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Algogenic substances and metabolic status in work-related Trapezius Myalgia: a multivariate explorative study

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BMC Musculoskeletal Disorders
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This study compares the levels of algesic substances between subjects with trapezius myalgia (TM) and healthy controls (CON) and explores the multivariate correlation pattern between these substances, pain, and metabolic status together with relative blood flow changes reported in our previous paper (Eur J Appl Physiol 108:657–669, 2010). 43 female workers with (TM) and 19 females without (CON) trapezius myalgia were – using microdialysis - compared for differences in interstitial concentrations of interleukin-6 (IL-6), bradykinin (BKN), serotonin (5-HT), lactate dehydrogenas (LDH), substance P, and N-terminal propeptide of procollagen type I (PINP) in the trapezius muscle at rest and during repetitive/stressful work. These data were also used in multivariate analyses together with previously presented data (Eur J Appl Physiol 108:657–669, 2010): trapezius muscle blood flow, metabolite accumulation, oxygenation, and pain development and sensitivity. Substance P was significantly elevated in TM (p=0.0068). No significant differences were found in the classical algesic substances (p: 0.432-0.926). The multivariate analysis showed that blood flow related variables, interstitial concentrations of metabolic (pyruvate), and algesic (BKN and K+) substances were important for the discrimination of the subjects to one of the two groups (R2: 0.19-0.31, p<0.05). Pain intensity was positively associated with levels of 5-HT and K+ and negatively associated with oxygenation indicators and IL-6 in TM (R2: 0.24, p<0.05). A negative correlation existed in TM between mechanical pain sensitivity of trapezius and BKN and IL-6 (R2: 0.26-0.39, p<0.05). The present study increased understanding alterations in the myalgic muscle. When considering the system-wide aspects, increased concentrations of lactate, pyruvate and K+ and decreased oxygenation characterized TM compared to CON. There are three major possible explanations for this finding: the workers with pain had relatively low severity of myalgia, metabolic alterations preceded detectable alterations in levels of algesics, or peripheral sensitization and other muscle alterations existed in TM. Only SP of the investigated algesic substances was elevated in TM. Several of the algesics were of importance for the levels of pain intensity and mechanical pain sensitivity in TM. These results indicate peripheral contribution to maintenance of central nociceptive and pain mechanisms and may be important to consider when designing treatments.
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R E S E A R C H A R T I C L E Open Access
Algogenic substances and metabolic status in
work-related Trapezius Myalgia: a multivariate
explorative study
Björn Gerdle
1*
, Jesper Kristiansen
2
, Britt Larsson
1
, Bengt Saltin
3
, Karen Søgaard
4
and Gisela Sjøgaard
4
Abstract
Background: This study compares the levels of algesic substances between subjects with trapezius myalgia (TM)
and healthy controls (CON) and explores the multivariate correlation pattern between these substances, pain, and
metabolic status together with relative blood flow changes reported in our previous paper (Eur J Appl Physiol
108:657669, 2010).
Methods: 43 female workers with (TM) and 19 females without (CON) trapezius myalgia were using microdialysis
- compared for differences in interstitial concentrations of interleukin-6 (IL-6), bradykinin (BKN), serotonin (5-HT),
lactate dehydrogenas (LDH), substance P, and N-terminal propeptide of procollagen type I (PINP) in the trapezius
muscle at rest and during repetitive/stressful work. These data were also used in multivariate analyses together
with previously presented data (Eur J Appl Physiol 108:657669, 2010): trapezius muscle blood flow, metabolite
accumulation, oxygenation, and pain development and sensitivity.
Results: Substance P was significantly elevated in TM (p=0.0068). No significant differences were found in the
classical algesic substances (p: 0.432-0.926). The multivariate analysis showed that blood flow related variables,
interstitial concentrations of metabolic (pyruvate), and algesic (BKN and K
+
) substances were important for the
discrimination of the subjects to one of the two groups (R
2
: 0.19-0.31, p<0.05). Pain intensity was positively
associated with levels of 5-HT and K
+
and negatively associated with oxygenation indicators and IL-6 in TM
(R
2
: 0.24, p<0.05). A negative correlation existed in TM between mechanical pain sensitivity of trapezius and BKN
and IL-6 (R
2
: 0.26-0.39, p<0.05).
Conclusion: The present study increased understanding alterations in the myalgic muscle. When considering the
system-wide aspects, increased concentrations of lactate, pyruvate and K
+
and decreased oxygenation characterized
TM compared to CON. There are three major possible explanations for this finding: the workers with pain had
relatively low severity of myalgia, metabolic alterations preceded detectable alterations in levels of algesics, or
peripheral sensitization and other muscle alterations existed in TM. Only SP of the investigated algesic substances
was elevated in TM. Several of the algesics were of importance for the levels of pain intensity and mechanical pain
sensitivity in TM. These results indicate peripheral contribution to maintenance of central nociceptive and pain
mechanisms and may be important to consider when designing treatments.
Keywords: Myalgia, Exercise, Human, Mental stress, Microdialysis, Pain
* Correspondence: bjorn.gerdle@liu.se
1
Department of Pain and Rehabilitation Center and Department of Medical
and Health Sciences, Linköping University, SE-581 85 Linköping, Sweden
Full list of author information is available at the end of the article
© 2014 Gerdle et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
Gerdle et al. BMC Musculoskeletal Disorders 2014, 15:357
http://www.biomedcentral.com/1471-2474/15/357
Background
Chronic pain conditions such as neck-shoulder pain in-
cluding trapezius myalgia have a prevalence in the popu-
lation of 10-20% and with a higher prevalence in women
[1,2]. The aetiology and pathophysiology of acute myal-
gia is not fully understood. The diagnoses of chronic
myalgia are settled by careful anamnesis and clinical
examination relied on a bio-psycho-social model of pain
[3]. Acute myalgia usually starts with a feeling of tired-
ness and stiffness. In an, initially intermittent stage, pain
often can be alleviated for short or long periods. Chronic
regional myalgia in the shoulder area often gradually
becomes more easily triggered and can be spread to
include most of the body; chronic wide spread pain.
Patients usually report more or less ongoing pain. Dur-
ing clinical examinations, palpation often reveals tender
muscles corresponding to the reported painful areas.
Pain is a complex process that involves the interaction
of an array of biochemical transmitters and receptors in
both the peripheral and central nervous systems. Chronic
pain is associated with alterations in the central nervous
system (CNS) such as central hyperexcitability, alterations
in the pain matrix in the cerebrum and in the descending
control of nociception [4-12]. Muscle nociception is
activated by stimulation of free nerve endings of group III
(Aδ) and IV afferent (C) fibres. Nociceptors respond to
single or combinations of noxious stimuli and their sensi-
tivity can be increased by endogenous substances [13-15].
So the question arises whether muscle alterations with
respect to metabolics and algesics are present in chronic
myalgia and contribute to maintenance of the central
alterations mentioned above.
The microdialysis (MD) technique offers an in vivo
method to study nociceptive and metabolic mechanisms
in chronic myalgia [16]. MD allows for continuous
sampling of compounds in the muscle interstitial space
(i.e., the extra cellular fluid), where nociceptor free nerve
endings terminate and in close proximity to the muscle
fibers providing accurate information on local biochem-
ical changes before such compounds are diluted and
cleared by the circulatory system. Hence, the extracellu-
lar matrix plays a key role in the functions of the noci-
ceptors [17]. We have investigated the interstitial milieu
of the myalgic trapezius muscle as part of a chronic
regional neck-shoulder pain condition in women with
respect to three degrees of severity [18-20]. Increases in
algesics e.g., serotonin (5-HT), glutamate, and kallidin in
chronic trapezius myalgia and other myalgic muscles
have been reported [18-24]. Increases in interstitial con-
centrations of lactate and pyruvate have also been found
in these cohorts of trapezius myalgia [19,20]. These
results were recently confirmed in female workers with
trapezius myalgia active in the labour market and with
relatively low severity [25].
Hence both the briefly referred studies and other stud-
ies indicate that a number of substances can be released
and altered in the milieus of the nociceptors not only in
acute nociception (the inflammatory soup) but also in
chronic myalgias [26]. There is growing consensus that a
panel of multiple biomarkers will perform better than
a single biomarker in the understanding of activated
nociceptive and pain mechanisms. Traditional statistical
methods can quantify level changes of individual sub-
stances [27] but assume variable independence and
disregard interrelationships between variables [28]. The
development of Omics methods meaning large-scale
data analysis for characterization and quantification of
pools of biological molecules has promoted the develop-
ment of statistical methods capable of handling a num-
ber of intercorrelated substances. In order to handle
situations when traditional classical statistical assump-
tions not are met or appropriate Multivariate Data
Analysis (MVDA) has been developed; e.g., advanced
principal component analyses and Partial Least Squares
regressions. Hence, these methods represent a comple-
mentary approach to the traditional statistical methods
for better understanding of the complex biochemical al-
terations that may occur in chronic musculoskeletal
pain; these methods have been applied in other MD
studies of chronic myalgia [23,29].
The present study focuses on mainly algesic substances -
possible to analyse from dialysate and investigated in earlier
MD studies - and how these substances interact with
earlier reported metabolic and blood flow alterations
in the same subjects [25]. Thus, this study has three
main aims:
1. to compare the concentrations of glutamate,
bradykinin (BKN), 5-HT, Lactate dehydrogenase
(LDH), interleukin-6 (IL-6), substance P (SP), and
N-terminal propeptide of procollagen type I (PINP)
between trapezius myalgia subjects (TM) and
healthy controls (CON);
2. to identify substances that in the multivariate
context best separate CON from TM;
3. to investigate the multivariate associations between
aspects of pain (intensity and sensitivity), algesics,
and metabolic status together with oxygenation and
blood flow changes reported in our previous paper
in the two groups of subjects [25].
Methods
Subjects
A casecontrol study was performed and female workers
were recruited from seven workplaces, which were charac-
terized by typically monotonous and repetitive work tasks;
for a full description of the recruitment process including
a flow-chart, see our previous article [25]. Two groups of
Gerdle et al. BMC Musculoskeletal Disorders 2014, 15:357 Page 2 of 15
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subjects were recruited: 1) subjects with trapezius myalgia
(TM) and 2) healthy subjects (CON).
The following criteria had to be fulfilled for inclusion
in the TM group: (1) pain or discomfort in the neck/
shoulder region for more than 30 days during the previ-
ous year; (2) not more than 30 days of pain or discom-
fort in no more than three out of eight major body
regions (neck/shoulder, low back, and left or right arm/
hand, hip, knee/foot) this criterion was used to ex-
clude widespread musculoskeletal diseases; (3) the pain
or discomfort should be at least quite a lot on an ordinal
5-step scale ranging from a little to very much; (4) the
pain or discomfort should be frequent (at least once a
week); and (5) the intensity of the pain or discomfort
should be at least 2 on a scale from 0 to 9, where 0 is no
pain and 9 is the worst imaginable pain [30]. 6) A clin-
ical standardized examination for the confirmation of
the diagnosis trapezius myalgia [31,32]; the main criteria
for a positive clinical diagnosis were (a) pain in the neck
area, (b) tightness of the trapezius muscle, and (c) palp-
able tenderness in the trapezius muscle. According to
the inclusion and exclusion criteria, TM had chronic
pain of relatively low severity compared to patients no
longer on the labour market. For inclusion in CON, the
following criteria had to be fulfilled: (1) pain or discom-
fort for less than eight days during the previous year in
the neck/shoulder region; and (2) no more than three
body regions with more than 30 days of pain or discom-
fort, and negative replies were requested regarding ques-
tion (3) to (5). Additionally, none of the participants
should suffer from serious conditions such as previous
trauma or injuries, life threatening diseases, cardiovascu-
lar diseases, or arthritis in the neck and shoulder. In
order to describe the work situation of all subjects an-
swered a brief questionnaire that included questions re-
garding the job and the work ability (i.e., work ability
index) [33,34]. In total, 43 TM and 19 CON participated
in this study and successful MD data were obtained
from all of the TM and 17 of the CON participants. As
earlier reported age, height, and weight showed no
group differences (Table 1) [25]. As also reported earlier
TM reported significantly higher pain intensity at rest, a
significantly lower work ability index but without signifi-
cant differences in sick leave (Table 1). The majority of
TM and CON reported that they seldom (never, hardly
never or 23 times recent month) used medication
(71.4% vs. 90%) and daily use of medication (once or
several times a day) were reported by 23.7% in TM and
10% in CON. Two thirds of the medication used was
analgesics.
All subjects gave written informed consent, which con-
formed to The Declaration of Helsinki and was approved
by the Capital Region of Denmark ethical committee (KF
01-138/04). The study qualified for registration in the
International Standard Randomized Controlled Trial
Number Register ISRCTN87055459, registration date: 14
March 2014. The cases of the present study form the base-
line population of a previously reported randomized con-
trolled trial (RCT) [35]. The present case control study is
included in the clinical trial registration. CONSORT
guideline related information and CONSORT flowchart is
found in the article reporting the RCT [35].
Procedures
Pressure pain thresholds (PPT) i.e., mechanical pain
sensitivity - were determined several days before the MD
session. The participants were asked not to use any
medications except for paracetamol preparations three
days before the MD session day and were instructed not
to perform any shoulder or neck-training exercises for
48 h before the session, except for ordinary daily work
and/or leisure activities. The participants reported to the
laboratory in the morning. They finished breakfast one
to two hours before the start of MD and had standard-
ized light meals at frequently set time-points throughout
the experiment to maintain blood glucose and digestion
as constant as possible. The MD catheters were inserted
into the trapezius muscle of the most painful side in case
of side differences for the TM group. For 30% of the TM
group (13 out of 43), the non-dominant side was most
affected and therefore 30% of the CON group had the
MD catheter inserted into the non-dominant side (5 out
of 17); in all, 10% were left-hand dominant. Then the
participants rested for 120 min to allow the tissue to re-
cover from possible changes in the interstitial environ-
ment induced by the catheter insertion. During the
resting period, near-infrared spectroscopy (NIRS) sen-
sors were mounted above the descending part of the tra-
pezius muscle above the MD permeable catheter part.
The resting period was followed by a 40-min repetitive
low-force exercise period performed unilaterally on a
pegboard (PEG) using the hand on the same side the
MD catheter had been inserted in the trapezius muscle.
Table 1 Background data together with current pain
intensity, work ability index and sick leave
Group variables CON
Mean ± SD
TM
Mean ± SD
Statistics
(p-value)
Age (years) 44 ± 9.1 44 ± 9.8 ns
Height (m) 1.68 ± 0.06 1.65 ± 0.06 ns
Weight (kg) 70 ± 10.6 72 ± 15.0 ns
Pain intensity (VAS, mm) 2.7 ± 3.5 27 ± 22 <0.001
Work ability index 39.1 ± 2.0 35.9 ± 3.5 0.01
Sick leave last year (days) 5 ± 8 8 ± 16 ns
CON denotes healthy controls) and TM denotes subjects with trapezius
myalgia; these data has been reported earlier [25]. Furthest to the right is
shown the statistical evaluation (p-values); ns denotes no significant
group difference.
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Following this exercise, the participants rested for
120 min (recovery). The final 20 min of the recovery
was used as a baseline for a stressful task: The STROOP
test (STR) for 10 min with a subsequent 30-min recov-
ery period [25].
Pressure pain thresholds (PPT)
PPTs were measured bilaterally over trapezius and
tibialis anterior muscles using an algometer (Algometer
Type 2, Somedic, Hörby, Sweden) with a diameter of
the contact area of 10 mm and a pressure applied
perpendicular to the skin at a speed of 30 kPa/s; for de-
tails see [36].
Pain intensity (VAS)
Pain intensity of the shoulder region was assessed
throughout the MD session with a 100-mm visual
analogue scale (VAS), ranging from 0 mm (no pain)to
100 mm (worst possible pain). The shoulder region
was defined as the area covered by m. trapeziusde-
scending part, m. supraspinatus and m. infraspinatus.
VAS was rated on the experimental working-day before
and immediately after insertion of the MD catheter and
every 60 min during rest; these values were not signifi-
cantly different from the recording at 160 min syn-
chronised to the MD sampling (see below) and taken
as baseline before the PEG. During the PEG task, VAS
was rated every 5 min (i.e., eight times during the
40 min PEG) and then at 10, 60, and 120 min post
exercise. VAS was also rated immediately before (320
MD time) and after the STR task and in the following
recovery period every 10 min.
Microdialysis (MD)
MD was performed as previously described [25]. In sum-
mary, two custom-made MD catheters (membrane
length 30 mm, molecular cut-off: 5 kDa and 3000 kDa,
inter-catheter distance approximately 2 cm) [37] were
inserted in the trapezius muscle parallel to the muscle fi-
bres. The MD catheters were perfused by a high preci-
sion syringe pump (CMA 100; Carnegie Medicine,
Solna, Sweden) at a rate of 5 μl min
1
with a Ringer
acetate solution (Pharmacia & Upjohn, Copenhagen,
Denmark) containing 3 mM glucose and 0.5 mM lactate
to minimise the risk of draining the interstitial space [38].
1.0 M [
14
C]-lactate (specific activity: 2.22 GBq mmol
1
;
Amersham, Bucks, UK) was added to the perfusate to de-
termine the in vivo relative recovery (RR) of lactate, pyru-
vate, and glucose (each approximately similar in molecular
size and weight) using the internal reference method
[25,39]. Furthermore, nutritive trapezius muscle blood
flow was estimated by the MD ethanol technique using
3
H
2
O instead of ethanol [40,41]. The ratio of
3
H
2
Ointhe
dialysate and the perfusate (the outflow-to-inflow ratio)
varies inversely with the local blood flow in the tissue
[40,41]. Microdialysates were collected continuously
into MD vials that were changed every 20 min starting
at t = 20 min until t = 320 min, and thereafter every
10 min up to t = 360 min (Figure 1). The samples col-
lected from t = 20-100 min were not used in this study.
As Dialysate samples were collected and the samples
were immediately frozen and stored at 80°C until ana-
lyses were performed. The sample volume collected at
each time point was relatively small (50100 μl), not all
biochemical components could be determined in all
samples. Thus, dialysate from t = 120 and t = 140 min
were pooled and used to determine PINP, serotonin,
and substance P (see below). Glutamate, lactate, pyru-
vate,glucose,potassium,LDH,BKN,aswellaslocal
blood flow were determined in samples collected at
160 min (baseline before PEG), 180 min (PEG), 200 and
220 min (recovery after PEG), 320 min (baseline before
STR), 330 min (STR), and 340, 350, and 360 min (recov-
ery after STR). The average number of dialysate samples
possible to use for the determination of concentrations
of algesics was 92% (except SP; see below). Because the
measured concentrations refer to the average interstitial
concentrations in the period during which the dialysate
was collected, the time assigned to each sample was the
time midway in the collection period. Lactate, pyruvate,
glucose, K
+
,5-HT,SP,andlocalmusclebloodflowwas
determined in microdialysate collected using a 5 kDa
catheter, and LDH, IL-6, PINP and BKN were deter-
mined in samples using a 3000 kDa catheter.
Concentration of muscle interstitial glutamate ([glu-
tamate]) was measured in a CMA 600 Microdialysis
Analyzer (CMA Microdialysis, Stockholm, Sweden). The
CMA 600 detection interval is 1.0 -150 μmol l
1
for glu-
tamate. Concentrations below the level of detection were
replaced with a value corresponding to the lower level of
detection and divided by two [24]. Muscle interstitial
LDH activity ([LDH]) was measured by a Cytotoxicity
Detection Kit (Roche Molecular Biochemicals, Roche
Diagnostics, Mannheim, Germany), which has a level of
detection of 21.5 mU/ml. Muscle interstitial IL-6 con-
centration ([IL-6]) was measured using a high-sensitivity
Quantikinew assay (R&D systems, Minneapolis, MN,
USA). In order to meet the minimum sample volume
requirements of the IL-6 assay, dialysate samples were
diluted 100-fold with calibrator diluent. The lowest cali-
bration standard was used as the level of detection.
Hence, the detection level for IL-6 in the dialysate was
15.6 pg/ml when adjusting for the dilution factor. Accur-
acy of the assay was checked by spiking buffer and a low
sample in duplicate with interleukin-6 international stand-
ard (NIBSC 89/548) [42]. Muscle interstitial BKN ([BKN])
was measured by a radioimmunoassay (Peninsula La-
boratories, Inc., Bachem AG, Bubendorf, Switzerland).
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Figure 1 (See legend on next page.)
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The limit of detection in the dialysate was 242 pg/ml.
Muscle interstitial 5-HT concentrations ([5-HT]) were
measured with an enzyme immunoassay (Immunotech,
Marseille, France) with a detection level of 0.28 ng/ml. In
order to make a meaningful statistical comparison of 5-
HT levels between groups, 5-HT results below the level of
detection was recorded as half of the detection level [43].
Muscle interstitial concentration of SP ([SP]) was deter-
mined with an enzyme immunoassay (Assay Designs,
Enzo Life Sciences, Farmingdale, NY, USA), the limit of
detection in the dialysate was 2.0 pg/ml. Muscle interstitial
collagen synthesis was determined as the concentra-
tion of PINP ([PINP]). [PINP] were determined using a
sandwich ELISA technique with a detection limit of
0.071 Ng/ml [44].
Previously described methods and reported results
Details concerning the methodology of Near-infrared
spectroscopy (NIRS) and the methods for determination
of concentration of metabolites have been described in
our previous article from this study and are not repeated
here [25]. The results concerning NIRS data, pain inten-
sity, muscle interstitial lactate, pyruvate, and glucose
concentrations ([lactate], [pyruvate], and [glucose], re-
spectively), muscle dialysate potassium concentration
([K
+
]) and blood flow (i.e., the ratio of
3
H
2
O in the di-
alysate and the perfusate - the outflow-to-inflow ratio -
varies inversely with the local blood flow in the tissue
flow) with respect to group and time as well as PPT data
have been described in detail in our previous article [25]
and are summarized in Additional files 1 and 2. Note
that this data from our previous article only is used in
the multivariate analyses of the present study.
Statistics
Data are presented as mean ± one standard deviation
(±1SD) unless otherwise specified. SPSS (Version 11.0,
SPSS Inc., Chicago) was used for the classical statistical
analyses. Analysis of variance (ANOVA) for repeated
measures using a first order autoregressive covariance
structure model was used to test for time and group ef-
fect during the two separate exercise periods and their
respective recovery periods; for details [25].
For investigating the multivariate correlation patterns
between the interstitial concentrations of different meta-
bolic and algesic substances, pain intensity, relative blood
flow changes, etc., Principal component analysis (PCA)
and Partial least squares or projection to latent structures
(PLS-OPLS/O2PLS) were applied using SIMCA-P + [45].
These methods are increasingly applied in situations
with large data sets and with low subject-to-variables
ratios [46,47].
Principal component analysis (PCA) can be viewed as
a multivariate correlation analyses. Variables loading
upon the same component (p) are positively correlated,
and variables with high loadings but with different signs
are negatively correlated. Variables with high absolute
loadings with respect to the component under consider-
ation were considered significant [45]. The obtained sig-
nificant components are per definition not correlated. R
2
describes the goodness of fit and Q
2
describes the good-
ness of prediction [45]. Outliers were identified using the
two methods available in SIMCA-P+. Two multivariate
outliers were identifiedone from CON and one from
TM and excluded in the multivariate analyses.
PLS-OPLS/O2PLS was used for the multivariate regres-
sion analysis of pain intensities, pressure pain thresholds,
and group membership (CON or TM; coded 0 and 1, re-
spectively) using the interstitial concentrations of the differ-
ent compounds and other variables as regressors [45]. The
VIP variable (variable influence on projection) indicates the
relative relevance of each X-variable. VIP 1.0 was consid-
ered significant. Coefficients were used to note the direc-
tion of the relationship (positive or negative). VIP values
are reported in descending order and the sign of the coeffi-
cient is also given. PLS regressions (except for group mem-
bership) were performed both for all subjects taken
together and in the two groups (TM and CON) separately.
This strategy gives the opportunity to detect substances
involved in sensitization in TM. A probability of 0.05
(two-tailed) was accepted as the criterion for significance
in all statistical tests.
Results
Interstitial concentrations of algesic substances
No group differences were found for the concentrations
of glutamate, IL-6, LDH and BKN (Table 2). All sub-
stances showed time effects (Table 2 and Figure 1). Simi-
lar results and without group differences were obtained
when the PEG and STR parts were analysed separately
for each of these substances (data not shown). No group
differences in [5-HT] (CON: 23.8 ± 29.1 vs. TM: 21.6 ±
33.2; p = 0.432) and [PINP] (CON: 20.1 ± 21.5 vs. TM:
16.4 ± 12.1; p = 0.489) were found (Figure 2). TM had
(See figure on previous page.)
Figure 1 Mean interstitial concentrations of glutamate (panel a), interleukin 6 (IL-6; panel b), lactate dehydrogenase (LDH; panel c),
and bradykinin (BKN; panel d) throughout the microdialysis experiment in women with trapezius myalgia (TM) and in healthy controls
(CON). X-axis gives min after insertion of the catheters and samples are plotted at midpoint of the sampling period. PEG = repetitive low-force exercise
performed unilaterally on a pegboard during 40 min (160200 min after catheter insertions), STR = STROOP test during 10 min (320330 min after catheter
insertions). TM is denoted by filled blue squares and CON is denoted with unfilled red squares.
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significantly higher [SP] than CON (TM: 220.0 ± 272.5
vs. CON: 47.3 ± 106.5; p = 0.0068) (Figure 2). Please note
that the number of subjects in CON (n = 6) was low due
to lack of dialysate when the analysis of this substance
was performed.
Multivariate analyses
Additional file 1 and Additional file 2 summarize the re-
sults presented in our previous study for all subjects
taken together concerning pain aspects, the interstitial
concentrations of metabolites, blood flow (i.e., outflow/
inflow ratio), and NIRS data [25]. Note that these data
are used in the present study only in the multivariate
analyses presented below.
Intercorrelations between biochemical substances, nirs
data, and blood flow in the two groups
The multivariate correlation patterns between algesics and
metabolites, NIRS data, and blood flow were investigated
using PCA in order to investigate if different patterns
existed in TM and CON.
The PCA in CON identified three significant compo-
nents (R
2
= 0.52). According to the first component (p1;
R
2
= 0.25), positive inter-correlations existed between
[lactate] (six of nine time points), [glutamate] (two out
of nine time points), [K
+
] (four of nine time points), and
[BKN] (two time points). These variables correlated
negatively with blood flow (at all nine time points) and
[PINP]. The second component (p2; R
2
= 0.15) mainly
showed positive intercorrelations between [glucose] (five
of nine time points) and deoxy-haemoglobin (HHb;
three of six time points). These variables were negatively
inter-correlated with [LDH] (five of nine time points).
According to the third component (p3; R
2
=0.11), oxy-
haemoglobin (OHb), HHb, and total haemoglobin (THb)
at the two recovery time points inter-correlated positively
mainly with [IL-6] (three of nine time points). These vari-
ables correlated negatively with blood flow (five of nine
time points), and with [pyruvate], [glutamate] and [BKN]
(two to three time points for each substance).
The PCA in TM identified nine significant compo-
nents (R
2
= 0.71) and the three most important compo-
nents (p1-p3) explained 36% of the variation (R
2
= 0.36).
According to the first component (p1; R
2
= 0.16), positive
inter-correlations existed mainly between [lactate], [pyru-
vate], and [glutamate] (at all nine time points for the three
substances), with [BKN] (four time points) and with
[5-HT] and [SP]. The second component (p2; R
2
=0.11)
mainly showed positive inter-correlations between [LDH]
(eight of nine time points) and blood flow (all nine time
Table 2 The statistical evaluations of the concentrations
of glutamate, IL-6, LDH and BKN
Substance Group
(p-value)
Time
(p-value)
Interaction
(p-value)
[glutamate] 0.524 <0.001* na
[IL-6] 0.679 <0.001* na
[LDH] 0.879 <0.01* na
[BKN] 0.926 <0.001* na
P-values for group (CON vs. TM) and time effects are shown. Interaction terms
were only calculated when both time and group were significant; na denotes
not applicable. *denotes significance.
Figure 2 Mean concentrations (± standard error of the mean; SEM) of N-terminal propeptide of procollagen type I (PINP), serotonin
(5-HT) and substance P (SP) in women with trapezius myalgia (TM; blue bars) and in healthy controls (CON; grey bars) based on pooled
dialysate (from t = 120 min and t = 140 min; see text for details). Please note that the number of subjects in CON (n = 6) for SP was low due
to lack of dialysate when this analysis was performed.
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points). According to the third significant component (p3;
R
2
= 0.09), [IL-6] (six of nine time points) correlated posi-
tively with blood flow (seven of nine time points) and
HHb (two of six time points). These variables correlated
negatively with the concentrations of [SP] and [lactate]
(three of nine time points).
Regression of group membership
Group membership TM versus CON - was regressed
using the relevant variables (biochemical substances,
NIRS data, and blood flow) at baseline. This significant
regression (R
2
= 0.19) identified that TM membership
compared to CON membership was associated with low
blood flow (VIP = 2.33(+)), low [BKN] (VIP = 1.30()),
high [pyruvate] (VIP = 1.20(+)), low OHb (VIP = 1.03
()), and high [K
+
] (VIP = 1.01(+)).
A PLS regression using all available time points was
also made (R
2
= 0.31) (Table 3). The blood flow variables
at different time points were important for predicting
group membership, but there were also several other im-
portant regressors: [K
+
] at four time points, [pyruvate] at
five time points, [IL-6] at two time points, [lactate] at
three time points, and [glutamate] at two time points.
Regressions of pain intensity in TM
a
Pain intensity at baseline correlated positively (R
2
= 0.24)
with [5-HT] (VIP = 1.53(+)) and [K
+
] (VIP = 1.50(+)),
and negatively with THb (VIP = 1.62()), HHb (VIP =
1.41()), OHb (VIP = 1.23()), and [IL-6] (VIP = 1.07()).
It was not possible to regress pain intensity through-
out the experiment (several Y-variables) in TM using
biochemical substances, NIRS data, and blood flow.
Regressions of mechanical pain sensitivity (PPT)
It was possible in TM to regress PPT of trapezius using
baseline data (R
2
= 0.26); a low PPT was associated with
high [BKN] (VIP = 2.18()), [IL-6] (VIP = 2.14()), THb
(VIP = 1.10()), and high blood flow (VIP = 1.02(); note
the inverse construction of this variable). Metabolic sub-
stances were not significant in this regression.
When regressing PPT of trapezius in TM using all
data (R
2
= 0.39) (Table 4) [IL-6] at six time points,
[BKN] at six time points, [pyruvate] at three time points,
[K
+
] at four time points, and [glucose] were the most
important regressors.
It was possible in CON to regress PPT of trapezius
using baseline data (R
2
= 0.66): Blood flow: VIP = 1.38
(+); [PINP]: VIP = 1.38(); OHb: VIP = 1.36(); [K
+
]: VIP =
1.35(+); [BKN]: VIP = 1.33(+); [5-HT]: VIP = 1.11(); and
THb: VIP = 1.10().
We also regressed PPT of trapezius using all time
points (R
2
= 0.51) (Table 5); blood flow at nine time
points and [K
+
] at six time points were the most import-
ant regressors.
Table 3 PLS regression of group membership using the
intramuscular variables as regressors (R
2
= 0.31)
Variable Time point VIP Sign of coeff
[BKN] 150 min 1.43 -
Blood flow 150 min 2.57 +
170 min 2.44 +
190 min 2.28 +
210 min 2.35 +
310 min 1.83 +
325 min 1.02 +
335 min 1.87 +
345 min 1.60 +
355 min 1.93 +
HHB Recov1b 1.20 -
OHb 21-40 min 1.44 -
PEG-0-20 min 1.13 -
recov2 1.02 -
STR 1.04 -
[Lactate] 150 min 1.02 +
170 min 1.05 +
190 min 1.21 +
210 min 1.20 +
325 min 1.02 +
325 min 1.39 +
335 min 1.02 +
[Pyruvate] 150 min 1.33 +
170 min 1.30 +
190 min 1.78 +
210 min 1.14 +
325 min 1.41 +
[Glucose] 310 min 1.15 +
[Glutamate] 150 min 1.06 +
170 min 1.11 -
[K
+
] 150 min 1.11 +
190 min 1.83 -
325 min 1.59 +
345 min 1.30 +
[IL-6] 210 min 1.71 -
310 min 1.35 -
[LDH] 335 min 1.07 +
[substance] denotes concentration of the substance. BKN = Bradykini n, HHB =
deoxy-haemoglobin, OHB = oxyhaemoglobin, K
+
= potassium, IL-6 = interleukin
6, LDH = Lactate dehydrogenase, PEG = repetitive low-force exercise performed
unilaterally on a pegboard, STR = STROOP test.
Trapezius myalgia (TM) was denoted 1 and healthy controls (CON) was
denoted 0. VIP values and sign of coefficient (coeff) are given. Note that the
variables are grouped and sorted within each variable with respect to the time
points. A positive coefficient indicates that TM has high values on this variable
compared to CON and vice versa. Note the inverse construction of blood flow.
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No significant regressions of PPT of tibialis anterior
were found.
Summing-up of multivariate analyses
A more diverse correlation pattern existed in TM com-
pared with CON. A mix of factors comprised by blood
flow related variables, algesic and metabolic substances
were important for group membership (TM or CON).
The three most important regressors of pain intensity at
baseline in TM were positively correlated [5-HT] and [K
+
] and negatively THb. Prominent differences existed be-
tween CON and TM with respect to important regres-
sors of PPTs of the trapezius muscles.
Discussion
The major results of the present study were:
[SP], but not the other investigated - mainly algesic
- substances (i.e., 5-HT, IL-6, BKN, glutamate, LDH
and PINP), was elevated in female workers with TM.
The correlation pattern between algesics,
metabolites and blood flow factors was more diverse
in TM than in CON.
Using a system-wide approach, increased [lacate],
[pyruvate] and [K
+
] and decreased oxygenation
characterized TM compared to CON; the classic
algesic substances investigated had little importance.
The pain intensity in TM correlated positively with
[5-HT] and [K
+
] and negatively with oxygenation
aspects.
The most important regressors of PPT in TM were
[BKN] (negatively), [IL-6] (negatively) and blood
flow variables (positively).
Algesics traditional statistical analyses
In our recent study we reported significant group dif-
ferences in [lacatate] and [pyruvate]. In the present
studybasedonthesamecohortwefoundincreased
[SP] among the primarily algesic substances examined
[25]. SP is a mediator of neurogenic inflammation and
Table 4 Regression of pressure pain threshold of
trapezius in TM using the intramuscular variables
(R
2
= 0.39)
Variable Time point VIP Sign of
coeff
Blood flow 150 min 1.14 -
170 min 1.07 -
190 min 1.05 -
210 min 1.40 -
335 min 1.18 -
345 min 1.56 -
HHB 21-40 min 1.09 -
recov1 1.47 -
recov2 1.36 -
STR 1.03 +
OHB recov1 1.27 -
recov2 1.35 -
THB 21-40 min 1.01 -
PEG-0-20
min
1.17 -
recov1 1.55 -
recov2 1.63 -
[Lactate] 170 min 1.27 -
210 min 1.06 -
335 min 1.11 -
[Pyruvate] 170 min 2.13 -
190 min 1.07 -
210 min 1.14 -
[Glucose] 170 min 1.67 -
335 min 1.49 -
345 min 1.29 -
[Glutamate] 345 min 1.09 -
[BKN] 150 min 2.52 -
170 min 1.13 -
310 min 1.42 +
325 min 1.53 +
335 min 1.73 +
355 min 1.22 +
[IL-6] 150 min 2.57 -
170 min 1.50 -
190 min 1.55 -
210 min 1.66 -
345 min 1.10 -
355 min 1.22 -
[K
+
] 170 min 1.77 +
Table 4 Regression of pressure pain threshold of
trapezius in TM using the intramuscular variables
(R
2
= 0.39) (Continued)
190 min 1.19 +
210 min 1.00 +
335 min 1.04 +
[substance] denotes concentration of the substance. HHB = deoxy-
haemoglobin, OHB = oxyhaemoglobin, THb = total haemoglobin, BKN =
Bradykinin, IL-6 = interleukin 6, K
+
= potassium, PEG = repetitive low-force exer-
cise performed unilaterally on a pegboard, STR = STROOP test.
VIP values and sign of coefficient (coeff) are given. Note that the variables are
grouped and sorted within each variable with respect to time point. A positive
coefficient indicates that this variable will be associated with high PPT values
and vice versa. Note the inverse construction of blood flow variables.
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associated hyperalgesia [48]. SP release in the periphery
can occur as consequences of peripheral nociception
and sensitization and SP binds to specific G protein-
coupled tachykinin (NK) receptors [48]. Lymphocytes,
granulocytes, and macrophages stimulated by SP produce
inflammatory mediators as well as pro-inflammatory cyto-
kines (IL-1, IL-6, and TNF) [48,49], which in turn can
stimulate adipocytes to synthesize SP [50]. Two MD studies
of active trigger points of the trapezius in myofascial pain
(MFP) found significant increases in [SP] [51,52]. The
present results agree with these two studies. However, the
number of subjects in CON as well as the number of sub-
jects in the studies of Shah et al. was low. The former cir-
cumstance may explain why [SP] was not an important
regressor in the multivariate analyses (Tables 3, 4 and 5).
Hence, the role of SP in chronic trapezius myalgia has to be
investigated in larger cohorts.
We found no significant group differences in [glutam-
ate], [IL-6], [BKN] and [5-HT]. Hence, it was not
possible to confirm earlier studies of more severe TM
[18-24,53]. The lack of group differences for these
algesics may be accounted by the degree of pain sever-
ity. Another possibility concerns the statistical methods
used. Classical statistical methods can quantify the level
of individual substances and assume variable independ-
ence when interpreting the results [27,28]. There is a
risk that more subtle alterations in several substances
simultaneously are not detected using classical statis-
tical methods [27,28]. Only focusing upon a few sub-
stances in an explanatory phase of understanding
peripheral alterations in chronic myalgia may not be
fully comprehensive. Thus, taking into account system-
wide aspects using multivariate analyses (Tables 3, 4
and 5) showed that peripheral alterations in algesics
and metabolites together with blood flow aspects were
linked to aspects of pain such as group membership,
mechanical pain sensitivity and pain intensity.
Different multivariate correlation patterns in CON and TM
The separate PCAs suggested a more diverse situation,
as indicated by number of components, in TM than in
CON.Onereasonforthismaybethatnociception
and peripheral sensitization were present in TM and
contributes to the increased degree of complexity.
Another factor may be heightened myogenic activity
(i.e., increased satellite cells and myonuclear content),
which recently have been reported in the same
subjects [54]. Also a recent proteomic study of the
interstitium of chronic myalgia showed profound al-
terations compared to controls [55]. The sample size
washigherinTMthaninCON,increasingthe
chance of obtaining more components. However, the
same pattern with more principal components in
chronic TM than in controls was found in another
project from our group with an equal number of
subjects in both groups (unpublished analyses based
on [20,24,56]).
Table 5 Regression of pressure pain threshold of trapezius
in CON using the intramuscular variables (R
2
=0.39)
Variable Timepoint VIP Sign of coeff
Blood flow 150 min 1.73 +
170 min 1.90 +
190 min 1.94 +
210 min 2.40 +
310 min 1.45 +
325 min 1.62 +
335 min 1.59 +
345 min 1.95 +
355 min 1.16 +
OHB 21-40 min 1.28 -
PEG-0-20 min 1.67 -
recov1 1.20 +
THB PEG-0-20 min 1.38 -
21-40 min 1.12 +
recov1 1.29 +
[Lactate] 190 min 1.17 +
210 min 1.37 +
[Glucose] 310 min 1.43 +
345 min 1.04 +
[Glutamate] 170 min 1.54 +
[BKN] 170 min 1.12 +
[IL-6] 210 min 1.50 +
310 min 1.42 +
325 min 1.06 +
355 min 1.17 +
[K
+
] 150 min 1.73 +
210 min 1.71 +
325 min 2.21 +
335 min 1.35 +
345 min 1.52 +
355 min 1.57 +
[5-HT] 1.45 -
[PINP] 1.39 -
[substance] denotes concentration of the subst ance. OHB = oxyhaemoglobin,
THb = total haemoglobin, BKN = Bradykinin, IL-6 = interleukin 6, K
+
= potassium,
5-HT = serotonin, PINP = N-terminal propeptide of procollagen type I, PEG =
repetitive low-force exercise performed unilaterally on a pegboard.
VIP values and sign of coefficient (coeff) are given. Note that the variables are
grouped and sorted within each variable with respect to time point. A positive
coefficient indicates that this variable will be associated with high PPT values
and vice versa. Note the inverse construction of blood flow variables.
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Regression of group membership
The regression of group membership showed that a mix
of factors comprised of blood flow related variables,
interstitial concentrations of metabolic, and, to a lesser
extent, algesic substances were important. Low oxygen-
ation (i.e., low blood flow and low OHb) and mainly
high [lactate], [pyruvate], and [K
+
] characterized belong-
ing to TM.
Originally, accumulation of lactate was thought to be
an end product of anaerobic glycolyisis [57]. This inter-
pretation is supported by trapezius muscle biopsy ana-
lyses from the same subjects of mRNA and proteins
showing that the capacity of carbohydrate oxidation was
reduced in TM compared with CON [58]. Such an in-
verse relationship between the metabolites and blood
flow was observed in p1 of the PCA in CON, but no
such relation existed according to the PCA of TM. As
[lactate], [pyruvate] and blood flow variables were not
correlated in TM they are not necessarily directly linked.
In the majority of MD studies of chronic trapezius myal-
gia (and independently of degree of severity of the
chronic myalgia) significant increases in [lactate] and
[pyruvate] have been reported [18-20,25,53], but the re-
sults with respect to blood flow alterations have not
been consistent [19,20,25]. Lactate is also produced dur-
ing adequate oxygen provision [59]. Muscle [lactate] in-
creases with exercise intensity [60]. Other possible
explanations for increases are signs of mithochondrial
insufficiency, physical inactivity due to pain [61,62], and
changes in the lactate-pyruvate metabolism via lactate
dehydrogenase isoforms [59]. Lactic acid is dissociated
at body pH [63]. Inflamed as well as ischemic tissues
show lowered pH [64,65]. Within the muscle cell, the
protons can be buffered or released to the interstitium;
to what extent buffering occurs in the interstitium is un-
known [66]. Lactate together with adenosine triphos-
phate (ATP) facilitate the response of acid-sensing ion
channel 3 (ASIC-3) to low pH [67-69]. ASIC channels
are considered molecular transducers for nociception
and mechanosensation. Other possible receptors for low
pH are TRPV1 and 4, TRPC4 and 5 [64,65,70]. Lactate
exposure can lead to reactive oxygen species (ROS) gen-
eration [71-73]. Hence, another possibility is that the in-
creased [lactate] induced ROS, which may directly
activate nociceptive pathways or activate algesics [74].
However, it has been suggested that pyruvate is an en-
dogenous antioxidant that protects various tissues from
ROS, cytokines, and ischemia/re-perfusion-induced in-
jury [75-77].
Both the multivariate analysis at baseline and the ana-
lysis using all data identified [K
+
] (Table 3) as a signifi-
cant regressor of group membership. This is in line with
our earlier results in severe chronic myalgia where we
have reported increased [K
+
] [56], although this was not
found in our recent paper of the present subjects [25].
Increased activity and altered activity pattern of the
chronic myalgic muscle have been reported and has also
been confirmed for the present workers with TM
[25,78]. Potassium efflux via K
+
-channels and possibly
increased metabolism, structural damage of cells, and
depolarization-associated flows would also cause an
interstitial potassium accumulation [56,79]. It is not pos-
sible, based on this analysis of group membership, to de-
termine whether the significantly increased [K
+
]inTM
is directly involved in the nociception and perception of
pain or if it is secondary consequences of pain e.g.,
deconditioning of the painful trapezius (see also below).
Both pro-inflammatory and anti-inflammatory roles have
been reported for IL-6 [80-82]. IL-6 also has metabolic
properties and increases as a consequence of exercise
can occur [81,83,84]. The extended analysis of group
membership (Table 3) showed that [IL-6] at two time
points were significant and lower in TM. Interestingly,
[IL-6] tended to be higher at recovery and at baseline
after PEG in CON than in TM (Figure 1), which may in-
dicate an effect of exercise [83,84]. Thus, a protective re-
sponse may be lacking for TM. Possibly the lack of such
increases in TM might be due to other muscle processes
in TM than in CON.
[BKN] was only important at one time point (at
150 min) according to the comprehensive analysis of
group (Table 3) and TM was associated with low [BKN]
(Figure 1). This result concerning a classical algesic
might be related to other muscle alterations e.g., in
blood flow [85-87].
Regression of pain intensity
As mentioned in the introduction ongoing pain is a
common characteristic and core symptom in TM. Thus,
the pain intensity variables reflect this habitual situation
and are important to investigate with respect to the bio-
chemical substances. The within-group regressions of
pain intensity in TM showed that algesic substances
were important as regressors; high pain intensity was
positively associated with [5-HT] and [K
+
] and nega-
tively with oxygenation factors (i.e., THb, HHb, and
OHb) and [IL-6]. This result indicates that [K
+
] in fact
has a role in chronic nociceptive processes as speculated
above. In severe chronic trapezius myalgia was also
found a positive correlation between [K
+
] and pain in-
tensity [56]. In acute tissue trauma K
+
is a component of
the inflammatory soupand characterized as an algesic
substance [88].
The fact that [5-HT] was important for pain intensity
in TM agrees with its role as an algesic in the periphery
as described in earlier studies of chronic myalgia [53]. In
the periphery, 5-HT sensitizes afferent nerve fibres [89].
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The negative correlation of [IL-6] with pain intensity
in TM favours an anti-inflammatory effect of IL-6 as
mentioned above [82]. The inverse relationship between
pain intensity and the three Hb variables indicate insuffi-
cient oxygenation as a factor involved in the habitual
pain intensity.
Regression of mechanical pain sensitivity
When clinically examining the patient with neck-
shoulder pain a frequently used sign is palpation of
muscle tenderness; TM patients show increased tender-
ness over the trapezius. PPT measurements (i.e., mech-
anical pain sensitivity) is a more standardized way of
determining muscle tenderness and concern the recogni-
tion of a new nociceptive stimulus (pressure) in painful
or non-painful tissues. The fact that it was not possible
to significantly regress PPTs of tibialis anterior reason-
ably indicates that the data registered from trapezius
really represent local alterations in the trapezius. The re-
gressions of PPT in the groups separately - both analyses
of baseline data and all time points (Tables 4 and 5) - in-
dicated that mechanical pain sensitivity in chronic pain
conditions are not just consequences of levels of certain
biochemical substances since several of the same and
significant variables in both regressions had different
signs: blood flow, [lactate], [IL-6], and [BKN]. Possible
explanations for these results are that nociceptive, hyper-
algesic, myogenic, and other processes are activated in
TM but not in CON as discussed above [54,55]. The
separate analyses of mechanical pain sensitivity in the
two groups of subjects give the opportunity to detect
whether a substance is linked to presence of peripheral
sensitization in TM. In TM, high concentrations of the
two algesics BKN and IL-6 were significantly associated
with low PPT. The results concerning BKN agree with
reports that BKN is an algesic kinin with pro-
inflammatory and hyperalgesic properties [5,13,90,91].
No significant group difference in [BKN] was found in
the present study or two other studies of TM [19,24],
but two small studies reported increased [BKN] in active
trigger points in MFP [51,52]. Increases in [BKN] might
be important only in acute nociception or localized to
the most painful areas of the afflicted muscle, hypoth-
eses that future studies should address.
Our results also confirm that IL-6 has hyperalgesic
properties with respect to recognizing a new nociceptive
stimuli (i.e., mechanical pain sensitivity; PPT) in the
chronically myalgic tissue [80,81]. In agreement with the
literature, we have reported both pro-inflammatory (with
respect to mechanical pain sensitivity; PPT) and anti- in-
flammatory (with respect to pain intensity) roles for IL-6
[80-82]. The role of involvement of IL-6 and other cyto-
kines in different aspects of chronic myalgia needs fur-
ther investigation. The result that blood flow correlated
positively with PPT in TM may be a consequence of e.g.,
alterations in algesics such as BKN and IL-6 [85-87].
Algesics versus metabolites
The present study of active female workers with pain in-
creased the possibilities to understand if muscle pain is
maintained by metabolic and algesic substances and
blood flow variables. Metabolites, potassium, and oxy-
genation factors, when considering the system-wide as-
pects, were the most important factors for group
belonging. According to the traditionally statistical ana-
lyses, the classic algesic substances, except SP, were not
increased, which is in contrast to other studies of
chronic trapezius myalgia. There are several possible
reasons for this observation: the workers with pain in
the present study reported relatively low severity of their
myalgia, metabolic alterations may precede detectable al-
terations in levels of algesics, or peripheral sensitization
and other muscle alterations present in TM. The within-
group analyses of TM gave some support to the latter
explanation as classical algesics were significant regres-
sors in the regressions of PPT and pain intensity and the
multivariate correlation analyses (PCA) indicated a di-
verse pattern from controls.
Strengths and limitations
As evident from above there exist several MD studies of
human chronic myalgia. Hence, the feasibility of MD
studies for the investigating biochemical alterations in
humans are very good with respect to the participating
patients and controls. With this said it is also important
to recognize that our study has several limitations that
have to be considered in future studies. It has not been
possible to investigate the development over time for
several of the biochemical substances (PINP, 5-HT and
SP) due to lack of dialysate. A possible way to increase
the number of substances investigated over time in the
small volumes of dialysate is to use more sensitive tech-
niques e.g. capillary electrophoresis and capillary electro-
chromatography [52]. In the present study a number of
predetermined biochemical substances were analysed.
However, our approach in the present study is to a cer-
tain extent explorative. Therefore more open-ended ex-
plorative methods could be used e.g. proteomics and
metabolomics to gain further insights in the activated
mechanisms and based on such analyses determine sub-
stances for detailed analyses [92,93].
Conclusion
With respect to the three aims of the study it can be
concluded that 1) Only SP, but not the other investigated
algesic substances, was elevated in female workers with
TM; 2) Increased [lacate], [pyruvate] and [K
+
] and
decreased oxygenation characterized TM compared to
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CON according to the multivariate analyses; the algesic
substances had little importance; 3) In TM several of the
algesics were of importance for the levels of pain inten-
sity (5-HT and K+) and mechanical pain sensitivity
(BKN and IL-6).
The present and earlier MD studies report muscle al-
terations in chronic myalgia. This may be an indication
of peripheral contribution to maintenance of central
nociceptive and pain mechanisms. It seems important to
investigate if clinically effective treatments normalize
these peripheral alterations in order to improve existing
and develop new treatments for chronic myalgia.
Endnote
a
Not possible to perform in CON due the fact that
these subjects had no pain.
Additional files
Additional file 1: Data (all subjects taken together; Mean ± 1SD) at
the different time points of the experiment presented in the earlier
article [25]. For details, concerning comparisons with respect to group
and time see the previous article [25]. This data together with data
presented in Supplement table b were only used in the present multivariate
analyses. PPT = pressure pain threshold, PEG = repetitive low-force exercise
performed unilaterally on a pegboard, STR = STROOP test.
Additional file 2: Data (all subjects taken together; Mean ± 1SD)
concerning Hb at the different time points of the experiment
presented in the earlier article [25]. For details concerning
comparisons with respect to group and time see the previous article
[25]. This data together with data presented in Supplement table a
were only used in the present multivariate analyses. OHB = oxyhaemoglobin,
HHB = deoxy-haemoglobin, T Hb = total haemoglobin. PEG = repetitive
low-force exercise performed unilaterally on a pegboard, STR = STROOP test.
Competing interests
The authors declare that they have no competing interests.
Authorscontributions
Design: all authors; Data collection; JK, GS, KS; Statistical analyses: JK, BG; First
draft of manuscript: JK, BG, BL. Revisions of different versions of the
manuscript: all authors. All authors read and approved the final manuscript.
Acknowledgments
This study was supported by grants from the Danish Medical Research
Council 22-03-0264, the Danish Rheumatism Association 233-1149-02.02.04,
the Swedish Research Council (K2011-69X-21874-01-6), and the Swedish
Council for Working Life and Social Research (20100913).
Author details
1
Department of Pain and Rehabilitation Center and Department of Medical
and Health Sciences, Linköping University, SE-581 85 Linköping, Sweden.
2
National Research Centre for the Working Environment, Copenhagen,
Denmark.
3
CRMC, University of Copenhagen, Copenhagen, Denmark.
4
Institute of Sport Sciences and Clinical Biomechanics, University of Southern
Denmark, Campusvej 55, 5230 Odense M, Denmark.
Received: 15 May 2014 Accepted: 23 September 2014
Published: 28 October 2014
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doi:10.1186/1471-2474-15-357
Cite this article as: Gerdle et al.:Algogenic substances and metabolic
status in work-related Trapezius Myalgia: a multivariate
explorative study. BMC Musculoskeletal Disorders 2014 15:357.
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... The association between TBF and neck pain in the present study indicates that muscle microcirculation and alternations in TBF may be involved in the pathogenesis of neck pain development, which is also consistent with previous studies (Gerdle et al. 2014;Knardahl 2002;Larsson et al. 2008;Larsson et al. 1999;Näslund et al. 2007;Rosendal et al. 2004;Sjogaard et al. 2010;Strøm et al. 2009b;Thorud et al. 2012). Strom et al. (2009b) showed significant correlations between neck pain and TBF during computer work for both subjects with chronic neck and shoulder pain and a healthy reference group; however, the associations were in opposite directions in the two groups. ...
... The mechanisms behind the link between TBF and pain development are unclear and need further elucidation. However, muscle microcirculation is correlated with muscle metabolism, and different levels of metabolites involved in both pain sensation and vasodilation may explain the correlation between symptoms and circulation in both the present study and in previous research (Gerdle et al. 2014;Knardahl 2002;Sjøgaard et al. 2000;Strøm et al. 2009a, b). ...
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... There may of course be some false positives among our findings, but all in all it does not seem sensible to dismiss all our results as a gigantic type I error. The MVDA methodology used in the present study is the same as used by the Linköping group in a number of recent peer-reviewed publications in different journals, 22,29,[62][63][64][65][66] and it is congruent with the principles argued for by Wheelock and Wheelock. 28 Finally, in order to ensure the robustness of our statistical methodology, the CSF data of the present study were recomputed using the statistical methodology described by Moen et al 32 (with use of false discovery rate); the result of this recomputation was exactly the same as the list presented in Table 1 (TG being the last author of both articles). ...
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Musculoskeletal disorders (MSDs) account for a large societal and economic burden throughout the world. In this chapter, the authors begin by providing a brief review of some of the more common MSDs, providing descriptions and characteristic features of the disorders, prevalence and incidence data, relevant anatomy and pathology, and the risk factors or activities associated with the development of the disorders. The common MSDs include low back pain, hand & wrist tendinopathy, lateral tendinopathy of the elbow, medial tendinopathy of the elbow, shoulder tendons, muscle fatigue, myalgia, muscle fibrosis, carpal tunnel syndrome, ulnar tunnel syndrome, and hand‐arm vibration syndrome. The authors also discuss some of the more common upper extremity disorders, their characteristics, prevalence and incidence, anatomy and pathology, and risk factors.
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The prevalence of chronic trapezius myalgia is high in women with high exposure to awkward working positions, repetitive movements and movements with high precision demands. The mechanisms behind chronic trapezius myalgia are not fully understood. The purpose of this study was to explore the differences in protein content between healthy and myalgic trapezius muscle using proteomics. Muscle biopsies from 12 female cleaners with work-related trapezius myalgia and 12 pain free female cleaners were obtained from the descending part of the trapezius. Proteins were separated with two-dimensional differential gel electrophoresis (2D-DIGE) and selected proteins were identified with mass spectrometry. In order to discriminate the two groups, quantified proteins were fitted to a multivariate analysis: partial least square discriminate analysis. The model separated 28 unique proteins which were related to glycolysis, the tricaboxylic acid cycle, to the contractile apparatus, the cytoskeleton and to acute response proteins. The results suggest altered metabolism, a higher abundance of proteins related to inflammation in myalgic cleaners compared to healthy, and a possible alteration of the contractile apparatus. This explorative proteomic screening of proteins related to chronic pain in the trapezius muscle provides new important aspects of the pathophysiology behind chronic trapezius myalgia.
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This book deals with physiological, neurophysiological, and psychological aspects of the mechanisms and treatment of pain. It also provides information on the latest research results regarding the influence of age and gender on the perception of pain. Finally, it presents the basic mechanisms of analgesia in terms of pharmacological and nonpharmacological treatments.
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