**3. Results**

Using the modified search strategy, we had 441 hits after searching PubMed. After screening, we identified 17 articles that fulfilled our inclusion criteria. Thirteen of these were not mentioned by Larsson et al. (Larsson et al., 2007). After scrutinizing these 13 articles and the articles selected by Larsson et al., we found 22 articles concerning different chronic pain conditions involving muscle. These articles are summarized in **Tables 1-7**. Moreover, we identified three articles concerning chronic tendinosis (**Table 8**).

#### **3.1 Chronic trapezius myalgia**

For chronic trapezius myalgia, we identified seven groups of patients reported in ten studies (**Table 1**). The majority of the studies reported increases in the interstitial concentrations of

Potential Muscle Biomarkers of Chronic Myalgia in Humans –

Study Condition

Gerdle et al. (Gerdle et al., 2008b)

Larsson et al. (Larsson et al., 2008)

Ghafouri et al. (Ghafouri et al., 2010)  Number of Subjects, % women (W) Muscles

myalgia (MYA; n=19), 100%W

associated disorders (WAD; n=22), 100%W HC (n=20), 100%W

Trapezius

myalgia (MYA; n=20), 100%W HC (n=20), 100%W

Trapezius

Chronic trapezius myalgia, (MYA; n=18), 100%W HC (n=30), 100%W

Trapezius

Chronic trapezius

Chronic trapezius

Chronic whiplash

A Systematic Review of Microdialysis Studies 109

Results

(Comparisons between patients and HC; p-values)

No other group differences

BKN-trapezius: No group differences. Kallidin-trapezius:

for this substance.

Lactate-trapezius: ns Pyruvate-trapezius: MYA > HC; P=0.032 Glutamate-trapezius: MYA > HC; P=0.005 5-HT-trapezius: MYA > HC; P=0.023 K+-trapezius: ns BKN- trapezius: ns GM-CSF- trapezius: ns IL-1β-trapezius: ns IL-6-trapezius: ns IL-8-trapezius: ns TNF-α-trapezius: ns IL-2-trapezius: ns IL-4-trapezius: ns IL-5-trapezius: ns IL-10-trapezius: ns

5-HT- trapezius: MYA>HC,

P=0.044

MYA>HC; P=0.018

Comments (Compensated for RR (Y/N) or low flow rate\* (NA or Y/N)

Compensated for RR: Y Low flow: NA

Compensated for RR: Y Low flow: NA

Compensated for RR: Y Low flow: NA

Substances investigated Flow rate

BKN Kallidin 5µl/min

Lactate Pyruvate Glutamate 5-HT K+ BKN GM-CSF IL-1β IL-6 IL-8 TNF-α IL-2 IL-4 IL-5 IL-10

5µl/min

5µl/min

5-HT

lactate (Flodgren et al., 2010; Flodgren et al., 2006; Larsson et al., 2008; Rosendal et al., 2004b; Sjogaard et al., 2010). However, the studies conducted by Flodgren et al. (Flodgren et al., 2010; Flodgren et al., 2006) did not compensate for relative recovery despite the fact that the flow rate was relatively high (2µl/min) compared to a flow rate associated with full recovery (0.3µ l/min).


lactate (Flodgren et al., 2010; Flodgren et al., 2006; Larsson et al., 2008; Rosendal et al., 2004b; Sjogaard et al., 2010). However, the studies conducted by Flodgren et al. (Flodgren et al., 2010; Flodgren et al., 2006) did not compensate for relative recovery despite the fact that the flow rate was relatively high (2µl/min) compared to a flow rate associated with full

Results

(Comparisons between patients and HC; p-values)

Glutamate-trapezius: ns PGE2-trapezius: ns

Lactate-trapezius: ns Pyruvate-trapezius: Glutamate-trapezius: MYA<HC, significant PGE2-trapezius: not

Lactate-trapezius: MYA > HC; P=0.001 Pyruvate-trapezius: MYA > HC; P=0.001 Glutamate-trapezius: MYA > HC; P=0.05 5-HT-trapezius: MYA > HC; P=0.01

K+-trapezius: MYA > HC; P=significant LDH-trapezius: ns IL-6-trapezius: ns Collagen turnovertrapezius: ns

reported.

Comments (Compensated for RR (Y/N) or low flow rate\* (NA or Y/N)

Compensated for RR: N Low flow: Y

Compensated for RR: N Low flow: N

Compensated for RR: Y Low flow: NA

Compensated for RR: Y Low flow: NA

Substances investigated Flow rate

Glutamate PGE2

0.3µl/min

Lactate Pyruvate Glutamate PGE2

2µl/min

Lactate Pyruvate Glutamate 5-HT

5µl/min

5µl/min

K+ LDH IL-6 Collagen turnover

recovery (0.3µ l/min).

Flodgren et al. (Flodgren et al., 2005)

Flodgren et al. (Flodgren et al., 2010)

Rosendal et al. (Rosendal et al., 2004b)

Rosendal et al. (Rosendal et al., 2005)

Study Condition

 Number of Subjects, % women (W) Muscles

pain (CSP; n=9), 100% W HC (n=9), 100%W Trapezius

Chronic shoulder

Chronic trapezius

(compared with healthy subjects (n=20) in (Flodgren et al.,

Chronic trapezius

Chronic trapezius

myalgia (MYA; n=14), 100% W HC

2006)), 100% W Trapezius

myalgia (MYA; n=19), 100%W HC (n=20), 100%W Trapezius

myalgia (MYA; n=19), 100%W HC (n=20), 100%W Trapezius


Potential Muscle Biomarkers of Chronic Myalgia in Humans –

Study Condition

Shah et al. (Shah et al., 2008)

 Number of Subjects, % women (W) Muscles

Myofascial trapezius pain with active trigger point (MFactive; n=3) HC with latent trigger point (HClatent; n=3) HC without trigger point (HC; n=3) Trigger points of Trapezius Gastrocnemius medialis without trigger points

A Systematic Review of Microdialysis Studies 111

Results

Sign

Sign

Sign

Sign

Sign

Sign

Sign

Sign

H+:ns

MFlatent:

MFactive: BKN: T>G; Sign CGRP: T>G; Sign Substance P: T>G; Sign IL-1β: T>G; Sign TNF-α: T>G; Sign IL-6: T>G; Sign IL-8: T>G; Sign 5-HT: T>G; Sign

(Comparisons between patients and HC; p-values)

BKN-gastrocnemius: MFactive>2 other groups;

CGRP-gastrocnemius: MFactive>2 other groups;

IL-1β-gastrocnemius: MFactive>2 other groups;

TNF-α-gastrocnemius: MFactive>2 other groups;

5-HT-gastrocnemius: MFactive>2 other groups;

H+-gastrocnemius: MFactive>2 other groups;

Norepinephrine-trapezius: MFactive>2 other groups;

Comparisons between trapezius (T) and gastrocnemius (G) in

Norepinephrine: T>G; Sign

BKN, IL-1β, IL-6, IL-8, 5-HT, Norepinephrine, H+: ns CGRP: T>G; Sign

Comparisons between trapezius (T) and gastrocnemius (G) in

Substance P-gastrocnemius: MFactive>2 other groups;

Comments (Compensated for RR (Y/N) or low flow rate\* (NA or Y/N)

Compensated for RR: Y Low flow: NA

Substances investigated Flow rate

BKN CGRP Substance P IL-1β TNF-α IL-6 IL-8 5-HT Norepineph

rine H+ 1 and 2µl/min


Results

for RR)

Lactate-trapezius: MYA>HC, significant Pyruvate-trapezius: MYA>HC, significant Glucose-trapezius: ns K+-trapezius: ns

BKN-trapezius:

CGRP-trapezius:

IL-1β-trapezius:

TNF-α-trapezius:

5-HT-trapezius:

P<0.01

P<0.01

P<0.01

P<0.01

P<0.01

P<0.01

P<0.01

other groups; P<0.01

MFactive>two other groups;

MFactive>two other groups;

MFactive>two other groups;

MFactive>two other groups;

MFactive>two other groups;

Norepinephrine-trapezius: MFactive>two other groups;

H+-trapezius: MFactive>two

Substance P- trapezius: MFactive>two other groups;

(Comparisons between patients and HC; p-values)

dialysate concentrations, but significant differences were found when compensated

PEA-trapezius: MYA>HC, P=0.011 SEA-trapezius: MYA>HC, P=0.002 (The statistics are for Comments (Compensated for RR (Y/N) or low flow rate\* (NA or Y/N)

Compensated for RR: Y Low flow: NA

Compensated for RR: Y Low flow: NA

Compensated for RR: Y Low flow: NA

Substances investigated Flow rate

PEA SEA 5µl/min

Lactate Pyruvate Glucose K+ 5µl/min

BKN CGRP Substance P IL-1β TNF-α 5-HT Norepineph

rine H+ 1and 2 µl/min

Study Condition

Ghafouri et al. (Ghafouri et al., 2011)

Sjøgaard et al (Sjogaard et al., 2010)

Shah et al (Shah et al., 2005)  Number of Subjects, % women (W) Muscles

myalgia, (MYA; n=11), 100%W HC (n=11), 100%W Trapezius

Chronic trapezius

Chronic trapezius myalgia (MYA; n=43), 100%W HC (n=19), 100%W Trapezius

Myofascial trapezius pain with active trigger point (MFactive; n=3) HC with latent trigger point (HClatent; n=3) HC without trigger point (HC;n=3) Trigger points of Trapezius


Potential Muscle Biomarkers of Chronic Myalgia in Humans –

RR (Flodgren et al., 2010; Flodgren et al., 2006).

 Number of Subjects, % women (W) Muscles

Chronic whiplash associated disorders (WAD; n=22), 100% W HC (n=20), 100% W

Trapezius

Trapezius

Healthy controls are abbreviated as HC.

Chronic trapezius myalgia (MYA; n=19), 100% W Chronic whiplash associated disorders (WAD; n=22), 100% W HC (n=20), 100%W

Study Condition

Gerdle et al. (Gerdle et al., 2008c)

Gerdle et al. (Gerdle et al., 2008b)

A Systematic Review of Microdialysis Studies 113

studies, potassium revealed no consistent pattern (Larsson et al., 2008; Rosendal et al., 2005; Sjogaard et al., 2010). PGE2 was not increased in two groups of patients (Flodgren et al., 2005; Flodgren et al., 2010; Flodgren et al., 2006), but the first of these groups was relatively small (Flodgren et al., 2005) and the other had possible methodological drawbacks related to

Results

p-values)

(Comparisons between patients and HC;

Lactate-trapezius: ns Pyruvate-trapezius: ns Glutamate-trapezius: ns K+- trapezius: ns 5-HT-trapezius: WAD>HC; P=0.05 IL-6-trapezius: WAD>HC; P=0.008

BKN- trapezius: No group differences. Kallidin-trapezius: MYA>HC; P=0.018 No other group differences for this

substance.

Comments (Compensated for RR (Y/N) or low flow rate\* (NA or Y/N)

Compensated for

Compensated for

RR: Y Low flow: NA

RR: Y Low flow: NA

Substances investigated Flow rate

Lactate Pyruvate Glutamate

5µl/min

5µl/min

\*Low flow rate associated with 100% relative recovery was defined as 0.3µl/min.

2005), and H+ (significant difference) (Shah et al., 2008; Shah et al., 2005).

Table 2. Studies of chronic WAD. The results of the different substances are baseline data.

In two studies, Shah et al. investigated P and CGRP (Shah et al., 2008; Shah et al., 2005). They found significant increases in active trigger points in the trapezius and found that

Substances only reported in single studies/patient groups were glucose (no difference) (Sjogaard et al., 2010), norepinephrine (significant difference) (Shah et al., 2008; Shah et al.,

these levels were higher in the aching trapezius than in a distant pain-free muscle.

BKN Kallidin

K+ 5-HT IL-6


\*Low flow rate associated with 100% relative recovery was defined as 0.3µl/min.

Table 1. Studies of chronic trapezius myalgia. The results of the different substances are baseline data. Healthy controls are abbreviated as HC. The bold horizontal lines indicate different patient groups.

A similar pattern was noted for the majority of studies reporting increased interstitial concentrations of pyruvate (Flodgren et al., 2010; Flodgren et al., 2006; Larsson et al., 2008; Rosendal et al., 2004b; Sjogaard et al., 2010). Flodgren et al. did not show any significant differences for pyruvate (Flodgren et al., 2010; Flodgren et al., 2006).

Three studies that focused on chronic trapezius myalgia investigated the interstitial muscle concentration of glutamate (Flodgren et al., 2005; Larsson et al., 2008; Rosendal et al., 2004b). In two of these studies (Larsson et al., 2008; Rosendal et al., 2004b), which were markedly larger than the third study (Flodgren et al., 2005), revealed significant increases in the interstitial concentrations of glutamate. In all the studies investigating glutamate, the interstitial muscle concentration of 5-HT was significantly increased (Ghafouri et al., 2010; Larsson et al., 2008; Rosendal et al., 2004b; Shah et al., 2008; Shah et al., 2005). Furthermore, glutamate was also increased in patients with chronic WAD (**Table 2**) (Gerdle et al., 2008c).

Four studies examined the interstitial concentrations of BKN and/or Kallidin (Gerdle et al., 2008b; Larsson et al., 2008; Shah et al., 2008; Shah et al., 2005). Shah et al. (Shah et al., 2008; Shah et al., 2005) found increased levels of BKN in subjects with active trigger points and the levels were higher in the trapezius (with pain) than in a pain-free distant muscle. In contrast, two studies - a field study and a laboratory study - found no differences between patients and controls (Gerdle et al., 2008b; Larsson et al., 2008). Kallidin was only investigated in one study and this study reported significantly higher interstitial levels in patients with chronic trapezius myalgia (Gerdle et al., 2008b).

Several studies have investigated cytokines, but only Shah et al. found significant differences for active trigger points (Shah et al., 2008; Shah et al., 2005). These authors also have compared the levels of cytokines in the myalgic trapezius (trigger points) with a muscle without pain and found higher levels in the aching muscle. These studies, however, are limited because their sample size was small. Larger studies have not found elevated levels of cytokines (Larsson et al., 2008; Rosendal et al., 2005). In three relatively large

Results

HC:

Table 1. Studies of chronic trapezius myalgia. The results of the different substances are baseline data. Healthy controls are abbreviated as HC. The bold horizontal lines indicate

A similar pattern was noted for the majority of studies reporting increased interstitial concentrations of pyruvate (Flodgren et al., 2010; Flodgren et al., 2006; Larsson et al., 2008; Rosendal et al., 2004b; Sjogaard et al., 2010). Flodgren et al. did not show any significant

Three studies that focused on chronic trapezius myalgia investigated the interstitial muscle concentration of glutamate (Flodgren et al., 2005; Larsson et al., 2008; Rosendal et al., 2004b). In two of these studies (Larsson et al., 2008; Rosendal et al., 2004b), which were markedly larger than the third study (Flodgren et al., 2005), revealed significant increases in the interstitial concentrations of glutamate. In all the studies investigating glutamate, the interstitial muscle concentration of 5-HT was significantly increased (Ghafouri et al., 2010; Larsson et al., 2008; Rosendal et al., 2004b; Shah et al., 2008; Shah et al., 2005). Furthermore, glutamate was also increased in patients with chronic WAD (**Table 2**)

Four studies examined the interstitial concentrations of BKN and/or Kallidin (Gerdle et al., 2008b; Larsson et al., 2008; Shah et al., 2008; Shah et al., 2005). Shah et al. (Shah et al., 2008; Shah et al., 2005) found increased levels of BKN in subjects with active trigger points and the levels were higher in the trapezius (with pain) than in a pain-free distant muscle. In contrast, two studies - a field study and a laboratory study - found no differences between patients and controls (Gerdle et al., 2008b; Larsson et al., 2008). Kallidin was only investigated in one study and this study reported significantly higher interstitial levels in patients with chronic

Several studies have investigated cytokines, but only Shah et al. found significant differences for active trigger points (Shah et al., 2008; Shah et al., 2005). These authors also have compared the levels of cytokines in the myalgic trapezius (trigger points) with a muscle without pain and found higher levels in the aching muscle. These studies, however, are limited because their sample size was small. Larger studies have not found elevated levels of cytokines (Larsson et al., 2008; Rosendal et al., 2005). In three relatively large

(Comparisons between patients and HC; p-values)

Substance P: T>G; Sign TNF-α: T>G; Sign

 BKN: T>G; Sign Other substances: ns

Comparisons between trapezius (T) and gastrocnemius (G) in

Comments (Compensated for RR (Y/N) or low flow rate\* (NA or Y/N)

Substances investigated Flow rate

\*Low flow rate associated with 100% relative recovery was defined as 0.3µl/min.

differences for pyruvate (Flodgren et al., 2010; Flodgren et al., 2006).

Study Condition

different patient groups.

(Gerdle et al., 2008c).

trapezius myalgia (Gerdle et al., 2008b).

 Number of Subjects, % women (W) Muscles

studies, potassium revealed no consistent pattern (Larsson et al., 2008; Rosendal et al., 2005; Sjogaard et al., 2010). PGE2 was not increased in two groups of patients (Flodgren et al., 2005; Flodgren et al., 2010; Flodgren et al., 2006), but the first of these groups was relatively small (Flodgren et al., 2005) and the other had possible methodological drawbacks related to RR (Flodgren et al., 2010; Flodgren et al., 2006).


\*Low flow rate associated with 100% relative recovery was defined as 0.3µl/min.

Table 2. Studies of chronic WAD. The results of the different substances are baseline data. Healthy controls are abbreviated as HC.

In two studies, Shah et al. investigated P and CGRP (Shah et al., 2008; Shah et al., 2005). They found significant increases in active trigger points in the trapezius and found that these levels were higher in the aching trapezius than in a distant pain-free muscle.

Substances only reported in single studies/patient groups were glucose (no difference) (Sjogaard et al., 2010), norepinephrine (significant difference) (Shah et al., 2008; Shah et al., 2005), and H+ (significant difference) (Shah et al., 2008; Shah et al., 2005).

Potential Muscle Biomarkers of Chronic Myalgia in Humans –

Number of Subjects, % women (W) Muscles

Localized myalgia of

temporomandibular

(LM; n=17), 76% W HC (n=10), 60%W

Localized myalgia of

temporomandibular

(LM; n=19), 74%W HC (n=11), 64% W

temporomandibular disorder pain (TMD; n=13), 77%W HC (n=10), 80%W

(e.g., BKN and PGE2) in the trapezius muscle (**Table 5**).

Fibromyalgia (FM; n=18), 100%W

the

the

system

Masseter

Masseter

**3.5 Chronic tension type headaches** 

**3.6 Polymyalgia rheumatica** 

Myofascial

system

Masseter

Fibromyalgia (FM; n=19), 89%W

Study Condition

Ernberg et al (Ernberg et al., 1999)

Hedenberg-Magnusson et al

(Hedenberg-Magnusson et al., 2001)

Castrillon (Castrillon et al., 2010)

A Systematic Review of Microdialysis Studies 115

Substances investigated Flow rate

(corrected for S-5-HT)

5-HT

7µl/min

PGE2 Leukotriene B4(LTB4)

7µl/min

Glutamate

2µl/min

In two studies of one group of patients (Ashina et al., 2002; Ashina et al., 2003) with chronic tension headaches, no differences were found in metabolites and some algesic substances

We found two studies of polymyalgia rheumatica based on the same groups of subjects (Kreiner & Galbo, 2011; Kreiner et al., 2010) (**Table 6**). These two studies reported marked

\*Low flow rate associated with 100% relative recovery was defined as 0.3µl/min.

substances are baseline data. Healthy controls are abbreviated as HC.

Table 4. Studies of temporomandibular pain disorders. The results of the different

Results (Comparisons between patients and HC; p-values)

5-HT

(corrected for S-5- HT)-traumamasseter: FM>HC: P=0.05 5-HT

(corrected for S-5- HT)-baselinemasseter: no group differences

PGE2-masseter: ns LTB4-masseter: FM>LM; P=0.05

Glutamatemasseter: TMD> HC; P=0.023

Comments (Compensated for RR (Y/N) or low flow rate\* (NA or Y/N)

Compensated for RR: N, but corrected for S-

Compensated for

Compensated for

RR: Low flow:

RR: N Low flow: N

5-HT Low flow:N
