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Three Part Question

In [patients with acute pain resulting from minor soft tissue injuries], is [DETP] an effective option for [reducing pain and time to pain resolution]?

Clinical Scenario

A 45 year old man presents with a painful swollen ankle. No fractures are seen on X-ray and he is diagnosed with an ankle sprain. He has a history of duodenal ulcers and gastrointestinal bleeding treated with proton pump inhibitors for the last 5 years. You wonder whether the topical non-steroidal anti-inflammatory drug (NSAID) patch, diclofenac epolamine topical patch (DETP) 1.3% (FLECTOR® Patch, King Pharmaceuticals® Inc., Bridgewater, NJ, USA), can be prescribed to manage pain instead of an oral NSAID formulation.

Search Strategy

A database (MEDLINE, Derwent Drug File, BIOSIS, and EMBASE) search was conducted for available literature published in any language between 1984 to the present using the search terms “diclofenac epolamine topical patch,” “diclofenac hydroxyethyl pyrrolidine patch,” and “Flector patch.” Clinical studies analysing the DETP for the treatment of pain due to soft tissue injury in adult patients were included. The bibliographies of included studies were also reviewed for relevant articles. Studies enrolling paediatric patients, as well as patients with other medical conditions, were excluded. Studies reporting on other diclofenac formulations, such as diclofenac sodium, were excluded. If results of a study appeared in more than one publication, only the most complete report or, if the same, the earliest report was included.

Search Outcome

DETP has been studied in 7 clinical studies that enrolled adult patients with a variety of soft tissue injuries, including 5 placebo controlled studies, one active controlled study comparing the effects of DETP with diclofenac diethylammonium (DDA) emulgel, and one uncontrolled, open label study (table). No studies were found comparing DETP and oral NSAIDs.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Jenoure P et al, 1993, Switzerland	101 patients with minor traumatic sport and overload injuries of <24 hours duration DHEP only 14 day treatment (2 patches/day)	Single centre, open design	Spontaneous pain, pain on pressure, investigator and patient global efficacy assessment	60% (verbal) and 56% (VAS) reduction in spontaneous pain at Day 14; 61% reduction in pain on pressure.	No placebo control group; small numbers; no sample size calculation; statistical analysis not conducted
			Assessments conducted on Days 7 and 14	Global efficacy rated as good to excellent in 58.4% (investigator rated) and 56.4% (patient rated) of patients. Global assessment for tolerability rated as good or excellent in all patients studied.
Saillant G et al, 1998, France	140 patients with benign ankle sprains occurring within previous 48 hours and VAS (0-100) score ≥50 mm 7 day treatment (single patch/day) DETP vs placebo patch	Multicentre, double blind study	Spontaneous pain, pain at rest, pain with passive pressure, pain upon monopedal support; periarticular oedema; investigator and patient global efficacy assessment; paracetamol use	Spontaneous pain on VAS was significantly reduced vs placebo starting at the 3rd hour after application of the first patch (p≤0.05) and at Days 3 (mean, 21 vs 30, p=0.004) and 7 (mean, 8 vs 18, p=0.0008).	No sample size calculation; values not reported for secondary endpoints
			Assessments reported for Days 0, 3, and 7	Pain at rest, upon palpation, upon provoked passive pressure, and upon monopedal support, as well as oedema, were significantly improved vs placebo at Days 3 and 7; physician and patient assessments were significantly better for DETP vs placebo at Days 3 (p=0.003 and p=0.03, respectively) and Day 7 (p=0.0003 and p=0.0001, respectively). Paracetamol use was low and did not differ between groups. Tolerability of DETP and placebo patch judged good or very good in 69/70 cases. No adverse events were reported for DETP.
Joussellin É, 2003, France	134 patients with ankle sprain <48 hours duration and VAS (0100) score ≥50 mm DETP vs placebo patch 7 day treatment (1 patch/day)	Multicentre, randomised, placebo controlled, parallel group study	Spontaneous pain on movement; pain at rest; pain on passive stretch; pain on pressure; pain while leaning on single foot; investigator and patient global assessments	DETP significantly reduced pain vs placebo starting from the 4th hour after the first application (p<0.02) and continuing until study end (p<0.001).	No sample size calculation
			Assessments conducted on Days 1, 3, and 7 for spontaneous pain and Days 3 and 7 for secondary endpoints	DETP had significant improvement vs placebo for secondary criteria on Days 3 and 7: pain on passive stretch (p=0.001). Day 7), pain on pressure (p=0.001, Day 7), pain when standing on a single foot (p=0.001, Day 7). DETP had significantly greater efficacy than placebo as shown by patient and investigator global assessments of efficacy at Days 3 and 7 (p=0.001, for both). No adverse events were observed during the study.
Rowbotham MC et al, 2003, USA	372 patients with minor sports injuries (sprain, strain, or contusion) <72 hours prior to study entry and with a numeric pain scale (010) score ≥5 DETP vs placebo patch 14 day treatment (1 patch every 12 hours)	Multicentre, randomised, placebo controlled, parallel group study	Time to pain resolution; patient daily assessment of pain; investigator and patient global assessments	DETP showed statistically significant faster time to pain resolution vs placebo patch (median, 8.8 days vs 12.4 days; p=0.009).	No sample size calculation
			Assessment of pain was conducted Days 114; global assessments were conducted on Day 14	Total scores for patient assessment of daily pain for DETP were significantly lower vs placebo (p=0.042) starting at Day 6 and continuing through Day 13. Investigator and patient global assessments were not statistically different between groups No significant differences seen between treatment groups in tolerability or adverse events.
Rosenthal M, Bahous I, 1993, Switzerland	190 patients with periarticular/ tendinous inflammation DHEP vs diclofenac diethylammonium (DDA) emulgel 14 day treatment DHEP (2 patches/day); 2 g DDA emulgel (4 applications/day)	Active drug controlled, randomised study	Spontaneous pain, pain on pressure, investigator and patient global efficacy assessment	DHEP reduced spontaneous pain on VAS to a greater extent vs DDA emulgel at Day 14 (-60.8% vs -40.8%; p<0.001); differences were not significant when stratified by diagnosis.	No placebo control group; no sample size calculation
			Assessments conducted on Days 7 and 14 and reported as variation across 14 days of treatment	Pain on pressure was significantly reduced in DHEP treated patients vs DDA emulgel (-57.7% vs -37.5%; p<0.001). Global efficacy was judged to be significantly greater for DHEP vs DDA emulgel by investigators and patients (p<0.0001). Both treatments well tolerated; patient-rated tolerability superior in DHEP treated patients vs DDA emulgel patients (p<0.0001).
Jenoure PJ et al, 1993, Switzerland	85 patients with humeroradial epicondyle pains of a tendinopathic nature DETP vs placebo patch 14-day treatment (2 patches/day) and Day 28 follow-up	Multicentre, double-blind study	Spontaneous pain; pain on pressure; pain on muscular testing	DETP and placebo patch both significantly decreased spontaneous pain and pain on pressure at Days 14 and 28, and pain on muscular testing at Day 28 (p<0.05 vs baseline, for all).	Small number; no sample size calculation; statistical differences between groups not calculated for all endpoints
			Assessments reported for Days 1, 7, 14, and 28	DETP-treated group showed significantly improved spontaneous pain scores at Days 14 and 28 compared with placebo (p<0.05); percentage of patients with spontaneous pain (moderate to intense), respectively: Day 14: 26.8% vs 60.6% (p<0.05); Day 28: 17.9% vs 47.3% (p<0.01). Tolerability of DETP was comparable with placebo; percentage of patients with physician-assessed excellent tolerability at Day 28: 88.6% vs 87.5%, respectively (p=NS).

Comment(s)

The studies demonstrated that DETP is more effective at managing acute pain due to minor soft tissue injuries than placebo. Pain scores for spontaneous pain and pain on pressure were improved compared with baseline, placebo, and DDA emulgel; time to pain resolution was shorter in DETP treated patients compared with placebo. Studies found DETP tolerability comparable to placebo; few adverse events were reported, and of these, most were mild dermatologic reactions.

Editor Comment

Author comments: DETP = diclofenac epolamine topical patch; DHEP = diclofenac hydroxyethyl pyrrolidine plaster; VAS = visual analogue scale. DETP and DHEP are abbreviations for the same salt; usage depends on the origin of the study. Dr. Miner and Dr. Gajraj have no competing interests to report. Funding: Funding for writing and editorial support was provided by King Pharmaceuticals® Inc., Bridgewater, NJ, USA.

Clinical Bottom Line

The DETP is an effective therapeutic option in the early treatment phase of acute pain associated with minor soft tissue injuries.

References

1. Jenoure PJ, Rostan A, Gremion G, et al. Studio multicentrico controllato in doppio cieco su diclofenac Tissugel plaster in pazienti con epicondilite [Multicentre, double-blind, controlled clinical study on the efficacy of diclofenac... Medicina Dello Sport 1997;50:285-92.
2. Saillant G, Auguste P, Boyer C, Janvier B, et al. Study comparing the efficacy and tolerability of Flector Tissugel to that of a placebo in the treatment of benign ankle sprain [French] Medecine du Sport 1998;72:1-5.
3. Galer BS, Rowbotham M, Perander J, et al. Topical diclofenac patch relieves minor sports injury pain: results of a multicenter controlled clinical trial. J Pain Symptom Manage 2000;19:287-94.
4. Joussellin É. Flector Tissugel. Flector Tissugel® in the treatment of painful ankle sprain [French]. J Traumatol Sport 2003;20:1S5-9.
5. Rowbotham MC, Galer BS, Block JA, et al. Flector Tissugel®: efficacy and safety in the treatment of minor sports injuries. Data from a controlled trial in the United States. J Traumatol Sport 2003;20:1S15-20.
6. Rosenthal M, Bahous I. A controlled clinical study on the new topical dosage form of DHEP plasters in patients suffering from localized inflammatory diseases. Drugs Exp Clin Res 1993;19:99-105.
7. Jenoure P, Segesser B, Lühti U, Gremion G. A trial with diclofenac HEP plaster as topical treatment in minor sport injuries. Drugs Exp Clin Res 1993;19:125-31.