• Jacqueline A Hannam, Brian J Anderson, and Amanda Potts.
• Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand.
• Paediatr Anaesth. 2018 Oct 1; 28 (10): 841-851.

BackgroundThe impact of tramadol in children given acetaminophen-ibuprofen combination therapy is uncertain in acute pediatric pain management. A model describing the interaction between these three drugs would be useful to understand the role of supplemental analgesic therapy.MethodsChildren undergoing tonsillectomy were given oral paracetamol and ibuprofen perioperatively. Blood was taken for paracetamol and ibuprofen drug assay on up to six occasions over 6 h after the initial dose. Tramadol was administered by caregivers for unacceptable postoperative pain. Pain was measured using the Parent's Postoperative Pain Measurement rating two hourly on the first postoperative day. A first-order absorption, one-compartment linear model with first-order elimination was used to describe acetaminophen and ibuprofen disposition. Analgesia was described using an EMAX model extended for three drugs, assuming additive effects. Curve fitting was performed using nonlinear mixed effects models.ResultsPharmacodynamic parameter estimates, expressed using fractional Hill equation, were maximum effect (EMAX ) 0.65 (95%CI 0.54, 0.74), the concentration of acetaminophen associated with 50% of the maximal drug effect (C50,ACET ) 7.06 (95%CI 7.03, 7.72) mg/L, and the ibuprofen C50 (C50,IBU ) 3.95 (95%CI 2.57, 7.53) mg/L. The Hill coefficient was 1.48 (95%CI 0.92, 2.62) and an interaction term was fixed at zero (additivity). The half-time (t1/2 keo) for equilibration between the plasma and effect site was 0.34 hour (95%CI 0.23, 1.98) for acetaminophen and 1.04 hour (95%CI 0.75, 1.77) for ibuprofen. Tramadol had a C50,TRAM of 0.07 (95%CI 0.048, 1.07) mg/L with a t1/2 keo,TRAM 1.78 hour (95%CI 1.06, 1.96).ConclusionIbuprofen has an EC50 for analgesia in children similar to that of adults (3.95 mg/L; 95%CI 2.57-7.53, vs 5-10 mg/L adults). The maximum effect from combination therapy (ie, 65% reduction in pain score) achieves satisfactory analgesia with commonly used doses but increased dose adds little additional benefit. The addition of tramadol to this analgesic mixture prolongs analgesia duration.© 2018 John Wiley & Sons Ltd.

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