Reversal of drug-affected breathing

Abstract

Opioid analgesics are frequently used for pain relief. However, they may cause respiratory depression which is life-threatening. Animal studies suggest an apparent maximum in respiratory depression by buprenorphine regardless of drug-dose (ceiling phenomenon). In the first part of this thesis, ceiling of buprenorphine-induced respiratory depression without loss of antinociception is reported in healthy volunteers, indicating that buprenorphine may be relatively safer than other opioids which show a dose-dependent increase of respiratory depression. Furthermore, despite the high affinity of buprenorphine for µ-opioid receptors, buprenorphine-induced respiratory depression can be antagonized (reversed) by naloxone, provided high doses are given within the correct dose-window. In the second part the focus is on the mechanisms of the hypoxic and hypercapnic ventilatory responses. Previous studies showed that antioxidants are able to stimulate the carotid bodies (small organs initiating the ventilatory response to hypoxia) when their output is reduced. In humans, we observed that depression of the hypoxic response by acetazolamide is reversed by ascorbic acid and α-tocopherol. In anesthetized cats, the carbonic anhydrase inhibitor acetazolamide but not methazolamide reduced the hypoxic response indicating that this inhibiting effect on the carotid bodies is caused by an effect other than by inhibition of carbonic anhydrase.