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BJA Advance Access published online on April 15, 2005
British Journal of Anaesthesia, doi:10.1093/bja/aei145
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2005. All rights reserved. For Permissions, please e-mail: journal.permissions@oupjournals.org
Accepted December 31, 2004

Clinical Investigation

Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats

A. Dahan 1*, A. Yassen 2, H. Bijl 1, R. Romberg 1, E. Sarton 1, L. Teppema 1, E. Olofsen 1, and M. Danhof 2

1 Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
2 Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratory, Leiden, The Netherlands

* To whom correspondence should be addressed.
A. Dahan, E-mail: a.dahan{at}lumc.nl


  Abstract

Background. There is evidence from animal studies suggesting the existence of a ceiling effect for buprenorphine-induced respiratory depression. To study whether an apparent ceiling effect exists for respiratory depression induced by buprenorphine, we compared the respiratory effects of buprenorphine and fentanyl in humans and rats.

Methods. In healthy volunteers, the opioids were infused i.v. over 90 s and measurements of minute ventilation at a fixed end-tidal PCO2 of 7 kPa were obtained for 7 h. Buprenorphine doses were 0.7, 1.4, 4.3 and 8.6 µg kg-1 (n=20 subjects) and fentanyl doses 1.1, 2.1, 2.9, 4.3 and 7.1 µg kg-1 (n=21). Seven subjects received placebo. In rats, both opioids were infused i.v. over 20 min, and arterial PCO2 was measured 5, 10, 15 and 20 min after the start of fentanyl infusion and 30, 150, 270 and 390 min after the start of buprenorphine infusion. Doses tested were buprenorphine 0, 100, 300, 1000 and 3000 µg kg-1 and fentanyl 0, 50, 68 and 90 µg kg-1.

Results. In humans, fentanyl produced a dose-dependent depression of minute ventilation with apnoea at doses ≥2.9 µg kg-1; buprenorphine caused depression of minute ventilation which levelled off at doses ≥3.0 µg kg-1 to about 50% of baseline. In rats, the relationship of arterial PCO2 and fentanyl dose was linear, with maximum respiratory depression at 20 min (maximum PaCO2 8.0 kPa). Irrespective of the time at which measurements were obtained, buprenorphine showed a non-linear effect on PaCO2, with a ceiling effect at doses >1.4 µg kg-1. The effect on PaCO2 was modest (maximum value measured, 5.5 kPa).

Conclusions. Our data confirm a ceiling effect of buprenorphine but not fentanyl with respect to respiratory depression.

Keywords: analgesics, opioid; complications, opioid-induced respiratory depression; complications, respiratory depression; receptors, µ-opioid; ventilation, analgesics, effects of respiration.
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