Buprenorphine
Clinical data | |
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Pronunciation | bew-pre-nor-feen |
Trade names | Subutex, Sublocade, Brixadi, others |
AHFS/Drugs.com | Monograph |
MedlinePlus | a605002 |
License data | |
Pregnancy category | |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | Sublingual: 30%[13] Intranasal: 48%[14] Buccal: 65%[15][16] |
Protein binding | 96% |
Metabolism | Liver (CYP3A4, CYP2C8) |
Onset of action | Within 30 min[17] |
Elimination half-life | 37 hours (range 20–70 hours) |
Duration of action | Up to 24 hrs[17] |
Excretion | Bile duct and kidney |
Identifiers | |
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Buprenorphine, sold under the brand name Subutex among others, is an
In the United States, the combination formulation of
Side effects may include
Buprenorphine was patented in 1965, and approved for medical use in the United States in 1981.[17][23] It is on the World Health Organization's List of Essential Medicines.[24] In addition to prescription as an analgesic it is a common medication used to treat opioid use disorders, such as addiction to heroin.[25] In 2020, it was the 186th most commonly prescribed medication in the United States, with more than 2.8 million prescriptions.[26][27] Buprenorphine may also be used recreationally for the high it can produce.[25] In the United States, buprenorphine is a schedule III controlled substance.[25]
Medical uses
Opioid use disorder
Buprenorphine is used to treat people with
Before starting buprenorphine, individuals are generally advised to wait long enough after their last dose of opioid until they have some withdrawal symptoms to allow for the medication to bind the receptors, since 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 of 8–16 mg.[29]: 99–100 [31] Because withdrawal is uncomfortable and a deterrent for many patients, many have begun to call for different means of treatment initiation.[32] Some providers have begun to use the Bernese method, also known as microdosing, in which very small doses of buprenorphine are given while patients are still using street opioids, and without precipitating withdrawal, with medicine levels slowly titrated upward.[33][34]
Buprenorphine versus methadone
Both buprenorphine and
Chronic pain
A transdermal patch is available for the treatment of chronic pain.[17] 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.[40]
Potency
With respect to equianalgesic dosing, when used sublingually, the potency of buprenorphine is about 40 to 70 times that of morphine.[41][42][43] When used as a transdermal patch, the potency of buprenorphine may be 100 to 115 times that of morphine.[41][44]
Adverse effects
Common adverse drug reactions associated with the use of buprenorphine, similar to those of other opioids, 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 central nervous system (CNS) effects are seen less frequently than with morphine.[46] Central sleep apnea has also been reported as a side effect of long-term buprenorphine use.[47][48]
Respiratory effects
The most severe side effect associated with buprenorphine is respiratory depression (insufficient breathing).[17] It occurs more often in those who are also taking benzodiazepines or alcohol, or have underlying lung disease.[17] The usual reversal agents for opioids, such as naloxone, may be only partially effective, and additional efforts to support breathing may be required.[17] Respiratory depression may be less than with other opioids, particularly with chronic use.[31] In the setting of acute pain management, though, buprenorphine appears to cause the same rate of respiratory depression as other opioids such as morphine.[49] Central sleep apnea is possible with long-term use, possibly resolving with dose reduction.[47][48]
Buprenorphine dependence
Buprenorphine treatment carries the risk of causing psychological or physiological (physical) dependencies. It has a slow onset of activity, with a long duration of action, and a long half-life of 24 to 60 hours. Once a patient has stabilised on the (buprenorphine) medication and programme, three options remain - continual use (buprenorphine-only medication), switching to a buprenorphine/naloxone combination, or a medically supervised withdrawal.[31]
Pain management
Achieving acute opioid
Pharmacology
Pharmacodynamics
Site | Ki (nM) | Action | Species | Ref |
---|---|---|---|---|
MOR |
0.7-2.3 0.081 |
Partial agonist | Human Monkey |
[53][54][55] [56] |
DOR |
2.9–6.1 0.82 |
Antagonist | Human Monkey |
[53][55][57] [56] |
KOR |
0.62–2.5 0.44 |
Antagonist | Human Monkey |
[53][55][57] [56] |
NOP | 77.4 | Partial agonist | Human | [54][55][57] |
σ1 | >100,000 | ND | ND | [58] |
σ2 | ND | ND | ND | ND |
NMDA |
ND | ND | ND | ND |
TLR4 | >10,000 | Agonist | Human | [59] |
SERT | >100,000 | ND | Rat | [60] |
NET | >100,000 | ND | Rat | [60] |
DAT | ND | ND | ND | ND |
VGSC | 33,000 (IC50) | Inhibitor | Rodent | [61] |
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 these following
- μ-Opioid receptor (MOR): Very high affinity partial agonist:[62] at low doses, the MOR-mediated effects of buprenorphine are comparable to those of other narcotics, but these effects reach a "ceiling" as the receptor population is saturated.[57] This behavior is responsible for several unique properties: buprenorphine greatly reduces the effect of most other MOR agonists,[63] can cause precipitated withdrawal when used in actively opioid dependent persons,[63] and has a lower incidence of respiratory depression and fatal overdose relative to full MOR agonists.[64]
- Nociceptin receptor (NOP, ORL-1): Weak affinity, very weak partial agonist[62]
In simplified terms, buprenorphine can essentially be thought of as a nonselective, mixed
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 opioid-intolerant individuals.
Buprenorphine is also known to bind to with high affinity and antagonize the putative
Full analgesic efficacy of buprenorphine requires both
The active metabolites of buprenorphine are not thought to be clinically important in its CNS effects.[74]
In positron emission tomography (PET) imaging studies, buprenorphine was found to decrease whole-brain MOR availability due to receptor occupancy by 41% (i.e., 59% availability) at 2 mg, 80% (i.e., 20% availability) at 16 mg, and 84% (i.e., 16% availability) at 32 mg.[79][80][81][82]
Other actions
Unlike some other opioids and opioid antagonists, buprenorphine binds only weakly to and possesses little if any activity at the sigma receptor.[83][84]
Buprenorphine also blocks voltage-gated sodium channels via the local anesthetic binding site, and this underlies its potent local anesthetic properties.[61]
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.[59]
Pharmacokinetics
Buprenorphine is
One of the major
The glucuronides of buprenorphine and norbuprenorphine are also biologically active, and represent major active metabolites of buprenorphine.[89] 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 semisynthetic derivative of thebaine,[90] and is fairly soluble in water, as its hydrochloride salt.[91] It degrades in the presence of light.[91]
Detection in body fluids
Buprenorphine and norbuprenorphine may be quantified in blood or urine to monitor use or non-medical recreational use, confirm a diagnosis of poisoning, or assist in a medicolegal investigation. A significant overlap of drug concentrations exists in body fluids within the possible spectrum of physiological reactions ranging from asymptomatic to comatose. Therefore, having knowledge of both the route of administration of the drug and the level of tolerance to opioids of the individual is critical when results are interpreted.[92]
History
In 1969, researchers at Reckitt and Colman (now
Society and culture
Regulation
United States
In the United States, buprenorphine and buprenorphine with naloxone were approved for opioid use disorder by the Food and Drug Administration in October 2002.[96] The DEA rescheduled buprenorphine from a schedule V drug to a schedule III drug just before approval.[97] The ACSCN for buprenorphine is 9064, and being a schedule III substance, it does not have an annual manufacturing quota imposed by the DEA.[98] The salt in use is the hydrochloride, which has a free-base conversion ratio of 0.928.
In the years before buprenorphine/naloxone was approved, Reckitt Benckiser had lobbied Congress to help craft the Drug Addiction Treatment Act of 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. Before this law was passed, such treatment was permitted only in clinics designed specifically for drug addiction.[99]
The waiver, which can be granted after the completion of an eight-hour course, was required for outpatient treatment of opioid addiction with buprenorphine from 2000 to 2021. Initially, the number of people each approved physician could treat was limited to 10. This was eventually modified to allow approved physicians to treat up to 100 people with buprenorphine for opioid addiction in an outpatient setting.[100] This limit was increased by the Obama administration, raising the number of patients to which doctors can prescribe to 275.[101] On 14 January 2021, the US Department of Health and Human Services announced that the waiver would no longer be required to prescribe buprenorphine to treat up to 30 people concurrently.[102]
New Jersey authorized paramedics to give buprenorphine to people at the scene after they have recovered from an overdose.[103]
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.[104] In the Netherlands, buprenorphine is a list II drug of the Opium Law, though special rules and guidelines apply to its prescription and dispensation. In France, where buprenorphine prescription by general practitioners and dispensed by pharmacies has been permitted since the mid-1990s as a response to HIV and overdose risk. Deaths caused by heroin overdose were reduced by four-fifths between 1994 and 2002, and incidence of AIDS among people who inject drugs in France fell from 25% in the mid-1990s to 6% in 2010.[105]
Brand names
Buprenorphine is available under the trade names Cizdol, Brixadi (approved in the US by FDA for addiction treatment in 2023), Suboxone (with naloxone), Subutex (typically used for opioid use disorder), Zubsolv, Bunavail, Buvidal (approved in the UK, Europe and Australia for addiction treatment in 2018), Sublocade (approved in the US in 2018),
Research
Microdosing
There is some evidence that a buprenorphine microdosing regime, started before opioid withdrawal symptoms have started, can be effective in helping people transitioning away from opioid dependence.[109]
Depression
Some evidence supports the use of buprenorphine for depression.
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).[112][113]
Neonatal abstinence
Buprenorphine has been used in the treatment of the
Veterinary uses
Veterinarians administer buprenorphine for perioperative pain, particularly in cats, where its effects are similar to morphine. The drug's legal status and lower potential for human abuse makes it an attractive alternative to other opioids.[119]
It has veterinary medical use for treatment of pain in dogs and cats, as well as other animals.[120][121][122]
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External links
- McGray D (1 April 2005). "The bitter pill". Wired.
- Wood G (7 May 2013). "Subu Must Die – How a nation of junkies went cold turkey". New Republic.