Overuse Tendon Injuries

*Allan McGavin Sports Medicine Centre and School of Human Kinetics, University of British Columbia, Vancouver, Canada
# Victorian Institute of Sport Tendon Study Group and Alphington Sports Medicine Clinic, Melbourne, Australia

Dr Karim Khan, School of Human Kinetics, 6081 University Boulevard, Vancouver V6T 1Z1, CANADA. Phone (604) 822 - 0056, Fax (604) 822 -0056 or 822-6842 Email kkhan@interchange.ubc.ca

Summary

Failure to appreciate how pain arises in tendinopathies may be limiting progress. It is assumed that tendon overuse causes inflammation, and thus pain. We critically review the inflammatory model of pain in tendinopathy, and find that it does not withstand scrutiny. The generally proposed alternative model is that of mechanical discontinuity of collagen fibers, but this as well is inconsistent with numerous surgical observations. We review data suggesting that pain of tendinopathy may be largely due to yet unidentified biochemical factors activating peritendinous nociceptors when they are exposed to the environs as a results of tendon overuse injury. The noxious agent could include matrix substances and minor collagens. Glutamate can mediate pain, and this is present in higher concentrations in subjects with Achilles tendinopathy than controls. Chondroitin sulphate is another candidate. Examining alternative models of pain, particularly a mixed biochemical-mechanical model, may allow significant progress in management of these troublesome conditions.

'Tendon disorders are a nemesis to both the athlete and the physician' [1]
(Douglas B Clement, Olympic athlete and sports medicine professor)

Overuse tendon injuries cause enormous costs in the work place [2] and they account for about 30-50% of all sports injuries [3, 4]. Despite decades of research and increasing clinical attention to these injuries, their clinical outcome remains unpredictable [4-11].
One factor that may limit successful management of overuse tendon injuries is a failure to appreciate how pain arises in these conditions. It is widely assumed that tendon overuse causes inflammation, and thus, pain. Despite the pervasiveness of this dogma, a large body of evidence contradicts this assumption [12-17]. The true cause of pain may be mechanical discontinuity of collagen fibers, or biochemical irritation that results from damaged tendon tissue activating nociceptors [18, 19]. Also, it has been proposed that unique anatomical features may produce pain in specific tendons (e.g., impingement causing pathology at the patellar tendon [20]).

Although understanding of pain in tendon overuse injuries is in its infancy, it is important that clinicians and researchers are aware of the inconsistencies in the prevailing paradigm. Therefore, this article is divided into two parts. The first provides the evidence that overuse tendon injuries (henceforth called tendinopathies [21]) are not primarily inflammatory conditions. The second part outlines some non-inflammatory mechanisms that may produce pain in tendons. This area of enquiry is clinically relevant because optimum patient management may differ greatly between the various mechanisms of pain production.

It remains widely believed that painful overuse tendon conditions have an inflammatory basis (Fig.1). [10] Pain and inflammation have been linked since Celsus (A.D. 14-37) reported the association of "rubor et tumor cum calor et dolor." Clinical labels such as Achilles tendinitis, patellar tendinitis, lateral epicondylitis," and "rotator cuff tendinitis" imply that inflammation is present. Furthermore, nonsteroidal and corticosteroidal anti-inflammatory agents are popular treatment modalities. Studies of ultrasound [22] and magnetic resonance imaging (MRI)[23] have reported the presence of "inflammatory fluid" around symptomatic tendons and thus have reinforced this model.

FIG 1 The classic, "inflammatory" model of tendon pain. From Khan et al., [19] with permission

Inflammation ('tendinitis')

Pain fibers in collagen respond to inflammation

Implication
Pain can be decreased by inhibiting inflammation

Nevertheless, in 1976, Giancarlo Puddu of Rome, Italy, documented that the pathologic condition in what was clinically known as "Achilles tendinitis" was separation and fragmentation of collagen - which Puddu et al. [13] labeled "tendinosis." Three years later, Bob Nirschl [12] of Virginia, reported that tennis elbow, the so-called lateral epicondylitis, was also a degenerative tendinosis without any inflammatory cells. Since then, numerous authors have shown that tendinosis is the predominant pathologic feature in painful overuse tendinopathies at various body sites, [17] and these findings are summarized in the present article. The reader should contrast the findings with those of normal tendon described by Maffulli and Benazzo in another article of this issue.

Tendon Histopathology in Athletes with Achilles Tendinopathy

Histopathologic examination of symptomatic Achilles' tendons reveals degeneration and disordered arrangement of collagen fibers as well as increased vascularity [13, 24-27]. Achilles tendon degeneration leaves the tendon softer than normal and grey or brown rather than its normal glistening white color. Light microscopy reveals collagen fibers that are thinner than normal. In addition to collagen fibers in symptomatic Achilles tendons being abnormal, their characteristic hierarchical structure is also lost [28, 29]. Vascularity is increased and blood vessels are randomly oriented, sometimes at right angles to collagen fibers. Inflammatory lesions and granulation tissue are infrequent, and, when present, are associated with partial ruptures [17].

In the best single illustration of these features, Astrom and Rausing [14] examined 163 patients (75% of whom participated in nonprofessional sports, particularly running) who had had classical symptoms and signs of Achilles tendinopathy for a minimum of 3 months [14]. There was obvious loss of the normal parallel bundling of collagen, and the birefringence to polarized light was reduced or lost. There was an increase in ground substance and neovascularization, even in cases where symptoms has only been present for a few months. Signs of bleeding, that is, erythrocytes and positive staining for iron pigment, were occasionally present. In partial ruptures, fibrin deposits bordered frayed tissue, but histopathology remained identical to those cases without rupture. 'Inflammatory cells, intracellular lipid aggregates and acellular necrotic areas were exceptional', and not regarded as normal elements of the degenerative process [14]. The authors concluded that 'the absence of inflammation and the poor healing response demonstrate a state of degeneration that conforms to the histopathology described by previous authors in total ruptures and in chronic tendinopathy' [14]. Thus, the major lesion in chronic Achilles tendinopathy 'is a degenerative process characterized by a curious absence of inflammatory cells and a poor healing response' [14].

Although Astrom and colleagues found the paratenon to be unremarkable, athletes with pain at or around the Achilles tendon suffer from Achilles paratenonitis [30, 31]. Whether this can occur alone, or always in conjunction with tendinosis of the tendon itself remains unclear. Although Kvist's work is often cited as demonstrating the inflammatory nature of Achilles tendinopathy, the Finnish clinician-scientist de-emphasized the extent of inflammation, even in paratenonitis. In his PhD thesis he stated 'the present findings agree with many earlier observations [32]; the affected paratendinous tissues are edematous and have only a modest inflammatory cell reaction' [33] (italics added). He also noted the presence of myofibroblasts and Alcian blue staining ground substance, which are both features of tendinosis [33].

Recent studies have correlated imaging appearances in Achilles tendinopathy with histopathology. These investigations found that areas of hypoechogenicity on ultrasonography, and increased signal on MR imaging, corresponded with collagen degeneration - areas of mucoid degeneration [34-36]. The morphologic appearance that had been presumed to be 'inflammatory fluid' in earlier speculations resulted from exposed hydrophilic proteoglycans of intercellular matrix that drew fluid into the injured tendon.
Hakan Alfredson and colleagues from Umea, in Northern Sweden, sought biochemical, rather than histological, evidence of inflammation. They used an in vivo microdialysis technique to sample Achilles' tendon matrix in controls and patients who had had symptoms for at least 6 months. They measured prostaglandin E2, which reflects inflammatory reactions, and found no difference between subjects and controls [18] (Figure 2). This argues against inflammation playing a large role in pain production in these subjects.

Figure 2 - The concentrations (pg/ml) of PGE2 (mean+/-SD) in tendons with tendinosis and normal tendons, during the 4-h sampling period [Alfredson, 1999 #40].

Tendon Histopathology in Athletes with Patellar Tendinopathy

As recently as 1994, it was reported that the pathology underlying patellar tendinopathy was not clearly defined [37], reflecting inconsistencies of nomenclature, rather than a paucity of data. Macroscopically, the patellar tendon of patients with patellar tendinopathy (also commonly called jumper's knee) contain soft, yellow-brown and disorganized tissue in the deep posterior portion of the patellar tendon adjacent to the lower pole of the patella [38-40]. This macroscopic appearance is often described as 'mucoid' degeneration [5, 41].
Under light microscopy, the tendons of patients suffering jumper's knee do not consist of birefringent, tightly bundled parallel collagen fibers (Figure 3a), but are instead separated by increased ground substance that causes a disorganized and discontinuous appearance. Clefts in collagen and occasional necrotic fibers suggested microtearing [42-44] (Figure 3b). Collagen degeneration with variable fibrosis and neovascularization was a consistent feature across studies. The collagen producing tenocytes themselves lost their fine spindle shape, and the nuclei were more rounded, and sometimes chondroid, a feature of fibrocartilaginous metaplasia [42, 45].

Figure 3 - Micrographs of tendon viewed under polarized light microscopy (a) - A specimen of normal patellar tendon reveals tightly bundled collagen with characteristic golden reflectivity, also referred to as birefringence. (b) - A specimen of tendon tissue obtained at surgery. The 26-yr old patient had had 4 months of patellar tendon pain. Polarized light microscopy reveals separation of collagen fibers and the presence of an amorphous (mucoid) ground substance.

When imaging studies in athletes with patellar tendinopathy were correlated with histopathology, areas of hypoechogenicity on ultrasonography [44], and increased signal on MR imaging [44, 46], corresponded with collagen degeneration and mucoid degeneration. These findings are identical with those in Achilles tendinopathy discussed above.

Histopathology in Athletes with Pain at the Lateral Epicondyle

At surgery of over 600 cases of lateral tennis elbow the extensor carpi radialis brevis tendon contained disrupted collagen fibers, increased cellularity (Figure 4) and neovascularization [12, 47]. The cellularity was due to myofibroblasts, not inflammatory cells (Figure 5). Occasionally there was a mild sprinkling of chronic inflammatory cells in supportive or adjacent tissues. When chronic inflammatory cells were present, they resulted from repair of partial tears [7].

In people with at least 6 months of lateral 'epicondylitis', areas of abnormal tissue on MR imaging corresponded with areas of neovascularization, disruption of collagen and mucoid degeneration on histopathologic examination [48] - not inflammatory fluid [48]. There was no histopathologic evidence of either acute or chronic inflammation in any of the specimens. The histopathology reported in lateral tennis elbow also exists in medial tennis elbow ('golfer's elbow') [49].

Tendon Histopathology in Athletes with Rotator Cuff Tendinopathy

Drs Uhthoff and Matsumoto discuss this topic in detail later in this monograph. To summarize briefly, histopathology of symptomatic rotator cuff tendons reveals mucoid degeneration and fibrocartilaginous metaplasia [50] as well as cellular distortion and necrosis, occasional calcium deposits and microtears. There is loss of the characteristic crimped pattern of tendon and parallel bundles of collagen separate and become disorganized [51] with 'disruption of fascicles, formation of foci of granulation tissue, dystrophic calcification, thinning of fascicles, associated with cell and vessel proliferation' [16]. The degeneration diminished load at tendon failure. Even the subacromial bursa, often considered to contribute to pain of rotator cuff tendinopathy via inflammation (so-called 'subacromial bursitis') lacked plasma cells and contained few or no neutrophils and lymphocytes. These cells are abundant in a true inflammatory bursitis in a condition such as rheumatoid arthritis.

Tendon Histopathology in Tibialis Posterior Tendon Rupture

Mosier and colleagues operated on cases of tibialis posterior tendon rupture in adults and found the tissue that had undergone a nonspecific reparative response characterized by mucoid degeneration, increased number of myofibroblasts and neovascularization. Thus, this tissue appeared identical with that of the tendons at other body sites as described above [52].

Can Nnon-inflammatory Mechanisms of Tendon Pain Explain the Pain-relieving Effect of Corticosteroid Injections?

We cannot exhort the reader to abandon the inflammatory model of chronic tendinopathy without discussing the effect of corticosteroid injections. One of the most frequent questions we are asked when presenting these histopathological findings in tendinopathy is 'Why do corticosteroids work?' Whether or not corticosteroids benefit patients with tendinopathy is an issue that is the focus of other articles [3, 53-56]. Nevertheless, both clinical experience and randomized studies [57, 58] have shown these medications provide at least short-term pain relief. Also, the protease inhibitor aprotinin has also been shown to relieve tendon pain [59, 60].

At present, the mechanism of pain relief from these agents remains unknown - and this will likely remain the case until the mechanism of pain in tendinosis itself is understood. It has been postulated that any chemical agent (e.g., corticosteroids) may bathe the region of tendinosis and alter the chemical composition of the matrix (e.g., pH level) [47]. Fenestration of an area of tendinosis with needling may promote beneficial bleeding into new channels created through degenerated mucoid tissue. This mechanical disruption may transform a failed intrinsic healing response to a therapeutic extrinsic one.

Does a Short-term Inflammatory 'Tendinitis' Precede the Non-inflammatory Tendinosis?

Some consider that tendinosis is the end-stage of a continuum that begins with normal tendon and passes through a period of painful 'tendinitis' (Figure 6). Although this is plausible, there is, no evidence for a significant interim phase of 'tendinitis' in overuse tendinopathy. Data to explore this question comes from biopsy samples in athletes with overuse tendinopathy, biopsies taken in cases of tendon rupture, and animal models of tendinopathy.

Normal Tendon

'acute' inflammatory tendinitis

'chronic' non-inflammatory tendinosis

Figure 6 - Proposed transition from normal tendon, through 'tendinitis' to tendinosis

In our histopathological study of athletes who underwent surgery for jumper's knee [44] several subjects were operated on after only 4 months of pain, and even in these cases inflammatory cells were absent. Clinical experience has suggested, and serial ultrasound scanning has proven, that patellar tendinopathy can extend distally from the proximal pole with time, as the hypoechoic region enlarges [61]. Thus, we identified the proximal patellar attachment of the specimens obtained at surgery with a suture, and the histopathologist was able to carefully scrutinize the transition from abnormal to normal (Figure 7). If 'tendinitis' were to always precede tendinosis, then this region should contain evidence of tendinitis. Such a phenomenon would be analogous to a 'cutting core' of osteoclast activity preceding osteoblast activity in cortical bone remodeling [62]. However, there were no inflammatory cells at this transition area, suggesting that, if there is such a phase of 'tendinitis', it is very brief.

Tomas Movin, from Stockholm, used a novel core biopsy method to sample tissue in 15 subjects with Achilles tendinopathy that had been present for a period ranging from 4-120 months [63]. There was no evidence of an inflammatory process even in subjects with 4 months of symptoms [63].

Further human evidence for tendinosis arising without a period of painful tendinitis comes from studies of tendon ruptures. Pekka Kannus and Laszlo Jozsa examined tendon tissue in 891 cases of spontaneous rupture and found that 97% of tendons revealed pre-existing degenerative tendon pathology (tendinosis) at sites near, but distinct from, the rupture. Similar findings were present in 34% of the control tendons. Two-thirds of the patients with ruptures had never had any tendon symptoms. Even allowing for recall bias, this provides convincing evidence that tendinosis can arise without symptoms. By deduction, painful 'tendinitis' is not a sine qua non for tendinosis.

Animal models permit histopathological examination of tendon tissue soon after injury and may provide insight as to the length of any inflammatory 'tendinitis' that precedes collagen degeneration. Two overuse tendinopathy models examined tendon tissue between 1 and 6 weeks after injury, and one surgical tendon transection model examined tissue after 5 days or healing.

Zamora and colleagues from Marseille, France [64] caused an overuse injury in the plantaris muscle of rats by dividing the Achilles tendon and obliterating the soleus muscle bilaterally. Control animals had sham surgery. Animals were sacrificed at 1 and 2 weeks and at both these times there was no evidence of inflammation. There was, however, strong evidence of tendon repair, as quiescent fibroblasts had transformed into rounded, active cells [64]. These cells were identical to those found in surgical specimens of symptomatic athletes as described above.

Backman and colleagues, also from Umea in Sweden, developed a rabbit model to study tendon overuse. Transcutaneous stimulation of the calf muscle generated 150 ankle plantarflexions/extensions per minute, 2 hours per day, 3 days per week for 5 to 6 weeks [65]. They reported degenerative collagen changes ('fibrillation') and neovascularization, together with some inflammatory cells in the adipose tissue close to the paratenon. They considered this histopathology to be 'identical to those reported in biopsy material from professional runners and joggers with sustained Achilles tendon complaints admitted for surgery after months or years of nonbeneficial conservative management' [65].

Chukuka Enwemeka from Kansas examined the issue of duration of tendon inflammation in a surgical tenotomy model [66]. Tendon rupture promotes inflammation. In this experiment, rats had the right Achilles tendon severed transversely and then reapproximated and sutured with three loops of 3/0 surgical silk. The skin was closed and the limb was immobilized. Serial sacrifice revealed a prominent inflammatory response that peaked at 5 days and disappeared by day 18. Myofibroblasts appeared around day 7 and became increasingly prominent. At that time, ground substance was abundant, giving the tendon an appearance not unlike that of degenerative tendinosis found in athletic individuals at surgery. Thus, even in a model predicted to stimulate more inflammation than an overuse injury model, inflammatory cells disappeared within 3 weeks of surgical insult [66]. Although healing of rat tendons does not necessarily translate directly into healing in humans, these data suggest that inflammation is not a lengthy process in tendon repair, even after surgical tenotomy.

Thus, from human and animal data, it appears that inflammation plays no appreciable role in the pain of chronic tendinopathy (more than 4 months). Although there may be a period of inflammatory pain for a few days after certain tendon injuries, symptoms that are present for more than one week are also likely to arise from a non-inflammatory mechanism. Potential mechanisms include the mechanical model of collagen separation, the biochemical irritant model and other models that may only operate in unique anatomical situations.

The 'Mechanical' Model of Collagen Separation

In this model, collagen fibers are thought to be pain free when intact and painful when disrupted (Figure 8). There is already a well-accepted scenario where collagen separation is known to mediate pain - acute ligament sprain. While nobody would deny that tearing of collagen causes pain (e.g., acute partial tendon tears) we have observed numerous situations where tendons are not completely intact, yet remain pain-free. These observations are listed to highlight that tendon pain may not be due to a straightforward relationship between mechanical collagen separation and pain.

Collagen separation (tendinosis, partial tears)

Pain fibers within tendon collagen respond to injury

Implication
Pain is related to collagen injury and repair

Two types of surgery performed on the patellar tendon - ACL autograft reconstruction and tenotomy for painful jumper's knee - provide illuminating models to examine the relationship between collagen and tendon pain. Consider first the middle third patellar tendon autograft ACL reconstruction. Individuals who undergo this operation have minimal donor site knee pain, yet collagen has been excised (Figure 9). Even at 2 years postoperatively, the donor site may have significant histologic abnormality [67, 68].

Some would argue that completely excised collagen contains no intact fibers to produce pain, just as a complete ligament rupture is less painful than a substantial partial rupture. Nevertheless, in the postoperative period some patients develop pain consistent with patellar tendinopathy indicating that healing collagen can become painful [69]. When imaged, the painful tendon donor site remains indistinguishable from that in individuals who remain pain free [69, 70]. This indicates that the relationship between pain and collagen status is not one that can be detected at the macroscopic level.

Clinical observations in athletes undergoing surgery for jumper's knee also provide thought-provoking data regarding collagen and pain. The Victorian Institute of Sport Tendon Study Group in Australia monitored athletes recovering from open patellar tenotomy with both ultrasound (3-monthly) and MR imaging (6 monthly) for one year. Tendons remained largely abnormal to imaging, but this correlated poorly with pain [71] (Figure 10). In a retrospective study of a similar post-operative population, ultrasound imaging at a mean of 4-years also did not correlate with pain and function [8]. Both these studies confirm that even substantial degrees of collagen insult do not automatically produce tendon pain.

Jumper's knee can also be treated by arthroscopic debridement of the posterior border of the patellar tendon [8], and this provides particularly interesting evidence regarding the role of collagen defects in tendon pain. In this procedure, the surgeon first debrides the adherent fat pad to expose the posterior aspect of the tendon (Figure 11) and then removes the cheesy, tendinosic tissue itself. The body of the tendon, however, remains largely untouched, and postoperative ultrasonography reveals that the intratendinous hypoechoic region, so often considered pathognomonic of this condition, is still evident, yet pain is obliterated.

This form of treatment could relieve pain by a number of mechanisms including denervation. However, the proportion of patients who reported skin paresthesia or numbness after patellar tendon was the same after arthroscopic or open patellar tenotomy [8]. Deliberate denervation has also been used as part of the treatment of tendinopathy at the elbow [72].

Longitudinal tenotomy, also known as 'carding', is a well-established treatment for overuse tendinopathy at various body sites including the patellar and Achilles tendons [73, 74]. This causes new injury to tendon and, although the tenotomy is directed longitudinally so as not to sever the tendon, it is inevitable that collagen is divided because of the normal spiraling of tendon, particularly the Achilles tendon. Nevertheless the procedure is often therapeutic rather than deleterious. This phenomenon cannot be explained by invoking a pure mechanical model of pain in tendinopathy.

Surgery of patients with rotator cuff tears revealed that partial (nonperforated) rotator cuff tears were more painful than patients with full-thickness [75] perforations. This differs from the complete rupture model, as the patients with a full thickness perforation have collagen that remains intact from origin to insertion.

Observations About Tendon Pain and Imaging Appearances

A variant of the structural model of pain in tendinopathy outlined above argues that it is not torn collagen that hurts per se, but the persisting, intact collagen that must sustain greater load because adjacent collagen is injured. Pain is presumed to occur when the proportion of collagen injured reaches a critical threshold and persisting collagen is stressed beyond its normal capacity into a painful overload zone. This model predicts that greater degrees of tendinosis should be more painful than lesser degrees, until complete tendon rupture, in which case pain disappears because there is no longer any collagen left under tension. The case of rotator cuff tendinopathy cited immediately above this subsection argues against this model, as do numerous imaging studies.

Ultrasonography assesses collagen continuity and has been used in patients with tendinopathies as well as for screening asymptomatic populations. In patients with tendon pain, the size of collagen abnormality as measured on ultrasound is not correlated with pain, either in cross-sectional studies [76, 77] or in longitudinal observational studies where change in area of abnormal tissue was monitored [61]. Patients with pain of patellar tendinopathy can have a normal MR scan [78]. Routine clinical experience provides many exceptions to the proposed theory as a patient may have a very small, or no, morphological abnormality, yet have significant symptoms.

In parallel studies conducted in large numbers of asymptomatic athletes, ultrasonographic hypoechoic regions (abnormal collagen) were common, even in subjects with no past history of jumper's knee [76, 77, 79] (Figure 12). Using MR imaging in asymptomatic controls, Louis Almekinders from North Carolina found abnormal signal consistent with collagen degeneration [78]. A similar appearance has been reported in asymptomatic individuals at the Achilles tendon [80].

These 7 examples demonstrate that there is more to tendon pain than discontinuity of collagen per se. However, we do not suggest that collagen disruption is unrelated to tendon pain. Another mechanism, by which it could contribute to tendon pain, is via biochemical activation of nociceptors rather than a pure mechanical effect.

The Biochemical Model of Pain in Tendinopathy

If one discards the inflammatory model of pain production, and has reservations about a purely mechanical model for the reasons listed above, the biochemical irritant model becomes increasingly attractive [19, 47] (Figure 13). Bob Nirschl said 'we suspect that the cause of pain in tendinosis is chemical irritation due to regional anoxia and the lack of phagocytic cells to remove noxious products of cellular activity' [47]. It may be that the pain of tendon overuse injury is largely due to biochemical factors activating peritendinous nociceptors.

As yet unidentified biochemical irritants (candidates include matrix substances such as chondroitin sulphate) become exposed because of collagen degeneration (tendinosis). Alternatively, excitatory neurotransmitters such as glutamate are exposed [Alfredson, 1999 #40]

Significant pain fibers are found in synovium and tissue around tendon, as well as in the tendon substance - Substance P may mediate pain

Implication

1. Tendon healing would reduce the concentration of biochemical irritants and thus, pain.
2. Pharmaceutical antidote to the biochemical irritants would decrease pain
3. Pharmaceutical antidote to substance-P may decrease pain3. Denervation of nociceptors (i.e., certain surgery) would decrease pain

The noxious agent could include matrix substances and minor collagens that are only currently being characterized in normal tissues. Chondroitin sulphate exposed through tendon damage may stimulate nociceptors [3, 19, 81]. In the knee, nociceptors are located in the retinaculum, fat pad, synovium and periosteum [82], and all these structures may play a role in the mechanism of pain in patellar tendinopathy. In 39 cadaver dissections of the proximal patellar tendon [44], we consistently identified a thin layer of fat adherent to the posterior portion of the patellar tendon (Figure 14). In the corresponding tissue specimens from patients operated on for chronic jumper's knee, this fat tissue contained increased Alcian Blue stain (and thus, glycosaminoglycans), that had presumably extravasated from the adjacent region of tendinosis.

Glutamate has been recognized as a mediator of pain [83]. Certain ionotropic glutamate receptors are present in unmyelinated and myelinated sensory axons [84], and glutamate antagonists reduce the pain that rats felt when given a test dose of formalin [85]. Using in vivo microdialysis, Hakan Alfredson and colleagues found that the neurotransmitter glutamate was present in higher concentrations in the Achilles tendon of subjects with tendinopathy than controls (Figure 15). The authors are now performing further experiments to determine whether the glutamate results from local hyperproduction by injured tendon cells or whether there is an increase in glutamate sensitive nerve terminals [18].

In the study of rotator cuff tendinopathy and shoulder pain (mentioned earlier), collagen damage was inversely related to pain, but the presence of substance-P (a nociceptive neurotransmitter) was significantly associated with pain [75]. Nerve fibers immunoreactive to substance-P were localized around vessels in the subacromial bursa, and in the non-perforated rotator cuff [75]. Substance-P, and the related neuropeptide - calcitonin gene related peptide (CGRP), has also been found in nerve afferents around the feline knee [86], and are thought to be involved in joint nociception.
A structural relationship has been observed between neuropeptide containing nerve fibers and collagen [86]. However, how tendon injury is transduced into nerve impulses, and perhaps in a pain signal, remains unclear [86]. Although there are some data on innervation of tendon [3, 87], and there is ultrastructural evidence of all 4 categories of nerve endings (Ruffini corpuscles, Vater-Pacini corpuscles, Golgi tendon organs and free nerve endings or pain receptors [3, 88]0 in normal tendons, this field requires much more work before the mechanism of tendon pain is unraveled. If substance-P proved to be a significant agent in tendinopathy, its already developed non-peptide antagonists could be appropriate for a therapeutic trial [89].

Eccentric Tendon Strengthening and the Biochemical Model

Although the mechanism whereby eccentric strengthening reduces tendon pain remains to be fully elucidated, Al Banes' group at the University of North Carolina has provided seminal evidence that tenocytes communicate via gap junctions and the cytoskeleton within tenocytes [90-93]. These authors have used in vivo animal models, intact tendon specimens and cell cultures to investigate the relationship between mechanical loading and tenocyte repair. Although it is far too early to correlate these findings with the pain reducing effect of eccentric strength programs [6, 94], it is apparent that the heel-drop program that may initially increase, but then decrease, the pain of Achilles tendinopathy [6, 94] may provide the type of mechanical stimulus that Banes has shown promotes DNA and collagen production. Banes' model and the data that underpin it are consistent with the clinical evidence that tendon repair can be stimulated by mechanical loading, without a need to invoke any inflammatory pathways. The interested reader is directed to the referenced papers for detailed explanation of the pathway between mechanical stimulus and collagen production in tendon.

Other Potential Mechanisms of Tendon Pain

Other tissues that could play a role in producing tendon pain are nerves, vessels, and bones that are intimately related to tendon. David Hart and colleagues at the University of Calgary have proposed that the close proximity between neural elements and tissue mast cells in tendon would permit the mast cell-neurite 'unit' to stimulate what they termed 'neurogenic inflammation' [95].

As paratenon is more highly innervated and vascularized than the tendon itself, it has been proposed that neurotransmitters such as substance P can influence mast cell degranulation and secretory activity. Neural activity could be amplified when mast cells release a panel of biologically active molecules which may impact on vascular elements and fibroblasts. Theoretically, the mediators contained in mast cells such as cytokines and growth factors could influence a number of potentially pain-producing factors such as cellular edema and chemotaxis for inflammatory cells. The proponents of this mechanism argue that the release of low amounts of these mediators could be part of the normal regulatory system, while higher levels may contribute to the adaptive response of tissues [95]. This type of 'neurogenic inflammation' has been seen in various body tissues, although not proven in tendon. The authors refer to this as an 'endogenous inflammatory system', in contrast to the 'exogenous inflammatory system' composed of blood borne cells generally associated with inflammation [95]. One criticism of this model is that mast cells are not prominent in tendon tissue. Nevertheless, the model may apply to paratenonitis, and it may explain the process of neovascularization in tendinosis.

Kvist [33] postulated that fibrinogen-fibrin and their degradation products may play an important role in the vascular lesions of Achilles paratenonitis [33]. In this model, increased tissue pressure due to edema may induce the typical vascular changes of chronic Achilles paratenonitis [30, 31, 33].

Bone appears an unlikely candidate in the search for the mechanism of tendon pain, even through it is located close to sites of tendinopathy in the shoulder, knee and foot. In athletes with jumper's knee, the patella itself is abnormal on both radionuclide scan [96] and MR imaging [44]. This, however, would appear to be a secondary reaction of bone near the osteotendinous junction rather than a primary pathological condition. Not all athletes with jumper's knee have these MR appearances.

Pain Resulting from a Unique Tendon Environment

Occam's razor would encourage researchers to seek a mechanism of pain in tendinopathy that would apply throughout the body. Nevertheless, certain authors have proposed site-specific mechanisms of pain that depend on unique anatomy at that site.
The fat pad in patellar tendon pain

The fat pad may have 'an important role in the production of intense pain in patellar tendinitis' when it adheres to the back of the patellar tendon and causes synovitis, and thus, an irritable joint [97]. This was also used to explain the therapeutic mechanism of corticosteroid injection in patellar tendinopathy (see corticosteroid injections, above) [97]. The infrapatellar fat pad is an extremely sensitive region [98] and contains a large number of nociceptors. However, surgical management of the main body of the patellar tendon in athletes revealed no evidence of involvement of the fat pad, either clinically, or at operation [99]. A parallel situation of the Achilles tendon and the fat of Kager's triangle similarly revealed no macroscopic association between symptoms and abnormality of the fat pad [100]. Intuitively, one would be loath to attribute tendon symptoms to a structure found only at one or two anatomical sites (i.e., the patellar fat pad, Kager's triangle) when tendinopathy occurs at various sites. On the other hand, the fat pad may be a specific form of the nociceptive peritendinous tissue that is sensitive to biochemical irritants. That is, given that the patellar tendon has no true paratenon, it plays the same role as the paratenon in Achilles tendinopathy and the subacromial bursa in rotator cuff tendinopathy.

The fat pad may play a role in anterior knee pain independently of any role in patellar tendinopathy. Jenny McConnell, the Australian physiotherapist renowned for her work in patellofemoral pain syndrome [101], recognized fat pad impingement as a cause of anterior knee pain, not necessarily tendon pain, over 10 years ago. Most clinicians would agree that some patients appear to suffer a chronic version of anterior knee pain aggravated by knee extension, similar to the condition referred to as Hoffa's syndrome when it present with acute trauma to the anterior knee [102].

Impingement as a Mechanism of Patellar Tendon Pain

Tension failure of the patellar tendon ought to affect the superficial fibers more than the deep surface. Thus, Johnson and colleagues [20] proposed an alternative mechanism of the pain and the lesion of jumper's knee - impingement of the inferior pole of the patella on the patellar tendon during flexion (Figure 16). This argument assumes that both the superficial and deep insertions of tendon to bone are equally strong, but biomechanical studies showed that the superficial attachment is far stronger [103, 104]. Given these data, tension failure can influence the deep fibers preferentially.

Also, three clinical factors are not consistent with impingement causing jumper's knee pain. Firstly, pain commences in the early phase of landing from a jump with quadriceps muscle contraction while the knee is still relatively extended. Secondly, patients with severe jumper's knee have pain even when the knee is fully extended and unloaded (e.g. lying in bed) whereas patients with impingement syndromes generally obtain substantial relief when the direct contact is relieved. Thirdly, the pain of jumper's knee does not disappear and may actually increase when palpation is performed with the knee in full extension. These observations all argue against impingement causing pain in patellar tendinopathy.

Evidence in favor of a traction mechanism of injury comes from a biomechanical study that calculated a force 17 times bodyweight on a weightlifter's patellar tendon during competition [105], a study that found athletes with jumper's knee perform better in jump tests than uninjured athletes [106] and a radiological study that found medial retinacular injury (a result of patellar traction) is present in a large proportion of patients with jumper's knee [23].

Testing Hypotheses about the Mechanism of Pain in Tendinopathy

Future research should address the question that is the title of this article, as the answer would permit alternative approaches to management. If, for example, a biochemical irritant proved to be the common noxious agent in tendinopathies, a simplistic view would suggest that a pharmaceutical agent could counteract this stimulus. Alternatively, the noxious agent could potentially be modified by infusion of exogenous growth factors, or even by gene therapy [107]. If continued sporting performance did not cause further mechanical injury to the tendon, this would be a valid solution.

Any model of pain mechanism in tendinopathy must be consistent with the following observations:

Conclusions

The aim of this article was to highlight significant inconsistencies between a widely prevailing dogma about pain in tendinopathy, and evidence from the published literature and clinical observation. Today, there remains little doubt that overuse tendinopathy has essentially a degenerative histopathology. Although collagen fiber injury is almost certainly involved in production of pain in tendinopathies, it may not fully explain the mechanism of tendon pain completely. Numerous observations illustrate that there is no perfect correlation between collagen injury and pain.

If the 'biochemical irritant' model of tendon pain proves to have some validity, it would have significant clinical and research implications. It would mean that part of the aim of clinical management would be to modify the biochemical milieu. Collagen repair would, of course, contribute to resolving tendinopathy, but researchers would be encouraged to pursue a pharmaceutical approach focused on reducing the irritant (but not necessarily inflammatory) biochemical compounds around the tendon. Furthermore, antagonists to neurotransmitters could alleviate chronic pain also. Glutamate is a candidate currently under investigation [18]. Surgery may play a role in treatment of biochemical irritation via a number of mechanisms including denervation, removal of tissue debris and stimulating a fresh healing response.

Clearly we are only at the beginning of the road that leads to understanding where pain comes from in tendinopathy. This article highlights inconsistencies between scientific observations and the currently accepted paradigms. Data are required to resolve key discussion areas of tendon physiology and pathophysiology. Nevertheless, acknowledging that the current paradigm is a flawed oversimplification is an important step. Examining other models of pain in tendinopathy may permit progress that could potentially revolutionize the management of these troublesome conditions [4, 19].

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OVERUSE TENDON INJURIES

Where Does The Pain Come From?

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