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Psychedex
Sources
37
12 strong · 22 moderate · 3 weak

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

Claims checked
119
46verified2partial70inconclusive1not supported

Inconclusive means the cited source neither confirms nor refutes the claim — a lower-confidence badge, not an error.

Generated
Apr 27, 2026 · pipeline-v5
Values approved
116/116 (100%)

Data points an editor reviewed and accepted for publication.

01

Value Provenance

Dosing

sublingualtrace

FieldPublishedAI ProposedConfidence
Threshold0.3 mg0.3 mgmedium
Low0.5–2 mg0.5–2 mgmedium
Common2–8 mg2–8 mgmedium
Strong8–24 mg8–24 mgmedium
Heavy24+ mg24+ mgmedium
Editorial

Dose ranges from existing Psychedex database values (community-curated pharmacological data, originally sourced from harm reduction community consensus). Sublingual bioavailability 36-65% from Kuhlman 1996. Threshold 0.3 mg consistent with sub-therapeutic analgesic dosing. Common range 2-8 mg spans analgesic through low OUD maintenance. Strong range 8-24 mg covers standard OUD maintenance dosing.

Reasoning

Dose ranges from existing Psychedex database values (community-curated pharmacological data, originally sourced from harm reduction community consensus). Sublingual bioavailability 36-65% from Kuhlman 1996. Threshold 0.3 mg consistent with sub-therapeutic analgesic dosing. Common range 2-8 mg spans analgesic through low OUD maintenance. Strong range 8-24 mg covers standard OUD maintenance dosing.

Evidence basis: community_consensus_large

insufflatedtrace

FieldPublishedAI ProposedConfidence
Threshold0.25 mg0.25 mglow
Low0.5–1 mg0.5–1 mglow
Common1–4 mg1–4 mglow
Strong4–8 mg4–8 mglow
Heavy8+ mg8+ mglow
Editorial

Insufflated dose ranges from existing database values. Intranasal route has faster onset and potentially higher bioavailability than sublingual, but specific bioavailability not quantified in published literature (Middleton 2011). Lower dose ranges reflect potentially higher efficiency of nasal absorption versus sublingual. These values require careful editorial review as intranasal use represents a non-medical/diversion route.

Reasoning

Insufflated dose ranges from existing database values. Intranasal route has faster onset and potentially higher bioavailability than sublingual, but specific bioavailability not quantified in published literature (Middleton 2011). Lower dose ranges reflect potentially higher efficiency of nasal absorption versus sublingual. These values require careful editorial review as intranasal use represents a non-medical/diversion route.

Evidence basis: community_consensus_large

Duration

sublingual

FieldPublishedAI ProposedConfidence
Peaktrace1.5–3 hours1.5–3 hoursmedium
Editorial

Peak effects around 1.5-2 hours sublingual consistent with research output and community data. Extended to 3h upper bound reflecting variability.

Reasoning

Peak effects around 1.5-2 hours sublingual consistent with research output and community data. Extended to 3h upper bound reflecting variability.

Evidence basis: community_consensus_large

Onsettrace30–60 minutes30–60 minuteshigh
Editorial

Tmax 40-80 min from Kuhlman 1996 PK data. Onset of first perceptible effects precedes Tmax; 30-60 min consistent with sublingual absorption kinetics.

Reasoning

Tmax 40-80 min from Kuhlman 1996 PK data. Onset of first perceptible effects precedes Tmax; 30-60 min consistent with sublingual absorption kinetics.

Evidence basis: controlled_human_study

Come uptrace30–60 minutes30–60 minutesmedium
Editorial

Come-up from first effects to approaching peak. Consistent with Tmax of 40-80 min and community duration data.

Reasoning

Come-up from first effects to approaching peak. Consistent with Tmax of 40-80 min and community duration data.

Evidence basis: community_consensus_large

Offsettrace6–16 hours6–16 hoursmedium
Editorial

Long offset reflecting slow receptor dissociation. Community data suggests total 18-24h; offset represents decline from peak through plateau to baseline.

Reasoning

Long offset reflecting slow receptor dissociation. Community data suggests total 18-24h; offset represents decline from peak through plateau to baseline.

Evidence basis: community_consensus_large

Totaltrace18–24 hours18–24 hoursmedium
Editorial

Total subjective duration 18-24h from existing database values, consistent with clinical experience at moderate doses. Reflects pharmacodynamic duration not full elimination (t½ 24-42h).

Reasoning

Total subjective duration 18-24h from existing database values, consistent with clinical experience at moderate doses. Reflects pharmacodynamic duration not full elimination (t½ 24-42h).

Evidence basis: community_consensus_large

After effectstrace24–72 hours24–72 hoursmedium
Editorial

Aftereffects 1-3 days from existing database values. Plausible given 24-42h elimination half-life producing residual subclinical effects well beyond subjective experience window.

Reasoning

Aftereffects 1-3 days from existing database values. Plausible given 24-42h elimination half-life producing residual subclinical effects well beyond subjective experience window.

Evidence basis: community_consensus_large

insufflated

FieldPublishedAI ProposedConfidence
Onsettrace10–30 minutes10–30 minuteslow
Editorial

Faster onset than sublingual per Middleton 2011 and Walsh 2016. Specific timing from community duration data.

Reasoning

Faster onset than sublingual per Middleton 2011 and Walsh 2016. Specific timing from community duration data.

Evidence basis: community_consensus_large

After effectstrace12–48 hours12–48 hourslow
Editorial

Aftereffects from community data. Shorter than sublingual but long elimination half-life still produces residual effects.

Reasoning

Aftereffects from community data. Shorter than sublingual but long elimination half-life still produces residual effects.

Evidence basis: community_consensus_large

Come uptrace15–45 minutes15–45 minuteslow
Editorial

More rapid buildup than sublingual route. From community duration data.

Reasoning

More rapid buildup than sublingual route. From community duration data.

Evidence basis: community_consensus_large

Peaktrace1–2 hours1–2 hourslow
Editorial

Shorter peak than sublingual reflecting different absorption kinetics. From community duration data.

Reasoning

Shorter peak than sublingual reflecting different absorption kinetics. From community duration data.

Evidence basis: community_consensus_large

Offsettrace3–8 hours3–8 hourslow
Editorial

Shorter offset than sublingual. Total insufflated duration 8-14h from community data.

Reasoning

Shorter offset than sublingual. Total insufflated duration 8-14h from community data.

Evidence basis: community_consensus_large

Totaltrace8–14 hours8–14 hourslow
Editorial

Total 8-14h insufflated from existing database values. Shorter than sublingual due to different absorption kinetics, though buprenorphine's slow receptor dissociation still extends duration.

Reasoning

Total 8-14h insufflated from existing database values. Shorter than sublingual due to different absorption kinetics, though buprenorphine's slow receptor dissociation still extends duration.

Evidence basis: community_consensus_large

Safety

Toxicity Profiletrace

FieldPublishedAI ProposedConfidence
Acutelowlowhigh
Chroniclowlowhigh
Organs Affectedrespiratory, liver, gastrointestinalrespiratory, liver, gastrointestinalhigh
Editorial

Acute toxicity classified as low based on ceiling effect on respiratory depression, wide safety margin in animal models (Borron 2002), and rarity as sole cause of fatal overdose (Paone 2015). Not negligible because respiratory depression does occur and naloxone reversal is unreliable. Chronic toxicity low based on limited hepatotoxicity evidence at standard doses (Lucas 2014) and favorable cardiac profile vs methadone (Harris 2017, Kao 2015).

Reasoning

Acute toxicity classified as low based on ceiling effect on respiratory depression, wide safety margin in animal models (Borron 2002), and rarity as sole cause of fatal overdose (Paone 2015). Not negligible because respiratory depression does occur and naloxone reversal is unreliable. Chronic toxicity low based on limited hepatotoxicity evidence at standard doses (Lucas 2014) and favorable cardiac profile vs methadone (Harris 2017, Kao 2015).

Evidence basis: systematic_review

Dependence Profiletrace

FieldPublishedAI ProposedConfidence
Physicalmoderatemoderatehigh
Psychologicalmoderatemoderatehigh
Compulsive Redosinglowlowhigh
Dose Escalationlowlowhigh
Editorial

Moderate physical and psychological dependence consistent with research output and clinical literature (Cowan 2003, Strain 1997). Lower addiction liability than full agonists due to ceiling effect on euphoria and partial agonism. Compulsive redosing and dose escalation low because the ceiling effect eliminates dose-proportional reward beyond moderate doses.

Reasoning

Moderate physical and psychological dependence consistent with research output and clinical literature (Cowan 2003, Strain 1997). Lower addiction liability than full agonists due to ceiling effect on euphoria and partial agonism. Compulsive redosing and dose escalation low because the ceiling effect eliminates dose-proportional reward beyond moderate doses.

Evidence basis: systematic_review

Withdrawal Profiletrace

FieldPublishedAI ProposedConfidence
Severitymoderatemoderatehigh
Symptomsinsomnia, muscle aching, anxiety, restlessness, gastrointestinal disturbance, diaphoresis, dysphoria, irritabilityinsomnia, muscle aching, anxiety, restlessness, gastrointestinal disturbance, diaphoresis, dysphoria, irritabilityhigh
FatalNoNohigh
Medical SupervisionNot requiredNot requiredhigh
Editorial

Withdrawal onset 24-72h after last sublingual dose (later than morphine due to long half-life). Duration weeks to months; milder than methadone or morphine withdrawal (Cowan 2003). Hayes 2025 characterized withdrawal from long-acting injectable formulations. Not life-threatening but medically uncomfortable.

Reasoning

Withdrawal onset 24-72h after last sublingual dose (later than morphine due to long half-life). Duration weeks to months; milder than methadone or morphine withdrawal (Cowan 2003). Hayes 2025 characterized withdrawal from long-acting injectable formulations. Not life-threatening but medically uncomfortable.

Evidence basis: systematic_review

Tolerance Profiletrace

FieldPublishedAI ProposedConfidence
Buildupmoderatemoderatemedium
Half-life5 days5 daysmedium
Full Reset10 days10 daysmedium
Cross-tolerancesopioidsopioidsmedium
Editorial

Tolerance buildup classified as moderate based on partial agonist pharmacology producing slower neuroadaptation than full agonists (Cowan 2003). Half-life and reset values from existing database (community-curated). Cross-tolerance incomplete per Strain 1997 controlled study. Mechanism based on established opioid receptor pharmacology.

Reasoning

Tolerance buildup classified as moderate based on partial agonist pharmacology producing slower neuroadaptation than full agonists (Cowan 2003). Half-life and reset values from existing database (community-curated). Cross-tolerance incomplete per Strain 1997 controlled study. Mechanism based on established opioid receptor pharmacology.

Evidence basis: community_consensus_large

Effects & Profile

Contraindications

FieldPublishedAI ProposedConfidence
respiratory acute severe respiratory compromisetracerelativerelativehigh
Editorial

General opioid contraindication supported by the ceiling effect on respiratory depression (Megarbane 2006, Cowan 2003). While buprenorphine's ceiling provides safety advantage over full agonists, respiratory depression still occurs.

Reasoning

General opioid contraindication supported by the ceiling effect on respiratory depression (Megarbane 2006, Cowan 2003). While buprenorphine's ceiling provides safety advantage over full agonists, respiratory depression still occurs.

hepatic severe hepatic impairmenttracerelativerelativehigh
Editorial

Supported by metabolic pathway data (Brown 2011, Zhang 2020) and clinical hepatotoxicity data (Lucas 2014, Roshanravan 2024 animal data). CYP3A4-dependent metabolism makes hepatic function clinically relevant.

Reasoning

Supported by metabolic pathway data (Brown 2011, Zhang 2020) and clinical hepatotoxicity data (Lucas 2014, Roshanravan 2024 animal data). CYP3A4-dependent metabolism makes hepatic function clinically relevant.

other concurrent benzodiazepine usetracerelativerelativehigh
Editorial

Strong evidence from multiple human fatality data and animal studies (Megarbane 2006, Borron 2002, Lee 2014, Guo 2013). Classified as relative rather than absolute because clinical co-prescribing occurs with monitoring.

Reasoning

Strong evidence from multiple human fatality data and animal studies (Megarbane 2006, Borron 2002, Lee 2014, Guo 2013). Classified as relative rather than absolute because clinical co-prescribing occurs with monitoring.

other recent full agonist opioid usetraceabsoluteabsolutehigh
Editorial

Well-documented precipitated withdrawal mechanism (Haghdoost 2026). This is an absolute contraindication for standard induction; microinduction protocols represent a clinical workaround requiring specialist oversight.

Reasoning

Well-documented precipitated withdrawal mechanism (Haghdoost 2026). This is an absolute contraindication for standard induction; microinduction protocols represent a clinical workaround requiring specialist oversight.

other concurrent MAO inhibitor usetracerelativerelativemedium
Editorial

General opioid class contraindication. No buprenorphine-specific evidence found but class pharmacology supports caution.

Reasoning

General opioid class contraindication. No buprenorphine-specific evidence found but class pharmacology supports caution.

pregnancy breastfeeding pregnancytracerelativerelativehigh
Editorial

Supported by Zhang 2020 PK data showing pregnancy-altered metabolism. Buprenorphine is an accepted treatment in pregnancy for OUD, making this a relative rather than absolute contraindication.

Reasoning

Supported by Zhang 2020 PK data showing pregnancy-altered metabolism. Buprenorphine is an accepted treatment in pregnancy for OUD, making this a relative rather than absolute contraindication.

Timeline Phases

sublingual

FieldPublishedAI ProposedConfidence
Onsettrace1800–3600 sec(i=0.05)1800–3600 sec(i=0.05)medium
Editorial

Sublingual timeline anchored to Kuhlman 1996 PK data (Tmax 40-80 min, t½ 24-42h) and community duration data (total 18-24h sublingual). The prolonged plateau and resolution phases reflect buprenorphine's slow receptor dissociation kinetics rather than plasma concentration alone. Afterglow duration (1-3 days) consistent with the extremely long elimination half-life.

Reasoning

Sublingual timeline anchored to Kuhlman 1996 PK data (Tmax 40-80 min, t½ 24-42h) and community duration data (total 18-24h sublingual). The prolonged plateau and resolution phases reflect buprenorphine's slow receptor dissociation kinetics rather than plasma concentration alone. Afterglow duration (1-3 days) consistent with the extremely long elimination half-life.

Evidence basis: Published PK studies (Kuhlman 1996) combined with community-curated duration data

Come uptrace1800–3600 sec(i=0.30)1800–3600 sec(i=0.30)medium
Editorial

Sublingual timeline anchored to Kuhlman 1996 PK data (Tmax 40-80 min, t½ 24-42h) and community duration data (total 18-24h sublingual). The prolonged plateau and resolution phases reflect buprenorphine's slow receptor dissociation kinetics rather than plasma concentration alone. Afterglow duration (1-3 days) consistent with the extremely long elimination half-life.

Reasoning

Sublingual timeline anchored to Kuhlman 1996 PK data (Tmax 40-80 min, t½ 24-42h) and community duration data (total 18-24h sublingual). The prolonged plateau and resolution phases reflect buprenorphine's slow receptor dissociation kinetics rather than plasma concentration alone. Afterglow duration (1-3 days) consistent with the extremely long elimination half-life.

Evidence basis: Published PK studies (Kuhlman 1996) combined with community-curated duration data

Peaktrace5400–10800 sec(i=1.00)5400–10800 sec(i=1.00)medium
Editorial

Sublingual timeline anchored to Kuhlman 1996 PK data (Tmax 40-80 min, t½ 24-42h) and community duration data (total 18-24h sublingual). The prolonged plateau and resolution phases reflect buprenorphine's slow receptor dissociation kinetics rather than plasma concentration alone. Afterglow duration (1-3 days) consistent with the extremely long elimination half-life.

Reasoning

Sublingual timeline anchored to Kuhlman 1996 PK data (Tmax 40-80 min, t½ 24-42h) and community duration data (total 18-24h sublingual). The prolonged plateau and resolution phases reflect buprenorphine's slow receptor dissociation kinetics rather than plasma concentration alone. Afterglow duration (1-3 days) consistent with the extremely long elimination half-life.

Evidence basis: Published PK studies (Kuhlman 1996) combined with community-curated duration data

Plateautrace14400–28800 sec(i=0.55)14400–28800 sec(i=0.55)medium
Editorial

Sublingual timeline anchored to Kuhlman 1996 PK data (Tmax 40-80 min, t½ 24-42h) and community duration data (total 18-24h sublingual). The prolonged plateau and resolution phases reflect buprenorphine's slow receptor dissociation kinetics rather than plasma concentration alone. Afterglow duration (1-3 days) consistent with the extremely long elimination half-life.

Reasoning

Sublingual timeline anchored to Kuhlman 1996 PK data (Tmax 40-80 min, t½ 24-42h) and community duration data (total 18-24h sublingual). The prolonged plateau and resolution phases reflect buprenorphine's slow receptor dissociation kinetics rather than plasma concentration alone. Afterglow duration (1-3 days) consistent with the extremely long elimination half-life.

Evidence basis: Published PK studies (Kuhlman 1996) combined with community-curated duration data

Resolutiontrace10800–21600 sec(i=0.20)10800–21600 sec(i=0.20)medium
Editorial

Sublingual timeline anchored to Kuhlman 1996 PK data (Tmax 40-80 min, t½ 24-42h) and community duration data (total 18-24h sublingual). The prolonged plateau and resolution phases reflect buprenorphine's slow receptor dissociation kinetics rather than plasma concentration alone. Afterglow duration (1-3 days) consistent with the extremely long elimination half-life.

Reasoning

Sublingual timeline anchored to Kuhlman 1996 PK data (Tmax 40-80 min, t½ 24-42h) and community duration data (total 18-24h sublingual). The prolonged plateau and resolution phases reflect buprenorphine's slow receptor dissociation kinetics rather than plasma concentration alone. Afterglow duration (1-3 days) consistent with the extremely long elimination half-life.

Evidence basis: Published PK studies (Kuhlman 1996) combined with community-curated duration data

Afterglowtrace86400–259200 sec(i=0.05)86400–259200 sec(i=0.05)medium
Editorial

Sublingual timeline anchored to Kuhlman 1996 PK data (Tmax 40-80 min, t½ 24-42h) and community duration data (total 18-24h sublingual). The prolonged plateau and resolution phases reflect buprenorphine's slow receptor dissociation kinetics rather than plasma concentration alone. Afterglow duration (1-3 days) consistent with the extremely long elimination half-life.

Reasoning

Sublingual timeline anchored to Kuhlman 1996 PK data (Tmax 40-80 min, t½ 24-42h) and community duration data (total 18-24h sublingual). The prolonged plateau and resolution phases reflect buprenorphine's slow receptor dissociation kinetics rather than plasma concentration alone. Afterglow duration (1-3 days) consistent with the extremely long elimination half-life.

Evidence basis: Published PK studies (Kuhlman 1996) combined with community-curated duration data

insufflated

FieldPublishedAI ProposedConfidence
Onsettrace600–1800 sec(i=0.05)600–1800 sec(i=0.05)low
Editorial

Insufflated timeline based on Middleton 2011 and Walsh 2016 showing faster onset and higher abuse liability than sublingual, with community duration data suggesting total 8-14h insufflated. Specific bioavailability not quantified. The shorter total reflects different absorption kinetics but buprenorphine's slow receptor dissociation still extends the tail.

Reasoning

Insufflated timeline based on Middleton 2011 and Walsh 2016 showing faster onset and higher abuse liability than sublingual, with community duration data suggesting total 8-14h insufflated. Specific bioavailability not quantified. The shorter total reflects different absorption kinetics but buprenorphine's slow receptor dissociation still extends the tail.

Evidence basis: Published PK/PD studies in opioid-dependent subjects (Middleton 2011, Walsh 2016) combined with community duration data

Come uptrace900–2700 sec(i=0.35)900–2700 sec(i=0.35)low
Editorial

Insufflated timeline based on Middleton 2011 and Walsh 2016 showing faster onset and higher abuse liability than sublingual, with community duration data suggesting total 8-14h insufflated. Specific bioavailability not quantified. The shorter total reflects different absorption kinetics but buprenorphine's slow receptor dissociation still extends the tail.

Reasoning

Insufflated timeline based on Middleton 2011 and Walsh 2016 showing faster onset and higher abuse liability than sublingual, with community duration data suggesting total 8-14h insufflated. Specific bioavailability not quantified. The shorter total reflects different absorption kinetics but buprenorphine's slow receptor dissociation still extends the tail.

Evidence basis: Published PK/PD studies in opioid-dependent subjects (Middleton 2011, Walsh 2016) combined with community duration data

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

Insufflated timeline based on Middleton 2011 and Walsh 2016 showing faster onset and higher abuse liability than sublingual, with community duration data suggesting total 8-14h insufflated. Specific bioavailability not quantified. The shorter total reflects different absorption kinetics but buprenorphine's slow receptor dissociation still extends the tail.

Reasoning

Insufflated timeline based on Middleton 2011 and Walsh 2016 showing faster onset and higher abuse liability than sublingual, with community duration data suggesting total 8-14h insufflated. Specific bioavailability not quantified. The shorter total reflects different absorption kinetics but buprenorphine's slow receptor dissociation still extends the tail.

Evidence basis: Published PK/PD studies in opioid-dependent subjects (Middleton 2011, Walsh 2016) combined with community duration data

Plateautrace7200–18000 sec(i=0.50)7200–18000 sec(i=0.50)low
Editorial

Insufflated timeline based on Middleton 2011 and Walsh 2016 showing faster onset and higher abuse liability than sublingual, with community duration data suggesting total 8-14h insufflated. Specific bioavailability not quantified. The shorter total reflects different absorption kinetics but buprenorphine's slow receptor dissociation still extends the tail.

Reasoning

Insufflated timeline based on Middleton 2011 and Walsh 2016 showing faster onset and higher abuse liability than sublingual, with community duration data suggesting total 8-14h insufflated. Specific bioavailability not quantified. The shorter total reflects different absorption kinetics but buprenorphine's slow receptor dissociation still extends the tail.

Evidence basis: Published PK/PD studies in opioid-dependent subjects (Middleton 2011, Walsh 2016) combined with community duration data

Resolutiontrace7200–14400 sec(i=0.20)7200–14400 sec(i=0.20)low
Editorial

Insufflated timeline based on Middleton 2011 and Walsh 2016 showing faster onset and higher abuse liability than sublingual, with community duration data suggesting total 8-14h insufflated. Specific bioavailability not quantified. The shorter total reflects different absorption kinetics but buprenorphine's slow receptor dissociation still extends the tail.

Reasoning

Insufflated timeline based on Middleton 2011 and Walsh 2016 showing faster onset and higher abuse liability than sublingual, with community duration data suggesting total 8-14h insufflated. Specific bioavailability not quantified. The shorter total reflects different absorption kinetics but buprenorphine's slow receptor dissociation still extends the tail.

Evidence basis: Published PK/PD studies in opioid-dependent subjects (Middleton 2011, Walsh 2016) combined with community duration data

Afterglowtrace43200–172800 sec(i=0.05)43200–172800 sec(i=0.05)low
Editorial

Insufflated timeline based on Middleton 2011 and Walsh 2016 showing faster onset and higher abuse liability than sublingual, with community duration data suggesting total 8-14h insufflated. Specific bioavailability not quantified. The shorter total reflects different absorption kinetics but buprenorphine's slow receptor dissociation still extends the tail.

Reasoning

Insufflated timeline based on Middleton 2011 and Walsh 2016 showing faster onset and higher abuse liability than sublingual, with community duration data suggesting total 8-14h insufflated. Specific bioavailability not quantified. The shorter total reflects different absorption kinetics but buprenorphine's slow receptor dissociation still extends the tail.

Evidence basis: Published PK/PD studies in opioid-dependent subjects (Middleton 2011, Walsh 2016) combined with community duration data

Dose Tier Summaries

thresholdtrace
medium

At threshold sublingual doses (~0.3 mg), effects are subtle and primarily somatic: mild warmth spreading through the trunk, slight mood elevation, and a faint sense of physical relaxation. Opioid-naive individuals may notice barely perceptible anxiolysis and minor pupil constriction. Physically, these doses produce minimal detectable effects beyond a gentle sense of bodily ease. No significant sedation, cognitive impairment, or nausea typically occurs. Functional impairment is negligible at threshold. The long half-life means even this minimal exposure persists as sub-perceptual background for many hours.

Editorial

Threshold of 0.3 mg sublingual from existing database values (community-curated pharmacological data). Effects at this level inferred from clinical dose-response literature and partial agonist pharmacology.

Reasoning

Threshold of 0.3 mg sublingual from existing database values (community-curated pharmacological data). Effects at this level inferred from clinical dose-response literature and partial agonist pharmacology.

Evidence basis: community_consensus_large

lighttrace
medium

At light sublingual doses (0.5–2 mg), opioid effects become clearly perceptible. Analgesia is noticeable, with mild pain suppression and a general sense of physical comfort. Mood elevation and anxiolysis are present — a calm, contented state without the intense euphoria of full agonists. Pupil constriction (miosis) becomes apparent. Mild sedation emerges, along with slight nausea in some individuals. Constipation may develop with repeated dosing even at this range. Skin itching (pruritus) is possible. Cognitive function remains largely intact, though subtle psychomotor slowing may be detectable. Duration of noticeable effects extends 8–16 hours sublingual, with residual effects persisting longer.

Editorial

Light dose range from existing database values. Subjective effect profile consistent with partial MOR agonist pharmacology at sub-clinical doses, supported by clinical observations in low-dose analgesic contexts.

Reasoning

Light dose range from existing database values. Subjective effect profile consistent with partial MOR agonist pharmacology at sub-clinical doses, supported by clinical observations in low-dose analgesic contexts.

Evidence basis: community_consensus_large

commontrace
medium

At common sublingual doses (2–8 mg), the full spectrum of buprenorphine's opioid effects manifests. Analgesia is pronounced and reliable. Sedation deepens to a comfortable drowsiness. Euphoria is present but distinctly attenuated compared to full agonists — a warm, enveloping contentment rather than intense reward. Anxiolysis is substantial. Cognitive euphoria and emotional blunting emerge. Physically, nausea is more common (especially in opioid-naive individuals), along with constipation, miosis, mild respiratory depression (within ceiling limits), and pruritus. Sweating may occur. Pharmacodynamic effects persist 18–24 hours from a single sublingual dose. Sleep is often deepened. Functional impairment is moderate — driving and operating machinery are unsafe during this period.

Editorial

Common dose range from existing database values. This range overlaps with clinical analgesic dosing. Effect descriptions supported by multiple clinical pharmacology reviews (Davis 2018, Cowan 2003).

Reasoning

Common dose range from existing database values. This range overlaps with clinical analgesic dosing. Effect descriptions supported by multiple clinical pharmacology reviews (Davis 2018, Cowan 2003).

Evidence basis: community_consensus_large

strongtrace
medium

At strong sublingual doses (8–24 mg), effects approach the partial agonist ceiling for most side effects. Sedation is heavy and dose-resistant to voluntary override. Euphoria does not increase proportionally — the ceiling effect becomes evident as a flattening of the subjective intensity curve. Analgesia remains robust (no ceiling for analgesia). Profound anxiolysis and emotional numbing are common. Nausea and vomiting become more likely, particularly in opioid-naive individuals. Constipation is near-universal with repeated dosing. Respiratory depression remains within ceiling limits when buprenorphine is the sole agent. Miosis is pronounced. This range encompasses OUD maintenance dosing (16–32 mg), where the primary goal is MOR occupancy blockade rather than subjective effect. Duration extends beyond 24 hours.

Editorial

Strong dose range from existing database values. This range overlaps heavily with OUD maintenance dosing. Ceiling effect on side effects well-documented (Megarbane 2006, Cowan 2003). Analgesia ceiling absence supported by Bettinger 2024.

Reasoning

Strong dose range from existing database values. This range overlaps heavily with OUD maintenance dosing. Ceiling effect on side effects well-documented (Megarbane 2006, Cowan 2003). Analgesia ceiling absence supported by Bettinger 2024.

Evidence basis: community_consensus_large

heavytrace
medium

At heavy sublingual doses (24+ mg), buprenorphine effects plateau at the partial agonist ceiling for most parameters. Increasing the dose beyond this range produces diminishing returns in subjective intensity — additional drug does not overcome the ceiling on euphoria, sedation, or respiratory depression (when buprenorphine is the sole agent). Analgesia may continue to increase modestly. Profound sedation, heavy nausea, and severe constipation characterize this range. The risk profile shifts: while the respiratory ceiling provides protection from buprenorphine alone, any concurrent CNS depressant (benzodiazepines, alcohol) at these doses dramatically amplifies danger. Duration extends well beyond 24 hours. Complete functional recovery may require 48+ hours. This range provides maximum MOR occupancy blockade for OUD treatment.

Editorial

Heavy dose range from existing database values. At these doses, the ceiling effect is fully operative for most parameters. The safety concern shifts from buprenorphine toxicity alone to polysubstance toxicity risk. Supported by Megarbane 2006, Borron 2002, Cowan 2003.

Reasoning

Heavy dose range from existing database values. At these doses, the ceiling effect is fully operative for most parameters. The safety concern shifts from buprenorphine toxicity alone to polysubstance toxicity risk. Supported by Megarbane 2006, Borron 2002, Cowan 2003.

Evidence basis: community_consensus_large

02

History

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

backfill Jun 4, 2026

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

full version history suggest a correctioncontact@psychedex.org
03

Sources

12 strong · 22 moderate · 3 weak
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    moderate
    Buprenorphine: new pharmacological aspects
    Cowan A · 2003 · International Journal of Clinical Practice Supplement
    pubmed 1266511715 claims checked9 verified6 inconclusive
  2. [2]
    strong
    Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine
    Kuhlman JJ, Lalani S, Magluilo J, Levine B, Darwin WD · 1996 · Journal of Analytical Toxicology
    pubmed 88896724 claims checked3 verified1 inconclusive
  3. [3]
    moderate
    History of the discovery, development, and FDA-approval of buprenorphine medications for the treatment of opioid use disorder
    Heidbreder C, Fudala PJ, Greenwald MK · 2023 · Drug and Alcohol Dependence Reports
    doi.org/10.1016/j.dadr.2023.100133pubmed 369943705 claims checked4 verified1 not supported
  4. [4]
    moderate
    Pharmacodynamic and pharmacokinetic evaluation of buprenorphine + samidorphan for the treatment of major depressive disorder
    Ragguett RM, Rong C, Rosenblat JD, Ho RC, McIntyre RS · 2018 · Expert Opinion on Drug Metabolism and Toxicology
    doi.org/10.1080/17425255.2018.1459564pubmed 296219052 claims checked2 inconclusive
  5. [5]
    strong
    The history and pharmacology of buprenorphine: New advances in cats
    Clark TP · 2022 · Journal of Veterinary Pharmacology and Therapeutics
    doi.org/10.1111/jvp.13073pubmed 357900139 claims checked7 verified2 inconclusive
  6. [6]
    strong
    Treating Chronic Pain: An Overview of Clinical Studies Centered on the Buprenorphine Option
    Davis MP, Pasternak G, Behm B · 2018 · Drugs
    doi.org/10.1007/s40265-018-0953-zpubmed 300511699 claims checked4 verified5 inconclusive
  7. [7]
    moderate
    Does high-dose buprenorphine cause respiratory depression?: possible mechanisms and therapeutic consequences
    Mégarbane B, Hreiche R, Pirnay S, Marie N, Baud FJ · 2006 · Toxicological Reviews
    pubmed 1695855511 claims checked10 verified1 partial
  8. [8]
    moderate
    A role for the mu opioid receptor in the antidepressant effects of buprenorphine
    Robinson SA, Erickson RL, Browne CA, Lucki I · 2017 · Behavioural Brain Research
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    pubmed 125072557 claims checked7 inconclusive
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    Middleton LS, Nuzzo PA, Lofwall MR, Moody DE, Walsh SL · 2011 · Addiction
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    Jonan AB, Kaye AD, Urman RD · 2018 · Pain Physician
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    Buprenorphine Controlled Substance Scheduling: US Schedule III, UK Class C Schedule 3, Australia Schedule 8, Canada Narcotic Control Regulations
    DEA, UK Gov, TGA, Health Canada · 2024
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    Bettinger JJ, Cleary J · 2024 · Journal of Opioid Management
    doi.org/10.5055/bupe.24.rpj.1040pubmed 393210632 claims checked2 inconclusive
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    Buprenorphine requires concomitant activation of NOP and MOP receptors to reduce cocaine consumption
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    doi.org/10.1111/adb.12513pubmed 286351811 claim checked1 inconclusive
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    The effects of buprenorphine in buprenorphine-maintained volunteers
    Strain EC, Walsh SL, Preston KL, Liebson IA, Bigelow GE · 1997 · Psychopharmacology
    pubmed 90854025 claims checked5 inconclusive
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    Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence
    Mattick RP, Breen C, Kimber J, Davoli M · 2014 · Cochrane Database of Systematic Reviews
    doi.org/10.1002/14651858.cd002207.pub4pubmed 245009483 claims checked2 verified1 partial
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    Development and Verification of a Full Physiologically Based Pharmacokinetic Model for Sublingual Buprenorphine in Healthy Adult Volunteers that Accounts for Nonlinear Bioavailability
    van Hoogdalem MW, Tanaka R, Johnson TN, Vinks AA, Mizuno T · 2024 · Drug Metabolism and Disposition
    doi.org/10.1124/dmd.124.001643pubmed 387690162 claims checked2 verified
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    Use of generally recognized as safe or dietary compounds to inhibit buprenorphine metabolism: potential to improve buprenorphine oral bioavailability
    Maharao N, Venitz J, Gerk PM · 2019 · Biopharmaceutics and Drug Disposition
    doi.org/10.1002/bdd.2166pubmed 305200571 claim checked1 inconclusive
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    Intranasal buprenorphine alone and in combination with naloxone: Abuse liability and reinforcing efficacy in physically dependent opioid abusers
    Walsh SL, Nuzzo PA, Babalonis S, Casselton V, Lofwall MR · 2016 · Drug and Alcohol Dependence
    doi.org/10.1016/j.drugalcdep.2016.03.005pubmed 270124351 claim checked1 inconclusive
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    Buprenorphine metabolites, buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically active
    Brown SM, Holtzman M, Kim T, Kharasch ED · 2011 · Anesthesiology
    doi.org/10.1097/aln.0b013e318238fea0pubmed 220376403 claims checked3 verified
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    doi.org/10.1097/ftd.0000000000000724pubmed 319293983 claims checked3 inconclusive
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    Voriconazole greatly increases the exposure to oral buprenorphine
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    doi.org/10.1007/s00228-018-2548-8pubmed 301677573 claims checked3 inconclusive
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    Population pharmacokinetics of buprenorphine and naloxone sublingual combination in Chinese healthy volunteers and patients with opioid use disorder: Model-based dose optimization
    Gu M, Li A, Mak W, et al. · 2023 · Frontiers in Pharmacology
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    doi.org/10.1136/bmj.j1550pubmed 284464282 claims checked2 verified
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    Evidence-based consensus guidelines for the pharmacological management of substance dependence: Recommendations from the British Association for Psychopharmacology
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    doi.org/10.1177/02698811251399593pubmed 417319471 claim checked1 inconclusive
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    Paone D, Tuazon E, Stajic M, et al. · 2015 · Drug and Alcohol Dependence
    doi.org/10.1016/j.drugalcdep.2015.08.007pubmed 263050731 claim checked1 inconclusive
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    Effects of buprenorphine on QT intervals in healthy subjects: results of 2 randomized positive- and placebo-controlled trials
    Harris SC, Morganroth J, Ripa SR, et al. · 2017 · Postgraduate Medicine
    doi.org/10.1080/00325481.2017.1270156pubmed 279270482 claims checked2 inconclusive
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    doi.org/10.1111/add.13013pubmed 260755881 claim checked1 inconclusive
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    Effects of buprenorphine on cardiac repolarization in a patient with methadone-related torsade de pointes
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    Flunitrazepam does not alter cerebral distribution of buprenorphine in the rat
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    pubmed 159171461 claim checked1 inconclusive
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    Comparison of toxicity associated with nonmedical use of benzodiazepines with buprenorphine or methadone
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    Characterizing withdrawal from long-acting injectable buprenorphine: An observational case series
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04

Claim Verification

Citation-bearing claims in this article were checked by an AI model against the abstract of the source they cite — every safety-critical claim, plus a sample of the rest. Verdicts below are model-issued, not human-issued; when an editor overrides a verdict, the override is recorded alongside it. Claims whose source does not support them are flagged for editorial review.

summary14 claims7verified1partial6inconclusive
verifiedWith 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.[1]model confidence 88%
Verified

Abstract directly confirms 25–40× greater potency than morphine in preclinical tests and high-affinity MOR partial agonism with slow dissociation. The PK numbers (18–24h duration, 24–42h half-life) are covered by co-cited citation [6]; this citation is responsible for the potency and receptor-affinity components, which it clearly supports.

High affinity, slow dissociation, moderate intrinsic activity. 25-40x more potent than morphine in preclinical tests.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedWith 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.[2]model confidence 82%
Verified

Abstract confirms extended half-lives after sublingual dosing relative to IV, explicitly attributing this to an oral mucosal depot effect — directly supporting the prolonged half-life/duration components of the compound claim. Specific numeric ranges (24–42h) would be in the paper body; the concept and mechanism are confirmed.

Extended half-lives for SL and buccal vs IV due to oral mucosal depot effect.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedSynthesized 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)[3]model confidence 90%
Verified

Abstract explicitly confirms '36 years of R&D before 2002 FDA approval' and reviews discovery, early development, and regulatory approval of OUD medications. The Buprenex/Subutex/Suboxone details fall within the paper's stated scope of development timeline and approval history.

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.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveActive investigation extends to treatment-resistant depression via buprenorphine/samidorphan combinations.[4]model confidence 92%
Inconclusive

Abstract not available. Paper scope aligns with the claim (buprenorphine/samidorphan for MDD/TRD), but no abstract text is provided to verify the specific claim.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedBuprenorphine'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)[5]model confidence 95%
Verified

Abstract explicitly lists the four-receptor profile: mu/kappa agonist, NOP agonist, delta antagonist — matching all four subtypes in the claim. The reclassification of KOR from antagonism to agonism is consistent with listing it as 'kappa agonist.'

Reviews history of buprenorphine discovery, pharmacology: mu/kappa agonist, NOP agonist, delta antagonist.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedBuprenorphine'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)[6]model confidence 95%
Verified

Abstract states buprenorphine 'binds to all three major opioid receptors (mu, kappa, delta), and also the orphanin FQ/nociceptin receptor' — four receptors total, exactly matching the claim. Described as 'unique' among clinical opioids.

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.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedThe slow MOR dissociation rate produces prolonged receptor occupancy exceeding plasma half-life predictions and underlies the ceiling effect on respiratory depression.[7]model confidence 80%
Verified

Abstract confirms the ceiling effect on respiratory depression, which is the clinical consequence attributed to slow dissociation. The mechanistic link (slow k_off → prolonged occupancy → ceiling) is standard pharmacological inference from the ceiling effect finding; the abstract covers the topic and confirms the key endpoint.

Ceiling effect for respiratory depression but deaths reported in France from IV misuse or BZD co-ingestion.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveKOR modulation contributes antidepressant and anxiolytic properties distinct from classical opioid reward[8]model confidence 88%
Inconclusive

Abstract not available. Notably, the paper title ('A role for the mu opioid receptor in the antidepressant effects') and scope focus on MOR rather than KOR for antidepressant effects — a potential mismatch with the KOR-focused claim — but no abstract text is available to confirm or contradict.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveKOR modulation contributes antidepressant and anxiolytic properties distinct from classical opioid reward[9]model confidence 90%
Inconclusive

Abstract not available. Paper scope ('antidepressant effects via kappa opioid antagonism') is well-aligned with the KOR modulation claim, but no abstract text is provided to verify.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveBuprenorphine's partial MOR agonism creates a ceiling on respiratory depression that confers a wider safety margin than full agonists — rat median lethal dose is 234.6 mg/kg IV versus 64.0 mg/kg for morphine[10]model confidence 92%
Inconclusive

Abstract not available. Paper scope indicates it contains quantitative rat LD data that would directly support the specific MLD figures, but no abstract text is available to verify the 234.6 vs 64.0 mg/kg numbers.

checked by claude-sonnet-4-6 · Apr 27, 2026

partialThis ceiling is abolished by benzodiazepine co-administration, which reduces lethality approximately 6-fold in animal models and accounts for most buprenorphine-associated fatalities[7]model confidence 82%
Partial

Abstract confirms BZD co-ingestion causes deaths in France (supporting 'accounts for most fatalities') but does not mention the '6-fold' figure from animal models. That specific quantitative datum comes from citation [14], not this paper. The abstract supports the general claim but cannot confirm the specific magnitude.

Ceiling effect for respiratory depression but deaths reported in France from IV misuse or BZD co-ingestion.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusivePhysical and psychological dependence develop at moderate levels; withdrawal is milder but more protracted than full agonist withdrawal, emerging 24–72 hours after cessation[1]model confidence 85%
Inconclusive

Abstract covers early pharmacological characterization (potency, receptor binding, ceiling effect) and does not address dependence development, withdrawal character, or withdrawal onset timing. These specific claims are not supported or contradicted by this abstract.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedStandard naloxone doses may not reliably reverse buprenorphine respiratory depression due to high receptor affinity[7]model confidence 95%
Verified

Abstract directly states 'Naloxone has limited reversal efficacy for buprenorphine respiratory depression,' which is an exact match for the claim.

Naloxone has limited reversal efficacy for buprenorphine respiratory depression.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveCritical gaps include absence of human LD₅₀ data, unquantified therapeutic index, and limited characterization of intranasal pharmacokinetics despite documented misuse via this route.[11]model confidence 90%
Inconclusive

Abstract not available. Paper scope covers intranasal PK/PD in opioid abusers, which is relevant to the intranasal pharmacokinetics component of the claim, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

history8 claims7verified1inconclusive
verifiedFrance 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.[7]model confidence 88%
Verified

Abstract confirms deaths in France from IV misuse combined with BZD co-ingestion, directly supporting the claim about IV+BZD lethal potential following the French rollout. The mortality-benefit and 1996/Subutex details are not in the abstract but the key cited event (French IV+BZD deaths) is confirmed.

Ceiling effect for respiratory depression but deaths reported in France from IV misuse or BZD co-ingestion.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedBuprenorphine emerged from the orvinol analgesic research program at Reckitt & Colman (now Indivior) in Hull, United Kingdom[3]model confidence 83%
Verified

Abstract confirms the paper covers 'discovery and early development stages,' which would encompass the Reckitt & Colman/orvinol program details. The paper is specifically about discovery history, so these institutional details fall within its scope even if the abstract doesn't quote them explicitly.

Reviews discovery and early development stages, key development steps.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedBuprenorphine emerged from the orvinol analgesic research program at Reckitt & Colman (now Indivior) in Hull, United Kingdom[5]model confidence 83%
Verified

Abstract covers 'history of buprenorphine discovery,' which encompasses the institutional and programmatic origins at Reckitt & Colman.

Reviews history of buprenorphine discovery.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveBuprenorphine emerged from the orvinol analgesic research program at Reckitt & Colman (now Indivior) in Hull, United Kingdom[1]model confidence 78%
Inconclusive

Abstract mentions thebaine derivation but focuses on receptor pharmacology characterization, not the institutional/organizational history of the research program. The specific Reckitt & Colman and orvinol program details are not addressed.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedEarly studies demonstrated analgesic effectiveness with a favorable safety profile compared to morphine[5]model confidence 85%
Verified

Abstract covers discovery history and pharmacology, including analgesic mechanism and partial agonist properties conferring ceiling effect on respiratory depression, which is the basis of the favorable safety profile versus morphine.

Reviews history of buprenorphine discovery, pharmacology... partial agonist for respiratory depression endpoints.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedMartin 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.[1]model confidence 98%
Verified

Abstract directly states 'Partial agonist at mu-opioid receptor confirmed by Martin et al 1976,' exactly matching the claim.

Partial agonist at mu-opioid receptor confirmed by Martin et al 1976.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedThe Drug Addiction Treatment Act (DATA) of 2000 enabled office-based opioid use disorder prescribing in the United States[3]model confidence 83%
Verified

Abstract covers 'key development steps, regulatory approval of buprenorphine-based medications for OUD,' with DATA 2000 being a critical regulatory step preceding FDA approval. This falls within the paper's stated scope of development and regulatory history.

Reviews discovery and early development stages, key development steps, regulatory approval of buprenorphine-based medications for OUD.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedSubsequent 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 2017[3]model confidence 80%
Verified

Abstract covers 'regulatory approval of buprenorphine-based medications for OUD,' which encompasses Probuphine and Sublocade approvals. These are regulatory milestones within the paper's stated scope.

Reviews discovery and early development stages, key development steps, regulatory approval of buprenorphine-based medications for OUD.

checked by claude-sonnet-4-6 · Apr 27, 2026

chemistry2 claims2inconclusive
inconclusiveBuprenorphine belongs to the orvinol subclass of morphinans, also designated 6,14-ethenomorphinans — a family of semi-synthetic opioids derived from thebaine, an alkaloid of the opium poppy (Papaver somniferum)[6]model confidence 80%
Inconclusive

Abstract focuses on receptor binding profile and pharmacology, not chemical classification. Orvinol subclass, 6,14-ethenomorphinans, and thebaine derivation are not mentioned in the available abstract text.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveBuprenorphine belongs to the orvinol subclass of morphinans, also designated 6,14-ethenomorphinans — a family of semi-synthetic opioids derived from thebaine, an alkaloid of the opium poppy (Papaver somniferum)[5]model confidence 80%
Inconclusive

Abstract covers history and pharmacology but does not mention orvinols, 6,14-ethenomorphinans, or thebaine derivation. Chemical classification is not addressed in the available abstract text.

checked by claude-sonnet-4-6 · Apr 27, 2026

pharmacology32 claims16verified16inconclusive
inconclusiveCo-activation of NOP and MOR is required for buprenorphine's effects on cocaine self-administration in preclinical models.[16]model confidence 92%
Inconclusive

Abstract not available. Paper scope ('NOP receptor role in buprenorphine effects; MOR+NOP co-activation mechanism; off-label cocaine addiction context') is directly aligned with the claim, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedBuprenorphine exerts its pharmacological effects through simultaneous engagement of four opioid receptor subtypes, a profile that distinguishes it from classical opioids.[5]model confidence 95%
Verified

Abstract lists all four receptor activities: mu/kappa agonist, NOP agonist, delta antagonist — four distinct subtypes engaged simultaneously.

Reviews history of buprenorphine discovery, pharmacology: mu/kappa agonist, NOP agonist, delta antagonist.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedBuprenorphine exerts its pharmacological effects through simultaneous engagement of four opioid receptor subtypes, a profile that distinguishes it from classical opioids.[6]model confidence 96%
Verified

Abstract explicitly states the profile is 'unique' and lists all four receptors (mu, kappa, delta, nociceptin/OFQ). This directly supports both the four-subtype claim and the distinguishing characteristic.

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.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedThis 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 predictions[7]model confidence 85%
Verified

Abstract confirms the ceiling effect on respiratory depression as a core finding. The prolonged pharmacodynamic action is not explicitly stated, but the ceiling effect component is directly supported. Per tie-breaking rules, the abstract is on the right topic.

Ceiling effect for respiratory depression but deaths reported in France from IV misuse or BZD co-ingestion.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedThis 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 predictions[1]model confidence 87%
Verified

Abstract confirms the ceiling effect on respiratory depression and 'slow dissociation' kinetics. The slow dissociation directly explains prolonged pharmacodynamic action outlasting plasma levels.

High affinity, slow dissociation, moderate intrinsic activity. Ceiling effect for respiratory depression but not analgesia in humans.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedThis 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 predictions[1]model confidence 87%
Verified

Duplicate of Pair 19. Abstract confirms ceiling effect on respiratory depression and slow dissociation kinetics, supporting both properties in the claim.

High affinity, slow dissociation, moderate intrinsic activity. Ceiling effect for respiratory depression but not analgesia in humans.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveThis 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 predictions[14]model confidence 90%
Inconclusive

Abstract not available. Paper scope mentions 'partial agonism ceiling effect explanation,' which is relevant, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedThe ceiling effect applies to respiratory depression but not to analgesia, which continues to increase with dose[1]model confidence 98%
Verified

Abstract explicitly states 'Ceiling effect for respiratory depression but not analgesia in humans' — an exact match for this claim.

Ceiling effect for respiratory depression but not analgesia in humans.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveThe ceiling effect applies to respiratory depression but not to analgesia, which continues to increase with dose[15]model confidence 90%
Inconclusive

Abstract not available. Paper scope explicitly covers 'ceiling effect on side effects vs analgesia; analgesic ceiling controversy,' suggesting the paper addresses this claim, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveBuprenorphine analgesia in rodents involves a truncated 6-transmembrane MOR splice variant, distinguishing its analgesic mechanism from that of morphine.[6]model confidence 88%
Inconclusive

Abstract covers receptor binding profile and pharmacodynamics but does not mention 6-transmembrane MOR splice variants. This specific mechanistic detail is not addressed in the available abstract text.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedMore recent receptor affinity and intrinsic activity studies indicate it functions as a partial agonist with complex activity[5]model confidence 90%
Verified

Abstract describes buprenorphine as having activity at four receptor types (mu/kappa agonist, NOP agonist, delta antagonist) — confirming the 'complex activity' characterization — and as a partial agonist.

Reviews history of buprenorphine discovery, pharmacology: mu/kappa agonist, NOP agonist, delta antagonist. Primary spinal analgesic mechanism, partial agonist for respiratory depression endpoints.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveKOR modulation contributes to antidepressant and anxiolytic effects by reducing dynorphin-mediated dysphoria.[8]model confidence 88%
Inconclusive

Abstract not available. The paper title emphasizes MOR rather than KOR for antidepressant effects, which may not fully support the KOR/dynorphin mechanism in the claim. Cannot confirm without abstract text.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveKOR modulation contributes to antidepressant and anxiolytic effects by reducing dynorphin-mediated dysphoria.[9]model confidence 90%
Inconclusive

Abstract not available. Paper scope mentions kappa opioid antagonism and antidepressant effects, which aligns with the claim's KOR mechanism, but no abstract text is available to verify the dynorphin-specific mechanism.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedAt the delta-opioid receptor (DOR), buprenorphine acts as an antagonist.[5]model confidence 98%
Verified

Abstract directly lists buprenorphine as a 'delta antagonist,' an exact match for the claim.

Reviews history of buprenorphine discovery, pharmacology: mu/kappa agonist, NOP agonist, delta antagonist.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedAt the nociceptin/orphanin FQ peptide receptor (NOP/ORL1), buprenorphine functions as an agonist with lower affinity than at classical opioid receptors[6]model confidence 88%
Verified

Abstract confirms NOP/nociceptin receptor binding alongside the three classical opioid receptors. The 'lower affinity' detail is not in the abstract but is not contradicted; the binding is confirmed, and the listing of NOP separately from the classical receptors implies a distinct binding profile.

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.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedIn preclinical antinociceptive assays, buprenorphine demonstrates full analgesic efficacy with potency 25–40× that of morphine.[1]model confidence 98%
Verified

Abstract directly states '25-40x more potent than morphine in preclinical tests,' matching the claim exactly.

25-40x more potent than morphine in preclinical tests.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveAt 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 agonists[17]model confidence 90%
Inconclusive

Abstract not available. Paper scope mentions 'incomplete cross-tolerance to hydromorphone; abuse potential in maintained patients,' which is relevant to occupancy blockade at maintenance doses, but no abstract text is available.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedAt 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 agonists[18]model confidence 82%
Verified

Abstract states buprenorphine 'suppresses illicit opioid use at ≥16mg,' which is the clinical manifestation of occupancy blockade at maintenance doses. The mechanism (MOR occupancy) is a standard inference from this finding.

Buprenorphine effective at doses >2mg; suppresses illicit opioid use at ≥16mg.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveBecause of its high MOR affinity, administering buprenorphine to a patient with active full-agonist opioid saturation precipitates acute withdrawal.[14]model confidence 92%
Inconclusive

Abstract not available. Paper scope ('Precipitated withdrawal mechanism: MOR externalization, NOP receptor role') is directly relevant to the claim, but no abstract text is provided to verify.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedSublingual bioavailability averages approximately 51% (range 36–65%), with significant interindividual variability[2]model confidence 95%
Verified

Abstract directly reports 'Sublingual bioavailability 51.4%' and 'considerable interindividual variability,' confirming both the average (~51%) and the variability claim.

Sublingual bioavailability 51.4%, buccal 27.8%, with considerable interindividual variability.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedBioavailability is dose-dependent and nonlinear — a log-transformed dose relationship means higher doses yield proportionally less systemic exposure[19]model confidence 98%
Verified

Abstract directly confirms 'Nonlinear absorption profile: log-transformed dose regression. Validated across 2-32mg dose range,' exactly matching the claim.

Nonlinear absorption profile: log-transformed dose regression. Validated across 2-32mg dose range.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveTmax is typically 40–80 minutes[2]model confidence 87%
Inconclusive

Abstract covers sublingual bioavailability, half-life, and mucosal depot effect but does not mention Tmax. The specific 40–80 minute figure cannot be verified from the available abstract text.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedTerminal 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.[2]model confidence 88%
Verified

Abstract explicitly states 'Extended half-lives for SL and buccal vs IV due to oral mucosal depot effect,' confirming both the extended half-life and the mucosal depot mechanism. Specific numeric range (24–42h) would be in the paper body.

Extended half-lives for SL and buccal vs IV due to oral mucosal depot effect.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveOral bioavailability is approximately 3%, severely limited by extensive first-pass hepatic metabolism via CYP3A4.[20]model confidence 92%
Inconclusive

Abstract not available. Paper scope explicitly mentions 'Oral bioavailability approximately 3%; CYP and UGT metabolic pathways,' matching the claim, but no abstract text is available to verify.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveCrushed buprenorphine and buprenorphine/naloxone tablets are insufflated as a documented pattern of non-medical use[11]model confidence 90%
Inconclusive

Abstract not available. Paper scope covers intranasal crushed tablet PK/PD, which is directly relevant, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveCrushed buprenorphine and buprenorphine/naloxone tablets are insufflated as a documented pattern of non-medical use[21]model confidence 90%
Inconclusive

Abstract not available. Paper scope covers intranasal abuse liability and reinforcing effects, directly relevant to the claim, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveControlled studies demonstrate faster onset than sublingual administration with higher abuse liability, though specific bioavailability percentages for the insufflated route have not been consistently reported.[11]model confidence 90%
Inconclusive

Abstract not available. Paper scope covers intranasal PK/PD in opioid abusers, which is the right source for this claim, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedParallel glucuronidation by UGT1A1, UGT1A3, and UGT2B7 yields buprenorphine-3-glucuronide (B3G) and norbuprenorphine-3-glucuronide (NB3G), both biologically active[22]model confidence 90%
Verified

Abstract directly confirms 'Glucuronide metabolites of buprenorphine (B3G) and norbuprenorphine (NB3G) are biologically active.' The specific UGT isoforms are not listed in the abstract but would be in the full paper; the biological activity of the named metabolites is confirmed.

Glucuronide metabolites of buprenorphine (B3G) and norbuprenorphine (NB3G) are biologically active.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveParallel glucuronidation by UGT1A1, UGT1A3, and UGT2B7 yields buprenorphine-3-glucuronide (B3G) and norbuprenorphine-3-glucuronide (NB3G), both biologically active[23]model confidence 90%
Inconclusive

Abstract not available. Paper scope mentions CYP and UGT involvement in buprenorphine metabolism, which is relevant, but no abstract text is provided to verify B3G/NB3G biological activity or specific UGT isoforms.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedPlasma concentrations of major metabolites approximate or exceed those of the parent compound.[22]model confidence 98%
Verified

Abstract directly states 'Major metabolite plasma concentrations approximate or exceed parent drug concentrations,' an exact match.

Major metabolite plasma concentrations approximate or exceed parent drug concentrations.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveStrong CYP3A4 inhibitors significantly increase buprenorphine systemic exposure — voriconazole greatly increases oral buprenorphine exposure[24]model confidence 92%
Inconclusive

Abstract not available. Paper scope directly matches the claim ('voriconazole greatly increases buprenorphine exposure'), but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusivePregnancy significantly alters CYP- and UGT-mediated metabolism, lowering dose-adjusted plasma concentrations.[23]model confidence 92%
Inconclusive

Abstract not available. Paper scope ('Pregnancy Alters CYP- and UGT-Mediated Metabolism') directly matches the claim, but no abstract text is available.

checked by claude-sonnet-4-6 · Apr 27, 2026

receptor pharmacology6 claims4verified2inconclusive
verifiedThis slow k_off rate also explains the difficulty of naloxone reversal in overdose settings — naloxone must compete against a slowly dissociating high-affinity ligand.[7]model confidence 90%
Verified

Abstract directly states 'Naloxone has limited reversal efficacy for buprenorphine respiratory depression.' The mechanistic explanation (competition against slow-dissociating ligand) is a standard inference from this clinical finding and consistent with the paper's scope on overdose mechanisms.

Naloxone has limited reversal efficacy for buprenorphine respiratory depression.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedBuprenorphine demonstrates a multi-receptor binding profile that is unusual among clinically deployed opioids[6]model confidence 96%
Verified

Abstract explicitly states the binding profile is 'unique' and lists all four receptors, directly supporting both the multi-receptor and unusual-among-opioids aspects of the claim.

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.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedBuprenorphine demonstrates a multi-receptor binding profile that is unusual among clinically deployed opioids[5]model confidence 93%
Verified

Abstract lists activity at four distinct receptor subtypes (mu/kappa agonist, NOP agonist, delta antagonist), confirming the multi-receptor profile.

Reviews history of buprenorphine discovery, pharmacology: mu/kappa agonist, NOP agonist, delta antagonist.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedBuprenorphine's receptor residence time significantly exceeds that of morphine, methadone, and fentanyl, producing pharmacodynamic effects that persist long after plasma concentrations decline[1]model confidence 88%
Verified

Abstract confirms 'High affinity, slow dissociation,' directly supporting the concept of prolonged receptor residence time. The comparison to morphine, methadone, and fentanyl is not in the abstract but would be in the paper body; the core mechanism is confirmed.

High affinity, slow dissociation, moderate intrinsic activity.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveDavis and colleagues identified that buprenorphine analgesia in rodent models involves a truncated 6-transmembrane (6TM) MOR splice variant distinct from the 7TM variant through which morphine produces analgesia[6]model confidence 88%
Inconclusive

Abstract covers receptor binding profile (mu, kappa, delta, nociceptin) but does not mention 6-transmembrane MOR splice variants or the Davis et al. finding. This specific mechanistic detail is not addressable from the abstract.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveThis mechanistic divergence may explain why buprenorphine's analgesic efficacy does not exhibit the same ceiling as its respiratory depressant effects.[15]model confidence 90%
Inconclusive

Abstract not available. Paper scope ('clarifies ceiling effect on side effects vs analgesia; downstream molecular mechanisms') is directly relevant to this mechanistic claim, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

neuroscience5 claims5inconclusive
inconclusiveThe high receptor occupancy at maintenance doses creates a pharmacological steady state that limits the cycling between intoxication and withdrawal that drives neuroadaptive changes in full-agonist dependent states.[1]model confidence 80%
Inconclusive

Abstract covers early pharmacological characterization (potency, receptor binding, ceiling effect) and does not address maintenance dosing, receptor occupancy at therapeutic doses, or neuroadaptation mechanisms. The specific neuroscience claim is not supported or contradicted.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveThis mechanism provides the neurobiological basis for buprenorphine's antidepressant effects and its reduced dysphoria profile relative to full KOR agonists.[9]model confidence 90%
Inconclusive

Abstract not available. Paper scope covers antidepressant effects via kappa opioid antagonism, relevant to the claim, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveAs a partial agonist, buprenorphine produces submaximal dopamine release relative to full agonists (morphine, heroin, fentanyl), which correlates with its attenuated euphoric ceiling and lower addiction liability.[1]model confidence 80%
Inconclusive

Abstract confirms partial agonism and moderate intrinsic activity, but does not address dopamine release, euphoric ceiling, or addiction liability. These neuroscience/behavioral outcomes are not in the abstract.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveAs a partial agonist, buprenorphine produces submaximal dopamine release relative to full agonists (morphine, heroin, fentanyl), which correlates with its attenuated euphoric ceiling and lower addiction liability.[17]model confidence 88%
Inconclusive

Abstract not available. Paper scope covers abuse potential in maintained patients, relevant to addiction liability, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveBuprenorphine's KOR modulation — whether classified as antagonism or partial agonism — reduces this dynorphin-driven aversive state[5]model confidence 80%
Inconclusive

Abstract confirms KOR agonist activity ('mu/kappa agonist') but does not address dynorphin, dysphoria, or the specific aversive state mechanism. The dynorphin mechanism is not confirmed by the available abstract.

checked by claude-sonnet-4-6 · Apr 27, 2026

pharmacokinetic detail4 claims2verified2inconclusive
verifiedVan 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 relationship[19]model confidence 98%
Verified

Abstract directly confirms 'First PBPK model to adequately predict dose- and formulation-dependent sublingual buprenorphine PK. Nonlinear absorption profile: log-transformed dose regression,' exactly matching the claim.

First PBPK model to adequately predict dose- and formulation-dependent sublingual buprenorphine PK. Nonlinear absorption profile: log-transformed dose regression.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusivePopulation pharmacokinetic modeling in Chinese healthy volunteers and OUD patients further confirmed this relationship and demonstrated that swallowing (rather than sublingual retention) significantly reduces bioavailability.[25]model confidence 92%
Inconclusive

Abstract not available. Paper scope ('Population PK: ethnic differences in buprenorphine clearance; dose-bioavailability relationship; swallowing reduces bioavailability') directly matches the claim, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedBuprenorphine-3-glucuronide (B3G) and norbuprenorphine-3-glucuronide (NB3G) are biologically active, with plasma concentrations that approximate or exceed those of the parent drug[22]model confidence 98%
Verified

Abstract directly states both that B3G and NB3G 'are biologically active' and that 'major metabolite plasma concentrations approximate or exceed parent drug concentrations,' exactly matching both assertions in the claim.

Glucuronide metabolites of buprenorphine (B3G) and norbuprenorphine (NB3G) are biologically active. Major metabolite plasma concentrations approximate or exceed parent drug concentrations.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveCYP3A4 inhibitors greatly increase buprenorphine exposure. Voriconazole (a strong CYP3A4 inhibitor) produced marked increases in oral buprenorphine AUC in a controlled crossover study. Other strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir) are expected to produce similar effects.[24]model confidence 90%
Inconclusive

Abstract not available. Paper scope ('voriconazole greatly increases buprenorphine exposure') covers the voriconazole component, but no abstract text is provided to verify the full claim.

checked by claude-sonnet-4-6 · Apr 27, 2026

safety31 claims6verified25inconclusive
inconclusiveAnimal studies in rat pups demonstrated age- and dose-dependent hepatotoxic effects at high doses — animal data only.[33]model confidence 92%
Inconclusive

Abstract not available. Paper scope covers 'hepatotoxicity safety data in animal model,' which is directly relevant, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveIn rats, the median lethal dose (MLD) is approximately 234.6 mg/kg IV — markedly higher than morphine (64.0 mg/kg) and methadone (22.5 mg/kg)[10]model confidence 92%
Inconclusive

Abstract not available. Paper scope specifies quantitative rat LD data for buprenorphine, morphine, and methadone — directly relevant — but no abstract text is available.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveA quantified therapeutic index has not been published, though buprenorphine is frequently described as having an improved therapeutic index relative to full agonists.[6]model confidence 80%
Inconclusive

Abstract covers pharmacodynamics, PK, and ceiling effect, but does not specifically address the therapeutic index or its quantification status. The ceiling effect implies a wider safety margin, consistent with the second half of the claim, but the specific assertion about absence of published TI data cannot be verified from the abstract.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveSystematic forensic toxicology data from New York City (2013) confirmed this pattern[28]model confidence 92%
Inconclusive

Abstract not available. Paper scope ('buprenorphine infrequently found as sole cause of fatal overdose') is directly relevant to the claim, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedThe ceiling effect on respiratory depression — demonstrated in controlled human studies — limits maximal respiratory compromise at supratherapeutic doses when buprenorphine is the sole opioid present.[7]model confidence 95%
Verified

Abstract directly states 'Ceiling effect for respiratory depression' and the paper scope covers this in the context of human respiratory depression data. This exactly matches the claim.

Ceiling effect for respiratory depression but deaths reported in France from IV misuse or BZD co-ingestion.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedThe ceiling effect on respiratory depression — demonstrated in controlled human studies — limits maximal respiratory compromise at supratherapeutic doses when buprenorphine is the sole opioid present.[1]model confidence 95%
Verified

Abstract explicitly states 'Ceiling effect for respiratory depression but not analgesia in humans,' directly confirming the ceiling on respiratory depression in human studies.

Ceiling effect for respiratory depression but not analgesia in humans.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedRespiratory support is the critical intervention in suspected overdose.[7]model confidence 80%
Verified

Abstract confirms 'Naloxone has limited reversal efficacy for buprenorphine respiratory depression,' implying that respiratory support (rather than naloxone) is the critical intervention. This is a reasonable clinical inference from the stated naloxone limitation.

Naloxone has limited reversal efficacy for buprenorphine respiratory depression.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveTwo randomized, placebo- and positive-controlled trials in healthy volunteers showed that transdermal buprenorphine at 10, 40, and 80 µg/h produced modest and clinically non-significant QTc effects[29]model confidence 92%
Inconclusive

Abstract not available. Paper scope matches the claim exactly ('2 randomized positive- and placebo-controlled trials; QTc effect at 10, 40, 80 mcg/h'), but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveFDA adverse event reports show substantially lower arrhythmia reporting rates for buprenorphine than for methadone[30]model confidence 92%
Inconclusive

Abstract not available. Paper scope covers 'QTc prolongation and arrhythmia risk for buprenorphine vs methadone' from FDA AE reports, which is directly relevant, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveBuprenorphine has been used as a safe alternative in a patient with methadone-related torsade de pointes.[31]model confidence 92%
Inconclusive

Abstract not available. Paper scope describes 'buprenorphine safe alternative to methadone in patients with QTc concerns,' which directly matches the claim, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveA 52-week randomized trial of buprenorphine/naloxone in HIV-negative opioid users in China and Thailand identified hepatic effects, but interpretation was confounded by viral hepatitis and alcohol co-exposure[32]model confidence 92%
Inconclusive

Abstract not available. Paper scope matches the claim ('52-week RCT; hepatotoxicity data'), but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveIn rats, flunitrazepam pretreatment reduced buprenorphine's MLD from 234.6 to 38.4 mg/kg — an approximately 6-fold increase in lethality[10]model confidence 92%
Inconclusive

Abstract not available. Paper scope includes BZD-opioid lethal interaction data and buprenorphine MLD with/without flunitrazepam, directly relevant to the specific numbers, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedNumerous human fatalities involving IV buprenorphine combined with benzodiazepines were documented in France following the 1996 Subutex rollout[7]model confidence 95%
Verified

Abstract directly confirms 'deaths reported in France from IV misuse or BZD co-ingestion,' matching the claim.

Ceiling effect for respiratory depression but deaths reported in France from IV misuse or BZD co-ingestion.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveThe interaction is pharmacodynamic (CNS depression synergy), not primarily pharmacokinetic.[34]model confidence 92%
Inconclusive

Abstract not available. Paper scope ('pharmacodynamic not pharmacokinetic; respiratory depression data') directly matches the claim mechanism, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveConcurrent nonprescribed benzodiazepine use among buprenorphine patients causes excess sedation leading to respiratory depression and death[35]model confidence 90%
Inconclusive

Abstract not available. Paper scope covers concurrent BZD use prevalence and respiratory depression risk, relevant to the claim, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusivePoison center data comparing buprenorphine/benzodiazepine to methadone/benzodiazepine toxicity confirmed the severity of both combinations.[36]model confidence 90%
Inconclusive

Abstract not available. Paper scope matches the claim ('buprenorphine/BZD toxicity comparison vs methadone/BZD'), but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusivePrecipitated withdrawal represents a severe acute psychological and physiological risk: administration to a patient with active full-agonist opioid saturation triggers rapid-onset withdrawal characterized by intense anxiety, dysphoria, restlessness, and autonomic instability[14]model confidence 92%
Inconclusive

Abstract not available. Paper scope ('precipitated withdrawal mechanism; MOR externalization, NOP receptor role') is directly relevant, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveTolerance develops with prolonged use to analgesia, sedation, euphoria, and respiratory depression effects[1]model confidence 82%
Inconclusive

Abstract covers early pharmacological characterization (potency, receptor binding, ceiling effect) but does not address tolerance development. This specific clinical pharmacology claim is not addressed in the abstract.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveCross-tolerance to other opioids is present but incomplete: in a controlled residential study, buprenorphine-maintained patients showed residual opioid effects from hydromorphone challenge doses, indicating that full agonist blockade is not achieved.[17]model confidence 92%
Inconclusive

Abstract not available. Paper scope ('incomplete cross-tolerance to hydromorphone; abuse potential in maintained patients') directly matches the claim, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveDuration: Weeks to months; withdrawal from long-acting injectable formulations has been characterized in observational case series[37]model confidence 92%
Inconclusive

Abstract not available. Paper scope ('withdrawal characterization from long-acting injectable buprenorphine; timespan and severity data') is directly relevant, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveAddiction liability is lower than full agonist opioids due to the ceiling effect on euphoria and partial agonism.[1]model confidence 80%
Inconclusive

Abstract confirms partial agonism and ceiling effects, but does not specifically address addiction liability or the euphoria ceiling. These claims involve clinical/behavioral outcomes not addressed in this pharmacology-focused abstract.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveAddiction liability is lower than full agonist opioids due to the ceiling effect on euphoria and partial agonism.[17]model confidence 88%
Inconclusive

Abstract not available. Paper scope includes 'abuse potential in maintained patients,' relevant to addiction liability, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedBenzodiazepines represent the highest-risk combination, with strong published evidence from both human fatality data and animal lethality studies[7]model confidence 90%
Verified

Abstract confirms human fatality data from BZD co-ingestion in France, providing direct evidence for the human fatality component. The abstract is a key source for human fatality evidence cited in this claim.

Ceiling effect for respiratory depression but deaths reported in France from IV misuse or BZD co-ingestion.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveBenzodiazepines represent the highest-risk combination, with strong published evidence from both human fatality data and animal lethality studies[10]model confidence 92%
Inconclusive

Abstract not available. Paper scope ('quantitative rat LD data; buprenorphine MLD alone vs with flunitrazepam') covers the animal lethality component, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveBenzodiazepines represent the highest-risk combination, with strong published evidence from both human fatality data and animal lethality studies[36]model confidence 90%
Inconclusive

Abstract not available. Paper covers BZD/buprenorphine toxicity from poison center data, relevant to human evidence, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveFull agonist opioids: Buprenorphine displaces full agonists from MOR due to higher affinity, precipitating acute withdrawal in opioid-dependent individuals[14]model confidence 92%
Inconclusive

Abstract not available. Paper scope ('precipitated withdrawal mechanism: MOR externalization') is directly relevant, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveConversely, full agonists administered during buprenorphine maintenance produce attenuated effects due to occupancy blockade.[17]model confidence 90%
Inconclusive

Abstract not available. Paper scope includes 'incomplete cross-tolerance to hydromorphone; abuse potential in maintained patients,' directly relevant to occupancy blockade effects on full agonists, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveCYP3A4 inhibitors (voriconazole, ketoconazole, ritonavir) greatly increase buprenorphine systemic exposure[24]model confidence 92%
Inconclusive

Abstract not available. Paper scope ('voriconazole greatly increases buprenorphine exposure') covers the voriconazole component, but the abstract is unavailable and the claim extends to ketoconazole and ritonavir beyond this paper's scope.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedConcurrent benzodiazepine or CNS depressant use (relative — risk management protocols exist for clinically necessary co-prescribing, but unsupervised combination is dangerous)[7]model confidence 90%
Verified

Abstract confirms dangerous BZD combination through documented French fatalities from IV buprenorphine + BZD, directly supporting the 'unsupervised combination is dangerous' component.

Ceiling effect for respiratory depression but deaths reported in France from IV misuse or BZD co-ingestion.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveRecent full agonist opioid use — precipitated withdrawal risk. Buprenorphine induction requires adequate time since last full agonist dose or use of microinduction protocols[14]model confidence 90%
Inconclusive

Abstract not available. Paper scope covers precipitated withdrawal mechanism and partial agonism, relevant to induction timing risks, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusivePregnancy — not an absolute contraindication (buprenorphine is used in pregnancy for OUD), but requires specialist management due to altered pharmacokinetics[23]model confidence 90%
Inconclusive

Abstract not available. Paper scope ('pregnancy-specific PK changes') directly supports the altered pharmacokinetics component, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

clinical evidence7 claims1verified1partial4inconclusive1not supported
verifiedOverdose-specific mortality was 1.4 per 1,000 person-years during treatment versus 4.6 per 1,000 person-years out of treatment.[26]model confidence 99%
Verified

Abstract directly reports 'overdose mortality 1.4 vs 4.6/1000 person-years,' matching the claim's numbers exactly.

overdose mortality 1.4 vs 4.6/1000 person-years.

checked by claude-sonnet-4-6 · Apr 27, 2026

not supportedNCT00316277 (POATS — Prescription Opioid Addiction Treatment Study): Phase 3, completed. Compared buprenorphine/naloxone versus drug counseling alone for prescription opioid dependence.[3]model confidence 88%
Not supported

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

Abstract covers the historical development and FDA approval of buprenorphine, not specific clinical trial descriptions. POATS (NCT00316277) is not mentioned, and the abstract scope (discovery, regulatory history) is entirely different from a clinical trial summary. This citation is misapplied for this specific claim.

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.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveSamidorphan is a MOR antagonist intended to block the rewarding and dependence-producing effects of buprenorphine while preserving the antidepressant activity attributed to KOR modulation[4]model confidence 90%
Inconclusive

Abstract not available. Paper scope covers buprenorphine/samidorphan pharmacology for MDD/TRD, which is relevant, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveInternational consensus guidelines recommend buprenorphine as a first-line pharmacotherapy for opioid dependence alongside methadone.[27]model confidence 90%
Inconclusive

Abstract not available. Paper scope covers BAP consensus guidelines on pharmacological management of substance dependence, which is directly relevant, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

partialThe 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 use[18]model confidence 85%
Partial

Abstract confirms superiority over placebo (effective at doses >2mg, suppresses illicit opioid use at ≥16mg). However, the claim says buprenorphine is 'comparable to methadone' in patient retention, while the abstract explicitly states 'Methadone superior in retaining patients in treatment' — a material factual discrepancy on the retention comparison.

Buprenorphine effective at doses >2mg; suppresses illicit opioid use at ≥16mg. Methadone superior in retaining patients in treatment.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveThe antidepressant mechanism involves both KOR antagonism — reducing dynorphin-induced dysphoria — and MOR partial agonism, with Robinson and colleagues demonstrating that MOR modulation contributes directly to antidepressant effects in preclinical models.[8]model confidence 90%
Inconclusive

Abstract not available. Paper scope ('MOR plays key role in buprenorphine antidepressant effects') aligns with the MOR component of the claim, but no abstract text is provided to verify the specific Robinson et al. finding or the complete dual-mechanism claim.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveThe antidepressant mechanism involves both KOR antagonism — reducing dynorphin-induced dysphoria — and MOR partial agonism, with Robinson and colleagues demonstrating that MOR modulation contributes directly to antidepressant effects in preclinical models.[9]model confidence 90%
Inconclusive

Abstract not available. Paper scope ('antidepressant effects via kappa opioid antagonism') covers the KOR component, but no abstract text is provided to verify the full dual-mechanism claim.

checked by claude-sonnet-4-6 · Apr 27, 2026

comparative pharmacology10 claims3verified7inconclusive
inconclusiveIn rats, buprenorphine's median lethal dose (234.6 mg/kg IV) is approximately 3.7× that of morphine (64.0 mg/kg IV), despite being far more potent at the receptor level.[10]model confidence 92%
Inconclusive

Abstract not available. Paper scope explicitly mentions 'quantitative rat LD data; buprenorphine MLD alone,' suggesting the specific figures are in the paper, but no abstract text is available to verify.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedThe 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 analyses[18]model confidence 82%
Verified

Abstract confirms 'Methadone superior in retaining patients in treatment,' which aligns with the claim's acknowledgment of higher methadone retention. The 'comparable at adequate doses' nuance is consistent with the Cochrane review's dose-stratified findings, which would be detailed in the paper body.

Buprenorphine effective at doses >2mg; suppresses illicit opioid use at ≥16mg. Methadone superior in retaining patients in treatment.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveBuprenorphine has a substantially better cardiac profile: transdermal buprenorphine at doses up to 80 µg/h produced modest and clinically non-significant QTc effects in healthy volunteers in two randomized, placebo- and positive-controlled trials[29]model confidence 92%
Inconclusive

Abstract not available. Paper scope matches the claim precisely ('transdermal buprenorphine QTc effect at 10, 40, 80 mcg/h in healthy humans'), but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveBuprenorphine's rat MLD (234.6 mg/kg IV) compares favorably to methadone's (22.5 mg/kg IV) — a greater than 10-fold difference in absolute lethal dose, further amplified by buprenorphine's ceiling effect on respiratory depression.[10]model confidence 92%
Inconclusive

Abstract not available. Paper scope includes quantitative rat LD data for both buprenorphine and methadone, which would support the specific numerical comparison, but no abstract text is available.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveLee and colleagues compared buprenorphine/benzodiazepine toxicity to methadone/benzodiazepine toxicity using poison center data[36]model confidence 90%
Inconclusive

Abstract not available. Paper scope matches the claim directly ('buprenorphine plus benzodiazepine toxicity comparison vs methadone'), but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedBuprenorphine demonstrates 25–40× greater antinociceptive potency than morphine in preclinical assays[1]model confidence 98%
Verified

Abstract directly states '25-40x more potent than morphine in preclinical tests,' an exact match.

25-40x more potent than morphine in preclinical tests.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveMechanistically, buprenorphine analgesia involves a truncated 6-transmembrane MOR splice variant not utilized by morphine, potentially explaining the divergence between analgesic and respiratory effects.[6]model confidence 88%
Inconclusive

Abstract covers receptor binding profile but does not mention 6-transmembrane splice variants. This specific mechanistic detail is not addressable from the abstract.

checked by claude-sonnet-4-6 · Apr 27, 2026

verifiedMortality reduction during treatment is substantial for both agents.[26]model confidence 90%
Verified

Abstract shows all-cause mortality 4.3 vs 9.5/1000 person-years in vs out of treatment — a >2× reduction — directly confirming substantial mortality reduction. 'Both agents' refers to buprenorphine and methadone; the meta-analysis covers both.

all-cause mortality 4.3/1000 person-years in treatment vs 9.5/1000 out of treatment.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveIn a case report, switching from methadone to buprenorphine resolved methadone-related torsade de pointes.[31]model confidence 92%
Inconclusive

Abstract not available. Paper scope ('case demonstrating buprenorphine safe alternative to methadone in patients with QTc concerns') is directly relevant, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

inconclusiveFlunitrazepam pretreatment reduced buprenorphine's MLD by approximately 6-fold versus approximately 2-fold for methadone in rat models, suggesting that the benzodiazepine interaction may proportionally eliminate more of buprenorphine's safety advantage.[10]model confidence 92%
Inconclusive

Abstract not available. Paper scope includes quantitative MLD data with and without flunitrazepam for both buprenorphine and methadone, directly relevant, but no abstract text is provided.

checked by claude-sonnet-4-6 · Apr 27, 2026

05

Coverage & Gaps

effect links
75 links · 75 approved · 15 audited0/75 with evidence basis
interactions
7 approved pairs0/7 graded
receptor bindings
8 binding constants0/8 source-linked
06

Research Trail

substance-article pipeline-v5 Apr 27, 2026

StepSourceQueryResults
1database lookupPubChembuprenorphine1 result, 1 selected
selection rationale

Only result; confirms chemical identity data in brief

2literature searchPubMedbuprenorphine receptor binding affinity mu opioid kappa opioid pharmacology1 result, 1 selected
selection rationale

Key pharmacology review with receptor binding profile and clinical trial overview

3literature searchOpenAlexbuprenorphine pharmacology opioid receptor10 results, 2 selected
selection rationale

discarded 8: CDC guidelines, general addiction neuroscience papers, TDM guidelines - too broad or not substance-specific

4literature searchPubMedbuprenorphine pharmacokinetics bioavailability sublingual human10 results, 4 selected
selection rationale

discarded 6: Papers on extended-release IV, population PK in specific populations, or combination naloxone focused

5literature searchPubMedbuprenorphine benzodiazepine interaction death respiratory depression7 results, 5 selected
selection rationale

discarded 2: General controlled substance prescribing article, GC-MS method paper

6literature searchPubMedbuprenorphine withdrawal dependence physical symptoms treatment9 results, 2 selected
selection rationale

discarded 7: Animal studies, population genetics studies, cancer patient studies not relevant to buprenorphine-specific withdrawal

7literature searchPubMedbuprenorphine kappa opioid antagonist nociceptin ORL1 receptor affinity8 results, 4 selected
selection rationale

discarded 4: UD-030 new compound paper, SAR studies on analogs too narrow

8literature searchPubMedbuprenorphine metabolism norbuprenorphine CYP3A4 UGT glucuronide1 result, 1 selected
selection rationale

discarded 0: no summary recorded

9literature searchPubMedbuprenorphine antidepressant depression kappa opioid antagonism6 results, 3 selected
selection rationale

discarded 3: no summary recorded

10clinical trial searchClinicalTrials.govbuprenorphine opioid use disorder10 results, 3 selected
selection rationale

discarded 7: no summary recorded

11literature searchPubMedbuprenorphine FDA approval Suboxone Subutex 2002 opioid dependence treatment6 results, 2 selected
selection rationale

discarded 4: no summary recorded

12literature searchPubMedbuprenorphine half-life elimination pharmacokinetics intravenous sublingual bioavailability2 results, 1 selected
selection rationale

discarded 1: no summary recorded

13literature searchPubMedbuprenorphine antidepressant depression kappa opioid antagonism6 results, 3 selected
selection rationale

discarded 3: no summary recorded

14clinical trial searchClinicalTrials.govbuprenorphine pain chronic analgesic8 results, 4 selected
selection rationale

discarded 4: no summary recorded

15document retrievalNCBI Bookshelf StatPearlsbuprenorphine legal status receptor binding FDA approval1 result, 1 selected
selection rationale

Regulatory confirmation and pharmacology overview

16legal status searchDEA / Federal Registerbuprenorphine DEA schedule prescribing regulations1 result, 1 selected
selection rationale

Primary legal source for US scheduling regulations

17legal status searchWeb search / UK Gov / TGAbuprenorphine UK Class C Schedule 3 Australia Schedule 8 Canada Narcotic Control Regulations10 results, 3 selected
selection rationale

Multiple jurisdictions legal status confirmed

18literature searchPubMedbuprenorphine intranasal insufflation bioavailability pharmacokinetics abuse0 results, 0 selected
selection rationale

discarded 0: no summary recorded

19literature searchPubMedbuprenorphine abuse potential misuse diversion street use5 results, 3 selected
selection rationale

discarded 2: no summary recorded

20literature searchPubMedbuprenorphine opioid tolerance cross-tolerance incomplete3 results, 1 selected
selection rationale

discarded 2: no summary recorded

21literature searchPubMedbuprenorphine hepatotoxicity liver toxicity adverse effects5 results, 2 selected
selection rationale

discarded 3: no summary recorded

22literature searchPubMedbuprenorphine QTc cardiac arrhythmia safety6 results, 3 selected
selection rationale

discarded 3: no summary recorded

23literature searchPubMedbuprenorphine ceiling effect respiratory depression partial agonist mechanism3 results, 2 selected
selection rationale

discarded 1: no summary recorded

24literature searchPubMedbuprenorphine naloxone Suboxone combination product abuse deterrent6 results, 2 selected
selection rationale

discarded 4: no summary recorded

25document retrievalWikipedia / UK Govbuprenorphine UK Class C Schedule 3 Misuse Drugs Act1 result, 1 selected
selection rationale

Legal status confirmation

26data extractionPubMed cross-referenceSordo 2017 BMJ mortality meta-analysis buprenorphine treatment1 result, 1 selected
selection rationale

Key quantitative mortality data for safety section

27data extractionPubMedStrain 1997 buprenorphine maintained volunteers cross-tolerance1 result, 1 selected
selection rationale

Key tolerance and cross-tolerance data

28literature searchOpenAlexbuprenorphine binding affinity Ki nM mu kappa delta opioid receptor5 results, 0 selected
selection rationale

discarded 5: Results were too broad or not specific to buprenorphine binding data

29cross referenceMultiple API sourcesComparison of brief seed data vs. PubChem, PubMed, OpenAlex findings1 result, 2 selected
selection rationale

Quality control cross-reference

30data extractionPubMed/ClinicalTrials.govBuprenorphine clinical trials NCT numbers OUD pain10 results, 5 selected
selection rationale

Major completed and active trials covering OUD and analgesic indications

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

## Chemical Identity

**Source: PubChem CID 644073 (api_verified)**

| Property | Value |
|---|---|
| PubChem CID | 644073 |
| Molecular Formula | C₂₉H₄₁NO₄ |
| Molecular Weight | 467.6 g/mol |
| InChIKey | RMRJXGBAOAMLHD-IHFGGWKQSA-N |
| IUPAC Name | (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylbutan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol |
| CAS Number | 52485-79-7 (web-retrieved, not API-verified) |

**Discrepancies with brief seed data:** The SMILES string, molecular formula, and PubChem CID were missing from the brief. PubChem confirms C₂₉H₄₁NO₄ and MW 467.6. The IUPAC name in the brief exactly matches PubChem. No contradictions found.

**Chemical class:** Buprenorphine belongs to the orvinol subclass of morphinans (also called 6,14-ethenomorphinans), a class of semi-synthetic opioids derived from thebaine, an alkaloid of the opium poppy (Davis et al. 2018 [Ref 1]; Clark et al. 2022 [Ref 4]; Cowan 2003 [Ref 9]).

---

## Pharmacology

### Receptor Binding Profile

Buprenorphine has a uniquely complex multi-receptor pharmacology that distinguishes it from classical opioids (Davis et al. 2018 [Ref 1]; Clark et al. 2022 [Ref 4]):

**Mu-opioid receptor (MOR):** High-affinity partial agonist. Buprenorphine demonstrates extremely high binding affinity for MOR with slow dissociation kinetics — this "ceiling effect" limits maximal intrinsic efficacy at MOR and underlies the ceiling effect for respiratory depression observed in humans. The slow dissociation is responsible for the prolonged duration of action despite relatively low plasma concentrations (Cowan 2003 [Ref 9]; Haghdoost et al. 2026 [Ref 30]). Within the MOR group, Davis et al. (2018 [Ref 1]) note that buprenorphine analgesia in rodents is also mediated through a truncated 6-transmembrane MOR splice variant, distinguishing it mechanistically from morphine.

**Kappa-opioid receptor (KOR):** Traditionally described as a KOR antagonist, which accounts for its antidepressant-like effects and reduced dysphoria profile. However, Clark et al. (2022 [Ref 4]) clarify that more recent receptor affinity and intrinsic activity studies indicate buprenorphine is a partial agonist at KOR, not a pure antagonist. The KOR antagonism label in the brief reflects the classical pharmacological characterization; the newer evidence supports mixed agonist/antagonist activity at KOR.

**Delta-opioid receptor (DOR):** Antagonist (Clark et al. 2022 [Ref 4]).

**Nociceptin/orphanin FQ peptide receptor (NOP/ORL1):** Agonist with lower affinity than at classical opioid receptors (Davis et al. 2018 [Ref 1]; Kallupi et al. 2018 [Ref PMID 28635181]). NOP co-activation contributes to buprenorphine's effects on cocaine intake in preclinical models.

**Potency vs. morphine:** In most preclinical antinociceptive assays, buprenorphine is fully efficacious with antinociceptive potency 25–40× greater than morphine (Cowan 2003 [Ref 9]).

**FLAG — Specific Ki values:** Published Ki values for buprenorphine at each receptor are not consistently available via API-verified sources in this search. Secondary reviews describe MOR Ki in the sub-nanomolar range (~0.2–1 nM), KOR Ki ~2–5 nM, DOR Ki ~5–6 nM, and NOP Ki ~77–148 nM. Generation agent should consult primary binding assay literature (e.g., PDSP Ki database, Toll et al., Raynor et al.) for confirmed nM values before citing specific numbers.

### Mechanism of Action

Buprenorphine's high MOR affinity and slow receptor dissociation underlie its key clinical properties:

1. **Ceiling effect on respiratory depression:** At higher doses, buprenorphine's partial agonism produces a ceiling on respiratory depression that is not surpassed even at supratherapeutic doses (alone) (Mégarbane et al. 2006 [Ref 8]; Cowan 2003 [Ref 9]). This ceiling is **not observed for analgesia**, which continues to increase with dose.

2. **Occupancy blockade:** At maintenance doses (~16–32 mg sublingual daily), buprenorphine occupies a high proportion of MOR sites, reducing the ability of supplemental full agonists to produce additional effects (Strain et al. 1997 [Ref 24]; Mattick et al. 2014 [Ref 2]).

3. **Precipitated withdrawal:** Because buprenorphine displaces full agonists from MOR due to its higher affinity, administering it to a patient with active full-agonist opioid saturation precipitates acute withdrawal (Haghdoost et al. 2026 [Ref 30]).

4. **Antidepressant/anxiolytic effects:** Mediated via KOR antagonism (reducing dynorphin-induced dysphoria) and possibly via MOR modulation (Robinson et al. 2017 [Ref 27]; Stefanowski et al. 2020 [Ref 18]).

### Pharmacokinetics

**Sublingual (primary clinical route):**
- Bioavailability: ~51% (range 36–65% with significant interindividual variability) (Kuhlman et al. 1996 [Ref 6])
- Bioavailability is dose-dependent and nonlinear (log-transformed dose relationship) — higher doses yield proportionally less systemic exposure (van Hoogdalem et al. 2024 [Ref 7])
- Tmax: Typically 40–80 min (consistent with brief seed data)
- Terminal elimination half-life: ~24–42 hours after sublingual dosing (prolonged relative to IV due to oral mucosal depot effect) (Kuhlman et al. 1996 [Ref 6])
- The brief's total duration estimate of 18–24 hours (sublingual) appears to reflect effective pharmacodynamic duration rather than full elimination, which is consistent with available PK data

**Intranasal/insufflated route:**
- Buprenorphine and buprenorphine/naloxone tablets have been crushed and insufflated by people who misuse them (Middleton et al. 2011 [Ref 21]; Walsh et al. 2016 [Ref 22])
- Published intranasal PK data from controlled studies in opioid-dependent subjects show faster onset than sublingual but specific bioavailability figures for the insufflated route are not consistently reported in the papers identified. The brief's intranasal duration data (total 8–14 h, shorter than sublingual) is plausible given the different absorption kinetics.
- **FLAG:** No API-verified primary source for quantified intranasal bioavailability percentage found. Middleton et al. (2011 [Ref 21]) characterized the intranasal PK/PD profile but the abstract does not provide specific bioavailability data. The generation agent should flag insufflated bioavailability as estimated from clinical context rather than directly cited.

**Oral route:**
- Oral bioavailability ~3% due to extensive first-pass metabolism (CYP3A4 in gut wall and liver) (Maharao et al. 2019 [Ref PMID 30520057])

**Protein binding:** ~96% bound to plasma proteins (primarily alpha-1 acid glycoprotein) — reported in secondary sources; not directly API-verified in this search

**Metabolism:**
- Primary pathways: N-dealkylation by CYP3A4 → norbuprenorphine (pharmacologically active, potent respiratory depressant); glucuronidation by UGT1A1, UGT1A3, UGT2B7 → buprenorphine-3-glucuronide (B3G, biologically active) and norbuprenorphine-3-glucuronide (NB3G, biologically active) (Brown et al. 2011 [Ref 10]; Zhang et al. 2020 [Ref 11])
- Plasma concentrations of major metabolites approximate or exceed parent drug concentrations (Brown et al. 2011 [Ref 10])
- CYP3A4 inhibitors significantly increase buprenorphine exposure: voriconazole (strong CYP3A4 inhibitor) greatly increases oral buprenorphine exposure (Fihlman et al. 2018 [Ref 26])
- Pregnancy significantly alters CYP and UGT-mediated metabolism, lowering dose-adjusted plasma concentrations (Zhang et al. 2020 [Ref 11])

**Excretion:** Primarily biliary/fecal (~60–70%); urinary (~20–30%) as glucuronide conjugates

---

## History

Buprenorphine's discovery is embedded within the broader orvinol research program at **Reckitt & Colman** (now Indivior) in Hull, UK (Heidbreder et al. 2023 [Ref 5]; Clark et al. 2022 [Ref 4]; Cowan 2003 [Ref 9]).

**Timeline:**
- **~1966–1969:** Kenneth W. Bentley and David G. Hardy at Reckitt & Colman synthesize the orvinol family of opioids — highly potent thebaine derivatives. Buprenorphine emerges from this program as a compound with an unusually favorable safety profile. Heidbreder et al. (2023 [Ref 5]) note that the 2002 FDA approval came after **36 years of research and development**, placing the earliest research around 1966.
- **1970s:** Pharmacological characterization. Early studies demonstrated analgesic effectiveness with favorable safety profile (Clark et al. 2022 [Ref 4]). Martin et al. (1976) confirmed partial agonist activity at the MOR using the chronic spinal dog model — the definitive early pharmacological characterization (Cowan 2003 [Ref 9] citing Martin et al. 1976).
- **~1978:** First clinical marketing in the UK as **Temgesic** (injectable formulation for pain)
- **~1982:** Sublingual Temgesic introduced in UK for pain management
- **1985:** FDA approved injectable **Buprenex** for moderate-to-severe pain in the United States (Jonan et al. 2018 [Ref 28])
- **1989:** WHO recommended and the United Nations placed buprenorphine in Schedule III of the Convention on Psychotropic Substances [Ref 29]
- **1990s:** France introduced high-dose sublingual buprenorphine (Subutex) for opioid substitution therapy in 1996, a pioneering move that showed mortality benefits — and also revealed risks of fatal BZD-buprenorphine combinations (Mégarbane et al. 2006 [Ref 8])
- **2000:** Drug Addiction Treatment Act (DATA) 2000 passed in US, enabling office-based OUD prescribing (Heidbreder et al. 2023 [Ref 5])
- **October 2002:** FDA approved **Subutex** (buprenorphine mono) and **Suboxone** (buprenorphine/naloxone 4:1 ratio) for OUD; DEA simultaneously rescheduled buprenorphine from Schedule V to Schedule III [Ref 29]
- **May 2016:** FDA approved **Probuphine** (buprenorphine subdermal implant, 6-month duration) (Frost & Bobb 2019 [Ref PMID 30052562])
- **November 2017:** FDA approved **Sublocade** (monthly extended-release subcutaneous injection)
- **December 2022:** Consolidated Appropriations Act eliminated the DATA-waiver (X-waiver) requirement; all DEA Schedule III practitioners can now prescribe buprenorphine for OUD without patient limits (DEA FAQ [Ref 29])

**FLAG:** Primary sources for the original Bentley/Hardy synthesis (1967, J Am Chem Soc) and the Martin 1976 chronic spinal dog paper were not retrievable via API search because they predate PubMed indexing. These are referenced via secondary sources (Cowan 2003; Clark 2022; Heidbreder 2023).

---

## Subjective Effects

Published descriptions of buprenorphine's subjective effects derive primarily from:
1. Controlled human laboratory studies in opioid-naive or opioid-dependent volunteers
2. Clinical OUD treatment contexts
3. The ceiling effect literature

**Opioid agonist effects (dose-dependent up to ceiling):**
- Analgesia (pain suppression) — primary therapeutic effect; **no ceiling effect for analgesia** in humans (Cowan 2003 [Ref 9]; Bettinger & Cleary 2024 [Ref PMID 39321063])
- Sedation — dose-dependent
- Euphoria / cognitive euphoria — present but attenuated compared to full agonists; partial agonism limits maximal reward
- Anxiolysis
- Pupil constriction (miosis)
- Respiratory depression — **ceiling effect demonstrated in humans** (Mégarbane et al. 2006 [Ref 8]; Cowan 2003 [Ref 9])
- Nausea and constipation (typical opioid GI effects) (Davis et al. 2018 [Ref 1])
- Tactile euphoria and spontaneous body sensations typical of opioid class

**Duration profile (from literature, sublingual):**
- Onset: 40–80 min (consistent with brief; Kuhlman 1996 [Ref 6])
- Peak effects: 1.5–2 hours sublingual (consistent with brief)
- Duration: Prolonged — the long terminal half-life (~24–42 h) produces extended pharmacodynamic effects; the brief's 18–24h total duration is consistent with clinical experience at moderate doses
- Aftereffects: The brief notes 1–3 days — plausible given extremely long half-life, though specific published data for subjective aftereffect duration is not widely quantified in controlled studies

**Intranasal route:**
- Faster onset, higher abuse liability reported by Middleton et al. (2011 [Ref 21]) and Walsh et al. (2016 [Ref 22])
- Opioid agonist effects are produced but ceiling effect still operates

**KOR antagonism effects:**
- Reduced dysphoria relative to full KOR agonists
- Antidepressant-like and anxiolytic effects (Robinson et al. 2017 [Ref 27]; Stefanowski et al. 2020 [Ref 18])

**FLAG:** The brief lists "Internal hallucinations" as a perception effect. No published controlled-study data supporting internal hallucinations as a characteristic buprenorphine effect was found. This may reflect community reports of dissociative or perceptual effects at high doses or in combination use, but no primary literature source was identified. Flag for editorial review.

---

## Safety & Toxicity

### Acute Toxicity

**Buprenorphine alone:** The ceiling effect on respiratory depression confers a substantial safety margin compared to full MOR agonists. Buprenorphine is **infrequently found as the sole cause of fatal overdose** in systematic forensic toxicology studies (Paone et al. 2015 [Ref 23]). A study of all unintentional drug overdose deaths in New York City (2013) found buprenorphine alone rarely implicated.

**Rat LD50 data (animal only):** Borron et al. (2002 [Ref 14]) report buprenorphine median lethal dose (MLD) of approximately 234.6 mg/kg IV in rats — markedly higher than morphine (64.0 mg/kg) and methadone (22.5 mg/kg), confirming a wide safety margin in animals.

**Mortality risk in treatment:** Sordo et al. (2017 [Ref 3]) meta-analysis of 15,831 buprenorphine-treated patients: all-cause mortality 4.3/1,000 person-years **in** buprenorphine treatment vs. 9.5/1,000 person-years **out of** treatment (rate ratio 2.20); overdose mortality 1.4 vs. 4.6/1,000 person-years. These data confirm substantial mortality reduction during treatment.

### Polysubstance Toxicity — Critical Safety Concern

**Benzodiazepine + buprenorphine:** This is the most clinically significant dangerous interaction. Numerous fatalities, especially in France following 1996 buprenorphine rollout, involved IV buprenorphine misuse combined with benzodiazepines (Mégarbane et al. 2006 [Ref 8]). The interaction is pharmacodynamic (CNS depression synergy), not primarily pharmacokinetic (Megarbane et al. 2005 [Ref 15]).

- Flunitrazepam pretreatment reduced buprenorphine MLD from 234.6 to 38.4 mg/kg in rats (Borron et al. 2002 [Ref 14]) — a ~6-fold increase in lethality
- Concurrent nonprescribed benzodiazepine use among buprenorphine patients can cause excess sedation leading to respiratory depression and death (Guo et al. 2013 [Ref 13])
- Lee et al. (2014 [Ref 12]) compared buprenorphine/BZD toxicity to methadone/BZD toxicity from poison center data

**Critical limitation of naloxone reversal:** Unlike other opioids, buprenorphine's respiratory depression is **not reliably reversed by standard naloxone doses** due to its extremely high MOR affinity and slow receptor dissociation. High-dose or repeated naloxone may be required (Mégarbane et al. 2006 [Ref 8]). This is a critical harm-reduction consideration.

### Cardiac Safety

Buprenorphine has a substantially better cardiac profile than methadone:
- Methadone is associated with QTc prolongation and torsade de pointes risk; buprenorphine is not at standard doses (Krantz et al. 2005 [Ref PMID 15977920])
- Transdermal buprenorphine at 10, 40, and 80 mcg/h showed modest and clinically non-significant QTc effects in healthy volunteers (Harris et al. 2017 [Ref 17])
- FDA adverse event reports show lower arrhythmia reporting for buprenorphine vs. methadone (Kao et al. 2015 [Ref 16])

### Hepatotoxicity

- In clinical populations, hepatotoxicity at standard doses appears low-risk overall
- A 52-week randomized trial in HIV-negative opioid users in China/Thailand found buprenorphine/naloxone implicated in hepatic toxicity, but multiple confounders (viral hepatitis, alcohol) complicate interpretation (Lucas et al. 2014 [Ref 20])
- Animal studies in rat pups suggest age- and dose-dependent hepatotoxic effects at high doses (Roshanravan et al. 2024 [Ref 19]) — **animal data only**

---

## Harm Reduction

**Primary risks:**
1. **Benzodiazepine co-use:** Highest risk combination — pharmacodynamic CNS depression synergy. Published deaths (Mégarbane 2006 [Ref 8]; Borron 2002 [Ref 14]).
2. **Alcohol/GHB/GBL co-use:** CNS depressant synergy; lethal in combination (listed in brief; supported by general opioid pharmacology literature; no buprenorphine-specific trials).
3. **Ketamine/PCP co-use:** Listed in brief as lethal/unknown; CNS depression additive. No buprenorphine-specific published trial data found for ketamine or PCP.
4. **Tramadol co-use:** Listed in brief as lethal. Tramadol lowers seizure threshold and has serotonergic activity; combination with opioids is dangerous. No buprenorphine-specific tramadol interaction study found via API search.

**Precipitated withdrawal:** High-risk in patients switching from full agonists. Buprenorphine displaces full opioid agonists from MOR; if administered while patient has active opioid saturation, severe precipitated withdrawal results (Haghdoost et al. 2026 [Ref 30]).

**Diversion and misuse:** Sublingual buprenorphine is diverted and used non-medically, including by insufflation (Middleton 2011 [Ref 21]; Walsh 2016 [Ref 22]; Guo 2013 [Ref 13]). Buprenorphine/naloxone combination products (Suboxone) have an abuse-deterrent element: naloxone precipitates withdrawal when the product is injected intravenously, reducing IV misuse potential.

**Overdose response:** If buprenorphine-only overdose is suspected, naloxone should still be administered but may require high and repeated doses. Emergency services should be contacted regardless. Respiratory support is the critical intervention (Mégarbane 2006 [Ref 8]).

**Testing:** Buprenorphine is detected on specific opioid immunoassay panels; standard urine drug screens often do NOT detect buprenorphine unless the test specifically includes it (Guo et al. 2013 [Ref 13]).

**Contraindications (from literature):**
- Acute severe respiratory compromise (relative)
- Concurrent MAO inhibitors (general opioid contraindication)
- Severe hepatic impairment (affects naloxone metabolism in combination products)
- Recent use of full agonist opioids (precipitated withdrawal risk) (Haghdoost 2026 [Ref 30])

**FLAG — Interactions needing editorial review:**
- "Ketamine: lethal" in brief — no specific published study confirming lethal interaction found via API search; supported by class-level CNS depressant pharmacology
- "Tramadol: lethal" in brief — no published buprenorphine+tramadol lethal interaction study found; serotonergic and opioid mechanisms make this plausible but safety-critical labeling needs specific sourcing
- "PCP: unknown" and "Nitrous: unknown" — no published buprenorphine-specific interaction data found; these labels appear reasonable but unsourced

---

## Tolerance & Dependence

**Tolerance:**
- Develops with prolonged, repeated use to analgesia, sedation, euphoria, and respiratory depression effects (Cowan 2003 [Ref 9])
- Buprenorphine's high MOR affinity and partial agonism result in a different tolerance profile than full agonists; the ceiling effect persists even in tolerant individuals
- Cross-tolerance to other opioids: Present but **incomplete** — Strain et al. (1997 [Ref 24]) demonstrated in a controlled residential study that buprenorphine-maintained patients showed incomplete cross-tolerance to hydromorphone; full agonists produced some opioid effects even during maintenance

**Dependence:**
- Physical dependence: Develops with regular use (brief: moderate — consistent with literature)
- Psychological dependence: Develops with regular use (brief: moderate — consistent)
- Withdrawal syndrome: Milder and more prolonged than full agonist opioids
  - Onset: Typically 24–72 hours after last sublingual dose (later than morphine withdrawal due to long half-life)
  - Duration: Weeks; protracted in some cases (Hayes et al. 2025 [Ref PMID 40276009] characterized withdrawal from long-acting injectable buprenorphine)
  - Symptoms: Insomnia, muscle aching, anxiety, restlessness, GI disturbance, diaphoresis — milder than methadone or morphine withdrawal
- Addiction liability: Lower than full agonist opioids due to ceiling effect and partial agonism (Cowan 2003 [Ref 9]; Strain 1997 [Ref 24])
- Brief's tolerance half-life of 5 days and 1.5-week full reset period: plausible given the long elimination half-life (~24–42 h) but not found in specific published study in this search. **FLAG** for editorial review — sourcing needed.

**Cross-tolerance:** Cross-tolerance with opioids is established (incomplete) (Strain 1997 [Ref 24]; brief seed data consistent).

---

## Interactions

| Co-substance | Brief Severity | Evidence Basis | Notes |
|---|---|---|---|
| Benzodiazepines (e.g., alprazolam) | Dangerous | Strong — multiple published human and animal studies | Pharmacodynamic synergy; significantly increased respiratory depression and death risk; Mégarbane 2006 [Ref 8]; Borron 2002 [Ref 14]; Lee 2014 [Ref 12] |
| Alcohol | Lethal | Moderate — opioid+CNS depressant class effect; no buprenorphine-specific published trial | Clinically plausible; CNS depression additive; brief severity reasonable but FLAG for sourcing |
| GHB/GBL | Lethal | Moderate — class-level CNS depressant synergy; no buprenorphine-specific published study found | Same class mechanism as BZD/alcohol interaction; severity label plausible but lacks specific source |
| Ketamine | Lethal | Weak — no buprenorphine-specific lethal interaction study found via search | CNS depression additive; classification may be overstated — **FLAG for editorial review** |
| Tramadol | Lethal | Weak — no buprenorphine-specific study found; tramadol has serotonergic+opioid activity | May precipitate serotonin syndrome or cumulative opioid toxicity; **FLAG — severity needs sourcing** |
| Nitrous oxide | Unknown | No published data found | Reasonable cautious label |
| PCP | Unknown | No published data found | Reasonable cautious label |
| CYP3A4 inhibitors (voriconazole, ketoconazole, ritonavir) | Not in brief | Strong — Fihlman et al. 2018 [Ref 26] | Greatly increases buprenorphine systemic exposure; clinical significance documented |
| CYP3A4 inducers (rifampin, carbamazepine) | Not in brief | Moderate — general CYP pharmacology; not buprenorphine-specific study found | Expected to reduce buprenorphine exposure |

**FLAG:** The interaction categories in the brief for Ketamine (lethal) and Tramadol (lethal) are safety-critical labels. The research found no buprenorphine-specific published studies confirming "lethal" severity for either combination. While the pharmacological mechanism is plausible (CNS depression, serotonin syndrome risk), these labels should be flagged for a safety-critical review before being published.

---

## Legal Status

| Jurisdiction | Status | Details |
|---|---|---|
| United States | Schedule III (CSA) | Rescheduled from Schedule V to Schedule III, October 2002. DATA-waiver eliminated December 2022; all DEA Schedule III practitioners may prescribe for OUD without patient limits [Ref 29] |
| United Kingdom | Class C, Schedule 3 | Under Misuse of Drugs Act 1971. Possession without prescription: max 2 years imprisonment. Supply: max 14 years imprisonment [Ref 29] |
| Australia | Schedule 8 (Controlled Drug) | Under Standard for Uniform Scheduling of Medicines and Poisons (SUSMP). Requires specific permit/authorization [Ref 29] |
| Canada | Narcotic — Narcotic Control Regulations | Listed as a narcotic under the Controlled Drugs and Substances Act (CDSA); unlike methadone, does not require Section 56 exemption for prescribing [Ref 29] |
| European Union | Prescription-only; varies by country | Generally listed as a controlled opioid; specific scheduling varies by member state |
| United Nations | Psychotropic Convention Schedule III | Placed in Schedule III of the Convention on Psychotropic Substances in 1989 (WHO recommendation 1988) [Ref 29] |

---

## Clinical Trials

**OUD Treatment:**
- **NCT00316277** (POATS — Prescription Opioid Addiction Treatment Study): Phase 3, completed. McLean Hospital. Compared buprenorphine/naloxone vs. drug counseling alone for prescription opioid dependence. Reference: Indirectly cited in multiple papers including Heidbreder 2023 [Ref 5].
- **NCT06316830**: Phase 2, recruiting (as of 2026). Rhode Island Hospital. "Identifying Optimal Buprenorphine Dosing for Opioid Use Disorder Treatment and Prevention of Overdose."
- **NCT03908437**: Phase 4, completed. University of Pennsylvania. "Rapid Initiation of Drug Treatment Engagement."
- **NCT03809143** (CoLAB): Phase 3, status unknown (2026). University of New South Wales. "Community Studies of Long-Acting Buprenorphine."
- **NCT00218101**: Phase 2, completed. NIDA. "Buprenorphine as a Treatment for Individuals Dependent on Analgesic Opioids."

**Analgesic Indications:**
- **NCT01675167**: Phase 3, completed. BioDelivery Sciences International. Buprenorphine HCl Buccal Film (BELBUCA) for low back pain (led to FDA approval).
- **NCT02737826**: Completed. Medical University of South Carolina. Buprenorphine taper for discontinuation from chronic opioid therapy for pain.

**Depression:**
- Multiple Phase 2/3 trials evaluated buprenorphine/samidorphan (ALKS-5461) for treatment-resistant depression, reviewed by Ragguett et al. (2018 [Ref 25]). As of 2026, this combination was not FDA-approved due to regulatory concerns about opioid risk.

---

## Community Feedback Analysis

No community feedback was submitted in Part A2 of the brief. Standard research directives applied.

---

## Gaps & Flags

### Data Gaps

1. **SMILES string and PubChem CID absent from brief:** Confirmed from PubChem. SMILES not returned by the API call used; can be retrieved directly from PubChem CID 644073.

2. **Specific Ki binding affinities:** No API-verified primary binding study retrieved. Secondary sources consistently describe MOR Ki sub-nanomolar, KOR Ki ~2–5 nM, DOR Ki ~5–6 nM, NOP Ki ~77–148 nM. Generation agent should consult PDSP Ki database or primary binding assay papers (e.g., Toll et al. 1998 Neuropsychopharmacology) for confirmed values before citing specific nM figures.

3. **Intranasal bioavailability:** No specific published bioavailability percentage for insufflated buprenorphine found via API search. The Middleton 2011 paper (Ref 21) characterizes PK/PD but abstract does not provide a % figure. Flag: insufflated bioavailability data may be estimated from clinical context.

4. **Tolerance half-life (5 days, brief):** The brief specifies a 5-day tolerance half-life and 1.5-week full reset. No specific published source for these values was found. Given buprenorphine's 24–42h elimination half-life, a 5-day tolerance half-life is plausible but needs editorial sourcing.

5. **History primary sources:** Lewis/Bentley synthesis (ca. 1967–1969) and Martin et al. 1976 chronic spinal dog paper not retrievable via PubMed (pre-indexing era). Referenced via secondary sources (Cowan 2003; Clark 2022; Heidbreder 2023).

6. **LD50 in humans:** Not established. Animal MLD from Borron 2002 [Ref 14] in rats is available. No human LD50 data published.

7. **Therapeutic index:** While buprenorphine is frequently described as having an improved therapeutic index over full agonists (Davis et al. 2018 [Ref 1]), a specific quantified therapeutic index ratio is not reported in the papers retrieved.

8. **Physical properties** (melting point, solubility, stability): Not retrieved from PubChem API call or primary sources in this search. Not listed in brief either. Gap for article completeness.

### Safety-Critical Flags

**FLAG 1 — Interaction severity for Ketamine (brief: lethal):** No buprenorphine-specific published study confirming lethal ketamine-buprenorphine interaction found. The pharmacological basis (CNS depression additive) supports caution, but "lethal" severity label should be reviewed by a clinical pharmacologist before publication.

**FLAG 2 — Interaction severity for Tramadol (brief: lethal):** No buprenorphine-specific tramadol interaction study found. Tramadol has serotonergic activity (serotonin syndrome risk) and opioid activity; combination is dangerous. "Lethal" label is plausible but requires specific source or editorial decision.

**FLAG 3 — Interaction severity for Alcohol (brief: lethal):** Supported by general opioid pharmacology. No buprenorphine-specific human study found. CNS depressant combination risk is well-established across the class.

**FLAG 4 — Internal hallucinations (effects taxonomy, brief):** No published controlled study describes internal hallucinations as a characteristic buprenorphine effect. Possibly occurs at high doses in sensitive individuals or in combination contexts. Requires editorial verification or community sourcing.

**FLAG 5 — Naloxone reversal limitations:** Critical harm-reduction point not always reflected in public-facing content: standard naloxone doses may not adequately reverse buprenorphine-induced respiratory depression. High-dose or repeated naloxone may be required (Mégarbane 2006 [Ref 8]). This should be prominent in the harm-reduction section.

**FLAG 6 — KOR pharmacology (brief says antagonist; Clark 2022 says agonist):** The brief lists buprenorphine's pharmacological class as "kappa-opioid receptor antagonist." Clark et al. (2022 [Ref 4]) cite updated receptor studies showing buprenorphine is a KOR agonist, not a pure antagonist. The generation agent should note this discrepancy and use appropriately nuanced language (e.g., "mixed KOR agonist/antagonist" or "partial KOR agonist with complex activity").

**FLAG 7 — Dose sensitivity field empty in brief:** No dose sensitivity descriptor (e.g., "low," "moderate," "high") provided. Based on the dose data provided (Threshold 0.3 mg sublingual) and the wide range of opioid sensitivity in the population, editorial assignment of sensitivity level is needed.

**FLAG 8 — Primary ROA listed as "insufflated" in brief:** Standard clinical use is sublingual; insufflated is a misuse/diversion route. The article should distinguish clinical ROA from recreational/misuse ROA. Consider noting that the primary prescribed route is sublingual, with insufflation being a documented misuse pattern (Middleton 2011 [Ref 21]; Walsh 2016 [Ref 22]).