Buprenorphine
From DrugPedia: A Wikipedia for Drug discovery
| Buprenorphine
| |
| Systematic (IUPAC) name | |
| N/A | |
| Identifiers | |
| CAS number | ? |
| ATC code | ? |
| PubChem | |
| Chemical data | |
| Formula | C29H42ClNO4 |
| Mol. mass | 504.10108 |
| SMILES | & |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | ? |
| Half life | ? |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
? |
| Legal status | |
| Routes | ? |
Contents |
[edit] Description
A derivative of the opioid alkaloid THEBAINE that is a more potent and longer lasting analgesic than MORPHINE. It appears to act as a partial agonist at mu and kappa opioid receptors and as an antagonist at delta receptors. The lack of delta-agonist activity has been suggested to account for the observation that buprenorphine tolerance may not develop with chronic use.
Buprenorphine (or colloquially, "Bupe") is a semi-synthetic opiate with partial agonist and antagonist actions. Buprenorphine hydrochloride was first marketed in the 1980s by Reckitt & Colman (now Reckitt Benckiser) as an analgesic, available generally as Temgesic 0.2 mg sublingual tablets, and as Buprenex in a 0.3 mg/ml injectable formulation. In October 2002, the Food and Drug Administration (FDA) of the United States of America additionally approved Suboxone and Subutex, buprenorphine's high-dose sublingual pill preparations for opioid addiction, and as such the drug is now also used for this purpose. In the European Union, Suboxone and Subutex, buprenorphine's high-dose sublingual pill 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 USA, it has been a Schedule III drug under the United Nations' Convention on Psychotropic Substances since it was rescheduled from Schedule V just before FDA approval of Suboxone and Subutex. In the recent years, buprenorphine has been introduced in most European countries as a transdermal formulation for the treatment of chronic pain.
[edit] Commercial preparations
British firm Reckitt & Colman (now Reckitt Benckiser) first marketed buprenorphine under the trade names Temgesic (sublingual/parenteral preparations, no active additives) and Buprenex (parenteral, no active additives). Two more recent formulations from Reckitt Benckiser have been approved for opioid addiction treatment throughout most of the world, alongside or instead of Methadone. Subutex (white color, bitter, no active additives) and Suboxone (orange color, lemon-lime flavored, one part naloxone for every four parts buprenorphine; hexagon shaped tablet). Subutex and Suboxone are available in 2 mg and 8 mg sublingual dosages.
Suboxone contains buprenorphine as well as the opioid antagonist naloxone to deter the abuse of tablets by intravenous injection. Controlled trials in human subjects suggest that buprenorphine and naloxone at a 4:1 ratio will produce unpleasant withdrawal symptoms if taken intravenously by patients who are addicted to opioids,but has no such effect when taken sublingually. However, 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.
A solution for injection (usually by the intramuscular route) is marketed for the British veterinary market by Alstoe Animal Health as Vetergesic, licensed for analgesia and sedation in dogs.
Since 2001 buprenorphine is also available transdermally as 35, 52.5 and 70 mcg per hour transdermal patches that delivers the dose over seventy-two hours. This application form is marketed as Transtec in most European countries by Grunenthal (Napp Pharmaceuticals in the UK, Norpharma in Denmark) for the treatment of moderate to severe cancer pain and severe non-cancer pain not responding to non-opioids. Moreover, a new 5, 10 and 20 mcg per hour patch is marketed as Butrans or Norspan, a once-weekly patch for severe chronic pain not responding to non-opioids, marketed by Napp Pharmaceuticals Ltd., and Mundipharma and Grunenthal respectively.
[edit] Pharmacology and pharmacokinetics
Buprenorphine is a thebaine derivative with powerful analgesia approximately twenty-five to forty times as potent as morphine, and its analgesic effect is due to partial agonist activity at μ-opioid receptors, i.e., when the molecule binds to a receptor, it is less likely to transduce a response in contrast to a full agonist such as morphine. Buprenorphine also has very high binding affinity for the μ receptor such that opioid receptor antagonists (e.g. naloxone) only partially reverse its effects. These two properties must be carefully considered by the practitioner, as an overdose cannot be easily reversed (although overdose is unlikely in addicted patients or people with tolerance to opioids who use the drug sublingually as meant in the case of Subutex/Suboxone, especially if there are no benzodiazepines involved), and use in persons physically dependent on full-agonist opioids may trigger opioid withdrawal that also cannot be easily reversed and can last over twenty-four hours, as the drug's mean half-life is thirty-seven hours.
Buprenorphine is also a κ-opioid receptor antagonist, and partial/full agonist at the recombinant human ORL1 nociceptin receptor.
Buprenorphine hydrochloride is administered by intramuscular injection, intravenous infusion, via a transdermal patch, or as a sublingual tablet. It is not administered orally, due to very high first-pass metabolism. Buprenorphine is metabolised by the liver, via the CYP3A4 isozyme of the cytochrome P450 enzyme system, into norbuprenorphine (by N-dealkylation) and other metabolites. The metabolites are further conjugated with glucuronic acid and 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 patients with renal impairment and in the elderly.
The main active metabolite, norbuprenorphine, is a δ-opioid receptor and ORL1 receptor agonist and a μ- and κ-opioid receptor partial agonist. However, buprenorphine antagonizes its effects at the δ-opioid receptor.
Plasma concentrations after application of transdermal buprenorphine increase steadily and the minimum effective therapeutic dose (100 pg/ml) is reached at eleven hours and twenty-one hours for a single 35 and 70 μg/h patch, respectively. Peak plasma concentration (Cmax) is reached in about sixty hours (305 and 624 pg/ml for the 35 and 70 μg/h strength patch, respectively), and is markedly longer than with 0.3 mg intravenous buprenorphine (0.41 hours). Transdermal buprenorphine has a half-life of approximately thirty hours, and a bioavailability of approximately 50%, which is comparable to sublingual buprenorphine.
[edit] Clinical use
[edit] Indications
[edit] Pain indications
Depending on the application form, buprenorphine is indicated for the treatment of moderate to severe chronic pain or for peri-operative analgesia. For the treatment of chronic pain, the transdermal formulations (not currently available in the U.S. as of January 2008) are nowadays preferred, which can be used both for chronic cancer pain as well as chronic non-malignant pain e.g. musculosceletal and neuropathic pain. The intravenous formulation is mainly used in postoperative pain (e.g. as PCA- patient controlled analgesia) and the sublingual formulation is e.g. used as breakthrough medication for patients with basic transdermal treatment. Advantages of buprenorphine in the treatment of chronic pain are, from a clinical perspective, its relatively long half-life, the option of sublingual and transdermal application and the excellent safety profile (ceiling effect for respiratory depression, lack of immunosuppressive effect, low pharmacokinetic interaction potential, no accumulation in renal impairment). Although not enough western literature is available, use of inj. buprenorphine in 'spinal' anaesthesia is rising in countries like India. Up to 150 micrograms of the drug (0.5 ml) of the preservative free solution is added to the local anaesthetic bupivacaine, and a smoother analgesia is obtained with the benefit of the patient remaining pain free till up to eight to ten hours of the spinal being given.
[edit] Antidepressant Potential
A clinical trial conducted at Harvard Medical School in the mid-1990s demonstrated that a majority of unipolar non-psychotic patients with major depression refractory to conventional thymoleptic antidepressants could be successfully treated with buprenorphine. See opioids for other (predominantly favorable) experiments with buprenorphine and other opioids for psychological relief. However, psychological distress is currently not an approved indication for the use of any opioid, and legally it falls in to a "gray zone". In the United States, the doctor still needs the proper DEA licensing under the Drug Addiction Treatment Act of 2000 to prescribe Subutex or Suboxone for opioid addiction/dependence. Treatment of clinical depression is not indicated either but some doctors are realising its potential as an antidepressant in cases where the patient cannot tolerate or is resistant to conventional thymoleptic antidepressants. Psychological relief differs from depression and psychological distress is not usually an indication for prescribing any type of drug especially opiates.
[edit] Contraindication
Like full agonist opiates, buprenorphine can cause drowsiness, vomiting and respiratory depression. Taking buprenorphine in conjunction with central nervous system (CNS) depressants such as sedatives, tranquilizers, alcohol, and especially benzodiazepines can be particularly dangerous. Falling asleep while abusing this drug, especially while combining it with other central nervous system depressants, can be extremely dangerous and thus greatly increases the chance of serious complications or death.
[edit] 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, itch, dry mouth, miosis, orthostatic hypotension, male ejaculatory difficulty, decreased libido, 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 antogonised with a continuous infusion of naloxone. Of course, concurrent use of buprenorphine and CNS depressants (such as alcohol or benzodiazepines) is contraindicated as it may lead to fatal respiratory depression.
In people on medium- to long-term maintenance with Suboxone or Subutex do not have a major risk of overdose, as long as the drug is used properly (as prescribed), and benzodiazepines are not prescribed to individuals without a tolerance to opioids.
People switching from other opiates should wait until mild to moderate withdrawal symptoms are encountered. Failure to do so can lead to the rapid onset of withdrawal symptoms, known as precipitated withdrawal.
[edit] Recreational use
Buprenorphine is also used recreationally, typically by opioid users. Typical effects include analgesia, a sense of euphoria and increased verbal communication. Due to the high potency of tablet forms of buprenorphine, only a small amount of the drug need be ingested to achieve the desired effects. The buprenorphine preparation, Suboxone, comes in an orange lemon-lime flavored tablet for sublingual administration. The taste of Suboxone is described by some to be very unpleasant. Possible explanations for this unpleasant taste could be the bitter taste of the buprenorphine itself, or that fact that it acts as a deterrent to abuse and was done intentionally by the pharmaceutical company, Reckitt Benckiser.
Buprenorphine abuse is very common in Scandinavia, especially in Finland and Sweden. In 2007, the authorities in Uppsala county in Sweden confiscated more buprenorphine than cocaine, ecstasy and GHB. In Finland, somewhere between 2005-2006, illegal use of Subutex (commonly intravenously) has preceeded the large number of amphetamine usage. Intravenous administration of dissolved Subutex pills and insufflation of pulverized pills are the most common ways of recreational buprenorphine use.
[edit] General Properties
*Molecular Weight
504.10108
*Molecular Formula
C29H42ClNO4
*IUPAC NAME
N/A
*Canonical Smiles
CC(C)(C)C(C)(C1CC23CCC1(C4C25CCN(C3CC6=C5C(=C(C=C6)O)O4)CC7CC7)OC)O.Cl
*Isomeric Smiles
CC(C)(C)[C@](C)([C@H]1C[C@@]23CCC1([C@H]4[C@@]25CCN([C@@H]3CC6=C5C(=C(C=C6)O)O4)CC7CC7)OC)O.Cl
*XLogP
N/A
*Topological Polar Surface Area
62.2
