Dorien Goubert

The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia patients: peripheral and central mechanisms as therapeutic targets?

Introduction: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are characterized by persistent pain and fatigue. It is hypothesized that reactive oxygen species (ROS), caused by oxidative and nitrosative stress, by inhibiting mitochondrial function can be involved in muscle pain and central sensitization as typically seen in these patients. Areas covered: The current evidence regarding oxidative and nitrosative stress and mitochondrial dysfunction in CFS and FM is presented in relation to chronic widespread pain. Mitochondrial dysfunction has been shown in leukocytes of CFS patients and in muscle cells of FM patients, which could explain the muscle pain. Additionally, if mitochondrial dysfunction is also present in central neural cells, this could result in lowered ATP pools in neural cells, leading to generalized hypersensitivity and chronic widespread pain. Expert opinion: Increased ROS in CFS and FM, resulting in impaired mitochondrial function and reduced ATP in muscle and neural cells, might lead to chronic widespread pain in these patients. Therefore, targeting increased ROS by antioxidants and targeting the mitochondrial biogenesis could offer a solution for the chronic pain in these patients. The role of exercise therapy in restoring mitochondrial dysfunction remains to be explored, and provides important avenues for future research in this area.

Pain following cancer treatment: Guidelines for the clinical classification of predominant neuropathic, nociceptive and central sensitization pain.

Abstract Background: In addition to fatigue, pain is the most frequent persistent symptom in cancer survivors. Clear guidelines for both the diagnosis and treatment of pain in cancer survivors are lacking. Classification of pain is important as it may facilitate more specific targeting of treatment. In this paper we present an overview of nociceptive, neuropathic and central sensitization pain following cancer treatment, as well as the rationale, criteria and process for stratifying pain classification. Material and methods: Recently, a clinical method for classifying any pain as either predominant central sensitization pain, neuropathic or nociceptive pain was developed, based on a large body of research evidence and international expert opinion. We, a team of 15 authors from 13 different centers, four countries and two continents have applied this classification algorithm to the cancer survivor population. Results: The classification of pain following cancer treatment entails two steps: (1) examining the presence of neuropathic pain; and (2) using an algorithm for differentiating predominant nociceptive and central sensitization pain. Step 1 builds on the established criteria for neuropathic pain diagnosis, while Step 2 applies a recently developed clinical method for classifying any pain as either predominant central sensitization pain, neuropathic or nociceptive pain to the cancer survivor population. Conclusion: The classification criteria allow identifying central sensitization pain following cancer treatment. The recognition of central sensitization pain in practice is an important development in the integration of pain neuroscience into the clinic, and one that is relevant for people undergoing and following cancer treatment.

Inventory of Personal Factors Influencing Conditioned Pain Modulation in Healthy People: A Systematic Literature Review

Conditioned pain modulation (CPM) is believed to play an important role in the development and exacerbation of chronic pain, because dysfunction of CPM is associated with a shift in balance between pain facilitation and pain inhibition. In many patients with central sensitization, CPM is less efficacious. Besides that, efficacy of CPM is highly variable in healthy people. Consequently, it seems that several individual variables may influence CPM. A systematic review examining personal factors influencing CPM was conducted.

Relations Between Brain Alterations and Clinical Pain Measures in Chronic Musculoskeletal Pain: A Systematic Review

UNLABELLED Compelling evidence has shown chronic widespread and exaggerated pain experience in chronic musculoskeletal pain (MSKP) conditions. In addition, neuroimaging research has revealed morphological and functional brain alterations in these patients. It is hypothesized that brain alterations play a role in the persistent pain complaints of patients with chronic MSKP. Nevertheless, lack of overview exists regarding the relations between brain alterations and clinical measures of pain. The present systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, to investigate the relations between structural or functional brain alterations, using magnetic resonance imaging scans, and clinical pain measures in patients with chronic MSKP. PubMed, Web of Science, Cinahl, and Cochrane databases were searched. First, the obtained articles were screened according to title and abstract. Second, the screening was on the basis of full-text. Risk of bias in included studies was investigated according to the modified Newcastle-Ottawa Scale. Twenty studies met the inclusion criteria. Moderate evidence shows that higher pain intensity and pressure pain sensitivity are related to decreased regional gray matter (GM) volume in brain regions encompassing the cingulate cortex, the insula, and the superior frontal and temporal gyrus. Further, some evidence exists that longer disease duration in fibromyalgia is correlated with decreased total GM volume. Yet, inconclusive evidence exists regarding the association of longer disease duration with decreased or increased regional GM volume in other chronic MSKP conditions. Inconclusive evidence was found regarding the direction of the relation of pain intensity and pressure pain sensitivity with microstructural white matter and functional connectivity alterations. In conclusion, preliminary to moderate evidence demonstrates relations between clinical pain measures, and structural and functional connectivity alterations within brain regions involved in somatosensory, affective, and cognitive processing of pain in chronic MSKP. Nevertheless, inconclusive results exist regarding the direction of these relations. Further research is warranted to unravel whether these brain alterations are positively or negatively correlated to clinical pain measures. PERSPECTIVE Structural and functional brain alterations within regions involved in somatosensory, affective, and cognitive pain processing play a crucial role in the persistent pain of chronic MSKP patients. Accordingly, these brain alterations have to be taken into account when assessing and treating patients with chronic MSKP.

Lumbar muscle structure and function in chronic versus recurrent low back pain: a cross-sectional study

BACKGROUND CONTEXT Heterogeneity exists within the low back pain (LBP) population. Some patients recover after every pain episode, whereas others suffer daily from LBP complaints. Until now, studies rarely make a distinction between recurrent low back pain (RLBP) and chronic low back pain (CLBP), although both are characterized by a different clinical picture. Clinical experiences also indicate that heterogeneity exists within the CLBP population. Muscle degeneration, like atrophy, fat infiltration, alterations in muscle fiber type, and altered muscle activity, compromises proper biomechanics and motion of the spinal units in LBP patients. The amount of alterations in muscle structure and muscle function of the paraspinal muscles might be related to the recurrence or chronicity of LBP. PURPOSE The aim of this experimental study is to evaluate differences in muscle structure (cross-sectional area and lean muscle fat index) and muscle activity of the multifidus (MF) and erector spinae (ES) during trunk extension, in patients with RLBP, non-continuous CLBP, and continuous CLBP. STUDY DESIGN AND SETTING This cross-sectional study took place in the university hospital of Ghent, Belgium. Muscle structure characteristics and muscle activity were assessed by magnetic resonance imaging (MRI). PATIENT SAMPLE Fifty-five adults with non-specific LBP (24 RLBP in remission, 15 non-continuous CLBP, 16 continuous CLBP) participated in this study. OUTCOME MEASURES Total cross-sectional area, muscle cross-sectional area, fat cross-sectional area, lean muscle fat index, T2-rest and T2-shift were assessed. METHODS A T1-weighted Dixon MRI scan was used to evaluate spinal muscle cross-sectional area and fat infiltration in the lumbar MF and ES. Muscle functional MRI was used to evaluate the muscle activity of the lumbar MF and ES during a lumbar extension exercise. Before and after the exercise, a pain assessment was performed. This study was supported by grants from the Special Research Fund of Ghent University (DEF12/AOP/022) without potential conflict of interest-associated biases in the text of the paper. RESULTS Fat cross-sectional area and lean muscle fat index were significantly higher in MF and ES in continuous CLBP compared with non-continuous CLBP and RLBP (p<.05). No differencesbetween groups were found for total cross-sectional area and muscle cross-sectional area in MF or ES (p>.05). Also, no significant differences between groups for T2-rest were established. T2-shift, however, was significantly lower in MF and ES in RLBP compared with, respectively, non-continuous CLBP and continuous CLBP (p<.05). CONCLUSIONS These results indicate a higher amount of fat infiltration in the lumbar muscles, in the absence of clear atrophy, in continuous CLBP compared with RLBP. A lower metabolic activity of the lumbar muscles was seen in RLBP replicating a relative lower intensity in contractions performed by the lumbar muscles in RLBP compared with non-continuous and continuous CLBP. In conclusion, RLBP differs from continuous CLBP for both muscle structure and muscle function, whereas non-continuous CLBP seems comparable with RLBP for lumbar muscle structure and with continuous CLBP for lumbar muscle function. These results underline the differences in muscle structure and muscle function between different LBP populations.

Effect of Pain Induction or Pain Reduction on Conditioned Pain Modulation in Adults: A Systematic Review.

Pain facilitation as well as pain inhibition might be present in chronic pain patients. A decreased efficacy of pain inhibition can be measured by conditioned pain modulation (CPM). The use of the CPM paradigm in scientific research has boosted over the last few years and is recognized for its high clinical relevance in chronic pain patients. It is, however, unclear whether the presence of pain and possible modulations of pain influences the efficacy of endogenous pain inhibition, measured by CPM. This systematic literature study aimed to provide an overview of the effects of clinical pain and experimental pain induction or pain reduction on CPM in adults.

Differences Between Women With Traumatic and Idiopathic Chronic Neck Pain and Women Without Neck Pain: Interrelationships Among Disability, Cognitive Deficits, and Central Sensitization

Background To date, a clear differentiation of disability, cognitive deficits, and central sensitization between chronic neck pain of a traumatic nature and that of a nontraumatic nature is lacking. Objective This study aimed to examine differences in disability, cognitive deficits, and central sensitization between women with traumatic and idiopathic (nontraumatic) chronic neck pain and women who were healthy. In addition, interrelationships among these variables were investigated. Design This was a case-control study. Methods Ninety-five women (28 women who were healthy [controls], 35 women with chronic idiopathic neck pain [CINP], and 32 women with chronic whiplash-associated disorders [CWAD] [traumatic]) were enrolled in the study. First, all participants completed standardized questionnaires to investigate pain-related disability and health-related quality of life. Next, cognitive performance was assessed. Finally, pressure pain thresholds and conditioned pain modulation were examined to investigate central sensitization. Results Pain-related disability, reduced health-related quality of life, and cognitive deficits were present in participants with CWAD and, to a significantly lesser extent, in participants with CINP. Local hyperalgesia was demonstrated in participants with CWAD and CINP but not in women who were healthy. However, distant hyperalgesia and decreased conditioned pain modulation efficacy were shown only in participants with CWAD; this result is indicative of the presence of central sensitization. Moderate to strong Spearman correlations (ρ=.456-.701) among disability, cognitive deficits, and hyperalgesia (local and distant) were observed in participants with CWAD. In participants with CINP, only local hyperalgesia and subjective cognitive deficits were moderately (ρ=.463) correlated. Limitations No conclusions about the causality of the observed correlations can be drawn. Conclusions This innovative research revealed important differences between women with CWAD and women with CINP and thus provided evidence of the clinical importance of distinguishing the assessment and rehabilitation approaches for both pain conditions.

Convergent validity of the Dutch Central Sensitization Inventory : associations with psychophysical pain measures, quality of life, disability, and pain cognitions in patients with chronic spinal pain

Symptoms of central sensitization (CS) have been described in patients with chronic spinal pain (CSP). Although a gold standard to diagnose CS is lacking, psychophysical pain measures are often used. The Central Sensitization Inventory (CSI) is proposed as an alternative method and indirect tool for the evaluation of CS symptomatology. The aim of the current study was to evaluate the convergent validity of the CSI by investigating the association with psychophysical pain measures and self‐reported measures of current pain intensity, quality of life, disability, and catastrophizing in CSP patients.

The association between back muscle characteristics and pressure pain sensitivity in low back pain patients

Abstract Background and aims: Some low back pain (LBP) patients recover after every pain episode whereas others develop chronicity. Research indicates that the amount of atrophy and fat infiltration differs between patients with LBP. Also enhanced pain sensitivity is present only in a subgroup of LBP patients. The relationship between pain sensitivity and muscular deformations in LBP, is however unexplored. This study examined the association between pressure pain sensitivity and the structural characteristics of the lumbar muscles in three different groups of non-specific LBP patients. Methods: This cross-sectional study examined the total cross-sectional area (CSA), fat CSA, muscle CSA and muscle fat index (MFI) of the lumbar multifidus (MF) and erector spinae (ES) at level L4 by magnetic resonance imaging in 54 patients with non-specific LBP (23 recurrent LBP, 15 non-continuous chronic LBP and 16 continuous chronic LBP). Pressure pain thresholds were measured at four locations (lower back, neck, hand and leg) by a manual pressure algometer and combined into one “pain sensitivity” variable. As a primary outcome measure, the association between pain sensitivity and muscle structure characteristics was investigated by multiple independent general linear regression models. Secondly, the influence of body mass index (BMI) and age on muscle characteristics was examined. Results: A positive association was found between pain sensitivity and the total CSA of the MF (p=0.006) and ES (p=0.001), and the muscle CSA of the MF (p=0.003) and ES (p=0.001), irrespective of the LBP group. No association was found between pain sensitivity and fat CSA or MFI (p>0.01). Furthermore, a positive association was found between BMI and the fat CSA of the MF (p=0.004) and ES (p=0.006), and the MFI of the MF (p<0.01) and ES (p=0.003). Finally, a positive association was found between age with the fat CSA of the MF (p=0.008) but not with the fat CSA of the ES (p>0.01), nor the MFI of the MF (p>0.01) and ES (p>0.01). Conclusions: A higher pain sensitivity is associated with a smaller total and muscle CSA in the lumbar MF and ES, and vice versa, but results are independent from the LBP subgroup. On the other hand, the amount of fat infiltration in the lumbar muscles is not associated with pain sensitivity. Instead, a higher BMI is associated with more lumbar fat infiltration. Finally, older patients with LBP are associated with higher fat infiltration in the MF but not in the ES muscle. Implications: These results imply that reconditioning muscular tissues might possibly decrease the pain sensitivity of LBP patients. Vice versa, therapy focusing on enhancement of pain sensitivity might also positively influence the CSA and that way contribute to the recovery of LBP. Furthermore, the amount of lumbar muscle fat seems not susceptible to pain sensitivity or vice versa, but instead a decrease in BMI might decrease the fat infiltration in the lumbar muscles and therefore improve the muscle structure quality in LBP. These hypothesis apply for all non-specific LBP patients, despite the type of LBP.