Background: Paracetamol combined with diclofenac is commonly used to control postoperative pain in children. Diclofenac pharmacokinetics, and paracetamol pharmacokinetics (PK) and dynamics (PD) (analgesia) have been described with these drugs used separately (1, 2). A model for the combination of paracetamol with diclofenac would be useful for improving analgesia in children.
Methods: A randomised, placebo controlled study in children following tonsillectomy was performed using oral and rectal paracetamol with oral diclofenac. Children (n=151) received paracetamol elixir 40 mg.kg-1 one hour preoperatively and 20mg.kg-1 rectally at the end of surgery. The same children received either placebo, diclofenac 0.1 mg.kg-1, diclofenac 0.5 mg.kg-1 or diclofenac 2.0 mg.kg-1 before surgery. A further group (n=93) were given diclofenac 0.1-2.0 mg.kg-1 only. Hourly pain assessments using visual analogue scales (0-10) were performed. Pain scores were measured up to 6 h postoperatively. Data were pooled with previously reported pharmacokinetic data from 152 children,(3) and a further 30 children and 70 adults (4) (total n= 496). PK and PD data were modelled simultaneously using NONMEM 7.1 with Intel 11 compiler. A one compartment model with first order absorption and first order elimination was used to describe the population PK of paracetamol and diclofenac. Placebo effects and combined drug effects were modelled using effect site concentration models. Combined drug effects were modelled using an Emax model with a quadratic interaction term.(5) An interval censored model (6) was used to describe the hazard of early study dropout.
Results: Pooled data from 496 individuals were studied (466 children, 30 adults) comprising 1552 pain scores, 829 paracetamol and 911 diclofenac plasma concentrations. The mean (range) age and weight of children were 7.7 (1.1 – 16.0) years and 32.4 (9.4 – 105.0) kg, respectively, while that of adults was 21.0 (18.0 – 28.0) years and 71.7 (48.0 – 93.8) kg, respectively. Paracetamol volume of distribution (VPARA) was 56.0 l.70kg-1, clearance (CLPARA) was 11.7 l.h -1.70kg-1, and equilibration half-time for onset of analgesia (T1/2eqPARA) was 0.5 h. Diclofenac volume (VDICL) was 16.0 l.70kg-1, clearance (CLDICL) was 53.2 l.h -1.70kg-1, and equilibration half-time (T1/2eqDICL) was 0.2 h. Maximum effect (EMAX) was 5 pain score units. The concentration associated with 50% of EMAX (C50) was 13.3 mg.l-1 for paracetamol and 1.2 mg.l-1 for diclofenac. An interaction term was zero indicating the effects are simply additive. A placebo model for the effects of placebo response had a T1/2keo of 2.7 h, an elimination half-life of 3.0 h and a potency of 1.8. Baseline hazard effects were estimated as 0.02 h-1, while that of current pain score as 0.3 units-1.
Conclusions: Paracetamol and diclofenac effects are additive for analgesia. We confirm previous simulations showing little analgesic benefit gained from diclofenac doses > 1.0 mg.kg-1 (2) and demonstrating large placebo effects for tonsillectomy pain.(3) A dose of 6.3 mg.kg-1 paracetamol with as little as 0.5 mg.kg-1 diclofenac may achieve analgesia comparable to that of 12.5 mg.kg-1 of paracetamol, or 2.0 mg.kg-1 diclofenac, alone. A reduction in pain score of 2.2 units can be achieved using either a target effect concentration of 10.0 mg.l-1 paracetamol alone, or 5.0 mg.l-1 paracetamol with diclofenac 0.5 mg.l-1.
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