Randomized, double-blind, noninferiority study of diclofenac diethylamine 2.32% gel applied twice daily versus diclofenac diethylamine 1.16% gel applied four times daily in patients with acute ankle sprain.

BACKGROUND: Diclofenac diethylamine (DDEA) gel has demonstrated efficacy for treatment of ankle sprains in both the 1.16% four-times-daily (QID) and 2.32% twice-daily (BID) formulations. The objective of this study was to compare, for the first time, the efficacy of DDEA 2.32% gel BID and DDEA 1.16% gel QID. METHODS: This was a phase 3, randomized, double-blind, multicenter, active-controlled, parallel-group study conducted in China from October 2019 to November 2020, designed to determine the noninferiority of DDEA 2.32% gel BID relative to DDEA 1.16% gel QID for treatment of grade I-II ankle sprain. At study entry, patients must have had pain on movement (POM) ≥50 mm on a 100-mm visual analogue scale (VAS), and not received any pain medication. The primary efficacy endpoint was the noninferiority of DDEA 2.32% gel BID vs DDEA 1.16% gel QID for POM as assessed by the patient using the 100-mm VAS, conducted on day 5. Secondary endpoints included measures of ankle tenderness, joint function, swelling, and patient-reported pain intensity and pain relief. RESULTS: A total of 302 patients were randomized and 95.4% completed the study. The mean (SD) change in POM from baseline to day 5 using the 100-mm VAS was - 42.8 mm (19.7 mm) with DDEA 2.32% gel BID and - 43.1 mm (18.1 mm) with DDEA 1.16% gel QID for the per-protocol population. The least squares mean difference (DDEA gel 2.32% - DDEA gel 1.16%) at this timepoint was 1.11 mm (95% CI - 3.00, 5.22; P = 0.595), and the upper limit (5.22 mm) of the 95% CI was less than the noninferiority margin of 13 mm, demonstrating that DDEA 2.32% gel BID was noninferior to DDEA 1.16% gel QID. Similar trends were seen for the secondary efficacy endpoints. There was no significant difference in the incidence of treatment-emergent adverse events or adverse events adjudicated as being treatment related. All treatment-related adverse events were dermatological; one patient discontinued from the DDEA 2.32% gel BID arm due to application-site inflammation. CONCLUSIONS: DDEA 2.32% gel BID offers a convenient alternative to DDEA 1.16% gel QID, with similar pain reduction and relief, anti-inflammatory effects, and tolerability. TRIAL REGISTRATION: NCT04052620.

Pain Medication Administered and Prescribed to Patients With an Ankle Sprain Treated in an Emergency Department: A Record-Based Cohort Study.

INTRODUCTION: Recent data indicate that patients treated in the emergency department for an ankle sprain receive multiple medications. However, research has not been able to accurately identify all the medications because of study limitations. The primary purpose of this study was to document the type of medication, number of doses, and number of encounters given a prescription at discharge or instructions to take over-the-counter medication. The secondary purpose was to determine if the proportion of encounters given each type of medication varied on the basis of age, sex, race, and year. METHODS: A retrospective record-based cohort study design was used to review the electronic medical records (N = 1740) of encounters reporting to a southeast academic level 1 trauma center and diagnosed with an ankle sprain between 2013 and 2017. All relevant data were extracted for nonsteroidal anti-inflammatory drugs, muscle relaxants, opioids, and nonopioid analgesics. RESULTS: Fifty-eight percent of the encounters had at least 1 dose of medication administered in the emergency department. Twenty-eight percent received a prescription at discharge, and 54.5% were instructed to take over-the-counter medication. Cumulatively, opioids accounted for most of the medications, but the yearly rates declined from 2013 to 2017. A greater proportion of patients aged ≤15 years received nonsteroidal anti-inflammatory drugs or nonopioid analgesics. Most of the patients aged >15 years received opioid medication. DISCUSSION: Patients are primarily given an opioid or nonsteroidal anti-inflammatory drug in the emergency department. Fewer patients receive a prescription at discharge but are regularly instructed to take over-the-counter medication.

Comparison of Regularly Scheduled Ibuprofen Versus "Pro Re Nata" for Ankle Sprains in Children Treated in the Emergency Department: A Randomized Controlled Trial.

OBJECTIVE: We compared pain and degree of disability in patients with acute ankle sprains receiving regular scheduled ibuprofen versus pro re nata (PRN). METHODS: This study is a randomized single-blinded controlled trial of children aged 7 to 17 years presenting with acute ankle sprain to an emergency department. Patients were randomized to receive 10 mg/kg of ibuprofen per dose (maximum 600 mg) every 6 hours regular scheduled versus PRN. Outcome measures included a 100-mm visual analog scale pain and degree of disability at day 4. A sample size of 72 children had a power of 80% to detect a clinically meaningful difference of 20 mm between the regular and PRN group. RESULTS: We randomly assigned 99 patients to receive regular scheduled (n = 50) or PRN (n = 49) ibuprofen. Pain scores and degree of disability at day 4 showed no significant differences between groups. The rate of reported adverse effects was higher in the regular scheduled group (11.4% vs 9.5%) versus the PRN group. CONCLUSIONS: Our study suggests that there is little benefit from routinely using a regular scheduled ibuprofen regimen for acute pediatric ankle sprains.

Topical Ketoprofen Versus Placebo in Children Presenting With Ankle Sprain to the Emergency Department: A Randomized Controlled Study.

OBJECTIVE: Despite the favorable data concerning topical agents use in outpatient clinics, they are not commonly in emergency departments (EDs). The present study aimed to compare the effect of 2.5% topical ketoprofen (gel form) to placebo in children presenting with ankle sprain to the ED. STUDY DESIGN: Children between 7 and 18 years old presenting with ankle sprain composed the study population. Study patients were randomized into 2 study arms: 2.5% ketoprofen gel and placebo administered in a 5-cm area locally. Pain improvements at 15 and 30 minutes were measured by visual analog scale. RESULTS: Median pain reductions at 15 minutes for ketoprofen and placebo groups were 27.5 (16-39) and 5 (4-10), respectively. Median changes in pain intensity at 30 minutes for ketoprofen and placebo gel groups were 48 (43-52) and 9 (6-16), respectively. When compared 2 arms for the pain improvement at 15 and 30 minutes, the differences between 2 study drugs were 20 (13-28) and 35 (29-41), respectively. There were 7 (12.7%) rescue drug needs in the placebo group and 1 (1.7%) in the ketoprofen group (difference, 10.9%; 95% confidence interval, -6% to 7%; P = 0.83). There were no adverse effects in either group. CONCLUSIONS: Ketoprofen gel is superior to placebo in ceasing pain in children presenting with ankle sprain to the ED with a high safety profile.

Medications Used in U.S. Emergency Departments for an Ankle Sprain: An Analysis of the National Hospital Ambulatory Medical Care Survey.

BACKGROUND: An ankle sprain is a common musculoskeletal injury treated in the emergency department. Rest, ice, compression, and elevation is the preferred method for managing the symptoms after an ankle sprain. However, many patients receive a medication, such as a nonsteroidal anti-inflammatory drug (NSAID) or an opioid. OBJECTIVES: We sought to quantify the type of medication(s) used for an ankle sprain and to examine those across age and sex. METHODS: This was a retrospective review of the publicly available data collected through the National Hospital Ambulatory Medical Care Survey from 2006-2015. All cases with an isolated diagnosis of an ankle sprain were identified. Medication listed for each case was classified based on its detailed category and further explored across all 10 years, age, and sex. RESULTS: An estimated 9,052,678 ankle sprain visits occurred in emergency departments from 2006-2015. NSAIDs (56.1%) and opioid analgesic combination (28.4%) were the 2 most common medications. Regardless of the type, most medications were prescribed at discharge. The use of NSAIDs appears to have increased while opioid analgesic combinations decreased in 2010. NSAIDs were the most common medication identified with each age cohort; however, there was no apparent trend in medication for sex. CONCLUSIONS: NSAIDs are the most common medication used for ankle sprain visits to the ED. Nevertheless, an opioid is also used at a relatively high rate for this injury. These findings provide awareness and opportunity to focus on strategies for reduction of opioid use.

National Variation in Opioid Prescribing and Risk of Prolonged Use for Opioid-Naive Patients Treated in the Emergency Department for Ankle Sprains.

STUDY OBJECTIVE: To inform opioid stewardship efforts, we describe the variation in emergency department (ED) opioid prescribing for a common minor injury, ankle sprain, and determine the association between initial opioid prescription intensity and transition to prolonged opioid use. METHODS: We analyzed 2011 to 2015 US private insurance claims (Optum Clinformatics DataMart) for ED-treated ankle sprains among opioid-naive patients older than 18 years. We determined the patient- and state-level variation in the opioid prescription rate and characteristics, and the risk-adjusted association between total morphine milligram equivalents (MMEs) of the prescription and transition to prolonged use (filling 4 or more opioid prescriptions 30 to 180 days after the index visit). RESULTS: A total of 30,832 patients met inclusion criteria. Of these patients, 25.1% received an opioid prescription with a median total MME of 100 (interquartile range 75 to 113), tablet quantity of 15 (interquartile range 12 to 20), and days supplied of 3 (interquartile range 2 to 4). State-level prescribing rates ranged from 2.8% in North Dakota to 40.0% in Arkansas. Among patients who received a total MME of greater than 225 (equivalent to >30 tabs of oxycodone 5 mg), the adjusted rate of prolonged opioid use was 4.9% (95% CI 1.8% to 8.1%) compared with 1.1% (95% CI 0.7% to 1.5%) among those who received at total MME of 75 and 0.5% (95% CI 0.4% to 0.6%) among those who did not fill an opioid prescription. CONCLUSION: Opioid prescribing for ED patients treated for ankle sprains is common and highly variable. Although infrequent in this population, prescriptions greater than 225 MME were associated with higher rates of prolonged opioid use. This is concerning because these prescriptions could still fall within 5- or 7-day supply limit policies aimed at promoting safer opioid prescribing.

Case 18: infected self-harm injury on the left ankle.

This patient, who not only had unstable disease but also a long history of self-harm, presented with an infected malodorous wound filled with soft necrotic tissue and slough. Treatment including octenilin Wound Gel and antibiotics helped kick start the wound towards healing.

Non-steroidal anti-inflammatory drugs (NSAIDs) for treating acute ankle sprains in adults: benefits outweigh adverse events.

PURPOSE: In the recent clinical guideline for acute lateral ankle sprain, the current best evidence for diagnosis, treatment and prevention strategies was evaluated. Key findings for treatment included the use of ice and compression in the initial phase of treatment, in combination with rest and elevation. A short period of taking non-steroidal anti-inflammatory drugs (NSAIDs) may facilitate a rapid decrease in pain and swelling can also be helpful in the acute phase. The objective was to assess the effectiveness and safety of oral and topical NSAID in the treatment for acute ankle sprains. METHODS: Randomised controlled trials comparing oral or topic NSAID treatment with placebo or each other were included. Primary outcome measures were pain at rest or at mobilisation and adverse events. Trials were assessed using the Cochrane risk of bias tool. RESULTS: Twenty-eight studies were included, and 22 were available for meta-analysis. Superior results were reported for oral NSAIDs when compared with placebo, concerning pain on weight bearing on short term, pain at rest on the short term, and less swelling on short- and intermediate term. For topical NSAIDs, superior results compared with placebo were found for pain at rest (short term), persistent pain (intermediate term), pain on weight bearing (short- and intermediate term) and for swelling (short and intermediate term). No trials were included comparing oral with topic NSAIDs, so conclusions regarding this comparison are not realistic. CONCLUSIONS: The current evidence is limited due to the low number of studies, lack of methodological quality of the included studies as well as the small sample size of the included studies. Nevertheless, the findings from this review support the use of NSAIDs for the initial treatment for acute ankle sprains. LEVEL OF EVIDENCE: Meta-analysis of RCTs, Level I.

Analgesia for people with acute ankle sprain.

Around 302,000 people with soft-tissue ankle injuries present to UK emergency departments every year (Ferran and Maffulli 2006). These patients are generally treated conservatively with analgesia, ice, compression and elevation, and rest. There is some discussion in the literature about whether or not people with these injuries should be treated with non-steroidal anti-inflammatory drugs (NSAIDs), with some authors claiming that the inflammatory response following injury is part of the healing process and should not be halted. This article examines the literature on the efficacy of administering NSAIDs as the first-line drug management for ankle sprain. It also considers cost of treatment, prescribing practice and contraindications of NSAIDs.

Recombinant human BMP-2 increases the incidence and rate of healing in complex ankle arthrodesis.

BACKGROUND: Although its FDA-approved applications are limited, the pro-osteogenic benefits of recombinant human BMP-2 (rhBMP-2) administration have been shown in off-label surgical applications. However, the effects of rhBMP-2 on ankle fusions are insufficiently addressed in the literature, which fails to include a case-control study of adequate sample size to evaluate the efficacy of rhBMP-2 treatment. QUESTIONS/PURPOSES: In this study we asked whether rhBMP-2 treatment (1) would increase the rate of successful ankle fusion in complex patients (patients with comorbidities associated with poor surgical healing) compared with a control group of patients undergoing ankle fusion who did not receive rhBMP-2; (2) would reduce total time wearing a frame when compared with the control group; (3) would result in a difference in the percentage of bone bridging between the group treated with rhBMP-2 and the control group, as determined by CT scans 3 months after surgery; and (4) would encounter an equal rate of complications different from untreated patients. METHODS: A retrospective chart study was performed on 82 patients who, because of a host of comorbidities associated with poor healing, required a complex ankle arthrodesis with the Ilizarov technique. The first 40 patients did not receive rhBMP-2, whereas the subsequent 42 patients received intraoperative rhBMP-2. Time wearing the frame was determined by chart review; decision to remove the frame was made by the surgeon based on quantitative bone bridging measured using a CT scan taken 3 months after fusion. RESULTS: Patients treated with rhBMP-2 were more likely to obtain fusion after the initial surgery (93% versus 53%, p < 0.001; OR, 11.76; 95% CI, 3.12-44.41), spent less total time wearing the frame (124 versus 161 days, p < 0.01), and showed more bone bridging on CT scans (48% versus 32%, p < 0.05). All patients with greater than 30% bone bridging observed on CT scans 3 months postoperatively achieved successful union without further intervention. CONCLUSIONS: Our findings suggest that rhBMP-2 is a beneficial adjunct for selected groups of patients undergoing complex ankle arthrodesis. CT is a promising modality in the assessment of bone healing in ankle fusion. A proper randomized controlled trial remains necessary to fully describe the efficacy of rhBMP-2 in accelerating bone healing.

Ultrasound-guided interventions of the foot and ankle.

Ultrasound (US) provides excellent delineation of tendons and ligaments in the foot and ankle and provides real-time visualization of a needle during interventions, yielding greater accuracy and efficacy than the traditional blind approach using anatomical landmarks. For this reason, US is rapidly gaining acceptance as the preferred modality for guiding interventions in the foot and ankle where the anatomy is complex, neurovascular structures should be identified, and precise technique is demanded. In the foot and ankle, US is especially useful to guide tendon sheath, bursal, and Achilles paratenon injections, Morton neuroma injections, plantar fascial injections, and joint aspirations and injections.

Traumeel vs. diclofenac for reducing pain and improving ankle mobility after acute ankle sprain: a multicentre, randomised, blinded, controlled and non-inferiority trial.

BACKGROUND: Acute ankle sprains are common and activity limiting injuries, and topical diclofenac gel has proven efficacy in alleviating pain and restoring function. This trial aimed to compare a topical natural agent, Traumeel with topical diclofenac gel (1%) in the management of acute ankle sprain. METHODS: This prospective, multicentre, randomised, blinded, active-control and non-inferiority study involved 449 physically active adults sustaining unilateral grade 1 or 2 ankle sprain within the past 24 h. Participants were randomised to receive 2 g of Traumeel ointment (T-O) (n = 152) or Traumeel gel (T-G) (n = 150) or diclofenac gel (D-G) (n = 147), administered topically to the ankle three times a day for 14 days, with 6-weeks follow up. RESULTS: Day 7 median percentage reductions in Visual Analogue Scale pain score were 60.6%, 71.1% and 68.9% for the T-O, T-G and D-G groups, respectively. Total pain relief was reported by 12 (8.5%), 7 (5.0%) and 8 (5.9%) participants in each group, respectively. Median improvements in Foot and Ankle Ability Measure Activities of Daily Living subscale score were 26.2, 26.2 and 25.0 points for T-O, T-G and D-G groups, respectively. Mann-Whitney effect sizes and lower bound confidence intervals demonstrated non-inferiority of Traumeel vs. diclofenac for reducing pain and functional improvement. At 6 weeks, participants reported total pain relief and normal functioning. Adverse events (n = 43) were reported by 31/447 participants (6.9%). Treatments were equally well tolerated. CONCLUSIONS: T-O and T-G decreased pain and improved joint function to the same extent as D-G in acute ankle sprain, and were well tolerated.

Efficacy and Safety of the Phytochemical Product Linfadren in the Management of Patients With Persistent Ankle Edema Following Trauma or Surgery: A Randomized Controlled Trial.

BACKGROUND: Persistent posttraumatic/postsurgery ankle edema (PPAE) is edema that persists from 2 weeks to 3 months after injury or surgery. PPAE has negative effects on the healing process and quality of life. This study aimed to evaluate the efficacy of a phytochemical product containing diosmin, coumarin, and arbutin (Linfadren) in addition to the conventional treatment, in patients with PPAE. METHODS: Between October 2018 and February 2020, 60 outpatients with PPAE (42 with ankle fractures and 18 with ankle sprains) were enrolled and randomized (1:1 ratio) to receive either 6-week conventional treatment plus Linfadren (study group) or conventional treatment alone (control group). Primary outcome was ankle edema as measured by the "figure-of-8-20" method. Secondary outcomes were ankle function measured by the Lower Extremity Functional Scale (LEFS), and patient's overall perceived treatment efficacy. Tolerability of Linfadren was also evaluated. Assessments were performed at baseline, at end of treatment (6 weeks after baseline), and 3 months after the end of treatment (follow-up). A subgroup analysis was also conducted for the injury type (fracture/sprain) to identify if this factor affected the results of the primary outcome measure. RESULTS: At the end of treatment, the study group had a significantly greater improvement in ankle edema, improved ankle function, and more patients who considered this treatment effective compared with the control group. The measured difference in circumference by the figure-of-8-20 method averaged 4% at 6 weeks and 5% at 3 months. No difference between groups was seen in rescue medication. No adverse events were recorded. Subgroup analysis revealed no significant influence of the injury type on the primary outcome measure. CONCLUSION: Linfadren in addition to conventional treatment was more effective than conventional treatment alone in patients with PPAE. LEVEL OF EVIDENCE: Level I, randomized controlled trial.

Comparison of intravenous ibuprofen and tenoxicam efficiency in ankle injury: a randomized, double-blind study.

BACKGROUND AND AIM: Pain after soft tissue injuries in and around the ankle is a troublesome process in terms of patient comfort and mobilization. The aim of this study was to compare the analgesic efficacy of intravenous ibuprofen and intravenous tenoxicam in patients with acute musculoskeletal pain due to ankle injury. METHODS: We conducted a prospective, double-blind, randomized controlled study in a tertiary hospital. The patients were divided into two groups as those administered IV 400 mg ibuprofen and IV 20 mg tenoxicam. After the treatment of the patients, visual analog scale (VAS) scores were recorded at 15, 30, 60, and 120 min. VAS scores were compared with the effectiveness of drugs, their side effects, and the need for rescue drugs. RESULTS: One hundred and twenty-four patients were included in the study. There were 62 patients in the tenoxicam group and 62 patients in the ibuprofen group. When VAS scores were compared, it was found that the VAS scores of the ibuprofen group were statistically significantly lower (p < 0.001). When the ΔVAS scores were compared, it was observed that the ΔVAS scores of the ibuprofen group were statistically significantly higher from 30 min (p < 0.001). There was a statistically significant difference in favor of ibuprofen between the two drug groups in terms of the need for rescue analgesics (p < 0.001). Conclusion. The analgesic efficacy of intravenous ibuprofen and tenoxicam is equal after an ankle injury. However, after 30 min of drug administration, ibuprofen provides more effective analgesia than tenoxicam.

Foot and Ankle Injections in Athletes.

CONTEXT: Injections are commonly used by health care practitioners to treat foot and ankle injuries in athletes despite ongoing questions regarding efficacy and safety. EVIDENCE ACQUISITION: An extensive literature review was performed through MEDLINE, Google Scholar, and EBSCOhost from database inception to 2021. Keywords searched were injections, athletes, sports, foot and ankle, corticosteroids, platelet-rich plasma, and placental tissue. Search results included articles written in the English language and encompassed reviews, case series, empirical studies, and basic science articles. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Corticosteroids, platelet-rich plasma/autologous blood, anesthetic, and placental tissue injections are commonly used in the treatment of foot and ankle injuries. Primary indications for injections in athletes include plantar fasciitis, Achilles tendinosis, isolated syndesmotic injury, and ankle impingement with varying clinical results. CONCLUSIONS: Despite promising results from limited case series and comparative studies, the data for safety and efficacy of injections for foot and ankle injuries in athletes remain inconclusive.

A protocol for a randomized clinical trial assessing the efficacy of hypertonic dextrose injection (prolotherapy) in chronic ankle instability.

BACKGROUND: Lateral ankle sprain (LAS) is a common injury. Conservative care is not uniformly effective. Chronic ankle instability (CAI) results in up to 70% of patients with LAS in the physically active population. LAS, together with subsequent osteochondral lesions and pain in many patients, leads to the development of post-traumatic osteoarthritis, resulting in a substantial direct and indirect personal and societal health burden. Dextrose prolotherapy (DPT) is an injection-based therapy for many chronic musculoskeletal conditions but has not been tested for CAI. This protocol describes a randomized controlled trial to test the efficacy of DPT versus normal saline (NS) injections for chronic ankle instability (CAI). METHODS AND ANALYSIS: A single-center, parallel-group, randomized controlled trial will be conducted at a university-based primary care clinic in Hong Kong. A total of 114 patients with CAI will be randomly allocated (1:1) to DPT and NS groups. The primary outcome will be the Cumberland Ankle Instability Tool scores at 1 year. The secondary outcomes will be the number of re-sprains in 1 year, the Star Excursion Balance Test, the 5-level of EuroQol 5-dimension questionnaire, and the Foot and Ankle Ability Measure. All outcomes will be evaluated at baseline and at 16, 26, and 52 weeks using a linear mixed model. DISCUSSION: We hypothesized the DPT is a safe, easily accessible, and effective treatment for patients with CAI. This RCT study will inform whether DPT could be a primary non-surgical treatment for CAI. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000040213 . Registered on 25 November 2020.

Efficacy of paracetamol versus diclofenac for Grade II ankle sprains.

BACKGROUND: Ankle sprains are usually treated with the RICE protocol often with nonsteroidal anti-inflammatory drugs (NSAID) for pain reduction. We evaluated the effect of diclofenac, an NSAID, versus paracematol in the reduction of pain and acute edema of severe ankle sprains. MATERIALS AND METHODS: Ninety patients, 18 to 60 years old, with Grade II acute ankle sprains were randomized into two groups. Group A (45 patients) received for the first 10 days diclofenac 75 mg orally twice per day. Group B (45 patients) received paracetamol 500 mg orally three times per day for the same period. We evaluated ankle joint edema with the Figure-of-Eight method and with the volumetric method, as well as pain with the Visual Analogue Scale (VAS) in both groups. RESULTS: The patients had no significant differences concerning their baseline values (p > 0.05). The ankle joint edema was decreased in both groups (p < 0.001) but there was more edema in group A than in group B at the third post-traumatic day with both measurement methods (p = 0.028/0.025). By the tenth post-traumatic day no difference was found. Pain decreased in both groups at the third day and at the tenth day (p < 0.001). CONCLUSION: According to these results, diclofenac and paracetamol had the same effect on pain reduction of ankle sprains but more acute ankle edema was present in patients who were treated with diclofenac than in patients who were treated with paracetamol.

Diclofenac epolamine plus heparin plaster versus diclofenac epolamine plaster in mild to moderate ankle sprain: a randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase III trial.

BACKGROUND: In general sports, ankle sprain is the most frequently reported ankle injury and can cause chronic lateral ankle pain and tenderness. Treatment with NSAIDs is preferred, and several topical NSAID formulations are now available, helping to avoid the systemic adverse events typically associated with oral preparations. OBJECTIVE: To compare the efficacy and tolerability of a newly developed fixed-dose diclofenac epolamine (diclofenac hydroxyethylpyrrolidine, DHEP)/heparin plaster (Flectoparin® Tissugel) with that of a DHEP (Flector EP Tissugel®) or placebo plaster in the treatment of mild to moderate ankle sprain in adults. METHODS: This was a randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase III study conducted in the emergency medical centres of hospitals or private clinics in Europe. Outpatients aged 18-65 years who had suffered an acute ankle sprain (O'Donoghue grade I or II in severity, with external lateral ligament involvement) within the previous 48 hours and had peri-malleolar oedema were eligible for inclusion. A total of 430 patients were randomized to receive a DHEP/heparin 1.3%/5600 IU (n = 142), DHEP 1.3% (n = 146) or placebo (n = 142) plaster, applied once daily to the injured ankle for a total of 7 days. The primary endpoint was the mean change from baseline in pain on movement on day 3, as measured by a visual analogue scale (VAS). RESULTS: The DHEP/heparin plaster was associated with a significantly (p = 0.002) greater mean reduction from baseline in pain on movement after 3 days of treatment than the DHEP plaster (-24.2 vs -18.8 mm VAS), with each active treatment providing significantly (p ≤ 0.005) greater pain relief than placebo (-13.7 mm VAS). Both DHEP/heparin and DHEP were also effective in relieving other measures of pain, with DHEP/heparin recipients experiencing significantly less daily pain while leaning on the injured limb than DHEP recipients (p < 0.001). In addition, oedema was reduced to a significantly greater extent with DHEP/heparin than with placebo (day 7 only; p = 0.012). The DHEP/heparin plaster and DHEP plaster were both well tolerated, with adverse event profiles similar to that of placebo. Local adverse events were infrequent and generally mild in severity and there were no systemic adverse effects. CONCLUSION: The fixed-dose DHEP/heparin plaster is effective and has advantages over the DHEP plaster in relieving pain, and possibly also swelling, associated with mild to moderate acute ankle sprains with oedema in adults.