Managing Refractor Tendinopathy: Topical Glyceryl Trinitrate

In February 2019 the BMJ published a review of topical nitroglycerin or glyceryl trinitrate (TGN) for the treatment of tendinopathies which I think is worth reviewing [1]. Tendinopathies account for up to 30% of an orthopedic or sports medicine practice. Patients typically present with pain and swelling at the affected tendon with a clear history of overuse from repetitive microtrauma, although acute injuries do occur. Tendinitis refers to acute injuries where inflammation of the tendon results in micro-tears that happen when the musculotendinous unit is acutely overloaded with a tensile force that is too heavy and/or too sudden [3]. Tendinosis is a degeneration and remodeling of the tendon’s collagen in response to chronic overuse; when overuse is continued without giving the tendon time to heal and rest, such as with repetitive strain injury. Although there is a lack of clear consensus, tendinitis can be thought of as an acute injury lasting up to 6 weeks, at which time histological changes are occuring, the tendon begins to remodel and the transition to tendinosis or tendinopathy begins to occur.

Because of the high incidence of tendinopathies, lets briefly review the current understanding of its pathophysiology. Tendons are designed to withstand considerable loads. At the histological level, changes include reduced numbers and rounding of fibroblasts, increased content of proteoglycans, glycosaminoglycans and water, hypervascularization and disorganized collagen fibrils. At the molecular level, upregulation of RNA for type I and III collagens, proteoglycans, angiogenic factors, stress and regenerative proteins and proteolytic enzymes occurs. Additionally, tendon microrupture and material fatigue have been suggested as possible injury mechanisms [2]. Inadequate rest likely contributes to collagen loss and vulnerability. Neovascularization occurs and the entire process can be accelerated by overloading. Despite this information, complete understanding of this pathogenesis remains unclear.

It is important to understand the distinction between tendinitis and tendinosis because these diseases require different treatment modalities and approaches by the clinician. Initial treatments generally include physical therapy, especially eccentric exercises and soft tissue modalities, oral and topical medications and corticosteroids. In cases where the patient has evolved to the more chronic tendinosis, treatment is often more challenging frustrating to both the patient and the physician. The purpose of this series is to review options for chronic, refractory tendinosis

One modality that may be helpful in treating refractory tendinosis is topical glyceryl trinitrate or TGN. The first use of this was reported in 1996 by Berrazueta et al successfully treating supraspinatus tendinitis. Nitroglycerin works by forming free radical NO molecules, leading to increased cyclic GMP, and subsequent smooth muscle relation. In patients with acute coronary syndrome, this vasodilatory effect can help reduce myocardial ischemia. In tendinopathies, where NO is known to be upregulated in mouse models, it may help relax collagen fibers. However, the exact role of NO in the pathologic and healing process of tendinopathies is yet to be established. One theory is that NO stimulates new collagen synthesis.

Challoumas et al were able to review 10 randomized clinical trials investigating nitroglycerin and tendinopathies: 4 for the rotator cuff, 3 for wrist extensors, 2 for achilles and 1 for patellar tendon. Although the evidence in the individual studies were not great, all of them reported improved pain with topical GTN compared to placebo. Across studies, GTN was superior to placebo for: patient satisfaction (strong evidence); chances of being asymptomatic with activities of daily living (strong evidence); range of movement (moderate evidence); strength (moderate evidence); pain (at night and with activity; poor evidence) and local tenderness (poor evidence).

One consistent adverse effect was headaches, something commonly seen when nitroglycerin is given for angina. The other side effect most patients report is skin rash. The medication should be avoided in patients on other nitrate medications (nitroglycerin for angina, sildenafil, etc), chronic hypotension, headache disorders, rosacea, head injuries or severe anemia. There are no clear guidelines on dosing however most trials either use one-fourth or one-half of a 5 mg/24-hour or 10 mg/24-hour patch left on continuously for 24 hours applied to the affected area.

In their systematic review, the authors concluded that “this systematic review provide good evidence for the effectiveness of topical GTN for the treatment of tendinopathies compared with placebo in the short and intermediate term (<6 months)” [1]. Thus it can be stated with some degree of confidence that topical GTN has a role in treatment tendinopathies, and especially the more refractory and challenging tendinosis we see regularly. Topical GTN is fairly inexpensive and relatively safe, further supporting its utilization. Additional high quality studies needed to further investigate the broader applications of GTN on other tendinitis and tendinosis diseases but the early research is favorable.

References

[1] Challoumas D, Kirwan PD, Borysov D, et al. Topical glyceryl trinitrate for the treatment of tendinopathies: a systematic review. British Journal of Sports Medicine 2019;53:251-262

[2] Magnusson SP, Langberg H, Kjaer M. The pathogenesis of tendinopathy: balancing the response to loading. Nat Rev Rheumatol. 2010 May;6(5):262-8. Doi: 10.1038/nrrheum.2010.43. Epub 2010 Mar 23. Review. PubMed PMID: 20308995.

[3] Bass E. Tendinopathy: why the difference between tendinitis and tendinosis matters. Int J Ther Massage Bodywork. 2012;5(1):14-7. Epub 2012 Mar 31. PubMed PMID: 22553479; PubMed Central PMCID: PMC3312643.

[4] Khan KM, Cook JL, Taunton JE, Bonar F. Overuse tendinosis, not tendinitis part 1: a new paradigm for a difficult clinical problem. Phys Sportsmed. 2000 May;28(5):38-48. doi: 10.3810/psm.2000.05.890. PubMed PMID: 20086639.

[5] Berrazueta, José Ramón, et al. "Successful treatment of shoulder pain syndrome due to supraspinatus tendinitis with transdermal nitroglycerin. A double blind study." Pain 66.1 (1996): 63-67.



