**5. Conclusion**

122 Biomarker

healthy subjects (Green et al., 2000). Repetitive work in healthy subjects may increase potassium levels (Rosendal et al., 2004a), although in the present systematic review no consistent pattern of increased potassium was found in patients with chronic trapezius myalgia (Larsson et al., 2008; Rosendal et al., 2005; Sjogaard et al., 2010) (**Table 1**) or with

There are several direct and indirect pathways that link cytokines with nociception or hyperalgesia (Coutaux et al., 2005; Sommer & Kress, 2004; Uceyler et al., 2009). Four studies investigated cytokines in chronic trapezius myalgia, but significant differences were only found for active trigger points (Shah et al., 2008; Shah et al., 2005). These studies, however, used very few subjects, an obvious limitation. Larger studies have not found elevated levels of cytokines (Larsson et al., 2008; Rosendal et al., 2005). On the other hand, these studies might have had some technical problems due to the catheters used, also a limitation.

As is obvious from the above, most studies concern metabolites and algesic substances. Little is known about changes in the pain-inhibitory signalling molecules. One interesting group of such molecules is the *N*-acylethanolamines (NAEs), which is a family of endogenous lipid mediators that have several roles including the regulation of inflammation and pain (Pacher et al., 2006). Examples of NAEs are *N*-palmitoylethanolamine (PEA), Nstearoylethanolamine (SEA), N-oleoylethanolamine (OEA), and N-arachidonoylethanolamine (anandamide, AEA). The most thoroughly studied of the NAEs is AEA, which interacts with cannabinoid receptors. At higher concentrations, AEA also targets transient receptor potential (vanilloid-1) receptors and has been shown to have anti-nociceptive actions in a number of animal models of pain (Calignano et al., 1998). The present review also includes one study of SEA and PEA (Ghafouri et al., 2011), which reported significantly increased

According to our review, microdialysis of painful muscles have also been investigated, but these studies have only been based on one group of patients of each condition: polymyalgia rheumatic, chronic tension-type headache, and mitochondrial myopathy. Hence no definite conclusions concerning potential biomarkers can be drawn for these conditions. The results concerning polymyalgia rheumatic were prominent for several algesics including cytokines. Kreiner et al. investigated the presence of muscle alterations (Kreiner & Galbo, 2011; Kreiner et al., 2010), and they found that the biochemical alterations were normalized after treatment with prednisolone. Although more studies are needed, their results suggest that

In the studies of different chronic tendinosis, the number of patients was low and no consistent patterns were seen. Larger studies are needed to identify biochemical

However, the chronic WAD study found increased IL-6 (Gerdle et al., 2008c).

chronic WAD (**Table 2**).

**4.3 Anti-analgesic substances** 

levels of two NAEs.

alterations.

**4.4 Other pain conditions identified** 

intramuscular mechanisms are important.

**4.2.5 Cytokines** 

This systematic review found that most of the studies focused on trapezius myalgia (seven patient groups reported in ten studies), temporomanidibular pain syndromes (two patient groups reported in three studies), and fibromyalgia (two patient groups but different muscles). Relatively strong scientific support identifies 5-HT as a potential biomarker in chronic myalgia. Moderately strong scientific support identifies glutamate, pyruvate, and lactate as potential biomarkers in chronic trapezius myalgia. There is a need for larger studies of well-characterized patient groups with respect to perceived situations, symptoms, and signs so as to investigate several substances simultaneously in order to improve the understanding of peripheral nociceptive processes in myalgia.
