generation run 2026-05-15
73 min completedmodel pipeline-v5plan not recordedrun/b07e68b9…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- sparse_evidence
- safety_data_unverified
Reproduce
- inputs
- 42 source keys (listed under Sources)
- plan
- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
- model
- pipeline-v5
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- none — agent transcripts are persisted from 2026-09 onward
19 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | sufentanil pharmacology receptor binding opioid | 14 | 3 | Volpe 2011 is key quantitative binding affinity data; Herman 2026 covers MOR mechanism; Hocker 2008 shows sufentanil does not interact with alpha2 receptors (selectivity data) |
| 2 | ClinicalTrials.gov | sufentanil | 15 | 3 | NCT01954368 and NCT03224039 specifically study sufentanil as intervention; NCT04897750 studies intranasal CT001 (sufentanil nasal spray) in children |
| 3 | PubMed | sufentanil pharmacokinetics human | 12 | 3 | Epidural PK study directly addresses sufentanil pharmacokinetics; PBPK model provides structural comparison data; CPB review mentions 50% increase in sufentanil post-bypass |
| 4 | PubChem | sufentanil | 1 | 1 | Core chemical identity data for the substance |
| 5 | PubMed | sufentanil metabolism CYP3A4 norsufentanil | 1 | 1 | Critical finding: establishes CYP3A4 as sufentanil's primary metabolic enzyme |
| 6 | PubMed | sufentanil overdose toxicity respiratory depression | 1 | 1 | General opioid class review with sufentanil mentioned |
| 7 | WebSearch | sufentanil legal status UK Europe Canada Australia scheduling | 10 | 3 | Legal scheduling information by jurisdiction |
| 8 | PubMed | sufentanil tolerance dependence opioid withdrawal | 6 | 3 | Key papers on sufentanil tolerance mechanisms and dependence liability |
| 9 | WebSearch | sufentanil Janssen Pharmaceutica synthesis 1974 Paul Janssen history | 10 | 2 | Historical data on sufentanil discovery |
| 10 | PubMed | sufentanil sublingual Dsuvia STISI acute pain phase III clinical trial | 1 | 1 | Key clinical trial data for sublingual sufentanil (Dsuvia) safety |
| 11 | WebSearch | sufentanil DEA Schedule II controlled substance FDA approval history | 10 | 2 | Legal status and clinical approval history not available via PubMed |
| 12 | PubMed · absence | sufentanil synthesis history discovery Paul Janssen | 0 | 0 | Used web search instead |
| 13 | WebSearch | sufentanil pharmacokinetics half-life volume distribution protein binding elimination | 10 | 1 | Core PK data needed for pharmacokinetics section |
| 14 | PubMed | PMID 12772 - Niemegeers et al. 1976 sufentanil original paper | 1 | 1 | Foundational pre-clinical data establishing sufentanil's safety profile and potency |
| 15 | PubMed | PMID 6238552 Bovill 1984 sufentanil PK surgical patients | 1 | 1 | Foundational PK parameters |
| 16 | WebSearch | sufentanil LD50 acute toxicity lethal dose animal data | 8 | 1 | Critical safety/toxicity data |
| 17 | DailyMed/FDA | Sufentanil FDA label DailyMed prescribing information | 1 | 1 | Authoritative clinical dosing and safety information |
| 18 | Multiple PubMed articles + web sources | Synthesize: sufentanil history, pharmacology, PK, safety, legal, clinical trials | 45 | 1 | Comprehensive research synthesis complete; ready for handoff file verification |
| 19 | Research Output vs Citation Registry | Verify all [Ref N] markers in research output against registry entries | 45 | 0 | Cross-reference verification for generation agent guidance |
75 claims by section — every cited sentence, checked against its source
safety21 · 17 ok
The preclinical therapeutic index data from Niemegeers et al. (1976) remain the definitive reference:supported
Original pharmacology paper. R 30730 (sufentanil). Mice: ED50 0.0028 mg/kg IV (2304x more potent than morphine). pmid:12772
All morphine-like effects were antagonized by nalorphine in these studiessupported
All effects antagonized by nalorphine. pmid:12772
The characterization of sufentanil as having "the highest therapeutic index of any opioid used in clinical practice" derives from these animal data; direct human measurement is ethically impossible.supported
highest therapeutic index of any opioid, high MOR affinity, high lipophilicity enabling 15μg nanotablet. pmid:27097966
A 2026 study specifically evaluated 4 mg intranasal naloxone (Narcan) for reversing sufentanil-induced moderate respiratory depression, selecting sufentanil because of its higher MOR affinity than fentanyl.supported
Evaluated 4 mg intranasal naloxone (Narcan) for reversing moderate respiratory depression from fentanyl and sufentanil. Sufentanil selected due to higher MOR affinity than fentanyl. aln.0000000000005931
Benzodiazepines contributed to fatal respiratory depression through synergistic CNS depression in four of nine cases across the seriespartially supported
Benzodiazepines contributed to deaths by synergistically inhibiting respiration. s12024-012-9374-6
In forensic toxicology, sufentanil may be undetectable post-mortem due to degradation at very low concentrations.supported
One case attributed to sufentanil (undetectable due to putrefaction, death attributed to respiratory depression). s12024-012-9374-6
Claim in safety — inconclusiveinconclusiveworking →
The occupational context of documented sufentanil misuse — healthcare professionals with anesthesia access — suggests a diversion-driven exposure pattern rather than street-level recreational use.supported
Review of 9 healthcare professional deaths from self-administered IV anesthetics 1998-2011. One case attributed to sufentanil. s12024-012-9374-6
Its high MOR endocytotic efficacy promotes receptor internalization and recycling, which counteracts the receptor desensitization that drives analgesic tolerance with morphinesupported
Sufentanil has high endocytotic efficacy at MOR. High endocytotic efficacy opioids counteract receptor desensitization but may facilitate dependence. pmid:15475572
At the molecular level, chronic sufentanil exposure produces spinal MOR uncoupling from inhibitory G-proteins (Gαo, Gαi2, Gαz, Gαq11) and switches supraspinal MOR signaling from inhibitory to stimulatory via caveolin-1-scaffolded Gsα–adenylyl cyclase coupling in lipid raft microdomains.partially supported
Chronic sufentanil in rats produced antinociceptive tolerance with uncoupling of spinal MOR from G proteins (reduced GTPγS binding, reduced AC inhibition). j.neuropharm.2008.02.004
At the molecular level, chronic sufentanil exposure produces spinal MOR uncoupling from inhibitory G-proteins (Gαo, Gαi2, Gαz, Gαq11) and switches supraspinal MOR signaling from inhibitory to stimulatory via caveolin-1-scaffolded Gsα–adenylyl cyclase coupling in lipid raft microdomains.partially supported
Chronic morphine/sufentanil exposure augments caveolin-1 scaffolding of MOR-Gsα-adenylyl cyclase signaling in caveolae. jnc.13852
Sufentanil-tolerant rats demonstrated cross-tolerance to intracerebroventricular morphine (tolerance index 3.6), intracerebroventricular DADLE (tolerance index 4.3, indicating mu-delta cross-tolerance), and subcutaneous morphine (tolerance index 6.6) — but not to intravenous morphine, highlighting how pharmacokinetics modulate the expression of cross-tolerance.supported
Rats tolerant to SC sufentanil showed cross-tolerance to ICV morphine (3.6), ICV DADLE (4.3), SC morphine (6.6) but not IV morphine. pmid:2138980
Physical dependence has been demonstrated in rats receiving continuous intrathecal sufentanil infusion: naloxone challenge produced dose-dependent withdrawal body shakes, with sufentanil producing fewer shakes (25.0) than DADLE (32.8) or morphine (30.2) but more than DAMGO (8.7) at highest tested doses.supported
At highest dose, 25 withdrawal body shakes post-naloxone. Less than DADLE and morphine (32.8, 30.2) but more than DAMGO (8.7). pmid:2553435
In clinical pediatric populations, cumulative dose and treatment duration are the strongest predictors of withdrawal syndrome following IV sufentanil. Treatment duration exceeding 177 hours predicts withdrawal syndrome with 81% sensitivity and 94% specificitysupported
Cumulative dose and duration of sufentanil therapy significantly increases withdrawal syndrome risk. Cut-off >177h treatment predicts WS with 81% sensitivity, 94% specificity. pmid:28006928
Claim in safety — inconclusiveinconclusiveworking →
Benzodiazepines synergistically potentiate sufentanil's respiratory depressant effects — this interaction has been directly documented in forensic fatality data and in clinical anesthesia co-induction literature.supported
Benzodiazepines contributed to deaths by synergistically inhibiting respiration. s12024-012-9374-6
Benzodiazepines synergistically potentiate sufentanil's respiratory depressant effects — this interaction has been directly documented in forensic fatality data and in clinical anesthesia co-induction literature.supported
Co-induction with midazolam + opioids (including sufentanil) exploits synergism. Fatal synergistic effects documented historically when opioids + benzodiazepines used outside appropriate clinical setting. pmid:8719667
Claim in safety — not_supportednot supportedworking →
As a CYP3A4 substrate, sufentanil's plasma concentrations are affected by CYP3A4 modulators:supported
CYP3A4 is responsible for sufentanil N-dealkylation in human liver microsomes. pmid:8712396
Claim in safety — inconclusiveinconclusiveworking →
Concurrent CYP3A4 inhibitors — co-administration with strong CYP3A4 inhibitors increases sufentanil plasma concentrations and potentiates all effects including respiratory depressionsupported
CYP3A4 is responsible for sufentanil N-dealkylation in human liver microsomes, confirmed by correlation with nifedipine oxidation, inhibitor studies. pmid:8712396
pharmacology14 · 8 ok
In a uniform radioligand binding assay using recombinant human MOR, sufentanil demonstrated the highest binding affinity of 19 approved opioid drugs tested, with a Ki of 0.1380 nMsupported
Ki values for 19 approved opioid drugs using a single binding assay in human MOR. Sufentanil Ki = 0.1380 nM, lowest (highest affinity) of all tested opioids. j.yrtph.2010.12.007
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Unlike meperidine, remifentanil, and tramadol, sufentanil does not interact with α₂-adrenoceptors at any tested concentration, as demonstrated in knockout mouse brain autoradiography studiessupported
Sufentanil did not interact with alpha-2 adrenoceptors, unlike meperidine, remifentanil, and tramadol. Demonstrates high receptor selectivity of sufentanil for MOR. j.ejphar.2007.12.022
Sufentanil follows a three-compartment pharmacokinetic model after intravenous administrationsupported
Three-compartment model. Distribution half-lives: pi=1.4 min, alpha=17.7 min. pmid:6238552
Approximately 98% of an IV dose leaves the plasma within 30 minutes due to rapid tissue redistribution — this redistribution, rather than elimination, governs the clinical duration of action at standard analgesic doses.supported
Terminal elimination half-life: 164 ± 22 min. 98% of dose left plasma within 30 min. pmid:6238552
Metabolism occurs via hepatic and intestinal CYP3A4-mediated N-dealkylation, producing norsufentanil as the primary metabolitesupported
CYP3A4 is responsible for sufentanil N-dealkylation in human liver microsomes. pmid:8712396
CYP3A4 responsibility was confirmed through multiple lines of evidence: significant correlation with nifedipine oxidation activity (r = 0.87), inhibition by gestodene, troleandomycin, and anti-CYP3A4 antibody, and selective activity in CYP3A4-expressing E. coli (absent in CYP1A2, CYP2C10, and CYP2E1 systems)supported
CYP3A4 is responsible for sufentanil N-dealkylation in human liver microsomes, confirmed by correlation with nifedipine oxidation, inhibitor studies, and recombinant CYP3A4 expression. pmid:8712396
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
After epidural administration, sufentanil concentrations decline more slowly than after IV dosing, and a "flip-flop" phenomenon has been observed — indicating absorption-rate-limited kinetics in which the rate of systemic absorption from the epidural space becomes the rate-limiting step.supported
Sufentanil concentrations decline more slowly after epidural vs IV administration; flip-flop phenomenon described. s40262-025-01543-y
Population PK modeling shows clearance increases 2.80-fold during CPB/warming phases and central compartment volume increases 2.74-fold.supported
Sufentanil clearance increased 2.80-fold during CPB/warming; central volume increased 2.74-fold. psp4.13205
Claim in pharmacology — not_supportednot supportedworking →
summary9 · 8 ok
Clinical duration of action following IV administration is short — onset within 1–2 minutes, peak effect at 5–10 minutes — governed by rapid tissue redistribution rather than elimination.supported
Distribution half-lives: pi=1.4 min, alpha=17.7 min. Terminal elimination half-life: 164 ± 22 min. 98% of dose left plasma within 30 min. pmid:6238552
Claim in summary — inconclusiveinconclusiveworking →
The foundational preclinical characterization, published by Niemegeers and colleagues in 1976, established its exceptional potency and the highest preclinical therapeutic index of any tested opioidsupported
Rats: ED50 0.00071 mg/kg (4521x morphine); LD50 17.9 mg/kg; safety margin 1:25211. pmid:12772
Sufentanil binds the human MOR with a Ki of 0.1380 nM — the highest affinity measured among 19 approved opioid drugs in a uniform radioligand assaysupported
Sufentanil Ki = 0.1380 nM, lowest (highest affinity) of all tested opioids, in the K<1 nM category. j.yrtph.2010.12.007
It signals through canonical Gi/o-protein coupling to inhibit adenylyl cyclase, activate GIRK potassium channels, and suppress voltage-gated calcium channels, collectively reducing neuronal excitability and pain transmissionsupported
Comprehensive review of MOR pharmacology, receptor mechanism, tissue distribution, MOR ligands including sufentanil as strong agonist. bph.16084
Unlike several other opioids in its class, sufentanil demonstrates no interaction with alpha-2 adrenoceptors, indicating exceptional receptor selectivity.supported
Sufentanil did not interact with alpha-2 adrenoceptors, unlike meperidine, remifentanil, and tramadol. Demonstrates high receptor selectivity of sufentanil for MOR. j.ejphar.2007.12.022
Sufentanil possesses the highest preclinical therapeutic index of any major opioid (safety margin 1:25,211 in rats by IV administration), yet respiratory depression remains the critical cause of death in overdose, as with all potent MOR agonistssupported
Rats: ED50 0.00071 mg/kg (4521x morphine); LD50 17.9 mg/kg; safety margin 1:25211. pmid:12772
Tolerance development involves a complex interplay: sufentanil's high MOR endocytotic efficacy may slow analgesic tolerance relative to morphine, but simultaneously facilitates compensatory cAMP pathway upregulation associated with physical dependencesupported
Sufentanil has high endocytotic efficacy at MOR. High endocytotic efficacy opioids counteract receptor desensitization but may facilitate dependence. pmid:15475572
In pediatric ICU settings, treatment durations exceeding 177 hours predict withdrawal syndrome with 81% sensitivity and 94% specificitysupported
Cut-off >177h treatment predicts WS with 81% sensitivity, 94% specificity. pmid:28006928
pharmacokinetic-detail8 · 7 ok
The definitive IV pharmacokinetic characterization of sufentanil was established by Bovill and colleagues in 1984 using a three-compartment model in surgical patients:supported
Classic PK study: 10 surgical patients, 5 μg/kg IV bolus. Three-compartment model. pmid:6238552
The rapid distribution half-life of 1.4 minutes explains sufentanil's fast onset of action; 98% of an administered IV dose leaves the plasma compartment within 30 minutessupported
Distribution half-lives: pi=1.4 min. 98% of dose left plasma within 30 min. pmid:6238552
Sufentanil undergoes hepatic and small-intestinal biotransformation primarily via CYP3A4-catalyzed N-dealkylation to norsufentanilsupported
CYP3A4 is responsible for sufentanil N-dealkylation in human liver microsomes. pmid:8712396
CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St. John's wort) may reduce sufentanil efficacy.supported
CYP3A4 is responsible for sufentanil N-dealkylation in human liver microsomes. pmid:8712396
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Population PK modeling reveals a 2.80-fold increase in clearance during CPB/warming phases and a 2.74-fold increase in central compartment volumesupported
Sufentanil clearance increased 2.80-fold during CPB/warming; central volume increased 2.74-fold. psp4.13205
After epidural administration, sufentanil exhibits a "flip-flop" kinetic pattern — systemic absorption from the epidural space becomes the rate-limiting step, causing plasma concentrations to decline more slowly than after IV administrationsupported
Sufentanil concentrations decline more slowly after epidural vs IV administration; flip-flop phenomenon described. s40262-025-01543-y
OPRM1 (A118G polymorphism, rs1799971): Heterozygous A/G patients undergoing epidural analgesia required approximately 2.3× more sufentanil injections and experienced twice the rate of opioid-induced adverse effects compared to A/A homozygotes.supported
OPRM1 118AG heterozygotes required more than twice the doses of 118AA homozygotes (5.25 vs 2.31 injections). AEs in 33% vs 15%. pmid:31755291
comparative-pharmacology5 · 4 ok
Sufentanil's preclinical therapeutic index (ratio of LD₅₀ to ED₅₀, IV route) is the highest of any major opioid tested under comparable conditions:supported
Mice: safety margin 1:6679. Rats: safety margin 1:25211. Dogs: safety margin ~1:50000. pmid:12772
The clinical characterization of sufentanil as having "the highest therapeutic index of any opioid used in clinical practice" derives from these preclinical datasupported
highest therapeutic index of any opioid, high MOR affinity, high lipophilicity enabling 15μg nanotablet. pmid:27097966
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
In a direct four-way comparison (morphine, meperidine, fentanyl, sufentanil) during balanced anesthesia, sufentanil produced the most favorable hemodynamic profile: lowest blood pressure deviation, lowest heart rate deviation, and lowest plasma catecholamine response to surgical stresssupported
Sufentanil produced lowest hemodynamic stress responses and plasma catecholamines of all four opioids. pmid:2862810
Paradoxically, clinical rotation from morphine to sufentanil has been reported to resolve morphine-induced hyperalgesia in a patient case report, suggesting mechanistic differences in how each opioid triggers opioid-induced hyperalgesia.supported
One case: morphine hyperalgesia/myoclonus resolved after switching to SC sufentanil infusion, suggesting sufentanil as an alternative to morphine in hyperalgesia cases. pmid:7892029
neuroscience5 · 3 ok
Claim in neuroscience — inconclusiveinconclusiveworking →
Claim in neuroscience — inconclusiveinconclusiveworking →
In supraspinal regions, chronic treatment augments stimulatory MOR signaling via caveolin-1 scaffolding of MOR–Gsα–adenylyl cyclase complexes within lipid raft microdomains, leading to paradoxical cAMP stimulation rather than the normal inhibitionsupported
Chronic morphine/sufentanil exposure augments caveolin-1 scaffolding of MOR-Gsα-adenylyl cyclase signaling in caveolae. Sufentanil used to demonstrate stimulatory MOR-cAMP signaling in chronic opioid context. jnc.13852
This mechanistic distinction may explain why opioid rotation from morphine to sufentanil has resolved hyperalgesia in clinical practice.supported
One case: morphine hyperalgesia/myoclonus resolved after switching to SC sufentanil infusion. pmid:7892029
The molecular evidence of cAMP overshoot and G-protein uncoupling following chronic sufentanil provides cellular-level support for this framework.supported
Chronic morphine/sufentanil exposure augments caveolin-1 scaffolding of MOR-Gsα-adenylyl cyclase signaling in caveolae. Sufentanil used to demonstrate stimulatory MOR-cAMP signaling in chronic opioid context. jnc.13852
receptor-pharmacology5 · 4 ok
In the most methodologically rigorous comparative study available — a uniform radioligand displacement assay using [³H]diprenorphine at recombinant human MOR — sufentanil achieved a Ki of 0.1380 nM, the lowest (highest affinity) of 19 clinically used opioidssupported
Ki values for 19 approved opioid drugs using a single binding assay in human MOR. Sufentanil Ki = 0.1380 nM, lowest (highest affinity) of all tested opioids. j.yrtph.2010.12.007
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
This contrasts sharply with meperidine, remifentanil, and tramadol, all of which displace α₂-adrenoceptor radioligands in the same assaysupported
Sufentanil did not interact with alpha-2 adrenoceptors, unlike meperidine, remifentanil, and tramadol. j.ejphar.2007.12.022
Cross-tolerance studies in rats suggest at least partial overlap with delta-opioid receptor activity, as sufentanil-tolerant animals showed cross-tolerance to the delta agonist DADLE (tolerance index 4.3), though this may reflect downstream convergence rather than direct DOR binding.supported
Rats tolerant to SC sufentanil showed cross-tolerance to ICV DADLE (4.3). pmid:2138980
However, the same high endocytotic efficacy facilitates compensatory upregulation of the cAMP signaling pathway — specifically, chronic sufentanil exposure can switch MOR signaling from inhibitory (Gi/o) to stimulatory (Gs) coupling within caveolae lipid membrane microdomains, mediated by increased caveolin-1 scaffolding of MOR–Gsα–adenylyl cyclase complexessupported
Chronic morphine/sufentanil exposure augments caveolin-1 scaffolding of MOR-Gsα-adenylyl cyclase signaling in caveolae. Sufentanil used to demonstrate stimulatory MOR-cAMP signaling in chronic opioid context. jnc.13852
clinical-evidence4 · 4 ok
Intrathecal sufentanil at varying doses (2.5–7.5 µg) was evaluated in a randomized controlled trial of elderly patients undergoing lower limb orthopedic surgery, demonstrating dose-dependent analgesia with extended time to first rescue analgesic.supported
Dose-finding RCT for intrathecal sufentanil in elderly surgical patients. Intrathecal sufentanil enhances analgesia, prolongs block duration. Dose-dependent effects studied. jpr.s512653
No patient in the sufentanil group required supplemental inhalational agents, while patients in the other three groups didsupported
No supplemental inhalational agents needed in sufentanil group. pmid:2862810
Intranasal sufentanil combined with ketamine has been documented in pediatric procedural sedation, providing rapid-onset analgesia via a non-invasive route.supported
Intranasal sufentanil/ketamine combination studied for procedural pain in children. pan.12268
A retrospective study compared sufentanil and fentanyl analgesia in ICU patients with traumatic brain injury, providing comparative safety and efficacy data in a critical-care context.supported
85 ICU TBI patients. Sufentanil vs fentanyl: both effective for analgosedation. msm.934611