Buprenorphine

Buprenorphine, sold under the brand name Subutex, among others, is an opioid used to treat opioid use disorder, acute pain, and chronic pain.[8] It can be used under the tongue, in the cheek, by injection, as a skin patch, or as an implant.[8][9] For opioid use disorder, it is typically started when withdrawal symptoms have begun and for the first two days of treatment under direct observation of a health care provider.[8] The combination formulation of buprenorphine/naloxone (Suboxone) is recommended to discourage misuse by injection.[8] Maximum pain relief is generally within an hour with effects up to 24 hours.[8]

Buprenorphine
Clinical data
Trade namesSubutex, others
AHFS/Drugs.comMonograph
MedlinePlusa605002
License data
Pregnancy
category
  • AU: C [1]
  • US: N (Not classified yet) [1]
    Dependence
    liability    		Psychological: High; Physical: Moderate[2]
    Routes of
    administration    		Under the tongue, through the cheek, IM, transdermal, intranasal, rectally, by mouth
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    BioavailabilitySublingual: 30%[4]
    Intranasal: 48%[5]
    Buccal: 65%[6][7]
    Protein binding96%
    MetabolismLiver (CYP3A4, CYP2C8)
    Onset of actionWithin 30 min[8]
    Elimination half-life37 hours (range 20–70 hours)
    Duration of actionUp to 24 hrs[8]
    ExcretionBiliary and kidney
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.052.664
    Chemical and physical data
    FormulaC29H41NO4
    Molar mass467.650 g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    Side effects may include respiratory depression (decreased breathing), sleepiness, adrenal insufficiency, QT prolongation, low blood pressure, allergic reactions, and opioid addiction.[8] Among those with a history of seizures, there is a risk of further seizures.[8] Opioid withdrawal following stopping buprenorphine is generally less severe than with other opioids.[8] It is unclear if use during pregnancy is safe and use while breastfeeding is not recommended.[8] Buprenorphine affects different types of opioid receptors in different ways.[8] Depending on the type of receptor it may be an agonist, partial agonist, or antagonist.[8]

    Buprenorphine was patented in 1965 and approved for medical use in the United States in 1981.[8][10] In 2017, 14.6 million prescriptions for the medication were written in the United States.[11] It is also a common drug of abuse, being used in place of heroin.[11] Buprenorphine may be used recreationally by injection or in the nose for the high it produces.[11] In the United States, it is a Schedule III controlled substance.[11]

    Medical uses

    Opioid use disorder
    Buprenorphine patches in the pouch with packaging. A removed patch is shown on the left.

    Buprenorphine is used to treat people with opioid use disorder.[8][12]:84–7 The combination formulation of buprenorphine/naloxone is generally preferred as naloxone, an opioid antagonist, has a higher bioavailability intravenously and results in acute withdrawal if the formulation is crushed and injected.[8][13]:99 Prior to starting buprenorphine, individuals should wait long enough after their last dose of opioid until they have some withdrawal symptoms to allow for the medication to bind the receptors, but if taken too soon, buprenorphine can displace other opioids bound to the receptors and precipitate an acute withdrawal. The dose of buprenorphine is then adjusted until symptoms improve, and individuals remain on a maintenance dose through treatment.[13]:99–100[14]

    Buprenorphine versus methadone

    Both buprenorphine and methadone are medications used for detoxification and opioid replacement therapy and appear to have similar effectiveness based on limited data[15] and are safe for pregnant women with opioid use disorder,[13]:101[14] although preliminary evidence suggests that methadone is more likely to cause neonatal abstinence syndrome.[16] In the US, only designated clinics can prescribe methadone for opioid use disorder in which people starting treatment must follow-up daily, which may be appropriate for those requiring a more structured environment. Alternatively, buprenorphine can be prescribed by any clinician with a waiver allowing people to receive treatment as a part of their routine care.[12]:84–5

    Chronic pain

    A transdermal patch is available for the treatment of chronic pain.[8] These patches are not indicated for use in acute pain, pain that is expected to last only for a short period of time, or pain after surgery, nor are they recommended for opioid addiction.[17]

    Potency

    With respect to equianalgesic dosing, when used sublingually, the potency of buprenorphine is about 40 to 70 times that of morphine.[18][19][20] When used as a transdermal patch, the potency of buprenorphine may be 100–115 times that of morphine.[18][21]

    Adverse effects
    A 2007 assessment of harm from recreational drug use (mean physical harm and mean dependence liability). Buprenorphine was ranked 9th in dependence, 8th in physical harm, and 11th in social harm.[22]

    Common adverse drug reactions associated with the use of buprenorphine are similar to those of other opioids and include: nausea and vomiting, drowsiness, dizziness, headache, memory loss, cognitive and neural inhibition, perspiration, itchiness, dry mouth, shrinking of the pupils of the eyes (miosis), orthostatic hypotension, male ejaculatory difficulty, decreased libido, and urinary retention. Constipation and CNS effects are seen less frequently than with morphine.[23]

    Respiratory effects

    The most severe side effect associated with buprenorphine is respiratory depression (insufficient breathing).[8] It occurs more often in those who are also taking benzodiazepines, alcohol, or have underlying lung disease.[8] The usual reversal agents for opioids, such as naloxone, may be only partially effective and additional efforts to support breathing may be required.[8] Respiratory depression may be less than with other opioids, particularly with chronic use.[14] However, in the setting of acute pain management, buprenorphine appears to cause the same rate of respiratory depression as other opioids such as morphine.[24]

    Buprenorphine dependence

    Buprenorphine treatment carries the risk of causing psychological or physical dependence. Buprenorphine has a slow onset and a long half-life of 24 to 60 hours. Once a person has stabilized on the medication, there are three options: continual use, switching to buprenorphine/naloxone, or medically supervised withdrawal.[14]

    Pain management

    It is difficult to achieve acute opioid analgesia in persons using buprenorphine for opioid replacement therapy.[25]

    Pharmacology

    Pharmacodynamics
    Buprenorphine[26]
    SiteKi (nM)ActionSpeciesRef
    MOR0.21–1.5
    0.081    		Partial agonistHuman
    Monkey    		[27][28][29]
    [30]
    DOR2.9–6.1
    0.82    		AntagonistHuman
    Monkey    		[27][29][31]
    [30]
    KOR0.62–2.5
    0.44    		AntagonistHuman
    Monkey    		[27][29][31]
    [30]
    NOP77.4Partial agonistHuman[28][29][31]
    σ1>100,000NDND[32]
    σ2NDNDNDND
    NMDANDNDNDND
    TLR4>10,000AgonistHuman[33]
    SERT>100,000NDRat[34]
    NET>100,000NDRat[34]
    DATNDNDNDND
    VGSC33,000 (IC50)InhibitorRodent[35]
    Values are Ki (nM), unless otherwise noted. The smaller
    the value, the more strongly the drug binds to the site.

    Opioid receptor modulator

    Buprenorphine has been reported to possess the following pharmacological activity:[29]

    • μ-Opioid receptor (MOR): Partial agonist. Binds with high affinity, but only partially activates the receptor. This property allows buprenorphine to act similarly to full opioid agonists at lower doses (mainly in non-tolerant individuals), reaching a ceiling/plateau at higher doses after which there is no further increase in typical opioid effects (therapeutic or recreational).[36] This behavior is responsible for buprenorphine's ability to block most MOR agonists and the phenomenon of precipitated withdrawal when used in actively opioid dependent persons.
    • κ-Opioid receptor (KOR): Antagonist.[37]
    • δ-Opioid receptor (DOR): Antagonist.[37]
    • Nociceptin receptor (NOP, ORL-1): Weak affinity. Very weak partial agonist.

    In simplified terms, buprenorphine can essentially be thought of as a non-selective, mixed agonist–antagonist opioid receptor modulator,[38] acting as a weak partial agonist of the MOR, an antagonist of the KOR, an antagonist of the DOR, and a relatively low-affinity, very weak partial agonist of the ORL-1.[31][39][40][41][42][43]

    Although buprenorphine is a partial agonist of the MOR, human studies have found that it acts like a full agonist with respect to analgesia in non-opioid-tolerant individuals.[44] Conversely, buprenorphine behaves like a partial agonist of the MOR with respect to respiratory depression.[44]

    Buprenorphine is also known to bind to with high affinity and antagonize the putative ε-opioid receptor.[45][46]

    Full analgesic efficacy of buprenorphine requires both exon 11-[47] and exon 1-associated μ-opioid receptor splice variants.[48]

    The active metabolites of buprenorphine are not thought to be clinically important in its central nervous system effects.[44]

    Other actions

    Unlike some other opioids and opioid antagonists, buprenorphine binds only weakly to and possesses little if any activity at the sigma receptor.[49][50]

    Buprenorphine also blocks voltage-gated sodium channels via the local anesthetic binding site, and this underlies its potent local anesthetic properties.[35]

    Similarly to various other opioids, buprenorphine has also been found to act as an agonist of the toll-like receptor 4, albeit with very low affinity.[33]

    Pharmacokinetics

    Buprenorphine is metabolized by the liver, via CYP3A4 (also CYP2C8 seems to be involved) isozymes of the cytochrome P450 enzyme system, into norbuprenorphine (by N-dealkylation). The glucuronidation of buprenorphine is primarily carried out by UGT1A1 and UGT2B7, and that of norbuprenorphine by UGT1A1 and UGT1A3. These glucuronides are then eliminated mainly through excretion into bile. The elimination half-life of buprenorphine is 20 to 73 hours (mean 37 hours). Due to the mainly hepatic elimination, there is no risk of accumulation in people with renal impairment.[51]

    One of the major active metabolites of buprenorphine is norbuprenorphine, which, in contrast to buprenorphine itself, is a full agonist of the MOR, DOR, and ORL-1, and a partial agonist at the KOR.[52][53] However, relative to buprenorphine, norbuprenorphine has extremely little antinociceptive potency (1/50th that of buprenorphine), but markedly depresses respiration (10-fold more than buprenorphine).[54] This may be explained by very poor brain penetration of norbuprenorphine due to a high affinity of the compound for P-glycoprotein.[54] In contrast to norbuprenorphine, buprenorphine and its glucuronide metabolites are negligibly transported by P-glycoprotein.[54]

    The glucuronides of buprenorphine and norbuprenorphine are also biologically active, and represent major active metabolites of buprenorphine.[55] Buprenorphine-3-glucuronide has affinity for the MOR (Ki = 4.9 pM), DOR (Ki = 270 nM) and ORL-1 (Ki = 36 μM), and no affinity for the KOR. It has a small antinociceptive effect and no effect on respiration. Norbuprenorphine-3-glucuronide has no affinity for the MOR or DOR, but does bind to the KOR (Ki = 300 nM) and ORL-1 (Ki = 18 μM). It has a sedative effect but no effect on respiration.

    Chemistry

    Buprenorphine is a semi-synthetic analogue of thebaine[56] and is fairly soluble in water, as its hydrochloride salt.[57] It degrades in the presence of light.[57]

    Detection in body fluids

    Buprenorphine and norbuprenorphine may be quantitated in blood or urine to monitor use or abuse, confirm a diagnosis of poisoning, or assist in a medicolegal investigation. There is a significant overlap of drug concentrations in body fluids within the possible spectrum of physiological reactions ranging from asymptomatic to comatose. Therefore, it is critical to have knowledge of both the route of administration of the drug and the level of tolerance to opioids of the individual when results are interpreted.[58]

    History

    In 1969, researchers at Reckitt & Colman (now Reckitt Benckiser) had spent 10 years attempting to synthesize an opioid compound "with structures substantially more complex than morphine [that] could retain the desirable actions whilst shedding the undesirable side effects". Physical dependence and withdrawal from buprenorphine itself remain important issues since buprenorphine is a long-acting opioid.[59] Reckitt found success when researchers synthesized RX6029 which had showed success in reducing dependence in test animals. RX6029 was named buprenorphine and began trials on humans in 1971.[60][61] By 1978, buprenorphine was first launched in the UK as an injection to treat severe pain, with a sublingual formulation released in 1982.

    Society and culture

    Regulation

    United States

    In the United States, buprenorphine and buprenorphine with naloxone were approved for opioid use disorder by the United States Food and Drug Administration in October 2002.[62] The DEA rescheduled buprenorphine from a Schedule V drug to a Schedule III drug just before approval.[63] The ACSCN for buprenorphine is 9064, and being a Schedule III substance it does not have an annual manufacturing quota imposed by the DEA.[64] The salt in use is the hydrochloride, which has a free base conversion ratio of 0.928.

    In the years prior to buprenorphine/naloxone's approval, Reckitt Benckiser had lobbied Congress to help craft the Drug Addiction Treatment Act of 2000 (DATA 2000), which gave authority to the Secretary of Health and Human Services to grant a waiver to physicians with certain training to prescribe and administer Schedule III, IV, or V narcotic drugs for the treatment of addiction or detoxification. Prior to the passage of this law, such treatment was not permitted in outpatient settings except for clinics designed specifically for drug addiction.[65]

    The waiver, which can be granted after the completion of an eight-hour course, is required for outpatient treatment of opioid addiction with buprenorphine. Initially, the number of people each approved physician could treat was limited to ten. This was eventually modified to allow approved physicians to treat up to a hundred people with buprenorphine for opioid addiction in an outpatient setting.[66] This limit was increased by the Obama administration, raising the number of patients to which doctors can prescribe to 275.[67]

    New Jersey authorized paramedics to give buprenorphine to people at the scene after they have recovered from an overdose.[68]

    Europe

    In the European Union, Subutex and Suboxone, buprenorphine's high-dose sublingual tablet preparations, were approved for opioid use disorder treatment in September 2006.[69] In the Netherlands, buprenorphine is a List II drug of the Opium Law, though special rules and guidelines apply to its prescription and dispensation.

    Brand names

    Buprenorphine is available under the trade names Cizdol, Suboxone (with naloxone), Subutex (typically used for opioid use disorder), Zubsolv, Bunavail, Sublocade (monthly injection, approved in the US in 2018),[70][71][72] Probuphine, Temgesic (sublingual tablets for moderate to severe pain), Buprenex (solutions for injection often used for acute pain in primary-care settings), Norspan and Butrans (transdermal preparations used for chronic pain).[57]

    Buprenorphine has been introduced in most European countries as a transdermal formulation (marketed as Transtec) for the treatment of chronic pain not responding to non-opioids.

    Veterinary medicine

    It has veterinary medical use for treatment of pain in dogs and cats.[73][74][75]

    Research

    Depression

    Some evidence supports the use of buprenorphine for depression.[76] Buprenorphine/samidorphan, a combination product of buprenorphine and samidorphan (a preferential μ-opioid receptor antagonist), appears useful for treatment-resistant depression.[77]

    Cocaine dependence

    In combination with samidorphan or naltrexone (μ-opioid receptor antagonists), buprenorphine is under investigation for the treatment of cocaine dependence, and recently demonstrated effectiveness for this indication in a large-scale (n = 302) clinical trial (at a high buprenorphine dose of 16 mg but not a low dose of 4 mg).[78][79]

    Neonatal abstinence

    Buprenorphine has been used in the treatment of the neonatal abstinence syndrome,[80] a condition in which newborns exposed to opioids during pregnancy demonstrate signs of withdrawal.[81] In the United States, use currently is limited to infants enrolled in a clinical trial conducted under an FDA approved investigational new drug (IND) application.[82] Preliminary research suggests that buprenorphine is associated with shorter time in hospital for neonates, compared to methadone.[83] An ethanolic formulation used in neonates is stable at room temperature for at least 30 days.[84]

    Obsessive–compulsive disorder

    In one study, buprenorphine was found to be effective in a subset of individuals with treatment-refractory obsessive–compulsive disorder.[85]

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