Addressing Pain in Oral Mucositis: Narrative Review of Current Practices and Emerging Treatments

Abstract

Objective: Oral mucositis (OM) is a debilitating complication of cancer therapies, affecting up to 85% of patients undergoing bone marrow transplantation and nearly all receiving head and neck radiotherapy. Characterized by mucosal inflammation, ulceration, and severe pain, OM significantly impairs oral intake, speech, and quality of life. These disruptions, compounded by complications such as infection, bleeding, and increased healthcare costs, often necessitate treatment delays or modifications, negatively impacting cancer prognosis. Recent insights into nociceptive and neuropathic mechanisms of OM-related pain have led to the development of innovative management strategies. Given the debilitating nature of OM in cancer patients and the critical need for effective pain control, this review aims to examine pharmacological advancements targeting the complex nature of OM-related pain, including agents such as lidocaine, doxepin, benzydamine, methylene blue, opioids, gabapentin, palifermin, caphosol, and ketamine.

Methods: A literature search was conducted in the PUBMED, COCHRANE, and MEDLINE databases, covering studies from 2000 to 2024. Studies focusing on OM pathogenesis and pain management strategies were screened. Inclusion criteria encompassed randomized controlled trials, meta-analyses, and systematic reviews involving adult patients treated with lidocaine, doxepin, benzydamine, methylene blue, opioids, gabapentin, palifermin, caphosol, or ketamine for OM-associated pain.

Conclusion: OM pain arises from nociceptive and neuropathic pathways involving inflammatory cytokines and neuropeptides. Current interventions, including topical and systemic agents, have shown promise, yet variability in treatment protocols and limited high-quality evidence hinder standardized practices. This review highlights the clinical applicability of emerging therapies, such as avasopasem manganese, which has demonstrated efficacy in mitigating OM progression. Ongoing clinical trials targeting novel pathways that modulate mucosal inflammatory response and limit disease severity offer hope for improved pain relief. Addressing the multifaceted nature of OM-associated pain is essential for enhancing quality of life and optimizing cancer treatment outcomes. Further research is needed to establish robust, evidence-based guidelines for OM pain management.

Keywords: head and neck cancer; mouth washes; mucosal ulceration; oral mucositis; oral pain; pain management.

Figure 1

Oral mucositis pathogenesis. Exposure to antineoplastic treatments triggers DNA damage, reactive oxygen species (ROS) generation, and death of basal oral mucosa epithelial cells. Pro-inflammatory cytokine release impairs tissue oxygenation and activates pathways that exacerbate connective tissue damage and cellular apoptosis. The high infection risk can further aggravate mucosal ulceration once the submucosal breaks form in the oral mucosa lining. The final phase involves oral mucosa re-epithelialization and tissue repair. Created in BioRender. Ramirez, (M) (2025) https://BioRender.com/ o32c149.

Figure 2

Nociceptive and neuropathic pain perception pathways in oral mucositis. Chemoradiation-induced mucosal injury leads to DNA damage, ROS generation, and proinflammatory cytokine release. TRP, ET-1, and TNF-α receptors in nearby Aδ and C fibers initiate the pain transduction process upon cytokine stimuli. Endothelial dysfunction further aggravates the inflammatory cascade by NF-ĸB pathway activation, with additional ROS and ET-1 release. The release of substance P, CGRP, glutamate, and proinflammatory cytokines sensitize neurons and amplify pain perception. ROS, reactive oxygen species; TRPV4, Transient Receptor Potential V4 channel; TNF-R, Tumor Necrosis Factor Receptor; ET-1, Endothelin-1; ET-1 R, Endothelin 1 receptor; CGRP, Calcitonin Gene-Related Peptide; NGFR, nerve growth factor receptor. Created in BioRender. Ramirez, (M) (2025) https://BioRender.com/w20d434.