Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Grünenthal GmbH, Zieglerstrasse 6, 52078 Aachen, Germany
Pharmacotherapeutic group: Opioids, Oripavine derivatives
ATC code: N02AE01
Buprenorphine is a strong opioid with agonistic activity at the mu-opioid receptor and antagonistic activity at the kappa-opioid receptor. Buprenorphine appears to have the general characteristics of morphine, but has its own specific pharmacology and clinical attributes.
In addition, numerous factors, e.g. indication and clinical setting, route of administration and the interindividual variability, have an impact on analgesia and therefore have to be considered when comparing analgesics.
In daily clinical practice different opioids are ranked by a relative potency, although this is to be considered a simplification.
The relative potency of buprenorphine in different application forms and in different clinical settings has been described in literature as follows:
Abbreviations:
p.o = oral; i.m. = intramuscular; s.l. = sublingual; TTS = transdermal; BUP = buprenorphine
Adverse reactions are similar to those of other strong opioid analgesics. Buprenorphine appears to have a lower dependence liability than morphine.
Buprenorphine has a plasma protein binding of about 96%.
Buprenorphine is metabolised in the liver to N-dealkylbuprenorphine (norbupren-orphine) and to glucuronide conjugated metabolites. ⅔ of the active substance is eliminated unchanged in the faeces and ⅓ eliminated as conjugates of unchanged or dealkylated buprenorphine via the urinary system. There is evidence of enterohepatic recirculation.
Studies in non-pregnant and pregnant rats have shown that buprenorphine passes the blood-brain and placental barriers. Concentrations in the brain (which contained only unchanged buprenorphine) after parenteral administration were 2-3 times higher than after oral administration. After intramuscular or oral administration buprenorphine apparently accumulates in the foetal gastrointestinal lumen – presumably due to biliary excretion, as enterohepatic circulation has not fully developed.
After the application of TRANSTEC, buprenorphine is absorbed through the skin. The continuous delivery of buprenorphine into the systemic circulation is by controlled release from the adhesive polymer-based matrix system.
After the initial application of TRANSTEC the plasma concentrations of buprenorphine gradually increase, and after 12-24 h the plasma concentrations reach the minimum effective concentration of 100 pg/ml. From the studies performed with the TRANSTEC 35 micrograms/h in healthy volunteers, an average Cmax of 200 to 300 pg/ml and an average tmax of 60-80 h were determined. In one volunteer study, TRANSTEC 35 micrograms/h and TRANSTEC 70 micrograms/h were applied in a cross-over design. From this study, dose proportionality for the different strengths was demonstrated.
After removal of TRANSTEC the plasma concentrations of buprenorphine steadily decrease and are eliminated with a half-life of approx. 30 hours (range 22-36). Due to the continuous absorption of buprenorphine from the depot in the skin elimination is slower than after intravenous administration.
Standard toxicological studies have not shown evidence of any particular potential risks for humans. In tests with repeated doses of buprenorphine in rats the increase in body weight was reduced.
Studies on fertility and general reproductive capacity of rats showed no detrimental effects. Studies in rats and rabbits revealed signs of fetotoxicity and increased postimplantation loss, although only at maternal toxic doses.
Studies in rats showed diminished intra-uterine growth, delays in the development of certain neurological functions and high peri/post natal mortality in the neonates after treatment of the dams during gestation or lactation. There is evidence that complicated delivery and reduced lactation contributed to these effects. There was no evidence of embryotoxicity including teratogenicity in rats or rabbits.
In vitro and in vivo examinations on the mutagenic potential of buprenorphine did not indicate any clinically relevant effects.
In long-term studies in rats and mice there was no evidence of any carcinogenic potential relevant for humans.
Toxicological data available did not indicate a sensitising potential of the additives of the transdermal patches.
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