Drug Alc Depend (2003) 72; 1:75-83
Pharmacokinetics of high-dose buprenorphine following single administration of sublingual tablet formulations in opioid naïve healthy male volunteers under a naltrexone block. McAleer SD, Mills RJ, Polack T, Hussain T, Rolan PE, Gibbs AD, Mullins FGP, Hussein Z.
Dear Colleagues,
At last we have some real data on buprenorphine half lives, absorption and effects from healthy volunteer studies. These researchers, who were working for the manufacturers, have taken 35 healthy males and given substantial doses of buprenorphine after 50-150mg naltrexone 'block'. They then measured clinical and blood parameters at regular intervals for up to 3 days in an in-patient setting. Techniques for measuring blood levels of buprenorphine are still being developed and are not generally available in clinical practice. This makes patient history and clinical observation even more important than otherwise. A liquid chromatographic tandem mass spectrometric (LC-MS/MS) assay was developed by these researchers and it was validated for the measurement of buprenorphine and nor-buprenorphine, its metabolite, in blood.
Mean half life was found to be 26 hours with a wide range from 9 to 69. Interestingly, these authors have confirmed some observations in clinical practice including highly variable half lives and the 'bi-exponential' decay sometimes reported by patients. Some had a 'secondary peak' at about 10 hours from dosing. The authors report that some had higher levels following meals and propose 'entero-hepatic recirculation' in some cases. Maximum or 'peak' levels occurred between 30 minutes and 3 hours.
The addition of naloxone in the sublingual preparation made no difference to blood levels. The time taken for the tablets to dissolve were similar for all dose levels from 2 to 16mg (range 6-12 min) and were no different for the combination product. It is worrying that the American FDA has approved the marketing of the combination product even before research of this nature had been established. One wonders if they have different standards for drugs used in the treatment of addiction.
The authors confusingly claim to have shown that the two formulations of buprenorphine - naloxone were 'bioequivalent'. This should not be read as their being bioequivalent to the pure product which for some reason they did not test or else did not report if they did. Also, and importantly, these patients had already been given a large dose of naltrexone, a close chemical cousin of naloxone. Unsurprisingly, they found approximately half the blood levels when half the buprenorphine dose was administered. To demonstrate bioequivelence between the old pure sublingual product and a new formulation will take specific research which is yet to be done to my knowledge. The manufacturers have sponsored numerous experts who have stated that for practical clinical purposes the pure product is bio-equivalent yet this is not based on any research to my knowledge and is also very unlikely based on the small amount of research there is out there.
Thus a major weakness of the present study is that it did not examine levels in on-going treatment, but just individual single doses. Thus is it more relevant to the initiation period, which is still a major problem for some patients and is thus a helpful contribution to the scientific literature. There were no opioid effects using the naltrexone block at between 50 and 150mg doses 4 hours prior to opioid administration. This is also helpful information for those using blocking therapies, despite their limited place in normal clinical practice.
