Buprenorphine
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Buprenorphine is a semi-synthetic opioid of the orvinol class. It is structurally related to morphine but distinguished by a partial agonist ceiling absent in full-agonist opioids. Buprenorphine is a partial agonist at µ-opioid receptors,[1] producing its effects by incompletely activating pain and reward pathways while limiting respiratory depression.[2]
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Synthesized in the late 1960s at Reckitt & Colman as part of a search for safer analgesics, buprenorphine first reached clinical markets as an injectable painkiller in the late 1970s.[3] FDA approval for opioid use disorder in 2002 repositioned it from analgesic to addiction treatment after 36 years of development.[3] It is now among the most widely prescribed medications for opioid dependence globally, with active investigation into antidepressant applications.[4]
Subjective effects include analgesia, sedation, anxiolysis, and attenuated euphoria. The experience is one of sustained, ceiling-limited warmth — physical pain and emotional tension recede into a quiet calm that plateaus rather than deepening with dose, with an anxiolytic quality driven by κ-opioid modulation[5] distinct from classical opioid reward.[6][7] Nausea, constipation, cognitive slowing, and pupil constriction are characteristic unsought effects.
Buprenorphine produces moderate physical and psychological dependence, with a wider safety margin than full-agonist opioids — the partial agonist ceiling limits respiratory depression when used alone.[8] That ceiling is abolished by benzodiazepine co-administration, which accounts for most buprenorphine-associated fatalities,[2] making the primary danger not the substance itself but what it is combined with. Decades of clinical deployment and controlled trials provide a robust evidence base, though human lethal dose data remain unestablished.
History[edit]
Discovery
Buprenorphine emerged from the orvinol analgesic research program at Reckitt & Colman in Hull, United Kingdom, where Kenneth W. Bentley and David G. Hardy synthesized it from thebaine between approximately 1966 and 1969.[3][5][1] Early pharmacological work through the 1970s revealed an unusual combination: analgesic potency 25–40 times that of morphine paired with a ceiling on respiratory depression.[5] Martin and colleagues confirmed its partial agonist character in 1976 using the chronic spinal dog model, establishing the ceiling effect concept that would define the compound's clinical identity.[1]
Clinical adoption
Buprenorphine first reached patients around 1978 as Temgesic, an injectable analgesic in the United Kingdom, followed by a sublingual formulation around 1982 and FDA approval of injectable Buprenex in the United States in 1985.[9] France pioneered high-dose sublingual buprenorphine (Subutex) for opioid substitution therapy in 1996 — a decision that demonstrated mortality benefits for opioid-dependent populations but also revealed the lethal potential of intravenous buprenorphine combined with benzodiazepines.[2] The United Nations placed buprenorphine in Schedule III of the Convention on Psychotropic Substances in 1989.[10]
Modern era
The Drug addiction Treatment Act of 2000 enabled office-based opioid use disorder prescribing in the United States, and in October 2002 the FDA approved Subutex and Suboxone (buprenorphine/naloxone 4:1) — the first medications a physician could prescribe for opioid dependence from a standard office.[3] Formulation innovation followed: Probuphine (six-month subdermal implant, 2016) and Sublocade (monthly depot injection, 2017) addressed adherence challenges, while the December 2022 elimination of the X-waiver requirement removed the last major prescribing barrier.[10] Investigation into buprenorphine's antidepressant potential continues through buprenorphine/samidorphan combinations evaluated for treatment-resistant depression, though regulatory approval has not followed.[4]
Chemistry[edit]
Structural class
Buprenorphine belongs to the orvinol subclass of morphinans — semi-synthetic opioids derived from thebaine, an alkaloid of the opium poppy (Papaver somniferum).[11][5][1] The orvinol scaffold retains the pentacyclic morphinan core with an additional 6,14-etheno bridge that constrains molecular geometry and profoundly affects receptor binding. Where the closely related orvinol etorphine is an ultrapotent full agonist, buprenorphine's cyclopropylmethyl group at the nitrogen position confers partial agonist character — this single substitution accounts for the ceiling effect that defines its clinical profile.
Molecular identity
| Molecular formula | C₂₉H₄₁NO₄ |
| Molecular weight | 467.6 g/mol |
The molecule features a hexacyclic ring system incorporating a furan ring, the morphinan nitrogen bridged by a cyclopropylmethyl group, a methoxy substituent, and a tert-butylcarbinol group — the latter a structural signature of the orvinol series. The phenolic hydroxyl participates in receptor binding interactions critical for opioid activity.
Stereochemistry
Buprenorphine possesses six defined stereocenters, and only the natural (-)-enantiomer is pharmacologically active. The rigid hexacyclic framework constrains the spatial orientation of key substituents relative to the opioid pharmacophore, making absolute configuration essential to its receptor binding profile.
Physical properties
The free base is a white crystalline powder; the hydrochloride salt is used in most clinical formulations. As a lipophilic compound, buprenorphine is approximately 96% protein-bound in plasma.citation needed
Pharmacology[edit]
Mechanism of action
Buprenorphine engages four opioid receptor subtypes simultaneously — a profile that sets it apart from most clinical opioids.[11][5]
At the µ-opioid receptor, buprenorphine acts as a high-affinity partial agonist with extremely slow dissociation. This combination creates two defining properties: a ceiling on respiratory depression that persists even at supratherapeutic doses when buprenorphine is the sole agent,[2][1] and pharmacodynamic action that outlasts what plasma levels alone would predict.[1][12] The ceiling applies to respiratory depression but not to analgesia, which continues to increase with dose.[1][13]
At the κ-opioid receptor, buprenorphine functions as a partial agonist — historically classified as a pure antagonist, but reclassified by more recent binding studies.[5] This activity contributes antidepressant and anxiolytic effects by reducing stress-related dysphoria.[6][7] At the δ-opioid receptor it acts as an antagonist,[5] and at the nociceptin receptor it functions as an agonist.[11]
In preclinical testing, buprenorphine demonstrates analgesic potency 25–40 times that of morphine.[1] At maintenance doses, high receptor occupancy creates a blockade that attenuates the effects of additional full agonists.[14][15] Administering buprenorphine to a patient with active full-agonist opioid saturation precipitates acute withdrawal because the higher-affinity partial agonist displaces the full agonist from receptors.[12]
Pharmacokinetics
Sublingual bioavailability averages approximately 51%, with significant individual variation and a nonlinear dose relationship — higher doses yield proportionally less systemic exposure.[16][17] Peak levels occur within 40–80 minutes, and the terminal half-life ranges from 24 to 42 hours after sublingual dosing, prolonged by an oral mucosal depot effect.[16]
Oral bioavailability is approximately 3%, severely limited by first-pass liver metabolism.[18] Crushed tablets are insufflated as a documented pattern of non-medical use, producing faster onset and higher abuse liability than sublingual administration.[19][20]
The primary metabolic pathway produces norbuprenorphine, an active metabolite that is itself a potent respiratory depressant.[21][22] Plasma concentrations of major metabolites approximate or exceed those of the parent compound.[21] Strong CYP3A4 inhibitors such as voriconazole significantly increase buprenorphine exposure,[23] while pregnancy substantially alters metabolism, lowering dose-adjusted plasma concentrations.[22] Excretion is primarily through bile and feces (~60–70%), with urinary elimination (~20–30%) as conjugated metabolites.citation needed
Neuroscience[edit]
Where it acts
Buprenorphine's reward effects originate in the mesolimbic pathway. Partial activation of µ-opioid receptors on inhibitory interneurons in the ventral tegmental area releases dopamine neurons from suppression, increasing dopamine release in the nucleus accumbens — but to a lesser degree than full agonists like morphine or heroin.[1][14] This submaximal dopamine release is the neurochemical basis for buprenorphine's attenuated euphoric ceiling and lower addiction liability.
Analgesic effects operate through the descending pain modulatory system: µ-opioid activation in the periaqueductal gray disinhibits projections to the rostral ventromedial medulla, which modulates pain signals at the spinal level. Buprenorphine may engage a distinct µ-opioid receptor splice variant for analgesia,[11] potentially explaining why its ceiling on respiratory depression does not extend to pain suppression.
Why it matters
The allostatic model of addiction offers the most explanatory framework for buprenorphine's therapeutic mechanism. Chronic opioid use shifts the brain's hedonic baseline by recruiting anti-reward systems — stress hormones, dynorphin, norepinephrine — that drive negative affect during withdrawal. Buprenorphine maintenance stabilizes this shifted state: partial µ-opioid agonism prevents the withdrawal-driven anti-reward surge, while κ-opioid modulation[5] directly counteracts dynorphin-mediated dysphoria.[6][7]
This dual mechanism distinguishes buprenorphine's neurobiological rationale from methadone, which relies solely on sustained µ-opioid activation. The high receptor occupancy at maintenance doses also limits the cycling between intoxication and withdrawal that drives neuroadaptive changes in full-agonist dependence.[1]
Several fundamental questions remain unresolved. How does buprenorphine's engagement of the truncated 6-transmembrane µ-opioid receptor variant produce analgesia without proportional respiratory depression, and what intracellular signaling pathways does this variant activate?
Subjective Effects[edit]
Buprenorphine's subjective character is defined by a pharmacological ceiling absent in every full-agonist opioid. Where morphine or heroin produce dose-proportional reward escalation, buprenorphine's partial agonism flattens the intensity curve above moderate doses — warmth, analgesia, and anxiolysis plateau, and further dose increases yield diminishing returns. Set and setting are less determinative of the acute experience than with full agonists, though psychological context matters considerably in the framework of dependence treatment. Route of administration significantly modulates the experience: sublingual dosing produces a slow, sustained arc, while insufflation compresses onset and amplifies perceived rush.[19]
Relative to its class, buprenorphine occupies a pharmacological middle ground — more rewarding than naltrexone but substantially less euphoriant than morphine, oxycodone, or methadone. The closest experiential comparison is to a ceiling-limited, extended-duration version of low-dose morphine: sustained calm without the escalating sedation and respiratory risk of higher full-agonist doses.
Effect Grid
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.
Modeled from the effect's dose-dependence curve — not per-substance measurements.
Visual acuity suppression · Visual haze / noise · Visual processing suppression · Internal hallucinations
Body high · Sedation · Nausea · Bodily heaviness · Muscle relaxation · Physical fatigue · Tactile euphoria · Spontaneous body sensations · Dizziness · Sexual arousal suppression · Appetite suppression · Excessive sweating · Dry mouth · Vomiting · Breathing alteration · Headache · Insomnia · Tingling / electric sensations · Respiratory depression · Heart rate perception changes · Abnormal heartbeat · Involuntary body movements · Nystagmus (eye wobbles) · Pain enhancement · Bodily dissociation
Bodily heaviness · Muscle relaxation · Physical fatigue · Tactile euphoria · Spontaneous body sensations · Dizziness · Sexual arousal suppression · Appetite suppression · Excessive sweating · Dry mouth · Vomiting · Breathing alteration · Headache · Insomnia · Tingling / electric sensations · Heart rate perception changes · Abnormal heartbeat · Involuntary body movements · Nystagmus (eye wobbles) · Pain enhancement · Bodily dissociation
Thought deceleration · Analysis suppression · Focus suppression · Information processing suppression · Motivation suppression · Memory suppression · Cognitive dysphoria · Confusion · Language suppression · Memory fragmentation · Thought disorganization
Motivation suppression · Memory suppression · Cognitive dysphoria · Confusion · Language suppression · Memory fragmentation · Thought disorganization
Anxiety · Irritability · Dysphoria
Disinhibition · Social disconnection · Sociability enhancement · Cognitive disconnection
Timeline
First effects emerge faster than sublingual due to nasal mucosal absorption. Warmth and mood shift detectable within 10–30 minutes.
More rapid buildup than sublingual route. Opioid effects intensify quickly — analgesia, sedation, and euphoria build to noticeable levels. Higher reported abuse liability via this route reflects the faster onset kinetics.
Peak intensity reached earlier and potentially felt as more acute than sublingual, though the partial agonist ceiling still limits maximum effect. Nausea, sedation, and euphoria peak during this window.
Sustained moderate effects. Duration is shorter than sublingual plateau due to different absorption kinetics, but receptor binding still drives prolonged action.
Gradual decline toward baseline. Residual sedation and mild analgesia persist.
Residual effects from the long elimination half-life. Mild mood changes and physical residue may persist for 12–48 hours.
⚠ Do not drive or operate machinery until all sedation and psychomotor slowing have resolved — wait at minimum 12 hours after last noticeable effects.
Safety[edit]
- Acute toxicity
- Low
- Chronic toxicity
- Low
- Withdrawal
- Moderate
- Tolerance buildup
- moderate
- Tolerance reset
- 10 days
- Physical
- Moderate
- Psychological
- Moderate
- Compulsive redosing
- Low
- Dose escalation
- Low
- Cross-tol.
- opioids
Toxicity
Acute toxicity
Buprenorphine's partial agonist ceiling provides a substantially wider safety margin than full-agonist opioids. The ceiling on respiratory depression — confirmed in controlled human studies — limits maximal respiratory compromise at supratherapeutic doses when buprenorphine is the sole opioid present.[2][1] Buprenorphine alone is rarely the sole cause of fatal overdose; systematic forensic data from New York City confirmed this pattern.[25]
Standard naloxone doses may not reliably reverse buprenorphine-induced respiratory depression due to its extremely high receptor affinity and slow dissociation. High-dose or repeated naloxone administration may be required. Respiratory support is the critical intervention in suspected overdose.[2]
Heart and circulation
Buprenorphine demonstrates a favorable cardiac safety profile. Controlled trials in healthy volunteers showed clinically insignificant effects on heart rhythm at therapeutic and supratherapeutic doses.[26] Adverse event reporting rates for irregular heartbeat are substantially lower than for methadone,[27] and buprenorphine has been used as a safe alternative in patients with methadone-related heart rhythm disturbances.[28]
Liver toxicity
At standard clinical doses, liver damage risk appears low. A 52-week trial identified hepatic effects, but results were confounded by viral hepatitis and alcohol co-exposure.[29] Animal studies showed age- and dose-dependent liver damage at high doses.[30]
Polysubstance toxicity
Co-administration of buprenorphine with benzodiazepines is the most dangerous interaction. In animal models, benzodiazepine pretreatment reduced buprenorphine's lethal dose approximately 6-fold.[8] Numerous fatalities involving intravenous buprenorphine combined with benzodiazepines were documented in France following the 1996 Subutex rollout.[2] The interaction is pharmacodynamic — benzodiazepines deepen respiratory depression beyond buprenorphine's partial-agonist ceiling — not primarily pharmacokinetic.[31]
Concurrent nonprescribed benzodiazepine use among buprenorphine patients causes excess sedation leading to respiratory depression and death.[32] Comparisons of buprenorphine/benzodiazepine and methadone/benzodiazepine toxicity confirm the severity of both combinations.[33]
Psychological risks
Buprenorphine's psychological risk profile centers on its role in opioid dependence rather than acute psychological disturbance. Cognitive impairment — sedation, psychomotor slowing — occurs in a dose-dependent manner but reaches a ceiling consistent with partial agonism.
Precipitated 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.[12] Depressive symptoms may emerge during withdrawal from chronic use, consistent with the rebound effect of stress-related dysphoria following removal of κ-opioid modulation.
Tolerance and dependence
Tolerance develops with prolonged use to analgesia, sedation, euphoria, and respiratory depression.[1] The partial-agonist ceiling persists even in tolerant individuals, distinguishing buprenorphine's tolerance profile from that of full agonists. Cross-tolerance to other opioids is present but incomplete — in a controlled study, buprenorphine-maintained patients showed residual effects from hydromorphone challenge doses, indicating full blockade is not achieved.[14]
Physical dependence develops at moderate intensity with regular use. Withdrawal is milder and more protracted than full-agonist opioid withdrawal:
- Onset: 24–72 hours after last sublingual dose
- Duration: Weeks to months; withdrawal from long-acting injectable formulations may be further extended[34]
- Symptoms: insomnia, muscle aching, anxiety, restlessness, gastrointestinal disturbance, sweating — milder than Methadone or morphine withdrawal
Addiction liability is lower than full-agonist opioids due to the ceiling on euphoria.[1][14]
Drug interactions
CNS depressant synergy
Benzodiazepines represent the highest-risk combination, supported by both human fatality data and animal lethality studies.[2][8][33] Benzodiazepines potentiate GABAergic inhibition, synergistically deepening respiratory depression beyond the partial-agonist ceiling.
Alcohol carries lethal risk through the same mechanism. No buprenorphine-specific human trial data exist, but the pharmacological basis is established across the opioid class.safety citation needed
GHB/GBL present equivalent risk. No buprenorphine-specific studies have been published.safety citation needed
Opioid interactions
Full-agonist opioids: Buprenorphine displaces full agonists from µ-opioid receptors due to higher affinity, precipitating acute withdrawal in dependent individuals.[12] Conversely, full agonists administered during buprenorphine maintenance produce attenuated effects due to receptor occupancy blockade.[14]
Tramadol: Combined opioid receptor activation and tramadol's serotonergic activity create risk of cumulative respiratory depression and potential serotonin syndrome.safety citation needed
Pharmacokinetic interactions
CYP3A4 inhibitors (voriconazole, ketoconazole, ritonavir) substantially increase buprenorphine exposure.[23] Patients receiving strong CYP3A4 inhibitors may experience enhanced opioid effects and require dose adjustment.
CYP3A4 inducers (rifampin, carbamazepine) are expected to reduce buprenorphine levels, potentially causing breakthrough withdrawal in maintenance patients.citation needed
Contraindications
- Concurrent benzodiazepine or CNS depressant use — unsupervised combination is dangerous; clinical co-prescribing requires risk management protocols[2]
- Recent full-agonist opioid use — precipitated withdrawal risk requires adequate time since last dose or use of microinduction protocols[12]
- Acute severe breathing difficulty — buprenorphine adds respiratory depression even if limited by its ceiling
- Severe liver impairment — affects metabolism of both buprenorphine and naloxone in combination products; dose adjustment may be required
- Concurrent MAO inhibitor use — general opioid contraindication due to risk of serotonergic and adrenergic crisiscitation needed
- Pregnancy — not an absolute contraindication (buprenorphine is used in pregnancy for opioid dependence), but requires specialist management due to altered metabolism[22]
Harm Reduction[edit]
Forms & Identification
Buprenorphine circulates primarily as pharmaceutical products — sublingual tablets, sublingual and buccal films, and transdermal patches — rather than as raw powder. The pharmaceutical origin means most buprenorphine encountered in both medical and non-medical settings has known composition, but diversion of pharmaceutical products and counterfeit tablets have been documented. Testing matters most when the source is uncertain: reagent kits confirm the presence of an opioid but cannot distinguish buprenorphine from other opioids, making product identification through imprint codes and manufacturer packaging the primary verification method.
Film formulations dissolve sublingually and should not be swallowed, as oral bioavailability is negligible. Tablets intended for sublingual use are sometimes crushed for insufflation — a route that increases abuse liability and introduces unpredictable dosing.[19]
Guidelines
- Verify unfamiliar tablets or films for authenticity using imprint code identification before use
- Start with lower doses when tolerance status is uncertain — buprenorphine's long half-life means effects accumulate
- Do not transition directly from a full-agonist opioid to buprenorphine without adequate washout time; precipitated withdrawal is severe and immediate
- Ensure someone is aware of your use and can check on you, particularly with a new source or changed dose
- Avoid redosing within the first 2–3 hours — sublingual absorption is slow and peak effects are delayed
- Keep naloxone available, noting that higher-than-standard doses may be needed to reverse buprenorphine effects
Set & Setting
Buprenorphine's long duration and slow onset make the immediate environment less acutely critical than with rapid-onset opioids, but psychological context shapes the experience. For those using buprenorphine in a treatment context, a stable, low-stress environment supports adherence and reduces the salience of cravings. For non-medical use, the extended duration means effects persist well beyond what users accustomed to shorter-acting opioids may expect.
Aftercare & integration. Post-use recovery from buprenorphine is shaped by its long half-life — residual sedation and cognitive dulling may persist for 24 hours or more. Adequate sleep, hydration, and light nutrition support physical recovery. Constipation, a universal opioid effect, may require attention for several days following use.
For those discontinuing maintenance treatment, the extended withdrawal timeline (weeks to months) benefits from structured support. Gradual tapering under medical supervision is preferred over abrupt cessation. Psychological support during tapering addresses the anxiety and low mood that accompany the protracted withdrawal period.
Recovery & Support
Buprenorphine occupies a unique position as both a substance of dependence and a primary tool for treating opioid dependence. For those seeking to discontinue buprenorphine itself, a slow medical taper remains the most supported approach — withdrawal is milder than from full agonists but more protracted.[1]
Peer support programs, including SMART Recovery and mutual aid groups, provide community structure during and after tapering. Medical providers experienced in opioid use disorder management can guide individualized taper schedules and address the psychological dimensions of recovery. Returning to buprenorphine maintenance after a period of instability is not failure — it is an evidence-supported decision.
Recovery resources, crisis lines, and support pathways → View all
Emergency Response
Recognizing an emergency: Dangerously slow or stopped breathing, blue or grey lips and fingertips, inability to be roused, gurgling or choking sounds, extreme unresponsiveness. These signal respiratory depression — buprenorphine's ceiling makes this rare when used alone, but the ceiling is abolished by benzodiazepines or alcohol.
Immediate steps:
- 1. Call emergency services immediately if breathing is slow, irregular, or absent
- 2. Administer naloxone if available — higher than standard doses may be required due to buprenorphine's strong receptor binding[2]
- 3. Place the person in the recovery position (on their side) to prevent choking
- 4. Perform rescue breathing if trained and breathing has stopped
- 5. Do not leave the person alone; do not induce vomiting
What to tell the dispatcher: Name the substance (buprenorphine), estimated amount and time taken, any other substances involved (especially benzodiazepines or alcohol), and current symptoms. Good Samaritan laws in many jurisdictions protect people who call for help during a drug emergency.
Reversal agent: Naloxone is the standard opioid reversal agent but may be less effective against buprenorphine than against full-agonist opioids due to its high receptor affinity. Repeated doses or continuous infusion may be necessary. Respiratory support — maintaining the airway and providing rescue breathing — is the critical intervention.[2]
Legal Status[edit]
Buprenorphine is internationally controlled as an opioid with recognized medical applications. The United Nations placed it in Schedule III of the Convention on Psychotropic Substances in 1989 following a WHO recommendation.[10] National scheduling varies but universally requires a prescription, with most jurisdictions classifying it under controlled substance or narcotic regulations. The December 2022 elimination of the US X-waiver requirement represented a significant regulatory liberalization for opioid use disorder prescribing.
| Jurisdiction | Classification | Key provisions |
|---|---|---|
| United States | Schedule III (Controlled Substances Act) | Rescheduled from Schedule V to Schedule III in October 2002. X-waiver eliminated December 2022; all Schedule III practitioners may prescribe for opioid use disorder without patient limits[10] |
| United Kingdom | Class C, Schedule 3 (Misuse of Drugs Act 1971) | Possession without prescription: maximum 2 years imprisonment. Supply: maximum 14 years imprisonment[10] |
| Australia | Schedule 8 (Controlled Drug) | Requires specific permit or authorization[10] |
| Canada | Narcotic (Controlled Drugs and Substances Act) | Listed as a narcotic under the CDSA. Unlike methadone, does not require Section 56 exemption for prescribing[10] |
| European Union | Prescription-only (varies by member state) | Generally controlled as an opioid; specific scheduling varies by member state |
| United Nations | Schedule III (Convention on Psychotropic Substances) | Placed in Schedule III in 1989 following WHO recommendation[10] |
references
- [1]
- [2]
- [3] ^abcdHeidbreder C, Fudala PJ, Greenwald MK (2023) History of the discovery, development, and FDA-approval of buprenorphine medications for the treatment of opioid use disorder — Drug and Alcohol Dependence Reports doi:10.1016/j.dadr.2023.100133
- [4] ^abRagguett RM, Rong C, Rosenblat JD, Ho RC, McIntyre RS (2018) Pharmacodynamic and pharmacokinetic evaluation of buprenorphine + samidorphan for the treatment of major depressive disorder — Expert Opinion on Drug Metabolism and Toxicology doi:10.1080/17425255.2018.1459564
- [5]
- [6] ^abcRobinson SA, Erickson RL, Browne CA, Lucki I (2017) A role for the mu opioid receptor in the antidepressant effects of buprenorphine — Behavioural Brain Research doi:10.1016/j.bbr.2016.10.050