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

The data indicate that the OPRM1:c.118A>G polymorphism affects opioid analgesic and respiratory effects differentially. Despite reduced analgesic responses to M6G the OPRM1:c.118A>G single-nucleotide polymorphism does not protect against the toxic effects of the tested opioid. However, some caution in the interpretation of the data is needed because of the small sample size. Further studies are needed to explore the link between this polymorphism and respiratory/analgesic responses beyond the small human sample. In OPRM1:c.118AA homozygotes, the potency parameters differed by a factor of 2 for analgesic versus respiratory effect. In this respect, M6G differs favorably from morphine.

Our data indicate that systems involved in morphine-induced analgesia and respiratory depression share important pharmacodynamic characteristics. This suggests similarities in central mu-opioid analgesic and respiratory pathways (e.g., similarities in mu-opioid receptors and G proteins). The clinical implication of this study is that after morphine administration, despite lack of good pain relief, moderate to severe respiratory depression remains possible.

The carbonic anhydrase inhibitor acetazolamide may have both inhibitory and stimulatory effects on breathing. In this placebo-controlled double-blind study we measured the effect of an intravenous dose (4 mg kg −1 ) of this agent on the acute isocapnic hypoxic ventilatory response in 16 healthy volunteers (haemoglobin oxygen saturation 83-85%) and examined whether its inhibitory effects on this response could be reversed by antioxidants (1 g ascorbic acid I.V. and 200 mg α-tocopherol P.O.). The subjects were randomly divided into an antioxidant (Aox) and placebo group. In the Aox group, acetazolamide reduced the mean normocapnic and hypercapnic hypoxic responses by 37% (P < 0.01) and 55% (P < 0.01), respectively, and abolished the O 2 -CO 2 interaction, i.e. the increase in O 2 sensitivity with rising P CO 2 . Antioxidants completely reversed this inhibiting effect on the normocapnic hypoxic response, while in hypercapnia the reversal was partial. In the placebo group, acetazolamide reduced the normo-and hypercapnic hypoxic responses by 33 and 47%, respectively (P < 0.01 versus control in both cases), and also abolished the O 2 -CO 2 interaction. Placebo failed to reverse these inhibitory effects of acetazolamide in this group. We hypothesize that either an isoform of carbonic anhydrase may be involved in the regulation of the redox state in the carotid bodies or that acetazolamide and antioxidants exert independent effects on oxygen-sensing cells, in which both carbonic anhydrase and potassium channels may be involved. The novel findings of this study may have clinical implications, for example with regard to a combined use of acetazolamide and antioxidants at high altitude.

We compared the effects of the carbonic anhydrase inhibitors methazolamide and acetazolamide (3 mg kg -1 , I.V.) on the steady-state hypoxic ventilatory response in 10 anaesthetized cats. In five additional animals, we studied the effect of 3 and 33 mg kg -1 methazolamide. The steady-state hypoxic ventilatory response was described by the exponential function:whereV I is the inspired ventilation , G is hypoxic sensitivity, D is the shape factor and A is hyperoxic ventilation. In the first group of 10 animals, methazolamide did not change parameters G and D, while A increased from 0.86 ± 0.33 to 1.30 ± 0.40 l min -1 (mean ± S.D., P = 0.003). However, the subsequent administration of acetazolamide reduced G by 44% (control, 1.93 ± 1.32; acetazolamide, 1.09 ± 0.92 l min -1 , P = 0.003), while A did not show a further change. Acetazolamide tended to reduce D (control, 0.20 ± 0.07; acetazolamide, 0.14 ± 0.06 kPa -1 , P = 0.023). In the second group of five animals, neither low-nor high-dose methazolamide changed parameters G, D and A. The observation that even high-dose methazolamide, causing full inhibition of carbonic anhydrase in all body tissues, did not reduce the hypoxic ventilatory response is reminiscent of previous findings by others showing no change in magnitude of the hypoxic response of the in vitro carotid body by this agent. This suggests that normal carbonic anhydrase activity is not necessary for a normal hypoxic ventilatory response to occur. The mechanism by which acetazolamide reduces the hypoxic ventilatory response needs further study.