Biology Review Series
The Association of Pain With Protein Inflammatory Biomarkers: A Review of the Literature
DeVon, Holli A.; Piano, Mariann R.; Rosenfeld, Anne G.; Hoppensteadt, Debra A.
Holli A. DeVon, PhD, RN, is Associate Professor; and Mariann R. Piano, PhD, RN, is Professor, College of Nursing, University of Illinois at Chicago.
Anne G. Rosenfeld, PhD, RN, FAAN, FAHA, is Professor and Associate Dean, College of Nursing, University of Arizona, Tucson.
Debra A. Hoppensteadt, PhD, MT (ASCP), is Professor, School of Medicine, Loyola University Chicago, Illinois.
Accepted for publication October 3, 2013.
The authors would like to thank Kevin Grandfield, Publication Manager of the UIC Department of Biobehavioral Health Science, for editorial assistance.
The authors acknowledge that their work was funded by NINR (R01NR012012).
The authors have no conflicts of interest to disclose.
Corresponding author: Holli A. DeVon, PhD, RN, College of Nursing, Department of Biobehavioral Health Science, University of Illinois at Chicago, 845 S. Damen Ave., M/C 802, Chicago, IL 60612 (e-mail: firstname.lastname@example.org).
Background: Pain is a key diagnostic criterion in many medical conditions. In the absence of self-reported pain, measurement of a proxy for pain, such as an inflammatory biomarker, could aid in diagnosis and disease management.
Objectives: The aim was to determine if there is an association between inflammatory biomarkers and self-reported pain in individuals with medical conditions associated with the symptom of pain and to clarify whether inflammatory biomarkers might aid in the diagnostic process.
Methods: An integrative literature review was conducted. PubMed, CINAHL, and Cochrane databases were searched for articles published between January 2000 and September 2012. Inclusion criteria were original research testing a relationship between inflammatory biomarkers and pain, pain measurement, laboratory measure of inflammatory biomarkers, and a prospective single-group experimental design or comparative nonrandomized or randomized design. Excluded were studies describing an association between inflammatory biomarkers and treatment, risk, and generation; pathophysiology; or genetic polymorphisms/transcripts. Ten studies meeting inclusion criteria were reviewed.
Results: In most of the studies, baseline elevations in both proinflammatory and anti-inflammatory cytokines were reported in painful conditions compared with healthy controls. In half of the studies, higher levels of proinflammatory markers (C-reactive protein, tumor necrosis factor-alpha, interleukin-2 [IL-2], IL-6, IL-8, IL-10, and CD40 ligand) were associated with greater pain. Proinflammatory cytokines decreased after treatment for pain in only two studies.
Discussion: The association between inflammatory markers varied in the direction and magnitude of expression, which may be explained by differences in designs and assays, disease condition and duration, variations in symptom severity, and timing of measurement. Elevation in anti-inflammatory cytokines in the presence of pain represents a homeostatic immune response. Further study is required to determine the value of cytokines as biomarkers of pain.
Pain is an important symptom that serves as a warning sign of a pathological condition and is also a key diagnostic criterion for several acute and chronic medical conditions (Montes-Sandoval, 1999; Thygesen et al., 2012). Pain is a somatic sensation and represents a constellation of unpleasant sensations arising from real or perceived tissue damage (Terman & Bonica, 2001). Pain is highly individualized and subjective. Nociception, or pain perception, can involve the integration of different types of transduction/conduction mechanisms and chemical mediators, depending on the nature and site of injury. Nociceptors are not uniformly sensitive to all types of injury signals; some are specific for mechanical, thermal, and toxic chemical or inflammatory mediators (Dubin & Patapoutian, 2010). Some patients lack the ability to perceive pain, because of inherited or acquired neuropathies or disease, and some have difficulty verbalizing the presence of pain, because of altered mentation or aphasia. The inability to perceive pain has been reported in conditions such as acute coronary syndrome, peripheral arterial disease, and diabetes mellitus. In fact, in the setting of acute coronary syndrome, approximately 43% of those diagnosed have no pain or silent ischemia (Lloyd-Jones et al., 2010), and it remains unknown as to why some individuals with inflammation as a key pathophysiological process have symptoms and some do not.
Recently, the relationship between proinflammatory biomarkers and pain has been examined in populations of patients with painful conditions in which inflammation is a key pathological feature of the disease process (Iannuccelli et al., 2010; Lin, Yokoyama, Rac, & Brooks, 2012; Parkitny et al., 2013; Üceyler, Häuser, & Sommer, 2011; Üceyler, Rogausch, Toyka, & Sommer, 2007; White et al., 2010). Chronic systemic inflammation has been implicated as a factor in an array of conditions associated with pain (Graham et al., 2006). For example, cytokines produced by macrophages and monocytes at the site of inflammation (Gebhardt et al., 2006) play a key role in atherogenesis and coronary heart disease (Frazier, 2003; Welsh, Woodward, Rumley, MacMahon, & Lowe, 2010). Proinflammatory biomarkers, such as cytokines, have been found in both chronic and acute pain states, suggesting either a direct or facilitator role in the occurrence of pain. Because cytokines reflect the pathophysiological process of inflammation, they may be potential candidate biomarkers of pain in conditions linked to inflammation, particularly when pain is absent or attenuated. Therefore, this integrative review was undertaken to (a) provide a synthesis of research, which has examined the association between inflammatory biomarkers (specifically cytokines) and pain in individuals with medical conditions often associated with inflammation, and (b) examine the types and variations in cytokine levels altered in painful states associated with inflammation. An integrative review approach was chosen, rather than a meta-analysis, because of the wide range of painful conditions included in this review and the heterogeneity of designs and methodologies. It was hypothesized that inflammatory markers could serve as biomarkers of pathological pain states and could enhance assessment of individuals with conditions in which there may be an altered ability to either sense or communicate the presence of pain (Figure 1).
Potential Role for Cytokines as Biomarkers of Pain
Multiple cytokines are produced during an inflammatory reaction. Cytokines contribute to inflammatory processes by activation of specific signal transduction mechanisms as well as the activation of other cell types (Gebhardt et al., 2006). Cytokines are found extracellularly (in blood) and in interstitial compartments, where they can activate cells in an autocrine/paracrine fashion (Gilbertson-White, Aouizerat, & Miaskowski, 2011). It has been postulated that increased levels of cytokines influence and contribute to the sensation of pain by increasing the sensitization of nociceptors (Babu et al., 2012; Stürmer et al., 2005). When tissue is invaded or destroyed by leukocytes during an inflammatory episode, several mediators such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha (TNF-α) migrate to the site. Also included in these mediators are nerve growth factor and prostaglandins (Rittner, Machelska, & Stein, 2005). These are all considered proalgesic. At the same time, some analgesic mediators are also released, which are produced in the inflamed tissue. These include anti-inflammatory cytokines and opioid peptides (Rittner et al., 2005). After tissue injury, cytokines and chemokines are released in the local environment of nerve endings, where they contribute to activation of pain nociceptors and potentially contribute to the development of hyperalgesia (Angst et al., 2008). Hyperalgesia occurs when a low-intensity stimulus that is typically not associated with pain becomes a painful stimulus. Intraneural application of proinflammatory cytokines induces pain and hyperalgesia, but hyperalgesia can be mitigated by treatment with anti-inflammatory cytokines (Üceyler et al., 2007). Cytokines may prove to be useful pain biomarkers because they can be objectively measured and may reflect the underlying inflammatory and pathophysiological processes as well as influence pain sensation. No studies specifically address whether inflammatory biomarkers could be a diagnostic aid in pathological conditions in which pain is absent. Finally, despite the use of standardized pain measures, such as the numeric rating scale or visual analog scale, pain cannot be defined or measured uniformly; hence, a biomarker for pain may supplement clinical measures of pain.
PubMed, CINAHL, and Cochrane databases were searched for articles from January 2000 to September 2012 using a combination of the search terms: “biomarkers, cytokines, pain, pain measures, inflammation, and symptoms.” The year 2000 was selected because Patarca-Montero and colleagues (Patarca-Montero, Antoni, Fletcher, & Klimas, 2001) published a comprehensive literature review of cytokines and neuropsychological factors, including pain in chronic fatigue syndrome (CFS) up to that date. CFS, as well as the chronic condition of fibromyalgia (FM), represents a significant amount of cytokine and pain research. The review was limited to human studies published in English with original articles investigating cytokines in painful conditions. Inclusion criteria were original research testing a relationship between inflammatory biomarkers and pain, pain measurement, laboratory measure of inflammatory biomarkers, and a prospective single-group experimental design or comparative nonrandomized or randomized design. We excluded review articles, as we sought to examine literature not previously evaluated. Reports of primary research studies were excluded if they described an association between inflammatory biomarkers and disease treatment, risk, or generation; pathophysiology; diurnal patterns; or genetic polymorphisms. Study quality was assessed by the following criteria: adequate description of materials and methods, adequate internal and statistical controls, sample size, time points of tissue/blood collection, and description of data assessment and analyses.
The study search and selection process is summarized in Figure 2. Twenty-two articles were identified by the search process as potentially relevant and independently reviewed by two authors (H.D. and A.R.). Seventeen additional articles were identified after hand-searching reference lists. Of these 39, 10 met the inclusion criteria.
Because of variation in study populations, designs, and methods, a brief synopsis of key findings for each study reviewed is provided in the Results section. Inflammatory biomarkers were categorized as proinflammatory or anti-inflammatory based on definitions in the literature (Angst et al., 2008; White et al., 2010). IL-6 has been labeled a mixed marker having both proinflammatory and anti-inflammatory effects (White et al., 2010).
Study Populations and Inflammatory Biomarkers
Ten studies were located in which the association between inflammatory biomarkers and pain had been studied; populations included individuals with chronic pain syndromes, painful pathological conditions, and healthy populations (Angst et al., 2008; Bazzichi et al., 2007; Eriksson, Andersson, Ekerfelt, Ernerudh, & Skogh, 2004; Iannuccelli et al., 2010; Manero & Alcazar, 2010; Mazzone et al., 2001; Üceyler et al., 2010, 2007; Wang, Moser, Schiltenwolf, & Buchner, 2008; White et al., 2010). All studies, except one (Angst et al., 2008), included patients with chronic pain conditions. Angst et al. included subjects exposed to an acute pain stimulus. In nine of the studies, both proinflammatory cytokines and anti-inflammatory cytokines were measured, whereas one study only measured proinflammatory cytokines (Manero & Alcazar, 2010). Details about participants and biomarkers are in Table 1; results for inflammation and pain are in Tables 2 and 3, respectively. Details about exclusion criteria, symptoms, comparison groups, and strengths and limitations are found in Table 4.
Medical Conditions in the Reviewed Studies
Mazzone et al. (2001) examined inflammatory cytokines in a male cohort with exercise-induced myocardial ischemia (n = 78) and found no differences in proinflammatory cytokine levels (IL-1β, TNF-α, IL-6, and interferon-γ [IFN-γ]) between symptomatic and asymptomatic groups. However, the asymptomatic group had significantly higher levels of anti-inflammatory cytokines (IL-4 and IL-10).
The greatest number of studies comparing cytokines to the occurrence of pain was in individuals with FM, a chronic pain disorder of unknown etiology (Wang et al., 2008). In a prospective study, Wang et al. compared serum cytokine levels and pain intensity in patients with FM (n = 20) and healthy controls (n = 80) before and after receiving biopsychosocial therapy. At baseline, serum IL-8 and TNF-α levels were significantly higher in patients with FM compared with controls, whereas IL-6 levels were similar between groups. IL-8 levels remained higher in the patients with FM through follow-up, but TNF-α was reduced after 10 days and remained reduced through 180 days. IL-8 and TNF-α declined significantly from baseline through day 10 for both groups. In the FM group, it remained significantly lower through 180 days and, thus, may be related to analgesia. IL-8 correlated with pain intensity at 180 days but not at baseline, suggesting no direct correlation between cytokines and pain intensity.
Bazzichi and colleagues (2007) examined cytokine levels in women with FM (n = 80) and age-matched controls (n = 45). To control for the possible influence of psychological conditions known to be associated with increased cytokine levels, patients with FM were divided into three groups based on psychological status: (a) presence of depression, (b) anxiety disorder, or (c) no psychiatric illness. IL-1 was significantly lower in all three FM subgroups compared with controls. All FM groups, regardless of psychological status, had pain and higher levels of IL-8, IL-10, and TNF-α compared with the control group, suggesting a relationship between pain and cytokine levels independent of psychological status.
Iannuccelli et al. (2010) compared cytokines in women with FM (n = 51), women with tension-type headaches (n = 25), and healthy controls (n = 15). Serum IL-1ra, IL-6, IL-10, and TNF-α serum levels were higher in patients with FM compared with those with tension-type headaches and controls. There was also a significant correlation between IL-10 and Fibromyalgia Impact Questionnaire scores in the FM group, suggesting that a higher burden of symptoms results in the expression of anti-inflammatory cytokines.
Chronic Fatigue Syndrome
White et al. (2010) examined cytokine levels and the occurrence of pain in individuals with CFS. Individuals with CFS become fatigued and often experience body-wide pain after exercise, referred to as symptom flare (SF). Patients with CFS (n = 19) and healthy controls (n = 17) were enrolled, and all completed a moderate exercise protocol to induce SF. Eleven of the patients with CFS were categorized as high SF, and eight were categorized as low SF. Pain (myalgia) was measured at each time point using a numeric rating scale that ranged from 0–100. At baseline, the only biomarker significantly different between healthy controls and both low and high SF groups was CD40 ligand (CD40L). CD40L is part of the TNF family and is a marker of platelet activation. At 8 hours, the high SF group had increased proinflammatory and anti-inflammatory cytokines levels, whereas the low SF and control groups had decreases or small increases in both proinflammatory and anti-inflammatory cytokines (with the exception of IL-8). Importantly, an increase in IL-6 in both CFS groups was strongly associated with pain.
In vitro cytokines released from isolated peripheral blood mononuclear cells and serum cytokines were examined in women with Sjögren syndrome, an autoimmune syndrome typically characterized by dry eyes and dry mouth (Eriksson et al., 2004). Serum and in vitro cytokine levels were compared between women with and without self-reported pain with Sjögren syndrome, and each of those groups was compared with women with rheumatoid arthritis and healthy controls. Peripheral blood mononuclear cell-stimulated cytokines (IL1β, IL-6, IL-10, TNF-α, and IFN-γ) were significantly lower in women with Sjögren syndrome and myalgia compared with controls. Serum IL-18 levels were significantly increased in both the Sjögren syndrome and rheumatoid arthritis groups compared with controls. Serum IL-8 was increased in those with rheumatoid arthritis but not Sjögren syndrome.
Üceyler and colleagues (2007) examined the differences in expression of cytokines in patients with neuropathies compared with healthy controls. Patients with painful neuropathy had two-fold higher IL-2 messenger ribonucleic acid (mRNA) levels and TNF-α mRNA, and IL-2 and TNF levels compared with patients with painless neuropathy and healthy controls. Serum mRNA levels of the anti-inflammatory cytokine IL-10 were two-fold higher in patients with painless neuropathy compared with those with pain and healthy controls. IL-4 was 20-fold higher in patients with painless neuropathy and 17-fold higher in patients with painful neuropathy compared with healthy controls.
In a subsequent study, Üceyler and colleagues (2010) examined proinflammatory cytokine expression in patients with small-fiber neuropathy (n = 24) compared with healthy controls (n = 72). Patients with neuropathies were furthered classified into three categories: (a) definite small-fiber neuropathy, (b) probable small-fiber neuropathy, or (c) possible small-fiber neuropathy. Patients with small-fiber neuropathy had a two-fold higher expression of circulating IL-2, IL-10, and TGF-β1 mRNA levels and significantly higher release of IL-6 and IL-8 compared with controls. Patients with length-dependent small-fiber neuropathy had significantly more impairment because of pain than patients with non-length-dependent, small-fiber neuropathy.
Manero and Alcazar (2010) examined correlations with IL-8 and the occurrence of pelvic pain in a cohort of women undergoing invasive treatment for ovarian endometriomas. Pain severity was assessed using a visual analog scale, and women were categorized as having or not having pelvic pain. Serum IL-8 levels did not vary by group after adjusting for gravidity, length of menses, infertility, and body mass index.
Experimental Inflammation and Noxious Stimulation
Angst and colleagues (2008) conducted two experiments in which sunburn was induced in healthy volunteers to evaluate the role of cytokines in an acute inflammatory pain condition. In Experiment 1, two sunburn lesions were induced on the thigh. Pain measures were completed, and microdialysate samples were compared with a noninflamed skin site. After analyses, noxious heat was applied to the sunburn. In the second phase of the study, a crossover, double-blind design was used to allocate participants to receive 400-mg ibuprofen, 800-mg ibuprofen, or placebo. Pain testing occurred 35 minutes after ingestion of the medication or placebo. Significant increases were found in IL-6, IL-8, IL-10, granulocyte-colony stimulating factor, and macrophage inflammatory protein 1 beta. Noxious heat increased IL-7 and IL-13. Tissue levels of IL-1β and IL-6 did not change after the 400-mg dose of ibuprofen but decreased significantly (44% ± 32% and 38% ± 13%) after an 800-mg dose.
In summary, there were several key findings in the relationship between proinflammatory and anti-inflammatory cytokines and pain in a variety of medical conditions associated with inflammation. In six of the studies reviewed, baseline elevations in cytokines were reported in populations with painful conditions compared with controls, although the magnitude of change by which cytokines were altered varied (Bazzichi et al., 2007; Eriksson et al., 2004; Iannuccelli et al., 2010; Mazzone et al., 2001; Wang et al., 2008; White et al., 2010; Figure 3). For example, for TNF-α, there was no difference in levels between those with FM and healthy controls in two studies (Iannuccelli et al., 2010; Wang et al., 2008), but in other studies, there was a large difference in levels between patients with FM and controls (Bazzichi et al., 2007) and between patients with Sjögren syndrome and controls (Eriksson et al., 2004). In half of the studies reviewed, higher levels of proinflammatory markers (CRP, TNF-α, IL-2, IL-6, IL-8, IL-10, and CD40L) were associated with greater pain intensity/severity (Bazzichi et al., 2007; Üceyler et al., 2010, 2007; Wang et al., 2008; White et al., 2010). The proinflammatory cytokines IL-8 and IL-18 were associated with pain in CFS, FM, and Sjögren syndrome only (Eriksson et al., 2004; Iannuccelli et al., 2010; White et al., 2010). In only 20% of the studies, proinflammatory cytokines (TNF-α, IL-1β, and IL-8) decreased after treatment for pain (Angst et al., 2008; Wang et al., 2008). Levels of cytokines (except IL-10) did not correlate with pain in FM (Iannuccelli et al., 2010), myocardial ischemia (Mazzone et al., 2001), or pelvic pain (Manero & Alcazar, 2010). Only one study examined the potential confounding influence of psychological disturbances on cytokines, and there was no significant association (Bazzichi et al., 2007).
The hypothesis that certain conditions, such as those reviewed here, would stimulate the release of inflammatory biomarkers and correlate to pain was partially supported. In addition, in half of the studies, higher levels of inflammatory cytokines were associated with more severe pain. However, these results were not found in all studies. Three variations to the hypothesized model (Figure 1) were noted following this review, including
* not all participants experienced pain in the presence of inflammatory cytokines;
* pain was associated with variations in cytokines, specifically no change in inflammatory cytokines, an increase in proinflammatory cytokines, and an increase in anti-inflammatory cytokines (depending on the study); and
* an increase in proinflammatory cytokines was related to the severity of pain.
Therefore, the hypothesized model of variables of interest in Figure 1 was revised and appears in Figure 4.
Findings showed that certain cytokines may be emerging or putative biomarkers of pain in specific chronic conditions. There was variability in the type of cytokine altered, as well as the magnitude of change, which may be attributable to differences in cytokine measurement modalities, timing of measurement, and type and duration of medical condition, which could markedly influence cytokine levels. The notion of cytokine biomarkers as a proxy measure of pain in conditions in which there is an absence or attenuation of the sensation of pain requires more investigation. In fact, only one study was found that included the measurement of cytokines in patients with both symptomatic and silent myocardial ischemia, but proinflammatory cytokine production did not differ between groups (Mazzone et al., 2001). However, anti-inflammatory cytokines (IL-4 and IL-10) were greater in patients experiencing pain, a potential relationship that requires more exploration. Because pain is a key symptom for many pathological conditions, but some patients do not have pain as a symptom, inflammatory biomarkers may hold potential in diagnosis and management of the condition.
It is important to note that cytokines present in different bodily fluids can be detected using classic solid-phase sandwich immunoassays, such as enzyme-linked immunosorbent assay (ELISA) or multiplex bead-based immunoassays (de Jager & Rijkers, 2006). Most of the studies reviewed used standard ELISA, whereas three studies used high-sensitivity, multiplex bead-based assays (Angst et al., 2008; Manero & Alcazar, 2010; Wang et al., 2008). The latter allows for simultaneous measurement of multiple cytokines. Both ELISA and bead-based assays capture or sandwich the cytokine of interest using two different antibodies (usually designated as a capture and reporter antibody). Both techniques are considered reliable and state-of the-art.
Strengths of the Studies
In some studies, rigorous control of possible confounders, such as anti-inflammatory medications, corticosteroids, smoking, inflammatory/autoimmune diseases, or infection, was built into the design (Angst et al., 2008; Mazzone et al., 2001). In some cases, small samples yielded statistically significant findings, suggesting large effect sizes (Angst et al., 2008; Eriksson et al., 2004; White et al., 2010). A strength of some studies was an a priori hypothesis and, in particular, strong rationale for the measurement of certain cytokines. For example, Angst et al. measured IL-1β, IL-6, and TNF-α and predicted that there would be significant increases with an inflammatory stimulus because other investigators had shown that these cytokines were involved in early proinflammatory responses and hyperalgesic action.
The studies included in this analysis were geographically diverse (e.g., United States and Europe), and several studies were longitudinal, providing an opportunity to analyze biomarkers over time and in response to treatment (Bazzichi et al., 2007; Wang et al., 2008; White et al., 2010). For instance, Wang et al. measured cytokines at baseline, 10 days, 21 days, and 180 days. This permitted an examination of what the authors labeled the “kinetic” course of cytokines over 6 months of treatment for the pain of FM.
Most studies did include a control group (Angst et al., 2008; Bazzichi et al., 2007; Eriksson et al., 2004; Iannuccelli et al., 2010; Üceyler et al., 2010, 2007; Wang et al., 2008; White et al., 2010). Factors such as pH and presence of other antibodies can affect cytokine results; yet, the most common reason for discrepancy or variation among results can relate to short half-life and wide ranges in cytokine levels (Bienvenu, Monneret, Fabien, & Revillard, 2005). Hence, a healthy control group may reveal differences in cytokine levels that would otherwise go undetected.
Limitations of the Studies
Similar to the studies reviewed by Üceyler et al. (2011) in their systematic review of cytokines in FM syndrome and Parkitny et al. (2013) in their review and meta-analysis of inflammation in complex regional pain syndrome, several of the studies described here did not meet basic quality criteria. Limitations included small sample sizes (Angst et al., 2008; Eriksson et al., 2004; Üceyler et al., 2010; White et al., 2010), lack of gender balance (Angst et al., 2008; Mazzone et al., 2001), cross-sectional measures (Bazzichi et al., 2007; Eriksson et al., 2004; Iannuccelli et al., 2010; Mazzone et al., 2001), insufficient numbers of older adults (Angst et al., 2008; White et al., 2010), and a preponderance of Caucasian participants. In addition, factors with the potential to affect inflammatory processes and the release of inflammatory biomarkers (such as alcohol, smoking, body mass index, physical activity, medications, and inflammatory or autoimmune diseases) were often not controlled for through design or statistical analyses (Eriksson et al., 2004; Iannuccelli et al., 2010; Manero & Alcazar, 2010; Mazzone et al., 2001). It is possible that the significant association between cytokines and pain would disappear after controlling for obesity. It is well established that obesity is associated with increased inflammation (Panagiotakos, Pitsavos, Yannakoulia, Chrysohoou, & Stefanadis, 2005). In several studies, levels of cytokines were low or negligible (Iannuccelli et al., 2010; Üceyler et al., 2010, 2007); so, whether statistical significance translates to clinical significance remains unknown. In several studies, levels of numerous cytokines were not normally distributed, necessitating log transformations and the use of nonparametric testing (Iannuccelli et al., 2010; Üceyler et al., 2010, 2007).
Some studies used plasma versus serum as the source for cytokines, whereas others did not indicate whether samples were prepared as plasma or serum. Plasma, rather than serum, is preferred for cytokine measurement because serum concentrations are lower for TNF-α, IL-6, and IL-10, as well as for other cytokines, because of degradation during the clotting process (Wong et al., 2008). In addition, it is important to note that venous samples were obtained from venipuncture rather than an indwelling catheter because others have shown that cytokine production increases in response to an indwelling venous catheter—possibly because of local tissue injury at the site of catheter insertion (Gudmundsson et al., 1997). It is vital to state the methodology used for cytokine measurement. As noted above, most studies used a standard ELISA or multiplex bead-based immunoassays. Finally, studies with limitations were included because so few high-quality studies were available and also to allow readers to evaluate the validity of findings. In addition, it was shown just how disparate the studies were that were identified and how difficult it is to control for clinical and individual variables when conducting research on pain and biomarkers. These data may aid investigators in increasing the rigor of future studies, thus improving internal validity.
Results indicated that cytokines were altered in the presence of pain, but there was inconclusive evidence and an overall lack of data to support the use of cytokines as a biomarker of pain. The occurrence and severity of pain was associated with changes in both proinflammatory and anti-inflammatory biomarkers. The association between inflammatory markers varied in the direction and magnitude of expression, which in part may be explained by differences among studies in design, assays, disease condition and duration, acute versus chronic pain, variation in and severity of symptoms, and timing of measurement. We suggest that evidenced-based guidelines for measuring, analyzing, and reporting inflammatory cytokines be compiled to facilitate meta-analysis. To elucidate the potential impact of cytokines on the clinical diagnosis or conditions in which pain is a known symptom but may be absent, future nursing research should investigate the association between pain and biomarkers of inflammation and leukocyte migration and activation. Information on inflammatory status will enable nurses to better understand the features of painful conditions, provide information to patients, and support patients in decision making.
Angst M. S., Clark J. D., Carvalho B., Tingle M., Schmelz M., Yeomans D. C. (2008). Cytokine profile in human skin in response to experimental inflammation, noxious stimulation, and administration of a COX-inhibitor: A microdialysis study. Pain, 139, 15–27.
Babu B. M. V., Reddy B. P., Priya V. H. S., Munshi A., Rani H. S., Latha G. S., Jyothy A. (2012). Cytokine gene polymorphisms in the susceptibility to acute coronary syndrome. Genetic Testing and Molecular Biomarkers, 16, 359–365.
Bazzichi L., Rossi A., Massimetti G., Giannaccini G., Giuliano T., De Feo F., Bombardieri S. (2007). Cytokine patterns in fibromyalgia and their correlation with clinical manifestations. Clinical and Experimental Rheumatology, 25, 225–230.
Bienvenu J., Monneret G., Fabien N., Revillard J. P. (2005). The clinical usefulness of the measurement of cytokines. Clinical Chemistry and Laboratory Medicine, 38, 267–285.
de Jager W., Rijkers G. T. (2006). Solid-phase and bead-based cytokine immunoassay: A comparison. Methods, 38, 294–303.
Dubin A. E., Patapoutian A. (2010). Nociceptors: The sensors of the pain pathway. The Journal of Clinical Investigation, 120, 3760–3772.
Eriksson P., Andersson C., Ekerfelt C., Ernerudh J., Skogh T. (2004). Sjögren’s syndrome with myalgia is associated with subnormal secretion of cytokines by peripheral blood mononuclear cells. Journal of Rheumatology, 31, 729–735.
Frazier L. (2003). Novel predictors of acute coronary syndrome outcomes. Biological Research for Nursing, 5, 30–36.
Gebhardt K., Brenner H., Stürmer T., Raum E., Richter W., Schiltenwolf M., Buchner M. (2006). The course of high-sensitive C-reactive protein in correlation with pain and clinical function in patients with acute lumbosciatic pain and chronic low back pain—A 6 months prospective longitudinal study. European Journal of Pain, 10, 711–719.
Gilbertson-White S., Aouizerat B. E., Miaskowski C. (2011). Methodologic issues in the measurement of cytokines to elucidate the biological basis for cancer symptoms. Biological Research for Nursing, 13, 15–24.
Graham J. E., Robles T. F., Kiecolt-Glaser J. K., Malarkey W. B., Bissell M. G., Glaser R. (2006). Hostility and pain are related to inflammation in older adults. Brain, Behavior, and Immunity, 20, 389–400.
Gudmundsson A., Ershler W. B., Goodman B., Lent S. J., Barczi S., Carnes M. (1997). Serum concentrations of interleukin-6 are increased when sampled through an indwelling venous catheter. Clinical Chemistry, 43, 2199–2201.
Iannuccelli C., Di Franco M., Alessandri C., Guzzo M. P., Croia C., Di Sabato F., Valesini G. (2010). Pathophysiology of fibromyalgia: A comparison with the tension-type headache, a localized pain syndrome. Annals of the New York Academy of Sciences, 1193, 78–83.
Lin S., Yokoyama H., Rac V. E., Brooks S. C. (2012). Novel biomarkers in diagnosing cardiac ischemia in the emergency department: A systematic review. Resuscitation, 83, 684–691.
Lloyd-Jones D., Adams R. J., Brown T. M., Carnethon M., Dai S., De Simone G.… American Heart Association Statistics Committee and Stroke Statistics Subcommittee. (2010). Executive summary: Heart disease and stroke statistics—2010 update: A report from the American Heart Association. Circulation, 121, 948–954.
Manero M. G., Alcazar J. L. (2010). Interleukin-8 serum levels do not correlate with pelvic pain in patients with ovarian endometriomas. Fertility and Sterility, 94, 450–452.
Mazzone A., Cusa C., Mazzucchelli I., Vezzoli M., Ottini E., Pacifici R., Falcone C. (2001). Increased production of inflammatory cytokines in patients with silent myocardial ischemia. Journal of the American College of Cardiology, 38, 1895–1901.
Montes-Sandoval L. (1999). An analysis of the concept of pain. Journal of Advanced Nursing, 29, 935–941.
Panagiotakos D. B., Pitsavos C., Yannakoulia M., Chrysohoou C., Stefanadis C. (2005). The implication of obesity and central fat on markers of chronic inflammation: The ATTICA study. Atherosclerosis, 183, 308–315.
Parkitny L., McAuley J. H., Di Pietro F., Stanton T. R., O’Connell N. E., Marinus J., Moseley G. L. (2013). Inflammation in complex regional pain syndrome: A systematic review and meta-analysis. Neurology, 80, 106–117.
Patarca-Montero R., Antoni M., Fletcher M. A., Klimas N. G. (2001). Cytokine and other immunologic markers in chronic fatigue syndrome and their relation to neuropsychological factors. Applied Neuropsychology, 8, 51–64.
Rittner H. L., Machelska H., Stein C. (2005). Leukocytes in the regulation of pain and analgesia. Journal of Leukocyte Biology, 78, 1215–1222.
Stürmer T., Raum E., Buchner M., Gebhardt K., Schiltenwolf M., Richter W., Brenner H. (2005). Pain and high sensitivity C reactive protein in patients with chronic low back pain and acute sciatic pain. Annals of the Rheumatic Diseases, 64, 921–925.
Terman G. W., Bonica J. J. (2001). Spinal mechanisms and their modulation. In Loeser J. (Ed.), Bonica’s management of pain (3rd ed., pp. 73–153). Philadelphia, PA: Lippincott Williams & Wilkins.
Thygesen K., Alpert J. S., Jaffe A. S., Simoons M. L., Chaitman B. R., White H. D.; the Writing Group on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction. (2012). Third universal definition of myocardial infarction. Journal of the American College of Cardiology, 60, 1581–1598.
Üceyler N., Häuser W., Sommer C. (2011). Systematic review with meta-analysis: Cytokines in fibromyalgia syndrome. BMC Musculoskeletal Disorders, 12, 245.
Üceyler N., Kafke W., Riediger N., He L., Necula G., Toyka K. V., Sommer C. (2010). Elevated proinflammatory cytokine expression in affected skin in small fiber neuropathy. Neurology, 74, 1806–1813.
Üceyler N., Rogausch J. P., Toyka K. V., Sommer C. (2007). Differential expression of cytokines in painful and painless neuropathies. Neurology, 69, 42–49.
Wang H., Moser M., Schiltenwolf M., Buchner M. (2008). Circulating cytokine levels compared to pain in patients with fibromyalgia—A prospective longitudinal study over 6 months. The Journal of Rheumatology, 35, 1366–1370.
Welsh P., Woodward M., Rumley A., MacMahon S., Lowe G. D. (2010). Does interleukin-18 or tumour necrosis factor-α have an independent association with the risk of coronary heart disease? Results from a prospective study in New Zealand. Cytokine, 50, 94–98.
White A. T., Light A. R., Hughen R. W., Bateman L., Martins T. B., Hill H. R., Light K. C. (2010). Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome. Psychophysiology, 47, 615–624.
Wong H.-L., Pfeiffer R. M., Fears T. R., Vermeulen R., Ji S., Rabkin C. S. (2008). Reproducibility and correlations of multiplex cytokine levels in asymptomatic persons. Cancer Epidemiology, Biomarkers & Prevention, 17, 3450–3456.
biological markers; cytokines; inflammation; pain
© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Highlight selected keywords in the article text.