PURPOSE: The objective of the study was to determine if mouthwashes with a morphine-containing solution decrease oral pain associated with radiotherapy- and/or chemotherapy-induced oral mucositis (OM). METHODS: Randomized double-blinded crossover study to evaluate the effect of topical oral application of 2 per thousand morphine solution in patients suffering from radiotherapy- and/or chemotherapy-induced OM. Participants assigned to either the morphine solution or a placebo mouthwash received one of the solutions days 1-3 and were then switched over to the other treatment for days 4-6. RESULTS: Nine patients were randomized in both groups. All patients (mean age, 55.1 +/- 3.0) except one had head and neck cancers. Mean intensity of pain associated with mucosal injury (World Health Organization [WHO] mucositis ≥ 2) was on a 10-point visual analogue scale: 6.0 +/- 2.7). The analysis of variance (ANOVA) model that included morphine or placebo, day and time of mouthwash, and mouthwash effect shows that pain alleviation 1 hour after mouthwash was significantly influenced by the gesture of the mouthwash (p < 0.001 with either morphine or placebo) and almost by the efficiency of morphine (p = 0.020). Duration of pain relief was 123.7 (standard deviation [SD] +/- 98.2) minutes for morphine. Most other reported symptoms were present at the baseline and were probably associated with the main disease and not secondary to the morphine mouthwash. CONCLUSIONS: Our results suggest a possible analgesic effect of topical morphine in line with previous studies. However, more efforts must be made for the adjustment of systemic analgesics and the development of new alternatives to treat locally OM-associated pain.