Search

Abstract: To obtain the correlation dimension and entropy from an experimental time series we derive estimators for these quantities together with expressions for their variances using a maximum likelihood approach. The validity of these expressions is supported by Monte Carlo simulations. We illustrate the use of the estimators with a local recording of atrial fibrillation obtained from a conscious dog.

Background. We measured the effect of two weight adjusted i.v. doses (0.2 mg per 70 kg and 0.4 mg per 70 kg) of the potent opioid buprenorphine on analgesia and respiratory depression in healthy volunteers. The aim of the study was to compare buprenorphine's behaviour with respect to the occurrence of ceiling (or apparent maximum) in these typical µ-opioid protein-(MOP) receptor effects. Methods. Ten subjects (5 males) received 0.2 mg per 70 kg, 10 others (5 males) 0.4 mg per 70 kg i.v. buprenorphine. Steady-state inspired minute ventilation at a fixed end-tidal Pco2 of 7 kPa was measured before drug infusion and at regular intervals after drug infusion. Experimental pain was induced using transcutaneous electrical stimulation and a gradually increasing current. Pain tolerance was measured at regular intervals before and after drug infusion. The studies lasted 8 h. Results. After infusion of the drug ventilation showed a rapid decline and reached peak depression between 150 and 180 min after drug administration. This effect was dose-independent with respect to timing and magnitude. At peak respiratory depression minute ventilation was 13.1 (sd 1.8) litre min−1 in the 0.2 mg group vs 12.0 (sd 1.3) litre min−1 in the 0.4 mg group (n.s.). At buprenorphine 0.2 mg a small short-lived analgesic effect was observed with a maximum increase in pain tolerance current of 6.7 (sd 2.8) mA occurring at 75 min after drug administration. Peak analgesic effect was 29% above baseline current. In contrast, buprenorphine 0.4 mg caused a large and long-lived analgesic effect with a maximum increase in pain tolerance current of 23.8 (sd 7.4) mA occurring at 130 min after drug administration. Peak analgesic effect was 160% above baseline current (0.4 vs 0.2 mg, P<0.01). Conclusions. While buprenorphine's analgesic effect increased significantly, respiratory depression was similar in magnitude and timing for the two doses tested. We conclude that over the dose range tested buprenorphine displays ceiling in respiratory effect but none in analgesic effect.

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.