generation run 2026-04-20
59 min completedmodel pipeline-v5plan not recordedrun/8a24d3f4…Selection
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20 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | fentanyl pharmacokinetics bioavailability half-life metabolism CYP3A4 | 4 | 1 | Most comprehensive PK review; directly relevant to ROA bioavailability data |
| 2 | PubMed | fentanyl respiratory depression overdose opioid-induced | 10 | 5 | Mechanistic OIRD papers and harm reduction reversal data |
| 3 | OpenAlex | fentanyl synthesis history Paul Janssen 1960 | 8 | 2 | Stanley 1992 is primary historical reference; Zawilska 2017 covers analog landscape |
| 4 | PubMed | fentanyl pharmacology mu-opioid receptor binding affinity mechanism | 10 | 5 | Core MOR pharmacology papers; efficacy ranking and binding mode data |
| 5 | PubMed | fentanyl tolerance GRK3 beta-arrestin mu-opioid receptor desensitization | 1 | 1 | Confirms GRK3-mediated desensitization mechanism in brief |
| 6 | PubChem | fentanyl | 1 | 1 | Primary chemical identity verification |
| 7 | ClinicalTrials.gov | fentanyl opioid use disorder addiction treatment | 8 | 3 | Relevant to fentanyl OUD treatment landscape |
| 8 | PubMed | PMID 31492824 | 1 | 1 | Important mechanism paper for why naloxone may fail in fentanyl WCS; distinct from morphine overdose |
| 9 | PubMed | fentanyl naloxone interaction reversal pharmacology | 5 | 3 | Drug interaction data for naloxone reversal and gabapentinoid potentiation |
| 10 | PubMed | PMID 1517629 Stanley 1992 history fentanyl | 1 | 1 | Confirms 1960 synthesis date and clinical introduction history |
| 11 | PubMed | fentanyl intranasal pharmacokinetics bioavailability Tmax nasal transmucosal | 4 | 1 | Direct PK data for intranasal route; confirms high bioavailability bypassing first-pass |
| 12 | PubMed | fentanyl transdermal patch pharmacokinetics Duragesic | 8 | 3 | Transdermal PK data; confirms long tmax for transdermal |
| 13 | PubMed | fentanyl cancer breakthrough pain palliative care clinical trial | 6 | 2 | Clinical evidence for fentanyl BTcP use |
| 14 | OpenAlex | fentanyl illicitly manufactured synthetic opioid overdose death United States epidemic | 8 | 4 | Key epidemiological data on fentanyl-driven overdose deaths |
| 15 | WebSearch | fentanyl Schedule II DEA UK Class A drug international scheduling UN Convention | 10 | 2 | Primary legal status data for US and international |
| 16 | WebSearch | fentanyl UK Misuse of Drugs Act Class A drug Australia Schedule 8 | 10 | 2 | Legal status for major non-US jurisdictions |
| 17 | PubMed | fentanyl pharmacokinetics intravenous clearance volume distribution half-life | 5 | 3 | Foundational IV PK data and major drug interaction data |
| 18 | EUDA | fentanyl drug profile | 1 | 3 | Key EU legal/clinical data not available in API databases |
| 19 | IUPHAR Guide to Pharmacology | fentanyl ligand 1626 | 1 | 3 | Standardized receptor binding affinity data from authoritative pharmacology database |
| 20 | PubMed | fentanyl subjective effects double-blind human abuse potential | 1 | 1 | Only controlled human subjective effects study found for fentanyl |
82 claims by section — every cited sentence, checked against its source
safety30 · 25 ok
Ritonavir reduces fentanyl clearance and prolongs half-lifesupported
Ritonavir (potent CYP3A4 inhibitor) reduces fentanyl clearance and prolongs its half-life. pmid:10485779
The primary mechanism of fentanyl fatality is opioid-induced respiratory depression (OIRD) — suppression of brainstem respiratory drive through MOR agonism at the preBötzinger complex and retrotrapezoid nucleus.supported
PreBotzinger complex less sensitive to MOR agonism after ROU. ajplung.00302.2024
The primary mechanism of fentanyl fatality is opioid-induced respiratory depression (OIRD) — suppression of brainstem respiratory drive through MOR agonism at the preBötzinger complex and retrotrapezoid nucleus.supported
RTN neurons retain ability to drive ventilation during OIRD; optogenetic stimulation after fentanyl caused greater increase in breathing than pre-fentanyl. ajplung.00025.2025
Wooden chest syndrome (WCS) is fentanyl-induced skeletal muscle rigidity causing ventilatory failuresupported
Wooden chest syndrome (WCS) describes fentanyl-induced skeletal muscle rigidity causing ventilatory failure in a 61-year-old female. 23247096211034036
Wooden chest syndrome (WCS) is fentanyl-induced skeletal muscle rigidity causing ventilatory failuresupported
A large percentage of opioid overdose fatalities involve fentanyl; review of WCS pharmacology and atypical overdose features. jcpt.13484
Torralva and Janowsky propose that WCS involves α-adrenergic and cholinergic receptor-mediated mechanical failure distinct from standard MOR-mediated respiratory rate suppression, which would explain why naloxone alone may be insufficient to reverse WCS-related respiratory compromise.supported
Reviews alpha-adrenergic and cholinergic receptor-mediated mechanical failure with wooden chest syndrome (WCS). Proposes that naloxone is ineffective against centrally mediated noradrenergic/cholinergic effects of fentanyl manifesting as WCS. jpet.119.258566
Claim in safety — inconclusiveinconclusiveworking →
Multiple or large IV doses cause accumulation in peripheral compartments (muscle, adipose tissue), with subsequent redistribution producing secondary plasma peaks and prolonged respiratory depressionsupported
Redistribution-limited duration of action. Multiple/large doses lead to delayed recovery and prolonged respiratory depression. pmid:6226471
Claim in safety — inconclusiveinconclusiveworking →
Xylazine (α₂-adrenergic agonist), increasingly found as an adulterant in illicit fentanyl supplies, produces additive cardiorespiratory depressionsupported
Fentanyl and xylazine exhibit additive cardiorespiratory depression. j.jpet.2025.103711
Claim in safety — inconclusiveinconclusiveworking →
Synthetic opioid-involved death rates in the United States increased 1,040% from 2013 to 2019supported
Synthetic opioid-involved death rate increased 1,040% from 2013 to 2019 (3,105 to 36,359 deaths). mmwr.mm7006a4
In 2017, 47,600 of 70,237 drug overdose deaths (67.8%) involved an opioid, driven primarily by illicitly manufactured fentanylsupported
Among 70,237 drug overdose deaths in 2017, 47,600 (67.8%) involved an opioid. Since 2013, driven largely by illicitly manufactured fentanyl. mmwr.mm675152e1
Fentanyl contamination of non-opioid drug supplies, including methamphetamine and cocaine, expands the at-risk population beyond intentional opioid users.supported
Community drug checking services detected widespread fentanyl contamination in stimulant supplies, raising specter of fentanyl adulterant deaths among stimulant users. j.drugalcdep.2023.110985
Claim in safety — inconclusiveinconclusiveworking →
Tolerance to fentanyl develops through GRK3-mediated phosphorylation of MOR, β-arrestin 2 recruitment, and receptor desensitization/internalizationsupported
GRK2, GRK3, GRK6 and beta-arrestin 2 involved in short- and long-term adaptive changes in MOR activity during opioid tolerance. pmid:11299311
Compensatory adenylyl cyclase upregulation (cAMP overshoot) establishes a new homeostatic set point that constitutes the cellular basis of physical dependence.supported
Chronic morphine promotes adenylyl cyclase superactivation, NMDAR alterations, GR and c-fos upregulation. MOR endocytosis prevents these tolerance/dependence biomarkers. fj.09-133223
Fentanyl-treated mice show more rapid tolerance development to anti-hyperalgesic effects compared to morphine-treated mice, associated with increased phosphorylated MOR and reduced Rab4-dependent resensitizationsupported
Fentanyl-treated mice showed more rapid disappearance of anti-hyperalgesic effect than morphine, associated with increased phosphorylated MOR and reduced Rab4-dependent resensitization. pmid:17240843
The claim that tolerance to analgesia develops faster than tolerance to respiratory depression is mechanistically supported by differential receptor reserve theory and incomplete animal data, but has not been confirmed in a controlled human study.supported
Divergent responses: some mice adaptive, some not. PreBotzinger complex less sensitive to MOR agonism after ROU. ajplung.00302.2024
Escalation of IV fentanyl self-administration and withdrawal behavior have been confirmed in mouse models.supported
Escalation of IV fentanyl self-administration in mice and assessment of withdrawal behavior. s00213-024-06739-x
Gabapentinoids: Gabapentin and pregabalin increase fentanyl potency and decrease naloxone's potency to antagonize fentanyl in ratssupported
Gabapentin and pregabalin shift fentanyl discrimination dose-effect curves leftward and decrease naloxone potency to antagonize fentanyl. jpet.124.002323
CYP3A4 inhibitors: Ketoconazole increases fentanyl AUC by 33%supported
CYP3A inhibition by ketoconazole increased fentanyl AUC to 133% and reduced clearance to 78%. jcph.469
Xylazine: Additive cardiorespiratory depression; naloxone insufficient for reversal of the xylazine component.supported
Fentanyl and xylazine exhibit additive cardiorespiratory depression. Naloxone reversed fentanyl but was slower and less effective against mixtures. j.jpet.2025.103711
Naloxone reversal modifiers: Fentanyl overdoses likely require higher naloxone doses than heroin overdosessupported
Fentanyl overdoses likely require higher naloxone doses than heroin overdoses. s40262-024-01355-6
Claim in safety — inconclusiveinconclusiveworking →
Nalmefene 1.5 mg IM achieved faster onset and longer duration of OIRD reversal compared to naloxone 4 mg IN.supported
Nalmefene 1.5 mg IM achieved faster onset, higher magnitude, and longer duration of OIRD reversal compared to naloxone 4 mg IN. jcph.70088
Buprenorphine 3.0 mg/kg reversed fentanyl-induced respiratory depression within 3.5 minutes in rats, comparable to naloxone, supporting investigation of buprenorphine as an alternative reversal agent.supported
Both naloxone 0.1 mg/kg and buprenorphine 3.0 mg/kg reversed fentanyl-induced respiratory depression within 3.5 minutes. j.jpet.2025.103768
Hepatic impairment alters fentanyl pharmacokinetics: as a high-extraction drug, reduced hepatic blood flow (cirrhosis, congestive heart failure) decreases clearance and prolongs exposuresupported
Fentanyl is a high-extraction drug (CYP3A4 substrate) and thus theoretically less vulnerable to drug interactions than low-extraction alfentanil. pmid:12657846
Gabapentinoid co-use warrants specific caution given the dual mechanism of enhanced fentanyl potency and impaired naloxone reversal.supported
Gabapentin and pregabalin shift fentanyl discrimination dose-effect curves leftward and decrease naloxone potency to antagonize fentanyl. Increases opioid overdose risk. jpet.124.002323
Elderly patients (terminal elimination half-life up to 15 hours) and those with renal impairment require dose adjustment due to altered distribution and clearance.partially supported
terminal t1/2 1.5-6h (up to 15h in elderly). pmid:6226471
pharmacology13 · 12 ok
Despite modest KOR affinity, fentanyl demonstrated the highest intrinsic activity among tested opioids at mouse KOR in HEK293 cells.supported
Fentanyl identified as the kappa agonist with the highest intrinsic activity in the set studied. pmid:16433932
Molecular simulation reveals that fentanyl engages MOR through two distinct binding modessupported
Fentanyl can form salt-bridge and secondary hydrogen bond with His297 on mOR; secondary binding mode only accessible when His297 adopts neutral HID tautomer. s41467-021-21262-9
This deep insertion involves enhanced hydrophobic contacts with transmembrane helix 6 (TM6) and produces a receptor residence time of approximately τ ≈ 38 secondssupported
Calculated fentanyl-mOR residence time tau ~38 s with deep binding mode; piperidine-Hid297 hydrogen bond strengthens hydrophobic contacts with TM6. jacsau.1c00341
A negative allosteric modulator (NAM) site on MOR's extracellular vestibule enhances naloxone affinity and cooperatively inhibits fentanyl-induced signaling, providing structural rationale for next-generation reversal strategies.supported
Discovery of a MOR negative allosteric modulator that enhances naloxone affinity; addresses fentanyl-driven overdose epidemic via NAM approach. s41586-024-07587-7
In GTPγS binding assays, Emmerson et al. established the ranking: etonitazene = sufentanil = DAMGO = fentanyl > morphine in C6 glioma cells expressing rat MORsupported
Rank order: etonitazene = sufentanil = DAMGO = PLO17 = fentanyl > morphine. Fentanyl is a full efficacy MOR agonist. pmid:8819494
Selley et al. confirmed DAMGO as most efficacious, with fentanyl = morphine >> buprenorphine in rat thalamus and SK-N-SH cells.supported
DAMGO most efficacious followed by fentanyl = morphine >> buprenorphine in rat thalamus and SK-N-SH cells. pmid:9016350
Fentanyl's high lipophilicity (logP 4.05; octanol:water >700) enables rapid CNS penetrationsupported
High lipophilicity (octanol:water partition coefficient >700); blood-brain transfer half-life 4.7-6.6 min. s40262-012-0016-7
The blood-brain plasma transfer half-life is 4.7–6.6 minutes, accounting for the rapid onset of both analgesia and respiratory depression following parenteral administration.supported
blood-brain transfer half-life 4.7-6.6 min. s40262-012-0016-7
Fentanyl undergoes hepatic N-dealkylation by CYP3A4 to the inactive metabolite norfentanyl as the primary metabolic pathwaysupported
Fentanyl N-dealkylated by CYP3A4 to inactive norfentanyl. j.pedneo.2014.06.002
Fentanyl is classified as a high-extraction hepatic drug, meaning clearance is more sensitive to changes in hepatic blood flow than to changes in enzyme activitysupported
Fentanyl is a high-extraction drug (CYP3A4 substrate) and thus theoretically less vulnerable to drug interactions than low-extraction alfentanil. pmid:12657846
Geist et al. reported that CYP3A activity showed only a weak correlation with fentanyl clearance in palliative cancer patients (mean total clearance 75.5 L/h), confirming that in vivo clearance is not entirely CYP3A-dependent.supported
CYP3A activity has weaker correlation with fentanyl clearance than expected; large pharmacokinetic variability in transdermal fentanyl. Mean total clearance 75.5 L/h. s41598-019-51279-6
Claim in pharmacology — inconclusiveinconclusiveworking →
Multiple or large IV doses lead to accumulation in peripheral compartments (muscle, fat) and delayed redistribution, producing prolonged respiratory depression or secondary peaks in plasma concentration — the mechanism underlying reported post-anesthetic re-narcotization.supported
Redistribution-limited duration of action. Multiple/large doses lead to delayed recovery and prolonged respiratory depression. pmid:6226471
summary8 · 5 ok
High lipophilicity (logP 4.05) drives a blood-brain transfer half-life of 4.7–6.6 minutes, producing rapid-onset analgesia with a single intravenous dose lasting 30–60 minutes due to redistribution-limited kinetics.partially supported
High lipophilicity (octanol:water partition coefficient >700); blood-brain transfer half-life 4.7-6.6 min. s40262-012-0016-7
Claim in summary — inconclusiveinconclusiveworking →
From 2013 onward, illicitly manufactured fentanyl drove a 1,040% increase in synthetic opioid overdose deaths in the United States, making it the single deadliest substance in the American drug supplysupported
Synthetic opioid-involved death rate increased 1,040% from 2013 to 2019 (3,105 to 36,359 deaths). mmwr.mm7006a4
Molecular simulation reveals a secondary "deep pocket" binding mode involving hydrogen bonding with His297 and enhanced hydrophobic contacts with transmembrane helix 6, yielding a receptor residence time of approximately 38 seconds.partially supported
Fentanyl can form salt-bridge and secondary hydrogen bond with His297 on mOR; secondary binding mode only accessible when His297 adopts neutral HID tautomer. s41467-021-21262-9
Molecular simulation reveals a secondary "deep pocket" binding mode involving hydrogen bonding with His297 and enhanced hydrophobic contacts with transmembrane helix 6, yielding a receptor residence time of approximately 38 seconds.supported
Calculated fentanyl-mOR residence time tau ~38 s with deep binding mode; piperidine-Hid297 hydrogen bond strengthens hydrophobic contacts with TM6. jacsau.1c00341
Claim in summary — inconclusiveinconclusiveworking →
Tolerance develops through GRK3-mediated MOR phosphorylation, β-arrestin recruitment, and compensatory adenylyl cyclase upregulation, with evidence suggesting analgesia tolerance outpaces respiratory depression tolerance — an asymmetry that escalates overdose risk with continued usepartially supported
GRK2, GRK3, GRK6 and beta-arrestin 2 involved in short- and long-term adaptive changes in MOR activity during opioid tolerance. pmid:11299311
Claim in summary — inconclusiveinconclusiveworking →
history7 · 2 ok
Drug overdose deaths involving opioids reached 47,600 of 70,237 total drug overdose deaths (67.8%) in 2017supported
Among 70,237 drug overdose deaths in 2017, 47,600 (67.8%) involved an opioid. mmwr.mm675152e1
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Synthetic opioid-involved death rates increased 1,040% from 2013 to 2019supported
Synthetic opioid-involved death rate increased 1,040% from 2013 to 2019 (3,105 to 36,359 deaths). mmwr.mm7006a4
Claim in history — inconclusiveinconclusiveworking →
pharmacokinetic-detail7 · 6 ok
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Plasma concentration declines rapidly as fentanyl redistributes from the highly perfused central compartment (brain, heart, lungs) into muscle and adipose tissue.supported
Redistribution-limited duration of action. pmid:6226471
Oral bioavailability and transmucosal data from Lötsch et al.supported
bioavailability ~30% oral, 50-90% transmucosal/intranasal. s40262-012-0016-7
Intranasal bioavailability from Nakhaee et al.supported
Intranasal fentanyl bioavailability 89% in pectin-containing formulations. Onset of analgesia 2 min intranasal. j.heliyon.2023.e23083
The primary metabolic pathway is N-dealkylation by CYP3A4 to the pharmacologically inactive metabolite norfentanylsupported
Fentanyl N-dealkylated by CYP3A4 to inactive norfentanyl. j.pedneo.2014.06.002
As a high-extraction hepatic drug, fentanyl clearance depends more on hepatic blood flow than on intrinsic enzyme activity — CYP3A4 inhibitors produce proportionally greater exposure changes for low-extraction substrates like alfentanil than for fentanylsupported
Fentanyl is a high-extraction drug (CYP3A4 substrate) and thus theoretically less vulnerable to drug interactions than low-extraction alfentanil. CYP3A4 inhibition has differential effects depending on extraction ratio. pmid:12657846
Ketoconazole interaction data from Ziesenitz et al.supported
CYP3A inhibition by ketoconazole increased fentanyl AUC to 133% and reduced clearance to 78%. jcph.469
neuroscience6 · 4 ok
Chen et al. confirmed these reward mechanisms translate to escalating self-administration behavior in mice, with animals progressively increasing fentanyl intake across sessions and exhibiting withdrawal behavior upon cessation.supported
Escalation of IV fentanyl self-administration in mice and assessment of withdrawal behavior. Translationally relevant model for fentanyl use disorder research. s00213-024-06739-x
Claim in neuroscience — inconclusiveinconclusiveworking →
The preBötzinger complex (preBötC), the principal inspiratory rhythm generator, shows reduced neuronal excitability under MOR activation, decreasing respiratory rate and tidal volumesupported
PreBotzinger complex less sensitive to MOR agonism after ROU. ajplung.00302.2024
Rai et al. demonstrated divergent ventilatory responses to repeated fentanyl exposure in mice: 77% developed adaptive (more resistant) ventilatory responses after 5 days, while 23% showed no adaptationsupported
77% of mice showed adaptive ventilatory response following ROU by day 5. Divergent responses: some mice adaptive, some not. ajplung.00302.2024
Compensatory upregulation of adenylyl cyclase (cAMP overshoot) and recruitment of stress systems (CRF, dynorphin/KOR, norepinephrine) establish a new homeostatic set pointpartially supported
Chronic morphine promotes adenylyl cyclase superactivation, NMDAR alterations, GR and c-fos upregulation. fj.09-133223
Claim in neuroscience — inconclusiveinconclusiveworking →
comparative-pharmacology4 · 2 ok
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Emmerson et al. established the ranking: etonitazene = sufentanil = DAMGO = fentanyl > morphinesupported
Rank order: etonitazene = sufentanil = DAMGO = PLO17 = fentanyl > morphine. pmid:8819494
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Imai et al. found that fentanyl-treated mice showed more rapid disappearance of anti-hyperalgesic effect compared to morphine-treated mice, associated with increased phosphorylated MOR and reduced Rab4-dependent receptor resensitizationsupported
Fentanyl-treated mice showed more rapid disappearance of anti-hyperalgesic effect than morphine, associated with increased phosphorylated MOR and reduced Rab4-dependent resensitization. pmid:17240843
receptor-pharmacology4 · 4 ok
G-protein coupling data (GTPγS assay) rank fentanyl among the most efficacious MOR agonists: etonitazene = sufentanil = DAMGO = fentanyl > morphine in C6 glioma cells expressing rat MORsupported
Rank order: etonitazene = sufentanil = DAMGO = PLO17 = fentanyl > morphine. pmid:8819494
In rat thalamic membranes, DAMGO was most efficacious, with fentanyl = morphine >> buprenorphine.supported
DAMGO most efficacious followed by fentanyl = morphine >> buprenorphine in rat thalamus and SK-N-SH cells. pmid:9016350
Fentanyl engages MOR through two distinct binding configurationssupported
Fentanyl can form salt-bridge and secondary hydrogen bond with His297 on mOR; secondary binding mode only accessible when His297 adopts neutral HID tautomer. s41467-021-21262-9
Dissociation kinetics modeling yielded a receptor residence time of τ ≈ 38 seconds in the deep binding configurationsupported
Calculated fentanyl-mOR residence time tau ~38 s with deep binding mode. jacsau.1c00341
chemistry1 · 0 ok
Claim in chemistry — inconclusiveinconclusiveworking →
clinical-evidence1 · 1 ok
Lin et al. conducted a multicenter, randomized, double-blind, placebo-controlled trial of fentanyl inhalant for breakthrough cancer pain, confirming efficacy of this novel administration route.supported
Multicenter RCT evaluating efficacy, safety, and tolerability of fentanyl inhalant 25 mcg/dose in opioid-tolerant patients with breakthrough cancer pain. s12904-024-01554-9
legal-status1 · 0 ok
Claim in legal-status — inconclusiveinconclusiveworking →