Anti-Inflammatory Therapy in Tendinopathy: the Role Of

22 Anti-Inflammatory Therapy in Tendinopathy: The Role of Nonsteroidal Drugs and Corticosteroid Injections Wayne B. Leadbetter Anti-inflammatory therapy is commonly prescribed for Tissue Response to Tendon Injury the treatment of musculoskeletal soft tissue injury and tendinopathy [1–6]. Since either acute macrotraumatic or Because the most common objectives of anti-inflamma- chronic microtraumatic injury is often associated with tory therapy in tendon injury are the relief of excessive pain, stiffness, swelling, and loss of function, historically pain and inflammation, the following brief discussion may cardinal signs of an inflammatory process, nonsteroidal prove useful in forming a rationale for such treatment. anti-inflammatory drugs (NSAIDs) and a variety of syn- Injury is characterized as acute (i.e. macrotraumatic) or thetic derivatives of cortisol, an adrenal glucocorticoid, chronic (i.e. microtraumatic, overuse, cumulative trauma, have achieved widespread endorsement [1,7]. The popu- or repetitive motion disorder) [16,17]. Acute human larity of these agents testifies to the prevalent belief that tissue response is characterized by three phases: 1) acute such medical intervention can relieve the initial dis- vascular-inflammatory; 2) repair-regeneration; and 3) ability and improve the rate of recovery from injury.This maturation [18]. In normal tissue healing, inflammation utilization pattern has been documented by surveys plays an important initial role in this complex dynamic revealing that more than 17 million Americans consume process. The resulting restoration of anatomic tissue NSAIDs daily, and some 50 million Americans use continuity is the product of an orderly, progressive, and NSAIDs intermittently or routinely yearly; up to 30 interdependent biologic repair sequence. In this context, million of the elderly take NSAIDs on a regular basis inflammation is often defined as a normally occurring, [8]. In a random survey of 400 orthopedic surgeons, localized protective response that serves to destroy, 90 used steroid injection in the treatment of their dilute, or wall off the injurious agent, the injured tissue, patients, administering an average of 193 extra-articular and the byproducts of such injury [25]. Acute inflamma- injections annually, most primarily for bursitis and tion is characterized by the classic signs of pain (dolor), tendinopathy [9]. heat (calor) redness (rubor), swelling (tumor), and loss of Such popular clinical treatment patterns persist despite function (functio laesa) [16]. The latter characteristic serious potential gastrointestinal, renal, and cardio- provides the primary impetus in the treatment of vascular side effects [10–13]. The issue is additionally tendon injury in recreation or the workplace. Histologi- compounded by concerns centering on difficulties in cally, acute inflammation involves a series of interactive substantiating the degree of clinical benefit achieved by events, including A) dilatation of arterioles, capillaries, such treatment [14,15].This chapter provides an overview and venules, with increased permeability and blood flow; of the pharmacologic effects, current therapeutic ratio- B) exudation of fluids, including plasma proteins; C) acti- nale, prescription guidelines, potential side effects, and vation and release of immunologically active mediators; known efficacy of these potential anti-inflammatory D) activation of humeral response mechanisms; and E) drugs.The reader’s attention is drawn to the relevant fea- leukocytic migration to the inflammatory focus [19] (see tures of the pathophysiology and healing of tendinopa- Figure 22-1). Subsequent neutrophilic activation results thy and paratendinopathy, and the implications to such in the so-called “respiratory burst” activity characterized therapeutic intervention. by the generation of high concentrations of oxygen-free 211 212 W.B. Leadbetter Pathologic Insult cellular events preceding tissue regeneration, repair, or scar formation [16]. Clinically, soft tissue inflammation Vasoactive Chemotactic Activation of Platelets may spontaneously resolve or too often may become a Mediators Factors and Coagulation System major part of the patient’s problem. The factors that cause an acute injury to evolve into a chronic inflamma- Vascular Leukocyte Thrombus Vasoactive tory condition are poorly understood; evidence suggests Permeability Activation Formation Mediators that continued abuse of load and irritation may stimulate the local release of cytokines, resulting in both autocrine Cytokines Arachidonic Proteases Oxidants Vascular (cell) and paracrine (adjacent cell) stimulation and Acid Permeability modulation of further cell activity [19]. So-called failed Metabolites healing responses or the abortion of the normal orderly healing progression in a wound often lead to granulation TISSUE INJURY tissue formation or tissue degeneration (i.e. a damaged or less functionally capable tissue) [16]. The aging process Figure 22-1. Mediator events in response to tissue injury. contributes to a tendency toward the chronic injury (From Fantone J. Basic concepts of inflammation. In: Leadbet- condition [24]. ter WB, Buckwalter JB, Gordon SL, eds. Sports-Induced Inflam- mation. Park Ridge, IL: American Academy of Orthopaedic In paratendinopathy, evidence is increasing in both Surgeons, 1990. P. 26, with permission [19].) acute and chronic synovitis for the role of immunologically mediated amplification, as well as propagation, which may itself lead to further tissue damage. Material radical species (e.g. O2,H202, OH, HOCL) [17,20]. These to be eliminated (i.e. antigen) is recognized as being free radicals are extremely reactive and chemically unsta- “foreign” by specific or nonspecific means [25]. Specific ble. They are known to chemically attack the phospholi- recognition is mediated by immunoglobulins (i.e. anti- pase structure of cell membranes by the process of lipid bodies) and by receptors on T lymphocytes that bind to peroxidation, forming unstable lipid peroxide radicals specific determinates (epitopes). For instance, activated that break down into smaller molecules, leading eventu- T-cell populations and monocyte-macrophage popula- ally to the dissolution of the cell wall and the generation tions have been identified in non-septic olecranon bursi- of arachidonic acid metabolites. Persistent inflammatory tis [26]. Similar activated T-cell populations have been signs and symptoms as well as further posttraumatic identified in chronic paratendinopathy [27]. Such findings tissue damage are directly related to these events. Theo- add credence to an autoimmune mechanism of synovial retically, tissue hypoxia caused by vascular disruption in injury response [28]. acute injury or intermittent tissue hypoxia that may occur Recognition of denatured proteins or nonspecific in the cyclic loading of such tissues as tendon may be a forms of recognition can be mediated directly by the stimulus for the cellular release of such oxygen-free rad- alternative complement pathway or by phagocytes [28]. icals. The possible occurrence of such events forms the Binding of a recognition component of the immune basis for one of the theoretical models of chronic tendon system to an antigen generally leads to activation of an degeneration [17,19,20]. amplification system, initiating production of pro- Tissue degeneration is a dominant finding in chronic inflammatory substances. The actual destruction of anti- tendinopathy complaints. In the great majority of spon- gens by immune mechanisms is mediated by phagocytic taneous tendon ruptures, chronic degenerative changes cells [25]. In synovial-lined structures, macrophages and are seen at the rupture site of the tendon [21]. Multiple related cells (e.g. Kupffer cells, type A synovial lining factors often catalyzed by overuse and overload, and cells) are central components of this system [25,29,30]. fatigue may alter the basal reparative ability of injured Such inflammatory activations have long formed the tendon. Intense cyclic, often eccentric load is thought to basis for the induction of synovial inflammation by artic- lead to cumulative microtraumatic effects, furthering ular cartilage matrix molecules released in association weakening collagen cross-linking noncollagenous matrix with degenerative joint disease, implant particle debris, or elements and vascular elements of tendon [21]. The chemical agents [30]. resulting tendinosis lesion characterized histologically by coexistence of degenerative histologies is presumed to be the result of profound perturbation and dysregulation Mode of Action and Pharmacologic of reparative fibroblastic activity. The infiltration of lymphocytes and macrophage-type cells is not a dominant Effects of Anti-Inflammatory feature of this aspect of tendon injury response [22,23]. Medication Inflammation may be initiated by injury or irritation of vascularized tissues, such as synovium, exposed to exces- Laboratory research into the mode of action and effects sive mechanical load or use [16]. It is a time-dependent, of anti-inflammatory medications has suffered from sig- evolving process characterized by vascular, chemical, and nificant limitations, both in vitro and in vivo. Most promi- 22. Anti-Inflammatory Therapy in Tendinopathy: The Role of Nonsteroidal Drugs and Corticosteroid Injections 213 nent is the lack of a reliable and consistently reproducible (i.e. polymorphonuclear leukocytes, monocytes, and tendinopathy animal model for demonstrating overuse macrophages) [37,38]. Glucocorticoids have little or no

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