1. 2017;20;509-520The Dose-Dependent Effects of Ketoprofen on Dynamic Pain after Open Heart Surgery
   Randomized Trial
   Bruno Pereira, PhD, Pierre Schoeffler, MD, Henri Boby, MD, Claire Biboulet, MB, Vedat Eljezi, MD, and Christian Duale, MD, PhD.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) can reduce postoperative pain, in both static (i.e., at rest) and dynamic contexts (e.g., during coughing or mobilization), and reduced doses could improve their efficacy/tolerance balance.

OBJECTIVES: To test this hypothesis of efficacy after open heart surgery, in which NSAIDs are poorly used, particularly for safety concerns.

STUDY DESIGN: Randomized, double-blind trial.

SETTING: Single-center, French university hospital.

METHODS: Patients. One hundred patients at low risk of postoperative complications undergoing scheduled open heart surgery (97 analyzed). Intervention. We tested intravenous ketoprofen, at a dose of 0.5 mg/kg-1 every 6 hours during the 48 hours following the end of sedation, after surgery. This standard protocol was compared to a similar one in which half doses were administered, to one with quarter doses, as well as to a placebo group. Analgesia was supplemented by acetaminophen plus self- and nurse-administered intravenous morphine. Measurement. The primary outcome was the intensity of dynamic pain, assessed over 48 hours on an 11-point numerical rating scale (NRS).

RESULTS: Only the full-dose ketoprofen group showed reduced dynamic and static postoperative pain vs. placebo (P < 0.00001 for both). The evolution of dynamic pain suggested a delayed and therefore non-significant effect with the low doses. Ketoprofen did not affect either the postoperative morphine consumption or the tolerance outcomes, such as the volumes of chest tube drainage and the renal function.

LIMITATIONS: This pilot trial was undersized to test major tolerance outcomes.

CONCLUSIONS: Although we failed to demonstrate any analgesic effects with low doses of ketoprofen, we confirmed the good efficacy/tolerance balance with this propionic NSAID of intermediate COX2-selectivity. Lower doses of NSAIDs, potentiated by a loading dose, should be tested in the future.

IRB approval: CPP Sud-Est VI (Clermont-Ferrand, France), on 12/23/2013.
Clinical trial registry: EudraCT (2013-003878-27); ClinicalTrials.gov (NCT02180087).

Key words: Non-steroidal anti-inflammatory drugs, ketoprofen, cyclooxygenase, pain, postoperative, sternotomy, postoperative rehabilitation, analgesia, side effects