title: Postoperative opioid sparing with injectable hydroxypropyl-β-cyclodextrin-diclofenac: pooled analysis of data from two Phase III clinical trials.
abstract: OBJECTIVE
  Use of nonopioid analgesics (including nonsteroidal anti-inflammatory drugs) for postoperative pain management can reduce opioid consumption and potentially prevent opioid-related adverse events. This study examined the postoperative opioid-sparing effect of repeated-dose injectable diclofenac formulated with hydroxypropyl-β-cyclodextrin (HPβCD)-diclofenac.
  
  
  METHODS
  Pooled data from two double-blind, randomized, placebo- and active comparator-controlled Phase III trials were analyzed. Patients received HPβCD-diclofenac, placebo, or ketorolac by intravenous injection every 6 hours for up to 5 days following abdominal/pelvic or orthopedic surgery. Rescue opioid use was evaluated from the time of first study drug administration to up to 120 hours following the first dose in the overall study population and in subgroups defined by baseline pain severity, age, and HPβCD-diclofenac dose.
  
  
  RESULTS
  Overall, 608 patients received ≥1 dose of study medication and were included in the analysis. While 93.2% of patients receiving placebo required opioids, the proportion of patients requiring opioids was significantly lower for patients receiving HPβCD-diclofenac (18.75, 37.5, or 50 mg) or ketorolac (P<0.005 for all comparisons). Mean cumulative opioid dose and number of doses were significantly lower among patients receiving HPβCD-diclofenac versus placebo for the 0-24 through 0-120 hour time periods (P<0.0001), as well as versus ketorolac for the 0-72 through 0-120 hour time periods (P<0.05). HPβCD-diclofenac significantly reduced opioid consumption versus placebo in subgroups based on baseline pain severity (moderate, severe) and age (<65 years, ≥65 years) from the 0-24 hour period onward. When compared to ketorolac, HPβCD-diclofenac also significantly reduced cumulative opioid consumption among patients with moderate baseline pain (0-72 through 0-120 hours) and opioid dose number among patients ≥65 years old (0-24 through 0-120 hours).
  
  
  CONCLUSIONS
  HPβCD-diclofenac can reduce postoperative opioid requirements. As this analysis was not powered to compare opioid-related adverse event rates, follow-up studies examining the clinical impact of HPβCD-diclofenac's opioid sparing are warranted.
authors.affiliation: Department of Anesthesiology, Stony Brook University, NY.
authors.forename: Tong J
authors.initials: TJ
authors.lastname: Gan
authors.affiliation: Lotus Clinical Research, LLC, Pasadena, CA.
authors.forename: Neil
authors.initials: N
authors.lastname: Singla
authors.affiliation: Premier Research, Austin, TX.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Daniels
authors.affiliation: Javelin Pharmaceuticals, Inc., Cambridge, MA; New Biology Ventures, LLC, San Mateo, CA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Hamilton
authors.affiliation: Magidom Discovery, LLC, St Augustine, FL; Department of Emergency Medicine, Brown University School of Medicine, Providence, RI.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Lacouture
authors.affiliation: Hospira Inc., Lake Forest, IL.
authors.forename: Christian Rd
authors.initials: CR
authors.lastname: Reyes
authors.affiliation: Javelin Pharmaceuticals, Inc., Cambridge, MA; Department of Anesthesiology, Tufts Medical Center, Boston, MA, USA.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Carr
keywords: cyclodextrin; diclofenac; multimodal analgesia; nonopioid analgesics; nonsteroidal anti-inflammatory drugs; postoperative pain