Accepted

Epidemiological studies have to a little extent addressed the potential fluctuations of chronic pain over time, and there is a lack of information about the long-term course of pain using repeated measurements. We wanted to identify different trajectories of pain during eight waves of follow-up over four years among individuals in the general population reporting pain lasting at least six months at baseline. Secondarily, we wanted to investigate whether biopsychosocial factors at baseline were associated with the different pain trajectories. Longitudinal Latent Class Analysis (LLCA) was performed to classify 1905 random participants from a larger population-based study (HUNT3) into groups based on their longitudinal pain severity reporting. A five-class solution gave the best fit. The terms chosen to describe the pain trajectories were: "fluctuating" (n = 586 [31 %]), "persistent mild" (n = 449 [24 %]), "persistent moderate" (n = 414 [22 %]), "persistent severe" (n = 251 [13 %]), and "gradual improvement" (n = 205 [11 %]). In a multinomial logistic regression model using "gradual improvement" as the reference category, the "persistent moderate", "persistent severe", and "fluctuating" pain groups were associated with chronic widespread pain (CWP), elevated levels of catastrophizing, and poorer mental health. The "persistent mild" group was associated with sleep difficulties only. This study finds that although most individuals have a stable pain course, individuals in the largest distinct trajectory reports pain that fluctuate between mild and moderate levels, thus fluctuating under and above the chronic pain definition using moderate pain or more as a criterion. Perspective: When examining the long-term course of chronic pain in the general population, five trajectories emerge. Although most individuals have stable pain, the largest distinct trajectory fluctuated under and above the chronic pain cut-off, using moderate pain or more as a criterion. A dichotomous categorization of chronic pain may be overly simplistic.

Specific components of physical activity, such as vigorous exercise and heavy occupational work, are known to increase the risk of chronic low back pain (CLBP) and knee pain (CKP), but impacts of other components are less known. This study aimed to assess the relationship between total physical activity and risk of CLBP and CKP from a public health perspective.

Non-invasive measures of neuroinflammatory processes in humans could substantially aid diagnosis and therapeutic development for many disorders, including chronic pain. Several proton Magnetic Resonance Spectroscopy (H-MRS) metabolites have been linked with glial activity (i.e. choline and myo-inositol) and found to be altered in chronic pain patients, but their role in the neuroinflammatory cascade is not well known. Our multimodal study evaluated resting fMRI connectivity and H-MRS metabolite concentration in insula cortex in 43 patients suffering from fibromyalgia, a chronic centralized pain disorder previously demonstrated to include a neuroinflammatory component, and 16 healthy controls. Patients demonstrated elevated choline (but not myo-inositol) in anterior insula (p=0.03), with greater choline levels linked with worse pain interference (r=0.41, p=0.01). In addition, reduced resting functional connectivity between anterior insula and putamen was associated with both pain interference (whole brain analysis, pcorrected<0.01) and elevated anterior insula choline (r=-0.37, p=0.03). In fact, anterior insula/putamen connectivity statistically mediated the link between anterior insula choline and pain interference (p<0.01), highlighting the pathway by which neuroinflammation can impact clinical pain dysfunction. In order to further elucidate the molecular substrates of the effects observed, we investigated how putative neuroinflammatory H-MRS metabolites are linked with ex-vivo tissue inflammatory markers in a nonhuman primate model of neuroinflammation. Results demonstrated that cortical choline levels were correlated with glial fibrillary acidic protein, a known marker for astrogliosis (Spearman r=0.49, p=0.03). Choline, a putative neuroinflammatory H-MRS assessed metabolite elevated in fibromyalgia and associated with pain interference, may be linked with astrogliosis in these patients.

Complex regional pain syndrome (CRPS) is a debilitating chronic pain disorder typically in the upper or lower limbs. Whilst CRPS usually develops from a peripheral event, it is likely maintained by central nervous system changes. Indeed CRPS is reported to be associated with sensorimotor cortex changes, or functional 'reorganisation', as well as deficits such as poor tactile acuity. Whilst the mechanisms underpinning cortical reorganisation in CRPS are unknown, some have hypothesised that it involves disinhibition, i.e. a reduction in gamma-Aminobutyric acid (GABA) activity. In this study we addressed this hypothesis by using edited magnetic resonance spectroscopy (MRS) to determine sensorimotor GABA and glutamate concentrations in 16 humans with CRPS and 30 matched controls and the relationship of these concentrations with tactile acuity. We found that individuals with upper limb CRPS displayed reduced tactile acuity in the painful hand compared with the non-painful hand and pain-free controls. Despite this acuity deficit, CRPS was not associated with altered GABA or glutamate concentrations within the sensorimotor cortex on either the side that represents the affected or unaffected hand. Furthermore, there was no significant relationship between sensorimotor GABA or glutamate concentrations and tactile acuity in CRPS or control subjects. Although our sample was small, these data suggest that CRPS is not associated with altered total sensorimotor GABA or glutamate concentrations. Whilst these results are at odds with the sensorimotor cortex disinhibition hypothesis, it is possible that GABAergic mechanisms other than total GABA concentration may contribute to such disinhibition. Complex regional pain syndrome is a debilitating chronic pain disorder that usually affects the limbs. It is associated with altered sensorimotor cortex function including reorganisation and reduced tactile acuity, which are thought to result from reduced on-going inhibition. However, we found that this pain condition is not associated with reduced on-going sensorimotor inhibition in the form of gamma-Aminobutyric acid concentration, the major inhibitory neurotransmitter in the brain. These findings strongly suggest that changes in sensorimotor function in individuals with complex regional pain syndrome are explained by factors other than neurotransmitter concentration.