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Meta-Analysis
. 2021 Jan 4;4(1):e2032236.
doi: 10.1001/jamanetworkopen.2020.32236.

Brain Responses to Noxious Stimuli in Patients With Chronic Pain: A Systematic Review and Meta-analysis

Anna Xu  1 , Bart Larsen  1 , Alina Henn  2 , Erica B Baller  1   3   4 , J Cobb Scott  1   5 , Vaishnavi Sharma  1 , Azeez Adebimpe  1 , Allan I Basbaum  6 , Gregory Corder  1 , Robert H Dworkin  7 , Robert R Edwards  8 , Clifford J Woolf  9   10 , Simon B Eickhoff  11   12 , Claudia R Eickhoff  12   13 , Theodore D Satterthwaite  1
Affiliations
Meta-Analysis

Brain Responses to Noxious Stimuli in Patients With Chronic Pain: A Systematic Review and Meta-analysis

Anna Xu et al. JAMA Netw Open. .

Abstract

Importance: Functional neuroimaging is a valuable tool for understanding how patients with chronic pain respond to painful stimuli. However, past studies have reported heterogenous results, highlighting opportunities for a quantitative meta-analysis to integrate existing data and delineate consistent associations across studies.

Objective: To identify differential brain responses to noxious stimuli in patients with chronic pain using functional magnetic resonance imaging (fMRI) while adhering to current best practices for neuroimaging meta-analyses.

Data sources: All fMRI experiments published from January 1, 1990, to May 28, 2019, were identified in a literature search of PubMed/MEDLINE, EMBASE, Web of Science, Cochrane Library, PsycINFO, and SCOPUS.

Study selection: Experiments comparing brain responses to noxious stimuli in fMRI between patients and controls were selected if they reported whole-brain results, included at least 10 patients and 10 healthy control participants, and used adequate statistical thresholding (voxel-height P < .001 or cluster-corrected P < .05). Two independent reviewers evaluated titles and abstracts returned by the search. In total, 3682 abstracts were screened, and 1129 full-text articles were evaluated.

Data extraction and synthesis: Thirty-seven experiments from 29 articles met inclusion criteria for meta-analysis. Coordinates reporting significant activation differences between patients with chronic pain and healthy controls were extracted. These data were meta-analyzed using activation likelihood estimation. Data were analyzed from December 2019 to February 2020.

Main outcomes and measures: A whole-brain meta-analysis evaluated whether reported differences in brain activation in response to noxious stimuli between patients and healthy controls were spatially convergent. Follow-up analyses examined the directionality of any differences. Finally, an exploratory (nonpreregistered) region-of-interest analysis examined differences within the pain network.

Results: The 37 experiments from 29 unique articles included a total of 511 patients and 433 controls (944 participants). Whole-brain meta-analyses did not reveal significant differences between patients and controls in brain responses to noxious stimuli at the preregistered statistical threshold. However, exploratory analyses restricted to the pain network revealed aberrant activity in patients.

Conclusions and relevance: In this systematic review and meta-analysis, preregistered, whole-brain analyses did not reveal aberrant fMRI activity in patients with chronic pain. Exploratory analyses suggested that subtle, spatially diffuse differences may exist within the pain network. Future work on chronic pain biomarkers may benefit from focus on this core set of pain-responsive areas.

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Conflict of interest statement

Conflict of Interest Disclosures: Ms Xu reported receiving grants from ACTTION (Analgesic, Anesthetic, and Addition Clinical Trial Translations, Innovations, Opportunities, and Networks) during the conduct of the study. Dr Corder reported receiving grants from the Alkermes Pathways Research Award program, the Whitehall Foundation, and the Brain and Behavior Research Foundation outside the submitted work. Dr Dworkin reported receiving grants from the US Food and Drug Administration (FDA) during the conduct of the study and personal fees from Abide, Acadia Pharmaceuticals, Inc, Adynxx, Inc, Analgesic Solutions, LLC, Aptinyx, Inc, Aquinox Pharmaceuticals, Asahi Kasei Corporation, Astellas Pharma, Inc, AstraZeneca, Biogen, Inc, Biohaven Pharmaceuticals, Boston Scientific Corporation, Braeburn, Inc, Celgene Corporation, Centrexion Therapeutics Corp, Chromocell Corporation, Clexio Biosciences, Ltd, Concert Pharmaceuticals, Inc, Coronado, Daiichi Sankyo Company, Limited, Decibel Therapeutics, Dong-A, Editas Medicine, Eli Lilly & Company, Eupraxia Pharmaceuticals, Glenmark Pharmaceuticals, Limited, W. R. Grace & Co, Hope Pharmaceuticals, Hydra, Immune Pharmaceuticals, Inc, Johnson & Johnson, Lotus Clinical Research, Mainstay, Medavante Technologies, Inc, Merck & Co, Neumentum, Inc, Neurana Pharmaceuticals, NeuroBo Pharmaceuticals, Inc, Novaremed AG, Novartis International AG, NSGene A/S, Olatec, Periphagen, Pfizer, Inc, Phosphagenics, Quark Pharmaceuticals, Reckitt Benckiser Group plc, Regenacy Pharmaceuticals, Relmada Therapeutics, Inc, Sanifit, Scilex Pharmaceuticals, Semnur Pharmaceuticals, Inc, SK Life Science, Inc, Sollis Therapeutics, Spinifex Pharma, Syntrix Pharmaceuticals, Teva Pharmaceuticals, Thar Pharmaceuticals, Inc, Theranexus, Trevena, Inc, Vertex Pharmaceuticals, Inc, and Vizuri Health Sciences, LLC, and having equity in Regenacy Pharmaceuticals outside the submitted work. Dr Woolf reported being a founder and equity holder in Nocion Therapeutics outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Flowchart Detailing Screening Process
In total, 37 experiments from 29 articles were included in the meta-analysis.
Figure 2.
Figure 2.. Distribution of Foci From Experiments Reporting Differences in Responses to Experimentally Induced Pain Between Patients With Chronic Pain and Healthy Controls
Peak coordinates of clusters where activation was reported to be different between patients and controls had a broad spatial distribution. Red foci represent coordinates in experiments reporting greater pain responses in patients, whereas blue foci denote locations in experiments reporting reduced pain responses in patients.
Figure 3.
Figure 3.. Unthresholded Maps of Differences Between Patients With Chronic Pain and Healthy Controls
Maps display unthresholded associations from analyses. No between-group differences were significant at our preregistered statistical threshold (voxel height, P < .001; familywise error–corrected cluster significance, P < .05). However, pain-related regions appeared to be enriched for (nonsignificant) associations, which motivated post hoc regional analyses.
Figure 4.
Figure 4.. Post hoc Regional Analyses of Pain Network
Histogram displays the distribution of the sum of activation likelihood estimation (ALE) scores within the pain network under the null distribution derived from spatial permutations. The observed value from our meta-analysis shows that our summed ALE score within the pain network exceeds that expected from the null distribution. This suggests a significant convergence of aberrant activity within the pain network in patients with chronic pain. Inset displays the pain network mask, defined by a prior meta-analysis of brain responses to pain in healthy volunteers.
See this image and copyright information in PMC

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References

    1. Jackson TP, Stabile VS, McQueen KAK. The global burden of chronic pain. ASA Newsl. 2014;78(6):24-27.
    1. Goldberg DS, McGee SJ. Pain as a global public health priority. BMC Public Health. 2011;11(1):770. doi:10.1186/1471-2458-11-770 - DOI - PMC - PubMed
    1. Volkow ND, Koroshetz WJ. The role of neurologists in tackling the opioid epidemic. Nat Rev Neurol. 2019;15(5):301-305. doi:10.1038/s41582-019-0146-8 - DOI - PubMed
    1. Apkarian AV. The brain in chronic pain: clinical implications. Pain Manag. 2011;1(6):577-586. doi:10.2217/pmt.11.53 - DOI - PMC - PubMed
    1. Lee MC, Tracey I. Unravelling the mystery of pain, suffering, and relief with brain imaging. Curr Pain Headache Rep. 2010;14(2):124-131. doi:10.1007/s11916-010-0103-0 - DOI - PubMed

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