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Chronic Pain: From Prevention to Therapeutic Strategies

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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 (30 June 2024) | Viewed by 41061

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Dr. Daniel Humberto Pozza

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1. Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
2. Institute for Research and Innovation in Health—I3S, University of Porto, 4200-135 Porto, Portugal
Interests: pain; biomarkers; quantitative sensory tests; cancer
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Prof. Dr. Isaura Tavares

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1. Unit of Experimental Biology, Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
2. IBMC-Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal
Interests: mechanisms of pain modulation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pain is a very complex and fascinating subject with three main components: physical, cognitive and emotional. These components are intrinsically connected and their mutual influences may account for individuality and subjectivity of pain responses.

Acute pain is usually an alert mechanism that protects the body from further tissue injury. On the other hand, chronic pain is considered a disease that is usually difficult to manage. Many chronic pain patients never achieve satisfactory pain relieve. Despite the huge investigation of pain treatment there is still the need for research, namely in chronic pain prevention by establishing the mechanisms involved in the earlier phases of the disease. This may pass from the experimental settings to the clinical. For example, and as to the latter, proper postoperative pain prevention and adequate management starting in the preoperative period is imperative and cancer management may lead to chronic pain, which is not usually prevented. Furthermore, a huge emphasis has been placed in the physical component of pain, whereas cognitive and emotional components of the pain experience are understudied, namely due to the challenges of animal pain models.

This special issue aims to provide the best up-to-date information on research related to prevention of chronic pain. The studies may include experimental and systematic reviews in that field and are expected to include the challenges in animal research, genetic tests, novel biomarkers, predictive sensory testing, cognitive behavioral approaches for emotional component of pain, and individualization of pain patients.

Prof. Dr. Daniel Humberto Pozza
Prof. Dr. Isaura Tavares
Guest Editors

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Keywords

pain pathophysiology
pain prevention
predictive sensory testing
pre- and postoperative chronic pain
new biomarkers in pain
pain management and novel treatments
preemptive analgesia
inflammatory pain

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Published Papers (10 papers)

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Research

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12 pages, 996 KiB

Open AccessArticle

Influence of Age and Sex on Post-Craniotomy Headache

by Jong-Ho Kim, Sung-Woo Han, Young-Suk Kwon, Jae-June Lee and Jong-Hee Sohn

Biomedicines 2024, 12(8), 1745; https://doi.org/10.3390/biomedicines12081745 - 2 Aug 2024

Viewed by 605

Abstract

Post-craniotomy headache (PCH) is a common postoperative complication, and some of these patients progress to chronic PCH (CPCH). We aimed to identify clinical variables associated with PCH and its progression to CPCH, especially possible associations between age and sex differences. Therefore, we examined clinical information on PCH using the Clinical Data Warehouse over 10 years. Of the 1326 patients included, 927 patients (69.9%) experienced PCH. In multivariate analysis for PCH, age was inversely related to risk (p = 0.003), and being female showed a significant association with an increased risk of PCH (p = 0.002). There was also a significant inverse relationship between age and severity of the worst headache, with younger female patients reporting greater severity of the worst headache (p < 0.001). Of the 927 patients who experienced PCH, 319 (34.4%) progressed to CPCH. Sex was a significant factor, with females having a higher risk of developing CPCH compared to males (p < 0.001). In addition, the presence of preoperative headaches significantly increased the risk of CPCH (p = 0.001). The occurrence of PCH is associated with younger age and female sex. In particular, female sex and preoperative headaches increased the risk of developing CPCH. These clinical factors should be considered in patients undergoing neurosurgery. Full article

(This article belongs to the Special Issue Chronic Pain: From Prevention to Therapeutic Strategies)

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14 pages, 1564 KiB

Open AccessArticle

Age- and Sex-Dependent Effects of Moderate Exercise on Endogenous Pain Inhibition in Rats

by Renan F. do Espírito-Santo, Sarah M. Margerison, Youping Zhang, Joshua Pak, Jin Y. Ro and Joyce T. Da Silva

Biomedicines 2024, 12(5), 1122; https://doi.org/10.3390/biomedicines12051122 - 18 May 2024

Viewed by 866

Abstract

Diffuse noxious inhibitory controls (DNICs), or the pain inhibits pain phenomenon, refer to reduced pain-like behaviors that are displayed following a noxious conditioning stimulus located far from the test stimulus and have also been referred to as “descending control of nociception” when measured in awake-behaving animals. In this study, we sought to determine the impact of moderate long-term exercise on the DCN response and determine if this effect differed across age and sex. After a six-week exercise program consisting of 30 min of moderate treadmill running 5 days a week, the animals’ forepaws were injected with capsaicin, and DCN responses were assessed using thermal withdrawal latencies of the hind paw. Young, exercised male and female rats displayed prolonged DCN responses relative to their sedentary counterparts, with the young exercised male group displaying longer-lasting DCN facilitation than the young exercised females. Exercise did not impact DCN responses in either male or female aged rats. Additionally, the serum testosterone levels did not change following exercise in any group. Importantly, the levels of corticosterone did not change following the exercise program, indicating that changes in the DCN response are not due to stress-induced analgesia. Our findings suggest that moderate exercise can facilitate the DCN response in young animals, even when this exercise does not change the levels of serum testosterone. Full article

(This article belongs to the Special Issue Chronic Pain: From Prevention to Therapeutic Strategies)

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20 pages, 5973 KiB

Open AccessArticle

Thalamocortical Mechanisms Underlying Real and Imagined Acupuncture

by Qiao Kong, Valeria Sacca, Kathryn Walker, Sierra Hodges and Jian Kong

Biomedicines 2023, 11(7), 1830; https://doi.org/10.3390/biomedicines11071830 - 26 Jun 2023

Cited by 3 | Viewed by 1751

Abstract

Both acupuncture and imagery have shown potential for chronic pain management. However, the mechanisms underlying their analgesic effects remain unclear. This study aims to explore the thalamocortical mechanisms underlying acupuncture and video-guided acupuncture imagery treatment (VGAIT), a combination of acupuncture and guided imagery, using the resting-state functional connectivity (rsFC) of three thalamic subdivisions—the ventral posterolateral thalamus (VPL), mediodorsal thalamus (MD), and motor thalamus subregion (Mthal)—associated with somatosensory, limbic, and motor circuity. Twenty-seven healthy individuals participated in a within-subject randomized crossover design study. Results showed that compared to sham acupuncture, real acupuncture altered the rsFC between the thalamus and default mode network (DMN) (i.e., mPFC, PCC, and precuneus), as well as the prefrontal and somatosensory cortex (SI/SII). Compared to the VGAIT control, VGAIT demonstrated greater rsFC between the thalamus and key nodes within the interoceptive network (i.e., anterior insula, ACC, PFC, and SI/SII), as well as the motor and sensory cortices (i.e., M1, SMA, and temporal/occipital cortices). Furthermore, compared to real acupuncture, VGAIT demonstrated increased rsFC between the thalamus (VPL/MD/Mthal) and task-positive network (TPN). Further correlations between differences in rsFC and changes in the heat or pressure pain threshold were also observed. These findings suggest that both acupuncture- and VGAIT-induced analgesia are associated with thalamocortical networks. Elucidating the underlying mechanism of VGAIT and acupuncture may facilitate their development, particularly VGAIT, which may be used as a potential remote-delivered pain management approach. Full article

(This article belongs to the Special Issue Chronic Pain: From Prevention to Therapeutic Strategies)

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15 pages, 1201 KiB

Open AccessArticle

Outcomes of a QST Protocol in Healthy Subjects and Chronic Pain Patients: A Controlled Clinical Trial

by Patrícia Dias, Isaura Tavares, Sara Fonseca and Daniel Humberto Pozza

Biomedicines 2023, 11(4), 1023; https://doi.org/10.3390/biomedicines11041023 - 27 Mar 2023

Viewed by 2042

Abstract

Chronic pain is an important cause of disability with a high burden to society. Quantitative sensory testing (QST) is a noninvasive multimodal method used to discriminate the function of nerve fibers. The aim of this study is to propose a new, reproducible, and less time-consuming thermal QST protocol to help characterize and monitor pain. Additionally, this study also compared QST outcomes between healthy and chronic pain subjects. Forty healthy young/adult medical students and fifty adult/elderly chronic pain patients were evaluated in individual sessions including pain history, followed by QST assessments divided into three proposed tests: pain threshold, suprathreshold, and tonic pain. In the chronic pain group, a significantly higher pain threshold (hypoesthesia) and a higher pain sensibility (hyperalgesia) were demonstrated at threshold temperature when compared to healthy participants. The sensitivity to the suprathreshold and tonic stimulus did not prove to be significantly different between both groups. The main results demonstrated that the heat threshold QST tests can be helpful in evaluating hypoesthesia and that the sensitivity threshold temperature test can demonstrate hyperalgesia in individuals with chronic pain. In conclusion, this study demonstrates the importance of using tools such as QST as a complement to detect changes in several pain dimensions. Full article

(This article belongs to the Special Issue Chronic Pain: From Prevention to Therapeutic Strategies)

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20 pages, 10248 KiB

Open AccessArticle

Role of Glutamatergic Projections from Lateral Habenula to Ventral Tegmental Area in Inflammatory Pain-Related Spatial Working Memory Deficits

by Mobina Alemi, Ana Raquel Pereira, Mariana Cerqueira-Nunes, Clara Monteiro, Vasco Galhardo and Helder Cardoso-Cruz

Biomedicines 2023, 11(3), 820; https://doi.org/10.3390/biomedicines11030820 - 8 Mar 2023

Cited by 5 | Viewed by 2722

Abstract

The lateral habenula (LHb) and the ventral tegmental area (VTA), which form interconnected circuits, have important roles in the crucial control of sensory and cognitive motifs. Signaling in the LHb-VTA pathway can be exacerbated during pain conditions by a hyperactivity of LHb glutamatergic neurons to inhibit local VTA DAergic cells. However, it is still unclear whether and how this circuit is endogenously engaged in pain-related cognitive dysfunctions. To answer this question, we modulated this pathway by expressing halorhodopsin in LHb neurons of adult male rats, and then selectively inhibited the axonal projections from these neurons to the VTA during a working memory (WM) task. Behavioral performance was assessed after the onset of an inflammatory pain model. We evaluated the impact of the inflammatory pain in the VTA synapses by performing immunohistochemical characterization of specific markers for GABAergic (GAD65/67) and dopaminergic neurons (dopamine transporter (DAT), dopamine D2 receptor (D2r) and tyrosine hydroxylase (TH)). Our results revealed that inhibition of LHb terminals in the VTA during the WM delay-period elicits a partial recovery of the performance of pain animals (in higher complexity challenges); this performance was not accompanied by a reduction of nociceptive responses. Finally, we found evidence that the pain-affected animals exhibit VTA structural changes, namely with an upregulation of GAD65/67, and a downregulation of DAT and D2r. These results demonstrate a role of LHb neurons and highlight their responsibility in the stability of the local VTA network, which regulates signaling in frontal areas necessary to support WM processes. Full article

(This article belongs to the Special Issue Chronic Pain: From Prevention to Therapeutic Strategies)

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18 pages, 2168 KiB

Open AccessArticle

A Retrospective Clinical Trial Regarding Oral Rehabilitation Diagnosis Strategies Based on Stomatognathic System Pathology

by Iulian Costin Lupu, Laura Elisabeta Checherita, Magda Ecaterina Antohe, Ovidiu Stamatin, Silvia Teslaru, Tudor Hamburda, Eugenia Larisa Tarevici, Bogdan Petru Bulancea, Mioara Trandafirescu, Cristina Gena Dascalu, Magdalena Cuciureanu, Irina Gradinaru, Lucian Stefan Burlea and Alina Elena Jehac

Biomedicines 2023, 11(2), 622; https://doi.org/10.3390/biomedicines11020622 - 19 Feb 2023

Cited by 1 | Viewed by 1997

Abstract

Introduction: Orofacial pain is a common occurrence in daily dental practice; it is frequently attributed to temporomandibular dysfunction, one of its major causes, followed by pathology of the salivary glands, without avoiding interference at the level of the pain pathways caused by complications of periodontal pathology. The main objective of this study is to identify an important cause of pain in the oral–maxillofacial territory by quantifying the changes at the salivary glandular level using stereological methods. The secondary objective of the present research is to identify the implications of periodontal changes as a consequence of salivary quantitative and qualitative changes, quantified using periodontal indices, on the balance of the temporomandibular joint, dysfunction of it being an important cause of facial pain and having a profound impact on the complex oral rehabilitation algorithm of each clinical case, a condition evaluated with the analysis of the results of the Souleroy questionnaire. Material and methods: In a retrospective study, we evaluated the clinical results obtained after applying complex rehabilitation treatment to 35 subjects, 20 women and 15 men with salivary and TMJ dysfunctions, selected between 2020 and 2021 from the Clinic of Maxillofacial Surgery, Iasi. Results and discussion: The most common symptoms of temporomandibular disorders (TMDs) that were identified through the Souleroy questionnaire were pain and different types of damage to the masticatory muscles. The most significant changes in elders are reported in the case of serous cells, which reduced their percentage volume from 46.7% to 37.4%. Conclusion: As regards stereological analysis in conjunction with histological images, there were significant changes in diameters, perimeters, and longitudinal axes in the adult patients as opposed to the elderly patients, which were also influenced by the type of pathology at this level. The scores recorded on the diagnostic Souleroy scale indicated a large number of patients with low efficiency and maximum stress levels: 20.0% in level 1, 25.7% in level 2, and 25.7% in level 3. Full article

(This article belongs to the Special Issue Chronic Pain: From Prevention to Therapeutic Strategies)

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Review

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15 pages, 1460 KiB

Open AccessReview

Pharmacological Proposal Approach to Managing Chronic Pain Associated with COVID-19

by Grisell Vargas-Schaffer

Biomedicines 2023, 11(7), 1812; https://doi.org/10.3390/biomedicines11071812 - 24 Jun 2023

Viewed by 2463

Abstract

Background: Post-COVID syndrome is widespread and chronic pain associated with this syndrome is increasingly being seen in pain clinics. Understanding and managing Chronic Post-COVID Pain (CPCoP) is essential in improving the quality of life of patients. Relevant sections: Identify the types of pain associated with post-COVID syndrome and look for ways to treat them. Results and Discussion: Based on our experience, we have identified five groups within CPCoP: (1) chronic pain post-hospitalization in intensive care or long hospitalizations, (2) pain associated with rehabilitation, (3) exacerbation of existing chronic pain pre-COVID-19 infection, (4) central and peripheral neuropathic pain post-COVID-19 infection, (5) chronic pain post vaccination. To fight against misinformation, we created an information capsule for doctors, nurses, and other health workers at a conference via the ECHO* program, delivered 2–3 times a year. Conclusions: In pandemic and post-pandemic periods, it is important to determine the sequelae that a disease can leave in the general population, and to understand and treat them. The model proposed may serve as an inspiration to other pain centers to treat the increasing number of patients with CPCoP. Full article

(This article belongs to the Special Issue Chronic Pain: From Prevention to Therapeutic Strategies)

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12 pages, 616 KiB

Open AccessReview

Scrotal Pain after Varicocelectomy: A Narrative Review

by Chien-Zhi Lai, Szu-Ju Chen, Chi-Ping Huang, Huey-Yi Chen, Ming-Yen Tsai, Po-Len Liu, Yung-Hsiang Chen and Wen-Chi Chen

Biomedicines 2023, 11(4), 1070; https://doi.org/10.3390/biomedicines11041070 - 1 Apr 2023

Cited by 1 | Viewed by 17468

Abstract

Varicocele is a frequently encountered urological disorder, which has a prevalence rate of 8 to 15% among healthy men. However, the incidence is higher in male patients with primary or secondary infertility, with up to 35 to 80% of varicocele cases occurring in this population. The clinical manifestations of varicocele typically include the presence of an asymptomatic mass that feels like a “bag of worms”, chronic scrotal pain, and infertility. Most patients with varicocele only undergo varicocelectomy after conservative treatments have failed. Unfortunately, some patients may still experience persistent scrotal pain due to a recurrence of varicocele, the development of hydrocele, neuralgia, referred pain, ureteral lesions, or nutcracker syndrome. Therefore, clinicians should consider these conditions as potential causes of postoperative scrotal pain, and take measures to address them. Several factors can assist in predicting surgical outcomes for patients with varicocele. Clinicians should consider these factors when deciding whether to perform surgery and what type of surgical intervention to use. By doing so, they can increase the likelihood of a successful surgical outcome and minimize the risk of complications such as postoperative scrotal pain. Full article

(This article belongs to the Special Issue Chronic Pain: From Prevention to Therapeutic Strategies)

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Other

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25 pages, 3481 KiB

Open AccessSystematic Review

Systematic Review of Platelet-Rich Plasma for Low Back Pain

by Edilson Silva Machado, Fabiano Pasqualotto Soares, Ernani Vianna de Abreu, Taís Amara da Costa de Souza, Robert Meves, Hans Grohs, Mary A. Ambach, Annu Navani, Renato Bevillaqua de Castro, Daniel Humberto Pozza and José Manuel Peixoto Caldas

Biomedicines 2023, 11(9), 2404; https://doi.org/10.3390/biomedicines11092404 - 28 Aug 2023

Cited by 10 | Viewed by 8189

Abstract

Background: Low back pain (LBP) has a high economic burden and is strongly related to the degenerative process of the spine, especially in the intervertebral disc and of the facet joints. Numerous treatment modalities have been proposed for the management of LBP, and the use of platelet-rich plasma (PRP) has emerged as an innovative therapeutic option for degenerative disease of the spine. The present study aims to evaluate the efficacy of PRP injections in managing low back pain. Methods: We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, a registered at PROSPERO Systematic Reviews Platform, under number CRD42021268491. The PubMed, Web of Science, and Scopus databases were searched to identify relevant articles, along with hand searching to identify gray literature articles, with no language restrictions. Randomized clinical trials (RCTs), nonrandomized trials (NRTs), and case series (CSs) with more than 10 patients were considered eligible. The quality assessment and the risk of bias of the randomized clinical trials were evaluated using the RoB II tool. An evaluation of the description of the preparation methods was performed using an adapted version of the MIBO checklist. Results: An electronic database search resulted in 2324 articles, and after the exclusion of noneligible articles, 13 RCTs and 27 NRTs or CSs were analyzed. Of the 13 RCTs, 11 found favorable results in comparison to the control group in pain and disability, one showed no superiority to the control group, and one was discontinued because of the lack of therapeutic effect at eight-week evaluation. Description of the PRP preparation techniques were found in almost all papers. The overall risk of bias was considered high in 2 papers and low in 11. An adapted MIBO checklist showed a 72.7% compliance rate in the selected areas. Conclusions: In this systematic review, we analyzed articles from English, Spanish and Russian language, from large databases and grey literature. PRP was in general an effective and safe treatment for degenerative LPB. Positive results were found in almost studies, a small number of adverse events were related, the risk of bias of the RCTs was low. Based on the evaluation of the included studies, we graded as level II the quality of the evidence supporting the use of PRP in LBP. Large-scale, multicenter RCTs are still needed to confirm these findings. Full article

(This article belongs to the Special Issue Chronic Pain: From Prevention to Therapeutic Strategies)

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7 pages, 247 KiB

Open AccessCase Report

Effects of Whole-Body Cryostimulation on Pain Management and Disease Activity in Active Rheumatic Polymyalgia: A Case-Report

by Federica Verme, Alessandra Scarpa, Giorgia Varallo, Paolo Piterà, Paolo Capodaglio and Jacopo Maria Fontana

Biomedicines 2023, 11(6), 1594; https://doi.org/10.3390/biomedicines11061594 - 31 May 2023

Cited by 6 | Viewed by 1536

Abstract

Polymyalgia rheumatica (PMR) is the most common inflammatory rheumatic disease among people over 50 and occurs with symptoms such as musculoskeletal pain and stiffness in the neck, shoulders, and hips. To date, corticosteroids represent the cornerstone of PMR treatment. However, it is well known that their prolonged use is associated with several adverse effects, making it crucial to find therapeutic alternatives. The purpose of this case report was to describe the effectiveness of 10 whole-body cryostimulation (WBC) sessions on a 74-year-old woman suffering from PMR. An improvement in disease impact, fatigue, pain, quality of sleep, and total physical activity was observed after WBC. Moreover, the patient reduced her daily drug intake by 67% following WBC treatments. Given the increasing prevalence of PMR and considering the side effects that drug treatments can lead to, WBC could represent a valuable adjuvant and well-tolerated alternative for treating PMR. Full article

(This article belongs to the Special Issue Chronic Pain: From Prevention to Therapeutic Strategies)

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