International Scientific Tendinopathy Symposium, Vancouver, 2012
Session 1
THE CHALLENGE OF TENDON PAIN
(tennis elbow) - Bill Vicenzino
1. Widespread hyperalgaesia -
pressure pain threshold assessed
2. Ipsilateral
thermohyperalgaesia & bilateral cold hyperalgaesia in the most severe
presentations
3. Nociceptive flexion reflex
threshold (Rhudy & France, 2007) response indicates spinal cord hyper
excitability in chronic lateral epichondylalgia, implying dorsal horn
changes (Lim et al, 2012)
4. Bisset L et al (2006) - MWM
& exercise reverse the NFR threshold changes in chronic patients
5. Conditioned pain modulation -
test stimulus (pressure pain stimulus) is increased by conditioning heat
stimulus in normal subjects - but no change in tennis elbow patients
This means that CPM might be augmented with manual therapy (Skyba et al, 2003 &
Paungmali et al, 2003)
Lim, E.C.W. et al (2012). Evidence of spinal cord hyperexcitability as measured with nociceptive flexion reflex (NFR) threshold in chronic lateral epicondylalgiawith or without a positive neurodynamic test. J of Pain; 13(7): pp676-684
ROLE OF NEUROPEPTIDES & OTHER NEUROMODULATORS IN TENDINOPATHY PATHOGENESIS - Patrik Danielson
Tendinopathy with tendonosis:
What induces tendonosis & pain? Biochemical in origin...micro dialysis
studies have shown elevated levels of glutamate (Alfredsson, 1999, 2000, 2005)
Receptors of Substance P & catecholamines are all present on blood vessel (arteries
& small vessels) cells (Danielson et al, 2006) & tenocytes (Andersson
et al, 2008)
“…biopsies from the proximal part of
normal and pain-free patellar tendons (11 men, mean age 33 years) were
examined. The specimens were evaluated by using antibodies against the general
nerve marker protein gene-product 9.5 (PGP 9.5) and the sensory neuropeptides
substance P (SP) and calcitonin gene-related peptide (CGRP), and
immunohistochemistry. It was observed that the arteries, and to some extent the
small vessels, in the loose paratendinous connective tissue were supplied with
PGP 9.5- as well as SP- and CGRP-innervations. There was a marked PGP 9.5-like
immunoreaction (LI), and to some extent also SP- and CGRP-LI, in the large
nerve fascicles in this tissue. In the tendon tissue proper, PGP 9.5-LI was
detected in nerve fibers located in the vicinity of some of the blood vessels
and in thin nerve fascicles. There was a low degree of SP- and CGRP-innervation
in the tendon tissue proper. The observations give a morphologic correlate for
the occurrence of nerve-mediated effects in the patellar tendon. Particularly
it seems as if there is a marked nerve-mediated regulation of the blood vessels
supplying the tendon, at the level where they course in the loose paratendinous
connective tissue.” (Danielson et al, 2006)
Cause & effect - Rabbit
model: production of substance P is increased after strain & this elevation
precedes the tendonosis tissue changes & is seen also on the contralateral
side
In the vitro model - rate of proliferation is increased in response to exogenesis
(Andersson, 2011)
Clinical implications - Blocking of receptors proven to be degenerative or
nerve irritating?
Andersson, G. et al (2011). Tenocyte
hypercellularity and vascular proliferation in a rabbit model of tendinopathy:
contralateral effects suggest the involvement of central neuronal mechanisms. Br J Sports Med;45: pp399-406
Andersson, G et al (2008) Presence of substance P & the neurokinin-1 receptor in tenocytes of the human Achilles tendon. Regulatory Peptides; 150(1-3): pp81-87
Danielson, P. et al (2006). Distribution of general (PGP 9.5) & sensory (substance P & CGRP) innervations in the human patellar tendon. Knee Surg Sports Traumatol Arthrosc; 14: pp125-132
PROTEASE-ACTIVATED RECEPTORS ARE
EXPRESSED IN HUMAN TENDON TISSUE & MAY EXPLAIN EXCESSIVE PAIN-SIGNALLING IN
TENDINOPATHY - Gustav Andersson
Where is the pain coming from?
Increase in mast cell populations present in tissue associated with regional pain syndromes
Tendinopathy is one such
condition where pain is not considered proportionate to tissue changes
Substance P, affects vascularity & nerves
Mast cells are known mediators
of inflammatory responses to injury but also regulate cell proliferation &
vasodilation in certain tissues by releasing histamine, tryptase, serotonin
& cytokines via PARs
Biopsies from Achilles' tendons
show that PAR1 receptor cell expression was present in vessels & nerve
fibres (stimulates angiogenesis, regulates vascular permeability
PAR 2 was found in tendon cells, cultured cells, vessels & nerve fibres (stimulate fibroblast proliferation)
PAR 3 was found on tenocytes, vessels & nerve fibres
Activation via PAR 4 in
tenocytes, cultured cells, vessels both in the tendon tissue proper as well as ventral
to the tendon & found on substance p nerve fibres (have pro inflammatory
effects, analgesic) may lead to increased nociception in joints
Clinical Implications – PAR4 may
be responsible for tenocyte proliferation & vascular regulation in addition
to enhanced pain signalling in tendinopathy through substance P positive
afferents
DOES SENSITIZATION PLAY A ROLE
IN THE PAIN OF PATIENTS WITH CHRONIC PATELLAR TENDINOPATHY - Johannes Zwerver
Pain system is ever changing - central sensitisation links pain & touch pathways, triggering pain at much lower thresholds
The aetiology & pain mechanisms of tendinopathy are not completely understood - Mismatch between pain & tendon pathology
Little is known as to whether or
to which degree somatosensory changes within the nervous system contribute to
pain in tendonopathy
Quantative sensory testing (Rolke, 2006)
Injured athletes had significantly lower mechanical pain & vibration disappearance thresholds
As this was only apparent in some athletes, suggesting success of painful
treatments in desensitising the tissue (shock wave), or central acting drugs,
whilst genetics might also contribute
The study by van Wilgen et al (2011) concluded that sensitisation may play a prominent role in the pain during & after sports activity in patella tendinopathy patients
Clinical Implications –
sensitisation may play a prominent role in the pain experienced during &
after sports activity by patellar tendinopathy patients
Van Wilgen, C.P. et al (2011). Do patients with chronic patellar tendinopathy have an altered somatosensory profile? - A Quantitative Sensory Testing (QST) study. Scand J Med Sci Sports; doi: 10.1111/j.1600-0838.2011.01375.x
UNILATERAL TENDON INJURY
ACCELERATES TENDON MINERALIZATION BILATERALLY - Etienne O'Brien
Tendon mineralisation might
occur bilaterally in response to unilateral injury
Mineralisation of tendons can lead to pain, resulting in underuse & a
weaker tendon
Low load through underuse can cause an increase in hysteresis & decrease in tendon stiffness
The impact of this mineralisation on these tendon properties is unknown
High load (failure)
biomechanical tests were performed in mice
Results showed mineralisation in
both the ipsilateral & contralateral tendons
Creep in the non injured leg was significantly greater than creep in the
injured leg - unilateral injury was shown to effect biomechanical changes in
the uninjured leg & increased creep
Tendons failed close to the insertion
Why?
1) Neurological (Decaris et al 1999, Arthritis Rheum)
2) Circulatory
3) Change in loading
Clinical Implications - consider
bilateral occurrence on assessment
O’Brien, E.J.O. et al (2012). Heterotopic mineralization (ossification or calcification) in tendinopathy or following surgical tendon trauma. Int J Exp Path; 93(5): pp319-331
Mikic, B. et al (2009). Sex matters in the establishment of murine tendon composition & material properties during growth. J Orthop Res; 28(5): pp 631-638
HUMAN TENOCYTES ARE STIMULATED
TO PROLIFERATE BY ACETYLCHOLINE THROUGH AN EGFR SIGNALLING PATHWAY - Gloria
Fong
Human tendons have the capacity to produce acetylcholine but also express acetylcholine receptors...increased production & receptor expression in tendinosis
Hypercellularity & angiogenesis are key histopathological features in tendonosis tissue
The proliferative effect of acetylcholine was decreased in response to atropine
Hypercellularity might be a part
of the healing or adaptive response in the early stage of tendinosis but
excessive tenocyte proliferation could be detrimental to tendon structure &
function in the chronic stage
The non-neuronal cholinergic system of tendon tissue is therefore a possible target for future modulation of these processes in tendinosis
UNDERSTANDING TENDON PAIN
MECHANISMS THROUGH A SYSTEMATIC REVIEW OF WIDESPREAD MANIFESTATIONS OF
UNILATERAL TEDINOPATHY - Luke Heales
Whilst the focus has been on tendon pathology in tendinopathy, the potentially
widespread systemic effects on the pain, motor & sensory systems are poorly
understood.
20 studies included, with concentration on lateral epicondylalgia
5 papers showed a significant decrease in sensory pressure thresholds on the contra lateral side
Heat pain thresholds were
overall shown to have decreased on the contralateral side
Reaction time & two-choice reaction time were seen to have significantly decreased in the studies
Grip strength studies were mixed, with one showing increased strength suggesting compensation but others showing a decrease
Clinical Implications: The
presence of widespread changes in measures of pain & sensorimotor function
in human studies imply that there is abnormal CNS processing
Genaidy, A.M. et al (2007). An epidemiological appraisal instrument – a tool for evaluation of epidemiological studies. Ergonomics; 50(6): pp920-960
Rees, J. et al (2009). Management of tendinopathy. AJSM; 37(9): pp1855-1867
Smeulders, M.J.C. et al (2002). Motor control impairment of the contralateral wrist in patients with unilateral chronic wrist pain. Am J Phys Med & Rehab; 81(3): pp177-181
Xu, Y. & Murrell, G. (2008). The basic science of tendinopathy. CORR; 466(7): pp1528-1538
TENDONS - TIME TO REVISIT
INFLAMMATION? - Jonathon Rees
Evidence of an active process incorporating an inflammatory response
Schubert et al 2005 - macrophages, T & B lymphocytes are seen in chronic
tendinopathy
Tenocytes proliferate in response to cytokines & growth factors that are
part of the inflammatory response
Neovessels - indicate active inflammation in a rheumatological context
Prostaglandins - prolonged expression of PG1 & PG2 cause tendon changes (Sullo et al, 2001; Zhang et al, 2010; Khan et al, 2005)...only visible at certain times
Tendon matrix is in total flux
Substance P increases in chronic tendinopathy
Treatments:
- Corticosteroids but issues
remain regarding symptom recurrence & integrity
- NSAIDS, have an effect on
nociception but the effect on healing is conflicting (studies show both
increase & decrease on stiffness)
- Anti TNF regulates
interleukins 1&6, MMP1&3, VEGF, PGE2
- Nerve growth factor linked
with nerve proliferation
The evidence for degeneration
alone as the cause of tendinopathy is weak.
There is compelling evidence that inflammation is a key component of
chronic tendinopathy. Newer anti-inflammatory
modalities provide alternative potential opportunities in treating chronic
tendinopathies
Khan, M.H. et al (2005). Repeated exposure of tendon to prostaglandin-E2 leads to localized tendon degeneration. Clin J Sport Med; 15(1): pp27-33
Sullo, A. et al (2001). The effects of prolonged peritendinous administration of PGE1 to the rat Achilles tendon: a possible animal model of chronic Achilles tendinopathy. J Ortho Sci; 6(4): pp349-357
Wang, J.H.C. (2006). Mechanobiology of tendon. J Biomech; 39: pp1563-1582
