Diclofenac potassium liquid-filled soft gelatin capsules in the management of patients with postbunionectomy pain: A phase III, multicenter, randomized, double-blind, placebo-controlled study conducted over 5 days

Riff, Dennis; Duckor, Steven; Gottlieb, Ira; Diamond, Eric; Soulier, Scott M.; Raymond, G.; Boesing, S.

doi:10.1016/j.clinthera.2009.09.011

Cited by 24 publications

(13 citation statements)

References 25 publications

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“…18 The numbers and types of patient AEs in this study were consistent with similar studies of patients who underwent bunionectomy. 16,19,20 The slightly higher percentage of patients who developed headaches in the indomethacin submicron particle capsule groups is consistent with the well-known safety profile of the drug. 1 Although widely used for acute and chronic pain, NSAIDs can be associated with a higher risk of doserelated gastrointestinal, cardiovascular, and renal events in patients.…”

supporting

confidence: 83%

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Indomethacin Submicron Particle Capsules Provide Effective Pain Relief in Patients with Acute Pain: A Phase 3 Study

Altman

Daniels

Young³

2013

The Physician and Sportsmedicine

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Although frequently prescribed to relieve acute pain in patients, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with dose-related gastrointestinal, cardiovascular, and renal complications. Investigational, submicron particle NSAIDs are being developed that could provide effective pain relief at lower doses than currently available oral NSAIDs. This is the first phase 3 study evaluating the analgesic efficacy and safety of lower-dose indomethacin submicron particle capsules in patients following elective surgery. This multicenter, double-blind study enrolled patients aged 18 to 68 years who underwent bunionectomy under regional anesthesia. Patients with a pain intensity rating of ≥40 mm on a 100-mm Visual Analog Scale were randomized to receive indomethacin submicron particle capsules (40 mg 3 times daily [TID], 40 mg twice daily [BID], or 20 mg TID), celecoxib (400 mg loading dose, then 200 mg BID), or placebo. The primary efficacy parameter was the overall (summed) pain intensity difference measured by a Visual Analog Scale during a period of 48 hours. Scheduled assessments measured secondary efficacy parameters such as patient pain intensity differences. Indomethacin submicron particle capsules 40 mg 3 times daily (509.6 ± 91.9 overall [summed] pain intensity difference), 40 mg twice daily (328.0 ± 92.9 overall [summed] pain intensity difference), and 20 mg 3 times daily (380.5 ± 92.9 overall [summed] pain intensity difference) reduced pain intensity from 0 to 48 hours (P ≤ 0.046 for all 3 groups) compared with placebo (67.8 ± 91.4 overall [summed] pain intensity difference). There was some evidence of patient analgesia for celecoxib (279.4 ± 91.9 overall [summed] pain intensity difference; P = 0.103). Some evidence of pain control was observed in patients as early as 2 hours following administration of indomethacin submicron particle capsules and was sustained throughout the treatment period. Indomethacin submicron particle capsules were generally well tolerated by patients. These results suggest that lower-dose indomethacin submicron particle capsules are a potentially promising treatment option for patients with acute pain.

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confidence: 83%

“…Patient pain intensity was assessed before the initial dose of study medication (time 0); at 15, 30, and 45 minutes; at 1, 1.5, 2, 3, 4, 5, 6,7,8,12,16,20,24,32,40, and 48 hours after the first dose of study medication; and immediately before the first dose of rescue medication if it was needed before the 8-hour time point.…”

Section: Study Design and Proceduresmentioning

confidence: 99%

Indomethacin Submicron Particle Capsules Provide Effective Pain Relief in Patients with Acute Pain: A Phase 3 Study

Altman

Daniels

Young³

2013

The Physician and Sportsmedicine

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“…Accordingly, diclofenac or related compounds may be of particular benefit in the treatment of rotavirus diarrhea. Furthermore, since clinical use of diclofenac is known to be associated with constipation [36], [37], our findings may provide a mechanistic insight into the cellular events underlying constipation in patients taking diclofenac.…”

Section: Discussionmentioning

confidence: 90%

Inhibition of cAMP-Activated Intestinal Chloride Secretion by Diclofenac: Cellular Mechanism and Potential Application in Cholera

et al. 2014

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Cyclic AMP-activated intestinal Cl− secretion plays an important role in pathogenesis of cholera. This study aimed to investigate the effect of diclofenac on cAMP-activated Cl− secretion, its underlying mechanisms, and possible application in the treatment of cholera. Diclofenac inhibited cAMP-activated Cl− secretion in human intestinal epithelial (T84) cells with IC50 of ∼20 µM. The effect required no cytochrome P450 enzyme-mediated metabolic activation. Interestingly, exposures of T84 cell monolayers to diclofenac, either in apical or basolateral solutions, produced similar degree of inhibitions. Analyses of the apical Cl− current showed that diclofenac reversibly inhibited CFTR Cl− channel activity (IC50∼10 µM) via mechanisms not involving either changes in intracellular cAMP levels or CFTR channel inactivation by AMP-activated protein kinase and protein phosphatase. Of interest, diclofenac had no effect on Na+-K+ ATPases and Na+-K+-Cl− cotransporters, but inhibited cAMP-activated basolateral K+ channels with IC50 of ∼3 µM. In addition, diclofenac suppressed Ca2+-activated Cl− channels, inwardly rectifying Cl− channels, and Ca2+-activated basolateral K+ channels. Furthermore, diclofenac (up to 200 µM; 24 h of treatment) had no effect on cell viability and barrier function in T84 cells. Importantly, cholera toxin (CT)-induced Cl− secretion across T84 cell monolayers was effectively suppressed by diclofenac. Intraperitoneal administration of diclofenac (30 mg/kg) reduced both CT and Vibrio cholerae-induced intestinal fluid secretion by ∼70% without affecting intestinal fluid absorption in mice. Collectively, our results indicate that diclofenac inhibits both cAMP-activated and Ca2+-activated Cl− secretion by inhibiting both apical Cl− channels and basolateral K+ channels in intestinal epithelial cells. Diclofenac may be useful in the treatment of cholera and other types of secretory diarrheas resulting from intestinal hypersecretion of Cl−.

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“…The safety and efficacy profile has been well documented and is comparable with that of other NSAIDs [4–9]. The analgesic efficacy of oral diclofenac formulations has been demonstrated across various acute pain models, such as postoperative dental pain [4,6,8], minor postsurgical gynecologic pain [5,10], and pain resulting from bunionectomy [11–13].…”

Section: Introductionmentioning

confidence: 95%

A Phase 2 Study Evaluating the Efficacy and Safety of a Novel, Proprietary, Nano-Formulated, Lower Dose Oral Diclofenac

2012

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Diclofenac potassium liquid-filled soft gelatin capsules in the management of patients with postbunionectomy pain: A phase III, multicenter, randomized, double-blind, placebo-controlled study conducted over 5 days

Cited by 24 publications

References 25 publications

Indomethacin Submicron Particle Capsules Provide Effective Pain Relief in Patients with Acute Pain: A Phase 3 Study

Indomethacin Submicron Particle Capsules Provide Effective Pain Relief in Patients with Acute Pain: A Phase 3 Study

Inhibition of cAMP-Activated Intestinal Chloride Secretion by Diclofenac: Cellular Mechanism and Potential Application in Cholera

A Phase 2 Study Evaluating the Efficacy and Safety of a Novel, Proprietary, Nano-Formulated, Lower Dose Oral Diclofenac

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