Advancing Multimodal Analgesia through Functional Selectivity in Perioperative and Cancer Pain

Pain management in perioperative and cancer care remains a challenge despite significant advances in clinical anesthesia and analgesic pharmacology. For decades, anesthesiologists and pain specialists have struggled to balance the undeniable efficacy of opioids against their substantial risk of adverse effects such as respiratory depression, tolerance, and gastrointestinal impairment. Multimodal analgesia (MMA) has therefore become a global strategy to reduce opioid exposure by combining agents and techniques that target complementary mechanisms. However, many currently used non-opioid adjuvants provide incomplete analgesia, have dose-limiting toxicities or are not equally effective across surgical procedures, cancer pain syndromes and vulnerable patient populations. Recent studies showed that functional selectivity, including biased agonism and pathway-selective receptor modulation, offers a promising framework for developing analgesics that preserve clinically meaningful pain relief while limiting adverse signaling pathways. This concept is particularly relevant to opioid receptor pharmacology, but also extends to multitarget ligands, non-opioid receptor systems, neuroimmune modulation and personalized analgesic strategies. Nevertheless, important translational and clinical questions remain regarding efficacy, safety, comparative benefit, integration into perioperative and oncology protocols, long-term outcomes and patient-specific optimization.This Research Topic aims to advance the scientific and clinical understanding of functionally selective analgesics within multimodal strategies for perioperative and cancer pain management. Therefore, the goal of this topic is to integrate evidence from molecular pharmacology, preclinical models, translational research, and clinical studies in terms of clarification how pathway-selective receptor modulation may improve analgesic efficacy while reducing opioid-related adverse effects. Key objectives include defining the real-world benefits and limitations of functionally selective analgesics, examining their role in reducing opioid tolerance and opioid-induced hyperalgesia (OIH), and establishing their safety profile in high-risk patient populations. The topic also strives to facilitate interdisciplinary discourse on optimizing analgesic protocols for complex pain scenarios.To achieve these objectives, this Research Topic invites submissions exploring the integration of functionally selective analgesics and novel multimodal strategies in both perioperative and cancer pain settings, with particular attention to high-risk or vulnerable populations. We welcome articles addressing, but not limited to, the following themes:• Evolution of MMA: Clinical studies incorporating biased μ-agonists (and other novel targets) into multimodal regimens for complex surgeries (e.g., thoracic, abdominal, spine).• Cancer Pain Frontiers: Strategies utilizing novel mechanisms to manage breakthrough cancer pain, with a focus on mitigating opioid tolerance and Opioid-Induced Hyperalgesia (OIH) in palliative care.• High-Risk Populations: Evidence focusing on the safety profile of these new strategies in elderly, obese (OSA), or fragile patients where respiratory preservation is paramount.• Mechanistic Studies: Functional selectivity and signal transduction at the MOR and beyond.• Comparative Effectiveness and Implementation: Protocol optimization in diverse clinical settings. Topic editors: Song Zhang, Maria Carmona, Justyna Piekielna-Ciesielska, Qi Chen, Zhaolan Hu Source: https://www.frontiersin.org/research-topics/82448/advancing-multimodal-analgesia-through-functional-selectivity-in-perioperative-and-cancer-pain