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Chronic Pain: From Prevention to Therapeutic Strategies—Second Edition

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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: 31 July 2025 | Viewed by 6858

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Dr. Isaura Tavares

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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: mechanisms of pain modulation

Dr. Daniel Humberto Pozza

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Guest Editor

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 the 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 relief. Despite the extensive 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 setting to the clinical. For example, and with regard 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 on 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. Studies may include experimental and comprehensive reviews in this field and are expected to include the challenges related to animal research, genetic tests, novel biomarkers, predictive sensory testing, cognitive behavioral approaches for emotional component of pain, and individualization of pain patients.

Dr. Isaura Tavares
Dr. Daniel Humberto Pozza
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 (5 papers)

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Research

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12 pages, 552 KiB

Open AccessArticle

Effectiveness of Generative Artificial Intelligence-Driven Responses to Patient Concerns in Long-Term Opioid Therapy: Cross-Model Assessment

by Giuliano Lo Bianco, Christopher L. Robinson, Francesco Paolo D’Angelo, Marco Cascella, Silvia Natoli, Emanuele Sinagra, Sebastiano Mercadante and Filippo Drago

Biomedicines 2025, 13(3), 636; https://doi.org/10.3390/biomedicines13030636 - 5 Mar 2025

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Abstract

Background: While long-term opioid therapy is a widely utilized strategy for managing chronic pain, many patients have understandable questions and concerns regarding its safety, efficacy, and potential for dependency and addiction. Providing clear, accurate, and reliable information is essential for fostering patient understanding and acceptance. Generative artificial intelligence (AI) applications offer interesting avenues for delivering patient education in healthcare. This study evaluates the reliability, accuracy, and comprehensibility of ChatGPT’s responses to common patient inquiries about opioid long-term therapy. Methods: An expert panel selected thirteen frequently asked questions regarding long-term opioid therapy based on the authors’ clinical experience in managing chronic pain patients and a targeted review of patient education materials. Questions were prioritized based on prevalence in patient consultations, relevance to treatment decision-making, and the complexity of information typically required to address them comprehensively. We assessed comprehensibility by implementing the multimodal generative AI Copilot (Microsoft 365 Copilot Chat). Spanning three domains—pre-therapy, during therapy, and post-therapy—each question was submitted to GPT-4.0 with the prompt “If you were a physician, how would you answer a patient asking…”. Ten pain physicians and two non-healthcare professionals independently assessed the responses using a Likert scale to rate reliability (1–6 points), accuracy (1–3 points), and comprehensibility (1–3 points). Results: Overall, ChatGPT’s responses demonstrated high reliability (5.2 ± 0.6) and good comprehensibility (2.8 ± 0.2), with most answers meeting or exceeding predefined thresholds. Accuracy was moderate (2.7 ± 0.3), with lower performance on more technical topics like opioid tolerance and dependency management. Conclusions: While AI applications exhibit significant potential as a supplementary tool for patient education on opioid long-term therapy, limitations in addressing highly technical or context-specific queries underscore the need for ongoing refinement and domain-specific training. Integrating AI systems into clinical practice should involve collaboration between healthcare professionals and AI developers to ensure safe, personalized, and up-to-date patient education in chronic pain management. Full article

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

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11 pages, 601 KiB

Open AccessArticle

Predictive Model for Opioid Use Disorder in Chronic Pain: A Development and Validation Study

by Mónica Escorial, Javier Muriel, César Margarit, Laura Agulló, Thomas Zandonai, Ana Panadero, Domingo Morales and Ana M. Peiró

Biomedicines 2024, 12(9), 2056; https://doi.org/10.3390/biomedicines12092056 - 10 Sep 2024

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Abstract

Background/Objective: There are several questionnaires for the challenge of anticipating opioid use disorder (OUD). However, many are not specific for chronic non-cancer pain (CNCP) or have been developed in the American population, whose sociodemographic factors are very different from the Spanish population, leading to scarce translation into clinical practice. Thus, the aim of this study is to prospectively validate a predictive model for OUD in Spanish patients under long-term opioids. Methods: An innovative two-stage predictive model was developed from retrospective (n = 129) and non-overlapping prospective (n = 100) cohorts of real-world CNCP outpatients. All subjects used prescribed opioids for 6 or more months. Sociodemographic, clinical and pharmacological covariates were registered. Mu-opioid receptor 1 (OPRM1, A118G, rs1799971) and catechol-O-methyltransferase (COMT, G472A, rs4680) genetic variants plus cytochrome P450 2D6 (CYP2D6) liver enzyme phenotypes were also analyzed. The model performance and diagnostic accuracy were calculated. Results: The two-stage model comprised risk factors related to OUD (younger age, work disability and high daily opioid dose) and provided new useful information about other risk factors (low quality of life, OPRM-G allele and CYP2D6 extreme phenotypes). The validation showed a satisfactory accuracy (70% specificity and 75% sensitivity) for our predictive model with acceptable discrimination and goodness of fit. Conclusions: Our study presents the results of an innovative model for predicting OUD in our setting. After external validation, it could represent a change in the paradigm of opioid treatment, helping clinicians to better identify and manage the risks and reduce the side effects and complications. Full article

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

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15 pages, 2171 KiB

Open AccessArticle

Green Light Exposure Reduces Primary Hyperalgesia and Proinflammatory Cytokines in a Rodent Model of Knee Osteoarthritis: Shedding Light on Sex Differences

by Laura Ventura, Renan F. do Espírito-Santo, Michael Keaser, Youping Zhang, Jin Y. Ro and Joyce T. Da Silva

Biomedicines 2024, 12(9), 2005; https://doi.org/10.3390/biomedicines12092005 - 3 Sep 2024

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Abstract

Knee osteoarthritis (OA) often causes chronic pain that disproportionately affects females. Proinflammatory cytokines TNF-α, IL-1β, and IL-6 are key effectors of OA pathological changes. Green light shows potential as an alternative intervention for various pain conditions. However, no studies have investigated green light′s analgesic effects in both sexes in chronic knee OA. We induced unilateral knee OA with intra-articular injection of monoiodoacetate (MIA) in male and female Sprague-Dawley rats. Two days post-injection, the rats were exposed to green-light-emitting diodes (GLED) or ambient room light eight hours daily for 24 days. Knee mechanical sensitivity was assessed using a small animal algometer. Blood serum concentrations of TNF-α, IL-1β, IL-6, and IL-10 were quantified at baseline and 23 days post-injection. MIA injection decreased the knee mechanical thresholds of the male and female rats. GLED exposure attenuated mechanical hypersensitivity in both sexes compared to the controls; however, GLED-induced analgesia occurred sooner and with greater magnitude in males than in females. In both sexes, the analgesic effects of green light lasted 5 days after the final GLED session. Finally, GLED exposure reversed the elevation of serum proinflammatory cytokines. These findings suggest that GLED exposure reduces primary hyperalgesia in OA, potentially by lowering proinflammatory cytokines, and indicate sex differences in GLED-induced analgesia. Full article

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

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Figure 1
GLED exposure attenuates mechanical hypersensitivity in male (left) and female (right) rats in the MIA model of osteoarthritis. Mechanical thresholds of the knee were assessed before and after MIA injection. The male rats exposed to GLED exhibited a significant reduction in mechanical hypersensitivity after five sessions (Day 6), while the females showed a significant reduction at the 11th GLED session (Day 12), compared to their ARL counterparts. The GLED′s analgesic effects were maintained 5 days after therapy termination. Group data were staggered for readability; all the groups were tested at the same time points. Each point represents data from one animal. The horizontal bars show the mean and the error bars show ± SD. n = 6–7 (* p < 0.05, ** p < 0.005, *** p < 0.0005, **** p < 0.0001 for group differences; # p < 0.05, ## p < 0.005, ### p < 0.0005, #### p < 0.0001 BL versus time points in ARL group, & p < 0.05 BL vs. time points in GLED group). BL = baseline. Full article ">Figure 2
The percentage change in mechanical threshold from baseline revealed a sparse sex difference in knee hypersensitivity between the ARL groups, but not the GLED groups. The male and female rats across both groups showed comparable drops in mechanical threshold 1 day after MIA injection. However, at days 3, 12, 21, and 30, the male and female rats exposed to ARL showed a significant difference in mechanical threshold. Although it did not reach statistical significance, the GLED-exposed females showed a trend of a greater decrease in mechanical threshold from baseline relative to their male counterparts. The data are mean with ± SD. n = 6–7. (* p < 0.05, ** p < 0.005, **** p < 0.0001 male ARL vs. female ARL). BL = baseline. Full article ">Figure 3
The percent difference in mechanical thresholds of GLED-exposed male and female rats relative to their sex-matched ARL counterparts revealed that male rats exhibited greater treatment effects than females. At GLED sessions 5, 8, and 11, male rats showed significant differences in mechanical threshold (%) compared to female rats. Data are mean with ± SD. n = 6–7 (* p < 0.05). Full article ">Figure 4
Blood serum cytokine levels at baseline and after 22 sessions of GLED or ARL (23 days after MIA injection). Male and female rats exposed to GLED showed significantly lower levels of cytokines TNF-α, IL-1β, and IL-10 at D23 compared to their ARL counterparts. Female rats, but not male rats, exposed to GLED showed significantly lower levels of IL-6 compared to their ARL counterparts at D23. ELISA assay results representing the average TNF-α, IL-1β, IL-6, and IL-10 concentrations in the serum samples at baseline and 23 days after osteoarthritis induction. All the results represent individual values, with the p values obtained from statistical analyses (* p < 0.05, ** p < 0.005, *** p < 0.0005, **** p < 0.0001). ns indicates not significant. n = 7. BL = baseline, D23 = Day 23. Full article ">Figure 5
No sex differences in blood serum cytokine levels at baseline or after 22 sessions of GLED or ARL (23 days after MIA injection). Data are mean with ± SD. n = 7. BL = baseline, D23 = Day 23. Full article ">

7 pages, 393 KiB

Open AccessCommunication

Rikkosan’s Short-Term Analgesic Effect on Burning Mouth Syndrome: A Single-Arm Cohort Study

by Tatsuki Itagaki, Keisuke Nakamura, Tougo Tanabe, Takumi Shimura, Yu Nakai, Ken-ichiro Sakata, Jun Sato and Yoshimasa Kitagawa

Biomedicines 2024, 12(5), 1013; https://doi.org/10.3390/biomedicines12051013 - 4 May 2024

Viewed by 1636

Abstract

Burning mouth syndrome (BMS) is a chronic oral pain disorder. There is a theory that BMS is a form of nociplastic pain. A standard treatment for BMS has not yet been established. Kampo medicine is a traditional oriental medicine. The purpose of this study is to evaluate the effectiveness of Rikkosan—a traditional Japanese herbal medicine (Kampo)—in the treatment of BMS. A single-center retrospective study was conducted on 20 patients who were diagnosed with BMS and treated with Rikkosan alone (total daily dose; 7.5 g) three times daily for approximately 4 weeks (29.5 ± 6.5 days). Rikkosan was dissolved in hot water and taken internally. They had an average age of 63 years, and 90% were being treated for other illnesses, but their medication status was the same during this study period, except for Rikkosan. No adverse events were observed in patients. Numerical rating scale (NRS) or visual analog scale (VAS)/10 scores decreased significantly between the time of the initiation of Rikkosan and one month after (−2.1 ± 1.2, p < 0.05). Rikkosan has a short-term effect of reducing NRS by two levels in BMS patients. Full article

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

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Review

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15 pages, 232 KiB

Open AccessReview

Basivertebral Nerve Ablation for Treatment of Lower Back Pain

by Esther Lee, Joaane Kim, Sadiq Rahman, Neil Daksla, William Caldwell and Sergio Bergese

Biomedicines 2024, 12(9), 2046; https://doi.org/10.3390/biomedicines12092046 - 9 Sep 2024

Viewed by 1612

Abstract

Lower back pain (LBP) is a widely prevalent global health issue, affecting over half a billion people and remaining the leading cause of years lived with disability (YLDs). LBP significantly impacts healthcare systems, with substantial costs related to surgical procedures and lost workdays. Vertebrogenic back pain (VBP), characterized by specific clinical symptoms and associated with Modic changes (MC) in vertebral endplates, best seen on MRI, is a significant subset of LBP. This paper explores the pathophysiology, diagnosis, and current reports and studies focusing on VBP and the role of basivertebral nerve (BVN) ablation as a therapeutic intervention. Multiple studies, including randomized controlled trials (RCTs) and meta-analyses, demonstrate the efficacy of BVN ablation in reducing pain and improving function in patients with chronic LBP associated with MC. Full article

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

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