- AU: C
- US: C (Risk not ruled out)
|Sublingual, buccal, IM, transdermal, intranasal, rectally, by mouth
||Liver (CYP3A4, CYP2C8)
|Onset of action
||Within 30 min
||37 hours (range 20–70 hours)
|Duration of action
||Up to 24 hrs
||Biliary and kidney
|Chemical and physical data
|3D model (JSmol)
| (what is this?) (verify)
Buprenorphine, sold under the brand name Subutex, among others, is an opioid used to treat opioid addiction, acute pain, and chronic pain. It can be used under the tongue, by injection, or as a skin patch. When used for opioid addiction it is recommended that a health care provider observe the person while they take the medication. For longer term treatment of addiction a combination formulation of buprenorphine/naloxone is usually recommended. 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, and opioid addiction. Among those with a history of seizures, there is a risk of further seizures. Opioid withdrawal following stopping is generally mild. It is unclear if use during pregnancy is safe and use while breastfeeding is not recommended. 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 approved for medical use in the United States in 1981. In 2012 9.3 million prescription for the medication were made in the United States. Buprenorphine may also be used recreationally by injection or in the nose for the high it produces. Some use it as a substitute for heroin. In the United States it is a Schedule III controlled substance. For the tablets the wholesale cost in the United States is between 0.86 and 1.32 USD per daily dose as of 2017.
Its primary use is for the initial treatment of those with opioid addiction. It should only be started once symptoms of withdrawal have begun. For longer term treatment of addiction a combination formulation of buprenorphine/naloxone is usually recommended. A once a month injection has been approved in the United States and should be on available in 2018.
Buprenorphine versus methadone
Both buprenorphine and methadone are medications used for detoxification, short- and long-term opioid replacement therapy. Effectiveness of buprenorphine and methadone appear similar, with similar side effects. Buprenorphine may have less respiratory depression in cases of abuse.
Inpatient rehabilitation and detoxification
Rehabilitation programs consist of "detox" and "treatment" phases. The detoxification ("detox") phase consists of medically supervised withdrawal from the drug of dependency onto buprenorphine, sometimes aided by the use of medications such as benzodiazepines like oxazepam or diazepam (modern milder tranquilizers that assist with anxiety, sleep, and muscle relaxation), clonidine (a blood-pressure medication that may reduce some opioid withdrawal symptoms), and anti-inflammatory/pain relief drugs such as ibuprofen and aspirin.
The treatment phase begins once the person is stabilized and receives medical clearance. This portion of treatment consists of multiple therapy sessions, which include both group and individual counseling with various chemical dependency counselors, psychologists, psychiatrists, social workers, and other professionals. In addition, many treatment centers utilize 12-step programs such as Narcotics Anonymous.
Butrans patches in the pouch with packaging. A removed patch is shown on the left.
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.
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.
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.
The most severe side effect associated with buprenorphine is respiratory depression (insufficient breathing). It occurs more often in those who are also taking benzodiazepines, 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.
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.
People on high-dose buprenorphine therapy may be unaffected by even large doses of opioids such as oxycodone, morphine, or hydromorphone.
It is also difficult to achieve acute opioid analgesia in persons using buprenorphine for opioid replacement therapy.
Opioid receptor modulator
Buprenorphine has been reported to possess the following pharmacological activity:
- μ-Opioid receptor (MOR): Weak partial agonist. Binds with high affinity, but only partially activates the receptor. This behavior is responsible for buprenorphine's ability to block most μ agonists and the phenomenon of withdrawal effects when used in actively opioid dependent persons.
- κ-Opioid receptor (KOR): Very weak partial agonist or functional antagonist. Possible therapeutic applications as animal models show antidepressive, anxiolytic, stress relieving, and anti-addictive properties with κ antagonists.
- δ-Opioid receptor (DOR): Antagonist. Possible attenuation of drug reward.
- Nociceptin receptor (NOP, ORL-1): Weak affinity. Very weak partial agonist. May be involved in lack of respiratory depression with buprenorphine in overdose.
In simplified terms, buprenorphine can essentially be thought of as a non-selective, mixed agonist–antagonist opioid receptor modulator, 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.
Although buprenorphine is a partial agonist of the MOR, human studies have found that it acts like a full agonist with respect to analgesia. Conversely, buprenorphine behaves like a partial agonist of the MOR with respect to respiratory depression.
Buprenorphine is also known to bind to with high affinity and antagonize the putative ε-opioid receptor.
Full analgesic efficacy of buprenorphine requires both exon 11- and exon 1-associated μ-opioid receptor splice variants.
The active metabolites of buprenorphine are not thought to be clinically important in its central nervous system effects.
Unlike some other opioids and opioid antagonists, buprenorphine binds only weakly to and possesses little if any activity at the sigma receptor.
Buprenorphine also blocks voltage-gated sodium channels via the local anesthetic binding site, and this underlies its potent local anesthetic properties.
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.
Buprenorphine is metabolised 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 the bile. The elimination half-life of buprenorphine is 20–73 hours (mean 37). Due to the mainly hepatic elimination, there is no risk of accumulation in people with renal impairment.
One of the major active metabolites of buprenorphine is norbuprenorphine, which, contrary 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 can 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.
Buprenorphine is a semi-synthetic analogue of thebaine and is fairly soluble in water, as its hydrochloride salt. It degrades in the presence of light.
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.
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, remains an issue because it is a long-acting opiate. 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 (Subutex) and buprenorphine with naloxone (Suboxone) were approved for opioid addiction by the United States Food and Drug Administration in October 2002. The FDA rescheduled buprenorphine from a Schedule V drug to a Schedule III drug just before approval of Subutex and Suboxone. 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 prior to Suboxone'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.
The waiver, which can be granted after the completion of an eight-hour course, is required for outpatient treatment of opioid addiction with Subutex and Suboxone. Initially, the number of patients each approved physician could treat was limited to ten. This was eventually modified to allow approved physicians to treat up to a hundred patients with buprenorphine for opioid addiction in an outpatient setting. This limit was recently increased by the Obama administration, raising the number of patients to which doctors can prescribe to 275. Still, due to this patient limit and the requisite eight-hour training course, many continuing patients can find it very difficult to get a prescription, despite the drug's effectiveness.
In the European Union, Subutex and Suboxone, buprenorphine's high-dose sublingual tablet preparations, were approved for opioid addiction 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, Suboxone, Subutex (typically used for opioid addiction), 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 non-opioids.
It has veterinary medical use for treatment of pain in dogs and cats.
A clinical trial conducted at Harvard Medical School in the mid-1990s demonstrated that a majority of persons with non‑psychotic unipolar depression who were refractory to conventional antidepressants and electroconvulsive therapy could be successfully treated with buprenorphine. Clinical depression is currently not an approved indication for the use of any opioid.
Buprenorphine/samidorphan (ALKS-5461), a combination product of buprenorphine and samidorphan (a preferential μ-opioid receptor antagonist), is currently undergoing phase III clinical trials in the United States for augmentation of antidepressant therapy 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. Use currently is limited to infants enrolled in a clinical trial conducted under an FDA approved investigational new drug (IND) application. An ethanolic formulation used in neonates is stable at room temperature for at least 30 days.
In one study, buprenorphine was found to be effective in a subset of individuals with treatment-refractory obsessive–compulsive disorder.
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