Acetaminophen, ibuprofen, and tramadol analgesic interactions after adenotonsillectomy.

Background: The 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.
Methods: Children 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 E _MAX model extended for three drugs, assuming additive effects. Curve fitting was performed using nonlinear mixed effects models.
Results: Pharmacodynamic parameter estimates, expressed using fractional Hill equation, were maximum effect (E _MAX ) 0.65 (95%CI 0.54, 0.74), the concentration of acetaminophen associated with 50% of the maximal drug effect (C _{50, ACET} ) 7.06 (95%CI 7.03, 7.72) mg/L, and the ibuprofen C ₅₀ (C _{50, 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 (t _1/2 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 C _{50, TRAM} of 0.07 (95%CI 0.048, 1.07) mg/L with a t _1/2 keo, _TRAM 1.78 hour (95%CI 1.06, 1.96).
Conclusion: Ibuprofen has an EC ₅₀ 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.)