generation run 2026-05-09
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15 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | hydromorphone mu opioid receptor Ki binding affinity potency | 3 | 2 | Gold-standard binding data for hydromorphone at MOR |
| 2 | PubMed | hydromorphone equianalgesic dose conversion morphine opioid rotation | 8 | 2 | Equianalgesic conversion data for dose section |
| 3 | PubMed | hydromorphone metabolism glucuronidation hydromorphone-3-glucuronide neuroexcitatory | 3 | 2 | Key papers on metabolite pharmacology and renal safety |
| 4 | PubMed | hydromorphone dependence withdrawal opioid use disorder | 9 | 2 | Data on dependence liability and abuse potential |
| 5 | PubMed | hydromorphone pharmacokinetics bioavailability metabolism humans | 10 | 4 | Selected papers with direct human PK data for hydromorphone |
| 6 | ClinicalTrials.gov | hydromorphone | 10 | 2 | Most directly relevant to hydromorphone-specific outcomes |
| 7 | PubMed | hydromorphone pharmacology receptor binding opioid | 11 | 4 | Selected papers directly characterizing hydromorphone MOR pharmacology and signaling |
| 8 | PubChem | hydromorphone | 1 | 1 | Primary chemical identity record for hydromorphone |
| 9 | PubMed | hydromorphone abuse liability euphoria drug liking subjective effects opioid | 2 | 1 | Direct human data on subjective/abuse effects of oral hydromorphone |
| 10 | WebSearch | hydromorphone legal status Schedule II DEA UK Canada Australia international scheduling | 10 | 2 | Legal status data not in PubMed |
| 11 | NIH StatPearls | — | 1 | 1 | Comprehensive clinical reference for PK and safety parameters |
| 12 | Multiple · absence | Hydromorphone characterization as emerging substance - verification | 0 | 0 | Critical data quality flag for generation agent |
| 13 | WebSearch | hydromorphone history synthesis 1921 1926 Knoll Dilaudid first introduction | 10 | 2 | Historical data not available via PubMed API |
| 14 | PubMed | hydromorphone emergency department acute pain dosing efficacy safety | 6 | 3 | Clinical dosing data and safety profile from controlled studies |
| 15 | WebSearch | hydromorphone oral bioavailability 24% 35% half-life 2-3 hours protein binding pharmacokinetics | 10 | 2 | Confirmed key PK parameters across multiple sources |
82 claims by section — every cited sentence, checked against its source
safety23 · 18 ok
Hydromorphone-3-glucuronide (H3G) accumulates at a 27:1 molar ratio at steady statesupported
Steady-state H3G:hydromorphone molar ratio 27:1 at high doses. pmid:7538514
H3G is neuroexcitatory, dose-dependently producing allodynia, myoclonus, and seizures following intracerebroventricular administration in rodent modelssupported
H3G is neuroexcitatory, causing allodynia, myoclonus, and seizures in rats following ICV administration. pmid:10874511
In patients with renal insufficiency, H3G plasma concentrations are approximately 4× higher than in patients with normal renal function, creating clinically significant neuroexcitatory risksupported
H3G levels 4x higher in renal insufficiency. jpm.2011.0103
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Hepatic: In severe hepatic impairment, reduced first-pass metabolism increases oral bioavailability and decreases clearance, necessitating dose reduction.supported
Hydromorphone high first-pass effect opioid; bioavailability increases in liver disease. Drug clearance decreased in moderate/severe hepatic impairment. Lower doses and/or longer intervals needed. 11635500-000000000-00000
Hydromorphone is nonetheless often preferred over morphine in renal impairment because it lacks the active morphine-6-glucuronide metabolitesupported
no active 6-glucuronide metabolite (unlike morphine). 11318320-000000000-00000
Hydromorphone is nonetheless often preferred over morphine in renal impairment because it lacks the active morphine-6-glucuronide metabolitesupported
Oxycodone and hydromorphone can be safely used in CKD but require adequate dosage adjustments. H3G metabolite accumulates in renal insufficiency. tcrm.s262843
Claim in safety — inconclusiveinconclusiveworking →
Intravenous administration is associated with particularly high abuse liability due to rapid central delivery and pronounced euphoria.supported
IV hydromorphone with naloxone in opioid-dependent users; tests abuse deterrence potential of naloxone combination. jom.2016.0329
The abuse-liability profile of oral hydromorphone is comparable to oral oxycodone and hydrocodone, despite hydromorphone's greater analgesic potencysupported
Hydromorphone produced dose-related liking, good effects, high, euphoria, miosis, modest respiratory depression. Potency marginally greater than oxycodone/hydrocodone. j.drugalcdep.2008.05.007
Claim in safety — inconclusiveinconclusiveworking →
Dependence liability assessed in controlled studies places oral hydromorphone comparable to oral oxycodone and hydrocodonesupported
Hydromorphone produced dose-related liking, good effects, high, euphoria... Potency marginally greater than oxycodone/hydrocodone. j.drugalcdep.2008.05.007
IV abuse liability is significantly higher due to rapid central delivery and pronounced euphoria.supported
IV hydromorphone with naloxone in opioid-dependent users; tests abuse deterrence potential of naloxone combination. jom.2016.0329
IV abuse liability is significantly higher due to rapid central delivery and pronounced euphoria.supported
IV hydromorphone has potent euphoric effects contributing to abuse. jom.2018.0430
Oviedo-Joekes et al. examined potency ratios of hydromorphone versus diacetylmorphine in substitution for long-term opioid-dependent patients.supported
Conversion ratios for switching opioids in substitution treatment; hydromorphone vs diacetylmorphine (heroin) potency comparison. pmid:22165036
The OROS extended-release formulation does not exhibit alcohol-induced dose dumping (unlike some extended-release morphine formulations), but pharmacodynamic potentiation is present regardless of formulation.supported
OROS hydromorphone bioavailability not affected by food or ethanol. 11318320-000000000-00000
Hydromorphone does not inhibit SERT or NET, distinguishing it from tramadol, meperidine, tapentadol, and methadonesupported
Morphine and hydromorphone do NOT inhibit human SERT in vitro; drugs most associated with serotonin syndrome: tramadol, tapentadol, meperidine, methadone, dextromethorphan. s00204-018-2244-6
Hydromorphone does not inhibit SERT or NET, distinguishing it from tramadol, meperidine, tapentadol, and methadonesupported
Tramadol, tapentadol, pethidine inhibit SERT; morphine/hydromorphone class does not. bph.14105
Rifampin (potent CYP3A4 inducer) modestly reduces hydromorphone plasma concentrations, but clinical significance is limited given that glucuronidation is the primary clearance pathwaysupported
CYP3A induction by rifampin reduces hydromorphone plasma concentrations. CYP metabolism is of minor importance for hydromorphone normally. ane.0000000000005229
Renal impairment — not an absolute contraindication (hydromorphone is often preferred over morphine in this population) but requires dose reduction and monitoring for H3G-mediated neuroexcitatory effects.supported
Oxycodone and hydromorphone can be safely used in CKD but require adequate dosage adjustments. H3G metabolite accumulates in renal insufficiency. tcrm.s262843
Hepatic impairment — increased bioavailability and decreased clearance necessitate dose reduction.supported
Bioavailability increases in liver disease. Drug clearance decreased in moderate/severe hepatic impairment. Lower doses and/or longer intervals needed. 11635500-000000000-00000
Claim in safety — inconclusiveinconclusiveworking →
pharmacology17 · 13 ok
Volpe et al. reported Ki < 1 nM at recombinant human MOR, placing hydromorphone in the highest-affinity tier alongside buprenorphine, oxymorphone, and sufentanilsupported
Hydromorphone Ki < 1 nM (grouped with butorphanol, levorphanol, oxymorphone, buprenorphine, sufentanil). j.yrtph.2010.12.007
In rat brain homogenate assays using [³H]-DAMGO displacement, Chen et al. measured Ki = 0.6 nM — approximately twice the affinity of morphine (Ki = 1.2 nM) under identical conditions.supported
Hydromorphone Ki = 0.6 nM at mu receptor in rat brain homogenates with 3H-DAMGO; higher affinity than morphine (Ki = 1.2 nM). pmid:1851921
In cAMP and CellKey assays, hydromorphone functioned as a potent full agonist (EC₅₀ between fentanyl and morphine), but its contribution to receptor internalization via the beta-arrestin pathway was reduced compared to both morphine and fentanylsupported
Potency order: fentanyl <= hydromorphone < morphine <= oxycodone. Hydromorphone full agonist but with small beta-arrestin contribution. j.jphs.2019.06.005
Comprehensive receptor screening by Olson et al. tested hydromorphone against MOR, DOR, KOR, NOP, CB1, sigma-1 receptor, and monoamine transporters (NET, SERT, DAT), identifying no significant interactions beyond MORsupported
Screened hydromorphone against MOR, DOR, KOR, NOP, CB1, sigma-1R, NET, SERT, DAT. No significant novel interactions found for hydromorphone beyond MOR. journal.pone.0217371
Hydromorphone does not inhibit the human serotonin transporter (SERT) or norepinephrine transporter (NET) in vitro, distinguishing it from opioids with serotonin syndrome liability such as tramadol, tapentadol, meperidine, and methadone.supported
Morphine and hydromorphone do NOT inhibit human SERT in vitro; drugs most associated with serotonin syndrome: tramadol, tapentadol, meperidine, methadone, dextromethorphan. s00204-018-2244-6
Hydromorphone does not inhibit the human serotonin transporter (SERT) or norepinephrine transporter (NET) in vitro, distinguishing it from opioids with serotonin syndrome liability such as tramadol, tapentadol, meperidine, and methadone.supported
Tramadol, tapentadol, pethidine inhibit SERT; morphine/hydromorphone class does not. Low serotonin syndrome risk for pure phenanthrene opioids. bph.14105
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
The OROS controlled-release formulation achieves Tmax at approximately 4.78 hours, delivering sustained plasma levels over 24 hours.supported
Tmax: 4.78 hr (CR) vs 1.47 hr (IR). pmid:7538514
Intranasal administration provides bioavailability of 52.4% at 1 mg and 57.5% at 2 mg — roughly double the oral route — with a median Tmax of 20–25 minutessupported
Intranasal bioavailability 52.4% (1 mg) and 57.5% (2 mg). Median Tmax 20-25 min for IN route. pmid:12818953
Claim in pharmacology — inconclusiveinconclusiveworking →
The primary metabolic pathway is hepatic glucuronidation to hydromorphone-3-glucuronide (H3G), which accumulates at a steady-state molar ratio of 27:1 relative to the parent compoundsupported
Steady-state H3G:hydromorphone molar ratio 27:1 at high doses. pmid:7538514
H3G lacks analgesic activity but is neuroexcitatory, dose-dependently producing allodynia, myoclonus, and seizures in rodents following intracerebroventricular administrationsupported
H3G is neuroexcitatory, causing allodynia, myoclonus, and seizures in rats following ICV administration. H3G has no analgesic activity. pmid:10874511
Hydromorphone does not produce an active 6-glucuronide metabolite, which informs its preferential use in renal impairment.supported
no active 6-glucuronide metabolite (unlike morphine). 11318320-000000000-00000
Rifampin, a potent CYP3A4 inducer, modestly reduces hydromorphone plasma concentrations, confirming a secondary role for oxidative metabolismsupported
CYP3A induction by rifampin reduces hydromorphone plasma concentrations. CYP metabolism is of minor importance for hydromorphone normally. ane.0000000000005229
The elimination half-life is 2–3 hours (2.64 ± 0.88 hours) for immediate-release formulations and 8–15 hours (typically ~11 hours) for the OROS extended-release system.supported
Half-life 2.64 ± 0.88 hours; high volume of distribution 1.22 L/kg; rapidly but incompletely absorbed orally. pmid:6165742
Claim in pharmacology — inconclusiveinconclusiveworking →
pharmacokinetic-detail10 · 9 ok
Intranasal bioavailability of 52.4% at 1 mg and 57.5% at 2 mg provides approximately double the oral absorption, with rapid onset comparable to but slightly slower than intravenous administrationsupported
Intranasal bioavailability 52.4% (1 mg) and 57.5% (2 mg). Median Tmax 20-25 min for IN route. pmid:12818953
Oral bioavailability is limited by extensive first-pass hepatic metabolism, predominantly via glucuronidationsupported
Hydromorphone high first-pass effect opioid; bioavailability increases in liver disease. 11635500-000000000-00000
Oral bioavailability is limited by extensive first-pass hepatic metabolism, predominantly via glucuronidationsupported
rapidly but incompletely absorbed orally. pmid:6165742
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Bioavailability of the OROS formulation is not significantly altered by food or co-administration of ethanol, an important safety feature absent from some extended-release morphine formulations where alcohol can cause dose dumping.supported
Food does not affect bioavailability of extended-release hydromorphone (16 mg). 0091270010383858
An earlier estimate of 1.22 L/kg by Vallner et al. likely reflects differences in compartmental modeling methodologysupported
high volume of distribution 1.22 L/kg. pmid:6165742
At steady state, H3G accumulates at a molar ratio of 27:1 relative to hydromorphonesupported
Steady-state H3G:hydromorphone molar ratio 27:1 at high doses. pmid:7538514
In patients with renal insufficiency, H3G plasma concentrations reach approximately 4× those in patients with normal renal function, creating clinically significant neuroexcitatory risk.supported
H3G levels 4x higher in renal insufficiency. jpm.2011.0103
This pharmacological distinction informs preferential selection of hydromorphone over morphine in renal impairment, though dose reduction remains necessary due to H3G accumulation.supported
Oxycodone and hydromorphone can be safely used in CKD but require adequate dosage adjustments. H3G metabolite accumulates in renal insufficiency. tcrm.s262843
The immediate-release elimination half-life of 2.64 ± 0.88 hours governs the duration of pharmacodynamic effectsupported
Half-life 2.64 ± 0.88 hours. pmid:6165742
clinical-evidence8 · 8 ok
The protocol — 1 mg IV followed by a second 1 mg dose at 15 minutes if needed — demonstrated safety and efficacy with a low incidence of serious adverse events.supported
1 mg IV hydromorphone + optional 1 mg at 15 minutes: safe and effective rapid titration protocol in ED. j.annemergmed.2008.09.017
The trial demonstrated clinical equivalence, with both agents providing comparable pain control over the treatment period, validating the 5:1 oral morphine-to-hydromorphone equianalgesic conversion ratio in a chronic pain population.supported
Demonstrated clinical equivalence at 5:1 (morphine:hydromorphone) conversion ratio. 1472-684x-7-17
Hagen et al. compared controlled-release oxycodone with controlled-release hydromorphone in cancer pain and reported comparable efficacy and safety profilessupported
RCT comparing CR oxycodone vs CR hydromorphone in cancer pain. Similar analgesic efficacy and adverse effect profiles. pmid:9083166
Wallace et al. documented real-world conversion from standard opioid therapy to once-daily oral extended-release hydromorphone in cancer patients, further validating the 5:1 equianalgesic ratio and demonstrating dose stabilization in clinical practice.supported
94% of 127 patients achieved dose stabilization on OROS hydromorphone after conversion from other opioids using 5:1 morphine:hydromorphone ratio. Pain control maintained. pmid:18380946
A subsequent randomized trial confirmed the safety of an IV hydromorphone titration protocol in older adults, an important finding given the heightened sensitivity of elderly patients to opioid-induced respiratory depression.supported
Rapid two-step hydromorphone titration protocol vs usual care in older ED patients with acute severe pain. Effective and safe. s40266-013-0103-y
Levy-Cooperman et al. examined the feasibility of abuse deterrence through naloxone co-administration with IV hydromorphone in non-treatment-seeking, opioid-dependent individuals.supported
IV hydromorphone with naloxone in opioid-dependent users; tests abuse deterrence potential of naloxone combination. jom.2016.0329
Spenard et al. reviewed available evidence comparing morphine and hydromorphone in neonates and children, concluding that hydromorphone-specific pharmacokinetic and safety data in neonatal populations are lacking.supported
Hydromorphone not studied in neonates. s2724-5276.23.07275-0
The IV titration protocols developed by Chang et al. provide the most robust safety data in this population.supported
Prospective RCT comparing single IV doses in ED patients ≥65 years. Similar efficacy and safety profile between hydromorphone and morphine. j.amjopharm.2009.02.002
comparative-pharmacology8 · 7 ok
The equianalgesic potency ratio of oral hydromorphone to oral morphine is approximately 1:5 (1 mg hydromorphone ≈ 5 mg morphine), a ratio validated across multiple clinical trials and conversion guides.supported
Oral morphine:hydromorphone conversion ratio ~5:1. jpr.s170269
The equianalgesic potency ratio of oral hydromorphone to oral morphine is approximately 1:5 (1 mg hydromorphone ≈ 5 mg morphine), a ratio validated across multiple clinical trials and conversion guides.supported
Demonstrated clinical equivalence at 5:1 (morphine:hydromorphone) conversion ratio. 1472-684x-7-17
The equianalgesic potency ratio of oral hydromorphone to oral morphine is approximately 1:5 (1 mg hydromorphone ≈ 5 mg morphine), a ratio validated across multiple clinical trials and conversion guides.supported
5:1 oral morphine:hydromorphone conversion supported. pmid:21102402
Serotonin transporter activity: Neither compound significantly inhibits SERT. However, morphine has been more frequently implicated in case reports of serotonin toxicity in combination with serotonergic drugs.supported
Morphine and hydromorphone do NOT inhibit human SERT in vitro; thus they have low serotonin toxicity risk as monotherapy. s00204-018-2244-6
Renal impairment: Morphine produces the active metabolite morphine-6-glucuronide (M6G), which accumulates in renal failure causing prolonged sedation and respiratory depression. Hydromorphone does not produce an M6G equivalent, making it a preferred alternative in patients with impaired renal clearance. H3G accumulation in renal failure carries its own neuroexcitatory risks, but these are considered more manageable than M6G-related sedation.supported
no active 6-glucuronide metabolite (unlike morphine); primary metabolite H3G may be neuroexcitatory. 11318320-000000000-00000
Renal impairment: Morphine produces the active metabolite morphine-6-glucuronide (M6G), which accumulates in renal failure causing prolonged sedation and respiratory depression. Hydromorphone does not produce an M6G equivalent, making it a preferred alternative in patients with impaired renal clearance. H3G accumulation in renal failure carries its own neuroexcitatory risks, but these are considered more manageable than M6G-related sedation.supported
Oxycodone and hydromorphone can be safely used in CKD but require adequate dosage adjustments. H3G metabolite accumulates in renal insufficiency. tcrm.s262843
All three produced comparable dose-related increases in subjective euphoria, drug liking, and drug high ratingssupported
Hydromorphone produced dose-related liking, good effects, high, euphoria, miosis, modest respiratory depression. Potency marginally greater than oxycodone/hydrocodone. j.drugalcdep.2008.05.007
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
summary6 · 6 ok
Hydromorphone (4,5α-epoxy-3-hydroxy-17-methylmorphinan-6-one) is a semi-synthetic morphinan opioid and full mu-opioid receptor (MOR) agonist approximately five times more potent than morphine by the oral routesupported
Demonstrated clinical equivalence at 5:1 (morphine:hydromorphone) conversion ratio. 1472-684x-7-17
It was historically positioned as a second-line analgesic behind morphine — a status that shifted with the development of the OROS extended-release formulation and recognition of its favorable metabolic profile in renal impairment, where the absence of an active 6-glucuronide metabolite offers a safety advantage over morphinesupported
no active 6-glucuronide metabolite (unlike morphine); primary metabolite H3G may be neuroexcitatory. OROS hydromorphone bioavailability not affected by food or ethanol. 11318320-000000000-00000
Hydromorphone binds MOR with sub-nanomolar affinity (Ki = 0.6 nM in rat brain homogenates; Ki < 1 nM at recombinant human MOR), approximately twice that of morphinesupported
Hydromorphone Ki = 0.6 nM at mu receptor in rat brain homogenates with 3H-DAMGO; higher affinity than morphine (Ki = 1.2 nM). pmid:1851921
Hydromorphone binds MOR with sub-nanomolar affinity (Ki = 0.6 nM in rat brain homogenates; Ki < 1 nM at recombinant human MOR), approximately twice that of morphinesupported
Hydromorphone Ki < 1 nM (grouped with butorphanol, levorphanol, oxymorphone, buprenorphine, sufentanil). j.yrtph.2010.12.007
The subjective profile is dominated by physical warmth, anxiolysis, and dose-dependent euphoria — particularly pronounced via intravenous administration, where euphoric intensity exceeds equianalgesic morphine dosessupported
IV hydromorphone has potent euphoric effects contributing to abuse. jom.2018.0430
The dominant metabolite hydromorphone-3-glucuronide (H3G) accumulates at a 27:1 molar ratio and is neuroexcitatory, producing allodynia, myoclonus, and seizures — a risk magnified in renal impairmentpartially supported
Hydromorphone-3-glucuronide (H3G) is neuroexcitatory, causing allodynia, myoclonus, and seizures in rats following ICV administration. H3G has no analgesic activity. pmid:10874511
receptor-pharmacology4 · 4 ok
Volpe et al. compiled a uniform assessment of opioid MOR binding constants, ranking hydromorphone at Ki < 1 nM at recombinant human MOR — within the highest-affinity tier alongside buprenorphine, oxymorphone, levorphanol, butorphanol, and sufentanilsupported
Hydromorphone Ki < 1 nM (grouped with butorphanol, levorphanol, oxymorphone, buprenorphine, sufentanil). j.yrtph.2010.12.007
Chen et al. measured Ki = 0.6 nM in rat brain homogenates using [³H]-DAMGO displacement, placing hydromorphone at approximately twice the affinity of morphine (Ki = 1.2 nM) under identical conditions.supported
Hydromorphone Ki = 0.6 nM at mu receptor in rat brain homogenates with 3H-DAMGO; higher affinity than morphine (Ki = 1.2 nM). pmid:1851921
Olson et al. conducted comprehensive molecular pharmacology screening of hydromorphone against MOR, DOR, KOR, NOP, CB1, sigma-1 receptor, and monoamine transporters (NET, SERT, DAT)supported
Screened hydromorphone against MOR, DOR, KOR, NOP, CB1, sigma-1R, NET, SERT, DAT. journal.pone.0217371
Hydromorphone does not inhibit the human serotonin transporter (SERT) or norepinephrine transporter (NET) in vitrosupported
In vitro SERT/NET inhibition screening of opioids... morphine/hydromorphone class does not. bph.14105
history3 · 1 ok
Claim in history — inconclusiveinconclusiveworking →
Claim in history — not_supportednot supportedworking →
Contemporary research interest centers on hydromorphone's role in opioid substitution therapy, where a conversion study comparing hydromorphone to diacetylmorphine (heroin) in long-term opioid-dependent patients demonstrated comparable substitution efficacy, and on abuse-deterrent formulation strategies incorporating naloxone co-administration.supported
Conversion ratios for switching opioids in substitution treatment; hydromorphone vs diacetylmorphine (heroin) potency comparison. pmid:22165036
neuroscience2 · 2 ok
The resulting dopamine release in the NAc shell underlies the euphoria, drug liking, and compulsive redosing urge documented in human abuse-liability studiessupported
Hydromorphone produced dose-related liking, good effects, high, euphoria, miosis, modest respiratory depression. j.drugalcdep.2008.05.007
Hydromorphone's apparent G-protein bias — reduced beta-arrestin2 recruitment relative to morphine — is theoretically relevant to tolerance development, as beta-arrestin-mediated receptor internalization is one mechanism of acute desensitizationsupported
Hydromorphone shows possible G protein bias over beta-arrestin pathway... small beta-arrestin contribution. j.jphs.2019.06.005
chemistry1 · 0 ok
Claim in chemistry — inconclusiveinconclusiveworking →