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.

Effects of Dangguixu-san in patients with acute lateral ankle sprain: a randomized controlled trial.

BACKGROUND: Dangguixu-san (DS), a herbal extract, is widely used in Korean medicine to treat pain and swelling caused by ankle sprain. However, there is insufficient evidence regarding the effects of DS on ankle sprains. Accordingly, we assessed the efficacy and safety of DS for the treatment of acute lateral ankle sprain (ALAS). METHODS: This study was a multicenter (two Korean hospitals), randomized, double-blind, placebo-controlled, parallel-arm clinical trial with a 1:1 allocation ratio that included a per-protocol analysis and sub-analysis based on symptom severity. Forty-eight participants (n = 28 at Semyung University Korean Medicine Hospital in Chungju; n = 20 at DongShin University Gwangju Korean Medicine Hospital) with grade I or II ALAS that occurred within 72 h before enrollment were randomized to a DS (n = 24) or placebo (n = 24) group. Both groups received acupuncture treatment once daily for 5 consecutive days and the trial medication (DS/placebo capsule) three times a day for 7 consecutive days. Primary (visual analog scale [VAS] scores for pain) and secondary (Foot and Ankle Outcome Scores [FAOS], edema, and European Quality of Life Five-Dimension-Five-Level Scale [EQ-5D-5L] scores) outcome measures were recorded at baseline (week 0), the end of the intervention (week 1), and 4 weeks after treatment completion (week 5). RESULTS: Forty-six participants completed the trial (n = 23 each). Changes in VAS scores, FAOS Symptom/Rigidity, and FAOS Ache from week 1 to week 5 showed significant differences between the two groups. Sub-analyses showed significant differences in changes of FAOS Ache (week 0 to week 5) and VAS scores, total FAOS, and EQ-5D-5L scores (week 1 to week 5) between the two subgroups (grade II). There were no adverse events and significant negative changes in clinical laboratory parameters in both groups. CONCLUSIONS: Overall, the results of this study are in favor of DS combined with acupuncture and suggest that DS combined with acupuncture is a safe treatment with positive long-term effects in terms of pain reduction and symptom alleviation in patients with grade I or II ALAS. TRIAL REGISTRATION: Clinical Research Information Service KCT0002374 . Registered on July 11, 2017; retrospectively registered.

Regeneration of grade 3 ankle sprain, using the recombinant human amelogenin protein (rHAM+ ) in a rat model.

Lateral ligament tears, also known as high-grade ankle sprains, are common, debilitating, and usually heal slowly. Ten to thirty percent of patients continue to suffer from chronic pain and ankle instability even after 3 to 9 months. Previously, we showed that the recombinant human amelogenin (rHAM+ ) induced regeneration of fully transected rat medial collateral ligament, a common proof-of-concept model. Our aim was to evaluate whether rHAM+ can regenerate torn ankle calcaneofibular ligament (CFL), an important component of the lateral ankle stabilizers. Right CFLs of Sabra rats were transected and treated with 0, 0.5, or 1 µg/µL rHAM+ dissolved in propylene glycol alginate (PGA). Results were compared with the normal group, without surgery. Healing was evaluated 12 weeks after treatment by mechanical testing (ratio between the right and left, untransected ligaments of the same rat), and histology including immunohistochemical staining of collagen I and S100. The mechanical properties, structure, and composition of transected ligaments treated with 0.5 µg/µL rHAM+ (experimental) were similar to untransected ligaments. PGA (control) treated ligaments were much weaker, lax, and unorganized compared with untransected ligaments. Treatment with 1 µg/µL rHAM+ was not as efficient as 0.5 µg/µL rHAM+ . Normal arrangement of collagen I fibers and of proprioceptive nerve endings, parallel to the direction of the force, was detected in ligaments treated with 0.5 µg/µL rHAM+ , and scattered arrangement, resembling scar tissue, in control ligaments. In conclusion, we showed that rHAM+ induced significant mechanical and structural regeneration of torn rat CFLs, which might be translated into treatment for grades 2 and 3 ankle sprain injuries.

Effects of Dangguixu-san on acute lateral ankle sprain: study protocol for a randomized controlled trial.

BACKGROUND: Ankle sprain is a common musculoskeletal injury. In Korean medicine, blood stasis is thought to be the main cause of pain and swelling in patients with ankle sprain. Dangguixu-san (DS), a herbal extract, is widely used in Korean medicine for the treatment of traumatic ecchymosis and pain by promoting blood circulation and relieving blood stasis. However, the effects of DS on ankle sprain have not been evaluated in a randomized clinical trial. Here, we describe the protocol for a randomized controlled trial that will evaluate the efficacy and safety of DS for the treatment of ankle sprain. METHODS/DESIGN: In this randomized, double-blinded, placebo-controlled, parallel-arm clinical trial with a 1:1 allocation ratio, participants (n = 48) with acute lateral ankle sprain (ALAS) that occurred within 72 h before enrollment will be randomly assigned to a DS (n = 24) or a placebo (n = 24) group. Both groups will receive acupuncture treatment once a day for 5 days a week (excluding Saturday and Sunday) and the trial medication (DS/placebo capsule) three times a day for seven consecutive days. The primary outcome measure will be pain relief evaluated using a Visual Analog Scale (VAS). Secondary outcome measures will include Foot and Ankle Outcome Scores (FAOS), edema, European Quality of Life Five-Dimension-Five-Level Scale (EQ-5D-5 L) scores, and the number of recurrent ankle sprains. VAS, FAOS, edema, and EQ-5D-5 L scores will be recorded before, at the end of, and at 4 weeks after treatment completion. EQ-5D-5 L scores will be additionally recorded at 26 weeks after treatment completion. The number of recurrent ankle sprains will be recorded at 4, 8, 12, and 26 weeks after treatment completion. DISCUSSION: This study is expected to provide evidence regarding the efficacy, safety, and usefulness of DS for the treatment of ALAS. TRIAL REGISTRATION: cris.nih.go.kr, registration number: KCT 0002374 . Registered on 11 July, 2017 and approved by the Ministry of Food and Drug Safety (registration number, 31244).

[Efficacy of Shangbai ointment in alleviating pain in patients with acute ankle joint lateral collateral ligament injury: a randomized controlled trial].

OBJECTIVE: To investigate the effect of Shangbai ointment in relieving pain in patients with acute ankle joint lateral collateral ligament injury. METHODS: Fifty patients with unilateral ankle injury were randomized into Shangbai ointment treatment group and control group (n=25). The Visual Analog Scale (VAS) pain scores, ankle joint circumference, Kofoed score and self-rated lower limb function were recorded before and at 3, 7, and 14 days after the treatment. RESULTS: The baseline data were comparable between the two groups. The VAS pain score and swelling elimination in the treatment group were better than those in the control group at 3, 7, and 14 days after treatment; the Kofoed ankle score was higher in the treatment group than in the control group at 7 and 14 days after treatment. The patients in the treatment also reported better self-rated lower limb function than those in the control group at 7 and 14 days after the treatment. CONCLUSION: Shangbai ointment treatment can rapidly relieve pain in patients with acute ankle joint lateral collateral ligament injury and improve the functional scores of the joint.

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.

Iridoid glycosides from Gardeniae Fructus for treatment of ankle sprain.

The iridoid glycosides, genipin 1-O-beta-D-isomaltoside (1) and genipin 1,10-di-O-beta-D-glucopyranoside (2), together with six known iridoid glycosides, genipin 1-O-beta-D-gentiobioside (3), geniposide (4), scandoside methyl ester (5), deacetylasperulosidic acid methyl ester (6), 6-O-methyldeacetylasperulosidic acid methyl ester (7), and gardenoside (8) were isolated from an EtOH extract of Gardeniae Fructus. The structures and relative stereochemistries of the metabolites were elucidated on the basis of 1D- and 2D-NMR spectroscopic techniques, high-resolution mass spectrometry, and chemical evidence. Geniposide (4), one of the main compounds of Gardeniae Fructus, was tested for treatment of ankle sprain using an ankle sprain model in rats. From the second to fifth day, the geniposide (4) (100mg/ml) treated group exhibited significant differences (p<0.01) with approximately 21-34% reduction in swelling ratio compared with those of the vehicle treated control group. This indicated the potential effect of geniposide (4) for the treatment of disorders such as ankle sprain.

High-resolution ultrasound and magnetic resonance imaging to document tissue repair after prolotherapy: a report of 3 cases.

High-resolution ultrasound imaging of musculoskeletal tissue is increasing in popularity because of patient tolerability, low cost, ability to visualize tissue in real-time motion, and superior resolution of highly organized tissue such as a tendon. Prolotherapy, defined as the injection of growth factors or growth factor production stimulants to grow normal cells or tissue, has been a controversial procedure for decades; it is currently gaining in popularity among physiatrists and other musculoskeletal physicians. This report describes imaging of tendons, ligaments, and medial meniscus disease (from trauma or degeneration). Although these tissues have been poorly responsive to nonsurgical treatment, it is proposed that tissue growth and repair after prolotherapy in these structures can be documented with ultrasound and confirmed with magnetic resonance imaging. Directions for future research application are discussed.

An in vivo and in vitro potential of Indian ayurvedic herbal formulation Triphala on experimental gouty arthritis in mice.

In the present study, we have investigated the efficacy of Indian ayurvedic herbal formulation Triphala on monosodium urate crystal-induced inflammation in mice; an experimental model for gouty arthritis and compared it with that of the non-steroidal anti-inflammatory drug, Indomethacin. The anti-arthritic effect of Triphala was evaluated by measuring changes in the paw volume, lysosomal enzyme activities, lipid peroxidation, anti-oxidant status and inflammatory mediator TNF-alpha in control and monosodium urate crystal-induced mice. The levels of beta-glucuronidase and lactate dehydrogenase were also measured in monosodium urate crystal-incubated polymorphonuclear leucocytes (PMNL). Triphala treatment (1 gm/kg/b.w. orally) significantly inhibited the paw volume and the levels of lysosomal enzymes, lipid peroxidation and inflammatory mediator tumour necrosis factor-alpha; however the anti-oxidant status was found to be increased in plasma, liver and spleen of monosodium urate crystal-induced mice when compared to control mice. In addition, beta-glucuronidase and lactate dehydrogenase level were reduced in Triphala (100 microg/ml) treated monosodium urate crystal-incubated polymorphonuclear leucocytes. In conclusion, the results obtained clearly indicated that Triphala exerted a strong anti-inflammatory effect against gouty arthritis.

Industrial medicine and acute musculoskeletal rehabilitation. 2. Medications for the treatment of acute musculoskeletal pain.

UNLABELLED: This self-directed learning module highlights medications used in the treatment of acute musculoskeletal pain in the context of industrial rehabilitation. It is part of the study guide on industrial rehabilitation medicine and acute musculoskeletal rehabilitation in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article compares various skeletal muscle relaxants, addresses issues related to nonsteroidal anti-inflammatory medications, provides an algorithm for acute pain management in an injured worker, and discusses topical medications for the treatment of pain. OVERALL ARTICLE OBJECTIVE: To summarize medication options in the treatment of acute musculoskeletal pain in the setting of injured workers.

Efficacy of a comfrey root extract ointment in comparison to a diclofenac gel in the treatment of ankle distortions: results of an observer-blind, randomized, multicenter study.

In the treatment of minor blunt injuries several topical drugs are known to have anti-inflammatory and analgesic properties. They represent, however, two fundamentally different major pharmacological therapy approaches: the "chemical-synthetical" and the "phytotherapeutical" approach. The main objective of this trial (CODEC_2004) was to compare the efficacy and tolerability of an ointment of Comfrey extract (Extr. Rad. Symphyti) with that of a Diclofenac gel in the treatment of acute unilateral ankle sprain (distortion). In a single-blind, controlled, randomized, parallel-group, multicenter and confirmatory clinical trial outpatients with acute unilateral ankle sprains (n=164, mean age 29.0 years, 47.6% female) received either a 6 cm long ointment layer of Kytta-Salbe f (Comfrey extract) (n=82) or of Diclofenac gel containing 1.16 g of diclofenac diethylamine salt (n=82) for 7 +/- 1 days, four times a day. Primary variable was the area-under-the-curve (AUC) of the pain reaction to pressure on the injured area measured by a calibrated caliper (tonometer). Secondary variables were the circumference of the joint (swelling; figure-of-eight method), the individual spontaneous pain sensation at rest and at movement according to a Visual Analogue Scale (VAS), the judgment of impaired movements of the injured joint by the method of "neutral-zero", consumption of rescue medication (paracetamol), as well as the global efficacy evaluation and the global assessment of tolerability (both by physician and patient, 4 ranks). In this study the primary variable was also to be validated prospectively. It was confirmatorily shown that Comfrey extract is non-inferior to diclofenac. The 95% confidence interval for the AUC (Comfrey extract minus Diclofenac gel) was 19.01-103.09h*N/cm2 and was completely above the margin of non-inferiority. Moreover, the results of the primary and secondary variables indicate that Comfrey extract may be superior to Diclofenac gel.

Efficacy and tolerance of a comfrey root extract (Extr. Rad. Symphyti) in the treatment of ankle distorsions: results of a multicenter, randomized, placebo-controlled, double-blind study.

Comfrey (Symphytum officinale L.) is a medicinal plant with anti-inflammatory, analgesic and tissue regenerating properties. In a double-blind, multicenter, randomized, placebo-controlled, group comparison study on patients suffering from unilateral acute ankle sprains (n = 142, mean age 31.8 years, 78.9% male), the percutaneous efficacy of an ointment of comfrey extract (Kytta-Salbe f, four treatments per day for 8 days) was confirmed decisively. Compared to placebo, the active treatment was clearly superior regarding the reduction of pain (tonometric measurement, p<0.0001, as the primary efficacy variable) and ankle edema (figure-of-eight method, p = 0.0001). Statistically significant differences between active treatment and placebo could also be shown for ankle mobility (neutral zero method), and global efficacy. Under active treatment, no adverse drug reactions were reported. The good local and global tolerance of the trial medication could also be confirmed. The study results are consistent with the known pre-clinical and clinical data concerning comfrey.

A double blind, randomised, parallel group study on the efficacy and safety of treating acute lateral ankle sprain with oral hydrolytic enzymes.

OBJECTIVE: To compare the effectiveness and safety of the triple combination Phlogenzym (rutoside, bromelain, and trypsin) with double combinations, the single substances, and placebo. DESIGN: Multinational, multicentre, double blind, randomised, parallel group design with eight groups structured according to a factorial design. SETTING: Orthopaedic surgery and emergency departments in 27 European hospitals. PARTICIPANTS: A total of 721 patients aged 16-53 years presenting with acute unilateral sprain of the lateral ankle joint. PRIMARY EFFICACY CRITERIA: (a) Pain on walking one or two steps, as defined by the patient on a visual analogue scale. (b) The range of motion, as measured by the investigator and expressed as a sum of flexion and extension. (c) The volume of the injured ankle measured with a volometer. RESULTS: At the primary end point at seven days, the greatest reduction in pain was in the bromelain/trypsin group (73.7%). The Phlogenzym group showed a median reduction of 60.3%, and the placebo group showed a median reduction of 73.3%. The largest increase in range of motion (median) was in the placebo group (60% change from baseline). The Phlogenzym group showed a median increase of 42.9%. The biggest decrease in swelling was in the trypsin group (3.9% change from baseline). The Phlogenzym group showed a -2.30% change from baseline and the placebo group a -2.90% change. In the subgroup analysis of patients who did not use a Caligamed brace, Phlogenzym was superior to placebo for the summarising directional test of the primary efficacy criteria (MW = 0.621; LB-CI 0.496; p = 0.029; one sided Wei-Lachin procedure). The vast majority of doctors and patients rated the tolerability of all treatments tested as very good or at least good. CONCLUSIONS: Phlogenzym was not found to be superior to the three two-drug combinations, the three single substances, or placebo for treatment of patients with acute unilateral sprain of the lateral ankle joint. The small subgroup of patients treated without the support of a Caligamed brace showed evidence of superiority of Phlogenzym over placebo. Further research is warranted to study this effect of Phlogenzym in patients treated without ankle support.

Efficacy and safety of topically applied Symphytum herb extract cream in the treatment of ankle distortion: results of a randomized controlled clinical double blind study.

In a controlled, double blind, randomized multicentre study, the efficacy and safety of the topical comfrey product Traumaplant (10% active ingredient of a 2.5:1 aqueous ethanolic pressed juice of freshly harvested, cultivated comfrey herb (Symphytum x uplandicum NYMAN), corresponding to 25 g of fresh herb per 100 g of cream; n = 104) was tested against a 1% product (corresponding to 2.5 g of fresh comfrey herb in 100 g of cream; n = 99) in 203 patients with acute ankle distortion. With the high concentration, decrease of the scores for pain on active motion, pain at rest and functional impairment was highly significant and clinically relevant on days T3-4 as well as T7 (p < 0.001). Amelioration of swellings as compared to reference was also significant on day 3-4 (p < 0.01). Efficacy was judged good to excellent in 85.6% of cases with verum and in 65.7% of cases with reference on day 3-4. Overall tolerability was excellent.

Cure of orthopaedic infection with Scedosporium prolificans, using voriconazole plus terbinafine, without the need for radical surgery.

Scedosporium prolificans infections of normal hosts usually require extensive debridement and sometimes amputation to effect cure, due to the intrinsic resistance of this species to available antifungal agents. Newer agents have not tested favourably. Variable results are obtained with voriconazole, and 100% resistance is described with echinocandins. Itraconazole and terbinafine has offered synergy against various moulds including S. prolificans. In vivo success is reported with the azole/terbinafine combination in S. apiospermum pulmonary infection and Pythium insidiosum periorbital cellulitis. We report a case of orthopaedic infection in a non-immunocompromised host with S. prolificans, in which the combinations of itraconazole/terbinafine and voriconazole/terbinafine showed synergy in vitro, and success was achieved without radical surgery, using voriconazole and terbinafine.

Efficacy of celecoxib versus ibuprofen in the treatment of acute pain: a multicenter, double-blind, randomized controlled trial in acute ankle sprain.

Ankle sprain is a common acute soft-tissue injury that often results in pain, inflammation, and ecchymosis. In this multicenter, double-blind, randomized parallel-group study, 445 adult patients received celecoxib 400 mg/day, ibuprofen 2,400 mg/day, or placebo for 10 days. Patients had experienced grade 1 or 2 ankle sprains within 48 hours and had moderate to severe ankle pain. Patient's Global Assessment of Ankle Injury responses, given on days 4 and 8, showed that the celecoxib group improved significantly more than the placebo group did, with 67% of the celecoxib group versus 55% of the placebo group improving at day 4 (P < .05). Patient's Assessment of Ankle Pain Visual Analog Scale on Weight Bearing responses, also given on days 4 and 8, showed that celecoxib was as efficacious in the treatment of ankle sprain as the maximum therapeutic dosage of ibuprofen and that, compared with placebo, it reduced pain significantly more (P < .05). The celecoxib group recovered and returned to function earlier (after 5 days) than did either the placebo group (8 days) or the ibuprofen group (6 days); the celecoxib-placebo difference was significant. Celecoxib, a cyclo-oxygenase-2-specific inhibitor with platelet-function-sparing properties, may be useful as a multimodal adjuvant in the treatment of ankle sprain.