Chronic pain conditions of the musculoskeletal system are common and of high socioeconomic relevance [1
]. This is especially true for pain conditions with widely unknown pathogeneses, such as non-specific chronic back pain (CBP), chronic widespread pain (CWP), and fibromyalgia syndrome (FMS). In addition, the prevalence of these conditions and the demand for consultation and treatment have increased over recent years [5
], which results in high direct and indirect costs [1
However, therapeutic approaches in chronic musculoskeletal pain patients are often of minor success [9
]. This is likely because the aetiology and pathogenesis of chronic musculoskeletal pain are still widely unknown. As a result, treatment for this condition involves predominantly unspecific interventions, although the group of chronic musculoskeletal pain patients is believed to be heterogeneous [17
]. Differences in response to the same treatment in patients with the same disease could be explained by different underlying mechanisms contributing to the generation and maintenance of pain [19
]. The situation is complicated by the finding that the same disease can derive from various pathophysiological mechanisms. Conversely, the same pathophysiological mechanism may be of interest in distinct diseases [20
The heterogeneity is supported by strong hints that subgroups exist that differ in terms of aetiopathology, clinical symptomatology, and psychophysiological patterns. A recent study revealed distinct somatosensory profiles in CBP and FMS: FMS patients showed increased sensitivity for different pain modalities in all measured body areas, which suggests central disinhibition (or a deficient pain inhibitory system) as a potential mechanism. CBP subjects, in contrast, exhibited localised alterations within the affected segment. Such alterations may be due to peripheral sensitisation [21
]. This finding is in accordance with the main hypothesis of a mechanism-based diagnosis in chronic pain syndromes, which proposes that defined symptoms and signs reflect possible underlying neurobiological pain mechanisms [19
]. Consequently, these subgroups should be treated with specific mechanism-based approaches, but to date, they have been treated with the same non-specific multimodal treatment programs. Therefore, the assessment of chronic pain and research identifying various factors associated with the development, maintenance, and spread of chronic pain, including their neurobiological correlates, is highly relevant.
Chronic pain has been found to be associated with a higher prevalence of mental co-morbidity. Patients with CBP [23
], CWP [25
], and FMS [26
] suffer from mental disorders significantly more often than pain-free controls. This finding is especially true for anxiety disorders and mood disorders, which were found to have prevalence rates of 20.9% and 12.7%, respectively, in a population-based sample of patients with chronic back pain [23
]. Of further interest is the role of psychological trauma, which has been neglected in previous research. Traumatic events have higher prevalence rates in patients with pain compared to pain-free controls or patients with other diseases [27
]. Concerning traumatic experiences, it was suggested that multiple traumas have a cumulative effect on physical health, including back pain and that the impact of the trauma on health may be independent of post-traumatic stress disorder (PTSD) symptomatology [30
The assessment of chronic pain and mental comorbidity on a psychobiological basis may detect common underlying pathophysiological changes. With regard to pain processing there are studies that suggest a role for central disinhibition mechanisms in depression and, to a lower extent, in patients with FMS compared to healthy controls [32
]. Alterations in pain processing among patients with depression or FMS were reported previously, but this study found that hyperalgesia was more pronounced in patients with FMS than in those with depression [33
]. In patients with FMS with comorbid depression or anxiety, pain processing was not altered in comparison to patients with FMS alone [34
]. Thus there seems to be an association of chronic pain or depression with altered pain processing, although chronic pain and comorbid depression did not interact with pain processing.
In regard to anxiety disorders and the neglected role of trauma, a study by Defrin et al. described a unique sensory profile of hyposensitivity to non-noxious stimuli, accompanied by hypoalgesia to at-pain-threshold noxious stimuli and hyper-reactivity to suprathreshold noxious stimuli in patients with PTSD and chronic pain compared with healthy controls [35
This pattern clearly differs from other patient groups with chronic pain, such as those with fibromyalgia, who tend to exhibit pain hypersensitivity [21
], and from alterations in PTSD, in which context a decreased sensitivity to painful stimuli has been reported [37
]. The results reported by Defrin et al. appear to be a hybrid of what has been found in pain-free PTSD patients and PTSD-free pain patients: decreased sensitivity to non-painful stimuli and increased hyperreactivity to painful stimuli. Sensory processing in anxiety disorders other than PTSD is believed not to differ from processing in healthy controls [35
]. Another aspect of the psychobiology of pain is pain inhibition. It was found that pain inhibition is deficient in FMS patients but normal in those with depressive disorder [33
]. Another study reports evidence that pain inhibition in FMS is more pronounced in patients with comorbid depressive symptoms compared to those with FMS alone [39
]. However, due to heterogenic sample selection and different testing methods, the results in regard to pain processing and pain inhibition in chronic pain and mental disorders are inconsistent and partially contradictory [40
]. Therefore, a comprehensive measurement of the clinical manifestation and psychobiological aspects of chronic pain is necessary.
To challenge the topic of a mechanism-based subgroup classification of chronic pain patients and to establish specific mechanism-based treatments [41
], further variables of interest must be considered to guarantee a more holistic approach, compared to that pursued in prior research. Therefore, we developed a theoretical framework (Figure ), which investigates the role of chemical sensitisation (nerve growth factor; NGF) [42
], the endocannabinoid system [47
], and other psychological variables (e.g. early stress exposure, stress and pain coping, resilience) [49
] as well as genetic variables [52
] in addition to mental comorbidity and psychophysiological patterns. NGF is an important key mediator of some forms of persistent pain and plays an important role in the switch from acute to chronic pain as well as the spatial spread of pain [42
]. The endocannabinoid system refers to a group of neuromodulatory lipids that is relevant for pain memory and pain extinction [47
]. Accordingly, these variables have proven to be of interest in chronic pain and to be promising in its treatment. In line with that, the current study addresses the association between the clinical manifestation of chronic musculoskeletal pain (including mental comorbidity) and neurobiological changes.
Theoretical framework of our project.
Therefore, the purpose of the present study is to 1) identify and describe subgroups of patients with musculoskeletal pain with regard to clinical manifestation (including mental comorbidity), 2) investigate whether distinct sensory profiles due to different underlying mechanisms can be distinguished in different subgroups of pain patients 3) and to measure plasma nerve growth factor levels and to analyse distinct endocannabinoid profiles in different subgroups of pain patients.