Accepted

Changes in gait characteristics have been reported in people with chronic neck pain (CNP).

It was not until the twentieth century that pain was considered a disease. Before that it was managed medically as a symptom. The motivations for declaring chronic pain a disease, whether of the body or of the brain, include increasing its legitimacy as clinical problem and research focus worthy of attention from healthcare and research organizations alike. But one problem with disease concepts is that having a disease favors medical solutions and tends to reduce patient participation. We argue that chronic pain, particularly chronic primary pain (recently designated a first tier pain diagnosis in ICD 11), is a learned state that is not intransigent even if it has biological correlates. Chronic pain is sometimes a symptom, and may sometimes be its own disease. But here we question the value of a disease focus for much of chronic pain for which patient involvement is essential, and which may need a much broader societal approach than is suggested by the disease designation. PERSPECTIVE: This article examines whether designating chronic pain a disease of the body or brain is helpful or harmful to patients. Can the disease designation help advance treatment, and is it needed to achieve future therapeutic breakthrough? Or does it make patients over-reliant on medical intervention and reduce their engagement in the process of recovery?

Neuroimaging is a powerful tool to investigate potential associations between chronic pain and brain structure. However, the proliferation of studies across diverse chronic pain syndromes and heterogeneous results challenges data integration and interpretation. We conducted a preregistered anatomic likelihood estimate meta-analysis on structural magnetic imaging studies comparing patients with chronic pain and healthy controls. Specifically, we investigated a broad range of measures of brain structure as well as specific alterations in gray matter and cortical thickness. A total of 7,849 abstracts of experiments published between January 1, 1990 and April 26, 2021 were identified from eight databases and evaluated by two independent reviewers. Overall, 103 experiments with a total of 5,075 participants met the pre-registered inclusion criteria. After correction for multiple comparisons using the gold standard family-wise error correction (p < .05), no significant differences associated with chronic pain were found. However, exploratory analyses using threshold-free cluster enhancement revealed several spatially distributed clusters showing structural alterations in chronic pain. The majority of clusters coincided with regions implicated in nociceptive processing including the amygdala, thalamus, hippocampus, insula, anterior cingulate cortex and inferior frontal gyrus. Taken together, these results suggest that chronic pain is associated with subtle, spatially distributed alterations of brain structure.

Previous studies have reported sex differences in irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) patients, including differences in visceral pain perception. Despite this, sex differences in behavioral manifestations of visceral pain and underlying pathology of the gastrointestinal tract have been largely understudied in preclinical research. In this study, we evaluated potential sex differences in spontaneous nociceptive responses, referred abdominal hypersensitivity, disease progression and bowel pathology in mouse models of acute and persistent colon inflammation. Our experiments show that females exhibit more nociceptive responses and referred abdominal hypersensitivity than males in the context of acute but not persistent colon inflammation. We further demonstrate that, following acute and persistent colon inflammation, pain-related behavioral responses in females and males are distinct, with increases in licking of the abdomen only observed in females and increases in abdominal contractions only seen in males. During persistent colon inflammation, males exhibit worse disease progression than females, which is manifested as worse physical appearance and higher weight loss. However, no measurable sex differences were observed in persistent inflammation-induced bowel pathology, stool consistency or fecal blood. Overall, our findings demonstrate sex differences in pain-related behaviors and disease progression in the context of acute and persistent colon inflammation, highlighting the importance of considering sex as a biological variable in future mechanistic studies of visceral pain as well as in the development of diagnostics and therapeutic options for chronic gastrointestinal diseases.

Predicting the development of chronic low back pain (LBP) at the time of an acute episode remains challenging. The Understanding persistent Pain Where it ResiDes (UPWaRD) study aimed to identify neurobiological and psychological risk factors for chronic LBP. Individuals with acute LBP (N=120) participated in a prospective cohort study with six-month follow-up. Candidate predictors were selected from the neurobiological (e.g. sensorimotor cortical excitability assessed by sensory and motor evoked potentials, Brain Derived Neurotrophic Factor genotype), psychological (e.g. depression and anxiety), symptom-related (e.g. LBP history) and demographic domains. Analyses involved multivariable linear regression models with pain intensity or disability degree as continuous variables. Secondary analyses involved a multivariable logistic model with presence of low back pain at six months (thresholding pain intensity and disability degree) as a dichotomous variable. Lower sensory cortex and corticomotor excitability, higher baseline pain intensity, higher depression, stress and pain catastrophizing were the strongest predictors (R2=0.47) of pain intensity at six months. Older age and higher pain catastrophizing were the strongest predictors (R2=0.30) of disability at six months. When LBP outcome was dichotomised, sensory cortex and corticomotor excitability, BDNF genotype, depression and anxiety, LBP history and baseline pain intensity, discriminated between those who did and did not report LBP at six months (c-statistic 0.91). This study identifies novel risk factors for the development of future LBP. Neurobiological risk factors, when added to a multivariable linear regression model, explained a further 15% of the variance in six-month pain intensity.