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Buprenorphine

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Buprenorphine
Buprenorphine.svg
Buprenorphine3DanBS.gif
Systematic (IUPAC) name
(2S)-2-[(5R,6R,7R,14S)-9α-Cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol
Clinical data
Trade names Buprenex, Subutex, Suboxone, Butrans
AHFS/Drugs.com monograph
MedlinePlus a605002
Pregnancy cat. C (AU) C (US)
Legal status Controlled (S8) (AU) Class C (UK) Schedule III (USA)
Routes

sublingual, IM, IV, transdermal, intranasal, rectally

on
Pharmacokinetic data
Bioavailability 55%(sublingual)1/48.2% +/- 8.35%(intranasal)2
Protein binding 96%
Metabolism hepatic
CYP3A4, CYP2C8
Half-life 20–70, mean 37 hours
Excretion biliary and renal
Identifiers
CAS number 52485-79-7 YesY
ATC code N02AE01 N07BC01
PubChem CID 644073
IUPHAR ligand 1670
DrugBank DB00921
ChemSpider 559124 YesY
UNII 40D3SCR4GZ YesY
KEGG D07132 YesY
ChEBI CHEBI:3216 YesY
ChEMBL CHEMBL1201894 N
Chemical data
Formula C29H41NO4 
Mol. mass 467.64 g/mol
 N (what is this?)  (verify)
Suboxone tablet

Buprenorphine is a semi-synthetic partial opioid agonist 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.3 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).4

In the European Union, Suboxone and Subutex, buprenorphine's high-dose sublingual tablet preparations, were approved for opioid addiction treatment in September 2006.5 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.6 In recent years, buprenorphine has been introduced in most European countries as a transdermal formulation for the treatment of chronic pain.

Medical uses

Its primary uses in medicine are in the treatment of those addicted to opioids, especially heroin, but it may also be used to treat pain; most often in transdermal patch form.3

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.4 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.7

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).89

Suboxone and naloxone

Suboxone 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.1011121314 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.1516 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.17 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.18 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.

Investigational uses

Antidepressant potential

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.19202122232425 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.

Neonatal abstinence

Buprenorphine has been used in the treatment of the neonatal abstinence syndrome,26 a condition in which newborns exposed to opioids during pregnancy demonstrate signs of withdrawal.27 Use currently is limited to infants enrolled in a clinical trial conducted under an FDA approved investigational new drug (IND) application.28 An ethanolic formulation used in neonates is stable at room temperature for at least 30 days.29

Physicochemical properties

It is a semi-synthetic analogue of thebaine30 and is fairly insoluble in water, as its hydrochloride salt.4 It also degrades in the presence of light.4

Pharmacokinetics

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.31

Buprenorphine's main active metabolite, norbuprenorphine, is a μ-opioid, δ-opioid, and nociceptin receptor full agonist, as well as a κ-opioid receptor partial agonist.3233 Due to these actions it is likely that buprenorphine would antagonise its effects.

The glucuronides are also biologically active.34 Buprenorphine-3-glucuronide has affinity for the μ-opioid receptor(Ki = 4.9±2.7 pM), δ-opioid receptor (Ki = 270±0.4 nM) and the nociceptin receptor (Ki = 36±0.3 µM). It shows no affinity for the kappa opioid receptor. It has a small antinoceptive effect and no effect on respiration. Norbuprenorphine-3-glucuronide has no affinity for the mu or delta opioid receptor. It does however bind to the kappa opioid receptor (Ki = 300±0.5 nM) and the nociceptin receptor (Ki= 18±0.2 µM). It has a sedative effect but no effect on respiration.

Adverse effects

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.35 Hepatic necrosis and hepatitis with jaundice have been reported with the use of buprenorphine, especially after intravenous injection of crushed tablets.citation needed

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.35 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.36 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.

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.37

See also

References

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  5. ^ Suboxone EU Approval
  6. ^ DEA Rescheduling
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