Epigenetic Landscapes of Pain: DNA Methylation Dynamics in Chronic Pain.

Chronic pain is a prevalent condition with a multifaceted pathogenesis, where epigenetic modifications, particularly DNA methylation, might play an important role. This review delves into the intricate mechanisms by which DNA methylation and demethylation regulate genes associated with nociception and pain perception in nociceptive pathways. We explore the dynamic nature of these epigenetic processes, mediated by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes, which modulate the expression of pro- and anti-nociceptive genes. Aberrant DNA methylation profiles have been observed in patients with various chronic pain syndromes, correlating with hypersensitivity to painful stimuli, neuronal hyperexcitability, and inflammatory responses. Genome-wide analyses shed light on differentially methylated regions and genes that could serve as potential biomarkers for chronic pain in the epigenetic landscape. The transition from acute to chronic pain is marked by rapid DNA methylation reprogramming, suggesting its potential role in pain chronicity. This review highlights the importance of understanding the temporal dynamics of DNA methylation during this transition to develop targeted therapeutic interventions. Reversing pathological DNA methylation patterns through epigenetic therapies emerges as a promising strategy for pain management.

Psychological Factors Influencing Healthcare Utilization in Breast Cancer Survivors with Pain.

INTRODUCTION: Pain is a prevalent side-effect seen in breast cancer survivors (BCS). Psychological factors are known role-players in pain mechanisms. Both pain and psychological factors contribute to or interact with healthcare use (HCU). However, the association between psychological factors and HCU has never been investigated in BCS with pain, which is aimed in this study. METHODS: Belgian BCS with pain (n = 122) were assessed by the Medical Consumption Questionnaire, Injustice Experienced Questionnaire, Pain Catastrophizing Scale, Pain Vigilance and Awareness Questionnaire, Brief Illness Perceptions Questionnaire, and the Depression, Anxiety and Stress Scale. Associations were analyzed using logistic and Poisson regressions. RESULTS: Opioid use was related to more catastrophizing and less psychological distress. Psychotropic drug was related to more psychological distress. Endocrine therapy related to less vigilance and awareness. Psychological distress related to all types of healthcare provider (HCP), with psychological distress negatively related to physiotherapy, psychology, and other primary HCP visits, and positively with visiting a general practitioner and secondary HCP. Catastrophizing related to more visiting behavior in primary HCP, except to a general practitioner. Perceived injustice related to more general practitioner and other primary HCP visits, but to fewer psychology visits. Illness perceptions are only related to visiting other primary HCP. Vigilance and awareness was related to more psychologist and secondary HCP visits. CONCLUSION: Our findings underscore the complex interplay between HCU and psychological factors in BCS with pain. Psychological distress was overall the most important psychological factor related to HCU, whether catastrophizing and perceived injustice were the most relevant related to HCP visits.

Cognitive Behavioral Therapy for Insomnia in Pain Management for Nonspecific Chronic Spinal Pain: A Randomized Clinical Trial.

Importance: Insomnia is highly prevalent in patients with nonspecific chronic spinal pain (nCSP). Given the close interaction between insomnia and pain, targeting sleep problems during therapy could improve treatment outcomes. Objective: To evaluate the effectiveness of cognitive behavioral therapy for insomnia (CBTi) integrated in best-evidence pain management (BEPM) vs BEPM only in patients with nCSP and insomnia. Design, Setting, and Participants: A multicenter randomized clinical trial with 1-year follow-up was conducted between April 10, 2018, and April 30, 2022. Data and statistical analysis were performed between May 1, 2022, and April 24, 2023. Patients with nCSP and insomnia were evaluated using self-report and at-home polysomnography, to exclude underlying sleep pathologic factors. Participants were treated at the University Hospital Brussels or University Hospital Ghent, Belgium. Intention-to-treat analysis was performed. Interventions: Participants were randomized to either CBTi-BEPM or BEPM only. Both groups received 18 treatment sessions over 14 weeks. The CBTi-BEPM treatment included 6 CBTi sessions and 12 BEPM sessions. The BEPM treatment included pain neuroscience education (3 sessions) and exercise therapy (9 sessions in the CBTi-BEPM group, 15 sessions in the BEPM-only group). Main Outcomes and Measures: The primary outcome was change in mean pain intensity (assessed with Brief Pain Inventory [BPI]) at 12 months after the intervention. Exploratory secondary outcomes included several pain- and sleep-related outcomes. Blinded outcome assessment took place at baseline, posttreatment, and at 3-, 6-, and 12-month follow-up. Results: A total of 123 patients (mean [SD] age, 40.2 [11.18] years; 84 women [68.3%]) were included in the trial. In 99 participants (80.5%) with 12-month BPI data, the mean pain intensity at 12 months decreased by 1.976 points (reduction of 40%) in the CBTi-BEPM group and 1.006 points (reduction of 24%) points in the BEPM-only group. At 12 months, there was no significant difference in pain intensity change between groups (mean group difference, 0.970 points; 95% CI, -0.051 to 1.992; Cohen d, 2.665). Treatment with CBTi-BEPM resulted in a response for BPI average pain with a number needed to treat (NNT) of 4 observed during 12 months. On a preliminary basis, CBTi-BEPM was, consistently over time and analyses, more effective than BEPM only for improving insomnia severity (Cohen d, 4.319-8.961; NNT for response ranging from 2 to 4, and NNT for remission ranging from 5 to 12), sleep quality (Cohen d, 3.654-6.066), beliefs about sleep (Cohen d, 5.324-6.657), depressive symptoms (Cohen d, 2.935-3.361), and physical fatigue (Cohen d, 2.818-3.770). No serious adverse effects were reported. Conclusions and Relevance: In this randomized clinical trial, adding CBTi to BEPM did not further improve pain intensity reduction for patients with nCSP and comorbid insomnia more than BEPM alone. Yet, as CBTi-BEPM led to significant and clinically important changes in insomnia severity and sleep quality, CBTi integrated in BEPM should be considered in the treatment of patients with nCSP and comorbid insomnia. Further research can investigate the patient characteristics that moderate the response to CBTi-BEPM in terms of pain-related outcomes, as understanding of these moderators may be of utmost clinical importance. Trial Registration: Clinical Trials.gov Identifier: NCT03482856.

The bidirectional relationship between sleep problems and chronic musculoskeletal pain: a systematic review with meta-analysis.

ABSTRACT: Chronic musculoskeletal pain and sleep problems/disorders exhibit a recognized bidirectional relationship; yet, systematic investigations of this claim, particularly in a prospective context, are lacking. This systematic review with meta-analysis aimed to synthesize the literature on the prospective associations between sleep problems/disorders and chronic musculoskeletal pain. A comprehensive search across 6 databases identified prospective longitudinal cohort studies in adults examining the relationship between sleep problems/disorders and chronic musculoskeletal pain. Random-effects meta-analyses, using the Hartung-Knapp adjustment for 95% confidence intervals (CIs), were conducted, and all results were presented as odds ratios (ORs). Certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations approach. Including 16 articles from 11 study populations (116,746 participants), meta-analyses indicated that sleep problems at baseline may heighten the risk of chronic musculoskeletal pain in both short term (OR 1.64, 95% CI 1.01-2.65) and long term (OR 1.39, 95% CI 1.21-1.59). The evidence for different sleep problem categories was very uncertain. Chronic musculoskeletal pain at baseline may increase the risk of short-term sleep problems (OR 1.56, 95% CI 1.02-2.38), but long-term evidence was very uncertain. The impact of only local or only widespread pain on short-term sleep problems was very uncertain, whereas widespread pain may elevate the risk of long-term sleep problems (OR 2.0, 95% CI 1.81-2.21). In conclusion, this systematic review with meta-analysis suggests that sleep problems are associated with an increased risk of chronic musculoskeletal pain, but the bidirectional nature of this relationship requires further investigation.

Phenotyping of chronic pain in breast cancer survivors: an original study using the cancer pain phenotyping (CANPPHE) Network multidisciplinary international guidelines.

PURPOSE: The primary aim of this cross-sectional study is to examine the prevalence of pain phenotypes in breast cancer survivors (BCS). A secondary aim entails examining whether health related quality of life differs between the main pain phenotypes in BCS. METHODS: BCS who experienced chronic pain were asked to complete the numeric pain rating scale for pain, Margolis pain diagram, and short form 36 (SF-36). Following administration of questionnaires and quantitative sensory examinations were applied. To determine the prevalence of the predominant type of pain, a recently proposed classification system by the Cancer Pain Phenotyping (CANPPHE) Network was used. RESULTS: Of the 86 female participants, 19 (22.09%) had dominant neuropathic pain, 18 (20.93%) had dominant nociceptive pain and 14 (16.28%) had dominant nociplastic pain. 35 participants (40.70%) were classified as having mixed pain. One-way ANOVA revealed a significant difference between the four pain groups for the SF-36 general health (F = 3.205, p = 0.027), social functioning (F = 4.093, p = 0.009), and pain (F = 3.603, p = 0.017) subscale scores. CONCLUSION: This study found that pain in BCS was mostly of mixed phenotype, followed by predominantly neuropathic and nociplastic pain. Furthermore, it was found that, compared to BCS with predominant neuropathic and nociceptive pain, BCS with predominant nociplastic pain have lower health related quality of life in the areas of bodily pain and social functioning.

Impaired Carbohydrate Metabolism among Women with Chronic Low Back Pain and the Role of Dietary Carbohydrates: A Randomized Controlled Cross-Over Experiment.

Background: Impaired glucose regulation is suggested to be related to chronic low back pain (CLBP), although it is not clear how they interact with each other. Thus, the primary aim of this study was to investigate differences in postprandial glycemic responses (PPGRs) (the first sign of impaired glucose metabolism) to high- (sucrose) and low-glycemic index (GI) (isomaltulose) beverages in normoglycemic women with CLBP and healthy controls (HCs) and explore whether any group that showed greater PPGRs to high-GI beverage intake would benefit when the high-GI beverage was replaced with a low-GI beverage. Secondly, this study aimed to explore the association between PPGR and pain in patients with CLBP. Methods: This study was registered at clinicaltrials.org (NCT04459104) before the start of the study. In this study, 53 CLBP patients and 53 HCs were recruited. After 11-12 h of fasting, each participant randomly received isomaltulose or sucrose. Blood glucose levels were measured during the fasting state and 15, 30, 45, 60, 90, and 120 min after the beverage intake, and each participant underwent experimental pain measures. Results: Compared to the HCs, the CLBP group showed significantly higher PPGRs to sucrose (p < 0.021). Additionally, the CLBP group showed a significantly higher decrease in PPGR (p = 0.045) when comparing PPGR to sucrose with PPGR to isomaltulose. Correlation analysis revealed a positive association between self-reported pain sensitivity and PPGR to sucrose, while there was no association found between any experimental pain measures and glycemic responses. Conclusions: Overall, these findings suggest that normoglycemic CLBP patients might have a higher risk of developing impaired glucose tolerance than the HCs and might benefit more when high-GI foods are replaced with low-GI ones.

The Role of Anxiety and Depression in Shaping the Sleep-Pain Connection in Patients with Nonspecific Chronic Spinal Pain and Comorbid Insomnia: A Cross-Sectional Analysis.

(1) Background: This exploratory study aims to explore the relationship between nonspecific chronic spinal pain (nCSP) and insomnia symptoms, by examining the interconnections, strengths, and directional dependence of the symptoms. In addition, we aim to identify the key symptoms of the nCSP-insomnia relationship and shed light on the bidirectional nature of this relationship. (2) Methods: This study is a secondary analysis of the baseline data (cross-sectional) from a randomized controlled trial, which examined the added value of Cognitive Behavioral Therapy for Insomnia (CBT-I) combined with cognition-targeted exercise therapy, conducted in collaboration with the Universiteit Gent and Vrije Universiteit Brussel (Belgium). One hundred and twenty-three nCSP patients with comorbid insomnia were recruited through the participating hospitals, advertisements, announcements in local newspapers, pharmacies, publications from support groups, and primary care. To explore the interconnections and directionality between symptoms and the strengths of the relationships, we estimated a regularized Gaussian graphical model and a directed acyclic graph. (3) Results: We found only one direct, but weak, link between sleep and pain, namely, between average pain and difficulties maintaining sleep. (4) Conclusions: Despite the lack of strong direct links between sleep and pain, pain and sleep seem to be indirectly linked via anxiety and depression symptoms, acting as presumable mediators in the network of nCSP and comorbid insomnia. Furthermore, feeling slowed down and fatigue emerged as terminal nodes, implying their role as consequences of the network.

The Mediating Role of Pain Cognitions and Pain Sensitivity in the Treatment Effect of Perioperative Pain Neuroscience Education in People Undergoing Surgery for Lumbar Radiculopathy.

Though perioperative pain neuroscience education (PPNE) positively influences patients' surgical outcomes, little is known about the mechanisms behind this treatment's success. Therefore, this study aims to evaluate the potential mediating role of pain cognitions and pain sensitivity in the treatment effect of PPNE on postoperative quality of life in people undergoing surgery for lumbar radiculopathy. This secondary analysis uses data from 120 participants of a randomized controlled trial who were randomized to receive either PPNE or perioperative biomedical education before undergoing surgery for lumbar radiculopathy. Quality of life was assessed 1-year postsurgery using the short form 36-item health survey (SF36) physical and mental component scores. Potential mediators included pain cognitions (ie, kinesiophobia, pain catastrophizing, and hypervigilance) and pain sensitivity (ie, endogenous nociceptive modulation), assessed 6 weeks postsurgery. Mediation models were constructed using structural equation modeling, and 95% confidence intervals (CIs) were calculated using 10,000 bootstrap samples. Analyses show a significant total effect for PPNE (estimate = .464, 95% CI [.105, .825]) and a significant indirect effect via pain catastrophizing on the SF36 physical component (estimate = .124, 95% CI [.001, .293]). No mediating effect was found through the remaining pain cognitions or pain sensitivity measures. Also, no potential mediators were identified for the treatment effect of PPNE on the SF36 mental component. Our findings suggest that pain catastrophizing mediates the treatment effect of PPNE on physical health-related quality of life in people undergoing surgery for lumbar radiculopathy. PERSPECTIVE: This secondary analysis identified pain catastrophizing as a mediator for PPNE in people undergoing surgery for lumbar radiculopathy. More so, its findings indicate that this educational intervention can enhance the postoperative physical health-related quality of life of these patients by addressing their catastrophizing thoughts. TRIAL REGISTRATION: Clinicaltrials.gov (NCT02630732).

Development of an interdisciplinary training program about chronic pain management with a cognitive behavioural approach for healthcare professionals: part of a hybrid effectiveness-implementation study.

BACKGROUND: Many applied postgraduate pain training programs are monodisciplinary, whereas interdisciplinary training programs potentially improve interdisciplinary collaboration, which is favourable for managing patients with chronic pain. However, limited research exists on the development and impact of interdisciplinary training programs, particularly in the context of chronic pain. METHODS: This study aimed to describe the development and implementation of an interdisciplinary training program regarding the management of patients with chronic pain, which is part of a type 1 hybrid effectiveness-implementation study. The targeted groups included medical doctors, nurses, psychologists, physiotherapists, occupational therapists, dentists and pharmacists. An interdisciplinary expert panel was organised to provide its perception of the importance of formulated competencies for integrating biopsychosocial pain management with a cognitive behavioural approach into clinical practice. They were also asked to provide their perception of the extent to which healthcare professionals already possess the competencies in their clinical practice. Additionally, the expert panel was asked to formulate the barriers and needs relating to training content and the implementation of biopsychosocial chronic pain management with a cognitive behavioural approach in clinical practice, which was complemented with a literature search. This was used to develop and adapt the training program to the barriers and needs of stakeholders. RESULTS: The interdisciplinary expert panel considered the competencies as very important. Additionally, they perceived a relatively low level of healthcare professionals' possession of the competencies in their clinical practice. A wide variety of barriers and needs for stakeholders were formulated and organized within the Theoretical Domain Framework linked to the COM-B domains; 'capability', 'opportunity', and 'motivation'. The developed interdisciplinary training program, including two workshops of seven hours each and two e-learning modules, aimed to improve HCP's competencies for integrating biopsychosocial chronic pain management with a cognitive behavioural approach into clinical practice. CONCLUSION: We designed an interdisciplinary training program, based on formulated barriers regarding the management of patients with chronic pain that can be used as a foundation for developing and enhancing the quality of future training programs.

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?

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.

Personalized Multimodal Lifestyle Intervention as the Best-Evidenced Treatment for Chronic Pain: State-of-the-Art Clinical Perspective.

Chronic pain is the most prevalent disease worldwide, leading to substantial disability and socioeconomic burden. Therefore, it can be regarded as a public health disease and major challenge to scientists, clinicians and affected individuals. Behavioral lifestyle factors, such as, physical (in)activity, stress, poor sleep and an unhealthy diet are increasingly recognized as perpetuating factors for chronic pain. Yet, current management options for patients with chronic pain often do not address lifestyle factors in a personalized multimodal fashion. This state-of-the-art clinical perspective aims to address this gap by discussing how clinicians can simultaneously incorporate various lifestyle factors into a personalized multimodal lifestyle intervention for individuals with chronic pain. To do so the available evidence on (multimodal) lifestyle interventions targeting physical (in)activity, stress, sleep and nutritional factors, specifically, was reviewed and synthetized from a clinical point of view. First, advise is provided on how to design a personalized multimodal lifestyle approach for a specific patient. Subsequently, best-evidence recommendations on how to integrate physical (in)activity, stress, sleep and nutritional factors as treatment targets into a personalized multimodal lifestyle approach are outlined. Evidence supporting such a personalized multimodal lifestyle approach is growing, but further studies are needed.

Comparing physical therapy students' attitudes and beliefs regarding chronic low back pain and knee osteoarthritis: an international multi-institutional comparison between 2013 and 2020 academic years.

BACKGROUND: In 2013, physical therapy students demonstrated low guideline-adherent recommendations regarding chronic low back pain (CLBP) for spinal pathology, activity, and work. OBJECTIVES: To assess the differences in physical therapy students' attitudes, beliefs, and adherence to guideline recommendations regarding CLBP and knee osteoarthritis between 2013 and 2020. METHODS: In 2013 and 2020, second and fourth-year physical therapy students were recruited from 6 Belgian and 2 Dutch institutions. Attitudes and beliefs regarding CLBP and knee OA were evaluated using the Pain Attitudes and Beliefs Scale for Physiotherapists (PABS-PT), the Health Care Providers' Pain and Impairment Relationship Scale (HC-PAIRS), and a questionnaire regarding therapeutic exercise and knee osteoarthritis. A clinical vignette was used to measure guideline-adherent recommendations regarding spinal pathology, activity, and work. RESULTS: In 2013, 927 second-year and 695 fourth-year students; in 2020, 695 second-year and 489 fourth-year students; were recruited to participate in the study. Compared to 2013, students had less biomedical and stronger biopsychosocial attitudes and beliefs regarding CLBP, more guideline-adherent recommendations for activity, and more biopsychosocial beliefs regarding the benefits of exercise for patients with knee osteoarthritis in both the second and fourth year. Only fourth-year students in 2020 scored significantly better on HC-PAIRS and guideline-adherent recommendation relating to spinal pathology. No differences were found regarding work recommendations. CONCLUSIONS: Between 2013 and 2020, physical therapy students made a positive shift towards a more biopsychosocial approach to CLBP and knee osteoarthritis management. Guideline-adherent recommendations for CLBP concerning activity improved, however, concerning work and spinal pathology, it remained low.

Nociceptive, neuropathic, or nociplastic low back pain? The low back pain phenotyping (BACPAP) consortium's international and multidisciplinary consensus recommendations.

The potential to classify low back pain as being characterised by dominant nociceptive, neuropathic, or nociplastic mechanisms is a clinically relevant issue. Preliminary evidence suggests that these low back pain phenotypes might respond differently to treatments; however, more research must be done before making specific recommendations. Accordingly, the low back pain phenotyping (BACPAP) consortium was established as a group of 36 clinicians and researchers from 13 countries (five continents) and 29 institutions, to apply a modified Nominal Group Technique methodology to develop international and multidisciplinary consensus recommendations to provide guidance for identifying the dominant pain phenotype in patients with low back pain, and potentially adapt pain management strategies. The BACPAP consortium's recommendations are also intended to provide direction for future clinical research by building on the established clinical criteria for neuropathic and nociplastic pain. The BACPAP consortium's consensus recommendations are a necessary early step in the process to determine if personalised pain medicine based on pain phenotypes is feasible for low back pain management. Therefore, these recommendations are not ready to be implemented in clinical practice until additional evidence is generated that is specific to these low back pain phenotypes.

The Role of the Brain-Derived Neurotrophic Factor in Chronic Pain: Links to Central Sensitization and Neuroinflammation.

Chronic pain is sustained, in part, through the intricate process of central sensitization (CS), marked by maladaptive neuroplasticity and neuronal hyperexcitability within central pain pathways. Accumulating evidence suggests that CS is also driven by neuroinflammation in the peripheral and central nervous system. In any chronic disease, the search for perpetuating factors is crucial in identifying therapeutic targets and developing primary preventive strategies. The brain-derived neurotrophic factor (BDNF) emerges as a critical regulator of synaptic plasticity, serving as both a neurotransmitter and neuromodulator. Mounting evidence supports BDNF's pro-nociceptive role, spanning from its pain-sensitizing capacity across multiple levels of nociceptive pathways to its intricate involvement in CS and neuroinflammation. Moreover, consistently elevated BDNF levels are observed in various chronic pain disorders. To comprehensively understand the profound impact of BDNF in chronic pain, we delve into its key characteristics, focusing on its role in underlying molecular mechanisms contributing to chronic pain. Additionally, we also explore the potential utility of BDNF as an objective biomarker for chronic pain. This discussion encompasses emerging therapeutic approaches aimed at modulating BDNF expression, offering insights into addressing the intricate complexities of chronic pain.