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The Biology of Chronic Pain: Applications in Clinical Practice

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Clinical Neurology".

Deadline for manuscript submissions: closed (25 May 2023) | Viewed by 55127

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Special Issue Editors

Dr. Andrea Polli

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Guest Editor

1. Pain in Motion Research Group (PAIN), Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium
2. Department of Public Health and Primary Care, Centre for Environment & Health, KU Leuven, Leuven, Belgium
3. Flanders Research Foundation (FWO), Brussels, Belgium
Interests: chronic pain; epigenetics; DNA methylation; exercise

Prof. Dr. Jo Nijs

E-Mail Website
Guest Editor

1. Pain in Motion Research Group (PAIN), Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium
2. Department of Physical Medicine and Physiotherapy, University Hospital Brussels, Brussels, Belgium
3. Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Interests: chronic pain; central sensitization; sleep
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Dear Colleagues,

Chronic pain is one of the most prevalent diseases worldwide, leading to suffering, disability and enormous social costs. Science has tremendously advanced our understanding of the pathophysiology of chronic pain. Breakthrough findings include functional and structural brain changes, neuro-inflammation, sensory changes, immune alterations, psychological problems, neurocognitive disorders, stress intolerance, sleep impairments, and (epi)genetic changes found in patients with chronic pain.

This Journal of Clinical Medicine Boutique Special Issue focuses on the exciting, broad field of the biology of chronic pain in humans. The Special Issue will include invited state-of-the-art papers, each addressing a key biological process of relevance to patients with chronic pain. These state-of-the-art papers are written by leading experts and key opinion leaders in the field, and will boost the impact and exposure of all papers to be included in the Special Issue. This Special Issue offers a unique opportunity to contribute to the breakthrough area of chronic pain, in sectors including, but not limited to: neuroimaging, neurophysiology, genetics, epigenetics, nutritional biology, stress physiology, sleep physiology, psychoneuroimmunology, immunology, and exercise physiology, among others.

We welcome submissions from anywhere in the world, as long as the focus of the paper is on the biology of chronic pain in humans. In line with the journal’s scope, preclinical studies cannot be considered. Manuscript formats can vary from literature reviews (systematic literature reviews, meta-analyses, narrative reviews, or perspective articles) to original research (trials, cohort studies, experimental lab work, case–control studies) and consensus statements, as long as they are of high quality and focused on the biology of chronic pain in humans. Case reports and study protocols cannot be included. Authors publishing in this Special Issue will contribute to an exciting area of tremendous advancements!

Dr. Andrea Polli
Prof. Dr. Jo Nijs
Guest Editors

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

neuroimaging
neurophysiology
genetics
epigenetics
stress physiology
sleep physiology
psychoneuroimmunology
immunology
chronic pain
stress
sleep
insomnia
exercise physiology
nutrition
pediatric pain
cancer pain
musculoskeletal pain
postsurgical pain
rheumatic pain
osteoarthritis
rheumatoid arthritis

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Published Papers (10 papers)

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Research

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20 pages, 1498 KiB

Open AccessArticle

The Role of Back Muscle Dysfunctions in Chronic Low Back Pain: State-of-the-Art and Clinical Implications

by Thomas Matheve, Paul Hodges and Lieven Danneels

J. Clin. Med. 2023, 12(17), 5510; https://doi.org/10.3390/jcm12175510 - 24 Aug 2023

Cited by 17 | Viewed by 6862

Abstract

Changes in back muscle function and structure are highly prevalent in patients with chronic low back pain (CLBP). Since large heterogeneity in clinical presentation and back muscle dysfunctions exists within this population, the potential role of back muscle dysfunctions in the persistence of low back pain differs between individuals. Consequently, interventions should be tailored to the individual patient and be based on a thorough clinical examination taking into account the multidimensional nature of CLBP. Considering the complexity of this process, we will provide a state-of-the-art update on back muscle dysfunctions in patients with CLBP and their implications for treatment. To this end, we will first give an overview of (1) dysfunctions in back muscle structure and function, (2) the potential of exercise therapy to address these dysfunctions, and (3) the relationship between changes in back muscle dysfunctions and clinical parameters. In a second part, we will describe a framework for an individualised approach for back muscle training in patients with CLBP. Full article

(This article belongs to the Special Issue The Biology of Chronic Pain: Applications in Clinical Practice)

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28 pages, 1851 KiB

Open AccessArticle

Current Evidence for Biological Biomarkers and Mechanisms Underlying Acute to Chronic Pain Transition across the Pediatric Age Spectrum

by Irina T. Duff, Kristen N. Krolick, Hana Mohamed Mahmoud and Vidya Chidambaran

J. Clin. Med. 2023, 12(16), 5176; https://doi.org/10.3390/jcm12165176 - 9 Aug 2023

Cited by 1 | Viewed by 2254

Abstract

Chronic pain is highly prevalent in the pediatric population. Many factors are involved in the transition from acute to chronic pain. Currently, there are conceptual models proposed, but they lack a mechanistically sound integrated theory considering the stages of child development. Objective biomarkers are critically needed for the diagnosis, risk stratification, and prognosis of the pathological stages of pain chronification. In this article, we summarize the current evidence on mechanisms and biomarkers of acute to chronic pain transitions in infants and children through the developmental lens. The goal is to identify gaps and outline future directions for basic and clinical research toward a developmentally informed theory of pain chronification in the pediatric population. At the outset, the importance of objective biomarkers for chronification of pain in children is outlined, followed by a summary of the current evidence on the mechanisms of acute to chronic pain transition in adults, in order to contrast with the developmental mechanisms of pain chronification in the pediatric population. Evidence is presented to show that chronic pain may have its origin from insults early in life, which prime the child for the development of chronic pain in later life. Furthermore, available genetic, epigenetic, psychophysical, electrophysiological, neuroimaging, neuroimmune, and sex mechanisms are described in infants and older children. In conclusion, future directions are discussed with a focus on research gaps, translational and clinical implications. Utilization of developmental mechanisms framework to inform clinical decision-making and strategies for prevention and management of acute to chronic pain transitions in children, is highlighted. Full article

(This article belongs to the Special Issue The Biology of Chronic Pain: Applications in Clinical Practice)

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16 pages, 1832 KiB

Open AccessArticle

Sex Differences in Opioid Response Linked to OPRM1 and COMT genes DNA Methylation/Genotypes Changes in Patients with Chronic Pain

by Laura Agulló, Javier Muriel, César Margarit, Mónica Escorial, Diana Garcia, María José Herrero, David Hervás, Juan Sandoval and Ana M. Peiró

J. Clin. Med. 2023, 12(10), 3449; https://doi.org/10.3390/jcm12103449 - 13 May 2023

Cited by 6 | Viewed by 2479

Abstract

Analgesic-response variability in chronic noncancer pain (CNCP) has been reported due to several biological and environmental factors. This study was undertaken to explore sex differences linked to OPRM1 and COMT DNA methylation changes and genetic variants in analgesic response. A retrospective study with 250 real-world CNCP outpatients was performed in which data from demographic, clinical, and pharmacological variables were collected. DNA methylation levels (CpG island) were evaluated by pyrosequencing, and their interaction with the OPRM1 (A118G) and COMT (G472A) gene polymorphisms was studied. A priori-planned statistical analyses were conducted to compare responses between females and males. Sex-differential OPRM1 DNA methylation was observed to be linked to lower opioid use disorder (OUD) cases for females (p = 0.006). Patients with lower OPRM1 DNA methylation and the presence of the mutant G-allele reduced opioid dose requirements (p = 0.001), equal for both sexes. Moreover, COMT DNA methylation levels were negatively related to pain relief (p = 0.020), quality of life (p = 0.046), and some adverse events (probability > 90%) such as constipation, insomnia, or nervousness. Females were, significantly, 5 years older with high anxiety levels and a different side-effects distribution than males. The analyses demonstrated significant differences between females and males related to OPRM1 signalling efficiency and OUD, with a genetic–epigenetic interaction in opioid requirements. These findings support the importance of sex as a biological variable to be factored into chronic pain-management studies. Full article

(This article belongs to the Special Issue The Biology of Chronic Pain: Applications in Clinical Practice)

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Review

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14 pages, 947 KiB

Open AccessReview

Towards a Real-Life Understanding of the Altered Functional Behaviour of the Default Mode and Salience Network in Chronic Pain: Are People with Chronic Pain Overthinking the Meaning of Their Pain?

by Elin Johansson, Huan-Yu Xiong, Andrea Polli, Iris Coppieters and Jo Nijs

J. Clin. Med. 2024, 13(6), 1645; https://doi.org/10.3390/jcm13061645 - 13 Mar 2024

Viewed by 3399

Abstract

Chronic pain is a source of substantial physical and psychological suffering, yet a clear understanding of the pathogenesis of chronic pain is lacking. Repeated studies have reported an altered behaviour of the salience network (SN) and default mode network (DMN) in people with chronic pain, and a majority of these studies report an altered behaviour of the dorsal ventromedial prefrontal cortex (vmPFC) within the anterior DMN. In this topical review, we therefore focus specifically on the role of the dorsal vmPFC in chronic pain to provide an updated perspective on the cortical mechanisms of chronic pain. We suggest that increased activity in the dorsal vmPFC may reflect maladaptive overthinking about the meaning of pain for oneself and one’s actions. We also suggest that such overthinking, if negative, may increase the personal “threat” of a given context, as possibly reflected by increased activity in, and functional connectivity to, the anterior insular cortex within the SN. Full article

(This article belongs to the Special Issue The Biology of Chronic Pain: Applications in Clinical Practice)

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13 pages, 1196 KiB

Open AccessReview

Central Sensitization in Cancer Survivors and Its Clinical Implications: State of the Art

by Tomohiko Nishigami, Masahiro Manfuku and Astrid Lahousse

J. Clin. Med. 2023, 12(14), 4606; https://doi.org/10.3390/jcm12144606 - 11 Jul 2023

Cited by 3 | Viewed by 2328

Abstract

Although the prevalence of cancer pain is 47% after treatment, cancer pain is often underestimated, and many patients are undertreated. The complexity of cancer pain contributes to the lack of its management. Recently, as the mechanism of cancer pain, it has become clear that central sensitization (CS) influences chronic pain conditions and the transition from acute to chronic pain. In this state-of-the-art review, we summarized the association of CS or central sensitivity syndrome with pain and the treatment for pain targeting CS in cancer survivors. The management of patients with CS should not only focus on tissue damage in either the affected body regions or within the central nervous system; rather, it should aim to target the underlying factors that sustain the CS process. Pain neuroscience education (PNE) is gaining popularity for managing chronic musculoskeletal pain and could be effective for pain and CS in breast cancer survivors. However, there is a study that did not demonstrate significant improvements after PNE, so further research is needed. Precision medicine involves the classification of patients into subgroups based on a multifaceted evaluation of disease and the implementation of treatment tailored to the characteristics of each patient, which may play a central role in the treatment of CS. Full article

(This article belongs to the Special Issue The Biology of Chronic Pain: Applications in Clinical Practice)

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25 pages, 2434 KiB

Open AccessReview

Habituation to Pain in Patients with Chronic Pain: Clinical Implications and Future Directions

by Maite M. van der Miesen, Catherine J. Vossen and Elbert A. Joosten

J. Clin. Med. 2023, 12(13), 4305; https://doi.org/10.3390/jcm12134305 - 27 Jun 2023

Cited by 5 | Viewed by 2042

Abstract

In this review, the latest insights into habituation to pain in chronic pain are summarized. Using a systematic search, results of studies on the evidence of habituation to (experimental) pain in migraine, chronic low back pain, fibromyalgia, and a variety of chronic pain indications are presented. In migraine, reduced habituation based on self-report and the EEG-based N1 and N2–P2 amplitude is reported, but the presence of contradictory results demands further replication in larger, well-designed studies. Habituation to pain in chronic low back pain seems not to differ from controls, with the exception of EEG measures. In fibromyalgia patients, there is some evidence for reduced habituation of the N2–P2 amplitude. Our analysis shows that the variability between outcomes of studies on habituation to pain is high. As the mechanisms underlying habituation to pain are still not fully understood and likely involve several pathways, it is now too early to conclude that habituation to pain is related to clinical outcomes and can be used as a diagnostic marker. The review ends with a discussion on future directions for research including the use of standard outcome measures to improve comparisons of habituation to pain in patients and controls, as well as a focus on individual differences. Full article

(This article belongs to the Special Issue The Biology of Chronic Pain: Applications in Clinical Practice)

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14 pages, 1116 KiB

Open AccessReview

The Biology of Chronic Pain and Its Implications for Pain Neuroscience Education: State of the Art

by Kory Zimney, Wouter Van Bogaert and Adriaan Louw

J. Clin. Med. 2023, 12(13), 4199; https://doi.org/10.3390/jcm12134199 - 21 Jun 2023

Cited by 12 | Viewed by 7654

Abstract

Pain is an individualized experience for the person suffering from chronic pain. Significant strides have been made in the last few decades in understanding various biological changes that coincide with chronic pain. This state-of-the-art overview looks at the current evidence related to the biology of chronic pain and the implications these findings have on the delivery of pain neuroscience education (PNE). The paper summarizes the various (epi)genetic, neural, endocrine, and immune factors discovered and explored in the scientific literature concerning chronic pain. Each of these biological factors has various implications for the content and delivery of PNE. We discuss the future directions these biological factors have for the clinical implementation of PNE by linking the importance of behavior change, optimizing the learning environment, and using an individualized multimodal treatment approach with PNE. In addition, future directions for research of PNE based on these biological factors are provided with importance placed on individualized patient-centered care and how PNE can be used with traditional modes of care and growing trends with other care methods. PNE was originally and continues to be rooted in understanding chronic pain biology and how that understanding can improve patient care and outcomes. Full article

(This article belongs to the Special Issue The Biology of Chronic Pain: Applications in Clinical Practice)

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24 pages, 2123 KiB

Open AccessReview

The Biology of Placebo and Nocebo Effects on Experimental and Chronic Pain: State of the Art

by Giacomo Rossettini, Francesco Campaci, Joel Bialosky, Eva Huysmans, Lene Vase and Elisa Carlino

J. Clin. Med. 2023, 12(12), 4113; https://doi.org/10.3390/jcm12124113 - 18 Jun 2023

Cited by 20 | Viewed by 6042

Abstract

(1) Background: In recent years, placebo and nocebo effects have been extensively documented in different medical conditions, including pain. The scientific literature has provided strong evidence of how the psychosocial context accompanying the treatment administration can influence the therapeutic outcome positively (placebo effects) or negatively (nocebo effects). (2) Methods: This state-of-the-art paper aims to provide an updated overview of placebo and nocebo effects on pain. (3) Results: The most common study designs, the psychological mechanisms, and neurobiological/genetic determinants of these phenomena are discussed, focusing on the differences between positive and negative context effects on pain in experimental settings on healthy volunteers and in clinical settings on chronic pain patients. Finally, the last section describes the implications for clinical and research practice to maximize the medical and scientific routine and correctly interpret the results of research studies on placebo and nocebo effects. (4) Conclusions: While studies on healthy participants seem consistent and provide a clear picture of how the brain reacts to the context, there are no unique results of the occurrence and magnitude of placebo and nocebo effects in chronic pain patients, mainly due to the heterogeneity of pain. This opens up the need for future studies on the topic. Full article

(This article belongs to the Special Issue The Biology of Chronic Pain: Applications in Clinical Practice)

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15 pages, 1134 KiB

Open AccessReview

The Biology of Stress Intolerance in Patients with Chronic Pain—State of the Art and Future Directions

by Arne Wyns, Jolien Hendrix, Astrid Lahousse, Elke De Bruyne, Jo Nijs, Lode Godderis and Andrea Polli

J. Clin. Med. 2023, 12(6), 2245; https://doi.org/10.3390/jcm12062245 - 14 Mar 2023

Cited by 16 | Viewed by 11738

Abstract

Stress has been consistently linked to negative impacts on physical and mental health. More specifically, patients with chronic pain experience stress intolerance, which is an exacerbation or occurrence of symptoms in response to any type of stress. The pathophysiological mechanisms underlying this phenomenon remain unsolved. In this state-of-the-art paper, we summarised the role of the autonomic nervous system (ANS) and hypothalamus-pituitary-adrenal (HPA) axis, the two major stress response systems in stress intolerance. We provided insights into such mechanisms based on evidence from clinical studies in both patients with chronic pain, showing dysregulated stress systems, and healthy controls supported by preclinical studies, highlighting the link between these systems and symptoms of stress intolerance. Furthermore, we explored the possible regulating role for (epi)genetic mechanisms influencing the ANS and HPA axis. The link between stress and chronic pain has become an important area of research as it has the potential to inform the development of interventions to improve the quality of life for individuals living with chronic pain. As stress has become a prevalent concern in modern society, understanding the connection between stress, HPA axis, ANS, and chronic health conditions such as chronic pain is crucial to improve public health and well-being. Full article

(This article belongs to the Special Issue The Biology of Chronic Pain: Applications in Clinical Practice)

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18 pages, 1028 KiB

Open AccessReview

The Putative Role of Neuroinflammation in the Interaction between Traumatic Brain Injuries, Sleep, Pain and Other Neuropsychiatric Outcomes: A State-of-the-Art Review

by Alberto Herrero Babiloni, Andrée-Ann Baril, Camille Charlebois-Plante, Marianne Jodoin, Erlan Sanchez, Liesbet De Baets, Caroline Arbour, Gilles J. Lavigne, Nadia Gosselin and Louis De Beaumont

J. Clin. Med. 2023, 12(5), 1793; https://doi.org/10.3390/jcm12051793 - 23 Feb 2023

Cited by 14 | Viewed by 6564

Abstract

Sleep disturbances are widely prevalent following a traumatic brain injury (TBI) and have the potential to contribute to numerous post-traumatic physiological, psychological, and cognitive difficulties developing chronically, including chronic pain. An important pathophysiological mechanism involved in the recovery of TBI is neuroinflammation, which leads to many downstream consequences. While neuroinflammation is a process that can be both beneficial and detrimental to individuals’ recovery after sustaining a TBI, recent evidence suggests that neuroinflammation may worsen outcomes in traumatically injured patients, as well as exacerbate the deleterious consequences of sleep disturbances. Additionally, a bidirectional relationship between neuroinflammation and sleep has been described, where neuroinflammation plays a role in sleep regulation and, in turn, poor sleep promotes neuroinflammation. Given the complexity of this interplay, this review aims to clarify the role of neuroinflammation in the relationship between sleep and TBI, with an emphasis on long-term outcomes such as pain, mood disorders, cognitive dysfunctions, and elevated risk of Alzheimer’s disease and dementia. In addition, some management strategies and novel treatment targeting sleep and neuroinflammation will be discussed in order to establish an effective approach to mitigate long-term outcomes after TBI. Full article

(This article belongs to the Special Issue The Biology of Chronic Pain: Applications in Clinical Practice)

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