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

Abstract

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

Supplementary materials

Table S1 Total rescue opioid consumption and total number of rescue opioid doses among patients receiving intravenous HPβCD-diclofenac, ketorolac, or placebo for acute postsurgical pain

Table S2 Total rescue opioid consumption, by baseline pain severity, among patients receiving intravenous HPβCD-diclofenac, ketorolac, or placebo for acute postsurgical pain

Table S3 Total number of rescue opioid doses, by baseline pain severity, among patients receiving intravenous HPβCD-diclofenac, ketorolac, or placebo for acute postsurgical pain

Table S4 Total number of rescue opioid doses, by age group, among patients receiving intravenous HPβCD-diclofenac, ketorolac, or placebo for acute postsurgical pain

Acknowledgments

Editorial/medical writing support was provided by Scott Paluszkiewicz, PhD and Tejaswi Worlikar, MS, MSE of Boston Strategic Partners, Inc., and was funded by Hospira, Inc., which was acquired by Pfizer Inc. in September 2015.

The studies included in the pooled analysis were sponsored by Javelin Pharmaceuticals, Inc., Cambridge, MA (acquired in 2010 by Hospira, Inc., Lake Forest, IL, USA) and Hospira, Inc., which was acquired by Pfizer in September 2015. The present analysis was funded by Hospira, Inc., a Pfizer company.

Disclosure

TJG, NS, and SED were paid investigators for the studies included in the analysis. PGL was an employee of Hospira, Inc. at the time the study was initiated. CRDR is an employee of Hospira, Inc., a Pfizer company. DAH was the full-time Chief Operating Officer for the study sponsor during the trials included in the present study, and served as a consultant to Hospira, Inc. following its acquisition of Javelin Pharmaceuticals in 2010. DBC was the full-time Chief Medical Officer for the study sponsor during the trials included in the present study, and served as a consultant to Hospira, Inc. following its acquisition of Javelin Pharmaceuticals in 2010.