efectos sensitivos y motores del dolor inducido en pacientes con epicondilalgia

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Sensory and motor effects of experimental muscle pain in patients withlateral epicondylalgia and controls with delayed onset muscle soreness

Helen Slatera,b, Lars Arendt-Nielsena, Anthony Wrightb, Thomas Graven-Nielsena,*

aLaboratory for Experimental Pain Research, Center for Sensory-Motor Interaction, Aalborg University, Fredrik Bajers Vej 7D, 9220 Aalborg E, Denmark

bSchool of Physiotherapy, Curtin University of Technology, Perth, WA, Australia

Received 1 July 2004; received in revised form 22 November 2004; accepted 2 December 2004

Abstract

This study compares the effect of experimental muscle pain on deep tissue sensitivity and force attenuation in the wrist extensors of

patients with lateral epicondylalgia (nZ20), and healthy controls (nZ20) with experimentally induced sensori-motor characteristics

simulating lateral epicondylalgia. Delayed onset muscle soreness (DOMS) in wrist extensors of healthy controls was induced by eccentric

exercise in one arm 24 h prior to injection (Day 0). Saline-induced pain intensity (visual analogue scale, VAS), distribution, and quality were

assessed quantitatively in both arms for both groups. Pressure pain thresholds (PPT) were assessed at three different sites in the wrist

extensors. Maximal grip force and wrist extension force were recorded. In response to saline-induced pain in the extensor carpi radialis

brevis, regardless of arm, the patient group demonstrated a significantly quicker pain onset ( P!0.01), mapped larger pain areas and more

referred pain areas, compared to healthy controls (P!0.03). Pain persisted significantly longer in the sore arm of the patient group, compared

with all other arms (P!0.02). Patients demonstrated significant bilateral hyperalgesia at extensor carpi radialis brevis during and post saline-

induced pain compared to pre-injection and healthy controls (P!0.04). The sore arm in patients and the DOMS arms in healthy subjects

showed significantly reduced maximal force (P!0.0001), at all Day 1 times compared with the control arms. In patients, the bilateral

increase in deep tissue sensitivity and enlarged referred pain areas during saline-induced pain might suggest involvement of central

sensitisation.

q 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Keywords: Experimental muscle pain; Hyperalgesia; Referred pain; Peripheral sensitisation; Central sensitisation; Lateral epicondylalgia; Delayed onset

muscle soreness (DOMS)

1. Introduction

Lateral epicondylalgia patients present with pain and

mechanical hyperalgesia at the common extensor origin,

pain radiating into the dorsal forearm and hand and force

attenuation of the wrist extensors (Haker, 1993; Pienimaki

et al., 2002a,b; Stratford et al., 1993; Vicenzino et al., 1996,1998). While the aetiology of lateral epicondylalgia remains

unclear, evidence of a tissue-based pathology includes

degenerative changes at the common extensor origin

consistent with tendinopathy (Khan et al., 1999); altered

recruitment and timing patterns contributing to repetitive

microtrauma of the extensor carpi radialis brevis (Bauer and

Murray, 1999; Riek et al., 1999); intrinsic muscle pathology

(Lieber et al., 1997; Ljung et al., 1999a,b) and increased

substance P immunoreactivity (Ljung et al., 2004; Uchio

et al., 2002).

Tissue-based pathology alone does not appear sufficient

to explain the chronic nature of lateral epicondylalgia, or

reports of referred pain (Leffler et al., 2000) and evidence ofhyperalgesia (Vicenzino et al., 1998; Wright et al., 1992,

1994). In response to initial tissue injury, the process of

sensitisation of peripheral nociceptive apparatus results in a

lowering of the normally high mechanical threshold for

nociceptors (Graven-Nielsen and Mense, 2001). In patients

with lateral epicondylalgia, the clinical correlate of this

peripheral sensitisation could be seen as local pain and deep

tissue tenderness associated with repeated load and move-

ment of damaged tissues. Additionally, sensitised

Pain 114 (2005) 118130

www.elsevier.com/locate/pain

0304-3959/$20.00 q 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.pain.2004.12.003

* Corresponding author. Tel.:C45 96 35 9832; fax: C45 98 15 4008.

E-mail address: [email protected] (T. Graven-Nielsen).
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nociceptors also demonstrate an increased responsiveness to

noxious stimuli that may be expressed clinically as a

mechanical hyperalgesia at the attachment of the common

extensor tendon to the lateral epicondyle. Widespread pain,

referred pain and changes in somatosensory sensitivity raise

the index of suspicion that patients with lateral epicondy-

lalgia may demonstrate alterations in the way in which thenervous system processes nociceptive and non-nociceptive

information. Expansion of experimentally induced referred

pain has been demonstrated in various musculoskeletal

conditions such as fibromyalgia, whiplash and osteoarthritis

and might reflect central sensitisation (Arendt-Nielsen and

Graven-Nielsen, 2003). However, the role of central

sensitisation in chronic lateral epicondylalgia has yet to be

investigated.

The aim of the current study was therefore to compare

the sensory manifestations and motor effects during

experimental muscle pain in patients with chronic lateral

epicondylalgia and in healthy controls with acute exper-

imentally induced pain simulating lateral epicondylalgia.

This combined experimental model has previously been

shown to be an effective vehicle for simulating character-

istics of lateral epicondylalgia (Slater et al., 2003).

The specific hypotheses to be tested in this study are:

(1)Saline-induced pain in the sore armof patients with lateral

epicondylalgia results in a more substantial increase in pain

areas, deep tissue sensitivity and force attenuation than in the

asymptomatic arm, and compared with matched controls; (2)

In healthy subjects with DOMS, saline-induced muscle pain

is associated with a more substantial increase in deep tissue

sensitivity and force attenuation than in the control arm, and

controls demonstrate similar sensory manifestations andmotor effects in response to saline-induced muscle pain as

seen in patients with lateral epicondylalgia.

2. Materials and methods

2.1. Subjects

Two groups, each of twenty subjects, participated in the study.

There were 10 males and 10 females in both the patient group

(mean age 48.25 years, range 3465 years) and the healthy controls

(mean age 47.45 years, range 3263 years). The patient populationwas drawn from volunteers who responded to a newspaper article

and radio interview discussing tennis elbow. Subjects were then

selected by satisfying the inclusion criteria for a clinical diagnosis

of chronic lateral epicondylalgia, that is, pain on palpation over the

lateral epicondyle and the associated common extensor myotendi-

nous unit; pain associated with functional activities such as

gripping and pain with resisted contraction of the wrist extensors or

extensor carpi radialis brevis, or with passive stretching of the wrist

extensors (Haker, 1993; Stratford et al., 1993). Symptoms had to

have persisted for at least 3 months and be unilateral.

A comprehensive musculoskeletal physical examination was

performed on both upper limbs to ensure that the unaffected arm

had full pain free range of elbow and wrist motion, and no

abnormal tenderness to palpation of the soft tissues in the extensor

muscles of the forearm and wrist (Haker, 1993; Travell and

Simons, 1983), or reduced muscle length. Exclusion criteria

included involvement of the contralateral arm, cervicothoracic

spinal pathology, other upper limb musculoskeletal disorders or

neurological disorders. A profile of the clinical characteristics ofthe patient group is shown in Table 1.

Subjects in the healthy controls were matched for age, gender

and affected arm (either dominant or non-dominant) with patients.

Exclusion criteria for subjects in the healthy controls included a

history of upper limb pain, fractures or neurological disorders, or

prior wrist extensor training. A bilateral upper limb physical

examination, with the same requirements as described for the

unaffected arm in the patient group, was performed. Clinical tests

of wrist stability were performed (Taleisnik, 1988) as a precaution

against excessive intercarpal motion during the experimental

exercise procedure. Patients and healthy controls taking regular

anticoagulant medication or medications known to influence pain

sensitivity (e.g. analgesics, non-steroidals, antidepressants) wereexcluded from the study. All subjects were requested to refrain

from using analgesic or non-steroidal medications during the

testing period. Written informed consent was obtained prior to

inclusion in the study. The study was performed in accordance with

the National Health and Medical Research Council guidelines and

with the Helsinki Declaration. The Human Research Ethics

Committee at Curtin University of Technology had approved the

study.

2.2. Study design

For each group (patient and control), and for both arms, a set of

quantitative tests (pressure pain thresholds, muscle soreness,maximal grip force and maximal wrist extension force) was

performed and repeated at each time period, as indicated in Fig. 1.

In the healthy controls, the effect of combined DOMS and

saline-induced pain on deep tissue sensitivity was assessed.

Subjects participated in three sessions (Day 0, Day 1 and Day 7).

For the healthy controls, exercise to induce DOMS in the arm

matched to the patients sore arm, was performed at Day 0, with

the set of pre-exercise and post-exercise measures recorded for

both the DOMS and control arms. There were 2325 h between

Day 0 and Day 1 sessions. At Day 1 prior to injection, subjects in

both groups were asked to rate the worst level of lateral elbow pain

experienced in the preceding 24 h using a 10 cm visual analogue

scale (VAS) where 0 cm indicated no pain and 10 cm most pain

Table 1

Clinical characteristics of patients (GSE, nZ20) on entry into study

Duration of current episode 6.5G1.1 months

Baseline VAS 3.2G0.4 cm

Right arm dominant nZ17

Right arm affected nZ17

Recurrence nZ8

Mechanism(s) of injuryInsidious nZ4

Tennis (increase volume, frequency,

changes in racquet)

nZ7

Trauma nZ4

Overuse (keying, painting) nZ5

VAS, visual analogue scale. Baseline VAS was described as the worst level

of lateral elbow pain experienced in the 24 h preceding injection at Day 1.

H. Slater et al. / Pain 114 (2005) 118130 119


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imaginable. This level of pain was defined as baseline VAS. For

both patients and controls, the Day 1 protocol was identical, with

saline-induced pain provoked in the extensor carpi radialis brevis

muscle of the DOMS and sore arms. At pre-injection, during the

saline-induced pain period and 20 min post-pain, quantitative

measures were repeated. To act as a control, the extensor carpi

radialis brevis of the contralateral arm in both groups was alsoinjected with hypertonic saline (using the same injection

paradigm), and the same Day 1 measures repeated in this arm.

The sequence of testing of arms was randomised. For each subject,

the time between consecutive injections into the affected (sore or

DOMS arm) and control arm was approximately 60 min. The Day

7 session involved a repeat of quantitative measures for both arms

(in randomised order) in both groups.

2.3. Saline-induced deep pain

Hypertonic saline was infused using a computer-controlled

pump (IVAC, model 770, USA), with a 10 ml plastic syringe

(Graven-Nielsen et al., 1997). A tube (IVAC G30303, extension setwith polyethylene inner line) was connected from the syringe to the

disposable needle (27G, 20 mm). A bolus injection of 1.0 ml of

sterile hypertonic (5.8%) saline was injected over 40 s. The needle

was removed at the completion of the injection. The site of

injection for extensor carpi radialis brevis belly was identified

using a technique described by Riek et al. (2000). Ultrasound

imaging was used in five subjects to confirm that this injection

protocol for needle localisation was reliable and valid. The

ultrasound imaging was performed with a 512 MHz linear probe

using an ATL HDI 5000 (Bothell, Wash, USA). One investigator

(HS) inserted a disposable needle vertically through the skin

surface approximately 10 mm into the extensor carpi radialis

brevis muscle belly according to the procedure described by

Riek et al. (2000). The needle tip was then identified with

ultrasound imaging and in all cases was shown to be correctly

located into the muscle belly of extensor carpi radialis brevis. To

avoid any direct contact with the posterior interroseus nerve, the

nerve was manually identified prior to injection.

Saline-induced pain intensity was scored continuously on a

10 cm electronic VAS where 0 cm indicated no pain and 10 cmmost pain imaginable. The VAS rating was sampled every 5 s by

a computer. The area under the VAS-time curve (Painauc), maximal

VAS (Painmax), time of pain onset and duration of pain were

determined from the VAS recordings. After the injection, subjects

described the pain using the McGill Pain Questionnaire (MPQ)

(Melzack, 1975). Words from the MPQ chosen by at least 30% of

the subjects were used in data analysis. The pain distribution

experienced by each subject was mapped on a body chart. The pain

circumference was later digitised (ACECAD D9000 Digitiser,

Taiwan) and the area calculated in arbitrary units (Sigma-Scan,

Jandel Scientific, Canada). Pain areas were also classified from the

body charts as local and/or referred. The arm was divided into five

areas for classifying local and referred pain areas (Fig. 2). Areas

were defined as: (A) proximal to the elbow joint; (B) elbow joint toupper third of forearm including the injection site; (C) mid third of

the forearm; (D) lower third of forearm; (E) distal to the proximal

wrist carpus, including the hand. Referred pain was defined as pain

outside the injection area.

2.4. Delayed onset muscle soreness

DOMS was induced with repeated eccentric wrist extension

contractions in the nominated matched arm. The exercise

protocol was performed using the isokinetic mode of the

KinCom dynamometer (Chattecx Corp. Hixson, TN). This allowed

the maximal wrist extensor effort produced by each subject in

Fig. 1. The experimental protocol for healthy controls and patients is shown. In order to generate delayed onset muscle soreness, healthy controls were required

to undertake the eccentric wrist extensor exercise protocol in the matched arm 24 h prior to injection (Day 0). A battery of quantitative tests was performed in

both the matched and control arm at pre-exercise and post-exercise. Day 1 involved the identical protocol for both groups with injection of hypertonic saline

into the extensor carpi radialis brevis muscle of first one arm (either the control or sore/exercised arm). Quantitative measures were recorded for the tested arm

at pre-injection, during injection and post-injection. Following a 30 min post-pain period, the protocol was repeated in the contralateral arm. The order of

testing of arms was randomised. At Day 7, quantitative measures were repeated in both arms for all subjects.

H. Slater et al. / Pain 114 (2005) 118130120


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the healthy controls to be matched by the dynamometer during

the eccentric phase. To allow familiarisation, prior to the eccentric

exercise protocol, subjects were required to complete a warm-up

on the KinCom. Subjects maximal eccentric effort was determined

as the force at which the subject could no longer prevent movement

initiation of wrist extension. The magnitude of the maximal

eccentric effort was marked on the computer screen. A minimum

force of 20 N was necessary in order to trigger an eccentric

contraction. Subjects were instructed to maximally resist the

dynamometers movement from wrist extension to wrist flexion.

The exercise protocol was designed to passively extend the wrist at

a speed of 1008/s and to cause flexion of the wrist at a speed of 258/s

when the subject exerted a wrist extensor torque (eccentric wrist

extension). The duration of each cycle of eccentric contraction/

passive recovery was set at 4 s contraction with a second of passive

recovery. The total exercise period was 25 min, with 5 bouts each

of 5 min duration (60 repetitions per bout), with each bout

separated by a minute rest interval (Slater et al., 2003).

Subjects were positioned in sitting with the pronated forearm

stabilised on a padded forearm rest attached to a seat. This forearm

rest could be adjusted in height and length to allow appropriate

alignment of the wrist joint with the KinCom axis of rotation. Ahand attachment was designed to provide fixation of the wrist joint

close to the axis of movement of the KinCom. The wrist position

was preset at 258 wrist extension and not less than 508 wrist flexion.

This allowed an extensive through-range eccentric exercise

without the associated risk of end range joint or soft tissue injury.

A visual display of successive efforts was also provided on the

computer screen and subjects were encouraged to use this as

feedback to assist them in maintaining the desired eccentric effort

throughout the exercise period. Each subjects maximal eccentric

effort was marked on the screen initially and subjects asked to try

and maintain this level of force for as long as possible. Subsequent

marks were made on the screen at each successive bout to match

the best eccentric effort if the effort had dropped considerably.

Subjects completed a Likert scale of muscle soreness (High et al.,

1989) specifically modified for the upper limb, with 1 defining a

light soreness and 6 indicating severe muscle soreness (Slater et al.,

2003). Soreness was also assessed in patients although they did not

undertake the exercise protocol.

2.5. Assessment of deep tissue sensitivity

Pressure pain thresholds (PPT) were recorded using an

electronic algometer (Somedic AB, Sweden) with a stimulation

area of 1.0 cm2. PPT was calculated as the mean of 3 trials with a

30 s interval between repetitions. The pressure was increased at a

rate of 30 kPa/s until the subject detected the pain threshold. Three

sites were assessed: the common extensor origin at the lateral

epicondyle, the belly of the extensor carpi radialis brevis muscle,

and the radial head laterally.

2.6. Assessment of grip force and wrist extension force

Grip force was assessed using an electronic digital dynanometer(MIE Medical Research Ltd., Leeds, UK). The subjects upper

limb was positioned in pronation and elbow extension. Peak values

determined the maximal grip force, and were found as the mean of

3 trials. Wrist extension force was recorded via a force gauge

(AFG, range 0500 N, Mecmesin Ltd., England). A specifically

designed padded hand attachment was connected to the underside

of the force gauge. The transducer was mounted on a flat platform

and placed on a table to the side of the plinth. The height of the

hand attachment and force transducer was adjustable to allow for

variations in hand sizes. The wrist was positioned in pronation and

wrist extension (208) with the 3rd knuckle abutting the centre of the

hand attachment. Subjects were instructed to maximally extend the

wrist by pushing the dorsal surface of the hand onto the padded

Fig. 2. Mean (nZ20) VAS profiles and the associated areas of pain for injections of hypertonic saline into extensor carpi radialis brevis muscle of the sore arm

(1)in the patient group andtheircontrol arm (2),and theDOMS arm in the healthy controls (3)and their control arm(4). The armwas divided into five areas for

assessing local and referred pain (5). Areas were defined as: (A) proximal to the elbow joint; (B) elbow joint to upper third of forearm including the injection

site; (C) mid third of the forearm; (D) lower third of forearm; (E) distal to the proximal wrist carpus, including the hand.



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surface of the hand attachment. The height of the device was noted

for each subject to ensure reliable measures. Peak values

determined the maximal extension force, and were found as the

mean of 3 trials. Subjects were requested to perform maximal

contractions for each motor task.

2.7. Statistical analysis

Mean and standard error (SE) values are given in the text, tables

and figures. A majority of measurements associated with PPTs and

VAS data met the requirements of a normal distribution as

determined by the ShapiroWilk normality test. A 2-way mixed

model analysis of variance (ANOVA), with factors group

(between-group: patient and healthy controls) and arm

(repeated: sore/DOMS and control), was used for analysis of

VAS data. For analysis of PPT, maximal grip force and maximal

wrist extension force, 2-way and 3-way repeated measures mixed

model ANOVA were used, with repeated measures (factors time

and arm) and a between-group factor (patient and healthy

controls). When significant this was followed by parametric

StudentNewmanKeuls (SNK) post-hoc tests. Spearmans corre-lation coefficient (R) was used to describe correlations between

parameters. Significance was accepted at P!0.05.

3. Results

3.1. Baseline assessments

3.1.1. Deep tissue sensitivity

The patient group demonstrated a significant hyperalge-

sia to pressure at common extensor origin in both sore and

control arms compared with healthy controls (Table 2;

F1,38Z4.7, P!0.04). For both groups, the PPT at the

common extensor origin in the sore arm and arms allocated

for DOMS was lower than for the control arms (F1,38Z15.1,

P!0.001). The symptomatic arm in the patient group

demonstrated more muscle soreness compared with all other

arms (F1,38Z49.4, P!0.001; Table 2).

3.1.2. Maximal grip force and maximal wrist extension force

As shown in Table 2, there were group differences for

maximal grip force (F1,38Z16.4, P!0.001) and maximal

wrist extension force (F1,38Z9.6, P!0.003). Patients had

significantly weaker maximal grip force and wrist extension

force in their sore arm compared with their contralateral arm

(SNK: P!0.001) and compared with both arms for healthy

subjects (SNK: P!0.001). The control arm in the patient

group was also weaker than the control arm in healthy

subjects (SNK: PZ0.002).

3.2. Effects of eccentric exercise in the healthy controls

3.2.1. Effects of exercise on deep tissue sensitivity

There was a bilateral decrease in PPT at the common

extensor origin at pre-injection (Table 3; F2,38Z6.6,

P!0.003), compared with pre-exercise and post-exercise

(SNK: P!0.02). Eccentric exercise did not significantly

alter pre-injection PPT at the extensor carpi radialis brevis.

Muscle soreness was different between arms (Table 3;

F2,38Z40.3, P!0.001), with the exercised arm demonstrat-

ing an increase in soreness at pre-injection (Day 1)

compared with post-exercise, pre-exercise (SNK:

P!

0.001) and compared with the control arm (SNK:P!0.001).

3.2.2. Effect of exercise on maximal grip force

and maximal wrist extension force

Maximal grip force and maximal wrist extension force

differed between the exercised and control arms (Table 3;

F2,38Z16.4, P!0.001). Maximal force for grip and wrist

extension was significantly decreased in the exercised arm at

pre-injection compared with pre-exercise and post-exercise

(SNK: P!0.001). Additionally, the DOMS arm was weaker

in both force measures compared with the control arm at

post-exercise and pre-injection (SNK: P!0.005).

3.3. Muscle pain and soreness

3.3.1. Saline-induced deep pain

Injection of hypertonic saline into the extensor carpi

radialis brevis muscle on Day 1 induced different pain

profiles in the two groups (Table 4; Fig. 2). The patient

group displayed a quicker pain onset than healthy controls,

regardless of arm (F1,38Z7.2, P!0.01). Saline-induced

pain duration varied between groups (ANOVA: F1,38Z6.3;

P!0.02), with substantially longer pain duration

Table 2Mean values (SE, nZ20) for pressure pain thresholds, muscle soreness, maximal grip force and maximal wrist extension force of pre-injection (Day 1)

measures in the patient group compared with pre-exercise (Day 0) measures in normal controls

Variables Patient group Healthy controls

Sore arm Control arm Pre-DOMS arm Control arm

PPT-CEO (kPa) 257 (34)*,** 357 (45)* 384 (38)** 464 (48)

PPT-ECRB (kPa) 228 (37) 239 (30) 257 (28) 306 (46)

PPT-RH (kPa) 284 (32) 291 (39) 331 (33) 332 (29)

Muscle soreness (AU) 2.0 (0.3)*,** 0.1 (0.1) 0.0 (0.0) 0.0 (0.0)

Max. grip force (N) 206 (18)*,** 303 (23) 317 (19) 311 (22)

Max. wrist extension force (N) 56 (8)*,** 87 (9)* 117 (4) 114 (7)

PPT, pressure pain threshold; CEO, common extensor origin; ECRB, extensor carpi radialis brevis; RH, radial head; AU, arbitrary units; Max, maximal; *P!

0.05 (SNK) compared with healthy controls comparable arm; **P!0.05 (SNK) compared with the contralateral control arm.



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experienced by patients in their sore arm, compared with

the contralateral control arm and compared with both arms

of the healthy subjects (SNK: P!0.004).

Regardless of arm, the patient group mapped signifi-

cantly larger areas of saline-induced pain (Table 4; F1,38Z

5.3; PZ0.03). Patients experienced more widespread pain

emanating from the injection site and more referred areas of

pain in the distal forearm compared with healthy controls

(Table 4; SNK: P!0.01). All subjects reported a localised

pain response around the ECRB muscle belly (Fig. 2).

Additionally, for the sore and DOMS arms, saline-induced

referred pain was described at the common extensor origin

(nZ

4 per group). The saline-induced pain descriptors mostcommonly used were intense and aching (Table 4).

Patients selected the word radiating as a pain descriptor,

while sharp and throbbing were chosen by patients and

by healthy controls but only for the DOMS arm.

3.3.2. The effect of saline-induced pain on deep

tissue sensitivity

The extensor carpi radialis brevis in the sore arm and

DOMS arms demonstrated a pronounced mechanical

hyperalgesia post-pain in both groups, and during saline-

induced pain only in patients. The magnitude of this

hyperalgesic effect was greater in the patient group than inhealthy controls, and in the sore arms compared with the

control arms. The statistical bases for these findings are

interactions between group and time for PPT at extensor

carpi radialis brevis (F3,114Z3.3, P!0.02; Fig. 3), and arm

and time (F3,114Z3.4, P!0.02). Compared to healthy

controls, and compared with pre-injection values, the PPT at

the extensor carpi radialis brevis in the patient group was

hyperalgesic to pressure during saline-induced pain and

post-pain (SNK: P!0.05). In the sore and DOMS arms,

this hyperalgesia persisted at post-pain compared with

pre-injection and Day 7 (SNK: P!0.02). Additionally,

the decrease in PPT at post-pain was greater in the sore arm

and DOMS arms than in the control arms (SNK: P!0.001).During saline-induced pain in the sore and DOMS arms,

Table 4

Mean (SE, nZ20) VAS parameters and pain areas after hypertonic saline injection into the extensor carpi radialis brevis muscle of patients and normal controls

VAS data Patient group Healthy controls

Sore arm Control arm DOMS arm Control arm

Painauc (cm s) 3251.7 (258.7) 2829.6 (317.9) 2663.4 (578.5) 2612.6 (302.4)

Painmax (cm) 7.5 (0.3) 7.5 (0.4) 6.6 (0.6) 6.9 (0.5)

Painonset (s) 17.0 (1.7)* 14.8 (1.9)* 21.3 (2.4) 22.3 (1.4)

Painduration (s) 889.3 (56.8)*# 669.8 (65.6) 585.3 (67.6) 606.0 (53.4)

Total pain area (AU) 5.8 (0.6)* 5.4 (0.9)* 3.8 (0.7) 3.3 (0.7)

Pain area (AU)

Area A 0.32 (0.17) 0.00 (0.00) 0.20 (0.19) 0.30 (0.29)Area B 1.64 (0.21)* 1.11 (0.17)* 0.67 (1.10) 0.78 (0.15)

Area C 2.20 (0.31)* 1.67 (0.33)* 1.14 (0.24) 0.93 (0.21)

Area D 0.55 (0.18) 0.78 (0.23) 0.79 (0.27) 0.47 (0.20)

Area E 0.43 (0.20) 1.24 (0.44) 0.35 (0.19) 0.47 (0.24)

Pain descriptors (% of subjects)

Intense 50 35 40 40

Aching 50 30 35 30

Radiating 35 35

Sharp 40 30 30

Throbbing 35 30

*P!0.05 (SNK) compared with healthy controls, #P!0.05 (SNK) compared with contralateral control arm. Pain areas were classified into five categories: A.

proximal to the elbow joint; B. elbow joint to upper third offorearm including the injection site; C. mid third of the forearm; D. lower third of forearm; E. distal

to the proximal wrist carpus, including the hand. Referred pain was defined as pain outside the injection area.

Table 3

Effects of exercise on mean (SE, nZ20) pressure pain thresholds, muscle

soreness, maximal grip force and maximal wrist extension force in normal

controls

Day 0,

pre-exercise

Day 0,

post-exercise

Day 1,

pre-injection

Deep tissue soreness

PPT-CEO (kPa)

DOMS arm 384 (38) 392(38) 325 (31)*

Control arm 464 (48) 409 (38) 359 (39)*

PPT-ECRB (kPa)

DOMS arm 257 (28) 257 (29) 234 (33)

Control arm 306 (46) 259 (41) 261 (38)

PPT-RH (kPa)

DOMS arm 331 (33) 332 (35) 331 (36)

Control arm 332 (29) 319 (29) 298 (26)

Muscle soreness (AU)

DOMS arm 0.00 (0.00) 1.21 (0.35)** 3.16 (0.38)*,**

Control arm 0.00 (0.00) 0.00 (0.00) 0.05 (0.05)

Maximal grip force (N)

DOMS arm 317 (19) 240 (17)** 276 (19)*,**

Control arm 311 (22) 304 (22) 302 (20)

Maximal wrist extension force (N)

DOMS arm 117 (4) 77 (7)** 81 (5)*,**

Control arm 114 (7) 107 (7) 101 (7)#

PPT,pressure pain threshold; CEO,common extensor origin; ECRB, extensor

carpi radialis brevis; RH, radial head; AU, arbitrary units *P!0.05 (SNK)

compared with post-exercise and pre-exercise; **P!0.05 (SNK) compared

with control arm; #P!0.05 (SNK) compared with pre-exercise only.



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higher clinical pain intensities and longer pain duration

were associated with a greater decrease in PPT at extensor

carpi radialis brevis (RO0.39; P!0.02).

Patients and healthy subjects demonstrated differences

in pressure pain sensitivity at the common extensor

origin in response to saline-induced pain (F1,38Z4.6,

P!0.04). Overall, compared with pre-injection there was

a hypoalgesic response at common extensor origin during

saline-induced pain, which was still evident at Day 7

(F3,114Z3, P!0.014; SNK: P!0.03). During saline-

induced pain, although this hypoalgesia was evident at

the common extensor origin in the sore arm of the

patient group, the PPT remained significantly lower than

all other arms (SNK: P!0.005; Fig. 3). Collectively, the

sore and DOMS arms demonstrated a lower PPT than

the control arms (F1,38Z12.3, P!0.001). The PPT at

radial head was not significantly changed in response to

any factor.

Fig. 3. Mean (CSE, nZ20) pressure pain thresholds for the sore and DOMS arms and the control arm for both groups Day 1 (pre-injection, injection and post-

injection) and Day 7. At Day 1, injection of hypertonic saline into the extensor carpi radialis brevis muscle was done in both the sore and control arms for both

groups. Pressure pain thresholds were assessed at extensor carpi radialis brevis (ECRB), common extensor origin (CEO) and radial head (RH). The PPT at

ECRB in patients demonstrated a significant decrease in both arms during saline-induced pain and post-pain compared with pre-injection and healthy

controls (*SNK, P!0.05). The PPT at ECRB in the sore and DOMS arm was significantly lower compared with pre-injection and compared with the control

arms (# SNK, P!0.05). The PPT at CEO in the patients sore arm was hyperalgesic pre-injection compared with all other arms (***SNK, P!0.05), butdemonstrated a generalised hypoalgesia for all arms during pain and Day 7, compared with pre-injection values (** SNK, P!0.05).



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In response to saline-induced pain, muscle soreness was

influenced according to group and arm (F3,114Z10.0, P!

0.001). The patient group experienced an increase in muscle

soreness in the sore arm during saline-induced pain and

post-pain compared with pre-injection (SNK: P!0.001).

Compared with pre-injection, during saline-induced pain

muscle soreness increased in the control arms of both

patients and healthy subjects (SNK: P!0.04). At all Day 1

times, the levels of muscle soreness were greater in the sore

and DOMS arms than for control arms (Fig. 4; SNK: P!

0.001). Muscle soreness had decreased significantly at Day

7 compared with pre-injection for all arms, except in the

patients sore arm. Muscle soreness and VAS area were

positively correlated in the sore and DOMS arms (RZ0.31;

P!0.05).

3.4. Saline-induced pain, maximal grip force


Changes in maximal grip force in response to saline-

induced pain differed between arms for patients and healthy

controls (F1,38Z8.7, P!0.005). The patients sore arm

demonstrated significantly weaker grip force than all other

arms (Fig. 5; SNK: P!0.001). The sore and DOMS arms

for both groups were weaker than the control arms at all

times (F 3,114Z3.1, P!0.03; SNK: P!0.001). Compared

with day 7, maximal grip force was significantly lower at

pre-injection, during saline-induced pain and post-pain

(SNK: P!0.03) in the sore arm and DOMS arms only.

Maximal wrist extension force was different between

group and arms at Day 1 and Day 7 (Fig. 5; F3,114Z6.0, P!

0.007). Regardless of time, the patient group demonstrated

more reduced maximal wrist extension force in their sore

arm compared with their control arm and compared with

both the DOMS and control arms of the healthy subjects

(SNK: P!0.005). Similar to the patients sore arms, healthy

subjects demonstrated reduced maximal wrist extension in

their DOMS arms compared with their control arm at all

Day 1 times, but not at Day 7 (SNK: P!0.001).

3.5. Correlation between clinical parameters

and experimental data

In the sore and DOMS arms, the duration of clinical pain

(in weeks of lateral epicondylalgia or DOMS) and baseline

VAS were correlated with saline-induced VAS Painauc area,

pain duration and mapped pain area (Table 5). The decrease

in PPT at extensor carpi radialis brevis during and post

saline-induced pain was also correlated with clinical pain

duration but only in the sore and DOMS arms.

4. Discussion

In the current study patients with lateral epicondylalgia

demonstrated bilateral hyperalgesia to saline-induced

muscle pain as compared to matched healthy controls. The

evidence of this was more rapid pain onset, longer pain

duration, more widespread pain, a greater number of

referred pain areas and pressure hyperalgesia at the

muscular part (extensor carpi radialis brevis) of the common

extensor myotendinous unit.

4.1. Group differences

A pressure hyperalgesia at the attachment of the common

extensor origin to the lateral epicondyle was most

pronounced in the sore arm of the patient group, consistent

with previous experimental findings in patients with lateral

epicondylalgia (Haker, 1993; Vicenzino et al., 2001; Wright

et al., 1992, 1994), but was also evident in the contralateral

(aymptomatic) arm. This finding may suggest a pre-existing

Fig. 4. Mean (CSE, nZ20) muscle soreness for the sore and DOMS arms and the control arm for both groups Day 1 (24 h after eccentric exercise: pre-

injection, injection and post injection) and Day 7. At Day 1, hypertonic saline was injected into the extensor carpi radialis brevis muscle in both the sore and

DOMS arms and control arms for both groups. A significant increase in muscle soreness compared with pre-injection (*SNK, P!0.05) and compared with the

control arms (# SNK, P!0.05), is shown.



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(subliminal) degree of pressure hypersensitivity in the

patient group. Healthy controls demonstrated no side-to-

side quantitative differences in any baseline parameter,

except an unexpected decrease in PPT at the common

extensor origin in the matched arm (17 from 20 of which

were right dominant) at pre-exercise. Data on handedness

and its effect on pressure pain sensitivity in healthy subjects

are conflicting since no side differences (Fischer, 1987;Greenspan and McGillis, 1994; Maquet et al., 2004; Rolke

et al., in press; Wright et al. 1995) and increased pain

thresholds on the right side compared to left (Brennum

et al., 1989; Jensen et al., 1992; Pauli et al., 1999) have been

reported. It is plausible that the decreased PPT at the

common extensor origin in the matched healthy controls

may relate to a higher frequency of daily loading of the right

common extensor tendonbone junction associated with

right hand dominance.

Both force parameters were most substantially reduced in

the patients sore arm. Maximal wrist extension force was

bilaterally attenuated in the patient group, with the greatest

deficit in the affected arm. Bilateral compromise of motor

performance in patients with chronic unilateral lateral

epicondylalgia has been reported previously (Pienimaki

et al., 1997).

4.2. Delayed onset muscle soreness in the healthy controls

Muscle soreness was maximal in the DOMS arms 24 h

post-exercise. No subjects reported muscle pain at rest, an

important feature of DOMS (Weerakkody et al., 2003).

Changes in pressure pain sensitivity in the arms of the

healthy controls were specific for site with a pressure

hyperalgesia at the common extensor origin, however both

the exercised and control arm were similarly affected. While

not excluding central sensitisation, this finding may suggest

a degree of peripheral sensitisation secondary to repeated

PPT measurement, although this effect was not seen at the

other PPT sites. Similar findings have been previously

Fig. 5. Mean (CSE, nZ20) maximal grip and maximal wrist extension force for the sore arm and exercised arm and the control arm for both groups Day 1

(pre-injection, injection and post-injection) and Day 7. At Day 1, injection of hypertonic saline into the extensor carpi radialis brevis (ECRB) muscle belly was

done in both the sore and exercised arm and control arms for both groups. A significant decrease in force compared with compared to all other arms (*SNK,

P!0.05), compared with control arms (**SNK, P!0.05), and compared with Day 7 (# SNK, P!0.05).



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reported using the same experimental protocol (Slater et al.,

2003).

The substantial attenuation in force measures in the

exercised arm at pre-injection is consistent with the

development of DOMS as previously demonstrated for

this model (Slater et al., 2003), and observed in other

models of DOMS (Bajaj et al., 2001b; Cleak and Eston,

1992; Paddon-Jones et al., 2000; Weerakkody et al., 2001).

4.3. Saline-induced muscle pain and referred pain

Injection of hypertonic saline into extensor carpi radialis

brevis in the patient group, triggered pain more quickly and

pain persisted for substantially longer in the sore arm

compared with the control arm and compared with healthy

controls. Patients reported more widespread pain and more

areas of pain referral compared with healthy controls. While

more pronounced in the sore arm these effects were also

evident in the control arm suggesting a greater degree of

central sensitisation in the patient group. Furthermore,

clinical pain duration and baseline VAS were positively

correlated with saline-induced pain area, duration and

mapped pain areas, possibly reflecting time-dependent

development of central sensitisation. Previous experimental

pain studies indicate that the nervous system is likely to be

centrally sensitised in musculoskeletal conditions including

whiplash (Curatolo et al., 2001; Johansen et al., 1999),

fibromyalgia (Graven-Nielsen, 2000; Sorensen et al., 1995,

1998; Staud et al., 2001, 2003), myofascial temporoman-

dibular pain disorders (Maixner et al., 1995, 1997, 1998;

Svensson et al., 2001) and osteoarthritis (Bajaj et al.,

2001a).

A number of interacting neurophysiologic mechanisms

may explain this facilitated pain response including the

awakening of previously subliminal or quiescent synaptic

connections with dorsal horn neurons (Mense, 1994). Once

afferent fibres are facilitated, quiescent or latent synapses

become operational, thereby providing an effective mech-

anism for convergence of inputs and information transfer

(Graven-Nielsen et al., 2002). Expansion of receptive fields

and unmasking of new receptive fields have previously been

demonstrated in response to noxious muscle stimuli inanimals (Cook et al., 1987; Hoheisel et al., 1993; Hu et al.,

1992). Additionally, due to the overlapping of excitatory

fields, the spatial organisation of convergence means that a

noxious stimulus can potentially activate a larger number of

wide-dynamic-range neurons (Le Bars, 2002). In this way,

the increased sensitivity in the sore arm at the common

extensor origin could effectively prime dorsal horn

neurons, which then potentially receive convergent group

III and IV afferents input from the extensor carpi radialis

brevis. Furthermore, both these sites receive innervation

from the radial nerve and are contained within the same

myotome (Bonica, 1990).

4.4. Deep tissue hyperalgesia and saline-induced

muscle pain

The findings of this study indicate hyperalgesia to saline-

induced pain in patients with chronic lateral epicondylalgia

and healthy controls with provoked DOMS. During

saline-induced pain, a bilateral mechanical hyperalgesia at

the extensor carpi radialis brevis developed within 510 min

in the patient group and was most profound in the sore arm.

The saline-induced hyperalgesia increased further at 20 min

post-pain in both arms for the patient group and alsodeveloped in healthy subjects DOMS arm. A similar

time course of neuronal facilitation has been found

experimentally in rats (Hu et al., 1992). Combined with

VAS data, the more profound hyperalgesia seen during and

after experimental muscle pain in the sore arm of the patient

group may be further evidence of enhanced of neuronal

excitability, the mechanisms possibly involving the

unmasking of latent synaptic connections associated with

the expansion of receptive fields and the generation of novel

receptive fields in dorsal horn neurones (Hoheisel et al.,

1993). An imbalance of descending pain modulation

coupled with an increase in endogenous pain facilitation,

as suggested in other chronic pain states (Ren and Dubner,

2002), could also lead to hyperalgesia. Hypervigilance is

unlikely to be a plausible explanation for the bilateral

hyperalgesia as this effect was isolated to the extensor carpi

radialis brevis. In both groups, the generalised hypoalgesia

at the common extensor origin during saline-induced

pain suggests facilitation of antinociceptive mechanisms.

Previously, deep tissue hypoalgesia in extra segmental

areas remote from a saline-induced pain locus has been

demonstrated (Graven-Nielsen et al., 1998; Svensson et al.,

1999) suggesting recruitment of descending noxious

inhibitory controls.

Table 5

Correlation coefficients for clinical data and experimental parameters in the

sore arm of patients with lateral epicondylalgia and in the DOMS arm of

normal controls (nZ20)

Experimental parameters Clinical parameters

Duration of clinical pain Baseline

VAS

Decrease in PPT at ECRB

during saline-induced

pain

RZ0.341

Decrease in PPT at ECRB

post saline-induced pain

RZ0.340

Saline-induced VAS area RZ0.310 RZ0.352

Saline-induced pain dur-

ation

RZ0.485 RZ0.505

Mapped pain area RZ0.404 RZ0.318

PPT, pressure pain threshold; ECRB, extensor carpi radialis brevis; DOMS,

delayed onset muscle soreness. Baseline VAS was taken as the worst pain

(10 cm scale) experienced in the symptomatic and matched arms over the

24 h prior to hypertonic saline injection at Day 1. Duration of pain was

defined as weeks of the current episode of lateral epicondylalgia or DOMS

(1/7 week). Spearman (R) correlations shown are significant at P!0.05.



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4.5. Saline-induced pain influence on maximal grip


Patients with lateral epicondylalgia demonstrate marked

deficits in their motor system (Pienimaki et al., 2002a,b;

Stratford et al., 1993; Vicenzino et al., 1996, 1998). While

de-conditioning of the intrinsic muscle apparatus andchanges in the load-capabilities of the extensor carpi

radialis brevis myotendinous unit will account for some of

the force attenuation evident in the sore arm of the patient

group (Benjamin et al., 2002; Stratford et al., 1989), the

bilateral effects indicate that alterations in peripheral and

central neural control must also be considered. Grip force

did not show this bilateral deficit in patients, suggesting that

wrist flexor activity (grip) may be facilitated as a

compensatory mechanism when wrist extensors are inhib-

ited or weak.

Both groups demonstrated no additional effect of saline-

induced pain on force generation. In the DOMS arms,

injection of hypertonic saline would normally be expected

to cause a further reduction in force-generating abilities of

the sensitised muscle (Slater et al., 2003). The eccentric

exercise in this study was effective in generating DOMS as

evidenced by the substantial decreases in maximum force

associated with eccentric exercise-induced muscle damage

(Friden and Lieber, 1997). One reason for this apparent

anomaly may relate to the different ways in which wrist

extension force was measured. In the current study, subjects

were better able to stabilise the wrist during maximal wrist

extension force possibly allowing recruitment of other

muscles to help compensate for reduced force.

5. Conclusion

We propose a simple conceptual model to reflect the

transition from unilateral localised, pain to a chronic

musculoskeletal pain condition. The model suggests a

time-dependent process whereby there is a progressive

increase in central sensitisation. The localised pain initially

expands regionally (still unilateral and segmental), the

clinical correlates of which are increased responsiveness to

pain, expanded pain areas and referred pain. As pain

persists, the potential for contralateral and plurisegmental

spread appears to increase and the associated sensory

manifestations indicate a greater degree of central sensitis-

ation. The findings of this study indicate that for patients

with chronic lateral epicondylalgia management needs to

extend beyond local tissue-based pathology, to incorporate

strategies directed at normalising the sensitivity of the

nervous system.

Acknowledgements

The authors would like to acknowledge the support of the

Danish National Research Foundation. Thanks to Mr Geoff

Strauss for the excellent technical instruction on use of the

KinCom; Mr Klaus Sussenbach for design of apparatus;

Mr Paul Davey for technical assistance and to volunteers for

participating in this study.

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