Pentazocine Pharmacodynamics in Children: Simulations to Assess Safety and Effectiveness.

Background: Pentazocine is used for postoperative pain but is known to cause respiratory depression. Although hepatic metabolic activity in children gradually reaches adult levels, the effect of multiple doses in children with decreased clearance has not been elucidated.

Aims: The objective of this study is to evaluate respiratory depression caused by pentazocine using a pharmacokinetic-pharmacodynamic model and to optimize the dosing frequency to maintain target concentrations for analgesia.

Methods: The pharmacokinetic model used the parameters of the three-compartment model reported by Hamunen et al. Pharmacodynamic parameters were estimated through sequential analysis, with the pharmacokinetic parameters fixed. Mean respiratory rate and oxygen saturation data were collected from Hamunen et al. after the administration of 0.5 mg/kg pentazocine. The pharmacodynamic model was a turnover model in which the plasma pentazocine concentration affected the respiratory rate and oxygen saturation. We used the pharmacokinetic-pharmacodynamic model to simulate changes in respiratory rate and oxygen saturation after 0.5 mg/kg pentazocine at 2-, 4-, and 6-h dosing intervals. We also simulated cases with 20% and 40% decreased clearance. Pain relief was assessed using our previous model.

Results: After a single dose, respiratory rate dropped with a delayed response to the plasma concentration, reaching a minimum within 15 to 30 min and falling below the normal range. It returned to baseline after about 75 min. With multiple dosing, respiratory rate and oxygen saturation considerably decreased every 2 h, regardless of clearance changes. At a 4-h interval, respiratory depression occurred due to decreased clearance, whereas at a 6-h interval, it was minimal. Pain was well controlled at 2-, 4-, and 6-h dosing intervals.

Conclusions: This pharmacokinetic-pharmacodynamic modeling study supports a 6-h dosing interval for pentazocine at 0.5 mg/kg in children. This interval strikes a balance between achieving effective analgesia and minimizing the risk of respiratory depression.