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Postoperative opioid sparing with injectable hydroxypropyl-β-cyclodextrin-diclofenac: pooled analysis of data from two Phase III clinical trials

Authors Gan TJ, Singla N, Daniels SE, Hamilton DA, Lacouture PG, Reyes CR, Carr DB

Received 17 February 2016

Accepted for publication 7 July 2016

Published 20 December 2016 Volume 2017:10 Pages 15—29

DOI https://doi.org/10.2147/JPR.S106578

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Minal Joshi

Peer reviewer comments 4

Editor who approved publication: Dr Richard Robinson

Tong J Gan,1 Neil Singla,2 Stephen E Daniels,3 Douglas A Hamilton,4,5 Peter G Lacouture,6,7 Christian RD Reyes,8 Daniel B Carr4,9

1Department of Anesthesiology, Stony Brook University, NY, 2Lotus Clinical Research, LLC, Pasadena, CA, 3Premier Research, Austin, TX, 4Javelin Pharmaceuticals, Inc., Cambridge, MA, 5New Biology Ventures, LLC, San Mateo, CA, 6Magidom Discovery, LLC, St Augustine, FL, 7Department of Emergency Medicine, Brown University School of Medicine, Providence, RI, 8Hospira Inc., Lake Forest, IL, 9Department of Anesthesiology, Tufts Medical Center, Boston, MA, USA

Purpose: 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.
Patients and 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).
Conclusion: 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.

Keywords:
postoperative pain, nonsteroidal anti-inflammatory drugs, nonopioid analgesics, multimodal analgesia, diclofenac, cyclodextrin

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Other article by this author:

A Phase I study evaluating the effect of age and weight on the pharmacokinetics of an injectable formulation of diclofenac solubilized with hydroxypropyl-β-cyclodextrin

Goldwater R, Kramer WG, Hamilton DA, Lang E, Wang J, Madden DE, Lacouture PG, Ramaiya A, Carr DB

Clinical Pharmacology: Advances and Applications 2016, 8:203-212

Published Date: 15 December 2016