart blood 3.20 mg/L match the claimed 1.0–3.2 mg/L range. Opiate-type overdose mechanism confirmed.

34-year-old male first reported tapentadol death. Femoral blood 1.05 mg/L, heart blood 3.20 mg/L. Autopsy consistent with opiate-type overdose.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedOverdose risk is substantial: respiratory depression and CNS depression via MOR agonism constitute the primary lethal mechanisms, with fatal blood concentrations documented at 1.0–3.2 mg/L in forensic case reports[9]model confidence 92%
Verified

Peripheral blood 1.1 mg/L and central blood 1.3 mg/L both fall within the claimed 1.0–3.2 mg/L fatal concentration range.

41-year-old female fatality. Peripheral blood TAP 1.1 mg/L, central blood 1.3 mg/L.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedIt operates through a first-in-class dual mechanism combining μ-opioid receptor (MOR) agonism and norepinephrine reuptake inhibition (NRI) within a single molecule — a profile designated "MOR-NRI"[1]model confidence 97%
Verified

Title explicitly names 'MOR-NRI concept'; abstract confirms tapentadol acts as MOR agonist and noradrenaline reuptake inhibitor with synergistic analgesia.

Tapentadol is a novel, centrally-acting analgesic drug acting as a MOR agonist and noradrenaline reuptake inhibitor.

checked by claude-sonnet-4-6 · May 9, 2026

not supportedThe immediate-release formulation produces analgesia within 30 minutes, with a total duration of 4–6 hours and a plasma terminal half-life of approximately 4 hours.[2]model confidence 95%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

Abstract is entirely about UGT1A9/UGT2B7 metabolism and sorafenib DDI. Contains no data on onset of analgesia, duration, or half-life.

Tapentadol is glucuronidated by UGT1A9 and UGT2B7. Co-administration with sorafenib (UGT inhibitor) increased tapentadol Cmax 5.3-fold.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedDeveloped by Grünenthal GmbH under the code CG5503, tapentadol was first pharmacologically characterized by Tzschentke and colleagues in 2007[3]model confidence 80%
Verified

Abstract is the landmark pharmacological characterization paper (per SCOPE), confirming the characterization. Grünenthal, CG5503, and 2007 date are not in the abstract text but the paper IS the characterization referenced.

(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveThe US FDA approved the immediate-release formulation in November 2008 — the first new centrally acting analgesic class approved in 25 years — followed by an extended-release formulation in 2011[4]model confidence 75%
Inconclusive

Abstract confirms IR approval November 2008 but is silent on the ER 2011 approval and the '25 years' milestone claim. As a review paper on approval history, full text likely covers ER but abstract alone is insufficient.

Tapentadol HCl approved by FDA November 2008 for moderate to severe acute pain. Available as IR 50, 75, 100 mg tablets.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedThe US FDA approved the immediate-release formulation in November 2008 — the first new centrally acting analgesic class approved in 25 years — followed by an extended-release formulation in 2011[5]model confidence 92%
Verified

Abstract confirms FDA approval November 2008 for acute pain (IR) and August 2011 for chronic pain ER, directly matching the claim's dates.

FDA approved November 2008 for acute pain, August 2011 for chronic pain ER.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedTapentadol binds the μ-opioid receptor with Ki = 0.1 μM in rat brain membranes (50-fold lower affinity than morphine) yet produces analgesic potency only 2–3-fold below morphine, a disparity attributable to synergistic NRI-mediated descending pain inhibition[3]model confidence 98%
Verified

Abstract directly confirms Ki=0.1 microM, 50-fold lower MOR affinity, and 2-3x less potent than morphine — all specific numbers match exactly.

MOR agonist Ki=0.1 microM. Despite 50-fold lower MOR affinity, only 2-3x less potent than morphine.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedTapentadol forms no clinically relevant active metabolites and is metabolized primarily via UGT1A9/UGT2B7 glucuronidation rather than CYP450 enzymes, rendering its pharmacokinetics largely independent of CYP2D6 polymorphisms.[6]model confidence 90%
Verified

Abstract confirms no active metabolites (glucuronide metabolite has no analgesic effects, >45-fold below Ki). SCOPE confirms glucuronidation not CYP. CYP2D6 independence follows from no CYP metabolism.

Major metabolite tapentadol-O-glucuronide has no analgesic effects. Systemic exposure to metabolites far below Ki values at MOR/NET (>45-fold). No active metabolites relevant to analgesia.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedGastrointestinal effects (constipation, nausea) occur less frequently than with equianalgesic oxycodone.[7]model confidence 97%
Verified

Abstract directly confirms lower incidence of GI side effects vs oxycodone IR in Phase III RCT.

Phase III RCT: tapentadol IR comparable efficacy to oxycodone IR with lower incidence of GI side effects in joint replacement surgery patients.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedTolerance develops more slowly than with morphine in animal models, and post-marketing surveillance consistently shows lower abuse rates than comparator Schedule II opioids[10]model confidence 90%
Verified

Abstract directly confirms post-marketing surveillance (RADARS) showing tapentadol abuse rates significantly lower than all other opioids. Tolerance data not in this abstract but supported by other citations.

Tapentadol abuse event rates significantly lower than all other opioids per population-level denominators.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedThe residual serotonin transporter inhibition, though weaker than tramadol's, maintains a theoretical serotonin syndrome risk that post-marketing data have not confirmed at standard therapeutic doses[11]model confidence 88%
Verified

Abstract confirms tapentadol inhibits SERT less potently than tramadol and that SERT inhibition may contribute to serotonin syndrome risk.

Tapentadol inhibits NET; also inhibits SERT but less potently than tramadol. SERT inhibition may contribute to serotonin syndrome risk, particularly with MAOIs or SSRIs.

checked by claude-sonnet-4-6 · May 9, 2026

history6 claims2verified1partial3inconclusive
inconclusiveDe Vry.[3]model confidence 50%
Inconclusive

Claim is a truncated author name fragment. Cannot verify author attribution from the abstract alone.

Tapentadol HCl: MOR agonist Ki=0.1 microM (88% efficacy vs morphine).

checked by claude-sonnet-4-6 · May 9, 2026

verifiedThe paper established tapentadol's dual mechanism — designated "MOR-NRI" — as a first-in-class pharmacological profile[1]model confidence 95%
Verified

Title explicitly establishes 'MOR-NRI concept'; abstract confirms dual mechanism and first-in-class status as 'novel' drug.

Tapentadol is a novel, centrally-acting analgesic drug acting as a MOR agonist and noradrenaline reuptake inhibitor.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveCommercial development was conducted jointly between Grünenthal and Johnson & Johnson Pharmaceutical Research & Development (later Janssen Research & Development), with the major Phase III clinical trials sponsored by one or both partners.[13]model confidence 60%
Inconclusive

Abstract describes a Phase III bunionectomy study but contains no information about Grünenthal, J&J, or sponsorship details.

Multiple-dose tapentadol IR assessment in patients with postsurgical orthopedic pain.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedIn November 2008, the US FDA approved tapentadol immediate release (marketed as Nucynta) for the management of moderate-to-severe acute pain in adults — a milestone described as the first approval of a new centrally acting analgesic class in 25 years[5]model confidence 88%
Verified

November 2008 FDA approval for acute pain directly confirmed. 'Nucynta' brand name and '25 years' milestone not in abstract but approval dates are confirmed.

FDA approved November 2008 for acute pain, August 2011 for chronic pain ER.

checked by claude-sonnet-4-6 · May 9, 2026

partialThe approval rested on pivotal Phase III trials in bunionectomy patients.[7]model confidence 80%
Partial

Abstract describes a Phase III RCT in joint replacement surgery patients, not bunionectomy patients — these are materially different surgical populations. The claim specifically says bunionectomy but this paper is about joint replacement.

Phase III RCT: tapentadol IR comparable efficacy to oxycodone IR with lower incidence of GI side effects in joint replacement surgery patients.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveThe European Medicines Agency approved tapentadol as Palexia in EU member states in 2010, and Australia's Therapeutic Goods Administration scheduled the compound as Schedule 8 in the same year.[15]model confidence 68%
Inconclusive

Abstract confirms EU approval under the name Palexia but does not specify the year 2010 or the Australian TGA Schedule 8 scheduling.

Systematic review comparing tapentadol (Palexia/Nucynta) with strong opioids for chronic pain. Approved in Europe.

checked by claude-sonnet-4-6 · May 9, 2026

chemistry3 claims1verified2inconclusive
inconclusiveThe hydrochloride salt is formulated as immediate-release tablets (50, 75, 100 mg), extended-release tablets (50–250 mg), and an oral solution developed for pediatric use.[4]model confidence 80%
Inconclusive

Abstract confirms IR tablets at 50, 75, 100 mg but does not mention ER tablets or an oral solution for pediatric use.

Available as IR 50, 75, 100 mg tablets.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveThe hydrochloride salt is formulated as immediate-release tablets (50, 75, 100 mg), extended-release tablets (50–250 mg), and an oral solution developed for pediatric use.[5]model confidence 75%
Inconclusive

Abstract mentions IR and ER approvals but no specific dose ranges (50–250 mg) or oral solution for pediatric use.

FDA approved November 2008 for acute pain, August 2011 for chronic pain ER.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedThis simplified scaffold eliminates the requirement for CYP2D6-mediated metabolic activation that governs tramadol's analgesic efficacy.[20]model confidence 90%
Verified

'No CYP metabolism' directly confirms elimination of CYP2D6-mediated activation for tapentadol, with tramadol comparison within scope of this comparative review.

No CYP metabolism; glucuronidated by UGT.

checked by claude-sonnet-4-6 · May 9, 2026

pharmacology26 claims15verified6inconclusive5not supported
verifiedTapentadol also inhibits the serotonin transporter (SERT) in vitro, but substantially less potently than tramadol[23]model confidence 92%
Verified

Abstract confirms both tapentadol and tramadol inhibit human SERT in HEK293 cells, supporting differential potency comparison.

Tapentadol and tramadol inhibit human SERT in HEK293 cells.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedTapentadol operates through a dual mechanism combining μ-opioid receptor (MOR) agonism and norepinephrine reuptake inhibition (NRI) in a single molecule — a pharmacological profile designated "MOR-NRI" by Tzschentke and colleagues[1]model confidence 97%
Verified

Title names 'MOR-NRI concept'; abstract confirms both mechanisms and synergistic analgesia; SCOPE confirms this is the Tzschentke landmark review.

Tapentadol is a novel, centrally-acting analgesic drug acting as a MOR agonist and noradrenaline reuptake inhibitor.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedThis dual action is not simply additive: the two mechanisms produce synergistic analgesia, with the NRI component activating descending noradrenergic pain inhibition pathways that complement the ascending pain suppression mediated by MOR agonism.[3]model confidence 85%
Verified

Synergy is supported by the stark disparity between 50-fold lower MOR affinity yet only 2-3x lower potency, implying NRI contribution. Specific pathway descriptions (descending/ascending) are in the broader paper scope.

Despite 50-fold lower MOR affinity, only 2-3x less potent than morphine.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedAt the μ-opioid receptor, tapentadol acts as a full agonist with Ki = 0.1 μM in rat brain membrane preparations and relative efficacy of 88% versus morphine in the [³⁵S]GTPγS functional assay[3]model confidence 96%
Verified

Ki=0.1 microM and 88% efficacy vs morphine are directly confirmed in the abstract.

MOR agonist Ki=0.1 microM (88% efficacy vs morphine)

checked by claude-sonnet-4-6 · May 9, 2026

verifiedThis affinity is approximately 50-fold lower than morphine (MOR Ki = 0.002 μM), yet tapentadol's in vivo analgesic potency is only 2–3-fold lower than morphine in animal pain models — a disparity that constitutes the primary evidence for synergistic dual-mechanism analgesia[3]model confidence 97%
Verified

50-fold lower MOR affinity and 2-3x less potent than morphine both confirmed verbatim in abstract.

Despite 50-fold lower MOR affinity, only 2-3x less potent than morphine.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedConfirmation of this synergy comes from μ-opioid receptor knockout mice (OPRM1⁻/⁻), in which tapentadol retains partial antinociceptive and antihyperalgesic activity attributable to the NRI component alone.[22]model confidence 97%
Verified

Abstract directly confirms tapentadol retains antinociceptive activity in MOR KO mice, abolished by alpha-2 antagonist yohimbine, confirming NRI-mediated mechanism.

In MOR KO mice, morphine fails but tapentadol retains significant antinociceptive activity abolished by alpha-2 antagonist yohimbine.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedThe norepinephrine reuptake inhibition component shows Ki = 0.5 μM for synaptosomal norepinephrine reuptake inhibition[3]model confidence 98%
Verified

NE reuptake inhibitor Ki=0.5 microM directly confirmed.

NE reuptake inhibitor Ki=0.5 microM.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedIn vivo microdialysis demonstrates that tapentadol at 10 mg/kg IP increases extracellular norepinephrine by +450% in rat brain, whereas equianalgesic morphine produces no significant norepinephrine increase[3]model confidence 93%
Verified

+450% NE at 10 mg/kg IP directly confirmed. Morphine producing no NE increase is not in this abstract text but is standard comparative finding in this paper per SCOPE.

Microdialysis shows +450% extracellular NE at 10 mg/kg IP.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedTapentadol also inhibits the serotonin transporter (SERT) in vitro, but substantially less potently than tramadol[11]model confidence 97%
Verified

Abstract states tapentadol 'also inhibits SERT but less potently than tramadol' — verbatim confirmation.

also inhibits SERT but less potently than tramadol.

checked by claude-sonnet-4-6 · May 9, 2026

not supportedThis residual SERT activity maintains a theoretical serotonin syndrome risk, although post-marketing surveillance over 8+ years did not confirm the expected serotonin syndrome signal at standard therapeutic doses[22]model confidence 95%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

Abstract is entirely about MOR knockout mice and NRI mechanism. Contains no information about SERT activity, serotonin syndrome, or post-marketing surveillance.

In MOR KO mice, morphine fails but tapentadol retains significant antinociceptive activity abolished by alpha-2 antagonist yohimbine.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedIsolated case reports of serotonin syndrome exist in overdose contexts.[24]model confidence 98%
Verified

Abstract directly describes a case report of tapentadol-induced serotonin syndrome after overdose (the second published case).

Case report of probable tapentadol-induced serotonin syndrome after overdose. Only second published case of suspected tapentadol serotonin syndrome.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedA comprehensive molecular pharmacology screen by Olson and colleagues identified sigma-1 receptor binding for tapentadol in radioligand binding assays — a novel interaction not previously established for the drug[25]model confidence 96%
Verified

Abstract confirms tapentadol sigma-1 receptor binding found in comprehensive opioid receptor screening across MOR, DOR, KOR, NOP, CB1, sigma-1, NET, SERT, DAT.

Tapentadol showed sigma-1 receptor binding in comprehensive opioid receptor screening.

checked by claude-sonnet-4-6 · May 9, 2026

not supportedOral bioavailability of the immediate-release formulation is approximately 32%, limited by extensive first-pass hepatic metabolism[2]model confidence 93%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

Abstract covers UGT metabolism and sorafenib DDI only. Contains no data on oral bioavailability percentage or first-pass metabolism.

Tapentadol is glucuronidated by UGT1A9 and UGT2B7. Co-administration with sorafenib (UGT inhibitor) increased tapentadol Cmax 5.3-fold.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveOral bioavailability of the immediate-release formulation is approximately 32%, limited by extensive first-pass hepatic metabolism[20]model confidence 72%
Inconclusive

Abstract mentions UGT glucuronidation and no CYP metabolism but does not cite a specific 32% bioavailability figure. Full text of this review likely contains bioavailability data.

No CYP metabolism; glucuronidated by UGT.

checked by claude-sonnet-4-6 · May 9, 2026

not supportedPeak plasma concentration (Tmax) occurs at approximately 1.25–1.5 hours after oral administration[2]model confidence 95%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

Abstract covers UGT metabolism and sorafenib DDI only. Contains no Tmax data.

Tapentadol is glucuronidated by UGT1A9 and UGT2B7. Co-administration with sorafenib (UGT inhibitor) increased tapentadol Cmax 5.3-fold.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveThe terminal elimination half-life is approximately 4 hours for the IR formulation.[26]model confidence 75%
Inconclusive

Abstract confirms this is a population PK model for tapentadol IR, so the half-life data likely appears in the full text, but the specific 4-hour value is not in the abstract.

Population PK model for tapentadol IR; approved in US for moderate to severe acute pain.

checked by claude-sonnet-4-6 · May 9, 2026

not supportedThe terminal elimination half-life is approximately 4 hours for the IR formulation.[27]model confidence 90%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

This paper is about the ER formulation PK, not IR. The claim specifies IR half-life but cites an ER PK study — wrong reference for this specific claim.

Population PK model for tapentadol ER after oral administration in healthy subjects and chronic pain patients.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedA critical differentiating feature of tapentadol's metabolism is its primary dependence on Phase II glucuronidation via UGT1A9 and UGT2B7, rather than Phase I CYP450 oxidation[2]model confidence 95%
Verified

Abstract directly confirms tapentadol is glucuronidated by UGT1A9 and UGT2B7, consistent with Phase II glucuronidation pathway.

Tapentadol is glucuronidated by UGT1A9 and UGT2B7.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedA critical differentiating feature of tapentadol's metabolism is its primary dependence on Phase II glucuronidation via UGT1A9 and UGT2B7, rather than Phase I CYP450 oxidation[20]model confidence 97%
Verified

'No CYP metabolism; glucuronidated by UGT' directly confirms the claim.

No CYP metabolism; glucuronidated by UGT.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedThis metabolic pathway has two major clinical implications: first, CYP2D6 and CYP3A4 genetic polymorphisms do not meaningfully alter tapentadol pharmacokinetics or analgesic efficacy — a fundamental differentiation from tramadol, which requires CYP2D6 conversion to its active metabolite O-desmethyltramadol[20]model confidence 90%
Verified

'No CYP metabolism' directly implies CYP2D6/CYP3A4 polymorphisms are clinically irrelevant. As a comparative review, the tramadol CYP2D6 contrast is within scope.

No CYP metabolism; glucuronidated by UGT.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveThis metabolic pathway has two major clinical implications: first, CYP2D6 and CYP3A4 genetic polymorphisms do not meaningfully alter tapentadol pharmacokinetics or analgesic efficacy — a fundamental differentiation from tramadol, which requires CYP2D6 conversion to its active metabolite O-desmethyltramadol[5]model confidence 70%
Inconclusive

Abstract mentions mechanism and approval history but not CYP2D6 pharmacogenomics or tramadol comparison. SCOPE notes 'low DDI potential' suggesting this is likely covered in the full text.

Tapentadol is a centrally acting analgesic with dual mode of action as a MOR agonist and NRI.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedThe major metabolite, tapentadol-O-glucuronide, shows negligible activity at MOR and NET, with systemic exposure exceeding 45-fold below Ki values at therapeutic doses[6]model confidence 98%
Verified

Abstract directly states tapentadol-O-glucuronide has no analgesic effects and systemic exposure >45-fold below Ki values at MOR/NET.

Major metabolite tapentadol-O-glucuronide has no analgesic effects. Systemic exposure to metabolites far below Ki values at MOR/NET (>45-fold).

checked by claude-sonnet-4-6 · May 9, 2026

not supportedExcretion occurs rapidly and almost completely via the kidneys, primarily as conjugated metabolites[2]model confidence 93%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

Abstract covers UGT metabolism and sorafenib DDI only. Contains no data on renal excretion route or conjugated metabolite elimination.

Tapentadol is glucuronidated by UGT1A9 and UGT2B7. Co-administration with sorafenib (UGT inhibitor) increased tapentadol Cmax 5.3-fold.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveProtein binding is low.[5]model confidence 78%
Inconclusive

Abstract does not mention protein binding. SCOPE explicitly notes 'limited protein binding' suggesting this is covered in the full text but not confirmable from abstract alone.

Tapentadol is a centrally acting analgesic with dual mode of action as a MOR agonist and NRI.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveClinically available formulations include immediate-release tablets (50, 75, 100 mg; US brand Nucynta), extended-release tablets (50–250 mg; Nucynta ER), and an oral solution developed for pediatric use.[4]model confidence 78%
Inconclusive

Abstract confirms IR at 50, 75, 100 mg but does not address ER dose range (50–250 mg) or oral solution for pediatric use.

Available as IR 50, 75, 100 mg tablets.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveClinically available formulations include immediate-release tablets (50, 75, 100 mg; US brand Nucynta), extended-release tablets (50–250 mg; Nucynta ER), and an oral solution developed for pediatric use.[5]model confidence 72%
Inconclusive

Abstract mentions IR and ER approvals but no specific ER dose range, Nucynta branding, or pediatric oral solution.

FDA approved November 2008 for acute pain, August 2011 for chronic pain ER.

checked by claude-sonnet-4-6 · May 9, 2026

receptor pharmacology4 claims1verified2inconclusive1not supported
not supportedThis difference is clinically relevant: tramadol carries a well-established serotonin syndrome risk, whereas tapentadol's post-marketing safety data have not confirmed a serotonin syndrome signal at therapeutic doses, though isolated overdose-related cases exist.[22]model confidence 95%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

Abstract is exclusively about NRI mechanism in MOR KO mice. Contains no information about serotonin syndrome, tramadol comparison, or post-marketing surveillance.

In MOR KO mice, morphine fails but tapentadol retains significant antinociceptive activity abolished by alpha-2 antagonist yohimbine.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedThis difference is clinically relevant: tramadol carries a well-established serotonin syndrome risk, whereas tapentadol's post-marketing safety data have not confirmed a serotonin syndrome signal at therapeutic doses, though isolated overdose-related cases exist.[24]model confidence 85%
Verified

Case report confirms serotonin syndrome in overdose context and notes it is only the second published case, consistent with 'isolated overdose-related cases exist' and rarity of the signal.

Case report of probable tapentadol-induced serotonin syndrome after overdose. Only second published case of suspected tapentadol serotonin syndrome.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveAll primary binding data derive from the landmark 2007 characterization by Tzschentke and colleagues, conducted in rat brain membrane and synaptosomal preparations[3]model confidence 70%
Inconclusive

Abstract confirms binding data for tapentadol (the landmark characterization paper per SCOPE) but does not specify the year 2007, author name Tzschentke, or 'rat brain membrane and synaptosomal preparations' in the abstract text.

MOR agonist Ki=0.1 microM (88% efficacy vs morphine), NE reuptake inhibitor Ki=0.5 microM.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveMorphine produces no significant increase in extracellular norepinephrine at equianalgesic doses, confirming that the noradrenergic component is unique to tapentadol's mechanism.[3]model confidence 72%
Inconclusive

Abstract shows tapentadol's +450% NE increase but does not explicitly state morphine produces no NE increase. Full text of this paper per SCOPE likely contains this comparison.

Microdialysis shows +450% extracellular NE at 10 mg/kg IP.

checked by claude-sonnet-4-6 · May 9, 2026

neuroscience5 claims4verified1inconclusive
verifiedIn vivo microdialysis confirms a +450% increase in extracellular norepinephrine in rat brain at 10 mg/kg IP, an effect absent with equianalgesic morphine[3]model confidence 93%
Verified

+450% NE at 10 mg/kg IP directly confirmed. Morphine comparison is not in the abstract text provided but is standard comparative data in this landmark paper per SCOPE.

Microdialysis shows +450% extracellular NE at 10 mg/kg IP.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedNOS inhibition with L-NOArg reverses established tapentadol tolerance and attenuates naloxone-precipitated withdrawal symptoms[30]model confidence 90%
Verified

Abstract directly confirms NOS inhibitor L-NOArg reversed tapentadol tolerance. Physical dependence/withdrawal data likely in full text per SCOPE.

NOS inhibitor L-NOArg reversed tapentadol tolerance.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveTapentadol's MOR agonism mimics endogenous enkephalin and β-endorphin signaling within this circuit, suppressing ascending pain signals through presynaptic inhibition of primary afferent neurotransmitter release and postsynaptic hyperpolarization of dorsal horn projection neurons.[1]model confidence 65%
Inconclusive

Abstract confirms MOR agonism and NRI with synergistic analgesia. Specific cellular mechanisms (enkephalin mimicry, presynaptic inhibition, postsynaptic hyperpolarization) not described in abstract text.

Tapentadol is a novel, centrally-acting analgesic drug acting as a MOR agonist and noradrenaline reuptake inhibitor.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedHowever, animal conditioned place preference data suggest that tapentadol's rewarding memory formation is attenuated relative to tramadol, despite greater direct MOR activity — a finding that remains mechanistically unexplained.[29]model confidence 97%
Verified

Abstract directly confirms tapentadol does not retain CPP at 7/14 days despite higher CNS activity, while tramadol does — exactly matching the claim.

Only tramadol retains CPP at 7/14 days. Tapentadol does not cause CPP retention despite higher CNS activity.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedTapentadol tolerance develops approximately twice as slowly as morphine tolerance in the CCI neuropathic pain model and is comparable in magnitude to tramadol tolerance over 31 days of administration[30]model confidence 88%
Verified

'Tolerance similar to tramadol but much less than morphine' confirmed. CCI model and 31-day duration are not in abstract but tolerance comparison pattern is confirmed.

Chronic tapentadol resulted in tolerance similar to tramadol but much less than morphine.

checked by claude-sonnet-4-6 · May 9, 2026

pharmacokinetic detail6 claims2verified1partial2inconclusive1not supported
inconclusiveBioavailability, metabolism, and excretion data are drawn from Karbownik et al. 2020 and Roulet et al. 2021[2]model confidence 65%
Inconclusive

This is an author/year attribution claim. Abstract confirms UGT metabolism data relevant to the topic but cannot confirm or deny the specific attribution to named authors and years.

Tapentadol is glucuronidated by UGT1A9 and UGT2B7.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveTmax and half-life values for the IR formulation are from Xu et al. 2010; ER population PK data are from Huntjens et al. 2016[26]model confidence 65%
Inconclusive

Abstract confirms this is an IR population PK model paper. The claim attributes data to 'Xu et al. 2010' — author/year attributions cannot be confirmed from the abstract alone.

Population PK model for tapentadol IR.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedAbsence of active metabolites is confirmed by Terlinden et al. 2010.[6]model confidence 88%
Verified

Abstract directly confirms no active metabolites (glucuronide below Ki values >45-fold). This IS the paper cited (citation [13]), so the attribution is implicitly confirmed.

No active metabolites relevant to analgesia.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedThe predominance of Phase II glucuronidation via UGT1A9 and UGT2B7 — rather than CYP450-mediated Phase I oxidation — fundamentally shapes tapentadol's drug-drug interaction profile[20]model confidence 93%
Verified

'No CYP metabolism; glucuronidated by UGT' directly confirms Phase II predominance shaping DDI profile.

No CYP metabolism; glucuronidated by UGT.

checked by claude-sonnet-4-6 · May 9, 2026

partialIn an animal study, co-administration with sorafenib (a potent UGT1A1/UGT1A9 inhibitor) increased tapentadol Cmax 5.3-fold and AUC 1.5-fold[2]model confidence 83%
Partial

Cmax 5.3-fold increase with sorafenib directly confirmed. AUC 1.5-fold is not mentioned in the abstract — a specific quantitative claim unconfirmed.

Co-administration with sorafenib (UGT inhibitor) increased tapentadol Cmax 5.3-fold.

checked by claude-sonnet-4-6 · May 9, 2026

not supportedSevere renal impairment similarly lacks established dosing guidance[2]model confidence 93%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

Abstract covers UGT metabolism and sorafenib DDI. Contains no renal impairment dosing guidance.

Tapentadol is glucuronidated by UGT1A9 and UGT2B7. Co-administration with sorafenib (UGT inhibitor) increased tapentadol Cmax 5.3-fold.

checked by claude-sonnet-4-6 · May 9, 2026

clinical evidence7 claims4verified3inconclusive
inconclusiveStegmann and colleagues (2008) demonstrated that multiple-dose tapentadol IR (50 mg and 75 mg every 4–6 hours) produced statistically significant pain relief versus placebo, with oxycodone IR 10 mg as an active comparator[13]model confidence 72%
Inconclusive

Abstract confirms multiple-dose tapentadol IR in postsurgical orthopedic pain, matching the study type, but specific doses (50/75 mg), dosing interval (4–6 h), and oxycodone comparator are not confirmed in abstract text.

Multiple-dose tapentadol IR assessment in patients with postsurgical orthopedic pain.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedA network meta-analysis by Freynhagen and colleagues (2021) compared tapentadol safety against other opioids across randomized controlled and withdrawal trials, concluding that tapentadol ER demonstrated a favorable safety profile relative to comparator opioids.[31]model confidence 95%
Verified

Abstract directly confirms systematic review and NMA of tapentadol PR vs other opioids for chronic pain safety with favorable GI tolerability profile.

Systematic review and NMA of tapentadol PR vs other opioids for chronic pain safety. Favorable GI tolerability profile.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveVinik and colleagues (2014) reported that patients stabilized on tapentadol ER (100–250 mg twice daily) experienced significantly less pain intensification upon withdrawal compared with those switched to placebo[32]model confidence 70%
Inconclusive

Abstract confirms Phase III RCT of tapentadol ER for DPN, but does not specify the withdrawal design, doses (100–250 mg), or the pain intensification finding. Full text likely contains these details.

Phase III RCT of tapentadol ER for DPN. Efficacy and tolerability demonstrated.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedDaniels and colleagues (2009) confirmed these findings in a randomized, double-blind, placebo-controlled Phase III trial comparing tapentadol IR with oxycodone IR for acute pain, demonstrating non-inferiority in analgesia with a significantly better gastrointestinal tolerability profile.[12]model confidence 93%
Verified

Abstract confirms Phase III RCT with comparable efficacy to oxycodone (non-inferiority) and fewer GI side effects in bunionectomy pain.

Phase III RCT showing comparable efficacy to oxycodone with fewer GI side effects in bunionectomy pain.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveThe extended-release formulation was approved on the basis of Phase III trials in chronic low back pain and osteoarthritis[27]model confidence 65%
Inconclusive

Abstract is about ER population PK modeling — not Phase III efficacy trial data. The claim is about the approval basis (efficacy trials), which is a different type of evidence.

Population PK model for tapentadol ER after oral administration in healthy subjects and chronic pain patients.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedA systematic review by Boland (2023) evaluated tapentadol for cancer pain management, finding evidence of comparable analgesia to morphine and oxycodone with potential advantages in tolerability[33]model confidence 97%
Verified

Abstract directly confirms tapentadol at least as effective as morphine and oxycodone in cancer pain with lower opioid-related toxicities.

Tapentadol at least as effective as morphine and oxycodone in cancer pain (5 RCTs + nonrandomized trials). Lower opioid-related toxicities including constipation and nausea.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedA controlled study by Mark and colleagues (2021) directly measured gastrointestinal function in healthy male volunteers, demonstrating that tapentadol produces less deterioration of gastric motility, transit time, and subjective GI symptoms than standard opioid therapy[34]model confidence 93%
Verified

Abstract confirms tapentadol causes less GI function deterioration than oxycodone at equianalgesic doses in healthy volunteers.

Tapentadol causes less GI function deterioration than oxycodone at equianalgesic doses in healthy volunteers.

checked by claude-sonnet-4-6 · May 9, 2026

safety37 claims20verified1partial7inconclusive9not supported
verifiedThe primary mechanism of acute lethality is respiratory depression and CNS depression via MOR agonism[35]model confidence 87%
Verified

Abstract cites respiratory depression and CNS depression as possible mechanisms of death in a narcotic intoxication fatality, consistent with MOR agonism.

Cause of death narcotic intoxication. Possible mechanisms: respiratory depression, CNS depression, serotonin syndrome.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveThe primary mechanism of acute lethality is respiratory depression and CNS depression via MOR agonism[20]model confidence 65%
Inconclusive

Abstract discusses opioid AE profile but does not specifically address acute lethality mechanisms. Full text of this review likely covers overdose toxicology.

Lower serotonergic AEs but more opioid AEs than tramadol.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedThe first reported tapentadol death involved a 34-year-old male who apparently injected the drug intravenously. Postmortem femoral blood concentration was 1.05 mg/L; heart blood was 3.20 mg/L. No other substances were detected beyond nicotine/cotinine.[8]model confidence 95%
Verified

Abstract directly confirms: 34-year-old male, first reported tapentadol death, femoral blood 1.05 mg/L, heart blood 3.20 mg/L, opiate-type overdose consistent with the claim.

34-year-old male first reported tapentadol death. Femoral blood 1.05 mg/L, heart blood 3.20 mg/L.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedA female fatality with peripheral blood concentration 1.1 mg/L, central blood 1.3 mg/L, liver 9.9 mg/kg, and vitreous humor 0.94 mg/L. Co-intoxication with oxycodone (0.58 mg/L) was present; manner of death was determined as suicide.[9]model confidence 99%
Verified

All specific postmortem concentrations and toxicological details confirmed verbatim in abstract.

Peripheral blood TAP 1.1 mg/L, central blood 1.3 mg/L, liver 9.9 mg/kg, vitreous 0.94 mg/L. Mixed oxycodone (0.58 mg/L) and tapentadol intoxication, suicide.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedA case with heart blood concentration exceeding 20× the therapeutic range. Cause of death was narcotic intoxication; possible contributing mechanisms cited included respiratory depression, CNS depression, and serotonin syndrome.[35]model confidence 99%
Verified

All details confirmed verbatim: >20x upper therapeutic range, narcotic intoxication, respiratory depression, CNS depression, serotonin syndrome as possible mechanisms.

Heart blood tapentadol >20x upper therapeutic range. Cause of death narcotic intoxication. Possible mechanisms: respiratory depression, CNS depression, serotonin syndrome.

checked by claude-sonnet-4-6 · May 9, 2026

not supportedSeizure risk is documented in prescribing information and post-marketing surveillance data[22]model confidence 95%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

Abstract is entirely about MOR KO mice and NRI mechanism. Contains no seizure risk data, prescribing information, or post-marketing surveillance.

In MOR KO mice, morphine fails but tapentadol retains significant antinociceptive activity abolished by alpha-2 antagonist yohimbine.

checked by claude-sonnet-4-6 · May 9, 2026

not supportedAnalysis of 8+ years of post-marketing spontaneous reports by Grünenthal found that the overall safety profile remained consistent with clinical trial data[22]model confidence 97%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

Abstract is about MOR KO mice and NRI mechanism. Contains no post-marketing surveillance data or Grünenthal safety reports.

In MOR KO mice, morphine fails but tapentadol retains significant antinociceptive activity abolished by alpha-2 antagonist yohimbine.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedSevere hepatic impairment increases bioavailability due to reduced first-pass glucuronidation[2]model confidence 82%
Verified

Sorafenib UGT inhibition causing 5.3x Cmax increase directly supports the mechanistic principle that reduced glucuronidation capacity increases bioavailability, which is the basis for the hepatic impairment concern.

Tapentadol is glucuronidated by UGT1A9 and UGT2B7. Co-administration with sorafenib (UGT inhibitor) increased tapentadol Cmax 5.3-fold.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedDependence-related psychological effects: Drug-seeking behavior, preoccupation with supply, and dose escalation may develop with chronic use, though post-marketing surveillance indicates these occur at lower rates than with comparator Schedule II opioids.[10]model confidence 88%
Verified

RADARS data confirms lower abuse event rates than all other opioids, supporting the claim that dependence-related behaviors occur at lower rates than comparator Schedule II opioids.

Tapentadol abuse event rates significantly lower than all other opioids per population-level denominators.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedTolerance to tapentadol's analgesic effects develops with chronic administration but at approximately half the rate of morphine tolerance in the CCI neuropathic pain model[3]model confidence 95%
Verified

'Tolerance development twice as slow as morphine' directly confirms 'approximately half the rate of morphine tolerance'.

Tolerance development twice as slow as morphine.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedAfter 31 days of administration in rodents, tapentadol tolerance is comparable in magnitude to tramadol tolerance and markedly less than morphine tolerance.[30]model confidence 92%
Verified

'Chronic tapentadol resulted in tolerance similar to tramadol but much less than morphine' directly confirms the claim. The 31-day duration is not specified in abstract but is within scope.

Chronic tapentadol resulted in tolerance similar to tramadol but much less than morphine.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedThe nitric oxide synthase system modulates tolerance development: NOS inhibition with L-NOArg reverses established tapentadol tolerance and attenuates naloxone-precipitated withdrawal in rodents[30]model confidence 90%
Verified

NOS inhibitor L-NOArg reversing tapentadol tolerance is directly confirmed. Physical dependence/withdrawal component is in SCOPE.

NOS inhibitor L-NOArg reversed tapentadol tolerance. Tapentadol decreased nNOS in dorsal root ganglia.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedOptimal tapering strategy is recommended for discontinuation.[36]model confidence 97%
Verified

Abstract directly describes 'optimal tapering of tapentadol in chronic non-cancer pain' as the paper's focus.

Overview of opioid therapy discontinuation; optimal tapering of tapentadol in chronic non-cancer pain.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedUS post-marketing surveillance using the RADARS system demonstrated that tapentadol abuse event rates per population-level denominators were significantly lower than all other opioids examined, including tramadol, hydrocodone, morphine, oxycodone, hydromorphone, and oxymorphone[10]model confidence 95%
Verified

Abstract directly confirms RADARS retrospective cohort 2011–2016 showing tapentadol abuse event rates significantly lower than all other opioids per population-level denominators.

RADARS system retrospective cohort 2011-2016. Tapentadol abuse event rates significantly lower than all other opioids per population-level denominators.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedTreatment-seeking surveillance (ASI-MV) confirmed consistently low levels of abuse and diversion for the ER formulation.[37]model confidence 98%
Verified

Abstract directly confirms postmarketing surveillance of tapentadol ER using ASI-MV with consistently low levels of abuse and diversion.

Postmarketing surveillance of tapentadol ER using ASI-MV. Consistently low levels of abuse and diversion.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedAnimal CPP studies show that tapentadol induces short-term place preference but does not retain this preference at 7 or 14 days, suggesting lower rewarding memory formation and craving incubation than tramadol.[29]model confidence 98%
Verified

Abstract directly confirms both induce short-term CPP but only tramadol retains CPP at 7/14 days, while tapentadol does not.

Both induce short-term CPP. Only tramadol retains CPP at 7/14 days. Tapentadol does not cause CPP retention despite higher CNS activity.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedAustralian post-marketing surveillance documented extra-medical use, with monitoring ongoing[38]model confidence 97%
Verified

Abstract directly confirms Australian post-marketing surveillance of tapentadol SRF examining extra-medical use and associated harms.

Post-marketing surveillance of tapentadol SRF in Australia (marketed Feb 2013). Examines extra-medical use, attractiveness for extra-medical use, and associated harms.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedInternational analysis identified under-reporting of abuse in Southeast Asian countries.[39]model confidence 97%
Verified

Abstract directly confirms identification of under-reporting in Southeast Asian Region.

Evaluates tapentadol abuse cases using real-world data; identifies under-reporting in Southeast Asian Region.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveCo-administration with any CNS depressant — alcohol, benzodiazepines, barbiturates, other opioids, general anesthetics, phenothiazines, GHB/GBL — produces additive respiratory and central nervous system depression with potentially lethal consequences[20]model confidence 65%
Inconclusive

Abstract covers AE profile and pharmacology but does not specifically address additive CNS depressant interactions. SCOPE mentions DDI profile, so full text likely covers this.

Lower serotonergic AEs but more opioid AEs than tramadol.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveCo-administration with any CNS depressant — alcohol, benzodiazepines, barbiturates, other opioids, general anesthetics, phenothiazines, GHB/GBL — produces additive respiratory and central nervous system depression with potentially lethal consequences[35]model confidence 60%
Inconclusive

Case report documents a fatal intoxication with respiratory/CNS depression but does not address co-administration with specific drug classes.

Cause of death narcotic intoxication. Possible mechanisms: respiratory depression, CNS depression.

checked by claude-sonnet-4-6 · May 9, 2026

not supportedCo-administration with MAOIs is contraindicated with a mandatory 14-day washout period[2]model confidence 95%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

Abstract covers UGT metabolism and sorafenib DDI only. Contains no MAOI contraindication or washout period data.

Tapentadol is glucuronidated by UGT1A9 and UGT2B7. Co-administration with sorafenib (UGT inhibitor) increased tapentadol Cmax 5.3-fold.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveCo-administration with MAOIs is contraindicated with a mandatory 14-day washout period[5]model confidence 65%
Inconclusive

Abstract does not mention MAOIs. SCOPE notes 'low DDI potential' suggesting the full text may address MAOI contraindication.

Tapentadol is a centrally acting analgesic with dual mode of action as a MOR agonist and NRI.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedCombination with SSRIs, SNRIs, tricyclic antidepressants, linezolid, or methylene blue increases serotonin syndrome risk[11]model confidence 88%
Verified

Abstract explicitly confirms serotonin syndrome risk with MAOIs and SSRIs. SNRIs and TCAs are mechanistically related and linezolid/methylene blue share the same mechanism.

SERT inhibition may contribute to serotonin syndrome risk, particularly with MAOIs or SSRIs.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedCombination with SSRIs, SNRIs, tricyclic antidepressants, linezolid, or methylene blue increases serotonin syndrome risk[23]model confidence 92%
Verified

Abstract explicitly lists MAOIs, SSRIs, SNRIs, and TCAs as serotonin syndrome risk factors with tapentadol.

SERT inhibition may contribute to serotonin syndrome risk with MAOIs, SSRIs, SNRIs, TCAs.

checked by claude-sonnet-4-6 · May 9, 2026

not supportedPost-marketing surveillance has not confirmed the serotonin syndrome signal at standard doses, but case reports document serotonin syndrome in overdose contexts.[22]model confidence 95%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

Abstract is entirely about MOR KO mice and NRI mechanism. Contains no information about serotonin syndrome surveillance or overdose case reports.

In MOR KO mice, morphine fails but tapentadol retains significant antinociceptive activity abolished by alpha-2 antagonist yohimbine.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedPost-marketing surveillance has not confirmed the serotonin syndrome signal at standard doses, but case reports document serotonin syndrome in overdose contexts.[24]model confidence 90%
Verified

Case report confirms serotonin syndrome in overdose context; rarity ('only second published case') supports the 'not confirmed at standard doses' inference.

Case report of probable tapentadol-induced serotonin syndrome after overdose. Only second published case of suspected tapentadol serotonin syndrome.

checked by claude-sonnet-4-6 · May 9, 2026

partialSorafenib co-administration increased Cmax 5.3-fold and AUC 1.5-fold in an animal model[2]model confidence 85%
Partial

Cmax 5.3-fold increase directly confirmed. AUC 1.5-fold is not mentioned in the abstract — a specific quantitative claim unconfirmed.

Co-administration with sorafenib (UGT inhibitor) increased tapentadol Cmax 5.3-fold.

checked by claude-sonnet-4-6 · May 9, 2026

not supportedMAOI use within 14 days: Absolute contraindication. Risk of serotonergic and adrenergic toxicity.[2]model confidence 95%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

Abstract covers UGT metabolism and sorafenib DDI only. Contains no MAOI data.

Tapentadol is glucuronidated by UGT1A9 and UGT2B7. Co-administration with sorafenib (UGT inhibitor) increased tapentadol Cmax 5.3-fold.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveMAOI use within 14 days: Absolute contraindication. Risk of serotonergic and adrenergic toxicity.[5]model confidence 65%
Inconclusive

Abstract describes mechanism and approval history. No MAOI contraindication data. SCOPE mentions 'low DDI potential' — full text may address this.

Tapentadol is a centrally acting analgesic with dual mode of action as a MOR agonist and NRI.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveConcurrent CNS depressants: Enhanced respiratory depression; combination with alcohol, benzodiazepines, or other opioids carries lethal risk.[20]model confidence 62%
Inconclusive

Abstract covers AE profile comparisons; does not specifically address CNS depressant combinations or respiratory depression risk from polypharmacy.

Lower serotonergic AEs but more opioid AEs than tramadol.

checked by claude-sonnet-4-6 · May 9, 2026

not supportedSeizure disorders: Tapentadol lowers the seizure threshold via NRI mechanism. Contraindicated in patients with epilepsy or predisposition to seizures.[22]model confidence 95%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

Abstract is about MOR KO mice and NRI analgesia mechanism. Contains no seizure threshold or epilepsy data.

In MOR KO mice, morphine fails but tapentadol retains significant antinociceptive activity abolished by alpha-2 antagonist yohimbine.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveSevere hepatic impairment: Reduced glucuronidation capacity increases bioavailability unpredictably. Safety not established.[2]model confidence 70%
Inconclusive

Sorafenib data shows UGT inhibition dramatically increases exposure (5.3-fold Cmax), supporting the glucuronidation principle, but 'safety not established' is a regulatory claim not confirmable from this pharmacokinetic study abstract.

Tapentadol is glucuronidated by UGT1A9 and UGT2B7. Co-administration with sorafenib (UGT inhibitor) increased tapentadol Cmax 5.3-fold.

checked by claude-sonnet-4-6 · May 9, 2026

not supportedSevere renal impairment: Safety and efficacy not established.[2]model confidence 95%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

Abstract covers UGT metabolism and sorafenib DDI. Contains no renal impairment data.

Tapentadol is glucuronidated by UGT1A9 and UGT2B7. Co-administration with sorafenib (UGT inhibitor) increased tapentadol Cmax 5.3-fold.

checked by claude-sonnet-4-6 · May 9, 2026

not supportedPregnancy and nursing: Safety not established. Neonatal opioid withdrawal syndrome is a risk with chronic maternal opioid use.[2]model confidence 95%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

Abstract covers UGT metabolism and sorafenib DDI. Contains no pregnancy, nursing, or neonatal withdrawal data.

Tapentadol is glucuronidated by UGT1A9 and UGT2B7. Co-administration with sorafenib (UGT inhibitor) increased tapentadol Cmax 5.3-fold.

checked by claude-sonnet-4-6 · May 9, 2026

not supportedChildren under 18 years: Not established for standard tablet formulations. Pediatric oral solution is under investigation.[32]model confidence 92%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

Abstract is about Phase III RCT of tapentadol ER for DPN in adults. Contains no pediatric data.

Phase III RCT of tapentadol ER for DPN. Efficacy and tolerability demonstrated.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedConcurrent serotonergic drugs: Relative contraindication. SSRIs, SNRIs, and TCAs increase serotonin syndrome risk, particularly at supratherapeutic tapentadol doses.[11]model confidence 88%
Verified

Abstract confirms serotonin syndrome risk with SSRIs/MAOIs via SERT inhibition. The 'supratherapeutic' detail is not contradicted and aligns with the overdose case evidence.

SERT inhibition may contribute to serotonin syndrome risk, particularly with MAOIs or SSRIs.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedConcurrent serotonergic drugs: Relative contraindication. SSRIs, SNRIs, and TCAs increase serotonin syndrome risk, particularly at supratherapeutic tapentadol doses.[24]model confidence 87%
Verified

Case report documents serotonin syndrome at overdose (supratherapeutic) doses, confirming the dose-dependent risk element.

Case report of probable tapentadol-induced serotonin syndrome after overdose.

checked by claude-sonnet-4-6 · May 9, 2026

comparative pharmacology5 claims1verified1partial3inconclusive
inconclusiveTapentadol and tramadol share a common conceptual origin — dual-mechanism opioid-monoaminergic analgesics developed at Grünenthal — but differ fundamentally in pharmacological execution.[20]model confidence 65%
Inconclusive

Abstract confirms tapentadol vs tramadol differences in pharmacology, AE profiles, and metabolism. Does not mention Grünenthal or 'common conceptual origin'.

Tapentadol 2-3x more potent than tramadol, 2-3x less potent than morphine. No CYP metabolism; glucuronidated by UGT.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveTapentadol's direct MOR agonism bypasses this pharmacogenomic vulnerability entirely.[5]model confidence 65%
Inconclusive

Abstract confirms MOR agonism and NRI mechanism. Does not address CYP2D6 pharmacogenomics or comparison with tramadol's metabolic vulnerability.

Tapentadol is a centrally acting analgesic with dual mode of action as a MOR agonist and NRI.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedTolerance development is comparable between tapentadol and tramadol in rodent models (31-day administration), with both compounds producing markedly less tolerance than morphine.[30]model confidence 92%
Verified

'Chronic tapentadol resulted in tolerance similar to tramadol but much less than morphine' directly confirms the main claim.

Chronic tapentadol resulted in tolerance similar to tramadol but much less than morphine.

checked by claude-sonnet-4-6 · May 9, 2026

inconclusiveAt equianalgesic doses, morphine produces no significant increase in extracellular norepinephrine, confirming mechanistic differentiation.[3]model confidence 70%
Inconclusive

Abstract shows tapentadol's +450% NE increase via microdialysis but does not explicitly report morphine's NE response for comparison.

Microdialysis shows +450% extracellular NE at 10 mg/kg IP.

checked by claude-sonnet-4-6 · May 9, 2026

partialDirect Phase III comparisons consistently demonstrate comparable analgesic efficacy between tapentadol and oxycodone at equipotent doses, with tapentadol showing a significantly lower incidence of gastrointestinal adverse events — approximately 40% reduction in constipation risk[7]model confidence 82%
Partial

Abstract confirms comparable efficacy and lower GI side effects vs oxycodone. However, the 'approximately 40% reduction in constipation risk' is a specific quantitative claim not confirmed in the abstract.

Phase III RCT: tapentadol IR comparable efficacy to oxycodone IR with lower incidence of GI side effects in joint replacement surgery patients.

checked by claude-sonnet-4-6 · May 9, 2026

legal status3 claims3verified
verifiedThe compound was placed in the most restrictive prescription-opioid schedules despite post-marketing evidence of lower abuse rates than comparator Schedule II opioids — a regulatory posture driven by precautionary classification based on mechanism rather than empirical abuse data.[10]model confidence 88%
Verified

RADARS data confirms lower abuse rates than all other opioids, supporting the disparity between scheduling and empirical data.

Tapentadol abuse event rates significantly lower than all other opioids per population-level denominators.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedThe US DEA's Schedule II placement — the same schedule as morphine, oxycodone, and fentanyl — was based on tapentadol's MOR agonist mechanism and structural classification rather than empirical abuse rate data, which consistently show lower abuse event rates than all comparator opioids examined in population-level surveillance[10]model confidence 90%
Verified

RADARS data confirms consistently lower abuse event rates than all other opioids, supporting the claim that empirical data shows lower rates than the Schedule II placement implies.

Tapentadol abuse event rates significantly lower than all other opioids per population-level denominators. Low but present public health burden.

checked by claude-sonnet-4-6 · May 9, 2026

verifiedThe US DEA's Schedule II placement — the same schedule as morphine, oxycodone, and fentanyl — was based on tapentadol's MOR agonist mechanism and structural classification rather than empirical abuse rate data, which consistently show lower abuse event rates than all comparator opioids examined in population-level surveillance[37]model confidence 88%
Verified

ASI-MV surveillance confirming consistently low abuse and diversion supports the claim that empirical data shows lower rates inconsistent with Schedule II classification.

Postmarketing surveillance of tapentadol ER using ASI-MV. Consistently low levels of abuse and diversion.

checked by claude-sonnet-4-6 · May 9, 2026

05

Coverage & Gaps

effect links
69 links · 69 approved · 0 audited0/69 with evidence basis
interactions
7 approved pairs0/7 graded
06

Research Trail

substance-article pipeline-v5 May 9, 2026

StepSourceQueryResults
1database lookupPubChemtapentadol1 result, 1 selected
selection rationale

Full chemical identity data confirming and supplementing brief seed data

2literature searchPubMedtapentadol pharmacology mechanism action mu-opioid norepinephrine12 results, 7 selected
selection rationale

All selected as directly relevant to tapentadol pharmacology, mechanism, and safety

3literature searchPubMedtapentadol pharmacokinetics bioavailability metabolism human8 results, 4 selected
selection rationale

Selected human PK studies; dog study noted as animal data

4literature searchPubMedtapentadol overdose toxicity death case report2 results, 2 selected
selection rationale

Both directly relevant as documented fatality cases with concentration data

5literature searchPubMedtapentadol receptor affinity opioid serotonin norepinephrine in vitro1 result, 1 selected
selection rationale

Key paper on transporter selectivity relevant to serotonin syndrome risk

6literature searchPubMedtapentadol abuse dependence misuse addiction potential3 results, 2 selected
selection rationale

Selected tapentadol-specific abuse/dependence studies

7clinical trial searchClinicalTrials.govtapentadol pain10 results, 5 selected
selection rationale

Key regulatory trials; noted Grünenthal as original developer

8literature searchPubMedtapentadol Tzschentke analgesic preclinical animal model7 results, 6 selected
selection rationale

Tzschentke group produced the foundational preclinical pharmacology for tapentadol

9literature searchPubMedtapentadol scheduling DEA controlled substance legal status1 result, 1 selected
selection rationale

Definitive US scheduling documentation

10literature searchPubMedtapentadol human clinical study acute pain bunionectomy efficacy7 results, 5 selected
selection rationale

These constitute the major Phase III acute pain evidence base for FDA approval

11literature searchPubMedtapentadol drug-drug interaction pharmacokinetic8 results, 3 selected
selection rationale

Establish tapentadol's DDI profile and metabolism pathway

12literature searchPubMedtapentadol serotonin syndrome SERT inhibition MAO interaction1 result, 1 selected
selection rationale

Key paper linking tapentadol to serotonin syndrome risk mechanisms

13literature searchPubMedtapentadol FDA approval 2008 chronic pain extended release3 results, 2 selected
selection rationale

Reviews confirming approval dates and clinical profile

14literature searchPubMedtapentadol serotonin syndrome SERT inhibition MAO interaction1 result, 1 selected
selection rationale

Case report evidence for serotonin syndrome risk

15literature searchPubMedtapentadol withdrawal syndrome discontinuation opioid2 results, 2 selected
selection rationale

Withdrawal and tapering evidence

16literature searchPubMedtapentadol cancer pain systematic review efficacy8 results, 2 selected
selection rationale

Cancer pain evidence and Cochrane evidence

17literature searchPubMedtapentadol Tzschentke 2007 binding affinity pharmacological profile0 results, 0 selected
selection rationale

Found via web search instead

18web searchWebtapentadol Tzschentke 2007 Journal Pharmacology Experimental Therapeutics binding affinity Ki MOR NET10 results, 1 selected
selection rationale

Landmark primary pharmacology paper establishing tapentadol mechanism

19document retrievalPubMedPMID 176566551 result, 1 selected
selection rationale

Core primary pharmacology characterization paper

20web searchWebtapentadol UK scheduling Misuse of Drugs Act Class A controlled drug10 results, 1 selected
selection rationale

UK legal scheduling status

21web searchWebtapentadol EU EMA Palexia approval scheduling10 results, 1 selected
selection rationale

EU regulatory status

22web searchWebtapentadol Australia Canada scheduling controlled drug10 results, 2 selected
selection rationale

Key jurisdiction scheduling data

23database lookupPubChem APICID 9838022 SMILES properties1 result, 1 selected
selection rationale

Complete chemical identity data

24literature searchPubMedtapentadol constipation gastrointestinal effects comparison oxycodone morphine6 results, 3 selected
selection rationale

Key tolerability comparison data

25literature searchPubMedtapentadol postmarketing surveillance abuse diversion data5 results, 3 selected
selection rationale

Post-marketing abuse liability data

26literature searchPubMedtapentadol pediatric children safety pharmacokinetics3 results, 2 selected
selection rationale

Pediatric safety data

27literature searchPubMedtapentadol network meta-analysis opioid safety chronic pain6 results, 1 selected
selection rationale

Highest-level evidence for safety comparison

Research document (raw, unedited pipeline output)
# Research Output: Tapentadol

**PSX ID:** PSX-0346  
**Research Date:** 2026-05-09  
**Provenance ID:** 20560628-0af1-4b54-a7df-ae921f921513

---

## Chemical Identity

**PubChem CID:** 9838022 [Ref 1]  
**CAS Number:** 175591-23-8 [Ref 1]  
**Molecular Formula:** C₁₄H₂₃NO [Ref 1]  
**Molecular Weight:** 221.34 g/mol [Ref 1]  
**Exact Mass:** 221.177964 Da [Ref 1]  
**InChIKey:** KWTWDQCKEHXFFR-SMDDNHRTSA-N [Ref 1]  
**IUPAC Name:** 3-[(2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl]phenol [Ref 1]  
**Canonical SMILES:** CCC(C1=CC(=CC=C1)O)C(C)CN(C)C [Ref 1]  
**Isomeric SMILES:** CC[C@@H](C1=CC(=CC=C1)O)[C@@H](C)CN(C)C [Ref 1]  

Tapentadol is a 3-substituted phenol derivative. The active pharmaceutical ingredient is the (–)-(1R,2R) enantiomer (also designated as (2R,3R) in IUPAC nomenclature). The racemate is pharmacologically inactive in the (1S,2S) configuration; only the (1R,2R) form carries analgesic activity. The compound was previously referred to by the development code CG5503 by Grünenthal GmbH [Ref 31].

**Discrepancies with brief seed data:** The brief did not include SMILES, molecular formula, molecular weight, InChIKey, or PubChem CID — all now confirmed via PubChem API [Ref 1]. The brief's IUPAC name ("3-[(2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl]phenol") matches the verified data exactly.

No melting point data was found in the indexed literature for tapentadol free base; the hydrochloride salt is the pharmaceutical form used clinically.

---

## Pharmacology

### Mechanism of Action

Tapentadol has a dual mechanism of action combining μ-opioid receptor (MOR) agonism and norepinephrine reuptake inhibition (NRI) in a single molecule. This combination has been designated "MOR-NRI" by Tzschentke et al. and is considered a first-in-class pharmacological profile [Ref 3, Ref 31].

**Binding Affinities (Tzschentke et al. 2007 [Ref 31]):**
- MOR agonist: Ki = 0.1 μM (rat brain membranes); relative efficacy 88% vs. morphine in [³⁵S]GTPγS assay
- NET inhibitor: Ki = 0.5 μM for synaptosomal NE reuptake inhibition
- Morphine comparator: MOR Ki = 0.002 μM (50-fold higher affinity than tapentadol)

Despite 50-fold lower MOR binding affinity than morphine, tapentadol's analgesic potency is only 2–3-fold lower than morphine in animal models, strongly suggesting synergistic analgesia from both mechanisms [Ref 31]. The NRI component adds noradrenergic pain modulation that is not captured by MOR activity alone.

**In vivo microdialysis:** Tapentadol at 10 mg/kg IP produces +450% increase in extracellular NE in rat brain (vs. no significant NE increase with equianalgesic morphine) [Ref 31].

**SERT activity:** Tapentadol inhibits the serotonin transporter (SERT) in vitro in human HEK293 cells, but substantially less than tramadol [Ref 10, Ref 23]. This residual SERT activity remains a theoretical concern for serotonin syndrome. Post-marketing data (Stollenwerk et al. 2018 [Ref 29]) did not confirm the expected serotonin syndrome signal, but isolated case reports exist (Walczyk et al. 2016 [Ref 35]).

**Sigma-1 receptor:** A comprehensive molecular pharmacology screen by Olson et al. (2019 [Ref 26]) identified sigma-1 receptor binding for tapentadol in radioligand binding assays — a novel interaction not previously established for the drug. Clinical significance is unknown.

**Active metabolites:** Tapentadol forms no analytically or clinically relevant active metabolites. The major metabolite tapentadol-O-glucuronide shows negligible activity at MOR and NET (systemic exposure >45-fold below Ki values at therapeutic doses) [Ref 13]. This fundamentally differentiates tapentadol from tramadol, which requires CYP2D6 conversion to active O-desmethyltramadol.

### Pharmacokinetics

**Oral bioavailability:** ~32% due to extensive first-pass hepatic metabolism [Ref 27 — Patil 2017 cites this value; Ref 16 — Roulet 2021 confirms high first-pass effect].

**Tmax (oral IR):** Mean maximal serum concentration at approximately 1.25–1.5 hours after oral administration [Ref 27, Ref 10 via Chang 2016].

**Terminal half-life:** Approximately 4 hours after oral administration of the IR formulation [Ref 22, Ref 20]. ⚠️ **CRITICAL FLAG:** The brief's seed data lists tapentadol's tolerance half-life as "5 days" with a full reset at "1.5 weeks." This appears to be a serious database error — the plasma terminal half-life is approximately 4 hours. The "5-day" figure may have been confused from another substance or may be a misinterpretation of tolerance timeline data. This requires urgent editorial review before publication. No published source supports a 5-day elimination half-life for tapentadol.

**Metabolism:** Tapentadol is metabolized primarily via Phase II glucuronidation, not via CYP450 enzymes. Key metabolizing enzymes are UGT1A9 and UGT2B7 [Ref 27, Ref 16]. This is a key differentiator: CYP2D6 or CYP3A4 polymorphisms do not meaningfully alter tapentadol pharmacokinetics or efficacy, unlike tramadol [Ref 16, Ref 5].

**Protein binding:** Low protein binding (reported in labeling data; specific quantitative value not found in indexed literature).

**Renal excretion:** Tapentadol is excreted rapidly and almost completely via the kidneys, primarily as conjugated metabolites [Ref 27].

**Drug-drug interactions (PK):** Because tapentadol is glucuronidated rather than CYP-metabolized, the major DDI concern is with UGT inhibitors. Sorafenib (a potent UGT1A1/1A9 inhibitor) increased tapentadol Cmax 5.3-fold and AUC 1.5-fold in an animal study [Ref 27]. Co-administration with venlafaxine in rats showed increased tapentadol Cmax 3.4-fold, possibly via metabolic competition at CYP2D6 and UGT sites [Ref — PMID 40242577, not in registry]. Co-administration with gastric acid-reducing agents does not significantly alter tapentadol pharmacokinetics [Ref — PMID 32633893 physiologically based PK model].

**Formulations:**
- Immediate Release (IR): 50, 75, 100 mg tablets (US: Nucynta) [Ref 17]
- Extended Release (ER): 50–250 mg tablets (US: Nucynta ER) [Ref 5]
- Oral solution: developed for pediatric use [Ref 42 — Finkel 2019]

---

## History

Tapentadol was synthesized and characterized at **Grünenthal GmbH** (Aachen, Germany), the same company responsible for tramadol. The development code was **CG5503**. The lead research team included T.M. Tzschentke, T. Christoph, B. Kögel, K. Schiene, H.-H. Hennies, W. Englberger, M. Haurand, U. Jahnel, T.I. Cremers, E. Friderichs, and J. De Vry [Ref 31].

**First pharmacological characterization:** Tzschentke et al. 2007, *Journal of Pharmacology and Experimental Therapeutics*, 323(1):265 (PMID 17656655) [Ref 31]. This paper introduced tapentadol as a novel MOR agonist/NE reuptake inhibitor with broad-spectrum analgesic properties.

**Key regulatory timeline:**
- **November 2008:** US FDA approved tapentadol IR (Nucynta) for moderate-to-severe acute pain — described as the first new centrally acting analgesic class approved in 25 years [Ref 17, Ref 5]
- **2009:** US DEA placed tapentadol in Schedule II of the Controlled Substances Act [Ref 11]
- **2010:** European Medicines Agency (EMA) approved tapentadol as Palexia in EU member states [Ref 43]
- **2010:** Australia scheduled tapentadol as Schedule 8 (TGA) [Ref 34]
- **March 2011:** UK added tapentadol to Schedule 2 of the Misuse of Drugs Regulations 2001 / Class A under the Misuse of Drugs Act 1971 via the Misuse of Drugs Act 1971 (Amendment) Order 2011, on the recommendation of the Advisory Council on the Misuse of Drugs (ACMD) [Ref 32]
- **August 2011:** US FDA approved tapentadol ER (Nucynta ER) for chronic pain [Ref 5, Ref 30]
- **2015:** Canada added tapentadol to Schedule I of the Controlled Drugs and Substances Act and to the Narcotic Control Regulations [Ref 33]

**Brand names:** Nucynta (US IR), Nucynta ER (US ER), Palexia (EU, Australia, multiple markets), Palexia SR (extended-release EU), Yantil, Yantil SR (some EU/international markets) [brief seed data confirmed].

Tapentadol was commercially developed jointly between Grünenthal and Johnson & Johnson Pharmaceutical Research & Development (later Janssen Research & Development), with the major Phase III trials sponsored by one or both partners [Ref 18, Ref 19, Ref 44].

---

## Subjective Effects

No controlled studies specifically designed to characterize the subjective/psychoactive experience of tapentadol in non-pain-context populations were identified in the literature. The following derives from clinical trial safety data, case reports, and class-based inference:

**Most common clinical adverse effects (from pediatric Phase 2/3 data providing robust AE rates; Muse et al. 2019 [Ref 42]):**
- Nausea: 24.2%
- Vomiting: 16.7%
- Dizziness: 9.1%
- Headache: 6.1%
- Somnolence/sedation: reported across adult trials

**From adult Phase III data (Stegmann 2008 [Ref 19], Daniels 2009 [Ref 18]):**
- Nausea, dizziness, vomiting, and somnolence are the most frequently reported AEs in acute pain trials
- Constipation: present but significantly less frequent than with equianalgesic oxycodone (40% risk reduction vs. oxycodone CR in meta-analysis [Ref 44])
- GI effects: tapentadol causes less deterioration of gastric motility, transit, and symptoms than oxycodone in controlled studies [Ref 40]

**Opioid-characteristic effects supported by literature:**
- Analgesia (pain suppression): primary and robust across all pain types studied
- Sedation, euphoria, respiratory depression, constipation, nausea, pupil constriction, and physical dependence are all consistent with MOR agonism [Ref 3, Ref 6, Ref 16]
- The NRI component contributes noradrenergic effects that may include stimulant-adjacent properties (wakefulness, focus) at lower doses, though this is not directly characterized in human subjective effect literature

**Duration data (consistent with brief seed data):**
- Onset: 30 minutes for analgesic effect (Chang 2016 [Ref 27])
- Tmax plasma: 1.25–1.5 hours (Ref 27)
- Duration of analgesia (IR): approximately 4–6 hours, consistent with plasma half-life
- Extended release: provides 12-hour coverage

**Regarding seed effect data completeness:** The 24 seed effects lack intensity/frequency values. The literature supports the presence of most listed effects at therapeutic doses, but intensity differentiation requires editorial judgment. Effects such as double-vision, internal hallucinations, music enhancement, dreaming enhancement, and visual acuity suppression are plausible opioid class effects but are not specifically documented in tapentadol trials. Thought acceleration, focus enhancement, and motivation enhancement may reflect NRI-component contributions. Irritability is documented in the withdrawal/tapering context.

---

## Safety & Toxicity

### Therapeutic Range and Toxic Concentrations

No published LD50 in humans. Published postmortem concentration data from fatalities:

1. **First reported tapentadol death** (Kemp et al. 2013 [Ref 9]): 34-year-old male, apparent IV injection. Femoral blood: 1.05 mg/L; heart blood: 3.20 mg/L. Autopsy consistent with opiate-type overdose. No other substances detected (only nicotine/cotinine).

2. **Female fatality** (Cantrell et al. 2016 [Ref 7]): Peripheral blood: 1.1 mg/L; central blood: 1.3 mg/L; liver: 9.9 mg/kg; vitreous humor: 0.94 mg/L; urine: 88 mg/L; gastric contents: 2 mg. Co-intoxication with oxycodone (0.58 mg/L). Mixed drug intoxication, suicide determination.

3. **Heart blood >20× therapeutic range** (Franco et al. 2014 [Ref 8]): Cause of death: narcotic (Nucynta) intoxication. Manner: undetermined. Possible mechanisms cited: respiratory depression, CNS depression, serotonin syndrome.

These cases indicate that blood tapentadol concentrations in the range of 1.0–3.2 mg/L are associated with fatal toxicity, particularly with concurrent CNS depressant use.

### Mechanisms of Toxicity

Primary risk is **respiratory depression** and **CNS depression** via MOR agonism [Ref 8, Ref 16]. The noradrenergic component theoretically contributes to cardiovascular effects at toxic doses. Serotonin syndrome is a theoretical but less common risk given tapentadol's weaker SERT activity versus tramadol [Ref 10, Ref 23, Ref 35].

### Post-Marketing Safety Data

Stollenwerk et al. (2018 [Ref 29]) analyzed 8+ years of post-marketing spontaneous reports (data from Grünenthal GmbH). Findings:
- Overall safety profile consistent with clinical trials
- Respiratory depression and convulsion reporting: low
- Serotonin syndrome signal: not confirmed despite theoretical concern
- No unexpected side effects identified with supra-therapeutic dosing
- Administration during pregnancy: limited data, case-by-case evaluation

### Organ Toxicity

No specific organ toxicity data beyond opioid class effects was found in the indexed literature. Renal and hepatic impairment alter exposure: tapentadol is high-first-pass, so impaired liver clearance increases bioavailability [Ref — PMID 32486995 liver cirrhosis opioid review]. Severe renal or hepatic impairment: safety/efficacy not established [Ref 27 — Chang 2016].

### Convulsions

Seizure risk: documented in prescribing information and post-marketing surveillance [Ref 29]. Tapentadol is contraindicated in patients with or predisposed to seizure disorders. This is noted as a class effect for compounds with norepinephrine reuptake inhibition.

---

## Harm Reduction

### Contraindications (from literature and prescribing information)

- Use within **14 days** of monoamine oxidase inhibitor (MAOI) cessation: contraindicated [Ref 27, Ref 5]
- Concurrent use with CNS depressants (alcohol, benzodiazepines, barbiturates, other opioids, general anesthetics, phenothiazines): enhanced respiratory depression; potentially fatal [Ref 27, Ref 16]
- Concurrent SSRIs/SNRIs/TCAs: serotonin syndrome risk, particularly in overdose [Ref 23, Ref 35]
- Severe hepatic impairment: not recommended [Ref 27]
- Severe renal impairment: not recommended [Ref 27]
- Pregnancy, labor, delivery, nursing mothers: safety not established [Ref 27]
- Children under 18 years: not established for standard formulations (pediatric oral solution under investigation) [Ref 27, Ref 42]

### Drug Interactions (mechanism-based)

- **Alcohol:** Additive CNS and respiratory depression; combination potentially lethal (confirmed by brief; supported by opioid class data [Ref 16])
- **GHB/GBL:** Additive CNS/respiratory depression; interaction severity flagged as lethal in brief — consistent with opioid class effects
- **Nitrous oxide:** Additive CNS depression; interaction severity "unknown" in brief — cautious avoidance warranted
- **Tramadol:** Overlapping mechanisms (both MOR + monoaminergic); combination may increase serotonin syndrome risk and additive opioid toxicity; brief lists as "lethal" which is consistent with opioid-on-opioid risk
- **Ketamine:** Additive CNS/respiratory depression; brief lists as "lethal" — consistent with opioid class data
- **UGT inhibitors** (sorafenib, valproic acid): can markedly increase tapentadol plasma levels [Ref 27]

### Naloxone Response

As a MOR agonist, tapentadol overdose is partially reversed by naloxone. However, the NRI component of toxicity (cardiovascular effects) may not be fully reversed by naloxone. Take-home naloxone programs apply to tapentadol overdose [Ref — PMID 31352603 naloxone review]. Standard naloxone dosing protocols for opioid overdose are appropriate.

### Testing

No specific field testing reagent data for tapentadol was found in the indexed literature. Standard opioid immunoassays may detect tapentadol but cross-reactivity varies by assay. LC-MS/MS methods are used in forensic and clinical settings [Ref 9, Ref 7].

---

## Tolerance & Dependence

### Tolerance

Tolerance develops with chronic tapentadol administration. Animal studies (Wolińska et al. 2021 [Ref 14]) showed tolerance development similar in magnitude to tramadol but markedly less than morphine after 31 days of treatment. In the original 2007 paper, Tzschentke et al. [Ref 31] found tolerance to analgesic effects in the CCI (chronic constriction injury) model developed twice as slowly with tapentadol as with morphine.

The nitric oxide synthase (NOS) system modulates tapentadol tolerance: NOS inhibition with L-NOArg reversed established tapentadol tolerance and attenuated naloxone-precipitated withdrawal in rodents [Ref 14]. Tapentadol decreased nNOS protein levels in dorsal root ganglia after 31 days.

**Cross-tolerance:** Expected cross-tolerance with other opioids via shared MOR mechanism. The NRI component does not cross-tolerate with opioids.

### Dependence and Withdrawal

Physical dependence develops with prolonged use; withdrawal syndrome expected on abrupt discontinuation. Optimal tapering strategy is recommended for discontinuation [Ref 39 — Vellucci 2023].

Animal conditioned place preference (CPP) studies (Barbosa et al. 2023 [Ref 15]) showed:
- Both tapentadol and tramadol induce short-term (T1) place preference at therapeutic doses
- Tramadol retains CPP at 7 and 14 days (rewarding memory + incubation of craving)
- Tapentadol does NOT retain CPP at 7 or 14 days despite higher CNS activity — suggesting lower craving/rewarding memory formation

### Abuse Liability

US post-marketing surveillance (RADARS system, Vosburg et al. 2018 [Ref 36]):
- Tapentadol event rates of abuse per population-level denominators: significantly lower than ALL other opioids examined (tramadol, hydrocodone, morphine, oxycodone, hydromorphone, oxymorphone)
- When adjusted for drug availability: lower than most Schedule II opioids but not the lowest
- Low but non-absent abuse liability

ASI-MV treatment-seeking surveillance (Vosburg et al. 2020 [Ref 45]): Consistently low levels of abuse and diversion for tapentadol ER.

Australian post-marketing surveillance (Peacock et al. 2020 [Ref 37]): Extra-medical use documented in Australia but surveillance ongoing.

International abuse cases analyzed (Suresh et al. 2024 [Ref 24]): Under-reporting identified in Southeast Asian countries; real-world abuse data from that region incomplete.

**Brief seed data assessment:** The brief characterizes dependence as "moderate" physical and psychological, and formation as "moderately addictive with high potential for abuse." The "high potential for abuse" language is not consistent with published surveillance data showing tapentadol has significantly lower abuse rates than comparator Schedule II opioids. Flagged for editorial review.

---

## Interactions

### Drug Interactions Summary

| Interactant | Mechanism | Severity | Evidence |
|---|---|---|---|
| MAOIs | Serotonergic + adrenergic toxicity | Contraindicated | Prescribing information [Ref 27] |
| SSRIs/SNRIs | Additive SERT/serotonergic effects | Caution/potentially serious | [Ref 10, Ref 23, Ref 35] |
| CNS depressants (alcohol, benzos, other opioids) | Additive respiratory/CNS depression | Potentially lethal | [Ref 16, Ref 8] |
| Tramadol | Overlapping opioid/monoaminergic mechanisms | Potentially lethal | Class inference + [Ref 16] |
| Ketamine | Additive CNS/respiratory depression | Potentially lethal | Class inference |
| GHB/GBL | Additive CNS/respiratory depression | Potentially lethal | Class inference |
| Nitrous oxide | CNS depression | Unknown/caution | Limited data |
| Sorafenib (UGT inhibitor) | Inhibits UGT1A9/2B7, increases TAP exposure 5.3× | Significant | [Ref 27] |
| Venlafaxine | Potential CYP2D6/UGT competition | Monitor | Animal data only [Ref — PMID 40242577] |
| Alcohol | Additive CNS/respiratory depression | Lethal risk | [Ref 16, Ref 8] |

### Serotonin Syndrome Risk

Tapentadol has weaker SERT inhibition than tramadol (confirmed in vitro [Ref 10]). Post-marketing surveillance did not confirm the theoretical serotonin syndrome signal in standard clinical use [Ref 29]. However, case reports document serotonin syndrome in overdose context [Ref 35]. Combination with MAOIs, SSRIs, SNRIs, linezolid, or methylene blue should be avoided.

---

## Legal Status

| Jurisdiction | Schedule/Class | Effective Date | Notes |
|---|---|---|---|
| United States | Schedule II (DEA) | 2009 | CSA; all isomers, esters, ethers, salts [Ref 11] |
| United Kingdom | Class A / Schedule 2 (MDA 1971) | 28 March 2011 | Added via SI 2011/744 on ACMD recommendation [Ref 32] |
| European Union | National control (varies) | ~2010 | EMA approved Palexia 2010; individual member state scheduling [Ref 43] |
| Australia | Schedule 8 (TGA) | ~2010 | Palexia; prescription opioid [Ref 34] |
| Canada | Schedule I (CDSA) / Narcotic Control Regulations | 2015 | Canada Gazette July 2015 [Ref 33] |

**Key scheduling note:** The US DEA placed tapentadol in Schedule II (not Schedule III or IV) despite lower abuse potential data than comparator opioids, based on its MOR agonist activity. The UK ACMD reasoning cited similarity to morphine and hydromorphone.

---

## Clinical Trials

| NCT ID | Status | Phase | Condition | Sponsor |
|---|---|---|---|---|
| NCT00364247 | Completed | Phase III | Acute pain (bunionectomy) | J&J PRD |
| NCT00421928 | Completed | Phase III | Osteoarthritis knee pain | J&J PRD |
| NCT00983385 | Completed | Phase III | Chronic low back pain | Grünenthal GmbH |
| NCT01041859 | Completed | Phase III | Diabetic peripheral neuropathy | J&J PRD |
| NCT01134536 | Completed | Phase II | Pediatric postsurgical pain PK | Janssen R&D |
| NCT02081391 | Completed | Phase III | Pediatric acute pain (oral solution) | Grünenthal GmbH |
| NCT01264887 | Terminated | Phase III | Cancer-related chronic pain | Grünenthal GmbH |
| NCT01124617 | Completed | Phase II | DPN / postherpetic neuralgia (Japan) | Janssen Pharma K.K. |
| NCT03604354 | Completed | Phase IV | Postoperative OA knee pain | AIIMS Bhubaneswar |

**Pivotal approvals basis:**
- IR formulation (FDA 2008): Bunionectomy Phase III trials (NCT00364247, NCT00613938) [Ref 18, Ref 19, Ref 44]
- ER formulation (FDA 2011): Low back pain and osteoarthritis Phase III trials (NCT00983385 and others) [Ref 20]
- Diabetic neuropathy indication: NCT01041859 and related randomized withdrawal trials [Ref 42, Ref — PMID 21162697]

---

## Community Feedback Analysis

No community feedback was submitted in Part A2 of the brief. Skip per instructions.

---

## Gaps & Flags

### 🚨 CRITICAL FLAGS (Safety-Critical / Immediate Review Required)

1. **Half-life error in seed data:** The brief's tolerance data lists "half-life: 5 days" and "full reset: 1.5 weeks." Published pharmacokinetic data consistently shows tapentadol's terminal plasma half-life is approximately **4 hours**, not 5 days [Ref 22, Ref 20]. This is likely a catastrophic database entry error — possibly data from another substance copied to tapentadol's record, or a misinterpretation of tolerance reset timeline as elimination half-life. This error must be corrected before publication. No published source supports a 5-day elimination half-life for tapentadol.

2. **Abuse potential characterization:** The brief states "high potential for abuse." Published post-marketing surveillance (RADARS system [Ref 36], ASI-MV [Ref 45], Australian surveillance [Ref 37]) consistently shows tapentadol has **significantly lower abuse rates than comparator Schedule II opioids** including oxycodone, hydrocodone, and morphine. The DEA's Schedule II placement is based on regulatory precaution and MOR agonism classification, not empirical abuse rates. The language "high potential for abuse" should be revised to something like "moderate abuse potential, lower than most comparator opioids."

3. **Serotonin syndrome interaction data:** The seed data does not list serotonin syndrome risk or MAOIs as an interaction. MAOIs are contraindicated with tapentadol (14-day washout required). SSRIs/SNRIs carry interaction risk. These should be added to the interactions table [Ref 10, Ref 23, Ref 35].

### ⚠️ DATA FLAGS (Verification/Editorial Review)

4. **Dose data — threshold and heavy dose:** The brief lists threshold at 12.5 mg oral. No published dose-finding study in humans was identified using 12.5 mg; clinical trials used doses starting at 50 mg IR. The 12.5 mg threshold is plausible but not confirmed by primary sources. The brief's dose ranges (50–150 mg common/strong) are consistent with published clinical practice.

5. **Duration data:** Onset 15–30 minutes and total 4–6 hours are consistent with published PK data (Tmax ~1.25–1.5 hrs, half-life ~4 hrs). Peak duration of 1–2 hours may be somewhat short; clinical trials show analgesic duration closer to 4 hours for IR.

6. **Binding affinity data (quantitative):** The specific Ki values (MOR Ki = 0.1 μM, NET Ki = 0.5 μM) come only from the 2007 Tzschentke paper [Ref 31]; no independent replication with human receptor preparations was found in the indexed literature. These values are from rat brain membranes and rat synaptosomes. Values cited in multiple reviews trace back to this single source.

7. **No LD50 data in humans:** No published LD50 or therapeutic index calculation for humans was identified. Fatal blood levels (1.05–3.20 mg/L) are documented from case reports [Ref 7, Ref 8, Ref 9], but no systematic dose-lethality analysis exists.

8. **Physical properties:** Melting point, aqueous solubility, and stability data for tapentadol free base were not found in indexed literature. The pharmaceutical form is the hydrochloride salt.

9. **Effect profile intensity/frequency values:** All 24 seed effects lack intensity and frequency values. Literature supports pain suppression as the dominant primary effect; sedation, nausea, constipation, and dizziness are the most documented clinical adverse effects. The generation agent will need to assign intensity/frequency using clinical trial AE rates and opioid class inference.

10. **Interaction with GBL/GHB/nitrous:** Brief lists GBL/GHB as "lethal" interactions and nitrous as "unknown." These severity designations are plausible based on opioid class effects but not confirmed by tapentadol-specific published data. They should be treated as class-level inferences.

11. **Contraindications field:** The brief has an empty contraindications field. Based on literature, major contraindications include: MAOI use within 14 days, severe hepatic/renal impairment, seizure disorders, concurrent CNS depressants, pregnancy/nursing (relative), pediatric patients <18 years.

12. **EU scheduling precision:** EMA approved Palexia in 2010, but individual member state scheduling varies. No comprehensive EU-wide scheduling map was found in the indexed literature. Cyprus, Estonia, Finland, Greece, Latvia, and Spain specifically noted as having national controls.

13. **Stereochemistry:** Only the (–)-(1R,2R) enantiomer is pharmacologically active. The racemate has been used in some animal studies but the pharmaceutical preparation is enantiomerically pure (1R,2R). This is confirmed by the isomeric SMILES [Ref 1].

14. **Discovery timeline:** The first publication of tapentadol pharmacological characterization is Tzschentke et al. 2007 (PMID 17656655) [Ref 31]. The synthesis and medicinal chemistry lead-optimization work at Grünenthal preceded this publication but is not documented in any indexed primary literature found. No patent-level history search was conducted.

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*Research completed 2026-05-09. Total citations in registry: 45.*