An update on pain mechanisms
– Written by Robert-Jan de Vos, The Netherlands
Chronic Achilles tendon disorders are frequent in the active population. The terminology used in the field of chronic tendon disorders has changed over the past decades; ‘tendinopathy’ is currently the preferred term as the best descriptor of the clinical picture. Histopathological studies show that tendinopathy is a degenerative process of the tendon tissue in the majority of the cases. Disorganisation of the tendon structure as a result of the degenerative process can be visualised with imaging techniques. This article discusses the association between Achilles tendon structure organisation, measured with a novel imaging technique and patient symptoms. New theories of potential pain generators in tendinopathy are described.
Overuse Achilles tendon disorders are commonly observed in active middle-aged people. Running athletes are at an increased risk, with a lifetime risk of 52% in elite long-distance runners1. In the last few decades, the emphasis on sports activities has increased in the general population. There are also increased physical demands on high-level competing athletes. These might also lead to an increased risk of overuse injuries.
The terminology for description of these chronic overuse tendon disorders has changed, as there are no classical signs of inflammation after biopsy or with microdialysis techniques. The term ‘tendinitis’ has therefore been abandoned. Histological studies on chronic painful tendons also show degeneration of the tendon tissue, frequently referred to as ‘tendinosis’. On histological assessment tendinosis encompasses a wide range of entities not only affecting tendon collagen fibres, but also tenocytes and other non-collagenous matrix components (Figure 1). Tendinosis is a histopathological diagnosis and since biopsies are not routinely used in daily clinical practice, a clinical descriptor is used in the current terminology. It is generally accepted to use the term ‘tendinopathy’ in presence of pain and swelling of the Achilles tendon and an impaired load-bearing capacity2. This clinical diagnosis is highly associated with the presence of degenerative changes on histology.
Tendinopathy in the Achilles region usually effects one of two locations; the tendon insertion or the midportion. The midportion is said to be located 2 to 7 cm proximal to the calcaneus. These conditions should be distinguished clinically, because of the differing pathology and clinical decision-making. Insertional tendinopathy is associated with an enlarged prominence of the postero-superior calcaneus, an enlarged retrocalcaneal bursa and tendinopathy of the Achilles tendon insertion. These structures are more susceptible to compressive forces and tensile forces may be less important. Midportion Achilles tendinopathy is more confined to the tendon itself and less susceptible to influence of surrounding structures (e.g. a bursa or bony prominence). It is more common, easily defined and recognised in clinical practice, which may explain why the majority of research focuses on midportion Achilles tendinopathy.
Another important feature is the distinction between acute and chronic tendinopathy. Both typically start insid-iously, but chronic tendinopathy is often defined as the presence of symptoms for more than 3 months. However, these distinctions are not based on histopathological features. There is also scarce scientific knowledge on the progression of tendon tissue disorders over time. A continuum model of tendon pathology has been proposed previously by Cook and Purdam3. This continuum model is based on findings in animal studies and imaging studies in humans. They propose that tendon overuse initially results in a reactive phase, followed by a dysrepair phase and finally a degenerative phase. The initial reactive stage is characterised by an increase in interfibrillar glycosaminoglycans (GAGs), which are water-attracting non-collagenous matrix components that probably explain the swelling typically seen in acute cases. Tendon cell proliferation is also observed, while the tendon collagen fibres remain unaffected in the initial stage of tendinopathy. If overuse continues or recurs, disorganised tendon tissue structure is the consequence in the dysrepair stage. Reactive tendinopathy and tendon dysrepair are thought to be more or less reversible, while degenerative tendinopathy is regarded as the irreversible end-stage of overuse tendon disorders.
IMAGING OF TENDON STRUCTURE AND ASSOCIATION WITH PAIN
Imaging with conventional ultrasound
Ultrasonography (US) has several benefits as it is readily accessible, quick to perform in experienced hands and there is a possibility of interaction with the patient. One of the most recognisable signs of chronic tendinopathy is the loss of a well-organised tendon tissue structure as a result of the degenerative process. US is a suitable imaging modality to visualise this degenerative process and the Achilles tendon is an ideal location for research purposes because of its superficial location4.
The major findings with conventional US in chronic midportion Achilles tendinopathy are:
1. Fusiform tendon thickening,
2. Presence of hypoechoic areas accompanied by disorganised tendon tissue structure and
3. Increased Power Doppler flow.
Hypoechoic areas and disorganised tendon structure are thought to be present in the majority of patients with chronic Achilles tendinopathy. Previous studies have focused on the prognostic value of hypoechoic lesions with conflicting results5. However, US is an operator-dependent technique which can easily influence appearance and size of a hypoechoic area, due to transducer-handling and machine settings. The reliability of the characteristics of conventional ultrasonographic tendon structure organisation assessment is not known. Moreover, it is challenging to compare changes over time.
Imaging with a novel technique – Ultrasonographic Tissue Characterisation
To overcome the above-mentioned problems, a novel ultrasonographic technique was introduced in veterinary medicine6. This computerised ultrasono-graphic tissue characterisation (UTC) was originally developed for use in horse tendons. Standardised collection of ‘raw’ ultrasonographic images can be performed with UTC and with the use of a custom-designed algorithm, it is possible to quantify the three-dimensional stability of echo patterns. The UTC developers showed a match between the underlying structure on histology and the stability of the echo patterns.
The standardised UTC procedure is further explained in Figure 2. All 'raw' transverse ultrasonographic images can be stored on a computer. Subsequently, the Achilles tendon can be tomographically visualised in three planes of view after reconstruction of the images (Figure 3). The thickest part of the tendon can be identified in the transversal view. Next, the border of the tendon can be drawn at its thickest part. The three-dimensional stability of the echo pattern within the tendon can be evaluated with the use of specialised software. The intensity and distribution of the echo patterns over the consecutive transverse images can be analysed with the software (Figure 4). The processing of these images enables the discrimination of four different echo-types: echo-types I and II (green and blue pixels in Figure 4) are generated from one single ultrasound reflection that typically belong to one interface structure and are therefore thought to represent more or less organised tendon bundles. Echo-types III and IV (red and black pixels in Figure 4) are generated by multiple reflections that interfere as a consequence of multiple interfaces that are thought to represent smaller, disorganised and more amorphous or fibrillar structures that have been described in tendinotic tissue7.
The colour-coded system of these different echo-types aids visualisation of the location of any disorganised structure within the tendon. The percentages of the four echo-types within the tendon can be calculated, allowing quantification of the amount of disorganised tendon structure.
For scientific purposes it could be useful to correlate the severity of tendon structure disorganisation with the severity of pain. Moreover, for the clinician it would be valuable if there is a prognostic value of the amount of tendon structure disorganisation. In other words – does bad tendon structure have a less favourable patient outcome?
CAN UTC DISCRIMINATE PATIENTS FROM CONTROLS?
In an initial study, UTC measurements were performed in 26 tendons of patients with midportion Achilles tendinopathy and 26 asymptomatic controls. This study reported significantly less stability of transverse echo patterns (less echo-types I and II) in symptomatic tendons compared to asymptomatic tendons5 (Figure 4). As such, UTC was able to discriminate between symptomatic and asymptomatic tendons, indicating its potential value for the evaluation of treatment in tendinopathy.
Test characteristics of UTC
In the same study, the inter-observer reliability of determining organised tendon structure (echo-types I+II) was excellent (intraclass correlation coefficient 0.95)5. However, the echo-types are representative for the tendon structure and this is a continuous outcome measurement. Therefore, information on the minimal detectable change (MDC) is also needed. The MDC for the different echo-types is defined as the minimum amount of change, in percentage, of the echo-types that ensures the change is not the result of measurement error. Five patients and controls (10 tendons) were included in a small pilot study with the aim to be better informed about the MDC. One trained researcher performed an UTC measurement and analysis for every Achilles tendon. This procedure was repeated 2 days later, to evaluate the intra-observer variation. The MDC for organised tendon structure (echo-types I+II) was 7%, which suggests that any change below 7% could be a result of a measurement error and should not be regarded as a true improvement or deterioration of tendon structure in a patient suffering from Achilles tendinopathy. The results are displayed in Table 1 (unpublished data, de Vos RJ and de Jonge S).
TENDON STRUCTURE CHANGES DURING TREATMENT PROTOCOLS
The first cohort study observed changes in echo-types in 25 patients with chronic midportion Achilles tendinopathy treated with a 16-week eccentric exercise programme8. The mean organised tendon structure did not change after 24 weeks, while patient symptoms improved significantly. In a second observational study the effects of eccentric exercises were combined with a saline injection (placebo) or a platelet-rich plasma injection. Platelet-rich plasma is defined as an increased concentration of platelets which can be isolated from the patients’ whole blood. This is thought to have a regenerative effect. Using improved machine settings of UTC, there was a significant improvement in both tendon structure (mean 12% improvement in organised tendon structure after 24 weeks) and perceived symptoms of the patient after the eccentric exercises and an injection (Figure 5)7. The platelet rich plasma injection did not result in an improved tendon structure compared to placebo. Interestingly, we showed that there was no association between the amount of improvement in tendon structure organisation and of the improvement of symptoms8. There was also no association between the amount of disorganised tendon structure and patient symptoms at a single point in time8. Furthermore, until now it has been impossible to predict recovery based on the ultrasonographic tendon structure organisation – a patient with poor tendon tissue quality does not have a worse prognosis than someone with only moderate disorganisation.
UTC AS A TOOL IN PREVENTION OF TENDON INJURY
It would be interesting to evaluate if tendon structure is of prognostic value for Achilles tendinopathy or Achilles tendon rupture in athletes. Ruptured Achilles tendons always show signs of degeneration on histology9. These Achilles tendons are usually not painful prior to rupturing. Therefore, development of screening tools for high-risk athletes might be interesting.
An ultrasonographic study in elite asymptomatic soccer players showed some prognostic value of tendon thickening10. This spindle-shaped thickening of the Achilles tendon is commonly associated with structure disorganisation. Almost half of the players with ultrasonographic abnormalities but no pain at the time of testing developed symptoms within one year. On the other hand, more than half of the players who had no symptoms but an abnormal ultrasound did not develop symptoms. A recent study showed a transient change in UTC echopattern of the Achilles tendon after an Australian football game11. The prognostic value of UTC in asymptomatic athletes has – to date – not been studied and its value as screening tool therefore remains unknown.
ASSOCIATION BETWEEN TENDON STRUCTURE AND PATIENT SYMPTOMS
As stated above, it is possible to quantify tendon structure with a high reliability and to observe objective effects of treatment protocols using the novel UTC-technique. UTC can discriminate tendon structure of patients from asymptomatic controls, nevertheless no association is present between the amount of disorganised tendon structure and patient symptoms and UTC cannot predict recovery.
Although appropriate knowledge of tendon structure might be important in preventing tendon ruptures, the use of improved imaging and quantifying tendon structure has shown that a simple paradigm of structure being related to pain does not work. A comparable phenomenon can be found in osteoarthritis research, where only a weak association could be found between patient symptoms and radiographic severity of osteoarthritis measured with the commonly used Kellgren Lawrence scale.
These findings are very relevant, as it is crucial to know about the pain generator before starting appropriate treatment options. It is therefore not surprising that tendinopathies are resistant to many tissue-based therapies.
POTENTIAL SOURCES OF PAIN IN TENDINOPATHY
Biomarkers and pain
Several sources of pain in tendinopathy have been proposed in the scientific literature. Previously, hypotheses were based on a missing link between tendon structure disorganisation and pain. Multiple biochemical irritants have been proposed as source of pain, with inflammatory markers amongst these. Animal studies have previously shown that repetitive exposure of tendons to prostaglandins eventually results in degeneration of the collagen tissue. These inflammatory markers cannot cause the pain in chronic tendinopathy because they are absent in this phase. Research on the role of macrophages and specific interleukins is evolving.
Other possible candidates could be the neuropeptides calcitonin gene-related peptide, substance P and glutamate, as increased levels of these neurochemical markers were found in patients with tendinopathy compared with healthy subjects. However, some patients with complete recovery after successful treatment still had elevated intratendinous glutamate levels. Therefore, glutamate should probably not be regarded as the sole cause of pain. Recently, an association was reported between an increased amount of GAGs after the analysis of biopsy material and worse symptoms in patients with patellar tendinopathy12. These negatively charged GAGs are thought to sensitise nociceptive afferents and cause pain. However, to date it is unknown if there are changes of GAG contents over time in tendinopathy patients.
Neovascularisation and pain
The presence of increased tendon Doppler flow is frequently said to be linked to pain. This phenomenon is referred to as 'neovascularisation' in the scientific literature because it is thought to represent the tortuous newly formed blood vessels observed in histopathological specimens. The accompanying nerves are frequently mentioned as a possible source of pain and these are the target of treatment in sclerosing therapies. However, increased blood flow measured with Doppler techniques is sometimes observed in asymptomatic individuals. Not all painful tendons have neovascularisation and a clear association with symptoms was found to be absent in a large cross-sectional study of 556 measurements13. Novel contrast-enhanced ultrasonography techniques are currently applied in tendon research to study blood flow.
New theories on pain mechanisms
New theories on the source of tendon pain are evolving, based on pain mechanisms in other musculoskeletal pain syndromes. First, researchers and clinicians should ask themselves whether the tendon pain is peripheral or central14. Peripheral pain is caused by an increased responsiveness and reduced threshold of nociceptive neurons in the periphery, while augmented responsiveness of noci-ceptive neurons in the central nervous system is the source in central pain. All the potential sources of pain above are based on the hypothesis that the pain is peripheral and is a result of local tissue damage and subsequent local changes. This is considered to result in activation of primary local nociceptors. This seems to be a logical explanation, as tissue damage is observed and it may be a helpful warning sign to prevent complete tendon rupture. There is rationale for local nociception because tendon pain usually responds to changes in load and in most cases the pain is confined to the tendon itself.
However, many clinicians will recognise the chronicity and sometimes unpredictable nature of tendon pain. These can be characteristics of central sensitisation, which is associated with functional changes within the nervous system that do not necessarily have an association with the degree of tissue damage. Examples are ectopic generation of action potentials, facilitation of synaptic transmission and cortical changes in the brain. This is the concept of centralisation mechanisms, where the response proﬁle of neurons is altered. There does not seem to be an evolutionary advantage with this type of pain and the pain cannot be seen as a reliable way of judging the state of the tissue. The pain is generated in the central nervous system, away from the location where the tissue damage was originated. Consequently, this type of pain does not respond to treatments focusing on local tissues. A recent study already showed that elements of central sensitisation are present in relatively young patients with chronic patellar tendinopathy15. In a recent small study, however, there were no signs of central sensitisation in patients with chronic Achilles tendinopathy measured with a small number of tests16.
The use of improved imaging to quantify tendon structure has shown that in chronic tendinopathy, a simple model of structure being associated with pain cannot be supported. Currently, many treatments aim at restoring tendon structure, but clinicians should be aware that this is not related to pain. The source of pain may be a combination of multiple mechanisms, such as local biochemical irritants, neovascularisation with accompanying nerves and central sensitisation. Future research should focus on understanding the pain generators in tendinopathies.
Robert-Jan de Vos M.D., Ph.D.
Sports Physician and Post-Doc Researcher
Erasmus University Medical Centre
Rotterdam, The Netherlands
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Image by Oscar Rethwill