|This article needs additional citations for verification. (October 2013)|
|Systematic (IUPAC) name|
|Trade names||Buprenex, Subutex, Suboxone, Butrans|
|Pregnancy cat.||C (AU) C (US)|
|Legal status||Controlled (S8) (AU) Class C (UK) Schedule III (USA)|
|Bioavailability||55%(sublingual)/48.2% +/- 8.35%(intranasal)|
|Half-life||20–70, mean 37 hours|
|Excretion||biliary and renal|
|ATC code||N02 N07|
|Mol. mass||467.64 g/mol|
|(what is this?)|
Buprenorphine is a semi-synthetic, mixed agonist–antagonist opioid receptor modulator that is used to treat opioid addiction in higher dosages, to control moderate acute pain in non-opioid-tolerant individuals in lower dosages and to control moderate chronic pain in even smaller doses. It is available in a variety of formulations: Subutex, Suboxone, Zubsolv (buprenorphine HCl and/or naloxone HCl; 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).
In the European Union, Suboxone and Subutex, 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. In the United States, it was rescheduled to Schedule III drug from Schedule V just before FDA approval of Suboxone and Subutex. In recent years, buprenorphine has been introduced in most European countries as a transdermal formulation for the treatment of chronic pain. Buprenorphine has a DEA ACSCN of 9064 and is not subject to DEA annual aggregate manufacturing quotas. The hydrochloride has a free base conversion ratio of 0.93.
- 1 Medical uses
- 2 Pharmacodynamics
- 3 Pharmacokinetics
- 4 Chemistry
- 5 Adverse effects
- 6 See also
- 7 References
- 8 External links
Buprenorphine versus methadone
Buprenorphine has the advantage of being 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, along with the statistical likeliness of any adverse effects except for more sedation among methadone users. At low doses from 2 to 6 mg, however, suboxone has a lower retention rate than low doses from 40 mg or less of methadone.
Inpatient rehabilitation and detoxification
The treatment phase begins once the person is stabilised and receives medical clearance. This portion of treatment comprises multiple therapy sessions, which include both group and individual counselling with various chemical dependency counsellors, psychologists, psychiatrists, social workers, and other professionals. In addition, many treatment centres utilise twelve-step facilitation techniques, embracing the 12-step programs practised 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 (using a program such as SMART Recovery).
Suboxone and naloxone
Suboxone (a controlled substance) contains buprenorphine as well as the opioid antagonist naloxone to deter the abuse of tablets by intravenous injection. Even though controlled trials in human subjects suggest that buprenorphine and naloxone at a 4:1 ratio will produce unpleasant withdrawal symptoms if taken intravenously by people who are addicted to opioids, these studies administered buprenorphine/naloxone to people already addicted to less powerful opiates such as morphine. These studies show the strength of buprenorphine/naloxone in displacing opiates, but do not show the effectiveness of naloxone displacing buprenorphine and causing withdrawal. The Suboxone formulation still has potential to produce an opioid agonist "high" if injected by non-dependent persons, which may provide some explanation to street reports indicating that the naloxone is an insufficient deterrent to injection of suboxone. The addition of naloxone and the reasons for it are conflicting. Published data clearly shows the Ki or binding affinity of buprenorphine is 0.2157 nM, while that for naloxone is 1.1518 nM. Furthermore, the IC50 or the half maximal inhibitory concentration for buprenorphine to displace naloxone is 0.52 nM, while the IC50s of other opiates in displacing buprenorphine, is 100 to 1,000 times greater. These studies help explain the ineffectiveness of naloxone in preventing suboxone abuse, as well as the potential dangers of overdosing on buprenorphine, as naloxone is not strong enough to reverse its effects.
Butrans for chronic pain relief
Butrans Transdermal Patch System is available in 5 mcg/hour, 7.5 mcg/hour, 10 mcg/hour, 15 mcg/hour, and 20 mcg/hour doses. Each patch is applied for 7 days of around-the-clock management of moderate to severe 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. It is also not indicated or recommended for use in the treatment of opioid addiction. 
Norspan is a similar patch with the same indications, but is currently unavailable in the United States.
A clinical trial conducted at Harvard Medical School in the mid-1990s demonstrated that a majority of unipolar non-psychotic persons with major depression 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, but some doctors are realizing its potential as an antidepressant in cases where the person cannot tolerate or is resistant to conventional antidepressants.
ALKS-5461, a combination product of buprenorphine and samidorphan (a selective μ-opioid receptor antagonist), is currently undergoing phase III clinical trials in the United States for augmentation of antidepressant therapy for treatment-resistant depression.
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 1969, researchers at Reckitt & Colman (now Reckitt Benckiser) had spend 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 (addiction)." 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.
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. 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 granted 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 doctor could treat was limited to ten. This was eventually modified to allow approved doctors to treat up to a hundred patients with buprenorphine for opioid addiction in an outpatient setting.
- μ-Opioid receptor (MOR): Ki = 1.5 nM; IA = 28.7%
- κ-Opioid receptor (KOR): Ki = 2.5 nM; IA = 0%
- δ-Opioid receptor (DOR): Ki = 6.1 nM; IA = 0%
- Nociceptin receptor (ORL-1): Ki = 77.4 nM; IA = 15.5%
In simplified terms, buprenorphine can essentially be thought of as a non-selective, mixed agonist–antagonist opioid receptor modulator, acting as a partial agonist of the MOR, an antagonist of the KOR, an antagonist of the DOR, and a relatively low-affinity, weak partial agonist of the ORL-1.
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.
The main active metabolite 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 are also biologically active. 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 biological fluids
Buprenorphine and norbuprenorphine (the major active metabolite of buprenorphine) 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.
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, miosis, orthostatic hypotension, male ejaculatory difficulty, decreased libido, and urinary retention. Constipation and CNS effects are seen less frequently than with morphine. Hepatic necrosis and hepatitis with jaundice have been reported with the use of buprenorphine, especially after intravenous injection of crushed tablets.
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, former doubts on 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 and CNS depressants (such as alcohol or benzodiazepines) is contraindicated as it may lead to fatal respiratory depression. Benzodiazepines, in prescribed doses, are not contraindicated in individuals tolerant to either opioids or benzodiazepines.
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