Tendinopathy, a broad term used to describe disorders in and around tendons,1,2 is associated with repetitive tensile forces exerted on tendons.3-5 Rapid increases in the duration and intensity of these forces may cause tendon injuries,6possibly the starting point in the pathogenesis of chronic tendinopathy. The exact incidence of chronic tendinopathy is unknown given the vast population of professional and recreational athletes suffering from this condition at different anatomic sites. Studies on incidence of tendinopathies are usually site7 or sport8 specific, and only provide an approximation of the magnitude of the problem faced by musculoskeletal and sports medicine clinicians in treating this disorder. In addition, a large number of sedentary subjects develop tendinopathy with no apparent history of increased physical activity.
Disorganized, haphazard healing, with frayed, separated, and otherwise disrupted collagen fibrils, are features of tendinopathy.3,9 These lesions are characterized by the absence of inflammatory cells and a poor healing response.1,9 Age-related tendon changes, and not just mechanical overload, may thus play a role in the pathogenesis of tendinopathy, although the exact etiologic, pathophysiologic, and healing mechanisms are still unknown.5,10
Gene expression studies have shown an absence of any inflammatory process in chronic Achilles tendinopathy.11Microdialysis experiments have shown no evidence of intratendinous chemical inflammation, with prostaglandin E2(PGE2) levels being normal in chronic tendinopathies.12Microdialysis has also shown higher levels of glutamate, an excitatory neurotransmitter and a potent modulator of pain in the central nervous system,13 in tendinopathic tendons compared with normal tendons.12,14 The same technique reveals that the local concentration of lactate in the tendinopathic Achilles tendon is almost twice that of the normal Achilles tendon.15
It is possible that there is an ischemic component in the pathogenesis of tendinopathy. Ischemia may precede the start of tendinopathy, but examination of tendinopathic lesions reveals neovascularization16 and increased blood flow in the affected area of the tendon.17 Neovascularization may be a response to a primary injury or may be the result of a metabolic disorder. It is possible that anaerobic conditions exist in areas of tendinopathy that have a poor blood supply, and are the primary cause of neovascularization.15Neovessels and their accompanying nerves, may be responsible for the pain in the tendinopathic tendon,18 which would account for the success of local injection of sclerosants such as Polidocanol in the management tendinopathy.18
Chronic tendinopathy may well be the final manifestation of a long-standing metabolic process in which inflammation, although an initiator, does not participate in the final histopathologic and biochemical features of chronic tendinopathy. It is important in understanding this hypothesis to recall the mechanism of tendon healing. A tendon heals by undergoing inflammatory (1-7 days of injury), proliferative (7-21 days), and remodeling (3 weeks-1 year) phases.3,19Despite collagen maturation and remodeling, tendons are biochemically and metabolically less active than bone and muscle.3,19 Type III collagen synthesized by fibroblasts in the proliferative phase is gradually replaced by type I collagen from days 12 to 14, with a progressive increase in tensile strength.3
In a rat Achilles tendinopathy model, different populations of inflammatory cells, such as neutrophils and macrophages, accumulate immediately after injury,20 followed by a further macrophage accumulation 1 to 3 days after injury.20Nonsteroidal antiinflammatory drugs (NSAIDs) decrease the accumulation of inflammatory cells in the acute phase of inflammation, but neither prevent tissue damage nor accelerate the overall healing process.21
No studies have been performed to date on animal models with chronic tendinopathy, but we could assume that injury followed by an inflammatory reaction could start a chain of events that ultimately leads to chronic tendinopathy, which, at the point of clinical relevance, does not show inflammatory features.1,9 From our understanding of the etiology and development of this condition, we believe that there is no scientific basis to manage chronic tendinopathy with NSAIDs.
NSAIDS IN TENDINOPATHIES
NSAIDs inhibit tissue inflammation by repressing cyclooxygenase (COX) activity, with a reduction in the synthesis of proinflammatory prostaglandins.22
Management of an anatomically defined medical condition is ideally based on an understanding of its pathophysiology. Although, as noted earlier, tendinopathy is a noninflammatory condition, NSAIDs are widely used in attempts at treatment.23-27 Ironically, the analgesic effect of NSAIDs28allows patients to ignore early symptoms, possibly imposing further damage on the affected tendon and delaying definitive healing. Topical Naproxen gel produced a marginal advantage in relieving symptoms after 3 and 7 days in patients with acute tendinopathies who had symptoms for less than 48 hours.29 Although NSAIDs may provide some pain relief in such patients, they do not actually result in sustained improvement in the healing process.2 It is still not known whether NSAIDs actually change the natural history of tendinopathy or whether they merely exert an analgesic action.2 Recent studies on rats with acute tendon injuries show that NSAID administration does not prevent collagen degradation and loss of tensile force in tendons.21 It is therefore questionable whether NSAIDs should be used to alleviate pain in so-called acute tendinopathy.21
NSAIDs are not effective in athletes with tendinopathy.23Most studies of NSAID treatment of tendinopathy have a short follow-up.2 Double-blind, randomized, placebo-controlled clinical trials of NSAIDs used in the management of tendinopathies based on clinical symptoms and signs only have shown no beneficial effects.30 Even these placebo-controlled clinical studies are difficult to interpret because of the inability to control for the severity of the lesion, level of athletic participation, and other variables.
NSAIDs could theoretically benefit patients with tendinopathy by increasing the tensile strength of tendons via accelerated formation of cross-linkages between collagen fibers.23,28,31 In animal models, COX inhibitors do show a beneficial effect on tendon regeneration after transection, in exactly this fashion.32 However, these studies were conducted on rats with Achilles tendons that had been surgically divided, a situation that does not reflect the conditions encountered in chronic tendinopathy. Another study using a rat model showed that, in the first few days after Achilles tendon transection, the inflammatory response was necessary for normal repair, and should not be inhibited.33 Early NSAID administration led to a reduction in the amount of force and stress required for the tendon to fail.33 During remodeling, on the other hand, inflammation has a negative influence, and NSAIDs such as COX-2 inhibitors might be valuable for the final outcome.33 Indeed, late treatment with COX-2 inhibitors leads to increased tensile strength, although they do not change the histopathologic picture.33 COX-2 inhibitors should therefore be avoided in the early period after tendon injury, given their deleterious effect on tensile strength.
Although in vitro studies on human tendon fibroblasts treated with NSAIDs have shown a decreased expression of PGE2, they also show an increased expression of leukotriene B4(LTB4).34 The reduction in PGE2 may give patients some pain relief; increased LTB4, however, could potentially exacerbate the situation via increased neutrophilic infiltration and lymphocyte activation,35 paradoxically causing inflammatory and degenerative changes in the tendon. Thus, in tendinopathy, leukotriene pathway activation occurs after cyclical strain on tendons, and treatment with NSAIDs may actually worsen the condition.34
CONCLUSION
Pharmacologic management strategies for tendinopathies vary considerably, and are frequently based on empirical evidence. Can the continued use of NSAIDs for the treatment of tendinopathies be justified? The available literature would suggest that in the absence of an overt inflammatory process, there is no rational basis for the use of NSAIDs in chronic tendinopathy, because they are unlikely to change its still ill-defined natural history. Despite this reality, many clinicians still anticipate a quicker and better recovery using these agents. There is no biologic basis for NSAID effectiveness in treating this condition, and no evidence of any benefit. NSAIDs appear to be effective, to some extent, for pain control. This causes patients to ignore early symptoms, and thus may lead to further damage of the tendon and delay definitive healing. Early NSAIDs administration after an injury may have a deleterious effect on long-term tendon healing. It would thus seem reasonable to shift our research efforts to other forms of conservative management. Examining strategies that promote the migration and activation of tenocytes to influence tendon healing and function might be an appropriate first step. It is equally appropriate to limit our use of NSAIDs in the management of tendinopathy. What may appear clinically as an acute tendinopathy is actually a well-advanced failure of a chronic healing response in which there is neither histologic nor biochemical evidence of inflammation.
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