“Efficacy and Safety of Topical Ketamine for Oral Mucositis Pain due to Chemotherapy: A Scoping Review”

Abstract

This article presents a scoping review investigating the efficacy and safety of topical ketamine, primarily in mouthwash form, for managing oral mucositis (OM) pain caused by chemotherapy. Oral mucositis is a frequent, debilitating complication in cancer patients undergoing chemotherapy or radiotherapy, characterized by painful inflammation and ulceration of the oral mucosa. The condition significantly impairs quality of life (QoL), causing severe pain, dysphagia, bleeding, infection risk, and nutritional compromise, sometimes leading to treatment interruptions. Conventional analgesics, including NSAIDs and opioids, often fail to provide adequate relief or carry systemic side effects, creating a need for effective topical analgesics. Background and Rationale Oral mucositis results from mucosal injury due to cancer therapies, with pathogenesis involving DNA damage, cytokine release, basal epithelial injury, and microbial colonization. Pain in OM has both nociceptive and neuropathic components, mediated by inflammatory substances activating peripheral nociceptors and leading to central sensitization. Current management guidelines from ASCO and MASCC/ISOO recommend supportive care with gentle rinses, topical anesthetics (e.g., morphine mouthwash), systemic analgesics, and in severe cases, opioids. However, these approaches have limitations such as systemic toxicity and incomplete pain control. Ketamine, an NMDA receptor antagonist with analgesic and anti-inflammatory properties, has been used topically in various forms (gels, creams, mouthwashes) for peripheral pain. NMDA receptors are present peripherally, including on keratinocytes and sensory nerve terminals, suggesting that topical ketamine could provide localized analgesia with minimal systemic absorption and side effects. Despite this potential, topical ketamine use for OM pain remains underexplored, controversial, and is not formally endorsed in clinical guidelines due to limited evidence, concerns about adverse effects (e.g., psychosis, drowsiness), and lack of standardized formulations. Objectives This review aims to systematically collate and synthesize available clinical and experimental evidence on topical ketamine’s efficacy, safety, dosing, and schedules for chemotherapy-induced OM pain, thereby clarifying its role in supportive cancer care. Methodology A comprehensive electronic search was conducted in PubMed, Medline, Embase, and CINAHL up to November 2025, using keywords “ketamine,” “mouthwash,” and “oral mucositis,” limited to human studies and English language. Additional sources included reference lists and manual journal searches. Inclusion criteria focused on studies assessing topical ketamine for OM pain treatment, excluding unpublished data, conference abstracts, reviews, protocols, and non-English publications. The search yielded 130 records; after removing duplicates and screening, six original studies met inclusion criteria, comprising case reports, retrospective audits, prospective interventional studies, and a randomized controlled trial. Discussion The review highlights topical ketamine mouthwash as a promising option for managing severe, intractable OM pain in cancer patients, attributable to its NMDA receptor antagonism and anti-inflammatory effects. Topical application targets peripheral NMDA receptors, potentially reducing nociceptor sensitization and neuropathic pain components locally, with minimal systemic absorption and side effects compared to systemic ketamine. Most studies reported significant pain reduction, improved tolerability compared to lidocaine, and some reduction in opioid requirements, which could mitigate opioid-related adverse effects. Adverse events were generally mild, transient, and resolved upon discontinuation. However, the evidence is limited by small sample sizes, heterogeneous study designs, variable ketamine concentrations (20 mg/5 ml to 40 mg/4 ml), inconsistent pain assessment methods, and lack of long-term safety data. The only randomized controlled trial, conducted in children, did not demonstrate significant benefit, suggesting the need to explore optimal dosing and population differences. The review underscores the absence of standardized dosing regimens and commercial formulations, which complicates clinical adoption and guideline inclusion. Concerns about psychotomimetic effects and systemic absorption remain, although topical use appears safer. Limitations The review itself is limited by restricting searches to three databases and English-language studies, potentially missing relevant data. Included studies’ methodological limitations, such as retrospective designs, lack of control groups, and small cohorts, restrict generalizability. Future Directions The authors advocate for larger, well-designed randomized controlled trials to establish ketamine mouthwash’s efficacy, safety, and optimal dosing. Comparative studies against standard treatments (e.g., morphine mouthwash) and investigations into synergistic combinations with other analgesics or anti-inflammatory agents are needed. Long-term follow-up should assess durability of pain relief and safety. Research should also explore ketamine’s effects on mucositis healing and prevention, beyond symptomatic pain relief, to evaluate broader therapeutic potential. Conclusion Topical ketamine mouthwash emerges as a safe and potentially effective adjunct for managing chemotherapy-induced oral mucositis pain, with advantages of localized analgesia, reduced systemic side effects, and possible opioid-sparing effects. While preliminary evidence is encouraging, current data are insufficiently robust to support routine clinical use or guideline endorsement. The proposed dosing protocol involves a 25 mg intravenous ketamine solution used as a 10-15 ml mouthwash every 2-4 hours or 1 mg/kg/day as co-analgesic with opioids. Incorporated into supportive care alongside professional oral hygiene, topical ketamine may improve patient comfort and QoL during cancer treatment. High-quality trials are essential to confirm efficacy, define optimal regimens, and ensure long-term safety.

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