|Trade names||Subutex, Sixmo, others|
|Psychological: High; Physical: Moderate|
|Under the tongue, through the cheek, IM, transdermal, intranasal, rectally, by mouth|
|Metabolism||Liver (CYP3A4, CYP2C8)|
|Onset of action||Within 30 min|
|Elimination half-life||37 hours (range 20–70 hours)|
|Duration of action||Up to 24 hrs|
|Excretion||Bile duct and kidney|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||467.650 g·mol−1|
|3D model (JSmol)|
|(what is this?)|
Buprenorphine is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection (intravenous and subcutaneous), as a skin patch (transdermal), or as an implant. 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. The combination formulation of buprenorphine/naloxone (Suboxone) is recommended to discourage misuse by injection. Maximum pain relief is generally within an hour with effects up to 24 hours.
Side effects may include respiratory depression (decreased breathing), sleepiness, adrenal insufficiency, QT prolongation, low blood pressure, allergic reactions, constipation, and opioid addiction. Among those with a history of seizures, a risk exists of further seizures. Opioid withdrawal following stopping buprenorphine is generally less severe than with other opioids. Whether use during pregnancy is safe is unclear, but use while breastfeeding is probably safe, since the dose the infant receives is 1-2% that of the maternal dose, on a weight basis. Buprenorphine affects different types of opioid receptors in different ways. Depending on the type of receptor, it may be an agonist, partial agonist, or antagonist.
Buprenorphine was patented in 1965, and approved for medical use in the United States in 1981. In 2017, 14.6 million prescriptions for the medication were written in the United States. It is also a common medication used to treat opioid use disorders, such as addiction to heroin. Buprenorphine may also be used recreationally by injection or in the nose for the high it produces. In the United States, it is a schedule III controlled substance.
Opioid use disorder
Buprenorphine is used to treat people with opioid use disorder.: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.: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.:99–100
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, and are safe for pregnant women with opioid use disorder,:101 although preliminary evidence suggests that methadone is more likely to cause neonatal abstinence syndrome. In the US and European Union, 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. If patients are drug free for a few weeks they can then reduce their visits to 5 days and so on until only visiting once a week. Alternatively, buprenorphine can be prescribed by any clinician in the US or assigned doctor within the EU with a waiver/licence allowing people to receive treatment as a part of their routine care.:84–5
A transdermal patch is available for the treatment of chronic pain. 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.
With respect to equianalgesic dosing, when used sublingually, the potency of buprenorphine is about 40 to 70 times that of morphine. When used as a transdermal patch, the potency of buprenorphine may be 100 to 115 times that of morphine.
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.
The most severe side effect associated with buprenorphine is respiratory depression (insufficient breathing). It occurs more often in those who are also taking benzodiazepines or alcohol, or have underlying lung disease. The usual reversal agents for opioids, such as naloxone, may be only partially effective, and additional efforts to support breathing may be required. Respiratory depression may be less than with other opioids, particularly with chronic use. In the setting of acute pain management, though, buprenorphine appears to cause the same rate of respiratory depression as other opioids such as morphine.
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.
|Values are Ki (nM), unless otherwise noted. The smaller|
the value, the more strongly the drug binds to the site.
Opioid receptor modulator
- μ-Opioid receptor (MOR): Very high affinity partial agonist: 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. This behavior is responsible for several unique properties: buprenorphine greatly reduces the effect of most other MOR agonists, can cause precipitated withdrawal when used in actively opioid dependent persons, and has a lower incidence of respiratory depression and fatal overdose relative to full MOR agonists.
- κ-Opioid receptor (KOR): High affinity antagonist -- this activity is hypothesized to underlie some of the effects of buprenorphine on mood disorders and addiction.
- δ-Opioid receptor (DOR): High affinity antagonist
- Nociceptin receptor (NOP, ORL-1): Weak affinity, very weak partial agonist
In simplified terms, buprenorphine can essentially be thought of as a nonselective, mixed agonist–antagonist opioid receptor modulator, acting as an unusually high affinity weak partial agonist of the MOR, a high affinity antagonist of the KOR and DOR, and a relatively low affinity, very weak partial agonist of the ORL-1/NOP.
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. Conversely, buprenorphine behaves like a partial agonist of the MOR with respect to respiratory depression.
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, no risk of accumulation exists in people with renal impairment.
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. However, relative to buprenorphine, norbuprenorphine has extremely little antinociceptive potency (1/50th that of buprenorphine), but markedly depresses respiration (10-fold more than buprenorphine). This may be explained by very poor brain penetration of norbuprenorphine due to a high affinity of the compound for P-glycoprotein. In contrast to norbuprenorphine, buprenorphine and its glucuronide metabolites are negligibly transported by P-glycoprotein.
The glucuronides of buprenorphine and norbuprenorphine are also biologically active, and represent major active metabolites of buprenorphine. 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.
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.
In 1969, researchers at Reckitt and 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. 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. 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
In the United States, buprenorphine and buprenorphine with naloxone were approved for opioid use disorder by the Food and Drug Administration in October 2002. The DEA rescheduled buprenorphine from a schedule V drug to a schedule III drug just before approval. The ACSCN for buprenorphine is 9064, and being a schedule III substance, it does not have an annual manufacturing quota imposed by the DEA. 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 not permitted in outpatient settings except for clinics designed specifically for drug addiction.
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 10. This was eventually modified to allow approved physicians to treat up to 100 people with buprenorphine for opioid addiction in an outpatient setting. This limit was increased by the Obama administration, raising the number of patients to which doctors can prescribe to 275. On January 14, 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.
New Jersey authorized paramedics to give buprenorphine to people at the scene after they have recovered from an overdose.
In the European Union, Subutex and Suboxone, buprenorphine's high-dose sublingual tablet preparations, were approved for opioid use disorder treatment in September 2006. In the Netherlands, buprenorphine is a list II drug of the Opium Law, though special rules and guidelines apply to its prescription and dispensation.
Buprenorphine is available under the trade names Cizdol, Brixadi (weekly and monthly depot injections approved in the US by FDA for addiction treatment in 2020), Suboxone (with naloxone), Subutex (typically used for opioid use disorder), Zubsolv, Bunavail, Buvidal (weekly and monthly depot injections, approved in the UK, Europe and Australia for addiction treatment in 2018), Sublocade (monthly injection, approved in the US in 2018), 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).
Buprenorphine has been introduced in most European countries as a transdermal formulation (marketed as Transtec) for the treatment of chronic pain not responding to nonopioids.
Some evidence supports the use of buprenorphine for depression. Buprenorphine/samidorphan, a combination product of buprenorphine and samidorphan (a preferential μ-opioid receptor antagonist), appears useful for treatment-resistant depression.
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).
Buprenorphine has been used in the treatment of the neonatal abstinence syndrome, a condition in which newborns exposed to opioids during pregnancy demonstrate signs of withdrawal. 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. Preliminary research suggests that buprenorphine is associated with shorter time in hospital for neonates, compared to methadone. An ethanolic formulation used in neonates is stable at room temperature for at least 30 days.
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Currently, methadone and buprenorphine are both widely used as the backbone of MAT [medication-assisted treatment]. The distinguishing outcomes in studies among these two opioid agonists are that infants exposed to buprenorphine in clinical trials required shorter treatment duration, less medication to treat the NAS symptoms and experienced shorter hospitalizations compared to infants exposed to methadone. A caveat to these findings is that some of the supporting data were based on using buprenorphine in combination with naloxone instead of buprenorphine as a single agent.
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