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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (15 June 2023) | Viewed by 27049

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Dr. Mats B. Eriksson

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Department of Surgical Sciences, Anaesthesiogy and Intensive Care Medicine, Uppsala University, 751 85 Uppsala, Sweden
Interests: anesthesiology; biomarkers, coagulation, cytokines, endotoxin; critical care medicine; intensive care; leptin; inflammation, intraosseous; sepsis; SAPS3; shock
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Prof. Dr. Anders O. Larsson

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Department of Medical Sciences, Clinical Chemistry, Uppsala University, 751 85 Uppsala, Sweden
Interests: endotoxin; intensive care; acute kidney injury; glomerular filtration rate markers; kidney tubular damage markers; cardiovascular risk markers; neutrophil activation markers; calprotectin
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Dear Colleagues,

Acute and chronic pain are two major reasons patients seek healthcare. Approximately 20% of the world’s population suffers from chronic pain, and in the USA alone, annual economic losses due to chronic pain are estimated to be 600 billion USD. Apart from being a major economic burden for society, chronic pain is also a major cause of decreased quality of life.

Chronic pain is often difficult to treat, and we have few objective measures for evaluating pain level. Pain patients therefore often struggle to get their pain problems acknowledged, as pain is a subjective experience that is difficult to verify. During the last decade, biomarkers related to chronic pain have been investigated. The discovery of such markers could not only be used to improve diagnoses and prognostication of patients with chronic pain but could also support those who file an insurance claim after an injury. Biomarkers of pain could also be used to distinguish different causes of pain, allowing for improved selection of treatments. Such markers could also provide pharmaceutical companies with a tool for evaluating pain relief effects in clinical trials.

The focus of this Special Issue of Biomedicines is on the value of biomarkers of pain in a broad perspective.

Biomarkers of pain may be used to identify and quantify pain of various origin in order to facilitate adequate therapeutic interventions. Extensive prescription of analgesics, especially opioids, is associated with overdose deaths. Although pain is a subjective experience, the use of determinants of pain as an end point in clinical trials may help to predict safety as well as the analgesic efficacy of new drugs.

Dr. Mats B. Eriksson
Prof. Dr. Anders O. Larsson
Guest Editors

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Keywords

analgesia
biomarker
CSF
cytokine
inflammation
neuropathy
neurotransmitter
pain
QoL
sensitization
sensory

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Related Special Issues

Biomedicines: 10th Anniversary in Biomedicines (46 articles)
Biomarkers in Pain in Biomedicines (1 article)

Published Papers (11 papers)

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Editorial

Jump to: Research, Review, Other

3 pages, 183 KiB

Open AccessEditorial

Biomarkers in Pain

by Anders O. Larsson, Emmanuel Bäckryd and Mats B. Eriksson

Biomedicines 2023, 11(9), 2554; https://doi.org/10.3390/biomedicines11092554 - 18 Sep 2023

Viewed by 1733

Abstract

The focus of this Special Issue on Biomedicines is on the value of “Biomarkers in Pain” from a broad perspective [...] Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Biomarkers in Pain)

Research

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10 pages, 539 KiB

Open AccessEditor’s ChoiceArticle

Cerebrospinal Fluid Metabolomics Identified Ongoing Analgesic Medication in Neuropathic Pain Patients

by Emmanuel Bäckryd, Katarina Thordeman, Björn Gerdle and Bijar Ghafouri

Biomedicines 2023, 11(9), 2525; https://doi.org/10.3390/biomedicines11092525 - 13 Sep 2023

Viewed by 1318

Abstract

Background: Cerebrospinal fluid (CSF) can reasonably be hypothesized to mirror central nervous system pathophysiology in chronic pain conditions. Metabolites are small organic molecules with a low molecular weight. They are the downstream products of genes, transcripts and enzyme functions, and their levels can mirror diseased metabolic pathways. The aim of this metabolomic study was to compare the CSF of patients with chronic neuropathic pain (n = 16) to healthy controls (n = 12). Methods: Nuclear magnetic resonance spectroscopy was used for analysis of the CSF metabolome. Multivariate data analysis by projection discriminant analysis (OPLS-DA) was used to separate information from noise and minimize the multiple testing problem. Results: The significant OPLS-DA model identified 26 features out of 215 as important for group separation (R² = 0.70, Q² = 0.42, p = 0.017 by CV-ANOVA; 2 components). Twenty-one out of twenty-six features were statistically significant when comparing the two groups by univariate statistics and remained significant at a false discovery rate of 10%. For six out of the top ten metabolite features, the features were absent in all healthy controls. However, these features were related to medication, mainly acetaminophen (=paracetamol), and not to pathophysiological processes. Conclusion: CSF metabolomics was a sensitive method to detect ongoing analgesic medication, especially acetaminophen. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Biomarkers in Pain)

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12 pages, 476 KiB

Open AccessArticle

Platelet Membrane Proteins as Pain Biomarkers in Patients with Severe Dementia

by Hugo Ribeiro, Raquel Alves, Joana Jorge, Ana Cristina Gonçalves, Ana Bela Sarmento-Ribeiro, Manuel Teixeira-Veríssimo, Marília Dourado and José Paulo Andrade

Biomedicines 2023, 11(2), 380; https://doi.org/10.3390/biomedicines11020380 - 27 Jan 2023

Cited by 2 | Viewed by 2316

Abstract

Pain is one of the most frequent health problems, and its evaluation and therapeutic approach largely depend on patient self-report. When it is not possible to obtain a self-report, the therapeutic decision becomes more difficult and limited. This study aims to evaluate whether some membrane platelet proteins could be of value in pain characterization. To achieve this goal, we used 53 blood samples obtained from palliative patients, 44 with non-oncological pain and nine without pain. We observed in patients with pain a decrease in the percentage of platelets expressing CD36, CD49f, and CD61 and in the expression levels of CD49f and CD61 when compared with patients without pain. Besides that, an increase in the percentage of platelets expressing CD62p was observed in patients with pain. These results suggest that the levels of these platelet cluster differentiations (CDs) could have some value as pain biomarkers objectively since they are not dependent on the patient’s participation. Likewise, CD40 seems to have some importance as a biomarker of moderate and/or severe pain. The identification of pain biomarkers such as CD40, CD49f, CD62p and CD61 can lead to an adjustment of the therapeutic strategy, contributing to a faster and more adequate control of pain and reduction in patient-associated suffering. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Biomarkers in Pain)

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19 pages, 1403 KiB

Open AccessArticle

Central Sensitization and Psychological State Distinguishing Complex Regional Pain Syndrome from Other Chronic Limb Pain Conditions: A Cluster Analysis Model

by Hana Karpin, Jean-Jacques Vatine, Yishai Bachar Kirshenboim, Aurelia Markezana and Irit Weissman-Fogel

Biomedicines 2023, 11(1), 89; https://doi.org/10.3390/biomedicines11010089 - 29 Dec 2022

Cited by 1 | Viewed by 2678

Abstract

Complex regional pain syndrome (CRPS) taxonomy has been updated with reported subtypes and is defined as primary pain alongside other chronic limb pain (CLP) conditions. We aimed at identifying CRPS clinical phenotypes that distinguish CRPS from other CLP conditions. Cluster analysis was carried out to classify 61 chronic CRPS and 31 CLP patients based on evoked pain (intensity of hyperalgesia and dynamic allodynia, allodynia area, and after-sensation) and psychological (depression, kinesiophobia, mental distress, and depersonalization) measures. Pro-inflammatory cytokine IL-6 and TNF-α serum levels were measured. Three cluster groups were created: ‘CRPS’ (78.7% CRPS; 6.5% CLP); ‘CLP’ (64.5% CLP; 4.9% CRPS), and ‘Mixed’ (16.4% CRPS; 29% CLP). The groups differed in all measures, predominantly in allodynia and hyperalgesia (p < 0.001, η² > 0.58). ‘CRPS’ demonstrated higher psychological and evoked pain measures vs. ‘CLP’. ‘Mixed’ exhibited similarities to ‘CRPS’ in psychological profile and to ‘CLP’ in evoked pain measures. The serum level of TNF-αwas higher in the ‘CRPS’ vs. ‘CLP’ (p < 0.001) groups. In conclusion, pain hypersensitivity reflecting nociplastic pain mechanisms and psychological state measures created different clinical phenotypes of CRPS and possible CRPS subtypes, which distinguishes them from other CLP conditions, with the pro-inflammatory TNF-α cytokine as an additional potential biomarker. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Biomarkers in Pain)

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12 pages, 1568 KiB

Open AccessArticle

FDG PET Imaging of the Pain Matrix in Neuropathic Pain Model Rats

by Yilong Cui, Hiroyuki Neyama, Di Hu, Tianliang Huang, Emi Hayashinaka, Yasuhiro Wada and Yasuyoshi Watanabe

Biomedicines 2023, 11(1), 63; https://doi.org/10.3390/biomedicines11010063 - 27 Dec 2022

Cited by 5 | Viewed by 1820

Abstract

Pain is an unpleasant subjective experience that is usually modified by complex multidimensional neuropsychological processes. Increasing numbers of neuroimaging studies in humans have characterized the hierarchical brain areas forming a pain matrix, which is involved in the different dimensions of pain components. Although mechanistic investigations have been performed extensively in rodents, the homologous brain regions involved in the multidimensional pain components have not been fully understood in the rodent brain. Herein, we successfully identified several brain regions activated in response to mechanical allodynia in neuropathic pain rat models using an alternative neuroimaging method based on 2-deoxy-2-[¹⁸F]fluoro-d-glucose positron emission tomography (FDG PET) scanning. Regions such as the medial prefrontal cortex, primary somatosensory cortex hindlimb region, and the centrolateral thalamic nucleus were identified. Moreover, brain activity in these regions was positively correlated with mechanical allodynia-related behavioral changes. These results suggest that FDG PET imaging in neuropathic pain model rats enables the evaluation of regional brain activity encoding the multidimensional pain aspect. It could thus be a fascinating tool to bridge the gap between preclinical and clinical investigations. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Biomarkers in Pain)

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9 pages, 490 KiB

Open AccessArticle

Association of Pain Phenotypes with Risk of Falls and Incident Fractures

by Maxim Devine, Canchen Ma, Jing Tian, Benny Antony, Flavia Cicuttini, Graeme Jones and Feng Pan

Biomedicines 2022, 10(11), 2924; https://doi.org/10.3390/biomedicines10112924 - 14 Nov 2022

Viewed by 1473

Abstract

Objective: To compare whether falls risk score and incident fracture over 10.7 years were different among three previously identified pain phenotypes. Methods: Data on 915 participants (mean age 63 years) from a population-based cohort study were studied at baseline and follow-ups at 2.6, 5.1 and 10.7 years. Three pain phenotypes were previously identified using the latent class analysis: Class 1: high prevalence of emotional problems and low prevalence of structural damage; Class 2: high prevalence of structural damage and low prevalence of emotional problems; Class 3: low prevalence of emotional problems and low prevalence of structural damage. Fractures were self-reported and falls risk score was measured using the Physiological Profile Assessment. Generalized estimating equations model and linear mixed-effects model were used to compare differences in incident fractures and falls risk score over 10.7 years between pain phenotypes, respectively. Results: There were 3 new hip, 19 vertebral, and 121 non-vertebral fractures, and 138 any site fractures during 10.7-year follow-up. Compared with Class 3, Class 1 had a higher risk of vertebral (relative risk (RR) = 2.44, 95% CI: 1.22–4.91), non-vertebral fractures (RR = 1.20, 95% CI: 1.01–1.42), and any site fractures (RR = 1.24, 95% CI: 1.04–1.46) after controlling for covariates, bone mineral density and falls risk score. Class 2 had a higher risk of non-vertebral and any site fracture relative to those in Class 3 (non-vertebral: RR = 1.41, 95% CI: 1.17–1.71; any site: RR = 1.44, 95% CI: 1.20–1.73), but not vertebral fracture. Compared with Class 3, Class 1 had a higher falls risk score at baseline (β = 0.16, 95% CI: 0.09–0.23) and over 10.7-year (β = 0.03, 95% CI: 0.01–0.04). Conclusions: Class 1 and/or Class 2 had a higher risk of incident fractures and falls risk score than Class 3, highlighting that targeted preventive strategies for fractures and falls are needed in pain population. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Biomarkers in Pain)

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11 pages, 960 KiB

Open AccessArticle

Potential Effects of Non-Surgical Periodontal Therapy on Periodontal Parameters, Inflammatory Markers, and Kidney Function Indicators in Chronic Kidney Disease Patients with Chronic Periodontitis

by Ahmed Chaudhry, Nur Karyatee Kassim, Siti Lailatul Akmar Zainuddin, Haslina Taib, Hanim Afzan Ibrahim, Basaruddin Ahmad, Muhammad Hafiz Hanafi and Azreen Syazril Adnan

Biomedicines 2022, 10(11), 2752; https://doi.org/10.3390/biomedicines10112752 - 29 Oct 2022

Cited by 4 | Viewed by 2283

Abstract

Chronic kidney disease (CKD) and chronic periodontitis (CP) contribute to the increased level of inflammatory biomarkers in the blood. This study hypothesized that successful periodontal treatment would reduce the level of inflammatory biomarkers in CKD patients. This prospective study recruited two groups of CP patients: 33 pre-dialysis CKD patients and 33 non-CKD patients. All patients underwent non-surgical periodontal therapy (NSPT). Their blood samples and periodontal parameters were taken before and after six weeks of NSPT. The serum level of high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), and periodontal parameters were compared between groups. On the other hand, kidney function indicators such as serum urea and estimated glomerular filtration rate (eGFR) were only measured in CKD patients. Clinical periodontal parameters and inflammatory markers levels at baseline were significantly higher (p < 0.05) in the CKD group than in the non-CKD group and showed significant reduction (p < 0.05) after six weeks of NSPT. CKD patients demonstrated a greater periodontitis severity and higher inflammatory burden than non-CKD patients. Additionally, CKD patients with CP showed a good response to NSPT. Therefore, CKD patients’ periodontal health needs to be screened for early dental interventions and monitored accordingly. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Biomarkers in Pain)

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13 pages, 1369 KiB

Open AccessArticle

Thrombin Activity in Rodent and Human Skin: Modified by Inflammation and Correlates with Innervation

by Valery Golderman, Shani Berkowitz, Shani Guly Gofrit, Orna Gera, Shay Anat Aharoni, Daniela Noa Zohar, Daria Keren, Amir Dori, Joab Chapman and Efrat Shavit-Stein

Biomedicines 2022, 10(6), 1461; https://doi.org/10.3390/biomedicines10061461 - 20 Jun 2022

Cited by 2 | Viewed by 1953

Abstract

Thrombin is present in peripheral nerves and is involved in the pathogenesis of neuropathy. We evaluated thrombin activity in skin punch biopsies taken from the paws of male mice and rats and from the legs of patients with suspected small-fiber neuropathy (SFN). In mice, inflammation was induced focally by subcutaneous adjuvant injection to one paw and systemically by intraperitoneal lipopolysaccharides (LPS) administration. One day following injection, thrombin activity increased in the skin of the injected compared with the contralateral and non-injected control paws (p = 0.0009). One week following injection, thrombin increased in both injected and contralateral paws compared with the controls (p = 0.026), coupled with increased heat-sensitivity (p = 0.009). Thrombin activity in the footpad skin was significantly increased one week after systemic administration of LPS compared with the controls (p = 0.023). This was not accompanied by increased heat sensitivity. In human skin, a correlation was found between nerve fiber density and thrombin activity. In addition, a lower thrombin activity was measured in patients with evidence of systemic inflammation compared with the controls (p = 0.0035). These results support the modification of skin thrombin activity by regional and systemic inflammation as well as a correlation with nerve fiber density. Skin thrombin activity measurments may aid in the diagnosis and treatment of SFN. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Biomarkers in Pain)

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11 pages, 1757 KiB

Open AccessArticle

Cerebrospinal Fluid in Classical Trigeminal Neuralgia: An Exploratory Study on Candidate Biomarkers

by Teodor Svedung Wettervik, Dick Folkvaljon, Torsten Gordh, Eva Freyhult, Kim Kultima, Hans Ericson and Sami Abu Hamdeh

Biomedicines 2022, 10(5), 998; https://doi.org/10.3390/biomedicines10050998 - 26 Apr 2022

Cited by 8 | Viewed by 3435

Abstract

Trigeminal neuralgia (TN) is a severe type of facial pain. A neurovascular conflict between cranial nerve V and a nearby vessel is the main pathophysiological mechanism, but additional factors are likely necessary to elicit TN. In this study, the primary aim was to explore differences in protein expression in the cerebrospinal fluid (CSF) of TN patients in relation to controls. Methods: Sixteen TN patients treated with microvascular decompression and 16 control patients undergoing spinal anesthesia for urological conditions were included. Lumbar CSF was collected preoperatively for the TN patients and before spinal anesthesia for the controls. A multiplexed proximity extension analysis of 91 CSF proteins was conducted using Proseek Multiplex Development 96, including biomarkers of cell communication, cell death, neurogenesis, and inflammation Results: The TN patients and the controls were of similar age, sex, and burden of co-morbidities. The TN patients exhibited higher concentrations of Clec11a, LGMN, MFG-E8, and ANGPTL-4 in CSF than the controls (q < 0.05). Conclusions: TN patients exhibited increased CSF biomarkers indicative of peripheral demyelinating injury (Clec11a), immune tolerance and destruction of myelin (LGMN), neuronal cell death (MFG-E8), and disturbances in myelin clearance (ANGPTL-8). Our findings are hypothesis-generating for candidate biomarkers and pathophysiological processes in classical TN. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Biomarkers in Pain)

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Review

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23 pages, 1440 KiB

Open AccessReview

The Role of miRNAs in Neuropathic Pain

by Martina Morchio, Emanuele Sher, David A. Collier, Daniel W. Lambert and Fiona M. Boissonade

Biomedicines 2023, 11(3), 775; https://doi.org/10.3390/biomedicines11030775 - 3 Mar 2023

Cited by 5 | Viewed by 3595

Abstract

Neuropathic pain is a debilitating condition affecting around 8% of the adult population in the UK. The pathophysiology is complex and involves a wide range of processes, including alteration of neuronal excitability and synaptic transmission, dysregulated intracellular signalling and activation of pro-inflammatory immune and glial cells. In the past 15 years, multiple miRNAs–small non-coding RNA–have emerged as regulators of neuropathic pain development. They act by binding to target mRNAs and preventing the translation into proteins. Due to their short sequence (around 22 nucleotides in length), they can have hundreds of targets and regulate several pathways. Several studies on animal models have highlighted numerous miRNAs that play a role in neuropathic pain development at various stages of the nociceptive pathways, including neuronal excitability, synaptic transmission, intracellular signalling and communication with non-neuronal cells. Studies on animal models do not always translate in the clinic; fewer studies on miRNAs have been performed involving human subjects with neuropathic pain, with differing results depending on the specific aetiology underlying neuropathic pain. Further studies using human tissue and liquid samples (serum, plasma, saliva) will help highlight miRNAs that are relevant to neuropathic pain diagnosis or treatment, as biomarkers or potential drug targets. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Biomarkers in Pain)

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Other

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18 pages, 10589 KiB

Open AccessSystematic Review

The Effects of Non-Pharmacological Interventions in Fibromyalgia: A Systematic Review and Metanalysis of Predominants Outcomes

by Isabel Hong-Baik, Edurne Úbeda-D’Ocasar, Eduardo Cimadevilla-Fernández-Pola, Victor Jiménez-Díaz-Benito and Juan Pablo Hervás-Pérez

Biomedicines 2023, 11(9), 2367; https://doi.org/10.3390/biomedicines11092367 - 24 Aug 2023

Cited by 4 | Viewed by 2457

Abstract

(1) Fibromyalgia (FM) is a chronic musculoskeletal condition with multiple symptoms primarily affecting women. An imbalance in cytokine levels has been observed, suggesting a chronic low-grade inflammation. The main aim of the meta-analysis was to examine the effect of multimodal rehabilitation on cytokine levels and other predominant variables in patients with FM. Furthermore, to examine which non-pharmacological tools have been used to investigate the effects that these can have on cytokines in FM patients. (2) Methods: Searches were conducted in PubMed, Scopus, Web of Science, Cochrane, and ScienceDirect databases. This systematic review and metanalysis followed the PRISMA statement protocol. The methodological quality of the studies was assessed using the PEDro scale, the risk of bias followed the Cochrane Manual 5.0.1, and the GRADE system was used for rating the certainty of evidence. (3) Results: Of 318 studies found, eight were finally selected, with a sample size of 320 women with a mean age of 57 ± 20. The proinflammatory cytokines IL-1β, IL-6, IL-8 and TNF-α were the most studied. Resistance exercise, aquatic exercise, dynamic contractions, cycling, treadmill, and infrared therapy were the main non-pharmacological tools used. (4) Conclusions: The systematic review with meta-analysis found evidence of elevated cytokine levels in patients with FM, suggesting low chronic inflammation and a possible contribution to central sensitization and chronic pain. However, the effects of physiotherapeutic interventions on cytokine levels are variable, highlighting the importance of considering different factors and the need for further research. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Biomarkers in Pain)

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