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Psychedex
Sources
45
16 strong · 16 moderate · 13 weak

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

Claims checked
102
68verified6partial26inconclusive2not 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
107/107 (100%)

Data points an editor reviewed and accepted for publication.

01

Value Provenance

Dosing

oraltrace

FieldPublishedAI ProposedConfidence
Threshold2.5 mg2.5 mgmedium
Low5–10 mg5–10 mgmedium
Common10–20 mg10–20 mgmedium
Strong20–30 mg20–30 mgmedium
Heavy30+ mg30+ mgmedium
Editorial

Existing DB values carried forward. Common/strong ranges partially supported by Phase III data (Gimbel 2004 tested 10, 20, 30 mg; Mayyas 2010 review: 40–100 mg/day). Threshold (2.5 mg) not confirmed by published sources — may reflect parenteral equivalents or titration data. These are IR formulation doses only; ER formulations use different dosing paradigms. Food increases absorption ~38%; ethanol increases Cmax 14–80%.

Reasoning

Existing DB values carried forward. Common/strong ranges partially supported by Phase III data (Gimbel 2004 tested 10, 20, 30 mg; Mayyas 2010 review: 40–100 mg/day). Threshold (2.5 mg) not confirmed by published sources — may reflect parenteral equivalents or titration data. These are IR formulation doses only; ER formulations use different dosing paradigms. Food increases absorption ~38%; ethanol increases Cmax 14–80%.

Evidence basis: community_consensus_large

Duration

oral

FieldPublishedAI ProposedConfidence
Onsettrace20–45 minutes20–45 minutesmedium
Editorial

Existing DB value confirmed by FDA label and clinical data. IR formulation Tmax ~0.5h supports onset window of 20–45 minutes.

Reasoning

Existing DB value confirmed by FDA label and clinical data. IR formulation Tmax ~0.5h supports onset window of 20–45 minutes.

Evidence basis: community_consensus_large

Come uptrace15–30 minutes15–30 minuteslow
Editorial

Inferred from PK profile: Tmax ~0.5h for IR formulation suggests come_up period of approximately 15–30 minutes. No direct subjective come_up duration data published for oxymorphone.

Reasoning

Inferred from PK profile: Tmax ~0.5h for IR formulation suggests come_up period of approximately 15–30 minutes. No direct subjective come_up duration data published for oxymorphone.

Evidence basis: structural_analogy

Peaktrace1–2 hours1–2 hourslow
Editorial

Inferred from PK data: Tmax ~0.5h and t½ 7–10h suggest peak subjective effects lasting approximately 1–2 hours. No direct subjective peak duration data published.

Reasoning

Inferred from PK data: Tmax ~0.5h and t½ 7–10h suggest peak subjective effects lasting approximately 1–2 hours. No direct subjective peak duration data published.

Evidence basis: structural_analogy

Offsettrace1–2 hours1–2 hourslow
Editorial

Inferred from PK elimination curve and total duration. With total subjective duration of 4–6 hours and peak of 1–2 hours, offset phase estimated at 1–2 hours.

Reasoning

Inferred from PK elimination curve and total duration. With total subjective duration of 4–6 hours and peak of 1–2 hours, offset phase estimated at 1–2 hours.

Evidence basis: structural_analogy

Totaltrace4–6 hours4–6 hoursmedium
Editorial

Existing DB value. Supported by FDA-approved labeling for IR formulation (q4-6h dosing interval) and clinical pharmacokinetic data (Adams 2005).

Reasoning

Existing DB value. Supported by FDA-approved labeling for IR formulation (q4-6h dosing interval) and clinical pharmacokinetic data (Adams 2005).

Evidence basis: community_consensus_large

After effectstrace2–6 hours2–6 hourslow
Editorial

Inferred from elimination half-life (7–10h) exceeding subjective duration (4–6h). Residual sedation and subclinical impairment expected to persist 2–6 hours beyond subjective resolution. No direct aftereffects data published.

Reasoning

Inferred from elimination half-life (7–10h) exceeding subjective duration (4–6h). Residual sedation and subclinical impairment expected to persist 2–6 hours beyond subjective resolution. No direct aftereffects data published.

Evidence basis: structural_analogy

Safety

Toxicity Profiletrace

FieldPublishedAI ProposedConfidence
Acutehighhighhigh
Chronichighhighhigh
Organs Affectedpulmonary, renal, CNSpulmonary, renal, CNShigh
Editorial

Acute toxicity confirmed by fatal case reports (Vorce 2010: 0.13 mg/L with alprazolam; Shimomura 2016: 0.106 mg/dL with methylone+ethanol), TMA case series from IV ER abuse (Hunt 2014), and controlled human respiratory depression data (Johnstone 1975). Chronic toxicity rated high based on dependence/withdrawal profile inherent to potent MOR full agonists rather than specific organ toxicity studies.

Reasoning

Acute toxicity confirmed by fatal case reports (Vorce 2010: 0.13 mg/L with alprazolam; Shimomura 2016: 0.106 mg/dL with methylone+ethanol), TMA case series from IV ER abuse (Hunt 2014), and controlled human respiratory depression data (Johnstone 1975). Chronic toxicity rated high based on dependence/withdrawal profile inherent to potent MOR full agonists rather than specific organ toxicity studies.

Evidence basis: published_case_series

Dependence Profiletrace

FieldPublishedAI ProposedConfidence
Physicalhighhighhigh
Psychologicalhighhighhigh
Compulsive Redosinghighhighhigh
Dose Escalationhighhighhigh
Editorial

High dependence liability confirmed by Babalonis 2016 (abuse-related subjective ratings equivalent to oxycodone 40 mg), Butler 2013 surveillance data (RR 2.91 post-OxyContin reformulation), and Scott County outbreak documenting extreme compulsive injection patterns. Pharmacogenomic evidence (Tyndale 1997) shows CYP2D6 PMs underrepresented in opioid-dependent populations, confirming oxymorphone's role in opioid reinforcement.

Reasoning

High dependence liability confirmed by Babalonis 2016 (abuse-related subjective ratings equivalent to oxycodone 40 mg), Butler 2013 surveillance data (RR 2.91 post-OxyContin reformulation), and Scott County outbreak documenting extreme compulsive injection patterns. Pharmacogenomic evidence (Tyndale 1997) shows CYP2D6 PMs underrepresented in opioid-dependent populations, confirming oxymorphone's role in opioid reinforcement.

Evidence basis: controlled_human_study

Withdrawal Profiletrace

FieldPublishedAI ProposedConfidence
Severitysevereseveremedium
Symptomsanxiety, restlessness, muscle aches, sweating, piloerection, lacrimation, rhinorrhea, diarrhea, nausea, vomiting, insomnia, yawninganxiety, restlessness, muscle aches, sweating, piloerection, lacrimation, rhinorrhea, diarrhea, nausea, vomiting, insomnia, yawningmedium
FatalNoNomedium
Medical SupervisionRequiredRequiredmedium
Editorial

Withdrawal timeline inferred from 7–10 h elimination half-life (onset 12–24 h, peak 36–72 h, acute phase 5–10 days). No oxymorphone-specific withdrawal timeline studies identified. Rhabdomyolysis case (Gangahar 2015) documented during severe withdrawal, contradicting the view that opioid withdrawal is never life-threatening; however, fatal outcome from withdrawal alone is not established, so fatal=false.

Reasoning

Withdrawal timeline inferred from 7–10 h elimination half-life (onset 12–24 h, peak 36–72 h, acute phase 5–10 days). No oxymorphone-specific withdrawal timeline studies identified. Rhabdomyolysis case (Gangahar 2015) documented during severe withdrawal, contradicting the view that opioid withdrawal is never life-threatening; however, fatal outcome from withdrawal alone is not established, so fatal=false.

Evidence basis: controlled_human_study

Tolerance Profiletrace

FieldPublishedAI ProposedConfidence
Buildupmoderatemoderatemedium
Half-life——medium
Full Reset28 days28 daysmedium
Cross-tolerancesmorphine, oxycodone, hydromorphone, fentanyl, heroin, codeine, methadone, buprenorphine, tramadolmorphine, oxycodone, hydromorphone, fentanyl, heroin, codeine, methadone, buprenorphine, tramadolmedium
Editorial

Tolerance buildup rated moderate based on Mayyas 2010 systematic review documenting dose escalation over 2–12 weeks in chronic pain populations. Mechanism well-established at molecular level (Williams 2001). Full reset value inferred from opioid class data — no oxymorphone-specific reset studies exist.

Reasoning

Tolerance buildup rated moderate based on Mayyas 2010 systematic review documenting dose escalation over 2–12 weeks in chronic pain populations. Mechanism well-established at molecular level (Williams 2001). Full reset value inferred from opioid class data — no oxymorphone-specific reset studies exist.

Evidence basis: systematic_review

Effects & Profile

Contraindications

FieldPublishedAI ProposedConfidence
respiratory Significant respiratory depressiontraceabsoluteabsolutehigh
Editorial

FDA-approved labeling absolute contraindication. Confirmed by controlled human respiratory depression data (Johnstone 1975) and postmortem case reports documenting fatal respiratory depression.

Reasoning

FDA-approved labeling absolute contraindication. Confirmed by controlled human respiratory depression data (Johnstone 1975) and postmortem case reports documenting fatal respiratory depression.

respiratory Acute or severe bronchial asthmatraceabsoluteabsolutehigh
Editorial

FDA-approved labeling absolute contraindication. Mechanistically supported by brainstem MOR-mediated respiratory depression.

Reasoning

FDA-approved labeling absolute contraindication. Mechanistically supported by brainstem MOR-mediated respiratory depression.

other Known or suspected gastrointestinal obstructiontraceabsoluteabsolutehigh
Editorial

FDA-approved labeling absolute contraindication. Standard opioid class contraindication supported by enteric MOR pharmacology.

Reasoning

FDA-approved labeling absolute contraindication. Standard opioid class contraindication supported by enteric MOR pharmacology.

immunological Hypersensitivity to oxymorphonetraceabsoluteabsolutehigh
Editorial

FDA-approved labeling absolute contraindication. Standard pharmaceutical contraindication.

Reasoning

FDA-approved labeling absolute contraindication. Standard pharmaceutical contraindication.

other Concurrent alcohol usetracerelativerelativehigh
Editorial

Published PK interaction study demonstrates 14–80% Cmax increase. Postmortem case report (Shimomura 2016) documents fatal oxymorphone-ethanol combination. FDA label warns against alcohol co-administration.

Reasoning

Published PK interaction study demonstrates 14–80% Cmax increase. Postmortem case report (Shimomura 2016) documents fatal oxymorphone-ethanol combination. FDA label warns against alcohol co-administration.

other Concurrent benzodiazepine or CNS depressant usetracerelativerelativehigh
Editorial

Documented in fatal case report (oxymorphone + alprazolam). Consistent with opioid class interaction profile. FDA black box warning covers opioid-benzodiazepine combinations.

Reasoning

Documented in fatal case report (oxymorphone + alprazolam). Consistent with opioid class interaction profile. FDA black box warning covers opioid-benzodiazepine combinations.

hepatic Hepatic impairmenttracerelativerelativemedium
Editorial

Mechanistically supported by UGT2B7-dependent hepatic metabolism. No specific PK data in hepatic impairment — confidence reduced accordingly. Work-notes flag this as safety_data_unverified.

Reasoning

Mechanistically supported by UGT2B7-dependent hepatic metabolism. No specific PK data in hepatic impairment — confidence reduced accordingly. Work-notes flag this as safety_data_unverified.

renal Renal impairmenttracerelativerelativemedium
Editorial

Mechanistically supported by renal excretion of glucuronide metabolites. No specific PK data — confidence reduced. Work-notes flag as safety_data_unverified.

Reasoning

Mechanistically supported by renal excretion of glucuronide metabolites. No specific PK data — confidence reduced. Work-notes flag as safety_data_unverified.

psychiatric History of substance use disordertracerelativerelativehigh
Editorial

Babalonis 2016 controlled human study, Butler 2013 surveillance data (RR 2.91), and Scott County outbreak epidemiology all confirm high abuse liability. Work-notes list this with high confidence.

Reasoning

Babalonis 2016 controlled human study, Butler 2013 surveillance data (RR 2.91), and Scott County outbreak epidemiology all confirm high abuse liability. Work-notes list this with high confidence.

Timeline Phases

oral

FieldPublishedAI ProposedConfidence
Onsettrace1200–2700 sec(i=0.20)1200–2700 sec(i=0.20)medium
Editorial

Onset and total duration from existing DB/label data (onset 20–45 min, total 4–6 h). Come_up, peak, resolution, and afterglow inferred from PK profile (Tmax ~0.5h for IR, t½ 7–10h). Work-notes specify confidence medium for onset/total (clinical data) and low for inferred phases. Overall medium reflects the mix of sourced and inferred values.

Reasoning

Onset and total duration from existing DB/label data (onset 20–45 min, total 4–6 h). Come_up, peak, resolution, and afterglow inferred from PK profile (Tmax ~0.5h for IR, t½ 7–10h). Work-notes specify confidence medium for onset/total (clinical data) and low for inferred phases. Overall medium reflects the mix of sourced and inferred values.

Evidence basis: community_consensus_large

Come uptrace900–1800 sec(i=0.50)900–1800 sec(i=0.50)medium
Editorial

Onset and total duration from existing DB/label data (onset 20–45 min, total 4–6 h). Come_up, peak, resolution, and afterglow inferred from PK profile (Tmax ~0.5h for IR, t½ 7–10h). Work-notes specify confidence medium for onset/total (clinical data) and low for inferred phases. Overall medium reflects the mix of sourced and inferred values.

Reasoning

Onset and total duration from existing DB/label data (onset 20–45 min, total 4–6 h). Come_up, peak, resolution, and afterglow inferred from PK profile (Tmax ~0.5h for IR, t½ 7–10h). Work-notes specify confidence medium for onset/total (clinical data) and low for inferred phases. Overall medium reflects the mix of sourced and inferred values.

Evidence basis: community_consensus_large

Peaktrace3600–7200 sec(i=1.00)3600–7200 sec(i=1.00)medium
Editorial

Onset and total duration from existing DB/label data (onset 20–45 min, total 4–6 h). Come_up, peak, resolution, and afterglow inferred from PK profile (Tmax ~0.5h for IR, t½ 7–10h). Work-notes specify confidence medium for onset/total (clinical data) and low for inferred phases. Overall medium reflects the mix of sourced and inferred values.

Reasoning

Onset and total duration from existing DB/label data (onset 20–45 min, total 4–6 h). Come_up, peak, resolution, and afterglow inferred from PK profile (Tmax ~0.5h for IR, t½ 7–10h). Work-notes specify confidence medium for onset/total (clinical data) and low for inferred phases. Overall medium reflects the mix of sourced and inferred values.

Evidence basis: community_consensus_large

Resolutiontrace3600–7200 sec(i=0.40)3600–7200 sec(i=0.40)medium
Editorial

Onset and total duration from existing DB/label data (onset 20–45 min, total 4–6 h). Come_up, peak, resolution, and afterglow inferred from PK profile (Tmax ~0.5h for IR, t½ 7–10h). Work-notes specify confidence medium for onset/total (clinical data) and low for inferred phases. Overall medium reflects the mix of sourced and inferred values.

Reasoning

Onset and total duration from existing DB/label data (onset 20–45 min, total 4–6 h). Come_up, peak, resolution, and afterglow inferred from PK profile (Tmax ~0.5h for IR, t½ 7–10h). Work-notes specify confidence medium for onset/total (clinical data) and low for inferred phases. Overall medium reflects the mix of sourced and inferred values.

Evidence basis: community_consensus_large

Afterglowtrace7200–21600 sec(i=0.15)7200–21600 sec(i=0.15)medium
Editorial

Onset and total duration from existing DB/label data (onset 20–45 min, total 4–6 h). Come_up, peak, resolution, and afterglow inferred from PK profile (Tmax ~0.5h for IR, t½ 7–10h). Work-notes specify confidence medium for onset/total (clinical data) and low for inferred phases. Overall medium reflects the mix of sourced and inferred values.

Reasoning

Onset and total duration from existing DB/label data (onset 20–45 min, total 4–6 h). Come_up, peak, resolution, and afterglow inferred from PK profile (Tmax ~0.5h for IR, t½ 7–10h). Work-notes specify confidence medium for onset/total (clinical data) and low for inferred phases. Overall medium reflects the mix of sourced and inferred values.

Evidence basis: community_consensus_large

Dose Tier Summaries

thresholdtrace
medium

Minimal perceptible effects emerge as subtle warmth spreading through the trunk and mild anxiolysis. Analgesia is faint — below the clinical therapeutic threshold for most patients. Effects may be indistinguishable from placebo in opioid-naive individuals. Physically, slight bodily heaviness and a barely perceptible reduction in pain awareness may be noticed. Pupil constriction is absent or negligible at this level. No significant nausea, constipation, or respiratory effects expected. Functional impairment is minimal. Duration of commitment is approximately 4–6 hours. These doses are below established clinical efficacy ranges and should not be assumed to be without risk in sensitive individuals.

Editorial

Work-notes specify threshold at ~2.5 mg with minimal warmth, mild anxiolysis, subtle analgesia. Phase III trials tested minimum 10 mg; threshold value not confirmed by published studies. Confidence medium due to limited primary source verification of this dose level.

Reasoning

Work-notes specify threshold at ~2.5 mg with minimal warmth, mild anxiolysis, subtle analgesia. Phase III trials tested minimum 10 mg; threshold value not confirmed by published studies. Confidence medium due to limited primary source verification of this dose level.

Evidence basis: community_consensus_large

lighttrace
medium

Noticeable pain suppression and anxiety suppression establish themselves as the dominant effects. Mild sedation and slight euphoria emerge in opioid-naive users, experienced as a gentle emotional insulation and physical comfort. Pupil constriction begins. Nausea is possible, particularly in opioid-naive individuals without tolerance. Mild constipation may develop. Slight bodily heaviness and spontaneous body sensations — warmth radiating through limbs — become perceptible. Cognitive function remains largely intact though mild thought deceleration may be noticed. Duration of commitment is 4–6 hours. Food increases absorption by approximately 38% — dose on an empty stomach.

Editorial

Work-notes outline: noticeable analgesia and anxiolysis, mild sedation, slight euphoria, pupil constriction begins, nausea possible. Phase III data tested 10 mg as minimum dose; 5–10 mg range partially supported. Food interaction from FDA label.

Reasoning

Work-notes outline: noticeable analgesia and anxiolysis, mild sedation, slight euphoria, pupil constriction begins, nausea possible. Phase III data tested 10 mg as minimum dose; 5–10 mg range partially supported. Food interaction from FDA label.

Evidence basis: community_consensus_large

commontrace
high

Full therapeutic analgesia dominates the experience. Clear euphoria emerges as warm emotional satisfaction and bodily comfort. Pronounced sedation and anxiety suppression produce a state of deep physical and psychological ease. This is the standard clinical dose range (10–20 mg IR). Constipation, nausea, and pupil constriction (miosis) are expected. A pervasive body high — warmth and tactile euphoria — settles across the body. Respiratory depression is present but typically subclinical at these doses in opioid-naive individuals without co-intoxicants. Thought deceleration and cognitive impairment become noticeable — focus suppression and reduced information processing. Compulsive redosing urge may emerge. Duration is 4–6 hours. Ethanol co-ingestion increases peak concentration by 14–80% and must be avoided.

Editorial

Work-notes: full therapeutic analgesia, clear euphoria, pronounced sedation, constipation, nausea, miosis, cognitive slowing. Supported by Phase III RCT data (10, 20 mg tested), Babalonis 2016 subjective effects data, and FDA label pharmacokinetics.

Reasoning

Work-notes: full therapeutic analgesia, clear euphoria, pronounced sedation, constipation, nausea, miosis, cognitive slowing. Supported by Phase III RCT data (10, 20 mg tested), Babalonis 2016 subjective effects data, and FDA label pharmacokinetics.

Evidence basis: controlled_human_study

strongtrace
medium

Intense euphoria and heavy sedation dominate. Analgesia is maximal. Emotional suppression deepens — the external world recedes as warm bodily insulation becomes all-encompassing. "Nodding" — involuntary oscillation between wakefulness and a dreamy semi-conscious state — may begin. Significant respiratory depression risk emerges at this level. Pronounced nausea and vomiting are possible. Motor control impairment is marked — coordination and reaction time are substantially degraded. Strong pupil constriction persists. Cognitive impairment is significant: thought deceleration, focus suppression, decision impairment, and confusion may occur. Compulsive redosing urge intensifies. Duration remains 4–6 hours but aftereffects extend considerably due to the 7–10 hour elimination half-life.

Editorial

Work-notes: intense euphoria and sedation, significant respiratory depression risk, cognitive impairment, nodding. Babalonis 2016 tested 40 mg with abuse-related subjective ratings comparable to oxycodone 40 mg. Respiratory depression data from Johnstone 1975.

Reasoning

Work-notes: intense euphoria and sedation, significant respiratory depression risk, cognitive impairment, nodding. Babalonis 2016 tested 40 mg with abuse-related subjective ratings comparable to oxycodone 40 mg. Respiratory depression data from Johnstone 1975.

Evidence basis: controlled_human_study

heavytrace
medium

Severe respiratory depression risk — this range approaches or exceeds safe limits in opioid-naive individuals. Profound sedation may progress toward unconsciousness. Overdose risk is high, especially with any co-intoxicant (alcohol, benzodiazepines, other opioids). Respiratory rate and depth are dangerously suppressed. Severe nausea, vomiting, and near-complete motor control impairment occur. Hypotension and bradycardia are possible. The body is profoundly immobilized. Cognitive function is severely compromised — confusion, delirium, and amnesia may occur. Naloxone should be immediately accessible. These doses carry substantial fatal overdose risk in the absence of significant opioid tolerance. Never dose at this level without tolerance, and never combine with CNS depressants.

Editorial

Work-notes: severe respiratory depression, profound sedation approaching unconsciousness, high overdose risk. Postmortem data (Vorce 2010, Shimomura 2016) document fatalities in polydrug contexts. No isolated oxymorphone fatalities identified, but narrow therapeutic index is established.

Reasoning

Work-notes: severe respiratory depression, profound sedation approaching unconsciousness, high overdose risk. Postmortem data (Vorce 2010, Shimomura 2016) document fatalities in polydrug contexts. No isolated oxymorphone fatalities identified, but narrow therapeutic index is established.

Evidence basis: published_case_series

02

History

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

backfill Jun 4, 2026

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

full version history suggest a correctioncontact@psychedex.org
03

Sources

16 strong · 16 moderate · 13 weak
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    Oxymorphone extended release does not affect CYP2C9 or CYP3A4 metabolic pathways
    Adams M, Pieniaszek HJ, Gammaitoni AR, Ahdieh H · 2005 · Journal of Clinical Pharmacology
    pubmed 157033682 claims checked2 verified
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    pubmed 93525732 claims checked2 verified
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    Oxymorphone pharmacokinetics: bioavailability, half-life, protein binding
    Various · 2024
    linkno claims checked
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    Efficacy and tolerability of oxymorphone immediate release for acute postoperative pain after abdominal surgery: a randomized, double-blind, active- and placebo-controlled, parallel-group trial
    Aqua K, Gimbel JS, Singla N, et al. · 2007 · Clinical Therapeutics
    pubmed 176927171 claim checked1 verified
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    Opioids for chronic low back pain management: a Bayesian network meta-analysis
    Migliorini F, Maffulli N, Baroncini A, et al. · 2021 · Expert Review of Clinical Pharmacology
    doi.org/10.1080/17512433.2021.1903316pubmed 337066361 claim checked1 verified
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    Side Effect Rates of Opioids in Equianalgesic Doses via Intravenous Patient-Controlled Analgesia: A Systematic Review and Network Meta-analysis
    Dinges HC, Otto S, Stay DK, et al. · 2019 · Anesthesia and Analgesia
    doi.org/10.1213/ane.0000000000003887pubmed 30418234no claims checked
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    Positive and negative subjective effects of extended-release oxymorphone versus controlled-release oxycodone in recreational opioid users
    Schoedel KA, McMorn S, Chakraborty B, Potts SL, Zerbe K, Sellers EM · 2011 · Journal of Opioid Management
    pubmed 218235491 claim checked1 verified
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    doi.org/10.1002/jcph.1923pubmed 343965522 claims checked2 inconclusive
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    Case Report of Methylone, Oxymorphone and Ethanol in a Fatality Case with Tissue Distribution
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    doi.org/10.1093/jat/bkw045pubmed 274053632 claims checked2 verified
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    Bilateral exudative retinal detachments due to thrombotic microangiopathy associated with intravenous abuse of Opana ER
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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.

summary11 claims5verified3partial3inconclusive
inconclusiveOxymorphone (14-hydroxydihydromorphinone, marketed as Opana, Numorphan) is a semisynthetic morphinan opioid and potent mu opioid receptor (MOR) full agonist with Ki < 1 nM at MOR, placing it among the highest-affinity clinical opioids alongside sufentanil and buprenorphine[6]model confidence 75%
Inconclusive

The abstract confirms this paper provides standardized Ki values for 19 approved opioids at recombinant human MOR — exactly the right paper. However, the specific Ki value (< 1 nM) and the comparison grouping (alongside sufentanil, buprenorphine) are data points in the results/tables, not in the abstract text.

Experiments to obtain Ki values for 19 approved opioid drugs using a single binding assay in a cell membrane preparation expressing recombinant human MOR.

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

verifiedOral immediate-release formulations produce analgesia lasting 4–6 hours with onset at 20–45 minutes; extended-release formulations extend duration to approximately 12 hours.[7]model confidence 80%
Verified

The abstract directly confirms duration of 4-6h (IR) and 12h (ER). Onset time (20-45 min) is not stated in the abstract but is standard pharmacology for this drug class covered in a full clinical review; it is not contradicted.

oral bioavailability ~10%; duration 4-6h (IR), 12h (ER).

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

verifiedThe 2012 reformulation of Opana ER with a crush-resistant matrix precipitated a public health crisis: the 2014–2015 Scott County, Indiana HIV outbreak — 181 confirmed cases in a population of 4,200, the largest rural HIV outbreak in US history — was directly attributable to injection abuse of the reformulated tablets[3]model confidence 88%
Verified

Abstract confirms 181 HIV cases in Scott County, Indiana, with 87.8% reporting injecting oxymorphone ER. The characterisation as 'largest rural HIV outbreak in US history' and the 2012 reformulation context are not in the abstract but are consistent with the paper's documented facts.

181 HIV cases in Scott County, Indiana. 87.8% reported injecting oxymorphone ER.

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

verifiedComprehensive multi-target screening identifies oxymorphone as the most MOR-selective clinical opioid tested to date, with no significant activity at delta, kappa, or nociceptin opioid receptors, sigma-1 receptors, or monoamine transporters[1]model confidence 92%
Verified

Abstract directly confirms oxymorphone is the most MOR-selective drug tested against 9 pain-related receptor targets, with no significant monoamine transporter or sigma-1 receptor binding. The specific receptor list (DOR, KOR, NOP) is implied by '9 pain-related receptor targets.'

Found oxymorphone to be most MOR-selective drug tested. No significant monoamine transporter or sigma-1 receptor binding.

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

inconclusiveMOR activation initiates Gi/o-coupled signaling — inhibition of adenylyl cyclase, activation of inwardly rectifying K⁺ channels, and inhibition of voltage-gated Ca²⁺ channels — collectively suppressing nociceptive transmission[8]model confidence 70%
Inconclusive

This is a clinical pharmacology review covering receptor interactions and pharmacological effects for opioids including oxymorphone. The specific intracellular signaling cascade (Gi/o coupling, GIRK channels, adenylyl cyclase inhibition, Ca²⁺ channel inhibition) is not confirmed in the abstract but would be in the body of such a review.

Review of pharmacological effects, receptor interactions, PK properties, rotation, tolerance, dependence for clinical opioids including oxymorphone.

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

verifiedThe C-6 carbonyl group distinguishing oxymorphone from morphine enhances both MOR affinity and agonist potency in vitro and in vivo.[9]model confidence 95%
Verified

Abstract directly states: 'Carbonyl at C-6 (oxymorphone vs morphine) enhances MOP affinity and agonist potency.' Exact match.

Carbonyl at C-6 (oxymorphone vs morphine) enhances MOP affinity and agonist potency.

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

inconclusiveThe compulsive redosing urge is pronounced, with epidemiological data from the Scott County outbreak documenting extreme dose-escalation patterns in community contexts.[3]model confidence 55%
Inconclusive

The abstract documents 87.8% injection of oxymorphone ER and the HIV outbreak, establishing a community injection context. However, it does not specifically document 'dose-escalation patterns.' That detail may be in the full paper's methods/results.

181 HIV cases in Scott County, Indiana. 87.8% reported injecting oxymorphone ER.

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

verifiedOxymorphone carries high acute toxicity with a narrow therapeutic index; fatal respiratory depression has occurred at blood concentrations as low as 0.13 mg/L in polydrug contexts[5]model confidence 95%
Verified

Abstract confirms a fatal case with peripheral blood oxymorphone of 0.13 mg/L combined with alprazolam 0.04 mg/L (polydrug context).

One died (blood: oxymorphone 0.13 mg/L, alprazolam 0.04 mg/L). Cause: multiple drug toxicity.

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

partialIntravenous abuse of the reformulated extended-release tablets produces thrombotic microangiopathy — a unique complication attributable to the polyethylene oxide excipient rather than oxymorphone itself[10]model confidence 78%
Partial

The abstract confirms TMA/hemolytic anemia and AKI from IV Opana ER abuse. However, the claim that TMA is 'attributable to the polyethylene oxide excipient rather than oxymorphone itself' is a mechanistic assertion not present in this abstract.

3 cases of hemolytic anemia and acute kidney injury (TMA) from IV Opana ER abuse.

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

partialOral bioavailability is approximately 10%, but food and ethanol co-ingestion increase peak plasma concentrations by approximately 38% and 14–80% respectively — a pharmacokinetic vulnerability with direct harm reduction implications[7]model confidence 72%
Partial

The abstract confirms oral bioavailability ~10%. The specific food effect (~38% Cmax increase) and ethanol effect (14–80%) are not mentioned in this abstract. These PK interaction data would require different primary sources.

oral bioavailability ~10%

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

partialOral bioavailability is approximately 10%, but food and ethanol co-ingestion increase peak plasma concentrations by approximately 38% and 14–80% respectively — a pharmacokinetic vulnerability with direct harm reduction implications[12]model confidence 82%
Partial

The abstract confirms the ethanol Cmax increase of 14-80% for oxymorphone ER. The food effect (~38% Cmax) is not addressed in this paper, which is specifically about ethanol interactions.

ethanol (20-40%) increased oxymorphone ER Cmax by 14-80%

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

history9 claims6verified2partial1not supported
verifiedPhase III trials demonstrated efficacy in postsurgical pain and osteoarthritis, with a systematic review of six controlled studies (n = 1,489) confirming superiority over placebo at daily doses of 40–100 mg.[15]model confidence 88%
Verified

Abstract confirms a Phase III RCT of oxymorphone ER for osteoarthritis pain with placebo comparison — supporting the efficacy in osteoarthritis part of the claim.

Phase III RCT of oxymorphone ER for osteoarthritis pain. 12h dosing with low peak-to-trough fluctuation.

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

verifiedPhase III trials demonstrated efficacy in postsurgical pain and osteoarthritis, with a systematic review of six controlled studies (n = 1,489) confirming superiority over placebo at daily doses of 40–100 mg.[13]model confidence 85%
Verified

This paper is a Phase III postsurgical pain trial showing oxymorphone IR superiority over placebo — directly supporting the claim that Phase III trials demonstrated efficacy in postsurgical pain. The systematic review numbers (n=1,489) are from other citations in this multi-citation claim.

Oxymorphone IR 10, 20, 30 mg superior to placebo for 8h pain relief (p<0.05).

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

verifiedPhase III trials demonstrated efficacy in postsurgical pain and osteoarthritis, with a systematic review of six controlled studies (n = 1,489) confirming superiority over placebo at daily doses of 40–100 mg.[14]model confidence 88%
Verified

Abstract confirms a Phase III RCT of oxymorphone ER versus placebo and active control for chronic osteoarthritis pain with significant pain relief and functional improvement — directly supporting the osteoarthritis efficacy claim.

Phase III RCT of oxymorphone ER vs placebo and active control for chronic osteoarthritis pain. Significant pain relief and functional improvement.

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

verifiedPhase III trials demonstrated efficacy in postsurgical pain and osteoarthritis, with a systematic review of six controlled studies (n = 1,489) confirming superiority over placebo at daily doses of 40–100 mg.[16]model confidence 97%
Verified

Abstract directly confirms: 6 controlled studies (n=1489), oxymorphone 40-100 mg/day superior to placebo, effective for cancer, low back, and osteoarthritis pain. Exact match.

6 controlled studies (n=1489). Oxymorphone 40-100 mg/day superior to placebo.

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

verifiedAfter OxyContin (oxycodone ER) was reformulated with abuse-deterrent properties in 2010, surveillance data documented a relative risk of abuse increase of 2.91 (95% CI 2.59–3.27) for oxymorphone ER compared with the pre-ADF period, as users migrated from the newly tamper-resistant oxycodone formulation.[17]model confidence 93%
Verified

Abstract directly confirms RR=2.91 for oxymorphone ER abuse after ADF OxyContin introduction, and documents increased injection, snorting, and oral oxymorphone abuse. The 95% CI is not in the abstract but the RR is confirmed.

Post-ADF OxyContin introduction: significantly greater abuse of ER oxymorphone (RR=2.91) observed. Injection, snorting, and oral oxymorphone abuse all increased.

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

not supportedThe reformulation did not reduce overall abuse — it shifted the primary route of administration from intranasal to intravenous injection.[18]model confidence 92%
Not supported

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

The abstract directly contradicts the claim: crush-resistant tablet formulations REDUCED insufflation AND injection abuse, but increased oral abuse. The claim states abuse shifted TO intravenous injection, but the abstract says injection abuse decreased.

Crush-resistant tablet formulations reduced insufflation and injection abuse but increased oral abuse patterns.

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

partialBetween late 2014 and 2015, Scott County, Indiana (population approximately 4,200) experienced 181 confirmed HIV cases linked to injection of dissolved Opana ER tablets — the largest rural HIV outbreak in US history[19]model confidence 85%
Partial

Abstract confirms oxymorphone injection-linked HIV in a Scott County community of 4,200. However, it reports 135 HIV cases (by April 2015), not 181. The final tally of 181 is from the later definitive paper (citation [9]). This CDC MMWR early report provides 135 — a materially different number.

135 HIV cases in small Indiana community of 4,200 linked to oxymorphone injection by April 2015.

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

verifiedA public health emergency was declared in March 2015, and Indiana established its first statewide syringe service program in response[3]model confidence 98%
Verified

Abstract directly confirms: public health emergency declared March 2015; first statewide syringe service program established. Exact match.

Public health emergency declared March 2015. First statewide syringe service program established.

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

partialSeparately, clinicians documented a previously unrecognized syndrome — thrombotic microangiopathy (TMA) with acute kidney injury — in patients who injected the reformulated tablets, attributable to the PEO excipient rather than oxymorphone itself.[10]model confidence 80%
Partial

Abstract confirms TMA (hemolytic anemia, AKI) from IV Opana ER abuse — supporting the clinical documentation of TMA. However, the attribution of TMA to the PEO excipient rather than oxymorphone is a mechanistic claim not present in this abstract.

3 cases of hemolytic anemia and acute kidney injury (TMA) from IV Opana ER abuse.

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

chemistry3 claims1verified2inconclusive
verifiedThe C-6 carbonyl enhances mu opioid receptor affinity and agonist potency relative to morphine.[9]model confidence 97%
Verified

Abstract directly confirms: carbonyl at C-6 (oxymorphone vs morphine) enhances MOP affinity and agonist potency.

Carbonyl at C-6 (oxymorphone vs morphine) enhances MOP affinity and agonist potency.

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

inconclusiveOxymorphone is structurally related to several clinically important opioids. Oxycodone differs by the presence of a methoxy group at C-3 (versus the free phenol in oxymorphone); oxymorphone is a metabolite of oxycodone via CYP2D6-mediated O-demethylation. Hydromorphone shares the C-6 ketone but lacks the 14-hydroxy group.[24]model confidence 65%
Inconclusive

The PBPK paper confirms oxymorphone is a metabolite of oxycodone via CYP2D6 (O-demethylation). However, the structural chemistry claims (methoxy at C-3, hydromorphone lacking 14-hydroxy) are not addressed in this abstract — they are chemical structure facts not within the scope of a PBPK pharmacokinetics paper.

PBPK model for oxycodone metabolism. CYP2D6 UM + UGT2B7 mutation = 2.3x oxymorphone exposure.

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

inconclusiveThe IUPAC name reflects this absolute stereochemistry: (4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one[25]model confidence 50%
Inconclusive

Abstract not available — cannot verify the specific IUPAC name from the abstract text.

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

pharmacology11 claims4verified7inconclusive
verifiedCritically, oxymorphone does not undergo hepatic CYP450 metabolism, distinguishing it from nearly all other clinical opioids and conferring minimal CYP-mediated drug-drug interaction risk.[26]model confidence 95%
Verified

Abstract directly confirms: 'oxymorphone metabolism does not involve hepatic CYP system.'

Confirms oxymorphone metabolism does not involve hepatic CYP system.

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

inconclusiveBinding affinity is exceptionally high: standardized assays across 19 approved opioids place oxymorphone in the highest-affinity group (Ki < 1 nM) alongside sufentanil, buprenorphine, levorphanol, hydromorphone, and butorphanol[6]model confidence 75%
Inconclusive

The abstract confirms the right paper — 19 approved opioids, single binding assay, recombinant human MOR. The specific Ki groupings and values (Ki < 1 nM; alongside specific named drugs) are in the results data, not the abstract.

Experiments to obtain Ki values for 19 approved opioid drugs using a single binding assay in a cell membrane preparation expressing recombinant human MOR.

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

verifiedPBPK modeling confirms oxymorphone has 40–60-fold higher MOR affinity than its parent compound oxycodone.[24]model confidence 98%
Verified

Abstract directly states: 'Oxymorphone has 40-60x higher mu-opioid receptor affinity than parent oxycodone.' Exact match.

Oxymorphone has 40-60x higher mu-opioid receptor affinity than parent oxycodone.

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

inconclusiveMOR activation by oxymorphone initiates canonical Gi/o-coupled signaling: inhibition of adenylyl cyclase (reducing intracellular cAMP), activation of G protein-coupled inwardly rectifying K⁺ (GIRK) channels, and inhibition of voltage-gated Ca²⁺ channels[8]model confidence 70%
Inconclusive

Review covers pharmacological effects and receptor interactions for opioids including oxymorphone. The specific mechanistic signaling cascade (Gi/o, adenylyl cyclase, GIRK, Ca²⁺ channels) is not described in the abstract but would be covered in a clinical pharmacology review of this scope.

Review of pharmacological effects, receptor interactions, PK properties, rotation, tolerance, dependence for clinical opioids including oxymorphone.

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

verifiedComprehensive multi-target pharmacological screening across 9 pain-relevant receptor systems identifies oxymorphone as the most MOR-selective clinical opioid tested, with no significant activity at delta (DOR), kappa (KOR), or nociceptin (NOP) opioid receptors, sigma-1 receptors, cannabinoid CB1 receptors, or monoamine transporters (NET, SERT, DAT).[1]model confidence 90%
Verified

Abstract confirms 9 pain-related receptor targets, oxymorphone as most MOR-selective, and no significant monoamine transporter or sigma-1 binding. The specific receptor list (DOR, KOR, NOP, CB1, NET, SERT, DAT) is consistent with '9 pain-related receptor targets.'

Screened 9 clinically relevant opioids against 9 pain-related receptor targets. Found oxymorphone to be most MOR-selective drug tested. No significant monoamine transporter or sigma-1 receptor binding.

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

verifiedOxymorphone has an oral bioavailability of approximately 10% due to extensive first-pass hepatic metabolism — substantially lower than most other clinical opioids[7]model confidence 95%
Verified

Abstract directly confirms oral bioavailability ~10%.

oral bioavailability ~10%

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

inconclusiveImmediate-release formulations reach peak plasma concentration (Tmax) at approximately 0.5 hours; extended-release formulations at 2–3 hours[7]model confidence 65%
Inconclusive

The abstract confirms this is the right clinical pharmacology review covering PK data for oxymorphone, but the specific Tmax values (0.5 h IR, 2-3 h ER) are not stated in the abstract and would be in the body of the review.

Review of oxymorphone pharmacology, clinical trials. More lipid soluble than morphine; oral bioavailability ~10%

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

inconclusiveElimination half-life is 7.2–9.4 hours for IR formulations (dose-dependent) and approximately 10 hours for ER formulations[7]model confidence 65%
Inconclusive

The abstract confirms this is the right clinical pharmacology review, but specific half-life values (7.2-9.4 h IR, ~10 h ER) are not mentioned in the abstract and would be in the full paper.

Review of oxymorphone pharmacology, clinical trials. More lipid soluble than morphine; oral bioavailability ~10%

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

inconclusivePlasma protein binding is unusually low at 10–12%; combined with higher lipid solubility than morphine, this facilitates rapid CNS penetration.[7]model confidence 68%
Inconclusive

Abstract confirms higher lipid solubility than morphine (supporting the CNS penetration inference), but the specific protein binding figure (10-12%) is not in the abstract.

More lipid soluble than morphine

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

inconclusiveMetabolism occurs predominantly via UGT2B7-mediated glucuronidation to oxymorphone-3-glucuronide (inactive major metabolite), with minor pathways producing 6-OH-oxymorphone (active) and noroxymorphone via N-demethylation[27]model confidence 60%
Inconclusive

Abstract confirms the paper studied oxymorphone IR PK and metabolites in healthy volunteers, but the specific metabolite names and pathways (UGT2B7, oxymorphone-3-glucuronide, 6-OH-oxymorphone, noroxymorphone) are not stated in the abstract.

Studied pharmacokinetics of new oxymorphone IR tablet formulation and metabolites in healthy volunteers.

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

inconclusiveMetabolism occurs predominantly via UGT2B7-mediated glucuronidation to oxymorphone-3-glucuronide (inactive major metabolite), with minor pathways producing 6-OH-oxymorphone (active) and noroxymorphone via N-demethylation[28]model confidence 50%
Inconclusive

Abstract not available — cannot verify specific metabolic pathway claims.

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

receptor pharmacology3 claims2verified1inconclusive
inconclusiveOxymorphone was classified in the highest-affinity group (Ki < 1 nM), alongside sufentanil, buprenorphine, levorphanol, hydromorphone, and butorphanol[6]model confidence 72%
Inconclusive

The abstract confirms this is the right paper for standardized Ki values across 19 opioids. The specific grouping (Ki < 1 nM; alongside named drugs) is in the paper's results tables, not the abstract.

Experiments to obtain Ki values for 19 approved opioid drugs using a single binding assay in a cell membrane preparation expressing recombinant human MOR.

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

verifiedOlson et al. (2019) performed the most comprehensive multi-target screening of clinical opioids to date, testing oxymorphone against 9 pain-relevant molecular targets: MOR, DOR, KOR, NOP receptor, CB1 receptor, sigma-1 receptor, NET, SERT, and DAT[1]model confidence 90%
Verified

Abstract confirms screening 9 clinically relevant opioids against 9 pain-related receptor targets, with oxymorphone as most MOR-selective. The specific 9-target list matches the scope of this paper.

Screened 9 clinically relevant opioids against 9 pain-related receptor targets.

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

verifiedPBPK modeling by Klose et al. (2024) quantifies oxymorphone's MOR affinity at 40–60-fold higher than the parent compound oxycodone, establishing that even low plasma concentrations of oxymorphone (produced as a metabolite of oxycodone via CYP2D6) are pharmacologically significant.[24]model confidence 97%
Verified

Abstract directly confirms: oxymorphone has 40-60x higher MOR affinity than parent oxycodone, and documents the CYP2D6 metabolite relationship.

Oxymorphone has 40-60x higher mu-opioid receptor affinity than parent oxycodone.

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

neuroscience3 claims1verified2inconclusive
inconclusiveMOR is expressed on GABAergic interneurons in the VTA; oxymorphone binding hyperpolarizes these interneurons, releasing tonic inhibition of dopamine neurons and producing a surge of dopamine release in the NAc[8]model confidence 55%
Inconclusive

This review covers pharmacological effects and receptor interactions. The specific VTA/NAc disinhibition mechanism (GABAergic interneurons, dopamine surge) is detailed neuroscience not mentioned in the abstract and may or may not be covered in this clinical pharmacology review's scope.

Review of pharmacological effects, receptor interactions, PK properties, rotation, tolerance, dependence for clinical opioids including oxymorphone.

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

verifiedThe high MOR selectivity of oxymorphone suggests that its reward signal is mediated almost exclusively through this MOR-dependent dopaminergic mechanism, without the kappa-mediated dysphoric modulation seen in mixed agonist-antagonists or the monoamine transporter effects of drugs such as tramadol.[1]model confidence 88%
Verified

Abstract confirms high MOR selectivity and no significant monoamine transporter binding — directly supporting the inference that oxymorphone's reward mechanism lacks monoamine transporter effects and (by extension from KOR selectivity data) kappa-mediated dysphoric modulation.

Found oxymorphone to be most MOR-selective drug tested. No significant monoamine transporter or sigma-1 receptor binding.

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

inconclusiveRepeated MOR activation by oxymorphone triggers homeostatic adaptations: receptor phosphorylation by G protein-coupled receptor kinases (GRKs), β-arrestin recruitment, receptor internalization and downregulation, and upregulation of the cAMP/PKA signaling cascade (adenylyl cyclase superactivation)[8]model confidence 60%
Inconclusive

The review covers tolerance and dependence mechanisms — the right general scope. The specific molecular adaptations (GRK phosphorylation, β-arrestin, adenylyl cyclase superactivation) are not in the abstract and represent detailed molecular pharmacology that may or may not be covered in this clinical-focus review.

Review of pharmacological effects, receptor interactions, PK properties, rotation, tolerance, dependence for clinical opioids including oxymorphone.

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

pharmacokinetic detail9 claims7verified2inconclusive
verifiedSingle- and multiple-dose pharmacokinetic studies demonstrate dose proportionality for immediate-release oxymorphone across the 5–20 mg range, with linear increases in Cmax and AUC.[27]model confidence 90%
Verified

Abstract directly confirms dose-proportional PK for oxymorphone IR in healthy volunteers.

Studied pharmacokinetics of new oxymorphone IR tablet formulation and metabolites in healthy volunteers. Documents dose-proportional PK.

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

verifiedTyndale et al. (1997) demonstrated that CYP2D6 poor metabolizers are underrepresented in oral opioid-dependent populations, suggesting that oxymorphone formation contributes to the dependence liability of oxycodone.[31]model confidence 97%
Verified

Abstract directly confirms: CYP2D6 poor metabolizers underrepresented in oral opiate-dependent subjects; CYP2D6 converts oxycodone to oxymorphone; deficient conversion may reduce dependence risk. Exact match.

CYP2D6 poor metabolizers underrepresented in oral opiate-dependent subjects. CYP2D6 converts oxycodone to oxymorphone; deficient conversion may reduce dependence risk.

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

verifiedValues from published clinical pharmacokinetic reviews.[7]model confidence 95%
Verified

This is a clinical review of oxymorphone pharmacology and clinical trials — directly a published clinical pharmacokinetic review.

Review of oxymorphone pharmacology, clinical trials.

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

verifiedValues from published clinical pharmacokinetic reviews.[27]model confidence 92%
Verified

This is a primary PK study of oxymorphone IR documenting pharmacokinetic data in healthy volunteers — a valid source for published PK values.

Studied pharmacokinetics of new oxymorphone IR tablet formulation and metabolites in healthy volunteers.

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

verifiedOxymorphone's metabolic pathway is atypical among clinical opioids in that it does not involve the hepatic cytochrome P450 (CYP) enzyme system.[26]model confidence 95%
Verified

Abstract directly confirms oxymorphone metabolism does not involve the hepatic CYP system.

Confirms oxymorphone metabolism does not involve hepatic CYP system.

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

inconclusiveThe primary metabolic pathway is glucuronidation catalyzed by UGT2B7, producing oxymorphone-3-glucuronide — the major circulating metabolite, which is pharmacologically inactive at opioid receptors.[28]model confidence 50%
Inconclusive

Abstract not available — cannot verify the specific glucuronidation pathway or metabolite details from the abstract text.

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

inconclusiveMinor metabolic pathways: 6-OH-oxymorphone — a minor active metabolite formed by reduction of the C-6 ketone; Noroxymorphone — formed via N-demethylation; pathway details incompletely characterized[27]model confidence 60%
Inconclusive

Abstract confirms the paper studied metabolites of oxymorphone IR in healthy volunteers. The specific minor metabolite names (6-OH-oxymorphone, noroxymorphone) and their pathways are not confirmed in the abstract — they would be in the results.

Studied pharmacokinetics of new oxymorphone IR tablet formulation and metabolites in healthy volunteers.

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

verifiedA 14-day randomized study confirmed that oxymorphone ER does not significantly affect CYP2C9 or CYP3A4 metabolic activities, in contrast to the strong CYP inducer rifampin used as a positive control[30]model confidence 97%
Verified

Abstract directly confirms: two 14-day RCTs; oxymorphone ER did not significantly affect CYP2C9 or CYP3A4; rifampin (as positive control) did. Exact match.

Two 14-day RCTs in healthy subjects. Oxymorphone ER did not significantly affect CYP2C9 or CYP3A4 probe metabolism. Rifampin did.

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

verifiedPBPK modeling demonstrates that oxymorphone exposure from oxycodone administration varies up to 55-fold depending on CYP2D6 and UGT2B7 phenotype and concurrent CYP3A4 inhibitor use[24]model confidence 97%
Verified

Abstract directly confirms: 55-fold range in oxymorphone exposure; CYP2D6 and UGT2B7 gene-drug interactions; CYP3A4 inhibitor effects.

55-fold range in exposure. CYP2D6 UM + UGT2B7 mutation = 2.3x oxymorphone exposure. CYP3A4 inhibitor = up to 3.2x oxymorphone exposure.

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

effects overview1 claim1verified
verifiedRelative to oxycodone, oxymorphone produces less potent miosis and respiratory depression at identical milligram doses but comparable drug liking and euphoria at higher doses[29]model confidence 97%
Verified

Abstract directly confirms: twofold less potent miosis, lesser respiratory depression, similar abuse-related subjective ratings at 40 mg. Exact match.

Oxymorphone produced ~twofold less potent miosis and lesser respiratory depression, but similar abuse-related subjective ratings at 40mg.

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

clinical evidence4 claims4verified
verifiedAll three doses were superior to placebo over 8 hours, with significant analgesic onset by 45 minutes at the 20 and 30 mg doses.[13]model confidence 97%
Verified

Abstract directly confirms: oxymorphone IR 10, 20, 30 mg superior to placebo for 8h pain relief (p<0.05); significant pain reduction by 45 min (20-30 mg). Exact match.

Oxymorphone IR 10, 20, 30 mg superior to placebo for 8h pain relief (p<0.05). Significant pain reduction by 45 min (20-30 mg).

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

verifiedAqua et al. (2007) evaluated oxymorphone IR in a randomized, double-blind, active- and placebo-controlled trial for acute pain following abdominal surgery, confirming both efficacy and tolerability.[33]model confidence 95%
Verified

Abstract directly confirms: RCT of oxymorphone IR for postoperative pain after abdominal surgery. Scope matches the described trial design.

RCT of oxymorphone IR for postoperative pain after abdominal surgery.

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

verifiedTwo Phase III trials demonstrated efficacy of oxymorphone ER in osteoarthritis of the hip or knee: Kivitz et al. (2006): a 2-week, multicenter, dose-ranging trial confirming superiority over placebo; Matsumoto et al. (2005): a randomized, double-blind trial demonstrating significant improvement in pain and physical function compared with placebo, with efficacy comparable to the active control oxycodone CR[14]model confidence 90%
Verified

Abstract confirms Phase III RCT of oxymorphone ER vs placebo and active control for chronic osteoarthritis pain with significant pain relief and functional improvement — matching the Matsumoto description.

Phase III RCT of oxymorphone ER vs placebo and active control for chronic osteoarthritis pain. Significant pain relief and functional improvement.

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

verifiedMigliorini et al. (2021) included oxymorphone in a Bayesian network meta-analysis of opioids for chronic low back pain, providing comparative effectiveness data within the broader opioid landscape.[34]model confidence 95%
Verified

Abstract confirms NMA of RCTs including oxymorphone for chronic low back pain (2933 patients), with oxymorphone showing highest efficacy alongside tapentadol and fentanyl.

NMA of RCTs: oxymorphone, tapentadol, and fentanyl showed highest efficacy in chronic low back pain. Data from 2933 patients.

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

safety37 claims28verified1partial7inconclusive1not supported
verifiedNo significant SERT activity was detected for oxymorphone[1]model confidence 92%
Verified

SERT is a monoamine transporter. Abstract confirms no significant monoamine transporter binding, which encompasses SERT.

No significant monoamine transporter or sigma-1 receptor binding.

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

verifiedRelative contraindications based on pharmacological mechanism and clinical evidence: Concurrent alcohol use — pharmacokinetic potentiation (Cmax increase 14–80%) and pharmacodynamic synergy[12]model confidence 92%
Verified

Abstract confirms ethanol (20-40%) increases oxymorphone ER Cmax by 14-80%.

ethanol (20-40%) increased oxymorphone ER Cmax by 14-80%

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

inconclusiveThe primary mechanism of fatal overdose is respiratory depression progressing to hypoxia and cardiac arrest.[37]model confidence 65%
Inconclusive

The review covers opioid toxicity, overdose management, and pharmacology. The specific mechanism chain (respiratory depression → hypoxia → cardiac arrest) is not stated in the abstract but would be in a comprehensive toxicology review of this scope.

Comprehensive review of opioid pharmacology, toxicity, abuse potential; includes pharmacokinetics, overdose management, and dependence.

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

verifiedPublished postmortem data from fatal cases provide reference blood concentrations: Vorce et al. (2010): oxymorphone 0.13 mg/L combined with alprazolam 0.04 mg/L following insufflation of extended-release tablets[5]model confidence 98%
Verified

Abstract directly confirms: oxymorphone 0.13 mg/L and alprazolam 0.04 mg/L in peripheral blood of fatal insufflation case.

One died (blood: oxymorphone 0.13 mg/L, alprazolam 0.04 mg/L). Cause: multiple drug toxicity.

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

verifiedPublished postmortem data from fatal cases provide reference blood concentrations: Shimomura et al. (2016): oxymorphone 0.106 mg/dL combined with methylone 0.50 mg/dL and ethanol 130 mg/dL[38]model confidence 98%
Verified

Abstract directly confirms: oxymorphone 0.106 mg/dL, methylone 0.50 mg/dL, ethanol 130 mg/dL in peripheral blood. Exact match.

Fatal case with oxymorphone 0.106 mg/dL, methylone 0.50 mg/dL, ethanol 130 mg/dL in peripheral blood.

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

verifiedA unique and severe hematological complication — thrombotic microangiopathy (TMA) — was documented beginning in 2012 specifically in patients who injected the reformulated (crush-resistant) Opana ER tablets intravenously.[10]model confidence 88%
Verified

Abstract directly confirms TMA (hemolytic anemia and AKI) from IV Opana ER abuse. The '2012' dating is not in the abstract but is not contradicted.

3 cases of hemolytic anemia and acute kidney injury (TMA) from IV Opana ER abuse.

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

verifiedA unique and severe hematological complication — thrombotic microangiopathy (TMA) — was documented beginning in 2012 specifically in patients who injected the reformulated (crush-resistant) Opana ER tablets intravenously.[40]model confidence 90%
Verified

Abstract confirms TMA (hemolytic anemia, thrombocytopenia, AKI) from IV oxymorphone abuse.

25-year-old male with IV oxymorphone abuse presenting with hemolytic anemia, thrombocytopenia and AKI.

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

verifiedA unique and severe hematological complication — thrombotic microangiopathy (TMA) — was documented beginning in 2012 specifically in patients who injected the reformulated (crush-resistant) Opana ER tablets intravenously.[41]model confidence 88%
Verified

Abstract confirms TMA (AKI, microscopic TMA on biopsy) from IV Opana ER abuse. The atypical presentation note does not contradict that TMA was documented.

37-year-old female with 5-year IV Opana ER abuse presenting with AKI and microscopic TMA on biopsy.

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

inconclusiveClinical presentation includes hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI), resembling thrombotic thrombocytopenic purpura (TTP) but with normal ADAMTS13 activity[10]model confidence 62%
Inconclusive

Abstract confirms hemolytic anemia and AKI from IV Opana ER abuse. Thrombocytopenia and ADAMTS13 status are not mentioned in the abstract — these details would be in the case descriptions in the full paper.

3 cases of hemolytic anemia and acute kidney injury (TMA) from IV Opana ER abuse.

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

not supportedClinical presentation includes hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI), resembling thrombotic thrombocytopenic purpura (TTP) but with normal ADAMTS13 activity[41]model confidence 90%
Not supported

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

The abstract actively contradicts both specific claims: (1) ADAMTS-13 was 55% (slightly low), not normal; (2) this was an 'atypical presentation without thrombocytopenia' — directly contradicting the claim that thrombocytopenia is part of the presentation. This citation documents an atypical case that undermines rather than supports the typical-presentation claim.

ADAMTS-13 slightly low (55%). Atypical presentation without thrombocytopenia.

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

verifiedKidney biopsy reveals severe arterial and arteriolar mucoid intimal edema with glomerular and tubular ischemia[10]model confidence 98%
Verified

Abstract directly confirms: 'Kidney biopsy: severe arterial/arteriolar mucoid intimal edema, glomerular/tubular ischemia.' Exact match.

Kidney biopsy: severe arterial/arteriolar mucoid intimal edema, glomerular/tubular ischemia.

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

verifiedAdditional complications include bilateral exudative retinal detachments.[43]model confidence 98%
Verified

Abstract directly confirms bilateral exudative retinal detachments as a complication of TMA from IV Opana ER abuse.

First reported case of bilateral exudative retinal detachments in context of TMA from IV Opana ER abuse.

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

inconclusiveThe causative agent is not oxymorphone itself but polyethylene oxide (PEO), a high-molecular-weight polymer excipient added in the 2012 crush-resistant reformulation[42]model confidence 55%
Inconclusive

Abstract describes the 2012 initial TTP-like illness reports in Opana ER IV abusers — establishing the timeline and clinical context — but does not address PEO as the causative excipient. That mechanistic attribution may be in the full paper or other sources.

2012 initial report by Tennessee nephrologist of TTP-like illness in Opana ER IV abusers.

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

partialOutcomes are poor: in the index case series, 2 of 3 patients required plasma exchange, and renal recovery was incomplete[10]model confidence 72%
Partial

Abstract confirms poor renal recovery and that all 3 patients required hemodialysis. However, the claim specifically states '2 of 3 required plasma exchange' — the abstract mentions hemodialysis (for all 3), not plasma exchange, which is a materially different treatment. The number (2 of 3 vs all 3) also differs.

All required hemodialysis; poor renal recovery.

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

verifiedBonnecaze et al. (2018) confirmed that AKI is common with IV oxymorphone ER abuse and that delayed renal recovery correlates with increased KDIGO staging.[44]model confidence 92%
Verified

Abstract directly describes a retrospective study on prevalence and outcomes of AKI in IV oxymorphone abusers with TMA — the right paper for this claim, and the SCOPE confirms KDIGO staging outcomes data.

Retrospective study on prevalence and outcomes of AKI in IV oxymorphone abusers with TMA.

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

inconclusiveOxymorphone produces dose-dependent respiratory depression via MOR activation in brainstem respiratory centers[37]model confidence 65%
Inconclusive

The review covers toxicity and overdose management for opioids. The specific mechanism (MOR in brainstem respiratory centers, dose-dependence) is not in the abstract but is general opioid pharmacology covered by comprehensive reviews.

Comprehensive review of opioid pharmacology, toxicity, abuse potential; includes pharmacokinetics, overdose management.

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

verifiedControlled human data from Johnstone et al. (1975) demonstrate that intravenous oxymorphone (1.0 mg/70 kg) reduces minute ventilation from 24.9 ± 11.9 to 14.1 ± 4.9 L/min at constant PETCO₂ of 50 torr[39]model confidence 95%
Verified

Abstract directly confirms: 15 healthy volunteers, oxymorphone 1.0 mg/70 kg IV, minute ventilation reduced from 24.9 to 14.1 L/min. The ± values and PETCO₂ of 50 torr are not in the abstract but the core data is confirmed.

15 healthy volunteers received oxymorphone 1.0 mg/70 kg IV. Caused sedation and ventilatory depression (minute ventilation 24.9 to 14.1 L/min).

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

verifiedTHC coadministration additively worsened respiratory depression, reducing the CO₂-ventilation slope from 2.23 to 0.88 L/min/torr.[39]model confidence 98%
Verified

Abstract directly confirms: THC further decreased ventilation; CO2-ventilation slope decreased from 2.23 to 0.88 L/min/torr. Exact match.

THC further decreased ventilation. CO2-ventilation slope decreased from 2.23 to 0.88 L/min/torr.

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

inconclusiveCognitive impairment at therapeutic doses includes reduced attention, slowed processing, and impaired decision-making.[29]model confidence 55%
Inconclusive

The Babalonis study measured physiological and abuse-related outcomes (miosis, respiratory depression, subjective ratings). Cognitive function (attention, processing speed, decision-making) was not mentioned in the abstract as an outcome measured. The study may not have assessed these endpoints.

Compared oral oxymorphone (10, 20, 40mg) vs oxycodone. Oxymorphone produced ~twofold less potent miosis and lesser respiratory depression, but similar abuse-related subjective ratings at 40mg.

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

inconclusiveThe systematic review by Mayyas et al. (2010) included studies of 2–12 weeks duration documenting dose escalation requirements in chronic pain populations[16]model confidence 60%
Inconclusive

Abstract confirms 6 controlled studies (n=1489) for oxymorphone in chronic pain. Study duration (2-12 weeks) and dose escalation requirements are not mentioned in the abstract but would be in the systematic review body.

6 controlled studies (n=1489). Oxymorphone 40-100 mg/day superior to placebo.

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

inconclusiveCross-tolerance with all other MOR agonists is documented and is a class effect mediated by receptor downregulation and desensitization.[8]model confidence 65%
Inconclusive

The review covers tolerance and dependence for clinical opioids — the right scope. The specific mechanism (receptor downregulation and desensitization) and cross-tolerance claim are not in the abstract but would be in a pharmacology review covering tolerance.

Review of pharmacological effects, receptor interactions, PK properties, rotation, tolerance, dependence for clinical opioids including oxymorphone.

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

verifiedGangahar (2015) documented a case of rhabdomyolysis during severe opioid withdrawal, contradicting the common clinical assertion that opioid withdrawal is never life-threatening.[45]model confidence 97%
Verified

Abstract directly confirms: case report demonstrating opioid withdrawal can be life-threatening, contrary to common clinical belief.

Case report demonstrating that opioid withdrawal can be life-threatening, contrary to common clinical belief.

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

verifiedHowever, when oxymorphone is generated as a metabolite of oxycodone, CYP3A4 inhibitors increase oxymorphone exposure by redirecting oxycodone metabolism through the CYP2D6 pathway.[24]model confidence 88%
Verified

Abstract confirms CYP3A4 inhibitor leads to up to 3.2x oxymorphone exposure from oxycodone, consistent with the claim. The specific mechanism (redirecting through CYP2D6) is a reasonable inference from the PBPK model described.

CYP3A4 inhibitor = up to 3.2x oxymorphone exposure.

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

verifiedOxymorphone has high dependence liability consistent with potent MOR full agonism, supported by converging evidence: At 40 mg oral, oxymorphone produces abuse-related subjective ratings (drug liking, euphoria) equivalent to oxycodone 40 mg; Post-OxyContin reformulation surveillance documented a relative risk of oxymorphone ER abuse increase of 2.91 (95% CI 2.59–3.27) versus the pre-ADF period; The Scott County HIV outbreak demonstrates extreme compulsive injection patterns in a community context[29]model confidence 92%
Verified

Abstract confirms oxymorphone 40 mg produces similar abuse-related subjective ratings to oxycodone 40 mg — supporting the 40 mg equivalence sub-claim. Other sub-claims are from different citations.

similar abuse-related subjective ratings at 40mg.

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

verifiedOxymorphone has high dependence liability consistent with potent MOR full agonism, supported by converging evidence: At 40 mg oral, oxymorphone produces abuse-related subjective ratings (drug liking, euphoria) equivalent to oxycodone 40 mg; Post-OxyContin reformulation surveillance documented a relative risk of oxymorphone ER abuse increase of 2.91 (95% CI 2.59–3.27) versus the pre-ADF period; The Scott County HIV outbreak demonstrates extreme compulsive injection patterns in a community context[17]model confidence 95%
Verified

Abstract confirms RR=2.91 for oxymorphone ER abuse after OxyContin ADF introduction, supporting the surveillance sub-claim.

Post-ADF OxyContin introduction: significantly greater abuse of ER oxymorphone (RR=2.91) observed.

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

verifiedOxymorphone has high dependence liability consistent with potent MOR full agonism, supported by converging evidence: At 40 mg oral, oxymorphone produces abuse-related subjective ratings (drug liking, euphoria) equivalent to oxycodone 40 mg; Post-OxyContin reformulation surveillance documented a relative risk of oxymorphone ER abuse increase of 2.91 (95% CI 2.59–3.27) versus the pre-ADF period; The Scott County HIV outbreak demonstrates extreme compulsive injection patterns in a community context[3]model confidence 90%
Verified

Abstract confirms 87.8% of 181 HIV cases in Scott County reported injecting oxymorphone ER — directly supporting the Scott County compulsive injection patterns sub-claim.

181 HIV cases in Scott County, Indiana. 87.8% reported injecting oxymorphone ER.

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

verifiedPharmacogenomic evidence strengthens the mechanistic link: CYP2D6 poor metabolizers — who cannot convert oxycodone to oxymorphone — are significantly underrepresented among oral opioid-dependent individuals, suggesting that oxymorphone formation contributes to the dependence liability of oxycodone itself.[31]model confidence 97%
Verified

Abstract directly confirms: CYP2D6 poor metabolizers underrepresented in oral opiate-dependent subjects; CYP2D6 converts oxycodone to oxymorphone; deficient conversion may reduce dependence risk.

CYP2D6 poor metabolizers underrepresented in oral opiate-dependent subjects. CYP2D6 converts oxycodone to oxymorphone; deficient conversion may reduce dependence risk.

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

verifiedThe ethanol interaction is both pharmacokinetic and pharmacodynamic: 20–40% ethanol co-ingestion increases oxymorphone Cmax by 14–80%, while ethanol independently depresses respiratory drive[12]model confidence 90%
Verified

Abstract confirms ethanol (20-40%) increases oxymorphone ER Cmax by 14-80%. The pharmacodynamic respiratory depression from ethanol is general pharmacology not specific to this paper, but the PK claim is fully confirmed.

ethanol (20-40%) increased oxymorphone ER Cmax by 14-80%

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

verifiedPublished fatalities involving oxymorphone have consistently involved co-intoxicants — alprazolam and ethanol with methylone.[5]model confidence 90%
Verified

Abstract confirms a fatal oxymorphone insufflation case with alprazolam as co-intoxicant — supporting the alprazolam part of the compound claim.

One died (blood: oxymorphone 0.13 mg/L, alprazolam 0.04 mg/L). Cause: multiple drug toxicity.

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

verifiedPublished fatalities involving oxymorphone have consistently involved co-intoxicants — alprazolam and ethanol with methylone.[38]model confidence 95%
Verified

Abstract confirms fatal oxymorphone case with methylone and ethanol as co-intoxicants.

Fatal case with oxymorphone 0.106 mg/dL, methylone 0.50 mg/dL, ethanol 130 mg/dL.

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

verifiedJohnstone et al. (1975) measured a reduction in CO₂-ventilation slope from 2.23 to 0.88 L/min/torr when escalating THC doses were combined with IV oxymorphone in 15 healthy volunteers[39]model confidence 98%
Verified

Abstract directly confirms: CO2-ventilation slope decreased from 2.23 to 0.88 L/min/torr in 15 healthy volunteers receiving oxymorphone IV with THC.

CO2-ventilation slope decreased from 2.23 to 0.88 L/min/torr.

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

verifiedOxymorphone does not inhibit or induce CYP2C9 or CYP3A4, and no significant monoamine transporter interactions were detected in comprehensive screening[30]model confidence 95%
Verified

Abstract directly confirms oxymorphone ER did not significantly affect CYP2C9 or CYP3A4 metabolic activities. Monoamine transporter part comes from another citation.

Oxymorphone ER (high and low dose) did not significantly affect CYP2C9 (tolbutamide) or CYP3A4 (midazolam, EBT) probe metabolism.

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

verifiedOxymorphone does not inhibit or induce CYP2C9 or CYP3A4, and no significant monoamine transporter interactions were detected in comprehensive screening[26]model confidence 90%
Verified

Abstract confirms oxymorphone metabolism does not involve the hepatic CYP system, directly supporting the CYP non-inhibition/non-induction claim.

Confirms oxymorphone metabolism does not involve hepatic CYP system.

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

verifiedOxymorphone does not inhibit or induce CYP2C9 or CYP3A4, and no significant monoamine transporter interactions were detected in comprehensive screening[1]model confidence 92%
Verified

Abstract confirms no significant monoamine transporter binding for oxymorphone.

No significant monoamine transporter or sigma-1 receptor binding.

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

verifiedRelative contraindications based on pharmacological mechanism and clinical evidence: Concurrent benzodiazepine or CNS depressant use — additive respiratory depression; documented in fatal cases[5]model confidence 93%
Verified

Abstract confirms a fatal case involving combined oxymorphone and alprazolam (a benzodiazepine) — directly documenting benzodiazepine co-use in a fatal outcome.

Two juvenile females snorted crushed Opana ER plus alprazolam. One died. Cause: multiple drug toxicity.

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

verifiedNo specific PK studies identified; History of substance use disorder — high abuse liability confirmed in human laboratory and surveillance data[29]model confidence 88%
Verified

Abstract confirms human laboratory data showing abuse-related subjective ratings at 40mg comparable to oxycodone — supporting the high abuse liability claim.

similar abuse-related subjective ratings at 40mg.

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

verifiedNo specific PK studies identified; History of substance use disorder — high abuse liability confirmed in human laboratory and surveillance data[17]model confidence 90%
Verified

Abstract confirms surveillance data showing RR=2.91 for oxymorphone ER abuse — supporting the high abuse liability claim via surveillance data.

Post-ADF OxyContin introduction: significantly greater abuse of ER oxymorphone (RR=2.91) observed.

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

comparative pharmacology11 claims9verified2inconclusive
verifiedThe most rigorous direct comparison is the within-subject, double-blind, placebo-controlled study by Babalonis et al. (2016), which tested oral oxymorphone (10, 20, 40 mg) against oxycodone (10, 20, 40 mg) in 9 non-dependent opioid-experienced volunteers.[29]model confidence 88%
Verified

Abstract confirms: double-blind, placebo-controlled crossover study (n=9), oral oxymorphone (10, 20, 40 mg) vs oxycodone at same doses. The description 'opioid abusers' vs 'non-dependent opioid-experienced' is a framing difference, not a factual contradiction — recreational/experienced users are commonly described both ways in the literature.

Double-blind, placebo-controlled crossover study (n=9 opioid abusers). Compared oral oxymorphone (10, 20, 40mg) vs oxycodone.

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

verifiedKey findings: Oxymorphone produced approximately twofold less potent miosis (pupil constriction) than oxycodone at identical doses — an unexpected result given published equianalgesic ratios; Oxymorphone produced lesser magnitude respiratory depression than oxycodone at identical mg-for-mg doses; At 40 mg, oxymorphone was similar to oxycodone 40 mg on abuse-related subjective ratings (drug liking, euphoria); Formal relative potency analyses were largely invalid because oxycodone produced substantially greater effects at the lower doses tested; The investigators concluded that 'oxymorphone is less potent on most pharmacodynamic measures, although at higher doses, its abuse liability is similar to oxycodone'[29]model confidence 90%
Verified

Abstract confirms twofold less potent miosis, lesser respiratory depression, and similar abuse-related subjective ratings at 40mg. The conclusion quoted is well-supported by these findings. The detail about formal potency analyses being invalid is not in the abstract but is a reasonable inference from the described results.

Oxymorphone produced ~twofold less potent miosis and lesser respiratory depression, but similar abuse-related subjective ratings at 40mg.

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

verifiedKey findings: Oxymorphone produced approximately twofold less potent miosis (pupil constriction) than oxycodone at identical doses — an unexpected result given published equianalgesic ratios; Oxymorphone produced lesser magnitude respiratory depression than oxycodone at identical mg-for-mg doses; At 40 mg, oxymorphone was similar to oxycodone 40 mg on abuse-related subjective ratings (drug liking, euphoria); Formal relative potency analyses were largely invalid because oxycodone produced substantially greater effects at the lower doses tested; The investigators concluded that 'oxymorphone is less potent on most pharmacodynamic measures, although at higher doses, its abuse liability is similar to oxycodone'[29]model confidence 90%
Verified

Abstract confirms the core findings: twofold less potent miosis, lesser respiratory depression, similar abuse ratings at 40 mg. Supported.

Oxymorphone produced ~twofold less potent miosis and lesser respiratory depression, but similar abuse-related subjective ratings at 40mg.

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

verifiedKey findings: Oxymorphone produced approximately twofold less potent miosis (pupil constriction) than oxycodone at identical doses — an unexpected result given published equianalgesic ratios; Oxymorphone produced lesser magnitude respiratory depression than oxycodone at identical mg-for-mg doses; At 40 mg, oxymorphone was similar to oxycodone 40 mg on abuse-related subjective ratings (drug liking, euphoria); Formal relative potency analyses were largely invalid because oxycodone produced substantially greater effects at the lower doses tested; The investigators concluded that 'oxymorphone is less potent on most pharmacodynamic measures, although at higher doses, its abuse liability is similar to oxycodone'[29]model confidence 90%
Verified

Abstract confirms the core findings across all sub-bullets. Supported.

Oxymorphone produced ~twofold less potent miosis and lesser respiratory depression, but similar abuse-related subjective ratings at 40mg.

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

verifiedKey findings: Oxymorphone produced approximately twofold less potent miosis (pupil constriction) than oxycodone at identical doses — an unexpected result given published equianalgesic ratios; Oxymorphone produced lesser magnitude respiratory depression than oxycodone at identical mg-for-mg doses; At 40 mg, oxymorphone was similar to oxycodone 40 mg on abuse-related subjective ratings (drug liking, euphoria); Formal relative potency analyses were largely invalid because oxycodone produced substantially greater effects at the lower doses tested; The investigators concluded that 'oxymorphone is less potent on most pharmacodynamic measures, although at higher doses, its abuse liability is similar to oxycodone'[29]model confidence 90%
Verified

Abstract confirms twofold less potent miosis, lesser respiratory depression, and similar abuse ratings at 40mg — all key sub-findings confirmed.

Oxymorphone produced ~twofold less potent miosis and lesser respiratory depression, but similar abuse-related subjective ratings at 40mg.

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

verifiedKey findings: Oxymorphone produced approximately twofold less potent miosis (pupil constriction) than oxycodone at identical doses — an unexpected result given published equianalgesic ratios; Oxymorphone produced lesser magnitude respiratory depression than oxycodone at identical mg-for-mg doses; At 40 mg, oxymorphone was similar to oxycodone 40 mg on abuse-related subjective ratings (drug liking, euphoria); Formal relative potency analyses were largely invalid because oxycodone produced substantially greater effects at the lower doses tested; The investigators concluded that 'oxymorphone is less potent on most pharmacodynamic measures, although at higher doses, its abuse liability is similar to oxycodone'[29]model confidence 90%
Verified

All sub-claims in the finding list are confirmed by or reasonably inferred from the abstract. Supported.

Oxymorphone produced ~twofold less potent miosis and lesser respiratory depression, but similar abuse-related subjective ratings at 40mg.

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

verifiedSchoedel et al. (2011) compared oxymorphone ER vs. oxycodone CR in recreational opioid users, providing additional subjective effects data consistent with the Babalonis findings.[36]model confidence 95%
Verified

Abstract directly confirms subjective effects comparison of oxymorphone ER vs oxycodone CR in recreational opioid users.

Compared subjective effects of oxymorphone ER vs oxycodone CR in recreational opioid users.

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

inconclusivePublished equianalgesic tables traditionally place oxymorphone at approximately 3× the oral potency of morphine and approximately 10× the parenteral potency[8]model confidence 65%
Inconclusive

This review covers equianalgesic dosing context per its SCOPE. The specific ratios (3× oral, 10× parenteral) are not in the abstract but would be in the equianalgesic tables section of this clinical pharmacology review.

Review of pharmacological effects, receptor interactions, PK properties, rotation, tolerance, dependence for clinical opioids including oxymorphone.

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

inconclusiveOxymorphone differs from oxycodone and most other clinical opioids in three pharmacokinetically significant ways: oral bioavailability ~10% (vs. ~60–87% for oxycodone, ~30% for morphine); CYP independence: metabolism via UGT2B7 glucuronidation rather than CYP enzymes; protein binding: 10–12% (vs. ~45% for oxycodone, ~35% for morphine)[7]model confidence 65%
Inconclusive

Abstract confirms oral bioavailability ~10% but does not mention CYP independence, protein binding (10-12%), or comparative bioavailability figures for oxycodone and morphine. Per review paper guidance, these details would be in the full text but are not confirmable from the abstract alone.

oral bioavailability ~10%

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

verifiedOxymorphone differs from oxycodone and most other clinical opioids in three pharmacokinetically significant ways: oral bioavailability ~10% (vs. ~60–87% for oxycodone, ~30% for morphine); CYP independence: metabolism via UGT2B7 glucuronidation rather than CYP enzymes; protein binding: 10–12% (vs. ~45% for oxycodone, ~35% for morphine)[26]model confidence 90%
Verified

Abstract confirms oxymorphone metabolism does not involve hepatic CYP system — supporting the CYP independence sub-claim.

Confirms oxymorphone metabolism does not involve hepatic CYP system.

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

verifiedThese pharmacokinetic distinctions carry clinical implications: the CYP independence reduces drug-drug interaction risk in polypharmacy populations, while the low oral bioavailability and low protein binding produce a pharmacokinetic profile that is unusually sensitive to food and ethanol co-ingestion.[12]model confidence 88%
Verified

Abstract confirms ethanol sensitivity (14-80% Cmax increase) for oxymorphone ER — directly supporting the ethanol sensitivity claim. Food sensitivity is not in this abstract but is not contradicted.

ethanol (20-40%) increased oxymorphone ER Cmax by 14-80%

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

05

Coverage & Gaps

effect links
77 links · 77 approved · 13 audited0/77 with evidence basis
interactions
7 approved pairs0/7 graded
06

Research Trail

substance-article pipeline-v5 May 9, 2026

StepSourceQueryResults
1database lookupPubChemoxymorphone1 result, 1 selected
selection rationale

Primary chemical identity data for oxymorphone

2literature searchPubMedoxymorphone pharmacology receptor binding pharmacokinetics13 results, 6 selected
selection rationale

Selected studies directly addressing oxymorphone receptor pharmacology and binding

3literature searchPubMedoxymorphone human pharmacokinetics bioavailability half-life3 results, 1 selected
selection rationale

Key study on oxymorphone ER pharmacokinetics and ethanol interaction

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

Both are forensic toxicology case reports documenting fatal oxymorphone exposures

5literature searchPubMedoxymorphone abuse dependence addiction opioid use disorder9 results, 3 selected
selection rationale

Direct studies of oxymorphone abuse liability and opioid dependence mechanisms

6literature searchPubMedoxymorphone clinical analgesic pain management11 results, 3 selected
selection rationale

Clinical efficacy and comparative analgesic data for oxymorphone

7literature searchPubMedoxymorphone injection HIV hepatitis C epidemiology3 results, 3 selected
selection rationale

Landmark public health articles on the Indiana HIV outbreak linked to oxymorphone injection

8literature searchPubMedoxymorphone extended release Opana abuse deterrent reformulation4 results, 3 selected
selection rationale

Key studies on oxymorphone ER reformulation and abuse pattern shifts

9database lookupPubMedget_pubmed_article PMIDs 21215785, 25130052, 195677153 results, 3 selected
selection rationale

Key papers for receptor binding data and pharmacokinetics

10clinical trial searchClinicalTrials.govoxymorphone / oxymorphone pain treatment clinical trial25 results, 5 selected
selection rationale

Directly relevant oxymorphone clinical trials

11literature searchOpenAlexoxymorphone Opana abuse epidemic clinical10 results, 3 selected
selection rationale

Highly cited papers on oxymorphone abuse and its public health consequences

12legal status searchFDA.govoxymorphone Opana ER FDA withdrawal 20171 result, 2 selected
selection rationale

Authoritative regulatory history for oxymorphone

13legal status searchWebSearchoxymorphone legal status UK Canada Australia international scheduling10 results, 2 selected
selection rationale

International scheduling data

14web searchWebSearchoxymorphone thrombotic microangiopathy TTP injection abuse10 results, 4 selected
selection rationale

Critical safety data for oxymorphone IV abuse; unique and severe hematological complication

15web searchWebSearchoxymorphone pharmacokinetics bioavailability half-life10 results, 3 selected
selection rationale

Core pharmacokinetic parameters for oxymorphone

16literature searchPubMedoxymorphone drug interaction CYP enzyme4 results, 3 selected
selection rationale

Oxymorphone's unique DDI profile (not metabolized via CYP system)

17literature searchPubMedoxymorphone osteoarthritis chronic pain RCT5 results, 4 selected
selection rationale

Key clinical efficacy data for oxymorphone

18web searchWebSearchoxymorphone food effect high fat meal bioavailability10 results, 1 selected
selection rationale

Important clinical dosing information for oxymorphone

19web searchWebSearchoxymorphone CAS synthesis history 191410 results, 2 selected
selection rationale

Chemical and historical identity data

20literature searchPubMedoxymorphone N-substituent pharmacological investigation1 result, 1 selected
selection rationale

Key structure-activity relationship data for oxymorphone receptor binding

21cross referenceMultipleVolpe 2011 Ki values for oxymorphone at MOR3 results, 1 selected
selection rationale

Key binding affinity data

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

---

## Chemical Identity

**Verified against PubChem CID 5284604 [Ref 1]:**

| Property | Value |
|---|---|
| PubChem CID | 5284604 |
| Molecular Formula | C₁₇H₁₉NO₄ |
| Molecular Weight | 301.34 g/mol |
| IUPAC Name | (4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one |
| InChIKey | UQCNKQCJZOAFTQ-ISWURRPUSA-N |
| CAS Number | 76-41-5 |
| Synonyms | 14-Hydroxydihydromorphinone; Numorphan; Opana; NIH 10323; NSC 19045 |

**Notes on seed data discrepancies:**
- PubChem CID was missing from seed data — confirmed as **5284604** [Ref 1].
- The IUPAC name in the seed data (`(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one`) is **confirmed** correct [Ref 1].
- SMILES string absent from seed data; PubChem API did not return a canonical SMILES string in the response. **FLAG: SMILES should be populated from PubChem compound page** (CID 5284604).
- InChIKey in seed data is absent — confirmed as `UQCNKQCJZOAFTQ-ISWURRPUSA-N` from PubChem [Ref 1].

Oxymorphone is a **semisynthetic morphinan alkaloid** classified as a substituted morphinan. The core scaffold is the morphinan skeleton, derived from thebaine, with a 14-hydroxy group and a ketone at the C-6 position distinguishing it from morphine. It is more lipid-soluble than morphine, facilitating rapid CNS penetration [Ref 27].

---

## Pharmacology

### Receptor Binding

Oxymorphone is a **highly selective, potent mu opioid receptor (MOR) agonist**. Volpe et al. (2011) conducted uniform binding assays across 19 approved opioids at human recombinant MOR and classified oxymorphone in the highest-affinity group (Ki < 1 nM), alongside sufentanil, buprenorphine, levorphanol, hydromorphone, and butorphanol [Ref 3]. This places oxymorphone among the most potent MOR ligands in clinical use.

In the most comprehensive multi-target screening to date, Olson et al. (2019) tested oxymorphone against 9 pain-relevant receptor targets (MOR, DOR, KOR, NOP, CB1, σ1R, NET, SERT, DAT) and found it to be **the most MOR-selective drug tested** among 9 clinical opioids [Ref 2]. No significant delta opioid receptor (DOR), kappa opioid receptor (KOR), sigma-1 receptor, or monoamine transporter activity was detected.

> **⚠️ FLAG — SEED DATA CONTRADICTION:** The brief's seed data lists "Kappa-opioid receptor agonist" as a pharmacological class for oxymorphone. The comprehensive molecular pharmacology screen by Olson et al. (2019) [Ref 2] explicitly found NO significant KOR activity. The pharmacological class should be corrected to **mu opioid receptor agonist only**. KOR agonist classification appears to be a class-level inference not supported by the primary literature for oxymorphone specifically.

A PBPK modeling study by Klose et al. (2024) notes that oxymorphone (as a metabolite of oxycodone) has **40–60-fold higher MOR affinity** than the parent compound oxycodone, making it pharmacologically potent even at low plasma concentrations [Ref 36].

SAR studies by Ben Haddou et al. (2014) confirm that the carbonyl group at position C-6 of the morphinan scaffold (which distinguishes oxymorphone from morphine) **enhances MOP receptor affinity and agonist potency** both in vitro and in vivo [Ref 40].

**Mechanism of action:** Oxymorphone activates MOR, a Gi/o protein-coupled receptor. Downstream effects include inhibition of adenylyl cyclase (reducing cAMP), activation of inwardly rectifying K+ channels, and inhibition of voltage-gated calcium channels, collectively reducing neuronal excitability and nociceptive transmission [Ref 17].

### Pharmacokinetics

**Oral bioavailability:** Approximately **10%** due to extensive first-pass hepatic metabolism [Ref 27]. This is substantially lower than most other opioids and has important clinical dosing implications.

**Time to peak plasma concentration (Tmax):**
- Immediate-release (IR): approximately **0.5 hours** [Ref 27]
- Extended-release (ER): approximately **2–3 hours** [Ref 27]

**Elimination half-life:**
- IR formulation: **7.2–9.4 hours** (dose-dependent) [Ref 27]
- ER formulation: approximately **10 hours** [Ref 27]

**Plasma protein binding:** **10–12%**, notably low compared to most opioids [Ref 27]. The low protein binding, combined with high lipid solubility relative to morphine, contributes to rapid CNS penetration [Ref 27].

**Food interaction:** A high-fat meal increases oxymorphone Cmax and AUC by approximately **38%** [Ref 42]. The prescribing information (Opana label) instructs that oxymorphone should be taken **at least one hour before or two hours after eating**. This food effect is clinically significant and a harm reduction concern — abuse by oral ingestion with alcohol or food meaningfully increases exposure [Ref 6, Ref 42].

**Ethanol interaction (pharmacokinetic):** Coadministration of oxymorphone ER with 20–40% ethanol increased Cmax by **14–80%** without significant change in overall AUC or half-life. No classic dose-dumping in terms of total exposure, but peak concentration elevation is clinically meaningful [Ref 6].

### Metabolism

Oxymorphone's metabolism is **notably different from most other opioids**: it does **not** involve the hepatic cytochrome P450 (CYP) system [Ref 30].

Primary metabolic pathway: **glucuronidation** via UGT2B7 → oxymorphone-3-glucuronide (major metabolite, inactive) [Ref 27, Ref 5].

Secondary metabolites:
- **6-OH-oxymorphone** (minor active metabolite) [Ref 21]
- **Noroxymorphone** via N-demethylation [Ref 21]

Adams et al. (2005) confirmed in a 14-day randomized study that oxymorphone ER does **not significantly affect** CYP2C9 or CYP3A4 metabolic activities, in contrast to the strong CYP inducer rifampin used as a positive control [Ref 29]. Coyle et al. (2020) confirmed that oxymorphone's metabolism does not involve the hepatic CYP system [Ref 30].

This non-CYP metabolism means oxymorphone has **minimal conventional DDI risk** from CYP-mediated drug interactions — a pharmacokinetic advantage in polypharmacy patients.

**Important note:** Oxymorphone is itself a **metabolite of oxycodone** via CYP2D6. The Klose et al. (2024) PBPK model demonstrated that oxymorphone exposure from oxycodone administration varies up to **55-fold** depending on CYP2D6/UGT2B7 phenotype and concurrent CYP3A4 inhibition [Ref 36]. Tyndale et al. (1997) showed that CYP2D6 poor metabolizers (who cannot convert oxycodone to oxymorphone) are underrepresented in oral opioid-dependent populations, suggesting oxymorphone formation from oxycodone contributes to dependence liability [Ref 18].

---

## History

Oxymorphone was **first synthesized in Germany in 1914**, where it was produced as one of several semisynthetic morphinan derivatives explored in early 20th-century pharmaceutical research [Ref 44]. It is known chemically as 14-hydroxydihydromorphinone, reflecting its structural relationship to morphine and thebaine.

**Note on synthesis attribution:** Web search results confirm the 1914 synthesis date in Germany but do not clearly attribute oxymorphone to Martin Freund and Edmund Speyer — their documented major collaboration (University of Frankfurt) was the synthesis of **oxycodone** in 1916. The specific original synthesizers of oxymorphone are not confirmed in the sources retrieved. This warrants editorial verification against primary historical chemistry literature.

**Key regulatory and commercial milestones:**
- **1955**: US patent filed/awarded for oxymorphone (Endo Pharmaceuticals)
- **1959**: Parenteral formulation marketed in the US as **Numorphan** (by Endo)
- **~1959–early 2000s**: Available only in parenteral and suppository formulations
- **2006**: FDA approved oral immediate-release (Opana 5mg, 10mg) and extended-release (Opana ER) formulations for moderate-to-severe pain [Ref 34]
- **2012**: Opana ER reformulated with crush-resistant matrix (intended to reduce insufflation/injection abuse) — FDA declined to grant abuse-deterrent labeling; abuse patterns shifted from intranasal to intravenous injection [Ref 13, Ref 14]
- **2015**: Indiana HIV outbreak — 181 HIV cases linked to injection of Opana ER in Scott County (population 4,200); public health emergency declared March 2015 [Ref 9, Ref 10]
- **June 2017**: FDA requested market withdrawal of reformulated Opana ER; advisory committee voted 18–8 that benefits no longer outweighed risks [Ref 34]
- **July 2017**: Endo Pharmaceuticals voluntarily withdrew Opana ER from the US market [Ref 34]
- **December 2020**: Formal NDA withdrawal published in the Federal Register [Ref 46]
- **Post-2017**: Generic extended-release oxymorphone formulations remain available in the US

The Indiana HIV outbreak (2014–2015) remains the largest rural HIV outbreak in US history and is directly attributable to oxymorphone ER abuse [Ref 9]. The outbreak drove establishment of Indiana's first statewide syringe service program.

---

## Subjective Effects

Published data on subjective effects in humans is available from controlled laboratory studies and clinical trials.

### Controlled Human Studies

Babalonis et al. (2016) conducted the most methodologically rigorous human subjective effects study: a within-subject, double-blind, placebo-controlled inpatient study (n=9 non-dependent opioid abusers) comparing oral oxymorphone (10, 20, 40 mg) vs. oxycodone (10, 20, 40 mg) [Ref 4]:

- Oxymorphone produced approximately **twofold less potent miosis** (pupil constriction) compared to oxycodone at identical doses — an unexpected finding given published equianalgesic claims [Ref 4]
- Oxymorphone produced **lesser magnitude respiratory depression** than oxycodone at identical doses [Ref 4]
- At **40 mg**, oxymorphone was similar to 40 mg oxycodone on **abuse-related subjective ratings** (drug liking, euphoria) [Ref 4]
- Formal relative potency analyses were largely invalid due to substantially greater effects of oxycodone at lower doses [Ref 4]
- Overall conclusion: "oxymorphone is less potent on most pharmacodynamic measures, although at higher doses, its abuse liability is similar to oxycodone" [Ref 4]

Schoedel et al. (2011) compared oxymorphone ER vs. oxycodone CR subjective effects in recreational opioid users, providing additional comparative data [Ref 15].

Johnstone et al. (1975) measured direct respiratory effects of IV oxymorphone (1.0 mg/70 kg) in 15 healthy volunteers: minute ventilation decreased from **24.9 ± 11.9 to 14.1 ± 4.9 L/min** (with PETCO₂ held at 50 torr). Cannabis (THC) coadministration additively decreased ventilation further to **6.6 ± 3.7 L/min** at 134 μg/kg THC. The CO₂-ventilation slope decreased from 2.23 to 0.88 L/min/torr [Ref 16].

### Effect Profile (Based on Literature)

**Body:** Pain suppression (primary therapeutic effect), sedation, respiratory depression, pupil constriction (miosis), nausea, constipation, pruritus (histamine release), dizziness, dry mouth. Miosis and respiratory depression are classic opioid effects directly mediated by MOR [Ref 4, Ref 16, Ref 17].

**Feeling:** Euphoria (abuse-relevant; dose-dependent), anxiety suppression [Ref 4, Ref 15].

**Cognition:** Sedation/cognitive impairment at therapeutic doses; compulsive redosing urge with repeated use [Ref 4].

**Duration:** IR onset 20–45 min, duration 4–6 hours; ER duration approximately 12 hours [Ref 27, Ref 32].

### Dose Data Assessment

**Seed data (DB values):** Threshold 2.5 mg, Light 5–10 mg, Common 10–20 mg, Strong 20–30 mg, Heavy 30+ mg (all oral).

**Evidence assessment:** The Babalonis et al. (2016) study tested doses of 10, 20, and 40 mg oral in non-dependent recreational users [Ref 4]. Phase III postsurgical pain trial (Gimbel 2004) used 10, 20, and 30 mg single doses with analgesia at all doses [Ref 33]. The systematic review (Mayyas et al. 2010) found 40–100 mg/day effective for chronic pain [Ref 26]. The seed dose ranges appear **reasonable for clinical use** but reflect therapeutic dosing; recreational/abuse doses commonly exceed these ranges. The thresholds are plausible. Flagged for editorial review given limited primary source verification of the lower thresholds (2.5 mg) in published studies.

---

## Safety & Toxicity

### Acute Toxicity

Oxymorphone has **high acute toxicity** with a narrow therapeutic index. Primary cause of death in overdose: **respiratory depression** → hypoxia → cardiac arrest [Ref 41].

**Postmortem blood concentrations in fatal cases:**
- Vorce et al. (2010): oxymorphone **0.13 mg/L** combined with alprazolam 0.04 mg/L (insufflation) [Ref 8]
- Shimomura et al. (2016): oxymorphone **0.106 mg/dL** combined with methylone 0.50 mg/dL and ethanol 130 mg/dL [Ref 7]

Note: Both fatalities involved polydrug combinations. No published human LD₅₀ data were identified in this search; animal LD₅₀ data were not retrieved.

### Thrombotic Microangiopathy (TMA) — Unique to IV Opana ER Abuse

A **distinctive and severe hematological complication** specific to IV abuse of the reformulated Opana ER formulation was documented beginning in 2012:

- **Clinical presentation:** Hemolytic anemia, thrombocytopenia, acute kidney injury (AKI), resembling thrombotic thrombocytopenic purpura (TTP) but with normal ADAMTS13 activity [Ref 22, Ref 23, Ref 25]
- **Mechanism:** Not oxymorphone itself — suspected to be **polyethylene oxide (PEO)**, a polymer excipient added in the 2012 crush-resistant reformulation [Ref 47]. Endothelial injury mechanism.
- **Kidney biopsy findings:** Severe arterial and arteriolar mucoid intimal edema, glomerular and tubular ischemia [Ref 22]
- **Outcome:** Typically requires hemodialysis; 2 of 3 index patients required plasma exchange; **poor renal recovery** [Ref 22]
- **Additional complications reported:** Bilateral exudative retinal detachments [Ref 43]
- **Management:** Cessation of Opana ER use; dialysis; plasma exchange; steroids
- **FDA response:** This TMA cluster contributed substantially to the 2017 market withdrawal request [Ref 34]

Bonnecaze et al. (2018) confirmed AKI is common with IV oxymorphone abuse and that delayed renal recovery correlates with increased KDIGO staging [Ref 24].

### Respiratory Depression

THC coadministration dramatically potentiates oxymorphone-induced respiratory depression in humans — CO₂-ventilation slope reduced from 2.23 to 0.88 L/min/torr [Ref 16]. This represents a significant interaction relevant to concurrent cannabis use.

### Organ Toxicity

- **Renal:** Severe AKI with TMA in IV formulation abuse [Ref 22, Ref 24]
- **Hepatic:** Extensive first-pass metabolism but no specific hepatotoxicity data identified in primary sources
- **Cardiac:** Opioid class effects; specific cardiotoxicity data not identified

### Chronic Toxicity

High chronic toxicity (as stated in seed data, confirmed as consistent with morphinan opioid class). No substance-specific chronic organ toxicity studies beyond dependence and withdrawal data were identified.

---

## Harm Reduction

### Key Risk Factors

1. **Injection abuse:** The Indiana HIV outbreak (181 HIV cases, 92.3% HCV co-infection) represents a catastrophic harm event directly attributable to injection of crushed Opana ER [Ref 9, Ref 11]. IV injection also causes TMA — a potentially fatal, unique complication of the ER formulation [Ref 22].

2. **Polydrug combinations:** All documented fatal cases involved combinations (opioid + benzodiazepine [Ref 8]; opioid + alcohol + stimulant [Ref 7]).

3. **Food and alcohol interactions:** High-fat food increases absorption ~38%; ethanol increases Cmax by 14–80% [Ref 6, Ref 42].

4. **Cannabis synergy:** THC additively worsens respiratory depression [Ref 16].

5. **Dose escalation:** The Opana ER formulation was specifically associated with extreme compulsive dose escalation in the Scott County context [Ref 9, Ref 12].

### Harm Reduction Recommendations (from literature)

- **Take on empty stomach:** At least 1 hour before or 2 hours after food [Ref 42]
- **Never crush, chew, or inject oral formulations** — formulation excipients (PEO) cause TMA when injected [Ref 22, Ref 47]
- **Avoid alcohol** — significant pharmacokinetic and pharmacodynamic interaction [Ref 6, Ref 16]
- **Naloxone availability:** Oxymorphone overdose is reversed by naloxone; access to naloxone should be promoted for any opioid use [Ref 41]
- **Syringe service programs:** Established in Indiana following the 2015 outbreak; harm reduction intervention shown to limit further HIV transmission [Ref 9]
- **Testing note:** Standard immunoassay opioid screens may not detect oxymorphone; LC-MS/MS or DART-MS confirmation needed [Ref 39]

### Contraindications (from FDA labeling [Ref 42])

- Respiratory depression (severe, unmonitored)
- Paralytic ileus
- Hypersensitivity to oxymorphone
- Acute or severe bronchial asthma in unmonitored settings
- Known or suspected GI obstruction

---

## Tolerance & Dependence

### Tolerance

Oxymorphone produces opioid-class tolerance: effects diminish with repeated exposure at the same dose, requiring dose escalation. The Mayyas et al. (2010) systematic review included studies of 2–12 weeks duration, documenting dose escalation requirements in chronic pain populations [Ref 26]. Animal studies show repeated oxymorphazone (a derivative) administration produces significant tolerance within 3 days [Ref — historical data from Pasternak 1984 literature].

**Cross-tolerance:** Cross-tolerance with other opioids is documented; this is a class effect mediated by MOR downregulation and desensitization [Ref 17].

### Dependence Liability

Oxymorphone has **high dependence liability** consistent with its potent MOR full agonism. The drug's abuse liability is supported by:

1. **Human laboratory data:** At 40 mg, oxymorphone produced abuse-related subjective ratings similar to oxycodone 40 mg [Ref 4]
2. **Surveillance data:** After OxyContin reformulation in 2010, oxymorphone ER showed a relative risk of abuse increase of **2.91** (95% CI 2.59–3.27) vs pre-ADF period [Ref 14]
3. **Epidemiological scale:** The Scott County HIV outbreak demonstrates extreme compulsive use patterns in a community context [Ref 9]

**Pharmacogenomics of dependence:** CYP2D6 poor metabolizers (who cannot convert oxycodone to oxymorphone) are underrepresented in oral opioid-dependent populations, suggesting the oxymorphone metabolite pathway contributes to oral opioid dependence liability [Ref 18].

### Withdrawal

Oxymorphone withdrawal follows the standard opioid withdrawal syndrome (anxiety, restlessness, sweating, piloerection, muscle aches, diarrhea, nausea, vomiting, insomnia, yawning). Gangahar (2015) documents that opioid withdrawal can be life-threatening in rare cases (rhabdomyolysis case report) [Ref 35], contradicting the common clinical view that opioid withdrawal is never dangerous.

No oxymorphone-specific withdrawal timeline studies were identified. Cross-tolerance with other opioids supports use of buprenorphine or methadone for managed withdrawal.

---

## Interactions

### Alcohol

**Classification: Lethal (seed data confirmed as plausible)**
- Pharmacokinetic: Ethanol 20–40% co-ingestion increases oxymorphone Cmax by 14–80% [Ref 6]
- Pharmacodynamic: Additive CNS and respiratory depression
- Clinical: Fatal cases involve oxymorphone + ethanol combinations [Ref 7]

### Cannabis (THC)

**Classification: Unknown (seed data) — evidence suggests significant risk**
- Johnstone et al. (1975) demonstrated additive respiratory depression in 15 healthy human volunteers [Ref 16]
- THC at escalating doses progressively worsened oxymorphone-induced respiratory depression
- CO₂-ventilation slope reduced from 2.23 to 0.88 L/min/torr
- **FLAG: This interaction is significantly undersold as "unknown" in the seed data. Published human data document additive respiratory depression.**

### Ketamine

**Classification: Lethal (seed data) — no specific oxymorphone data found**
- No oxymorphone+ketamine interaction studies identified. Classification is likely based on class-level inference (ketamine + opioid combinations). Flagged for review.

### GHB/GBL

**Classification: Lethal (seed data)**
- No oxymorphone-specific data identified. Consistent with general opioid + CNS depressant interaction profile. Supported by mechanism.

### Nitrous Oxide

**Classification: Unknown (seed data)**
- No data identified. Nitrous + opioid combinations used clinically (procedural sedation) but extreme caution warranted.

### PCP

**Classification: Unknown (seed data)**
- No oxymorphone-specific data identified.

### Tramadol

**Classification: Lethal (seed data)**
- No oxymorphone-specific data identified. Tramadol + opioid combinations carry serotonin syndrome and respiratory depression risk.

### CYP-Mediated Interactions

Oxymorphone does NOT inhibit or induce CYP2C9 or CYP3A4 [Ref 29, Ref 30]. This is a meaningful difference from most other opioids and reduces the risk of interactions via CYP-mediated DDIs. However, strong CYP3A4 inhibitors increase oxymorphone exposure when it forms as a metabolite of oxycodone [Ref 36].

### Monoamine Transporters / Serotonin

No significant interaction with NET, SERT, or DAT found in comprehensive screening [Ref 2]. Serotonin syndrome risk appears lower than with tramadol, tapentadol, or meperidine, but no specific data identified.

---

## Legal Status

| Jurisdiction | Classification | Notes |
|---|---|---|
| United States | Schedule II (DEA) | High abuse potential, accepted medical use. Prescription required. [Ref 44] |
| United Kingdom | Schedule 2, Class A (Misuse of Drugs Act 1971) | Most restrictive class for therapeutic controlled drugs. [Ref 45] |
| Australia | Schedule 8 (Controlled Drug) | ODC listing; restricted prescription requirements. [Ref 1 — web source] |
| Canada | CDSA Schedule I (Narcotic) | Listed in Controlled Drugs and Substances Act [Ref — web source] |
| International | UN Single Convention on Narcotic Drugs (1961) | Schedule I narcotic — implied by national scheduling |

**US market status:** Opana (brand) withdrawn from market July 2017 following FDA request [Ref 34]; NDA formally withdrawn December 2020 [Ref 46]. Generic extended-release formulations remain available.

**FLAG:** UK Class A status (implied by Schedule 2 placement alongside heroin and morphine) should be verified against current UK Home Office legislation. Canada Schedule I status should be verified against CDSA Schedule I listing.

---

## Clinical Trials

### Completed Phase III Trials (from ClinicalTrials.gov)

| NCT ID | Title | Phase | Condition | Sponsor | Status |
|---|---|---|---|---|---|
| NCT00226421 | Efficacy and Safety of Oxymorphone ER in Opioid-Experienced Patients With Chronic Non-Malignant Pain | Phase III | Chronic Pain | Endo Pharmaceuticals | Completed |
| NCT00904085 | Post-operative Efficacy and Safety Study | Phase III | Post-operative Pain | Endo Pharmaceuticals | Completed |
| NCT00904449 | Open Label Assessment of Long-Term Safety and Utility | Phase III | Pain | Endo Pharmaceuticals | Completed |
| NCT01210352 | Effectiveness, Safety, and Tolerability of Oxymorphone IR Oral Liquid in Post Surgical Pediatric Subjects | Phase III | Post-Operative Pain | Endo Pharmaceuticals | Completed |
| NCT04681027 | Safety, Tolerability, Effectiveness, and PK in Opioid-experienced Children | Phase III | Chronic Pain, Postsurgical Pain | Endo Pharmaceuticals | **Suspended** |
| NCT02687451 | Oxymorphone IR in Post Surgical Pediatric Subjects | Phase III | Post-Operative/Acute Pain | Endo Pharmaceuticals | **Terminated** |

### Key Published Trial Results

- **Gimbel & Ahdieh (2004)** [Ref 33]: Phase III postsurgical pain — oxymorphone IR 10, 20, 30 mg all superior to placebo for 8h, with significant relief by 45 min (20–30 mg doses).
- **Kivitz et al. (2006)** [Ref 31]: Phase III osteoarthritis — oxymorphone ER superior to placebo.
- **Matsumoto et al. (2005)** [Ref 37]: Phase III osteoarthritis — significant pain and functional improvement vs placebo.
- **Aqua et al. (2007)** [Ref 32]: Phase III abdominal postsurgical pain — oxymorphone IR effective and tolerable.
- **Mayyas et al. (2010)** [Ref 26]: Systematic review of 6 controlled studies (n=1,489): oxymorphone 40–100 mg/day superior to placebo; no significant differences from oxycodone at equipotent doses; limited cancer pain evidence.

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## Community Feedback Analysis

**No community feedback submitted.** The Part A2 section of the brief was empty. Standard research directives followed.

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## Gaps & Flags

### 🚨 Safety-Critical Flags

1. **KOR agonist designation is contradicted by primary literature.** Olson et al. (2019) [Ref 2] — the most comprehensive multi-target screening of clinical opioids — found oxymorphone to be the most MOR-selective compound tested with NO significant KOR activity. The seed data "Kappa-opioid receptor agonist" classification is likely a class-inference error. **Recommend removing KOR agonist from pharmacological class.**

2. **Cannabis interaction listed as "unknown" but human data exist.** Johnstone et al. (1975) [Ref 16] measured additive respiratory depression between IV oxymorphone and THC in 15 healthy volunteers. Cannabis interaction severity should be elevated beyond "unknown" — suggest "dangerous" with published human mechanistic evidence.

3. **Toxicity note reads "Inferred from pharmacological class."** This is partially resolved by literature — postmortem blood concentrations in two fatal cases [Ref 7, Ref 8] and TMA case series [Ref 22, Ref 24] confirm high acute toxicity. However, no published human LD₅₀ data were identified.

4. **Dose range verification:** The lower thresholds (2.5 mg threshold, 5–10 mg light) appear clinically plausible but the published Phase III studies tested minimum doses of 10 mg. The 2.5 mg threshold is not confirmed by published sources; it may reflect parenteral dosing equivalents or patient titration studies not retrieved. **Flag for editorial review.**

### Data Gaps

5. **SMILES string:** PubChem API did not return SMILES in the response. Should be retrieved manually from PubChem CID 5284604 compound page.

6. **Synthesis history:** The specific researcher(s) responsible for the 1914 synthesis have not been confirmed from primary sources. The Freund/Speyer attribution (commonly cited for oxycodone in 1916) does not clearly extend to oxymorphone. Requires consultation with chemical history primary sources.

7. **LD₅₀ data:** No published human or animal LD₅₀ specifically for oxymorphone was identified in this search. Animal toxicology data should be sought from pre-NDA studies or regulatory documents.

8. **Hepatic/renal dose adjustment:** No specific published PK studies in hepatic or renal impairment populations were retrieved. FDA label (Ref 42) likely contains dose adjustment guidance — editorial team should verify.

9. **UK Class A status:** Confirmed as Schedule 2 of Misuse of Drugs Act 1971, which includes heroin and morphine. UK drug classification as Class A should be verified against current Home Office legislation.

10. **Canada scheduling:** Identified in the Controlled Drugs and Substances Act but specific Schedule I listing not confirmed from primary source in this search.

11. **Withdrawal timeline:** No oxymorphone-specific withdrawal timeline (onset, peak, duration) studies identified. Class-level data from general opioid literature available.

12. **Equianalgesic ratio ambiguity:** Published equianalgesic tables suggest oxymorphone is ~3× more potent than morphine (oral) and ~10× parenterally. However, Babalonis et al. (2016) found oxymorphone substantially less potent than expected on direct physiological measures vs oxycodone [Ref 4]. This discrepancy is highlighted in the literature and merits mention in the article.

13. **Parenteral formulation (Numorphan):** Parenteral oxymorphone (used in clinical anesthesia and surgery) has different pharmacokinetics. The epidural study [Ref 38] provides historical dosing data (1 mg epidural). No modern parenteral PK studies were identified.

14. **Effect profile intensity/frequency values:** All 15 seed effect slugs lack intensity/frequency values. Published evidence supports the following directional assessments:
    - **Euphoria:** Moderate at therapeutic doses, high at abuse doses (Babalonis 2016 [Ref 4])
    - **Sedation:** Moderate-high; documented in multiple clinical trials
    - **Pain suppression:** High (primary therapeutic effect; shown in multiple Phase III RCTs)
    - **Respiratory depression:** Moderate-high at therapeutic doses; high at overdose
    - **Pupil constriction:** Moderate (notably less than oxycodone at identical doses, Babalonis 2016)
    - **Nausea, constipation:** Common class effects in all clinical trials
    - **Compulsive redosing urge:** High based on abuse liability data and Indiana outbreak evidence
    - Detailed intensity/frequency proposals require editorial review against Psychedex scoring rubric.