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Biomedicines
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Advances in Pain Management: Exploring Molecular Mechanisms and Novel Therapies
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Advances in Pain Management: Exploring Molecular Mechanisms and Novel Therapies

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

Deadline for manuscript submissions: closed (31 May 2026) | Viewed by 4340

Special Issue Editors

Dr. Christopher Robinson

E-Mail Website
Guest Editor
Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA
Interests: drug discovery; therapeutics; stem cells; regenerative medicine; artificial intelligence-driven screening
Special Issues, Collections and Topics in MDPI journals
Dr. Samuel Ang

E-Mail Website
Guest Editor Assistant
Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, MA, USA
Interests: pain medicine; regenerative medicine
Dr. Rodrigo Diez-Tafur

E-Mail Website
Guest Editor Assistant
1. Pain Management Unit, Clínica Angloamericana, San Isidro 15073, Peru
2. Centro MDRS: Sports, Spine & Pain Centers, Miraflores 15073, Peru
Interests: pain medicine; regenerative medicine

Special Issue Information

Dear Colleagues,

Pain is now recognized as a complex pathological state involving sophisticated interactions between peripheral sensory pathways, central nervous system processing, immune activation, and psychological factors. Over the past decade, there have been remarkable advancements in pain research, particularly in the areas of neuroinflammation, sensory signaling, and genetic susceptibility.

This Special Issue provides an opportunity to bring together cutting-edge research that deepens our understanding of the molecular mechanisms underlying pain while also highlighting promising therapeutic approaches aimed at improving patient outcomes. Research areas may include, but are not limited to, the following:

  • Molecular and cellular mechanisms of pain;
  • Genetic and epigenetic factors in pain susceptibility and chronic pain conditions;
  • Neuroimmune interactions in pain modulation;
  • Emerging pharmacological targets for pain relief;
  • Novel pain therapies, including gene therapy, stem cell therapy, and biologics;
  • Innovative drug delivery systems for targeted pain relief.

We look forward to receiving your contributions and collaborating to advance the field of pain management.

Dr. Christopher Robinson
Guest Editor

Dr. Samuel Ang
Dr. Rodrigo Diez-Tafur
Guest Editor Assistants

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

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

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

Keywords

  • chronic pain
  • neuroinflammation
  • sensory signaling
  • epigenetics
  • neuroimmune interactions
  • regenerative medicine
  • stem cells

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Further information on MDPI's Special Issue policies can be found here.

Published Papers (4 papers)

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Research

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18 pages, 2281 KB  
Article
Effects of IncobotulinumtoxinA in the Infraorbital Nerve Chronic Constriction Injury Model of Trigeminal Pain in Rats
by Wojciech Danysz, Paulina Nunez-Badinez, Andreas Gravius, Klaus Fink and Jens Nagel
Biomedicines 2026, 14(5), 1175; https://doi.org/10.3390/biomedicines14051175 - 21 May 2026
Viewed by 401
Abstract
Background/Objectives: Trigeminal neuralgia (TN) is a debilitating neurological condition characterized by recurrent, severe pain linked to peripheral and central sensitization within trigeminal pathways. Current pharmacologic treatments are limited by inadequate efficacy or dose-limiting side effects, and botulinum neurotoxin type A (BoNT/A) has [...] Read more.
Background/Objectives: Trigeminal neuralgia (TN) is a debilitating neurological condition characterized by recurrent, severe pain linked to peripheral and central sensitization within trigeminal pathways. Current pharmacologic treatments are limited by inadequate efficacy or dose-limiting side effects, and botulinum neurotoxin type A (BoNT/A) has emerged as a viable option. However, its potential use in the management of TN is hampered by methodological limitations in existing studies and a lack of pivotal clinical trials. This study investigated the efficacy, optimal treatment site, preventive utility, and duration of effect of incobotulinumtoxinA (Inco/A), a BoNT/A, in a model of TN. Methods: An infraorbital nerve chronic constriction injury model was used to induce mechanical allodynia in male Sprague–Dawley rats, reproducing the trigeminal sensitization seen in TN. The effects of subcutaneous Inco/A (1, 2, and 4 U) were measured using the mechanical sensitivity (von Frey) test to evaluate the dose response, effect of injection location, potential preventive nature of treatment, and duration of benefit. Results: Inco/A produced a robust, dose-dependent reduction in mechanical allodynia, predominantly via a local mechanism of action. Both preventive and therapeutic administration of Inco/A was efficacious, with significant reduction in allodynia even when administered up to 28 days before nerve injury. The anti-allodynic effect persisted up to 56 days post-injection. Conclusions: Inco/A is highly effective in alleviating mechanical allodynia in a validated rat model of TN. The findings highlight Inco/A as a promising candidate for clinical translation in TN and related neuropathic pain syndromes and support systematic investigation in well-controlled human trials. Full article
(This article belongs to the Special Issue Advances in Pain Management: Exploring Molecular Mechanisms and Novel Therapies)
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14 pages, 1526 KB  
Article
Effectiveness of an Oral Supplementation of Phycocyanin and Palmitoylethanolamide for a Short-Term Prophylaxis of Menstrual Migraine: A Retrospective Observational Study
by Gianni Allais, Massimo Autunno, Florindo D’Onofrio, Luisa Fofi, Maria Gabriella Saracco, Fabiola Bergandi, Chiara Benedetto, Francesca Silvagno and Loredana Bergandi
Biomedicines 2026, 14(4), 865; https://doi.org/10.3390/biomedicines14040865 - 10 Apr 2026
Viewed by 741
Abstract
Background: Menstrual migraine (MM), including pure menstrual migraine (PMM) and menstrually related migraine (MRM), is characterized by attacks occurring in close temporal association with menstruation and is often more severe, longer lasting, and less responsive to treatment than non-menstrual migraine. Prostaglandin-mediated inflammation [...] Read more.
Background: Menstrual migraine (MM), including pure menstrual migraine (PMM) and menstrually related migraine (MRM), is characterized by attacks occurring in close temporal association with menstruation and is often more severe, longer lasting, and less responsive to treatment than non-menstrual migraine. Prostaglandin-mediated inflammation and calcitonin gene-related peptide (CGRP) release play a key role in MM pathophysiology. Phycocyanin (PC) and palmitoylethanolamide (PEA) are nutraceutical compounds with anti-inflammatory, analgesic, and neuroprotective properties that may be beneficial as short-term perimenstrual prophylaxis. Objectives: To evaluate the effectiveness of an oral supplementation combining phycocyanin and palmitoylethanolamide as a short-term prophylaxis for menstrual migraine in a real-world clinical setting, a retrospective observational study without a control group was conducted in five Italian centers between May 2023 and June 2025. Methods: Clinical records of 800 women were reviewed, and 220 patients receiving perimenstrual supplementation with phycocyanin and palmitoylethanolamide were screened. Sixty-one women diagnosed with migraine without aura, according to the International Classification of Headache Disorders, met all inclusion criteria and were analyzed. Phycocyanin and palmitoylethanolamide were taken at a dosage of two capsules daily from five days before to five days after the onset of menstruation for three consecutive months. Outcomes during the perimenstrual window were compared with a three-month period without supplementation. Primary outcomes included migraine severity, frequency, and duration of the attacks; secondary outcomes included analgesic consumption and menstrual migraine-associated symptoms. Results: Among the 61 included patients, phycocyanin and palmitoylethanolamide supplementation was associated with a significant reduction in migraine severity across all monitored perimenstrual days (p < 0.0001). While the overall monthly frequency of migraine attacks did not change, the number of migraine days during the perimenstrual window significantly decreased from the first month of supplementation (p < 0.05). Moreover, migraine duration during the perimenstrual window was significantly reduced at one, two, and three months of phycocyanin and palmitoylethanolamide supplementation compared with baseline. Analgesic use and the number of days with migraine-associated symptoms (nausea, vomiting, photophobia/phonophobia) were also significantly reduced. Treatment was well tolerated. Conclusions: In this real-world retrospective study, perimenstrual supplementation with phycocyanin and palmitoylethanolamide was associated with reduced severity, duration, and perimenstrual frequency of menstrual migraine attacks, along with decreased analgesic use, suggesting a safe and potentially beneficial short-term prophylactic strategy for women with menstrual migraine. Full article
(This article belongs to the Special Issue Advances in Pain Management: Exploring Molecular Mechanisms and Novel Therapies)
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Review

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15 pages, 448 KB  
Review
Cannabinoid Effects of Metamizol/Dipyrone: A Possible Second Life in Pediatric Anesthesia for a Vintage Drug
by Alessandro Vittori, Cecilia Di Fabio, Andrea Scardaci, Francesco Smedile, Ilaria Mascilini, Elisa Francia, Corrado Cecchetti, Franco Marinangeli, Giuliano Marchetti, Teresa Grimaldi Capitello and Marco Cascella
Biomedicines 2026, 14(2), 358; https://doi.org/10.3390/biomedicines14020358 - 4 Feb 2026
Viewed by 1209
Abstract
Background: Metamizol (dipyrone) is a widely used analgesic and antipyretic drug in several European countries, particularly for postoperative pain management in both adult and pediatric populations. Methods: A narrative literature review was conducted to evaluate the efficacy, safety, and pharmacological mechanisms of metamizol [...] Read more.
Background: Metamizol (dipyrone) is a widely used analgesic and antipyretic drug in several European countries, particularly for postoperative pain management in both adult and pediatric populations. Methods: A narrative literature review was conducted to evaluate the efficacy, safety, and pharmacological mechanisms of metamizol in postoperative pain management. A comprehensive search of PubMed, Scopus, and the Cochrane Library was performed, and included articles published up to 2024. Search terms included metamizol, dipyrone and children. Results: The available evidence indicates that metamizol provides effective postoperative analgesia, with an efficacy comparable to that of other non-steroidal anti-inflammatory drugs and paracetamol. Pediatric studies similarly support its effectiveness in postoperative settings. Regarding safety, short-term use of metamizol appears to be well tolerated, with a low incidence of serious adverse events. Mechanistic studies suggest that metamizol exerts analgesic effects through a multimodal pathway, involving not only cyclo-oxygenase inhibition but also modulation of opioid and endocannabinoid systems. Conclusions: Metamizol represents an effective and generally well-tolerated option for short-term postoperative pain management in both adults and children when used under appropriate clinical monitoring. Current evidence supports a favorable benefit-to-risk balance for short-term use while highlighting the need for caution during prolonged therapy. Further large-scale, prospective studies are warranted to better define rare adverse events, clarify interindividual risk factors, and refine the understanding of their non-classical mechanisms of action. Full article
(This article belongs to the Special Issue Advances in Pain Management: Exploring Molecular Mechanisms and Novel Therapies)
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25 pages, 1400 KB  
Review
Emerging Nonpharmacologic Analgesic Technologies in Anesthesia: Mechanisms, Evidence, and Future Directions for Pharmacologic Alternatives
by Alyssa McKenzie, Rachel Dombrower, Sophia McKenzie, Nitchanan Theeraphapphong and Alaa Abd-Elsayed
Biomedicines 2026, 14(1), 225; https://doi.org/10.3390/biomedicines14010225 - 20 Jan 2026
Cited by 1 | Viewed by 1426
Abstract
Perioperative pain remains a major clinical challenge, with many surgical patients experiencing inadequate analgesia and progression to chronic postsurgical pain. Conventional opioid-centered strategies are limited by narrow therapeutic windows, systemic toxicity, tolerance, opioid-induced hyperalgesia, and poor efficacy in neuroimmune-driven pain states. Advances in [...] Read more.
Perioperative pain remains a major clinical challenge, with many surgical patients experiencing inadequate analgesia and progression to chronic postsurgical pain. Conventional opioid-centered strategies are limited by narrow therapeutic windows, systemic toxicity, tolerance, opioid-induced hyperalgesia, and poor efficacy in neuroimmune-driven pain states. Advances in molecular neuroscience and biomedical engineering have catalyzed the development of nonpharmacologic analgesic technologies that modulate pain pathways through biophysical rather than receptor–ligand mechanisms. This narrative review synthesizes emerging nonpharmacologic analgesic platforms relevant to anesthesiology, integrating molecular, cellular, and systems-level mechanisms with clinical evidence. It examines how peripheral sensitization, spinal dorsal horn plasticity, glial and neuroimmune activation, and supraspinal network dysfunction create ideal targets for device-based interventions. Electrical neuromodulation strategies, including peripheral and central techniques, are discussed alongside temperature-based, photonic, and focused-energy modalities. These include cryoneurolysis, radiofrequency techniques, photobiomodulation, and low-intensity focused ultrasound. Clinical integration within enhanced recovery pathways, patient selection, workflow considerations, and limitations of the current human evidence base are reviewed. While many of these technologies are established in chronic pain management, this review emphasizes available human perioperative data and discusses how chronic pain evidence informs perioperative translation within opioid-sparing multimodal anesthesia care. Collectively, these technologies support a mechanism-based, systems-level approach to pain modulation, with perioperative relevance varying by modality and strength of available human evidence. Full article
(This article belongs to the Special Issue Advances in Pain Management: Exploring Molecular Mechanisms and Novel Therapies)
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