Topical Glyceryl Trinitrate (GTN) and Eccentric Exercises in the Treatment of Midportion Achilles Tendinopathy

Condition(s) targeted: Tendinopathy; Achilles Tendinopathy

Intervention: glyceryl trinitrate (Drug); Placebo Patch (Other); Eccentric exercise program (Other)

Phase: N/A

Status: Not yet recruiting

Sponsored by: Royal College of Surgeons, Ireland

Official(s) and/or principal investigator(s):
Helen French, PhD, Study Director, Affiliation: Royal College of Surgeons, Ireland
Trevor Duffy, MD, MBA, Study Director, Affiliation: Connolly Hospital, Dublin 15, Ireland

Overall contact:
Paul D Kirwan, BSc, MSc, Phone: 0879219611, Email: paulkirwan@rcsi.ie

The primary objective of this research is to determine if the addition of topical GTN over 24 weeks to a 12 week exercise programme improves clinical outcomes more than placebo GTN for people with Achilles Tendinopathy. Pain in the Achilles tendon is a common condition seen by physiotherapists and doctors. It affects people involved in sports and those who are not. It can limit the ability to walk, hop, jump and run. If the pain persists for longer than 3 months it can become extremely difficult to abolish. As a result, people with this common condition can suffer from prolonged pain and often the pain will persist and affect everyday activities. While this is an easy injury to diagnose, it is not so easy to treat. Many treatments do exist, but often just provide short-term relief until the pain returns. Specific strengthening exercises have been shown to be beneficial in treating this condition. The current project will study Achilles tendon pain in Irish adults at Connolly Hospital, Dublin, and will take place from 2015 to 2019. In this study, there are two groups of patients. Both groups will perform an exercise program for 12 weeks. Physiotherapists will instruct them on how to perform the exercises. Each group will be given a patch to place on the sore tendon. This patch will be replaced daily for 6 months with a new patch. One group will use a patch containing nitroglycerin, the other group will use a patch with no active ingredient. This is called a placebo patch. The patients will change the patch daily for 6 months. The patients will be assessed at the start of the program and after 6, 12 and 24 weeks. Our main question is to see whether this exercise program when combined with a nitroglycerin patch placed directly over the sore tendon can improve the outcomes and recovery time for people who suffer with Achilles tendon pain.

Official title: The Use of Topical Glyceryl Trinitrate (GTN) and Eccentric Exercises in the Treatment of Midportion Achilles Tendinopathy: a Randomized Placebo Controlled Trial

Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome:

VISA A, Victoria Institute of Sport Assessment - Achilles

VISA A, Victoria Institute of Sport Assessment - Achilles

VISA A, Victoria Institute of Sport Assessment - Achilles

Secondary outcome:

Lower Extremity Functional Scale (LEFS)

Pain Detection Threshold, PDT using pressure algometry

Ultra sound measure of Achilles thickness

Numeric Rating Scale (NRS) for pain

Star Excursion Balance Test (SEBT)

Heel raise for endurance

Heel raise for endurance

Hopping tests

Hopping tests

Detailed description: Study Design The study will be designed to meet CONSORT guidelines. A randomized placebo controlled trial will be carried out at the Physiotherapy Department of Connolly Hospital, Blanchardstown, Dublin 15. The study will be conducted on patients who present to the department with a diagnosis of Achilles tendinopathy. The diagnosis will be confirmed based on a history of an insidious onset of Achilles tendon pain, a tender nodule/thickening of the tendon to the region 2 to 6cm from the calcaneal insertion, and an ultrasound examination that excludes a frank tear. Participants will be randomly allocated to one of 2 groups. Group 1 will receive GTN for 24 weeks in combination with a supervised eccentric exercise programme delivered over 12 weeks. Group 2 will receive placebo GTN in addition to the same exercise programme. Ethical Considerations Ethics approval will be sought from Connolly Hospital Research and Ethics Committee. All participants will give written informed consent. At the patient's initial assessment, the following will be completed

- Outcome measure questionnaires - Victorian Institute of Sport Assessment-Achilles

(VISA-A), Lower Extremity Functional Scale (LEFS), Numeric Rating Scale for pain (NRS)

- Assessment of Achilles tendon tenderness using pressure algometry

- Ultra-sound assessment of the Achilles tendon - tendon thickness measurements

- Proprioception testing (modified Star Excursion Balance Test)

- Simple strength tests of the Achilles, Hopping and heel raises

It is anticipated that the baseline assessment will take 60-75 minutes to complete. The follow-up assessment should take no more than 45 minutes to complete. Outcome Measures All outcomes will be administered at baseline, and at week 6, 12 and 24 by the principal investigator. Data on adverse effects, compliance with the patch application and the exercise program will be recorded at these scheduled visits. Upon completion of the initial assessment by the principal investigator, participants will be scheduled to have their first exercise intervention session with one of the physiotherapists in Connolly Hospital. The treating physiotherapists will be trained in the exercise protocol and will be blinded to the type of GTN patch provided to the patient. This appointment will be scheduled within one week of the lead investigator's assessment. This tendon rehabilitation program is designed to encompass current methods of non-operative treatment of Achilles tendinopathy (Paoloni et al, 2004) and will involve the following:

- Instruction in performance of the Alfredson heavy load eccentric exercise program.

- Patients will be advised to avoid weight bearing sporting activities for the first 4 to

6 weeks, after which time gradual return to sports will be encouraged. Participation in sports will be continued so long as the pain does not increases above NRS>3 and no increase in Achilles morning stiffness is experienced.

- Instruction in the performance of daily static stretches of the gastrocnemius and

soleus muscle groups

- Patients will be advised to avoid the use of co-interventions or complimentary

treatments for the duration of the study. Exercise interventions: Participants will be instructed on how to perform the Alfredson heavy load eccentric exercise protocol (Alfredson, 1998) by the physiotherapists in Connolly Hospital. This will be performed during their first treatment session, which will take place approximately one week after the initial assessment. The participants will be given practical instructions and a written manual on the exercise program, which will include advice on progression of the exercise regimen. Topical nitroglycerin patches (GTN) Two types of trans-dermal patches will be used in the study, active and placebo patches. The active trans-dermal patches to be used in this trial (Nitrodur) deliver 5mg of GTN over a 24-hour period. The placebo patch will be a demonstration/sample patch but will have no active component. Patients will be advised to use this patch daily for 24 hours in the same fashion as the active patches. The patches will be cut into quarters. Thus the active GTN patches will contain 1. 25mg of GTN. Participants will be instructed in the use of the patches during their initial visit with the lead investigator. They will be informed that the dosing regimen calls for one quarter patch to be applied to the painful area of the Achilles tendon and left in situ for 24 hours. This will then be discarded and replaced with a new patch. Participants will be advised to apply the patch to the site of maximal tenderness within a region of 1-2 cm around this point. The participants will be advised to rotate the patch about the site of maximal tenderness on a regular basis for the six-month duration of the study in an effort to minimize irritation of the skin.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Current diagnosis of Achilles tendinopathy 2. 18 years of age and old 3. Achilles pain of 3 months or more 4. Mid-portion Achilles tenderness and thickening on palpation Exclusion Criteria: 1. Previous corticosteroid injection to the affected tendon in the past 3 months 2. Symptoms of less than 3 months duration 3. Previous use of topical GTN for Achilles tendinopathy 4. Contra-indication to GTN therapy 5. Current pregnancy, breastfeeding or planning pregnancy 6. VISA-A score > 80 7. Previous surgery to the affected Achilles tendon 8. Seronegative spondyloarthropathy with Achilles enthesitis 9. Previous performance of a heavy load eccentric exercise program of the Achilles in the last 6 months 10. Inability to perform the exercise program due to serious illness, such as unstable angina/blood pressure, myocardial infarction in past three months, cardiomyopathy, uncontrolled metabolic disease, recent ECG changes, advanced respiratory disease or third degree heart block. 11. Staff or students of Connolly Hospital, Blanchardstown.

Paul D Kirwan, BSc, MSc, Phone: 0879219611, Email: paulkirwan@rcsi.ie

Related publications:

Paoloni JA, Appleyard RC, Nelson J, Murrell GA. Topical glyceryl trinitrate treatment of chronic noninsertional achilles tendinopathy. A randomized, double-blind, placebo-controlled trial. J Bone Joint Surg Am. 2004 May;86-A(5):916-22.

Alfredson H, Pietilä T, Jonsson P, Lorentzon R. Heavy-load eccentric calf muscle training for the treatment of chronic Achilles tendinosis. Am J Sports Med. 1998 May-Jun;26(3):360-6.

Robinson JM, Cook JL, Purdam C, Visentini PJ, Ross J, Maffulli N, Taunton JE, Khan KM; Victorian Institute Of Sport Tendon Study Group. The VISA-A questionnaire: a valid and reliable index of the clinical severity of Achilles tendinopathy. Br J Sports Med. 2001 Oct;35(5):335-41.

Tumilty S, McDonough S, Hurley DA, Baxter GD. Clinical effectiveness of low-level laser therapy as an adjunct to eccentric exercise for the treatment of Achilles' tendinopathy: a randomized controlled trial. Arch Phys Med Rehabil. 2012 May;93(5):733-9. doi: 10.1016/j.apmr.2011.08.049.

Binkley JM, Stratford PW, Lott SA, Riddle DL. The Lower Extremity Functional Scale (LEFS): scale development, measurement properties, and clinical application. North American Orthopaedic Rehabilitation Research Network. Phys Ther. 1999 Apr;79(4):371-83.

Hertel J, Braham RA, Hale SA, Olmsted-Kramer LC. Simplifying the star excursion balance test: analyses of subjects with and without chronic ankle instability. J Orthop Sports Phys Ther. 2006 Mar;36(3):131-7.

Silbernagel KG, Gustavsson A, Thomeé R, Karlsson J. Evaluation of lower leg function in patients with Achilles tendinopathy. Knee Surg Sports Traumatol Arthrosc. 2006 Nov;14(11):1207-17. Epub 2006 Jul 21.

Silbernagel KG, Thomeé R, Thomeé P, Karlsson J. Eccentric overload training for patients with chronic Achilles tendon pain--a randomised controlled study with reliability testing of the evaluation methods. Scand J Med Sci Sports. 2001 Aug;11(4):197-206.

Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin Nurs. 2005 Aug;14(7):798-804. Review.

Starting date: August 2015
Last updated: July 13, 2015