The frequency of soft tissue injuries has risen during recent years with increasing awareness of the health benefits of exercise (3,26). Most common among soft tissue trauma sites and types are ankle sprains (9,12), accounting for 10%–15% of all sports injuries (8,13,19), the majority of which are inversion sprains of the lateral ligaments (14,29). Uncomplicated ankle sprains tend to be benign and self-limiting (20). However, with inadequate management, the pain, stiffness, and swelling (11) of an ankle sprain injury may impair function and delay the time to recovery.
Conventional treatment for lateral ankle sprains focuses on controlling pain and swelling (15). PRICE (protection, rest, ice, compression, and elevation) is a well-established protocol for the treatment of ankle injury (15), combined with early mobilization and early weight bearing, with or without the use of external support (e.g., tape, bandage, or brace) (18,28). Nonsteroidal anti-inflammatory drugs (NSAIDs) can also be used to reduce pain, decrease swelling, and improve short-term ankle function, thus speeding recovery (1,4,7,10,15,22). Topical NSAIDs, available “over-the-counter” in most countries, are proven effective and are particularly well tolerated for the short-term management of acute mild-to-moderate pain and inflammation, including soft tissue injuries such as ankle sprains. Diclofenac is a well-known NSAID that has been used for more than 30 yr to treat pain and inflammation. Applied topically, diclofenac penetrates the skin barrier to reach joints, muscles, and synovial fluid. It preferentially distributes and persists in the target inflamed tissues (2), achieving sufficiently high concentration to exert local therapeutic activity (30). Diclofenac diethylamine (DDEA) 1.16% gel (Voltaren Emulgel®; Novartis Consumer Health SA, Basel, Switzerland) is currently the most widely used over-the-counter topical NSAID formulation worldwide (21). Applied three to four times per day, DDEA 1.16% gel has been proven effective and well tolerated in relieving pain and reducing inflammation of acute painful musculoskeletal conditions (30), including ankle sprain, thereby improving the functional capacity of the patients and accelerating healing (6,23,25).
Despite the demonstrated efficacy of topical diclofenac in treating ankle sprain, the high frequency of applications each day may affect patient compliance and thus compromise the efficacy of the product. A new higher concentration DDEA 2.32% topical gel has been developed to effectively restore pain-free movement by providing lasting pain relief with fewer applications per day, thus improving patient compliance and increasing convenience. This randomized double-blind placebo-controlled study was conducted to evaluate the efficacy and safety of DDEA 2.32% gel applied either two times per day (bid) or three times per day (tid) to treat acute ankle sprain with respect to the clinically relevant outcomes of pain, function, mobilization of the affected joint, and swelling.
This was a randomized double-blind three–treatment arm multicenter (n = 6, all in Germany, all primary care centers specializing in sports or internal medicine) placebo-controlled parallel group study in patients with acute ankle sprain grades I and II, a clinical model considered appropriate to assess efficacy in acute pain conditions. Patients were to be randomized and treated within 12 h after the injury to minimize variability of response. At the initial visit (day 1), patients assessed baseline severity of symptoms and were randomized in a 1:1:1 ratio among three treatment arms (DDEA 2.32% bid vs DDEA 2.32% tid vs placebo). Patients then returned to the study site for follow-up visits on days 3, 5, and 8 to complete the efficacy and safety assessments. A 3-d window (days 7 to 9) was allowed for the day 8 visit.
The study was performed in accordance with Good Clinical Practice, and the study protocol was reviewed and approved by the independent ethics committee or institutional review board of each participating center. Informed consent was obtained from each patient in writing at the screening visit, before performing any study procedures.
The main objective of this study was to evaluate the efficacy of DDEA 2.32% used by patients with acute ankle sprain either bid or tid under “in-use” conditions. The primary efficacy outcome variable was pain relief after the first 5 d of treatment. A secondary objective was to assess the safety of DDEA 2.32% used under these conditions for 1 wk.
The study population consisted of male and female patients, 18 yr and older, experiencing acute grade I–II sprain of the lateral ankle (as assessed by the investigator) within the previous 12 h. Inclusion criteria included a score for pain on movement (POM) of ≥50 mm on a 100-mm visual analog scale (VAS) and no use of any pain medication within the 12 h preceding randomization. Treatment by rest, ice, compression, or elevation was allowed before randomization. Main exclusion criteria included any concurrent injury affecting the lower extremities that was painful at rest or on movement or could affect the mobilization of the patient, use of topical analgesics or anti-inflammatories during the previous month in the area to be treated, a grade I sprain of the same ankle within 3 months, a grade II–III sprain or any other significant injury or surgery (except for skin or nails) of the same ankle or foot within 6 months of the study start, pain or instability in the same ankle attributed to a previous ankle sprain, or any other trauma or ankle sprain attributed to a known disease affecting the ligaments.
All patients received three tubes of the study drug. Each tube contained either DDEA 2.32% gel (Voltaren Emulgel®) or a placebo gel (vehicle), labeled for treatment in the morning, noon, or evening. The control gel was identical in composition, appearance, texture, and smell to DDEA 2.32%, without the active ingredient. The tid group received three tubes of DDEA 2.32%, and the vehicle group received three tubes of vehicle. The bid group received two tubes of DDEA 2.32% labeled for morning and evening and one tube of vehicle labeled for noon. The first dose was applied at the study center, and patients were instructed to apply a 5-cm-long ribbon (approximately 2 g) of the gel with the fingertips to both sides of the ankle for around 1 min over an area of approximately 200 cm2, tid for 7 d.
Rescue medication (500-mg paracetamol tablets, maximum = 2000 mg·d−1) was given to the patient at the baseline visit to treat pain in the ankle or any other pain (e.g., headache) or fever (e.g., due to common cold) that he or she might experience during the trial. No rescue medication was allowed within 12 h before the study visits. To minimize additional sources of variability in response, adhesive and/or immobilizing casts, bandages, splints, and treatment by rest, ice, compression, or elevation were not allowed after randomization. The use of a crutch was allowed, and patients were instructed to start Achilles tendon stretching on day 1 and muscle strengthening exercises only after range of motion had been regained.
Efficacy measurements were assessed on days 1, 3, 5, and 8 (±1) (visits 1–4). After sitting for 15 min, patients assessed pain at rest, i.e., the amount of ankle pain “right now,” on a 100-mm VAS (0 = no pain, 100 = extreme pain). After investigator manipulation of the ankle, subjects assessed POM using the VAS scale described previously. Tenderness (pressure pain threshold) was measured by the investigator using a calibrated algometer (pressure pain meter); efficacy was assessed as the difference in tenderness between the treated painful area and the corresponding anatomical position on the healthy uninjured ankle. Ankle swelling was determined by the investigator using the circumference measurement of swelling by the “figure-of-eight method” as described previously (27) and subtracting the corresponding measurement of the healthy uninjured ankle. Ankle joint function was evaluated by the patient at the study center using the validated Karlsson Scoring Scale (16,17) over eight categories (pain, swelling, subjective instability, stiffness, stair climbing, running, work activities, use of a support device) to give a total score ranging from 0 to 90.
On days 3, 5, and 8 (±1) (visits 2–4), patients evaluated the global assessment of benefit on a five-point Likert scale (0 = very good to 4 = very poor), i.e., how well the patient was doing in consideration of the ankle sprain and the effects of the study medication. On days 5 and 8 (±1) (visits 3 and 4), patients evaluated the global assessment of treatment satisfaction using the same Likert scale. The global assessment of treatment satisfaction asked how well the subject rated the study medication as a treatment for ankle sprain.
The primary efficacy outcome was ankle POM, assessed by VAS on day 5. Regulatory guidelines recommend specification before unblinding of a dichotomous response criterion. Therefore, before unblinding, a response defined as a reduction of 50% or more in POM from baseline to day 5 was designated as an important secondary outcome. Other secondary efficacy variables included ankle POM (VAS) on days 3 and 8; ankle pain at rest (VAS) on days 3, 5, and 8; tenderness (algometer) on days 3, 5, and 8; ankle swelling on days 3, 5, and 8; ankle joint function (Karlsson Scoring Scale) on days 3, 5, and 8; total rescue medication consumed (paracetamol) overall and for ankle pain specifically; global assessment of benefit (five-point Likert scale) on days 3, 5, and 8; global assessment of treatment satisfaction (five-point Likert scale) on days 5 and 8; time to improvement of POM on VAS of at least 40 mm; time to first POM on VAS of 30 mm or less; and time to a 50% reduction in POM from day 1.
A brief general physical examination was performed at randomization (day 1) and upon study termination (day 8), as well as when judged necessary by the investigator. Vital signs (including systolic blood pressure, diastolic blood pressure, and pulse rate) were also measured on days 1 and 8. Details of any adverse events (AEs) and serious AEs were recorded at all study visits. The main safety assessment was the frequency of treatment-related AEs.
The data were analyzed using SAS Version 9.1 (SAS Institute, Cary, NC). All statistical tests were two sided, with probability of type I error = 0.05. The safety analysis set and the intent-to-treat population included all randomized patients who received at least one dose of the study drug. All study visits occurred within the protocol-defined visit windows, and there were no centers with minimal enrollment that required pooling.
To control for multiple comparisons, efficacy on each outcome was first tested for DDEA 2.32% tid versus placebo at the level α = 0.05. Only if separation was statistically significant, then efficacy was tested for DDEA 2.32% bid versus placebo at the level α = 0.05.
For quantitative outcomes, efficacy was tested with an ANCOVA model including treatment group and center as main effects and the baseline value as a covariate. Treatment/center interactions were carefully considered but were discarded because even when statistically significant, they had no meaningful effect on the statistical significance of the main effect of treatment. Treatment effects were estimated as mean differences between the active and placebo groups with 95% confidence intervals.
For the global assessments, efficacy was tested with the Cochran–Mantel–Haenszel test of treatment mean ridits, stratified by center. Differences in the use of rescue medication were tested with the Cochran–Mantel–Haenszel test of treatment means or of general association (as appropriate) stratified by center. Time to event outcomes were summarized by quartiles using Kaplan–Meier methods and tested with the log-rank statistic, stratified by center. If the event was not achieved, it was censored at the day of the final visit. If a patient discontinued because of lack of efficacy, it was censored at day 8.
If an assessment for day 3 or 5 was missing, it was imputed as the average of the preceding and the following assessments. Fractional values were rounded in the direction of a worse outcome. If a patient terminated prematurely, all subsequent visits were imputed by carrying the last nonmissing observation forward. As noted below, premature termination was minimal.
The sample size of 80 per group was chosen to provide 80% power to separate DDEA 2.32% bid from placebo on the primary efficacy outcome based on the sequential testing procedure to control for multiple comparisons, given the following specifications: two-sided α = 0.05, SD = 20 mm, Δ = 9.3 mm for DDEA 2.32% bid, and Δ = 11 mm for DDEA 2.32% tid.
Patient Disposition and Baseline Characteristics
Of the 242 randomized patients, 80 were randomized to DDEA 2.32% bid, 80 were randomized to DDEA 2.32% tid, and 82 were randomized to placebo (Table 1). Of these, 236 patients (98%) completed the study. Of the six who discontinued prematurely, only one patient (in the placebo group) discontinued because of an AE not related to treatment (increasing foot pain). One underage patient was accidentally included in the study population but was immediately discontinued once the investigator realized the protocol violation. The data from this patient were excluded from the efficacy analysis but were included in the safety analysis.
Thus, the patients’ ages ranged from 17 to 81 yr, with an overall mean of 32.4 yr. The majority of patients in all three groups were male (63% overall), and almost all (97%) were Caucasian. All three groups were well balanced with respect to their demographic characteristics (Table 1).
Table 1 also shows ankle sprain baseline characteristics by treatment group on day 1. Overall, 72% of patients had a grade I ankle sprain. Levels of baseline efficacy assessments were similar among the treatments, and the mean VAS score for POM was approximately 75 mm in all three groups. Generally, a mean of 3–4 h (median = 2.5 h) elapsed from ankle sprain to application of the first dose of study medication.
Overall, compliance was rated good. In all three treatment groups, the typical subject made >90% of scheduled applications and applied roughly 100% of the amount of study medication by weight that would correspond to the number of applications made (based on 2 g of study medication per application).
Primary Efficacy Variable
Figure 1 indicates that the onset of efficacy was rapid with both bid and tid DDEA 2.32% treatment regimens, and improvements in POM were sustained during the entire 7-d treatment period. By day 5 (the primary efficacy variable), the decrease in POM with DDEA 2.32% bid and tid (49.1 and 49.7 mm, respectively) was twice that observed with placebo (25.4 mm, P < 0.0001; Table 2). The difference between the DDEA 2.32% bid and tid groups was not significant.
Secondary Efficacy Variables
Response to treatment.
Table 2 compares the treatments by the percent of patients whose POM was reduced by 50% or more from baseline to day 5. The percent of responders in both active treatment groups exceeded the percent of responders to placebo by greater than 50% (P < 0.0001).
POM, days 3 and 8.
At both time points, the decrease in POM was significantly greater with DDEA 2.32% applied bid or tid compared with placebo (P < 0.0001; see Appendix, Supplemental Digital Content, http://links.lww.com/MSS/A168, Change in secondary efficacy variables). The mean change from baseline in the DDEA 2.32% groups was superior to placebo by roughly 14 mm at day 3, increasing to roughly 25 mm on day 8 (as well as day 5). At day 8, the mean VAS scores for POM in the DDEA 2.32% bid and tid treatment groups were well below 20 mm compared with a mean of 40 mm in the placebo group. Already on day 3, the decrease in POM in the DDEA 2.32% bid and tid treatment groups (32.4 and 32.2 mm, respectively) was almost twice that observed with placebo (18.1 mm) (P < 0.001). The mean decreases from baseline in POM in the DDEA 2.32% bid and tid groups were similar at all visits.
Pain at rest.
At all time points, there was a significantly greater decrease in the mean pain-at-rest scores in the groups treated with DDEA 2.32% compared with placebo (P < 0.0001, apart from DDEA 2.32% bid at day 3, P < 0.001, see Appendix, Supplemental Digital Content, http://links.lww.com/MSS/A168, Change in secondary efficacy variables). The mean change from baseline in the DDEA 2.32% groups was superior to placebo by roughly 5 mm at day 3, increasing to roughly 8 mm on days 5 and 8.
Tenderness (pressure pain threshold).
At all time points, the decrease in the mean tenderness in the groups treated with DDEA 2.32% was approximately twice the decrease with placebo (P < 0.0001, see Appendix, Supplemental Digital Content, http://links.lww.com/MSS/A168, Change in secondary efficacy variables). The mean change from baseline in the DDEA 2.32% groups was superior to placebo by roughly 0.6 N·cm−2 at day 3, increasing to roughly 1 N·cm−2 on days 5 and 8. The mean decreases from baseline in tenderness in the DDEA 2.32% bid and tid groups were similar at all visits.
At all time points, there was a significantly greater decrease in the mean swelling in the groups treated with DDEA 2.32% compared with placebo (P < 0.0001, apart from DDEA 2.32% bid at day 3, P = 0.0012, see Appendix, Supplemental Digital Content, http://links.lww.com/MSS/A168, Change in secondary efficacy variables). The mean change from baseline in the DDEA 2.32% groups was superior to placebo by roughly 0.4 cm at day 3, increasing to roughly 0.6 cm on days 5 and 8. By day 8, the swelling in the DDEA 2.32% bid and tid groups (0.3 cm in both groups) was one-third that observed in the placebo group (0.9 cm). The mean decreases from baseline in swelling were minimally larger in the DDEA 2.32% tid versus the bid group, but the differences were not statistically significant.
Ankle joint function.
At all time points, there was a significantly greater improvement in mean ankle joint function in the groups treated with DDEA 2.32% compared with placebo (P < 0.0001, see Appendix, Supplemental Digital Content, http://links.lww.com/MSS/A168, Change in secondary efficacy variables). The mean change from baseline in the Karlsson score in the DDEA 2.32% groups was superior to placebo by roughly 5 at day 3, increasing to roughly 15–20 on days 5 and 8. By day 8, patients treated with placebo had still not achieved the level of ankle joint function that patients treated with DDEA 2.32% had achieved on day 5. The mean improvements from baseline in Karlsson score were slightly larger in the DDEA 2.32% tid versus the bid group, but the differences were not statistically significant.
Use of rescue medication.
More than 90% of patients in all three treatment groups used no rescue medication during the 7-d treatment period. Of the 19 patients who used rescue medication, the majority (n = 10) used three tablets or less during the whole treatment period. There was no significant difference between treatment groups either in the number of tablets used or in the number of days on which rescue medication was used.
Global assessment of benefit.
The global assessment of benefit was significantly higher in both active treatment groups compared with the placebo group at each time point (P < 0.0001) (Table 3). At day 3, 76.3% and 62.5% of patients in the DDEA 2.32% tid and bid groups, respectively, rated their status as “good” or “very good” compared with 23.2% in the placebo group. By day 8, the number of patients had increased to 91.3% and 85.0% of patients in the active treatment groups (DDEA 2.32% tid and bid, respectively) versus 29.3% of patients in the placebo group. No patients in the placebo group assessed their treatment as “Excellent.”
Global assessment of treatment satisfaction.
Treatment satisfaction in both active treatment groups was significantly greater than that in the placebo group on day 5 and day 8 (P < 0.0001, Table 3). At day 5, 88.8% and 83.8% of patients in the DDEA 2.32% tid and bid groups, respectively, rated treatment as “good” to “excellent” versus 23.2% of placebo patients. At day 8, separation increased to 93.8% and 85% versus 25.6%, respectively. No patients in the placebo group assessed their treatment as “excellent.”
Time to reduction in VAS scores.
Symptom relief and restoration of functional capacity was roughly twice as fast with DDEA 2.32% gel (bid or tid) compared with placebo (Table 2), as reflected by the median times to (i) a reduction in POM from day 1 of 40 mm, (ii) a score of 30 mm or less, and (iii) a 50% reduction in score from day 1 (all 4 d for DDEA 2.32% gel vs 8 d for placebo, apart from 9 d for placebo for the time to 30-mm reduction). The differences of either active treatment group versus placebo were highly significant (P < 0.0001), but no significant difference was observed between the two active treatment groups.
Subgroup analysis of patients with baseline pain ≥80 mm on a 100-mm VAS.
A post hoc subgroup analysis assessed the efficacy of DDEA 2.32% treatment bid or tid in a subgroup of patients experiencing more severe pain (a baseline POM score of ≥80 mm on a 100-mm VAS vs <80 mm) (Table 2). Both bid and tid treatments were significantly superior to placebo in reducing POM in patients with baseline pain ≥80 mm at the primary efficacy time point (day 5, P < 0.0001) as well as the secondary time points on days 3 and 8. In this patient subset, mean change from baseline with DDEA 2.32% exceeded that in the placebo group by roughly 30 mm. In contrast, for the <80-mm subgroup, the active groups were superior to placebo by only 15–20 mm. Similarly, in the ≥80-mm subgroup treated with DDEA 2.32%, Karlsson scores in both the bid and tid groups were significantly better than placebo at all visits, whereas in the <80-mm subgroup, there was significant superiority only at days 5 and 8. Global assessments of benefit and of treatment satisfaction showed similar results (data not shown).
DDEA 2.32% and its vehicle were well tolerated. AEs were reported by two patients (2.5%) each in the DDEA 2.32% bid and tid groups versus four patients (4.9%) in the placebo group (Table 4). Three AEs were suspected to be study drug related: application site pruritus in a patient treated with DDEA 2.32% tid and application site pain and skin exfoliation in the placebo group. These were all mild-to-moderate skin conditions. No AE was rated as severe. There were no meaningful changes in vital signs or findings on physical examination at the end of the study, and there was no evidence of toxicity to a major organ system. There were no unexpected AEs, deaths, or serious AEs recorded during the study.
In this 8-d randomized double-blind placebo-controlled study, DDEA 2.32%, applied twice daily, was highly significantly superior to placebo in reducing POM, pain at rest, tenderness, and swelling caused by an acute grade I–II ankle sprain and in improving ankle joint function. No significant treatment difference was observed between two or three applications per day. Clinically significant reduction in POM was achieved substantially faster after treatment with DDEA 2.32%. DDEA 2.32% applied bid was clearly effective within 2 d after starting treatment with efficacy persisting through day 8. Patient assessments of benefit and satisfaction with treatment with DDEA 2.32% were generally favorable and were significantly higher than those with placebo.
This study has clearly demonstrated that significant efficacy compared with placebo is achieved with just two applications of DDEA 2.32% per day. Concerning the issue of bid versus tid dosing, there were small differences between two- and three-times-daily application of DDEA 2.32% with respect to POM, pain at rest, ankle function, swelling, and tenderness at any time point. The study was not powered to detect such differences, and the observed differences cannot be described as clinically significant. Although slightly more pronounced differences between DDEA 2.32% bid and tid were found in the patients’ own assessments of benefit and treatment satisfaction, the assessments made by patients who applied treatment twice daily were still highly favorable. Furthermore, it is important to note that all patients in this study applied study medication three times daily. Patients randomized to bid dosing applied placebo gel at midday.
Considering that, in this study, patients randomized to bid dosing applied active medication in the morning and evening, it is reasonable to conclude that the product is effective during an entire 24-h period when applied approximately every 12 h. The treatment dosing and the efficacy results indicate that the product provides pain relief up to 12 h. This additional convenience should greatly improve patient compliance during the treatment period and minimize the incidence of underdosing and subsequent lack of efficacy and patient dissatisfaction.
The post hoc comparison of efficacy in subgroups of patients with baseline POM above or below 80 mm on a 100-mm VAS scale demonstrated that both bid and tid treatments were effective in patients with more severe pain (pain ≥80 mm). In fact, superiority over placebo was more pronounced in this group, suggesting that DDEA 2.32% can be applied bid to treat even severe pain due to ankle sprain.
DDEA 2.32% gel and its vehicle were generally well tolerated. The low rate of local reactions observed (application site pruritus in one patient) was similar to placebo and no higher than what is commonly seen with DDEA 1.16% gel (30). Topical diclofenac formulations were developed to target delivery directly to the affected tissue so as to reduce pain and inflammation while minimizing the risk of systemic AEs (30). Diclofenac preferentially targets inflamed tissues, so that drug is concentrated in the event compartment (2), with minimal systemic absorption (5,24). Pharmacokinetic studies (data not shown) confirmed that diclofenac absorption after two or three applications per day of DDEA 2.32 % is similar to absorption after four applications per day of DDEA 1.16%. There was no evidence of drug-related systemic AEs experienced after application of DDEA 2.32% in this study, which is consistent with the tolerability profile observed in clinical studies with DDEA 1.16% gel, probably because application of these products does not result in any meaningful systemic exposure.
There are some limitations associated with this study, the biggest of which is that no objective measurement of ligament healing was included. This information would have been useful to confirm whether DDEA 2.32% gel aids healing in addition to reducing pain and speeding recovery. Furthermore, a placebo gel was used as a comparison, but a second control group that did not use a gel would have led to even more robust results. Finally, comparison with an oral NSAID would be beneficial to determine the comparative efficacy and safety of DDEA 2.32% gel.
DDEA 2.32% gel, applied bid, was highly effective in relieving the symptoms of uncomplicated ankle sprain, i.e., pain, tenderness, and inflammation, including more severe pain. DDEA 2.32% gel speeded recovery compared with placebo by 4–5 d. There were no meaningful differences in efficacy between the two treatment regimens (two or three applications per day). Thus, two applications per day (morning and evening) suffice to exert a therapeutic effect that could last for up to 12 h. Patients were highly satisfied with both dosing frequencies and significantly more satisfied than patients treated with placebo. In addition, DDEA 2.32% gel was well tolerated.
The study was sponsored by Novartis Consumer Health. Sandra Hamelsky used to work for Novartis Consumer Health, and Morris Gold is currently an employee of Novartis Consumer Health.
The authors thank Thorsten Schiffer, Axel Schaefer, Helmut Pabst, Alexander Böse, Volker Smasal, and the study personnel for overseeing this study; Grigorios Fotopoulos for his input in the article; Christian Milliet for providing clinical operations support; Ian Burnett for providing clinical research support; and the professional medical writers Marcia Hammond and Deborah Nock for editorial support for the article.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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DICLOFENAC DIETHYLAMINE; ACUTE ANKLE SPRAIN; PAIN ON MOVEMENT; PAIN RELIEF; SAFETY
Supplemental Digital Content
©2012The American College of Sports Medicine