**2. Methods**

106 Biomarker

replace animal experiments (Langley et al., 2008). The microdialysis technique offers a wellestablished *in vivo* method for studying the local biochemistry of individual tissues in the body (Ungerstedt, 1991), e.g., nociceptive and metabolic mechanisms. This technique has been used in neuroscience to monitor neurotransmitter release, but has also found application in monitoring the biochemistry of peripheral tissues in both animals and

Microdialysis mimics the function of a capillary blood vessel by perfusing a thin dialysis tube (catheter) implanted into the tissue with a physiological saline solution. Through simple diffusion, substances can move across the dialysis membrane along the concentration gradient. The chemical analysis of the dialysate reveals the composition of the extracellular fluid. Thus microdialysis allows for continuous sampling of compounds in the interstitial space of the muscle, where nociceptor free nerve endings terminate close to the muscle fibres, providing accurate information on regional biochemical changes before such compounds are diluted and cleared by the circulatory system. The trapezius muscle has been used as a *human model muscle* for chronic myalgia both due to its clinical importance and to its accessibility for invasive investigations. Some studies use the masseter, vastus

To determine the concentrations of small molecules such as lactate, pyruvate, glutamate, and glucose, a catheter with a 20 kDa cut-off is usually used (Waelgaard et al., 2006). To determine the concentrations of larger molecules such as cytokines, a catheter with a 100

A crucial parameter in microdialysis is relative recovery (RR): the ratio between substance concentrations in the dialysate to that in the perfusate (Afinowi et al., 2009; Dahlin et al., 2010 ; Ungerstedt, 1991). RR is used to determine the true concentration of extracellular fluid. Because the perfusate constantly flows across the membrane, a state of equilibrium will never be achieved and as a result the dialysate will only represent a certain percentage of the actual concentration of the extracellular fluid (Afinowi et al., 2009; Hamrin et al., 2002). Therefore, the final concentration in the dialysate partially depends on the flow rate of the perfusate. Low flow rate results in higher RR; high flow rates, result in lower RR. At a very low flow (i.e., < 0.3µl/min), the recovery is near 100%, but factors such as alterations in the osmotic pressure, temperature, weight cut-off, area of the membrane, concentration gradient, and composition of the perfusate can influence RR (Dahlin et al., 2010 ; Hamrin et al., 2002 ; Plock & Kloft, 2005 ). Between cytokines have been reported marked variation in

Microdialysis has several important advantages, but studies with patients are expensive and time consuming. Hence a systematic review of the literature is needed. Systematic knowledge of the results of such studies might help provide new assessment approaches of patients with chronic myalgia, new treatments, and new rehabilitation techniques for patients with chronic myalgia. Most research on muscle pain has been conducted on animals; however, this review will primarily focus on human studies of neck and shoulder myalgia, for which the frequently affected trapezius muscle often serves as a model muscle. This study systematically reviews studies in the literature that have investigated alterations

RR; molecular weight correlated negatively with RR (Helmy et al., 2009).

humans (Ungerstedt, 1991).

**1.8 Aim** 

lateralis, and gastrocnemius muscles to examine myalgia.

kDa cut-off is usually used (Waelgaard et al., 2006).
