||Suboxone (when combined with naloxone), Subutex, others
- AU: C
- US: C (Risk not ruled out)
|Sublingual, buccal, IM, IV, transdermal, intranasal, rectally, by mouth
||Hepatic (CYP3A4, CYP2C8)
||37 hours (range 20–70 hours)
||Biliary and renal
|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, moderate acute pain and moderate chronic pain. The combination buprenorphine/naloxone is also used for opioid addiction.
It is a semisynthetic derivative of thebaine. It is a mixed partial agonist opioid receptor modulator.
Buprenorphine was approved for medical use in the United States in 1981.
Butrans 10mcg/hr patches in the pouch with packaging. A removed patch is shown on the left.
Its primary uses in medicine are in the treatment of those addicted to opioids, such as heroin and oxycodone, but it may also be used to treat pain, and sometimes nausea in antiemetic intolerant individuals, most often in transdermal patch form.
It has veterinary medical use for treatment of pain in dogs and cats.
Buprenorphine versus methadone
Both buprenorphine and methadone are medications used for detoxification, short- and long-term opioid replacement therapy. Buprenorphine has the advantage of being only a partial agonist; hence negating the potential for life-threatening respiratory depression in cases of abuse. Studies show the effectiveness of buprenorphine and methadone are almost identical, and largely share adverse-effect profiles apart from more sedation among methadone users. At low flexible doses from 2 to 6 mg, however, buprenorphine has a lower retention rate than from low doses 40 mg or less of methadone.
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 twelve-step facilitation techniques, embracing the 12-step programs practiced by such organizations as Alcoholics Anonymous and Narcotics Anonymous. Some people on maintenance therapies have veered away from such organizations as Narcotics Anonymous, instead opting to create their own twelve-step fellowships (such as Methadone Anonymous) or depart entirely from the twelve-step model of recovery, seeking a program which is secular and based on science (such as SMART Recovery) rather than faith.
Chronic pain relief
A transdermal patch is available for the treatment of chronic pain. It is not indicated for use in acute pain, pain that is expected to last only for a short period of time, or post-operative pain, nor is it indicated or recommended for use in the treatment of opioid addiction.
Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis
regarding 20 popular recreational drugs. 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.
Buprenorphine treatment carries the risk of causing psychological and/or physical dependence. Buprenorphine has a slow onset, mild effect, and is very long acting with a half-life of 24 to 60 hours. Once a patient has stabilized on the drug, there are two treatment options: continual use/maintenance, or medically supervised withdrawal from the physical dependence to the drug.
The most severe and serious adverse reaction associated with opioid use, in general, is respiratory depression, the mechanism behind fatal overdose.
Buprenorphine behaves differently than other opioids in this respect, as it shows a ceiling effect for respiratory depression. Moreover, doubts about the antagonisation of the respiratory effects by naloxone have been disproved: Buprenorphine effects can be antagonised with a continuous infusion of naloxone.
Concurrent use of buprenorphine with other CNS depressants (such as alcohol or benzodiazepines) is contraindicated as it may lead to fatal respiratory depression. Benzodiazepines, in recommended doses, are not contraindicated in individuals tolerant to either opioids or benzodiazepines.
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.
Buprenorphine has been reported to possess the following pharmacological activity:
Buprenorphine receptor activity
||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.
||Possible therapeutic applications as animal models show antidepressive, anxiolytic, stress relieving, and anti-addictive properties with κ antagonists.
||Possible attenuation of drug reward
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.
Buprenorphine is also known to bind to with high affinity and antagonize the putative ε-opioid receptor.
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.
Full analgesic efficacy of buprenorphine requires both exon 11- and exon 1-associated μ-opioid receptor splice variants.
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 also 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.
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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