BUPRENORPHINE

Chemical Properties

White Solid

Uses

Controllled substance (narcotic). Analgesic that demonstrates narcotic agonist-antagonist properties.

Definition

ChEBI: A morphinane alkaloid that is 7,8-dihydromorphine 6-O-methyl ether in which positions 6 and 14 are joined by a -CH2CH2- bridge, one of the hydrogens of the N-methyl group is su stituted by cyclopropyl, and a hydrogen at position 7 is substituted by a 2-hydroxy-3,3-dimethylbutan-2-yl group.

brand name

Buprenex (Reckitt Benckiser); Subutex (Reckitt Benckiser);Buprex;Buprx;Finibron;Prefin;Temagesic.

World Health Organization (WHO)

Buprenorphine, an opioid analgesic with both morphine agonist and antagonist activity, was introduced in 1978. It was originally considered to possess low dependence potential. However, it has latterly been identified as causing a socially significant abuse problem in several countries which have consequently subjected it to control in 1989 under Schedule III of the 1971 Convention of Psychotropic Substances. (Reference: (UNCPS3) United Nations Convention on Psychotropic Substances (III), , , 1971)

Biological Functions

Buprenorphine (Temgesic) is a mixed agonist–antagonist and a derivative of the naturally occurring opioid thebaine. Buprenorphine is highly lipophilic and is 25 to 50 times more potent than morphine as an analgesic. The sedation and respiratory depression it causes are more intense and longer lasting than those produced by morphine. Its respiratory depressant effects are not readily reversed by naloxone. It binds to the -receptor with high affinity and only slowly dissociates from the receptor, which may explain the lack of naloxone reversal of respiratory depression.
Buprenorphine has more agonist than antagonist effects and is often considered a partial agonist rather than a mixed agonist–antagonist, although it precipitates withdrawal in opioid-dependent patients. Its pharmacological effects are similar to those produced by both morphine and pentazocine. Indications for its use are similar to those of pentazocine, that is, for moderate to severe pain. Sublingual preparations are available, but have a slow onset and erratic absorption. The abuse potential of buprenorphine is low.While high doses of the drug are perceived by addicts as being morphinelike, it does reduce the craving for morphine and for the stimulant cocaine. Thus, buprenorphine is a potential new therapy for the treatment of addiction to both classes of drugs.
Drug interactions and contraindications are similar to those described for pentazocine and morphine.

General Description

Buprenorphine is a semisynthetic, highly lipophilic opiate derivedfrom thebaine. Pharmacologically, it is classified as amixed μ-agonist/antagonist (a partial agonist) and a weak κ-antagonist. It has a high affinity for the μ-receptors(1,000 times greater than morphine) and a slow dissociationrate leading to its long duration of action (6–8 hours). Atrecommended doses, it acts as an agonist at the μ-receptorwith approximately 0.3 mg IV equianalgesic to 10 mg of IVmorphine. One study in humans found that buprenorphine displaysa ceiling effect to the respiratory depression, but not theanalgesic effect over a dose range of 0.05 to 0.6 mg.In practice,this makes buprenorphine a safer opiate (when usedalone) than pure μ-agonists. Relatively few deaths frombuprenorphine overdose (when used alone) have been reported.113 The tight binding of the drug to the receptor also hasled to mixed reports on the effectiveness of using naloxone toreverse the respiratory depression. In animal studies, normaldoses of the pure antagonist naloxone were unable to removebuprenorphine from the receptor site and precipitate withdrawal.In a human study designed to precipitate withdrawalfrom buprenorphine, a naloxone dose (mean=35 mg) 100times the dose usually needed to precipitate withdrawal inmethadone-dependent subjects was used. For comparison, approximately0.3 mg, 4 mg, 4 mg, and 10 mg of naloxonewould be required to precipitate withdrawal from heroin, butorphanol,nalbuphine, or pentazocine respectively.

Contact allergens

This semisynthetic opioid analgesic drug is derived fromwith transdermal systems (TDS). In case of localized or generalized allergic contact dermatitis due to buprenorphine in TDS, TDS containing fentanyl can be safely used thebaine. It can be used parenterally, orally, and topically

Pharmacology

Buprenorphine is the only partial agonist in common use. It binds to the MOP receptor and dissociates from it very slowly. Consequently, although significant respiratory depression is less likely compared with morphine, it may be more difficult to reverse. It has poor oral bioavailability, and parenteral, sublingual or transdermal formulations are used. In addition to partial agonism at the MOP receptor, it is also a partial agonist at the NOP receptor and an antagonist at the KOP receptor. This may contribute to some of its analgesic effects. Increasingly it is also used instead of methadone for the management of opioid abuse (usually in relatively large doses up to 24 mg day?1).

Clinical Use

Opioid analgesic

Drug interactions

Potentially hazardous interactions with other drugs
Analgesics: possible opiate withdrawal with other opioids.
Antidepressants: possible CNS excitation or depression (hypotension or hypertension) if administered with MAOIs or moclobemide - avoid; sedative effects possibly increased when given with tricyclics.
Antifungals: metabolism inhibited by ketoconazole - reduce buprenorphine dose.
Antihistamines: sedative effects possibly increased with sedating antihistamines.
Antipsychotics: enhanced hypotensive and sedative effects.
Antivirals: concentration possibly increased by ritonavir; possibly reduced tipranavir concentration.
Dopaminergics: avoid with selegiline.
Sodium oxybate: avoid concomitant use.

Metabolism

Elimination of buprenorphine is bi- or triphasic; metabolism takes place in the liver by oxidation via the cytochrome P450 isoenzyme CYP3A4 to the pharmacologically active metabolite N-dealkylbuprenorphine (norbuprenorphine), and by conjugation to glucuronide metabolites. Buprenorphine is subject to considerable first-pass metabolism after oral doses. However, when given by the usual routes buprenorphine is excreted mainly unchanged in the faeces; there is some evidence for enterohepatic recirculation. Metabolites are excreted in the urine, but very little unchanged drug is excreted in this way.