John Lawrence Kipling Kramer

Chronic pain affects most individuals with spinal cord injury (SCI) and frequently impairs daily function, and nearly half experience neuropathic pain. Neuropathic pain is commonly thought to develop months after injury and to persist once established. These views rest on classifying each patient as having neuropathic pain or not, although patients often report several pains. The same binary label is the usual target of prognostic and biomarker studies that aim to predict life-limiting pain. We tracked up to three of the worst pains per interview from injury to one year in 140 TRACK-SCI participants, using the DN4 interview (DN4i, threshold 3). Within three days of injury, half of all pain areas and three quarters of participants met the threshold, and pain-area prevalence changed little over the year. Individual pains, however, often changed. Only a third remained above the threshold throughout, one third resolved or fluctuated, and pains in the same person often followed different courses. At more than half of interviews with several pains, one pain met the threshold while another did not, so that the patient’s classification depended on the pain considered. We therefore derived a threshold-free Pain Composite Score from the DN4i items and pain intensity. The items formed a single dimension, and the composite was associated with sleep and mood interference whereas the binary classification was not. Neuropathic pain after SCI thus appears early, does not invariably persist, and differs between a person’s pains, and graded pain-level measures may offer a more stable target for predicting life-limiting pain. Summary: Neuropathic pain after spinal cord injury appears early and does not always persist. A threshold-free score, unlike binary classification, tracks how pain limits daily life.

Chronic pain is a leading contributor to all-cause morbidity and disability, encompassing numerous biopsychosocial dimensions that persistently engage complex networks of brain regions. Meta-analyses have advanced our understanding of structural brain differences in chronic pain but rely exclusively on summary statistics which may introduce heterogeneity related to completeness of reporting and differences in methodological approaches. To address these limitations, we conducted the first individual participant data (IPD) meta-analysis of brain structure alterations in chronic pain. Using traditional morphometric measures (i.e. volume, cortical thickness, and surface area) and differential-geometric shape metrics (i.e. intrinsic and extrinsic curvature), we aimed to reveal alterations in brain structure convergent across chronic pain conditions. We hypothesized that chronic pain would be associated with region-specific grey matter reductions in regions previously implicated in chronic pain (e.g. parahippocampal gyrus and insula) and explored whether curvature metrics would reveal additional structural changes. Anatomical MRI images from eight publicly available datasets spanning five conditions and 401 individuals with chronic pain (and 245 age- and sex- matched healthy controls) were analysed: (i) knee osteoarthritis, (ii) chronic low back pain, (iii) fibromyalgia, (iv) migraine, and (v) primary trigeminal neuralgia. FreeSurfer was used to parcellate T1-weighted anatomical images, and metrics for cortical and subcortical regions were extracted. Meta-analysis revealed a range of structural changes in the brain associated with chronic pain. Cortical thinning and volume loss were small and localized to the temporo-occipital regions, including bilateral volumetric reductions in the entorhinal cortex in individuals with chronic pain. Increases in intrinsic curvature were widespread, involving 49 out of 68 cortical regions. No significant alterations were detected in subcortical volumes. Intrinsic curvature and subcortical volumetric estimates had higher levels of inter-study heterogeneity compared to other metrics, reflecting potential condition and sample-specific variability. Leveraging harmonized processing across a large sample size, our novel IPD meta-analysis highlights both widespread and region-specific structural remodelling of chronic pain-related neuroanatomy.

Study Design Retrospective cohort study. Objectives The primary objective was to examine changes in gabapentinoid prescribing among individuals with acute spinal cord injury. The secondary objective was to examine the effects of gabapentinoid prescriptions on neurological recovery. Setting Intensive Care Unit, Vancouver General Hospital, British Columbia, Canada. Methods Individuals admitted between 2010 and 2019 with cervical spinal cord injuries were identified from the Rick Hansen Spinal Cord Injury Registry (RHSCIR). The primary outcome was first gabapentinoid prescription following injury, and exposure was year of injury. The secondary outcome was recovery in sensorimotor function, measured by changes in American Spinal Injury Association (ASIA) Impairment Scale (AIS) grades between admission and discharge. We analyzed associations between gabapentinoid prescriptions and year of injury using Cox regression, and neurological recovery using multivariable logistic regression. Results Of 257 individuals with cervical spinal cord injury, 79% (n = 204) were prescribed a gabapentinoid within 30 days of injury. Rates of gabapentinoid prescription in the 30 days following injury increased from 41% in 2010/2011 to 93% in 2018/2019. In a subgroup analysis of individuals with incomplete injuries, early (i.e., hyperacute; <5 days post-injury) gabapentinoid use was significantly associated with greater neurological recovery (adjusted OR = 2.9, 95% CI, 1.1 to 7.9). Conclusions Gabapentinoid prescribing in acute spinal cord injury shifted markedly between 2010 and 2019, and was associated with improved neurological recovery in individuals with incomplete injuries. Further study is warranted to assess prescribing practices at other acute care hospitals and to characterize long-term safety.

Background: Evaluating safety of emerging interventions is important in clinical trials. To support reporting of safety outcomes, a harms extension of the Consolidated Standards of Reporting Trial (CONSORT) guidelines was published in 2004. Objective: To examine safety reporting in pivotal trials of disease-modifying therapies (DMTs) in patients with multiple sclerosis (MS). Methods: Published phase III clinical trials from 1995 to 2022 included in FDA approval material for MS DMTs were compiled and reviewed by two independent examiners. Criteria derived from the CONSORT harms extension were used to evaluate safety reporting. Linear regression was applied to examine associations between quality of safety reporting and study level factors. Results: 30 publications were included in the analysis. Overall, safety reporting quality was fair with an average score of 10.2 out of 15. Trials examining small molecule versus biologic interventions ( p = 0.001) and recent publication ( p = 0.005) were associated with higher quality reporting. Items related to laboratory-defined toxicity and defining adverse events were among reporting items notably lacking (present in 53% and 40% of publications, respectively). Conclusion: While the reporting of phase III clinical trials for DMTs for the treatment of MS has improved with time, there remain gaps and opportunities for further improvement.

Meta-analyses are a valuable tool in evidence-based research and have contributed to our understanding of structural brain changes in chronic pain. Meta-analyses are also limited by published summary statistics and quality/completeness of underlying studies. To address these limitations, we conducted the first individual participant data (IPD) meta-analysis of brain structure alterations in chronic pain. Using traditional morphometric measures (i.e., volume, cortical thickness, and surface area) and differential-geometric shape metrics (i.e., intrinsic and extrinsic curvature), we aimed to reveal alterations in brain structure convergent across chronic pain conditions. Eight publicly available datasets spanning five conditions and 401 individuals with chronic pain were analyzed: 1) knee osteoarthritis, 2) chronic low back pain, 3) fibromyalgia, 4) migraine, and 5) primary trigeminal neuralgia. FreeSurfer was used to parcellate T1-weighted anatomical images, and metrics for cortical and subcortical structures were extracted. Meta-analysis of study-level comparisons revealed a range of structural changes in the brain associated with chronic pain. Cortical thinning and volume loss were small and localized to the temporo-occipital regions, including bilateral volumetric reductions in the entorhinal cortex. Increases in intrinsic curvature were widespread, involving 49 out of 68 cortical regions. No significant alterations were detected in subcortical volumes. Intrinsic curvature and subcortical volumetric estimates had higher levels of inter-study heterogeneity compared to other metrics, reflecting potential condition and sample specific variability. Leveraging harmonized processing across a large sample size, our novel IPD meta-analysis highlights both widespread and region-specific structural remodeling of chronic pain-related neuroanatomy.

Our findings support a proactive suppression model of attention under unpredictability, in which cognitive resources are reallocated via enhanced alpha activity that aims to suppress forthcoming sensory processing to facilitate motor preparation of goal-directed movement. Furthermore, neural preparatory activity returns to baseline with the removal of pain suggesting preparatory activity is dynamic and current measures only provide a read-out of transient cortical states.

This scientific commentary refers to ‘Combinatorial approaches increasing neuronal activity accelerate recovery after spinal cord injury’ by Chen et al. (https://doi.org/10.1093/brain/awaf099).

Kramer et al. examine the reasons put forth by investigators for excluding a sham condition in trials of neuromodulation therapies for individuals with spinal cord injury. They conclude that current dogma does not justify this design, and emphasize the need for future trials to include appropriate controls.

In a large, sex-balanced sample of healthy individuals, we demonstrate that average regional differences (rostral to caudal) in cingulate cortex glutamate exist, using optimized experimental conditions and 3 T magnetic resonance spectroscopy techniques. Results align with observations from 7 T. A novel clustering approach was introduced to determine the number of patterns for glutamate in the healthy adult brain for the first time. These findings demonstrate that regional differences are detectable at 3 T when present and suggest the occurrence of multiple glutamate metabolism patterns in the cingulate.