Pain 114 (2005) 118–130

www.elsevier.com/locate/pain

Sensory and motor effects of experimental muscle pain in patients with

lateral epicondylalgia and controls with delayed onset muscle soreness
Helen Slatera,b, Lars Arendt-Nielsena, Anthony Wrightb, Thomas Graven-Nielsena,*
a
Laboratory for Experimental Pain Research, Center for Sensory-Motor Interaction, Aalborg University, Fredrik Bajers Vej 7D, 9220 Aalborg E, Denmark
b
School 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 Murray, 1999; Riek et al., 1999); intrinsic muscle pathology

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
* Corresponding author. Tel.: C45 96 35 9832; fax: C45 98 15 4008.
E-mail address: tgn@smi.auc.dk (T. Graven-Nielsen).
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
(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 of
hyperalgesia (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
 H. Slater et al. / Pain 114 (2005) 118–130
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 the
nervous 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 arm of 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 and
motor 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 34–65 years) and the healthy controls
(mean age 47.45 years, range 32–63 years). The patient population
was 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
119
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 injury
Insidious nZ4
Tennis (increase volume, frequency, nZ7
changes in racquet)
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.
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 of
the 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) were
excluded 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 patient’s 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 23–25 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
120 H. Slater et al. / Pain 114 (2005) 118–130

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.

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 also
injected 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 set
with 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 5–12 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 cm
‘most 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 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. 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
 H. Slater et al. / Pain 114 (2005) 118–130 121

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 and their control arm (2), and the DOMS arm in the healthy controls (3) and their control arm (4). The arm was 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.

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. Subject’s 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
dynamometer’s 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. A
hand 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 subject’s 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 subject’s 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 0–500 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
122 H. Slater et al. / Pain 114 (2005) 118–130
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 Shapiro–Wilk 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
Student–Newman–Keuls (SNK) post-hoc tests. Spearman’s 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
Table 2
Mean 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
Sore arm
PPT-CEO (kPa) 257 (34)*,**
PPT-ECRB (kPa) 228 (37)
PPT-RH (kPa) 284 (32)
Muscle soreness (AU) 2.0 (0.3)*,**
Max. grip force (N) 206 (18)*,**
Max. wrist extension force (N) 56 (8)*,**
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.
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
Healthy controls
Control arm Pre-DOMS arm Control arm
357 (45)* 384 (38)** 464 (48)
239 (30) 257 (28) 306 (46)
291 (39) 331 (33) 332 (29)
0.1 (0.1) 0.0 (0.0) 0.0 (0.0)
303 (23) 317 (19) 311 (22)
87 (9)* 117 (4) 114 (7)
 H. Slater et al. / Pain 114 (2005) 118–130 123

Table 3 emanating from the injection site and more referred areas of
Effects of exercise on mean (SE, nZ20) pressure pain thresholds, muscle pain in the distal forearm compared with healthy controls
soreness, maximal grip force and maximal wrist extension force in normal
controls
(Table 4; SNK: P!0.01). All subjects reported a localised
pain response around the ECRB muscle belly (Fig. 2).
Day 0, Day 0, Day 1, Additionally, for the sore and DOMS arms, saline-induced
pre-exercise post-exercise pre-injection
referred pain was described at the common extensor origin
Deep tissue soreness (nZ4 per group). The saline-induced pain descriptors most
PPT-CEO (kPa)
commonly used were ‘intense’ and ‘aching’ (Table 4).
DOMS arm 384 (38) 392(38) 325 (31)*
Control arm 464 (48) 409 (38) 359 (39)* Patients selected the word ‘radiating’ as a pain descriptor,
PPT-ECRB (kPa) while ‘sharp’ and ‘throbbing’ were chosen by patients and
DOMS arm 257 (28) 257 (29) 234 (33) by healthy controls but only for the DOMS arm.
Control arm 306 (46) 259 (41) 261 (38)
PPT-RH (kPa)
DOMS arm 331 (33) 332 (35) 331 (36) 3.3.2. The effect of saline-induced pain on deep
Control arm 332 (29) 319 (29) 298 (26) tissue sensitivity
Muscle soreness (AU) The extensor carpi radialis brevis in the sore arm and
DOMS arm 0.00 (0.00) 1.21 (0.35)** 3.16 (0.38)*,** DOMS arms demonstrated a pronounced mechanical
Control arm 0.00 (0.00) 0.00 (0.00) 0.05 (0.05) hyperalgesia post-pain in both groups, and during saline-
Maximal grip force (N) induced pain only in patients. The magnitude of this
DOMS arm 317 (19) 240 (17)** 276 (19)*,** hyperalgesic effect was greater in the patient group than in
Control arm 311 (22) 304 (22) 302 (20)
healthy controls, and in the sore arms compared with the
Maximal wrist extension force (N) control arms. The statistical bases for these findings are
DOMS arm 117 (4) 77 (7)** 81 (5)*,**
Control arm 114 (7) 107 (7) 101 (7)#
interactions between group and time for PPT at extensor
carpi radialis brevis (F3,114Z3.3, P!0.02; Fig. 3), and arm
PPT, pressure pain threshold; CEO, common extensor origin; ECRB, extensor and time (F3,114Z3.4, P!0.02). Compared to healthy
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
controls, and compared with pre-injection values, the PPT at
with control arm; #P!0.05 (SNK) compared with pre-exercise only. the extensor carpi radialis brevis in the patient group was
hyperalgesic to pressure during saline-induced pain and
experienced by patients in their sore arm, compared with post-pain (SNK: P!0.05). In the sore and DOMS arms,
the contralateral control arm and compared with both arms this hyperalgesia persisted at post-pain compared with
of the healthy subjects (SNK: P!0.004). pre-injection and Day 7 (SNK: P!0.02). Additionally,
Regardless of arm, the patient group mapped signifi- the decrease in PPT at post-pain was greater in the sore arm
cantly larger areas of saline-induced pain (Table 4; F1,38Z and DOMS arms than in the control arms (SNK: P!0.001).
5.3; PZ0.03). Patients experienced more widespread pain 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 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.
124 H. Slater et al. / Pain 114 (2005) 118–130

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 patient’s sore arm was hyperalgesic pre-injection compared with all other arms (***SNK, P!0.05), but
demonstrated a generalised hypoalgesia for all arms during pain and Day 7, compared with pre-injection values (** SNK, P!0.05).

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.
 H. Slater et al. / Pain 114 (2005) 118–130
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.
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
patient’s 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
and maximal wrist extension 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 patient’s 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
125
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
126 H. Slater et al. / Pain 114 (2005) 118–130

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).

(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 tendon–bone junction associated with
right hand dominance.
Both force parameters were most substantially reduced in
the patient’s 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
 H. Slater et al. / Pain 114 (2005) 118–130
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 RZ0.341 – animals (Cook et al., 1987; Hoheisel et al., 1993; Hu et al.,
during saline-induced
pain
Decrease in PPT at ECRB RZ0.340 – fields, the spatial organisation of convergence means that a
post saline-induced pain
Saline-induced VAS area RZ0.310 RZ0.352
Saline-induced pain dur- RZ0.485 RZ0.505
ation
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.
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; Sörensen 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
127
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 in
1992). Additionally, due to the overlapping of excitatory
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 5–10 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 also
developed in healthy subject’s 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.
128 H. Slater et al. / Pain 114 (2005) 118–130
4.5. Saline-induced pain influence on maximal grip
and maximal wrist extension force
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 and
changes 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
(Fridén 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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