1. 2016;19;341-348Synergistic Effect of Intravenous Ibuprofen and Hydromorphone for Postoperative Pain: Prospective Randomized Controlled Trial
   Randomized Trial
   Eun Jung Oh, MD, Jin Young Lee, MD, PhD, Woo Seog Sim, MD, PhD, and Hyun Joo Ahn, MD, PhD.

BACKGROUND: An intravenous form of ibuprofen has recently been approved by the Food and Drug Administration (FDA) and reports are rare on its co-administration with opioids.

OBJECTIVES: We researched whether an intravenous ibuprofen-hydromorphone combination is synergistic, additive, or infra-additive on postoperative pain.

STUDY DESIGN: A parallel-group, 1:1:1 allocation, randomized, double-blind controlled trial. 

SETTING: University teaching hospital in Korea.

METHODS: Ninety patients, undergoing breast surgery, were divided into one of the 3 groups (I, H, IH groups). Positive analgesic efficacy was defined as a numeric rating scale (NRS) </= 3 on a 0 – 10 NRS, 30 minutes after the drug administration. Drugs were administered by the Dixon’s up-and-down method. Starting doses were ibuprofen (I) 50 mg, hydromorphone (H) 0.25 mg, or ibuprofen 25 mg + hydromorphone 0.125 mg (IH). The maximum doses were ibuprofen 800 mg, hydromorphone 2 mg, or ibuprofen 400 mg + hydromorphone 1 mg. Combination index (CI) (additive: 0.9 – 1.1, synergism: < 0.9, antagonism: > 1.1), dose reduction index (DRI, a measure of how much the dose of each drug in a combination can be reduced), and isobologram were used to define the nature of their interaction.

STATISTICS: One way ANOVA, Kruskal Wallis test, and Chi square test, significance level P < 0.05.

RESULTS: The median effective doses (ED50) of ibuprofen and hydromorphone were 1,447 mg and 1.5 mg, respectively. The median ED50 of the combination was ibuprofen 71 mg and hydromorphone 0.3 mg. Ibuprofen and hydromorphone showed a strong synergy (CI 0.2, DRI 20 and 5 for ibuprofen and hydromorphone at ED50).

LIMITATION: Analgesic efficacy was observed during post-anesthesia care unit (PACU) period only.

CONCLUSIONS: The combination of intravenous ibuprofen and hydromorphone produces a strong synergistic analgesia on postoperative pain.