Systemic alterations in plasma biomarkers levels in patients with chronic pain

Alterações nos níveis plasmáticos de biomarcadores de pacientes com dor crônica

Leticia Meda Vendrusculo-Fangel Renan Fangel Rita de Cássia Marqueti About the authors

ABSTRACT

BACKGROUND AND OBJECTIVES:

To analyze the scientific evidence on the changes in plasma levels of interleukins, nitric oxide, extracellular matrix metalloproteinases, bradykinins, and cortisol in patients with chronic pain.

CONTENTS:

The studies were identified by searching the following electronic databases: Pubmed/Medline, Scopus, LILACS, and Web of Science, published from June of 2016 to December of 2016. The selected articles were presented in a flow chart based on their identification, selection, eligibility and inclusion and exclusion criteria. The content of the articles included in the study was analyzed to identify the biomarkers present in patients with chronic pain. Thirteen articles that addressed the plasma biomarkers levels in humans with chronic pain were selected. Most of the articles presented the cytokines levels, followed by cortisol. Only one article mentioned the nitric oxide, and none mentioned what plasma levels of extracellular matrix metalloproteinases and bradykinins were identified.

CONCLUSION:

Changes were observed in inflammatory and anti-inflammatory cytokine plasma levels, and that cortisol is related to anxiety and depression symptoms in patients with chronic pain. However, it was not possible to identify the changes in plasma levels of nitric oxide, bradykinin, and extracellular matrix metalloproteinases due to the absence of scientific evidence.

Keywords:
Biomarkers; Chronic pain; Plasma

RESUMO

JUSTIFICATIVA E OBJETIVOS:

Analisar as evidências científicas sobre alterações nos níveis plasmáticos de interleucinas, óxido nítrico, metaloproteinases de matriz extracelular, bradicinina e cortisol em pacientes com dor crônica.

CONTEÚDO:

Os estudos foram identificados por meio das bases de dados eletrônicas: Pubmed/Medline, Scopus, LILACS e Web of Science, publicados no período de junho a dezembro de 2016. Os artigos selecionados foram classificados em ficha de identificação, seleção dos participantes, elegibilidade, critérios de inclusão e exclusão. Os artigos selecionados foram avaliados por meio de análise de conteúdo, buscando identificar os biomarcadores presentes nos pacientes com dor crônica. Foram selecionados 13 artigos que abordavam a dosagem plasmática de biomarcadores em humanos com dor crônica. A maior parte dos artigos apresentou a dose de citocinas, seguidos pelo cortisol. Apenas um artigo apresentou a dose de óxido nítrico e nenhum artigo identificou a dosagem de níveis plasmáticos de metaloproteinases de matriz extracelular e bradicinina.

CONCLUSÃO:

Pôde-se verificar modificações nos níveis plasmáticos de citocinas inflamatórias e anti-inflamatórias, e que os níveis plasmáticos de cortisol estão relacionados com os sintomas de ansiedade e depressão nos pacientes com dor crônica. No entanto, não foi possível verificar as alterações nos níveis de plasma do óxido nítrico, bradicinina e metaloproteinase de matriz extracelular devido à ausência de evidências científicas.

Descritores:
Biomarcadores; Dor crônica; Plasma

INTRODUCTION

Chronic pain is generally defined as persistent pain lasting longer than three months. However, other definitions favor the inclusion of psychosocial factors and the severity of pain in the diagnosis of chronic pain. The severity is graded based on its intensity, suffering, and impacts related to pain and functional impairment11 Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, et al. A classification of chronic pain for ICD-11. Pain. 2015;156(6):1003-7..

Due to these characteristics, it is considered a complex and multi-factorial affliction, which makes it difficult to evaluate and justify the need for several techniques, such as questionnaires, numeric scales, and non-verbal indices, as well as biochemical and biomechanical parameters22 Ferreira EA, Marques AP, Matsutani LA, Vasconcellos EG, Mendonça LL. Avaliação da dor e estresse em pacientes com fibromialgia. Rev Bras Reumatol. 2002;42(2):104-10.,33 De Peuter S, Van Diest I, Vansteenwegen D, Van den Bergh O, Vlaeyen JW. Understanding fear of pain in chronic pain: interoceptive fear conditioning as a novel approach. Eur J Pain. 2011;15(9):889-94. that although provide for an adequate investigation of the disease, make it difficult for the use at a large scale. Therefore, it is necessary to understand the biological and psychosocial parameters to facilitate the diagnosis of the patient with chronic pain.

Due to the complex features of chronic pain, it remains a major challenge for clinical management and assessment as it is often only examined with one-dimensional scales that do not reflect the diversity of factors that encompass the care and the experience of chronic pain. An aspect that could facilitate the control and treatment of chronic pain could be the use of blood biomarkers. However, the relationships between chronic pain and the continuous presence of nociceptors or inflammatory markers in the plasma of patients with chronic pain are not yet understood. In addition, there is a lack of clinical diagnostic requirements regarding the use of physiological and biochemical biomarkers44 DeVon HA, Piano MR, Rosenfeld AG, Hoppensteadt DA. The association of pain with protein inflammatory biomarkers a review of the literature. Nurs Res. 2014;63(1):51-62..

Biomarkers are biochemical molecules that aid in the diagnosis and the accompaniment of diseases. In pain, the relationship between proinflammatory biomarkers and pain had been examined in patients with painful inflammation such as a key pathological feature of the disease process55 Kraychete DC, Calasans MT, Valente CM. Citocinas pró-inflamatórias e dor. Rev Bras Reumatol. 2006;46(3):199-206.. In these cases, high-stress levels may compromise the hypothalamic-pituitary-adrenal axis, interfering with cortisol secretion, and alter cytokine expression and tumor necrosis factor66 Aronoff GM. What do we know about the pathophysiology of chronic pain? Implications for treatment considerations. Med Clin North Am. 2016;100(1):31-42.,77 Burska A, Boissinot M, Ponchel F. Cytokines as biomarkers in rheumatoid arthritis. Mediators Inflamm. 2014;2014:545493..

Inflammatory cytokines, as well as nitric oxide (NO), play a key role in the pathogenesis of persistent and exacerbated pain states88 Koch A, Zacharowski K, Boehm O, Stevens M, Lipfert P, von Giesen HJ, et al. Nitric oxide and pro-inflammatory cytokines correlate with pain intensity in chronic pain patients. Inflamm Res. 2007;56(1):32-7.. Some publications present the relation of these biomarkers with oncologic pain and neuropathic pain99 Marchi A, Vellucci R, Mameli S, Rita Piredda A, Finco G. Pain biomarkers. Clin Drug Investig. 2009;29(Suppl 1):41-6.. However, the relationships between biomarkers and chronic musculoskeletal pain have not been discussed until now.

Therefore, this scoping review was undertaken to evaluate the scientific evidence on the changes in plasma levels of interleukins, NO, matrix metalloproteinases (MMP), bradykinins, and cortisol in patients with chronic pain.

CONTENTS

Studies were identified by searching the following electronic databases: Pubmed/Medline (via National Library of Medicine) (1990 - present), Scopus (1990 - 2013), ScienceDirect (1990 - present) and Web of Science (1990 - present), indicated in the period from June 2016 to December 2016. The research question was: “Do patients with chronic pain have changes in the plasma levels of cytokines, nitric oxide, bradykinin, MMP, and cortisol?

Definition of terms

For that, we selected articles published in the last 10 years, published in English, Portuguese, and Spanish. Keywords were selected by Mesh Terms in order to identify the correct nomenclatures. They were: “chronic pain” with the AND search operator “Nitric Oxide”, “Hydrocortisone”, “Cytokines” “Bradykinin”, “Matrix Metalloproteinases”, with the OR operator between them. In order to restrict the search for the type of analysis, the word plasma was used as the free term with the AND search operator.

After this initial selection, the titles and abstracts were read and evaluated based on our inclusion and exclusion criteria for relevance. Two reviewers independently reviewed the full texts of all potentially relevant articles, and the eligibility of each was discussed and resolved. If there had been disagreements between two evaluators, a third evaluator was consulted. This review was performed in order to understand changes in biomarkers plasma levels in patients with chronic pain.

Inclusion and exclusion criteria

Studies included in this scoping review: articles describing the plasma levels of biomarkers in patients with chronic musculoskeletal pain; observational and experimental studies that presented plasma levels of biomarkers in this population prior to treatment and only full-text article citations with no restrictions on language. In addition, the following exclusion criteria were used: articles that presented dosages of biomarkers in animals; studies that showed biomarker dosages that were collected in other sample types that are not human plasma. Furthermore, meeting abstracts, unpublished data, review articles, and duplicate articles were excluded from the current study.

The initial search resulted in 193 articles fully assessed in this review, 94 articles were from Pubmed, 40 from the Web of Science, 58 from SCOPUS and one from LILACS. Of these, 62 were duplicates. The remaining 131 articles were evaluated by their abstracts, verifying whether they corresponded to the inclusion criteria. After this stage, 47 articles were included for the complete evaluation of the study. At this stage, 34 articles were excluded, because (although not observed in the summary reading) they did not match the inclusion criteria of this study, since they did not present biomarker plasma evaluation, or these analyses were performed only after some type of treatment.

Regarding the causes of chronic pain, it is possible to observe that four articles referred to patients with fibromyalgia, three articles were related to chronic pelvic pain, one article reported chronic pain caused by sports, one article referred to burning mouth syndrome, and one article mentioned temporomandibular pain. Other articles indicated participants with chronic pain without specifying the cause.

Selected articles were published between 2007 and 2016. There were two articles published in each of the following years: 2007, 2012, 2014, 2015 and 2016 with only one article published each year in 2008, 2009 and 2013.

Regarding biomarkers analyses (Table 1), it is possible to observe that with a total of thirteen articles, nine studies presented cytokine analyses, one study showed NO analyses and four articles described cortisol analyses, all in plasma samples. Among the most common cytokines were interleukins 6, 2, and 10 (IL-6, IL-2, IL-10), tumor necrosis factor alpha (TNF-α) and interferon gamma (INF-γ).

Table 1
Biomarker analysis of selected articles

In summary, six articles identified an increase in interleukins correlated to chronic pain. The biomarker with the highest number of alterations was IL-6 with three articles reporting increases in patients. One study reported decreased levels of IL-6, IL-4, IL-1, IL-2, IL-8, and TNF-α, was also indicated to increase in serum levels in the chronic pain group. Anti-inflammatory cytokines, IL-4, IL-5, and IL-13 are reported to have decreased in these studies.

Finally, one study reported a direct correlation between increased NO plasma concentration and disease severity. Moreover, in relation to cortisol, it was observed that despite being related to depression and other emotional aspects, such as the response to stress, there is no difference in plasma concentrations between the patient and control group.

In this scoping review, no study was found evaluated plasma bradykinin and MMP in patients with chronic musculoskeletal pain.

DISCUSSION

The present scoping review sought to understand the changes in plasma levels of biomarkers cytokines, nitric oxide, bradykinin, MMP, and cortisol presented in patients with chronic pain. In this review, thirteen articles were found to address these questions. A greater number of articles with cytokines were identified, followed by cortisol, only one article regarding NO and none for the other biomarkers.

Among the articles which included cytokines, it was possible to observe that cytokines were the most evaluated biomarker, mainly IL-6, IL-2, and IL-10. However, the one that had the strongest relationship to chronic pain was IL-666 Aronoff GM. What do we know about the pathophysiology of chronic pain? Implications for treatment considerations. Med Clin North Am. 2016;100(1):31-42.. Interleukin-6 is related to both the innate and adaptive immune response. It arises in response to microorganisms, but also to stimulation by other cytokines such as IL-1 and TNF-α. It is also considered the main myosin produced by active skeletal muscles and has an acute pro-inflammatory effect, but its presence stimulates the increase of other interleukins, such as IL-10, which presents a chronic anti-inflammatory effect2222 de Oliveira CM, Sakata RK, Issy AM, Gerola LR, Salomão R. [Cytokines and pain]. Rev Bras Anestesiol. 2011;61(2):255-65. English, Portuguese, Spanish.. In studies by Koch et al.88 Koch A, Zacharowski K, Boehm O, Stevens M, Lipfert P, von Giesen HJ, et al. Nitric oxide and pro-inflammatory cytokines correlate with pain intensity in chronic pain patients. Inflamm Res. 2007;56(1):32-7. and Malhotra et al.1414 Malhotra D, Saxena AK, Dar SA, Kumar V, Nasare N, Tripathi AK, et al. Evaluation of cytokine levels in fibromyalgia syndrome patients and its relationship to the severity of chronic pain. J Musculoskeletal Pain. 2012;20(3):164-9., a direct relationship was found between the concentration of pro-inflammatory interleukins, mainly IL-6, and the severity of chronic pain. Pro-inflammatory cytokine concentrations in this review were related to the presence of chronic pain, as six articles have shown that these cytokine concentrations were higher in patients with chronic pain than in healthy controls1313 Behm FG, Gavin IM, Karpenko O, Lindgren V, Gaitonde S, Gashkoff PA, et al. Unique immunologic patterns in fibromyalgia. BMC Clin Pathol. 2012;12:25.. These studies presented different chronic pain charts, so this finding may be related to chronic musculoskeletal pain of different origins. Another relationship found in the cytokine and chronic pain ratio was the decrease of anti-inflammatory cytokines in patients with chronic pain when compared to controls1313 Behm FG, Gavin IM, Karpenko O, Lindgren V, Gaitonde S, Gashkoff PA, et al. Unique immunologic patterns in fibromyalgia. BMC Clin Pathol. 2012;12:25.,1414 Malhotra D, Saxena AK, Dar SA, Kumar V, Nasare N, Tripathi AK, et al. Evaluation of cytokine levels in fibromyalgia syndrome patients and its relationship to the severity of chronic pain. J Musculoskeletal Pain. 2012;20(3):164-9.,1717 Sturgill V, MgGee E, Menzies V. Unique cytokine signature in the plasma of patients with fibromyalgia. J Immunol Res. 2014;2014:938576.,1919 Nenke MA, Haylock CL, Rankin W, Inder WJ, Gagliardi L, Eldridge C, et al. Low-dose hydrocortisone replacement improves wellbeing and pain tolerance in chronic pain patients with opioid-induced hypocortisolemic responses. A pilot randomized, placebo-controlled trial. Psychoneuroendocrinology. 2015;56:157-67.. This information may facilitate the modification of pain perception, since IL-10, for example, plays an important role as a pain perception blocker2323 Zhang JM, An J. Cytokines, inflammation and pain. Int Anesthesiol Clin. 2007;45(2):27-37..

Concerning NO, only one article was found to evaluate plasma dosage. A study by Koch et al.88 Koch A, Zacharowski K, Boehm O, Stevens M, Lipfert P, von Giesen HJ, et al. Nitric oxide and pro-inflammatory cytokines correlate with pain intensity in chronic pain patients. Inflamm Res. 2007;56(1):32-7. showed that serum NO levels increase in patients with chronic pain at all severity levels when compared to healthy controls. However, although these authors also find modifications in the dosages of cytokines, there are no references as to the correlation between these variables. It is known that NO plays an important role in the synthesis of cytokines and inhibitory factors involved in inflammation2424 Okazaki Y, Sawada T, Nagatani K, Komagata Y, Unoue T, Muto S, et al. Effect of nuclear factor-kappaB inhibition on rheumatoid fibroblast-like synoviocytes and collagen induced arthritis. J Rheumatol. 2005;32(8):1440-7..

Regarding plasma cortisol levels, five studies with this type of analysis were found. Among them, only Vaisberg et al.1010 Vaisberg M, de Mello MT, Seelaender MC, dos Santos RV, Costa Rosa LF. Reduced maximal oxygen consumption and overproduction of proinflammatory cytokines in athletes. Neuroimmunomodulation, 2007;14(6):304-9. evaluated plasma cortisol and cytokine levels for chronic pain in athletes, but it did not show a relationship between the two biomarkers. In Vaisberg et al.1010 Vaisberg M, de Mello MT, Seelaender MC, dos Santos RV, Costa Rosa LF. Reduced maximal oxygen consumption and overproduction of proinflammatory cytokines in athletes. Neuroimmunomodulation, 2007;14(6):304-9., no significant changes were found between the groups with chronic pain or chronic pain in serum cortisol levels. Additionally, no studies showed a relationship between cytokines and cortisol. Cytokines can aid in the activation of the neuroendocrine axis, increasing the cortisol secretion, and a modification in this system, due to the cytokines, the increase could explain a chronic release and increase in plasma cortisol77 Burska A, Boissinot M, Ponchel F. Cytokines as biomarkers in rheumatoid arthritis. Mediators Inflamm. 2014;2014:545493..

Among the five articles that measured plasma cortisol, three presented significant changes. Wingenfeld et al.1111 Wingenfeld K, Heim C, Schmidt I, Wagner D, Meinlschmidt G, Hellhammer DH. HPA axis reactivity and lymphocyte glucocorticoid sensitivity in fibromyalgia syndrome and chronic pelvic pain. Psychosom Med. 2008;70(1):65-72. showed higher concentrations of plasma cortisol in the fibromyalgia group than in the other groups, which is related to a difficulty in responding to stress. Koike et al.88 Koch A, Zacharowski K, Boehm O, Stevens M, Lipfert P, von Giesen HJ, et al. Nitric oxide and pro-inflammatory cytokines correlate with pain intensity in chronic pain patients. Inflamm Res. 2007;56(1):32-7. reported a direct relationship between depressive symptoms and serum cortisol rates. Nenke et al.1919 Nenke MA, Haylock CL, Rankin W, Inder WJ, Gagliardi L, Eldridge C, et al. Low-dose hydrocortisone replacement improves wellbeing and pain tolerance in chronic pain patients with opioid-induced hypocortisolemic responses. A pilot randomized, placebo-controlled trial. Psychoneuroendocrinology. 2015;56:157-67. showed that patients on opioids treatment had reduced cortisol rates. In this view, it seems that patients experiencing chronic pain with emotional changes may present changes in plasma cortisol levels.

Taken together, our findings provide evidence that chronic musculoskeletal pain can increase pro-inflammatory cytokines, mainly IL-6 and NO in serum, as well as decrease IL-10. Cortisol seems to be related to the presence of anxiety and depression symptoms, which may make it difficult for these patients to cope in the face of chronic pain2525 Borsook D, Becerra L, Hargreaves R. Biomarkers for chronic pain and analgesia. Part 1: the need, reality, challenges, and solutions. Discov Med. 2011;11(58):197-207.. Another important aspect is the type of chronic pain evaluated. The most cited were not fibromyalgia and chronic pelvic pain but unspecified chronic pain. This aspect identifies many possible factors that develop chronic pain, which, after being established, becomes a health problem itself, with its own particularities2626 Borsook D, Becerra L, Hargreaves R. Biomarkers for chronic pain and analgesia. Part 2: how, where, and what to look for using functional imaging. Discov Med. 2011;11(58):209-19..

No study was found in the literature to have measured plasma MMP or bradykinin content in patients with chronic musculoskeletal pain. This may be related to the fact that MMP and bradykinins influence the local inflammatory process when patients present tissue injury, but this not always happens in patients with chronic pain2727 Rio E, Moseley L, Purdam C, Samiric T, Kidgell D, Pearce AJ, et al. The pain of tendinopathy: physiological or pathophysiological? Sports Med. 2014;44(1):9-23.. However, it would be important to understand the systemic impact of the presence of these biomarkers and their impact on chronic pain processes when acute tissue injury ceases.

In this review, it was found that most of the articles deal with a cross-sectional observational study, which is justified by the guiding question used since this study sought to identify the modifications in the biomarkers in patients with chronic pain. However, despite being observational studies, they presented a high level of evidence, which makes it possible to use them as scientific evidence for these biomarkers modifications.

Because of the guiding question, this study did not include randomized clinical trials that could better explain the relationships between these biomarkers as well as factors that aggravate or ameliorate clinical symptoms and possibly modify biomarker dosages. Further studies are required to understand the relationship between biomarkers and other problems associated with chronic pain, such as psycho-social aspects.

CONCLUSION

This scoping review can conclude that there are changes in inflammatory and anti-inflammatory cytokine plasma levels of patients with chronic pain, and that cortisol is related to anxiety and depression symptoms. Regarding NO, bradykinin, and MMP, it was not possible to establish this relationship due to the absence of studies.

REFERENCES

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    Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, et al. A classification of chronic pain for ICD-11. Pain. 2015;156(6):1003-7.
  • 2
    Ferreira EA, Marques AP, Matsutani LA, Vasconcellos EG, Mendonça LL. Avaliação da dor e estresse em pacientes com fibromialgia. Rev Bras Reumatol. 2002;42(2):104-10.
  • 3
    De Peuter S, Van Diest I, Vansteenwegen D, Van den Bergh O, Vlaeyen JW. Understanding fear of pain in chronic pain: interoceptive fear conditioning as a novel approach. Eur J Pain. 2011;15(9):889-94.
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    DeVon HA, Piano MR, Rosenfeld AG, Hoppensteadt DA. The association of pain with protein inflammatory biomarkers a review of the literature. Nurs Res. 2014;63(1):51-62.
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    Kraychete DC, Calasans MT, Valente CM. Citocinas pró-inflamatórias e dor. Rev Bras Reumatol. 2006;46(3):199-206.
  • 6
    Aronoff GM. What do we know about the pathophysiology of chronic pain? Implications for treatment considerations. Med Clin North Am. 2016;100(1):31-42.
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    Burska A, Boissinot M, Ponchel F. Cytokines as biomarkers in rheumatoid arthritis. Mediators Inflamm. 2014;2014:545493.
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    Koch A, Zacharowski K, Boehm O, Stevens M, Lipfert P, von Giesen HJ, et al. Nitric oxide and pro-inflammatory cytokines correlate with pain intensity in chronic pain patients. Inflamm Res. 2007;56(1):32-7.
  • 9
    Marchi A, Vellucci R, Mameli S, Rita Piredda A, Finco G. Pain biomarkers. Clin Drug Investig. 2009;29(Suppl 1):41-6.
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    Vaisberg M, de Mello MT, Seelaender MC, dos Santos RV, Costa Rosa LF. Reduced maximal oxygen consumption and overproduction of proinflammatory cytokines in athletes. Neuroimmunomodulation, 2007;14(6):304-9.
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    Wingenfeld K, Heim C, Schmidt I, Wagner D, Meinlschmidt G, Hellhammer DH. HPA axis reactivity and lymphocyte glucocorticoid sensitivity in fibromyalgia syndrome and chronic pelvic pain. Psychosom Med. 2008;70(1):65-72.
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    Behm FG, Gavin IM, Karpenko O, Lindgren V, Gaitonde S, Gashkoff PA, et al. Unique immunologic patterns in fibromyalgia. BMC Clin Pathol. 2012;12:25.
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    Malhotra D, Saxena AK, Dar SA, Kumar V, Nasare N, Tripathi AK, et al. Evaluation of cytokine levels in fibromyalgia syndrome patients and its relationship to the severity of chronic pain. J Musculoskeletal Pain. 2012;20(3):164-9.
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    Lundh D, Hedelin H, Jonsson K, Gifford M, Larsson D. Assessing chronic pelvic pain syndrome patients: blood plasma factors and cortisol saliva. Scand J Urol. 2013;47(6):521-8.
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    Koike K, Shinozaki T, Hara K, Noma N, Okada-Ogawa A, Asano M, et al. Immune and endocrine function in patients with burning mouth syndrome. Clin J Pain. 2014;30(2):168-73.
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    Sturgill V, MgGee E, Menzies V. Unique cytokine signature in the plasma of patients with fibromyalgia. J Immunol Res. 2014;2014:938576.
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    Ciszek BP, Khan AA, Dang H, Slade GD, Smith S, Bair E, et al. MicroRNA expression profiles differentiate chronic pain condition subtypes. Transl Res. 2015;166(6):706-20.e.11.
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    Nenke MA, Haylock CL, Rankin W, Inder WJ, Gagliardi L, Eldridge C, et al. Low-dose hydrocortisone replacement improves wellbeing and pain tolerance in chronic pain patients with opioid-induced hypocortisolemic responses. A pilot randomized, placebo-controlled trial. Psychoneuroendocrinology. 2015;56:157-67.
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    Bäckryd E, Ghafouri B, Larsson B, Gerdle B. Plasma pro-inflammatory markers in chronic neuropathic pain: a multivariate, comparative, cross-sectional pilot study. Scand J Pain. 2016;10:1-5.
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    Park JW, Chung JW. Inflammatory cytokines and sleep disturbance in patients with temporomandibular disorders. J Oral Facial Pain Headache. 2016;30(1):27-33.
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    de Oliveira CM, Sakata RK, Issy AM, Gerola LR, Salomão R. [Cytokines and pain]. Rev Bras Anestesiol. 2011;61(2):255-65. English, Portuguese, Spanish.
  • 23
    Zhang JM, An J. Cytokines, inflammation and pain. Int Anesthesiol Clin. 2007;45(2):27-37.
  • 24
    Okazaki Y, Sawada T, Nagatani K, Komagata Y, Unoue T, Muto S, et al. Effect of nuclear factor-kappaB inhibition on rheumatoid fibroblast-like synoviocytes and collagen induced arthritis. J Rheumatol. 2005;32(8):1440-7.
  • 25
    Borsook D, Becerra L, Hargreaves R. Biomarkers for chronic pain and analgesia. Part 1: the need, reality, challenges, and solutions. Discov Med. 2011;11(58):197-207.
  • 26
    Borsook D, Becerra L, Hargreaves R. Biomarkers for chronic pain and analgesia. Part 2: how, where, and what to look for using functional imaging. Discov Med. 2011;11(58):209-19.
  • 27
    Rio E, Moseley L, Purdam C, Samiric T, Kidgell D, Pearce AJ, et al. The pain of tendinopathy: physiological or pathophysiological? Sports Med. 2014;44(1):9-23.

Publication Dates

  • Publication in this collection
    23 Sept 2019
  • Date of issue
    Jul-Sep 2019

History

  • Received
    16 Sept 2018
  • Accepted
    07 Jan 2019
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