generation run 2026-04-27
62 min completedmodel pipeline-v5plan not recordedrun/18411a6b…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- medium_confidence
- depot_formulation_gap
- no_specific_reduction_rate
Reproduce
- inputs
- 37 source keys (listed under Sources)
- plan
- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
- model
- pipeline-v5
- streams
- none — agent transcripts are persisted from 2026-09 onward
30 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | buprenorphine pharmacokinetics bioavailability sublingual human | 10 | 4 | — |
| 2 | OpenAlex | buprenorphine pharmacology opioid receptor | 10 | 2 | — |
| 3 | PubMed | buprenorphine antidepressant depression kappa opioid antagonism | 6 | 3 | — |
| 4 | PubMed | buprenorphine benzodiazepine interaction death respiratory depression | 7 | 5 | — |
| 5 | PubChem | buprenorphine | 1 | 1 | Only result; confirms chemical identity data in brief |
| 6 | PubMed | buprenorphine receptor binding affinity mu opioid kappa opioid pharmacology | 1 | 1 | Key pharmacology review with receptor binding profile and clinical trial overview |
| 7 | PubMed | buprenorphine metabolism norbuprenorphine CYP3A4 UGT glucuronide | 1 | 1 | — |
| 8 | PubMed | buprenorphine withdrawal dependence physical symptoms treatment | 9 | 2 | — |
| 9 | ClinicalTrials.gov | buprenorphine opioid use disorder | 10 | 3 | — |
| 10 | PubMed | buprenorphine kappa opioid antagonist nociceptin ORL1 receptor affinity | 8 | 4 | — |
| 11 | PubMed | buprenorphine antidepressant depression kappa opioid antagonism | 6 | 3 | — |
| 12 | Web search / UK Gov / TGA | buprenorphine UK Class C Schedule 3 Australia Schedule 8 Canada Narcotic Control Regulations | 10 | 3 | Multiple jurisdictions legal status confirmed |
| 13 | DEA / Federal Register | buprenorphine DEA schedule prescribing regulations | 1 | 1 | Primary legal source for US scheduling regulations |
| 14 | PubMed | buprenorphine abuse potential misuse diversion street use | 5 | 3 | — |
| 15 | PubMed | buprenorphine FDA approval Suboxone Subutex 2002 opioid dependence treatment | 6 | 2 | — |
| 16 | PubMed · absence | buprenorphine intranasal insufflation bioavailability pharmacokinetics abuse | 0 | 0 | — |
| 17 | NCBI Bookshelf StatPearls | buprenorphine legal status receptor binding FDA approval | 1 | 1 | Regulatory confirmation and pharmacology overview |
| 18 | PubMed | buprenorphine opioid tolerance cross-tolerance incomplete | 3 | 1 | — |
| 19 | ClinicalTrials.gov | buprenorphine pain chronic analgesic | 8 | 4 | — |
| 20 | PubMed | buprenorphine half-life elimination pharmacokinetics intravenous sublingual bioavailability | 2 | 1 | — |
| 21 | PubMed | buprenorphine naloxone Suboxone combination product abuse deterrent | 6 | 2 | — |
| 22 | PubMed | buprenorphine ceiling effect respiratory depression partial agonist mechanism | 3 | 2 | — |
| 23 | Multiple API sources | Comparison of brief seed data vs. PubChem, PubMed, OpenAlex findings | 1 | 2 | Quality control cross-reference |
| 24 | OpenAlex | buprenorphine binding affinity Ki nM mu kappa delta opioid receptor | 5 | 0 | — |
| 25 | PubMed | buprenorphine QTc cardiac arrhythmia safety | 6 | 3 | — |
| 26 | PubMed/ClinicalTrials.gov | Buprenorphine clinical trials NCT numbers OUD pain | 10 | 5 | Major completed and active trials covering OUD and analgesic indications |
| 27 | Wikipedia / UK Gov | buprenorphine UK Class C Schedule 3 Misuse Drugs Act | 1 | 1 | Legal status confirmation |
| 28 | PubMed cross-reference | Sordo 2017 BMJ mortality meta-analysis buprenorphine treatment | 1 | 1 | Key quantitative mortality data for safety section |
| 29 | PubMed | buprenorphine hepatotoxicity liver toxicity adverse effects | 5 | 2 | — |
| 30 | PubMed | Strain 1997 buprenorphine maintained volunteers cross-tolerance | 1 | 1 | Key tolerance and cross-tolerance data |
119 claims by section — every cited sentence, checked against its source
pharmacology32 · 16 ok
Claim in pharmacology — inconclusiveinconclusiveworking →
Buprenorphine exerts its pharmacological effects through simultaneous engagement of four opioid receptor subtypes, a profile that distinguishes it from classical opioids.supported
Reviews history of buprenorphine discovery, pharmacology: mu/kappa agonist, NOP agonist, delta antagonist. jvp.13073
Buprenorphine exerts its pharmacological effects through simultaneous engagement of four opioid receptor subtypes, a profile that distinguishes it from classical opioids.supported
Buprenorphine receptor binding profile is unique in that it binds to all three major opioid receptors (mu, kappa, delta), and also the orphanin FQ/nociceptin receptor. s40265-018-0953-z
This combination produces two clinically consequential properties: a ceiling effect on respiratory depression that is not surpassed even at supratherapeutic doses when buprenorphine is the sole agent, and prolonged pharmacodynamic action that outlasts plasma concentration predictionssupported
Ceiling effect for respiratory depression but deaths reported in France from IV misuse or BZD co-ingestion. pmid:16958555
This combination produces two clinically consequential properties: a ceiling effect on respiratory depression that is not surpassed even at supratherapeutic doses when buprenorphine is the sole agent, and prolonged pharmacodynamic action that outlasts plasma concentration predictionssupported
High affinity, slow dissociation, moderate intrinsic activity. Ceiling effect for respiratory depression but not analgesia in humans. pmid:12665117
This combination produces two clinically consequential properties: a ceiling effect on respiratory depression that is not surpassed even at supratherapeutic doses when buprenorphine is the sole agent, and prolonged pharmacodynamic action that outlasts plasma concentration predictionssupported
High affinity, slow dissociation, moderate intrinsic activity. Ceiling effect for respiratory depression but not analgesia in humans. pmid:12665117
Claim in pharmacology — inconclusiveinconclusiveworking →
The ceiling effect applies to respiratory depression but not to analgesia, which continues to increase with dosesupported
Ceiling effect for respiratory depression but not analgesia in humans. pmid:12665117
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
More recent receptor affinity and intrinsic activity studies indicate it functions as a partial agonist with complex activitysupported
Reviews history of buprenorphine discovery, pharmacology: mu/kappa agonist, NOP agonist, delta antagonist. Primary spinal analgesic mechanism, partial agonist for respiratory depression endpoints. jvp.13073
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
At the delta-opioid receptor (DOR), buprenorphine acts as an antagonist.supported
Reviews history of buprenorphine discovery, pharmacology: mu/kappa agonist, NOP agonist, delta antagonist. jvp.13073
At the nociceptin/orphanin FQ peptide receptor (NOP/ORL1), buprenorphine functions as an agonist with lower affinity than at classical opioid receptorssupported
Buprenorphine receptor binding profile is unique in that it binds to all three major opioid receptors (mu, kappa, delta), and also the orphanin FQ/nociceptin receptor. s40265-018-0953-z
In preclinical antinociceptive assays, buprenorphine demonstrates full analgesic efficacy with potency 25–40× that of morphine.supported
25-40x more potent than morphine in preclinical tests. pmid:12665117
Claim in pharmacology — inconclusiveinconclusiveworking →
At maintenance doses (~16–32 mg sublingual daily), buprenorphine occupies a high proportion of MOR sites, creating an occupancy blockade that attenuates the effects of supplemental full agonistssupported
Buprenorphine effective at doses >2mg; suppresses illicit opioid use at ≥16mg. 14651858.cd002207.pub4
Claim in pharmacology — inconclusiveinconclusiveworking →
Sublingual bioavailability averages approximately 51% (range 36–65%), with significant interindividual variabilitysupported
Sublingual bioavailability 51.4%, buccal 27.8%, with considerable interindividual variability. pmid:8889672
Bioavailability is dose-dependent and nonlinear — a log-transformed dose relationship means higher doses yield proportionally less systemic exposuresupported
Nonlinear absorption profile: log-transformed dose regression. Validated across 2-32mg dose range. dmd.124.001643
Claim in pharmacology — inconclusiveinconclusiveworking →
Terminal elimination half-life ranges from 24 to 42 hours after sublingual dosing, prolonged relative to the intravenous route due to an oral mucosal depot effect.supported
Extended half-lives for SL and buccal vs IV due to oral mucosal depot effect. pmid:8889672
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Parallel glucuronidation by UGT1A1, UGT1A3, and UGT2B7 yields buprenorphine-3-glucuronide (B3G) and norbuprenorphine-3-glucuronide (NB3G), both biologically activesupported
Glucuronide metabolites of buprenorphine (B3G) and norbuprenorphine (NB3G) are biologically active. aln.0b013e318238fea0
Claim in pharmacology — inconclusiveinconclusiveworking →
Plasma concentrations of major metabolites approximate or exceed those of the parent compound.supported
Major metabolite plasma concentrations approximate or exceed parent drug concentrations. aln.0b013e318238fea0
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
safety31 · 6 ok
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
The ceiling effect on respiratory depression — demonstrated in controlled human studies — limits maximal respiratory compromise at supratherapeutic doses when buprenorphine is the sole opioid present.supported
Ceiling effect for respiratory depression but deaths reported in France from IV misuse or BZD co-ingestion. pmid:16958555
The ceiling effect on respiratory depression — demonstrated in controlled human studies — limits maximal respiratory compromise at supratherapeutic doses when buprenorphine is the sole opioid present.supported
Ceiling effect for respiratory depression but not analgesia in humans. pmid:12665117
Respiratory support is the critical intervention in suspected overdose.supported
Naloxone has limited reversal efficacy for buprenorphine respiratory depression. pmid:16958555
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Numerous human fatalities involving IV buprenorphine combined with benzodiazepines were documented in France following the 1996 Subutex rolloutsupported
Ceiling effect for respiratory depression but deaths reported in France from IV misuse or BZD co-ingestion. pmid:16958555
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Benzodiazepines represent the highest-risk combination, with strong published evidence from both human fatality data and animal lethality studiessupported
Ceiling effect for respiratory depression but deaths reported in France from IV misuse or BZD co-ingestion. pmid:16958555
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Concurrent benzodiazepine or CNS depressant use (relative — risk management protocols exist for clinically necessary co-prescribing, but unsupervised combination is dangerous)supported
Ceiling effect for respiratory depression but deaths reported in France from IV misuse or BZD co-ingestion. pmid:16958555
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
summary14 · 8 ok
With antinociceptive potency 25–40× that of morphine and a sublingual pharmacodynamic duration of 18–24 hours sustained by a terminal elimination half-life of 24–42 hours, it occupies a distinctive position among clinically deployed opioids as a high-affinity mu-opioid receptor (MOR) partial agonist.supported
High affinity, slow dissociation, moderate intrinsic activity. 25-40x more potent than morphine in preclinical tests. pmid:12665117
With antinociceptive potency 25–40× that of morphine and a sublingual pharmacodynamic duration of 18–24 hours sustained by a terminal elimination half-life of 24–42 hours, it occupies a distinctive position among clinically deployed opioids as a high-affinity mu-opioid receptor (MOR) partial agonist.supported
Extended half-lives for SL and buccal vs IV due to oral mucosal depot effect. pmid:8889672
Synthesized in the late 1960s at Reckitt & Colman as part of the orvinol analgesic research program, buprenorphine reached FDA approval in October 2002 after 36 years of development — first as the injectable analgesic Buprenex (1985), then as Subutex and Suboxone for opioid use disorder (OUD)supported
36 years of R&D before 2002 FDA approval. Reviews discovery and early development stages, key development steps, regulatory approval of buprenorphine-based medications for OUD. j.dadr.2023.100133
Claim in summary — inconclusiveinconclusiveworking →
Buprenorphine's pharmacology is defined by simultaneous activity at four opioid receptor subtypes: high-affinity partial agonism at MOR with extremely slow dissociation kinetics, partial agonism at the kappa-opioid receptor (KOR) — historically classified as pure antagonism but reclassified by more recent binding studies — antagonism at the delta-opioid receptor (DOR), and lower-affinity agonism at the nociceptin receptor (NOP/ORL1)supported
Reviews history of buprenorphine discovery, pharmacology: mu/kappa agonist, NOP agonist, delta antagonist. jvp.13073
Buprenorphine's pharmacology is defined by simultaneous activity at four opioid receptor subtypes: high-affinity partial agonism at MOR with extremely slow dissociation kinetics, partial agonism at the kappa-opioid receptor (KOR) — historically classified as pure antagonism but reclassified by more recent binding studies — antagonism at the delta-opioid receptor (DOR), and lower-affinity agonism at the nociceptin receptor (NOP/ORL1)supported
Buprenorphine receptor binding profile is unique in that it binds to all three major opioid receptors (mu, kappa, delta), and also the orphanin FQ/nociceptin receptor. s40265-018-0953-z
The slow MOR dissociation rate produces prolonged receptor occupancy exceeding plasma half-life predictions and underlies the ceiling effect on respiratory depression.supported
Ceiling effect for respiratory depression but deaths reported in France from IV misuse or BZD co-ingestion. pmid:16958555
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
This ceiling is abolished by benzodiazepine co-administration, which reduces lethality approximately 6-fold in animal models and accounts for most buprenorphine-associated fatalitiespartially supported
Ceiling effect for respiratory depression but deaths reported in France from IV misuse or BZD co-ingestion. pmid:16958555
Claim in summary — inconclusiveinconclusiveworking →
Standard naloxone doses may not reliably reverse buprenorphine respiratory depression due to high receptor affinitysupported
Naloxone has limited reversal efficacy for buprenorphine respiratory depression. pmid:16958555
Claim in summary — inconclusiveinconclusiveworking →
comparative-pharmacology10 · 3 ok
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
The Cochrane review found buprenorphine retention comparable to methadone at adequate doses (above 7 mg/day sublingual), though methadone showed higher retention at flexible dosing in some analysessupported
Buprenorphine effective at doses >2mg; suppresses illicit opioid use at ≥16mg. Methadone superior in retaining patients in treatment. 14651858.cd002207.pub4
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Buprenorphine demonstrates 25–40× greater antinociceptive potency than morphine in preclinical assayssupported
25-40x more potent than morphine in preclinical tests. pmid:12665117
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Mortality reduction during treatment is substantial for both agents.supported
all-cause mortality 4.3/1000 person-years in treatment vs 9.5/1000 out of treatment. bmj.j1550
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
history8 · 7 ok
France pioneered high-dose sublingual buprenorphine (marketed as Subutex) for opioid substitution therapy in 1996 — a landmark decision that demonstrated mortality benefits for opioid-dependent populations but simultaneously revealed the lethal potential of intravenous buprenorphine combined with benzodiazepines.supported
Ceiling effect for respiratory depression but deaths reported in France from IV misuse or BZD co-ingestion. pmid:16958555
Buprenorphine emerged from the orvinol analgesic research program at Reckitt & Colman (now Indivior) in Hull, United Kingdomsupported
Reviews discovery and early development stages, key development steps. j.dadr.2023.100133
Buprenorphine emerged from the orvinol analgesic research program at Reckitt & Colman (now Indivior) in Hull, United Kingdomsupported
Reviews history of buprenorphine discovery. jvp.13073
Claim in history — inconclusiveinconclusiveworking →
Early studies demonstrated analgesic effectiveness with a favorable safety profile compared to morphinesupported
Reviews history of buprenorphine discovery, pharmacology... partial agonist for respiratory depression endpoints. jvp.13073
Martin and colleagues confirmed buprenorphine's partial agonist activity at the mu-opioid receptor in 1976 using the chronic spinal dog model — the definitive early pharmacological characterization that established the ceiling effect concept for this compound.supported
Partial agonist at mu-opioid receptor confirmed by Martin et al 1976. pmid:12665117
The Drug Addiction Treatment Act (DATA) of 2000 enabled office-based opioid use disorder prescribing in the United Statessupported
Reviews discovery and early development stages, key development steps, regulatory approval of buprenorphine-based medications for OUD. j.dadr.2023.100133
Subsequent formulation innovation expanded the clinical toolkit. Probuphine (subdermal implant providing 6 months of sustained release) received FDA approval in May 2016, and Sublocade (monthly extended-release subcutaneous injection) followed in November 2017supported
Reviews discovery and early development stages, key development steps, regulatory approval of buprenorphine-based medications for OUD. j.dadr.2023.100133
clinical-evidence7 · 2 ok
Overdose-specific mortality was 1.4 per 1,000 person-years during treatment versus 4.6 per 1,000 person-years out of treatment.supported
overdose mortality 1.4 vs 4.6/1000 person-years. bmj.j1550
Claim in clinical-evidence — not_supportednot supportedworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
The definitive efficacy evidence for buprenorphine in OUD comes from the Cochrane systematic review by Mattick and colleagues, which concluded that buprenorphine maintenance is superior to placebo and comparable to methadone maintenance in retaining patients in treatment and suppressing illicit opioid usepartially supported
Buprenorphine effective at doses >2mg; suppresses illicit opioid use at ≥16mg. Methadone superior in retaining patients in treatment. 14651858.cd002207.pub4
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
receptor-pharmacology6 · 4 ok
This slow k_off rate also explains the difficulty of naloxone reversal in overdose settings — naloxone must compete against a slowly dissociating high-affinity ligand.supported
Naloxone has limited reversal efficacy for buprenorphine respiratory depression. pmid:16958555
Buprenorphine demonstrates a multi-receptor binding profile that is unusual among clinically deployed opioidssupported
Buprenorphine receptor binding profile is unique in that it binds to all three major opioid receptors (mu, kappa, delta), and also the orphanin FQ/nociceptin receptor. s40265-018-0953-z
Buprenorphine demonstrates a multi-receptor binding profile that is unusual among clinically deployed opioidssupported
Reviews history of buprenorphine discovery, pharmacology: mu/kappa agonist, NOP agonist, delta antagonist. jvp.13073
Buprenorphine's receptor residence time significantly exceeds that of morphine, methadone, and fentanyl, producing pharmacodynamic effects that persist long after plasma concentrations declinesupported
High affinity, slow dissociation, moderate intrinsic activity. pmid:12665117
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
neuroscience5 · 0 ok
pharmacokinetic-detail4 · 2 ok
Van Hoogdalem and colleagues developed a full physiologically based pharmacokinetic (PBPK) model demonstrating that higher sublingual doses yield proportionally less systemic exposure — a log-transformed dose–bioavailability relationshipsupported
First PBPK model to adequately predict dose- and formulation-dependent sublingual buprenorphine PK. Nonlinear absorption profile: log-transformed dose regression. dmd.124.001643
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Buprenorphine-3-glucuronide (B3G) and norbuprenorphine-3-glucuronide (NB3G) are biologically active, with plasma concentrations that approximate or exceed those of the parent drugsupported
Glucuronide metabolites of buprenorphine (B3G) and norbuprenorphine (NB3G) are biologically active. Major metabolite plasma concentrations approximate or exceed parent drug concentrations. aln.0b013e318238fea0
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →