Volume 17 Video Transcripts

Transcription

1 Volume 17 Video Transcripts Introduction This month s presentation is based on a paper published in the British Journal of Sports Medicine titled Is tendon pathology a continuum? A pathology model to explain the clinical presentation of load induced tendinopathy ; by Jill Cook and Craig Purdam. It was published in I recently had the opportunity to interview Professor Jill Cook to talk about this model, if there has been any updates to the model since it was published, and how she treats a tendon conditions. So please listen to the podcast but let s first review the original paper. Tendinopathy Tendinopathy, which we will define as an overuse injury of the tendon, can occur in any loaded tendons of the upper extremity or lower extremity. It can affect people of all ages. Common characteristics include pain, decreased exercise tolerance and decreased physical function. Histological studies have shown that changes occur in tendon structure which makes the tendon less capable of tolerating repeated tensile loads. Location of Injury The most common location of tendinopathy pathology within the tendon is where the tendon attaches to the bone. Examples include the patellar tendon, medial and lateral elbow tendons, and the tendons of the groin region. Pathology in mid-tendon is also possible, for example the Achilles tendon. From a structural or morphologically stand-point, mid-tendon and insertional tendinopathies are very different, but from a pathology stand-point the changes in cell matrix appear to be the similar. (Maffulli et al., 2004). From a treatment stand-point, despite similar pathology it appears exercise selection is important for optimal clinical outcomes. For example insertional tendinopathy in the Achilles tendon seems to respond better with eccentric heel raises that just go to neutral while mid tendon Achilles tendinopathy tends to respond better with eccentric heel raises that goes all the way into full dorsiflexion.

2 Tendon Loading Tendons are always adapting to load, they are both anabolic and catabolic. (Benjamin 2002) Meaning loading of a tendon creates adaptations that can either build up the tendon or break it down. Tendinopathy Causes The two key factors involved in the onset of tendinopathy appear to be repetitive energy storage and release; and excessive compression. The amount of load needed to cause tendinopathy is not clear in terms of volume, intensity, or frequency. However time between loading events appears to be an important factor. Loading of tendons in general is not a bad thing, in fact both normal & pathological tendons need a specific volume and frequency of intense loading to maintain health and load capacity of the tendon. (Langberg & Shovgaard 2000) Other Causes Despite loading being a major contributor to tendinopathy, it s almost most certainly modulated by other factors specific to the individual. These include genes, age, circulating and local cytokine production, sex, biomechanics and body composition. The authors suggest that considering both the loading history as well as these individual factors should be part of any clinical reasoning process. Traditional Management The management of overuse tendinopathy can be very challenging due to the variability in the condition. Recovery can vary. Some appear to recover with simple interventions, while others have persistent symptoms. Traditionally it has not been uncommon that a first time tendinopathy in a young athlete has been treated exactly the same as a chronic teninopathy in a postmenopausal female. Angiofibroblastic Some researchers have suggested that in tendinopathy an injured tendon is in a stuck in a healing phase with active cells and increased protein production. Yet there is also a disorganization of the matrix and neovascularization. Neovascularization refers to the proliferation of blood vessels within the tissue. This type of tendinopathy has been termed Failed Healing (Clancy 1989) or Angiofibroblastic Hyperplasia (Jozsa & Kannus 1997) Degenerative Tendinopathy Other researchers have described tendinopathy with pathological terms such as hypoxic degeneration, hyaline degeneration and mucoid degeneration. These descriptions suggest irreversible, degenerative changes to the cells and matrix. (Jozsa & Kannus 1997)

3 Overloading Vs Unloading Both Failed Healing and degeneration have been associated with chronic overloading of tendons but pathology has also been described at least experimentally when a tendon is unloaded. In research this has been referred to as Stress-shielded. Unloading a tendon induces cell and matrix change similar to that seen in an overloaded state (Ohno et al., 1993) plus decreases the mechanical integrity of the tendon (Kubo et al., 2004) In animals these changes have been shown to be reversible (Yamamoto et al., 1996); however few human studies have been conducted. Since complete long term unloading is not the usually presentation for tendinopathy it will not be discussed further in this paper. A New Model of Tendon Pathology The authors suggest that a plausible explanation for the varied descriptions and presentations of tendon pathology is that may we may be describing pathology along a continuum. The model consists of 3 stages of tendon pathology. 1. Reactive Tendinopathy 2. Tendon Dysrepair or (Failed Healing) 3. And Degenerative Tendinopathy The authors note for easy of understanding the model it is described in 3 distinct stages but in reality it is a continuum where one flows into the next. The primary stimulus that drives tendons up or down the continuum is adding or removing load. This is especially true in early stages. Reducing load may allow the tendon to return to its previous level of structure and capacity. (Cook et al., 2001) This new model also proposes that the pathology and therefore the response to treatment is different in each of the different stages. The model can therefore better aid clinicians target their interventions. Reactive Tendinopathy Let s define each of the 3 stages of the continuum, starting with Reactive Tendinopathy. Reactive tendinopathy is a non-inflammatory proliferative response that occurs in the cells and the matrix. It occurs following acute tensile or compressive overloading of the tendon. Adaption Response This overloading results in a short-term adaptation where there is a thickening of a portion of the tendon. The purpose of this adaption is to reduce stress on the tendon by increasing cross-sectional area, which will decrease the force per unit area. A healthy tendon usually responds to tensile load by stiffening but not thickening. (Magnusson et al., 2008)

4 Supporting Evidence Evidence to support the presence of the reactive stage of tendinopathy is fairly strong. Most of this support comes from in-vitro laboratory research work. (Scott et al., In Press) There is a homogeneous, non-inflammatory cell response to load that leads to metaplastic changes in cells, causing cell proliferation. Tendon cells become more chondroid in shape with more cytoplasmic organelles that aid in the production of protein. The primary proteins are large proteoglycans, which attracts water. The water that surrounds the protein is referred to as bound water. Collagen The integrity of the collagen is mostly maintained in this stage but there may be some longitudinal separation but no change in neurovascular structure. Quick Adaptations These initial quick adaptations in ground substance may occur as a temporary solution. In other words a way to buffer the forces until longer term change in either tendon structure or mechanical properties can occur. The quick response is possible as larger proteoglycans associated with tendionpathy (aggrecan and versican) and some glycoproteins (hyaluronan) can be upregulated in as fast as a few minutes to a few days. It takes the smaller proteoglycans at least 20 days to make these same adaptations. (Samiric et al., 2004) Reactive Tendinopathy In summary the reactive response is a short term adaption to tendon overload that thickens the tendon, reduces stress and increases stiffness. The tendon has the potential to revert back to normal if the overloading is reduced or if there is sufficient time between loading sessions to allow for tendon adaption. Imaging Viewing a tendon with imaging in the Reactive Phase will reveal a swollen tendon. The swelling is often described as being fusiform, meaning wider in the middle than at the ends. A MRI will show an increase in diameter of the tendon with minimal or no increase in signal. On ultrasound, you ll also see an increase in diameter plus intact collagen. An increased reflection from intact collagen fascicles with diffuse hypoechogenicity. Hypoechogenicity means areas of less reflection. Change in imaging in this phase mainly occur due to the increase in bound water associated with the proteoglycans Clinical Presentation The typical history for someone in the reactive tendinopathy stage is an acute tendon overload, usually

5 a burst of unaccustomed physical activity; or after a direct blow to the tendon, for example falling directly on to or a direct blow the patellar, Achilles or elbow tendons. (Garau et al., 2008) It s interesting that s direct blow, which is a non-tensile and transiently compressive load can induce a considerable reaction within the tendon s cells and matrix. Reactive tendinopathy is more commonly seen in younger patients. For example patellar tendon swelling and pain in a young jump athlete who dramatically increases the number of jumps they do in a week. Tendons chronically exposed to low levels of load may also be vulnerable to this stage of tendinopathy when exposed to a moderate increase in load. For example a detrained athlete returning from illness or injury, or a sedentary person starting activity. Tendon Dysrepair The second stage is Tendon Dysrepair. Tendon dysrepair refers to an attempt to repair or heal the tendon. In some ways it is similar to reactive tendinopathy, but there is greater breakdown of the matrix. In this phase there is an overall increase in number of cells in the tendon; mainly chondrocytes and myofibroblasts. This results in a marked increase in protein production, primarily proteoglycan and collagen. This increase in proteoglycans causes a separation of the collagen and disorganization of the matrix. These changes are often localized. There may also be an increase in vascularity within the matrix with associated neuronal ingrowth (Danielson et al., 2006) Imaging During this stage, on imaging, we will see swelling of the tendons with increased evidence of collagen disorganization and matrix disorganization. On MRI, the tendon will be swollen with an increased signal within the tendon. On Ultrasound, there is some discontinuity of the collagen fascicles and small focal areas of hypoechogenicity. The increase in vascularity may be evident on color or power Doppler. Adding activities that enhance vascularity may aid in showing a greater number of vessels. For example heat, exercise, or hanging the limb. Clinical Presentation Clinically, patients in this stage of can be of any ages and from various loading environments. This pathology has even been reported in chronically overloaded tendons in the young. (Cook et al., 2000)

6 It is often challenging to identify this stage. Tendons are usually thick with localized changes in one area of the tendon. Imaging may be the best method to detect some of these localized structural changes, with or without changes in vascularity. Frequency, Volume & Duration Clues from patient s history that may aid in identifying someone in this phase include the frequency, volume or length of time over which load has been applied. For example months or years rather than days. Older people with stiffer tendons have less adaptive ability in their tendons than younger people. This is why an older person may develop this stage of tendinopathy with relatively low loads. Some reversibility of pathology is possible in this stage with load management; plus exercise to stimulate the organization of the matrix structure. (Ohberg et al., 2004) Degenerative Tendinopathy The third phase is Degenerative Tendinopathy. In Degenerative Tendinopathy there has been a progression of both matrix and cell changes (Kraushaar & Nirschi 1999). These include areas of cell death due to apoptosis, trauma or tenocyte exhaustion. Tenocytes produce collagen. (Lian et al., 2007) Exhaustion of these cells causes areas of acellularity, in other words areas absent of any cells. There are large areas of disorganization in the matrix with many blood vessels. You will also find very little collagen and the byproducts of matrix breakdown. It should be noted that the whole tendon is not degenerated. In fact it is more like islands of degenerative pathology surrounded by normal tendon and areas of tendon in other stages of pathology. Unfortunately for the areas of tendon in the degenerative stage there is little capacity to recover. Imaging On imaging, you will see compromised matrix and sometimes extensive vascular changes. On MRI, you will see increased tendon size and intratendinous signal, indicating localized changes rather than the whole tendon. On ultrasound, you will see hypoechoic regions, meaning very few reflections, with some reflections from collagen fascicles Numerous and larger vessels are usually visible on Doppler US. Clinical Presentation Clinically, this stage of tendinopathy is primarily seen in older people; but it s possible in younger people or elite athlete with chronically overloaded tendons. A classic presentation is a middle aged recreational athlete with focal Achilles tendon swelling and pain having one or more focal nodular areas with or without general thickening of the tendon. It s not

7 uncommon to hear of repeated bouts of tendon pain over a period of time which has often resolved but returns as tendon loading changes. Rupture If degeneration is extensive enough or if the tendon is placed under enough high load, a tendon in this phase can rupture. (Nehrer et al., 1997) In fact in one study of 891 spontaneous tendon ruptures, 97% had degenerative changes (Kannus & Jozsa 1991) Evidence to Support this Model In this next section the authors present the evidence that help support this new model. They draw from Histopathological Studies, Imaging Studies and Clinical Studies. Histopathological Studies The authors note that longitudinal monitoring of histopathological change in human tendons is ethically difficult. The previously listed stages and progressions have been derived from integrating evidence from crosssectional studies with findings from animal model studies. Limited weight has been placed on outcomes from animal studies as animal tendons behave slightly differently compared to human tendons. If we look at the histopathological studies referenced in this article we see the following findings. - Cell change were always present when matrix changes became apparent in human asymptomatic tendons (Cook et al., 2004) - Changes to the matrix were primarily in the ground substance, followed by collagen and then (theoretically but not demonstrated) in vascularity o The authors note this supports the concept for a progression from normal to reactive response and tendon dysrepair. This study did not examine tendons that would be classified as degenerative. - In an animal study, Scott et al (In Press) reported a similar progression in pathology in overloaded rat supraspinatous tendons - Degenerative tendinopathy has been extensively described in the literature but the transition of the tendon from dysrepair to degenerative has not been demonstrated in the laboratory. Articular Cartlidge The authors note that the concepts suggested by this model are similar to a proposed model for articular cartilage pathology proposed by Pollard et al., That model suggested that in osteoarthritis, the cartilage can progress from a reversible stage through to an advanced OA stage. - In the earlier phases there is reversible proteoglycan upregulation, initial swelling and cellular upregulation. In the later stages there is irreversible heterogeneous tissue changes including cell and cartilage degeneration and erosion; and subchondral bone remodeling.

8 Imaging Studies The use of longitudinal imaging studies in humans allow for the tracking of changes in the tendon over time. The following studies demonstrate that some transition up and down the proposed pathology model can occur. If we start with the Acute Tendon Response. The first imaging study mentioned looked at the Achilles tendon immediately following strength training. They found an increased in the MRI volume and signal in abnormal Achilles tendons (Shalabi et al., 2004). This suggests tendons respond rapidly. The response of the tendon was to increase volume, or circumference, and increase water, either bound water or as part of ground substance or within the vessels. Normal to Reactive In Malliaras & Cook (2006) study they found nearly half of normal patellar tendons became abnormal, mainly reactive tendinopathy, in the presence of an ongoing load from a season of volleyball. One tendon even became hypoechoic suggesting a transition from the reactive tendinopathy phase to the tendon dysrepair or degenerative phase. Reactive to Normal Longitudinal imaging studies have consistently demonstrated that between 10-30% of tendons reported as abnormal at baseline become normal by follow up (Cook et al., 2000; Fredberg & Bolvig 2002; Khan et al., 1997). This support that a transition of a tendon from reactive phase back to normal is possible. Reactive to Dysrepair In Cook et al., 2000; they observed that within a group of young athletes who were at risk of tendon overload and pathology, there was a subgroup with microhypoechoic areas on ultrasound. (Cook et al., 2000) Where small islands of the tendon had started to develop collagen disorganization. This may represent evidence of a transition from the reactive phase to the tendon dysrepair phase. At the time of publishing there is little evidence to support the reversal of this transition in longitudinal imaging studies. Dysrepair to Degenerative Unfortunately the transition from dysrepair to degenerative has not been clearly demonstrated in the literature. One reason for this is traditionally these two phases have been considered one. Clinical Studies The authors note that as of the time of publishing there is still limited evidence available from clinical studies to help support this model. They do however draw from the fact that the load can have a cumulative effect on tendons. For example retired elite athletes who placed a high load on their Achilles tendons in early adulthood have a

9 higher incidence of tendinopathy and rupture when compared to age-matched controls. (Kujala et al., 2005) Since rupture represents end-stage degenerative tendinopathy (Kannus & Jozsa 1997), it can be concluded that high chronic load may be an important factor in tendon pathology. Non-Reversibility This conclusion also supports the concept that these degenerative changes may be non-reversible, as the tendon of these older ex-athletes has not recovered with time. The inability of the tendon to recover once reaching the degenerative stage is also supported by studies that have examined tendons many years after injury or rupture. Degenerative tendons can show improved function despite not returning to normal size or structure. In fact several studies have shown that large hypoechoic areas do not change (Adriani et al., 1995; Karjalainen et al., 1997; Sanchis-Alfonso et al., 1999) Another example is tendons used as the graft site for ACL reconstruction surgery remain abnormal for many years post surgery. (Kiss et al., 1998) Placing Clinical Treatments in Pathology Model The model up to this point has focused just on the pathology in the three different phases of tendinopathy. But how can the model help with directing treatment? The first step is to decide where on the continuum a patient resides. For ease of use, the authors have divided pathology into two clear groups o o Reactive / early Tendon Dysrepair And Late Tendon Dysrepair / Degenerative From a clinical examination and imaging results the authors feel that most clinicians should be able to place patients into one of these two categories. For example an older person with a thick nodular tendon will more likely be a degenerative tendon and therefore fit in the Late Tendon Dysrepair / Degenerative category. Where a younger athlete with fusiform swelling of their tendon after an acute overload will more likely be a reactive tendinopathy and therefore fit in the Reactive / early Tendon Dysrepair category. Role of Imaging The authors recognize that not all tendons will be so clear cut. In these patients imaging may play an important role. For example if a tendon is generally swollen and mildly hypoechoic or has one or several small focal hypoechoic areas with no or minimal vascular changes, this will more likely fall in to the reactive / early tendon disrepair category.

10 Whereas a tendon with large discrete areas of hypoechogencity, multiple vessels and more focal swelling will fit in the late tendon dysrepair/ degenerative category. Threshold By dividing the pathology into two categories, it defines a threshold point. This threshold point, or where tendons progress from the reactive / early tendon dysrepair category to the late tendon dysrepair/ degenerative category signifies a cross over point where once crossed the tendon in unable to cross back. Tendons in the late tendon dysrepair / degenerative category have significant enough cell dysfunction or death that matrix protein production is compromised. It s this inability of the matrix to regain structural integrity that means the tendon is incapable of ever fully repairing itself. For example in Ohberg et al., 2004, they demonstrated improvement in Achilles tendon pain, structure and vascularity after an eccentric exercise program, yet the tendon remained thicker for several years. (Ohberg et al., 2004) Placing Pain in this Model of Tendinopathy There is often dissociation between pathology and pain in tendinopathy. Meaning that tendons can appear normal on imaging but be painful (Malliaras & Cook 2006). Another study found that 2/3rds of tendons with enough degenerative damage that placed then at risk of rupturing, reported no pain prior to rupturing. (Cook et al., 2000) Basically, pain can occur at any point along the continuum. Pain Sources Since pain can occur anywhere along the continuum, it is likely that there are multiple contributors to pain. For the late dysrepair/degenerative phase, the pain generating sources have been associated with neurovascular in growth (Alfredson 2005). Another possible pain source is the presence of biochemical substances stimulated by either compression or tension acting on sensitized nerves in the matrix. Pain in the reactive and tendon dysrepair phases, where there is a lot of cellular activity, may be explained by autocrine or paracrine signaling from the release of substances such as catecholamines, acetylcholine and glutamate. Autocrine signaling refers to cell signaling stimulating changes within the cell, paracrine signaling refers to stimulating changes in neighboring cells. (Danielson et al., 2006) Pain Since pain is the single most important clinical feature that clinicians and patients alike seek to change, the success of treatment is judged by the ability to reduce pain.

11 This is one of the reasons why the authors have listed pain separately in the model. As a clinician it is important to consider both pain levels and response to load within the different stages of pathology. Tendinopathic Pain There is two key features of tendinopathy pain. 1. Pain is dose dependent. This can refer to either load from a single exposure or from cumulative loading. In other words pain will usually increase with increasing load. 2. Pain is well localized to either the tendon or insertional site of the tendon Assessment Ideally, in order to assess functional levels, during assessment the tendon should be provocatively loaded to fully evaluate the level of pain With that being said, this loading should occur within the context of the stage and level of pathology. There may be occasions where this is just not appropriate. For example an extensively degenerated tendon with mild pain may have insufficient integrity to tolerate high loads and even be at risk of rupturing. Or an acute tendinopathy in the reactive stage is usually irritable and will therefore be further aggravated by this type of assessment. Treatment of Tendinopathy The goals of treatment should be, 1) to reduce pain, and 2) effect changes in tendon structure or pathology. Since pain can occur anywhere along the pathology continuum, interventions that reduce pain and are appropriate in any stage. Whereas inappropriate treatment in any stage may increase pain and therefore lead to poorer clinical outcomes (Fredberg et al., 2008). In an attempt to simplify the management of tendinopathy, polymodal interventions will not be discussed in this paper, instead we will focus on Physical Treatments & Pharmacological Management. Reactive tendinopathy / tendon dysrepair Let s start with tendons in the Reactive Tendinopathy / Tendon Dysrepair Category. Physical Treatments Under the category of physical management the number one intervention is load management, meaning reduce the load on the tendon. For tendons in this stage, time is needed to allow adaptations; including allowing cells to become less reactive and the matrix to resume its normal structure. Pain will likely reduce if these things occur. Good load management includes both assessment and modification of intensity, duration, frequency and type of load. This may be as simple as allowing a day or two rest between high or very high tendon load activities.

12 Studies have shown that type 1 collagen precursors peak in tendons around 3 days after a single bout of intense exercise. This is why allowing adequate time between bouts of activity may be an important factor in managing tendinopathies in the early stage. (Langber et al., 1999) Exercise Exercise or tendon loading that doesn t involve the storage and release of energy can be maintained during this time. For example cycling or strength-based weight training High load elastic or eccentric loading, particularly with little recovery time, especially on successive days, is not recommended and will tend to aggravate the tendon. Pharmacotherapies The use of NSAIDs in this stage has been controversial. They may reduce pain but have also been reported to slow tissue healing and therefore have a negative effect on tendon repair. (Ferry et al., 2007) Interesting enough in reactive tendinopathy slowing the healing response may actually be a desirable effect to slow tenocyte upregulation and excessive ground substance expression. (Cook et al., 2004) Ibuprofen Ibuprofen, as well as indomethacin and naproxen sodium, have been shown to inhibit the expression of key ground substance proteins responsible for tendon swelling (aggrecan) in in-vitro tendon studies. (Wilson et al., 2000) Ibuprofen and celecoxib have also been reported to have specific effects on down regulating the cellular response. (Tsai et al., 2004; Tsai et al., 2007) Ibuprofen may be the favored NSAID as it has not been shown to have a detrimental effect on long term tendon repair. (Ferry et al., 2007) Corticosteriods Corticosteriods also decreases cell proliferation, protein production and pain are therefore may be appropriate in the reactive phase. Although repeated peritendinous corticosteroid injections have been shown to reduce tendon diameter, at 7 & 21 days post injection (Fredberg et al., 2004) Peritendinous injections have been clinically accepted, but it is not known currently whether peritendinous injection actually induces cell and matrix changes within the tendon. Late Tendon Dysrepair / Degenerative Tendinopathy Now let s look at the Late Tendon Dysrepair / Degenerative Tendinopathy category. Physical Treatments Under Physical Management, any treatments that stimulate cell activity, increases protein production, including both collagen or ground substance; and helps restructure the matrix are appropriate for this stage.

13 Frictions Friction massage has been proposed as an effective treatment in tendon injuries in this phase. The rational for this technique is that it helps improve tendon structure. As of publishing, there are few human studies to support this and the ones that have been performed show mixed results. (Wilson et al., 2000). It has been shown to increase protein production in animals. (Gehlsen et al., 1999) Overall, when compared to exercise, frictions are less effective in reducing pain (Stasinopoulos & Stasinopoulos 2004 ) Extracorporeal Shock Wave Therapy Extracorporeal Shock wave therapy (ESWT) has been shown to reduce pain in a number of studies. Although ESWT has not consistently shown to be superior to placebo. Animal studies have shown variable results in terms of morphological and mechanical benefits. (Maier et al., 2002) Ultrasound Ultrasound has been shown to increase protein production in tendons. (Enwemeka 1989). But in studies involving patellar tendinopathy, ultrasound has been shown to be less effective than exercise. (Stasinopoulos & Stasinopoulos 2004; Warden, In Press) Surgery Despite studies showing variable outcomes, surgery is still considered a reasonable option for those who fail conservative treatment. In an athletic population, several studies have reported that between 50-80% of athletes undergoing tendon surgery were able to return to their sport at their previous level. (Coleman et al., 2000; Paavola et al., 2000, Tallon et al., 2001) It should be noted that in surgical studies the surgical techniques is often very different but the results are very similar (Coleman et al., 2000) For patellar tendinopathy surgery, outcomes are comparable to outcomes achieved with eccentric exercise training (Bhar et al., 2006) or ESWT (Peers et al., 2003). In non-athletic people surgery has produced poorer results. (Maffulli et al., 2006) Pharmacotherapies When looking at the use of medication in this phase, any treatments that stimulate the healing response is considered appropriate. Prolotherapy Injections into the tendon of various substances or even the process of the injection itself have been proposed as being beneficial in a degenerated tendon. Examples of substances injected include Prolotherapy, which uses glucose and blood to stimulate a tissue response.

14 The injection of blood stimulates cell proliferation within the tendon which in turn produces vascular endothelial growth factor. (Anitua et al., 2005) This has been demonstrated to induce changes in the matrix. Other studies have shown reduced vascularity and a decrease in the diameter of the tendon. (Suresh et al., 2006) Injection Process It has been proposed that perhaps it is the injections itself and not the substance being injected that has the beneficial effect on the structure of the tendon. One study found improved structure in degenerative tendons at 1 year after multiple tendon biopsies when compared with an untreated group. (Shalabi et al., 2004) Another study showed similar outcomes when comparing the injections of an active substance (poidocinol) with a placebo (anaesthetic and adrenaline). (Zeisig et al., 2008) Aprotinin Another medications that has shown some promise it Aprotinin. Aprotinin is a collagenase inhibitor which may preserve collagen in a remodeling matrix. A Randomized Placebo controlled trial showed benefits of Aprotinin over a placebo, (Brown et al., 2006) while another studies show a reduction in pain with the use of this medication. (Capasso et al., 1997) Sclerosing Therapy Sclerosing therapy, which is the injecting of a scarring agent, has repeatedly been shown to be effective in treating pain and improving structure in tendinopathy. (Lind et al., 2006) (Hoksrud et al., 2006) Alfredson & Ohberg 2006 suggested that the positive effect on pain may be more through chemical neurolysis, or the destruction of neural structures, rather than vascular changes. (Alfredson & Ohberg 2006) Glyceryl Trinitrate Glyceryl trinitrate has been shown in several studies to provide additional relief of tendon pain on top of what has already been achieved from eccentric exercise (Paoloni et al., 2004; Paoloni et al., 2003; Paoloni et al., 2005) This topical application is reported to deliver increased amounts of nitric oxide to injured tendon leading to collagen synthesis. Although another study did not support that the tissue actually had increased levels of NO or actually benefited from the treatment.(kane et al., 2008) Further research is needed to examine the long term effect of this treatment on tendon structure and tendon vascularity. Placing Exercise in this Model Lastly in the treatment section, and probably most importantly for Physical Therapists the authors discuss exercise.

15 Eccentric Exercise Exercise, particularly eccentric exercise has been shown to effect tendon structure both in the short term (Shalabi et al., 2004)and the long term. (Ohberg et al., 2004). Eccentric exercise has been shown to increase collagen production in abnormal tendons but does not produce the same result in normal tendons. (Langberg et al., 2007) Eccentric exercise has also been shown to decrease the proliferation of tendon vessels (Ohberg & Alfredson 2004). Eccentric Exercise (2) Eccentric exercise is effective in relieving pain with changes in pain levels typically occurring in the first 4-6 weeks. (Roos et al., 2004) A meta-analysis by Woodley et al., 2007 supported eccentric exercise in the management of pain, while having the added benefit of also improving function. Exercise Prescription - Earlier Stages For athletes in the earlier stage of tendinopathy, who had already been loading their tendons significantly, adding exercise, whether painful or not, may not be beneficial. (Langberg et al., 1999; Visnes et al., 2005) Exercise is a potent stimulus to tendons, especially when they may already have upregulated cells. Additional exercise may overstimulate an intact but sensitized matrix. Exercise Prescription - Later Stages In degenerative tendinopathy, exercise appears to be a positive stimulus for cell activity and matrix restructuring. The Alfredson eccentric exercise program suggests that pain during exercise in this stage may be OK and tolerated by the tendon. (Alfredson et al., 1998) This was suported by Silbernagel et al., 2007 who also studied Achilles Tendinopathy patients and allowed a pain level of less than 5/10 during exercise. It is hypothesized that pain in degenerative tendinopathy may be more due to neurovascular structures than cellular products. For this reason tendons in this stage appear to be less reactive and less irritable. Discussion Although presented as discrete stages of pathology, it is highly probably that some tendons may have discrete regions that are in different stages at the same time. (Kahn et al., 1999) For example a tendon that contains degenerative changes may get acutely overloaded and therefore develop reactive changes in a previously normal part of the tendon. The evaluation of these more complex presentations has deliberately not been discussed in this paper.

16 Research It is the hopes of the authors that the presentation of this model may aid future research and may explain to some extent the variable response to treatment seen in other studies. It may be important to recognize subpopulations within the wide continuum of tendon pathologies. For example the most consistent outcomes in research has occurred when the participants are clearly in same group such as the Alfredson s eccentric exercise research in older, presurgical patients. Very little research has been conducted on early stage tendinopathy. This is probably because of the difficulties in assembling a large enough sample size to study, the variability of pain presentation and the capacity to spontaneously recover. Other Factors Individual factors may also play an important role on the patient s ability to progress either direction along the continuum (September et al., 2008) Factors such as genes, age, circulating & local cytokine production, sex, biomechanics and body composition most likely have an important role in the response to treatment. For example some athletes just appear to be completely resistance to tendon issues despite withstanding high loads while others seem to sustain tendon ruptures relatively early in their careers. Identifying and early load management in these at-risk athletes may keep them in the early stages of tendon pathology and limit progression along the continuum. Time for recovery The ability for tendons to transition up and down the continuum makes estimating the time needed for recovery difficult but overall tendons respond very slowly both in improving load capacity as well as resolving pain. Conclusion In conclusion this model explains most clinical presentations and most findings in the tendon literature. It can even encompass primary collagen tearing and some form of inflammation underpinning the cell and matrix response. Conclusion Emerging mechanisms for injury, complex interactions between the cell and matrix and systemic and local factors (growth factors, cytokines and treatments) will need to be built into this model. The integrity of the model will only be as good as its capacity to withstand additional research. This model now requires scientific and clinical evaluation.

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