Median effective dose (ED₅₀) of paracetamol and morphine for postoperative pain: a study of interaction

Abstract

Background: Paracetamol is widely used to treat postoperative pain and is well known for its morphine-sparing effect. Therefore, the effect of morphine-paracetamol combination can be synergistic, additive, or infra-additive. The primary aim of our study is to define the median effective analgesic doses (ED₅₀s) of paracetamol, morphine, and the combination of both. Also, the nature of the interaction for postoperative pain after moderately painful surgery using an up-and-down method and isobolographic analysis was determined.

Methods: Ninety patients, undergoing moderately painful surgery, were included in one of the three groups. Determination of the median ED₅₀s was performed by the Dixon and Mood up-and-down method. Initial doses were 1.5 g and 5 mg, with dose adjustment intervals of 0.5 g and 1 mg, in the paracetamol and morphine groups, respectively. The initial doses of paracetamol and morphine were 1.5 g and 3 mg, in the paracetamol-morphine combination group with dose adjustment intervals of 0.25 g for paracetamol and 0.5 mg for morphine. Analgesic efficacy was defined as a reduction to or <3 on a 0-10 numeric rating scale, 45 min after the beginning of drug administration. Isobolographic analysis was used to define the nature of their interaction.

Results: The median ED₅₀s of paracetamol and morphine were 2.1 g and 5 mg, respectively. The median ED₅₀ of the combination was 1.3 g for paracetamol and 2.7 mg for morphine.

Conclusions: Our study showed that the combination of the paracetamol and morphine produces an additive analgesic effect. Clinical trial registration NCT01366313.

Keywords: median effective dose; morphine; pain; paracetamol; postoperative.