An isobolographic analysis of diamorphine and levobupivacaine for epidural analgesia in early labour.

Abstract

Few data describe the pharmacological interactions between local anaesthetics and opioids. The aim of this study was to measure the median effective concentration (MEC) of diamorphine and levobupivacaine when given separately and as mixtures for epidural analgesia, and determine whether the combination is additive or synergistic. One hundred and twenty patients were enrolled in this prospective randomized, two-phase, double-blind study. In the first phase, 60 women were randomized to receive a fixed 20 ml volume of either levobupivacaine or diamorphine epidurally . Dosing was determined using up-down sequential allocation with testing intervals, respectively, of 0.01%w/v and 12.5 microg ml(-1). After estimations of the MEC of levobupivacaine and diamorphine, a further 60 patients were randomized in the second phase to one of the three mixtures: (a) diamorphine 70 microg ml(-1) (fixed) and levobupivacaine (testing interval 0.004%w/v, starting at 0.044%w/v); (b) levobupivacaine 0.044%w/v (fixed) and diamorphine (testing interval 7 microg ml(-1), starting at 70 microg ml(-1)); and (c) bivariate diamorphine and levobupivacaine (testing intervals of 7 microg ml(-1) and 0.004%w/v starting at 70 microg ml(-1) and 0.044% w/v respectively). The MEC estimates from the first phase were 143.8 microg ml(-1) (95% CI 122.2-165.3) for diamorphine and 0.083%w/v (95% CI 0.071-0.095) for levobupivacaine. In the second phase, the MEC and interaction index (gamma) of the three combinations were: diamorphine 65.5 microg ml(-1) (56.8-74.2), gamma = 0.99; levobupivacaine 0.041%w/v (0.037-0.049), gamma = 0.98; and for the fixed combination diamorphine 69.5 microg ml(-1) (60.5-78.5) and levobupivacaine 0.044%w/v (0.039-0.049), gamma = 1.02. The combination of diamorphine and levobupivacaine is additive and not synergistic when used for epidural analgesia in the first stage of labour.