Allopurinol is a medication that is primarily used to treat gout and reduce uric acid levels. It prevents uric acid production by blocking activity of an enzyme that converts purines to uric acid. Allopurinol is an antagonist of some chemotherapeutic agents, and, as such, may reduce some effects. Allopurinol mouthwash has been evaluated in patients with cancer for its potential local effects in the prevention and management of mucositis.
Effectiveness Not Established
Clarkson, J.E., Worthington, H.V., Furness, S., McCabe, M., Khalid, T., & Meyer, S. (2010). Interventions for treating oral mucositis for patients with cancer receiving treatment. Cochrane Database of Systematic Reviews, 8, CD001973.doi: 10.1002/14651858.CD001973.pub4
To assess the effectiveness of interventions for treatment of oral mucositis or its associated pain for patients receiving chemotherapy or radiation therapy
Databases searched were MEDLINE, CancerLIT, EMBASE, CINAHL, LILACS (Latin American and Caribbean Health Sciences Literature), Cochrane Oral Health Group and PaPaS Trials Registers, Cochrane Central Register of Controlled Trials (CENTRAL), OpenSIGLE, and Current Controlled Trials. Handsearching carried out by the Cochrane Collaboration was included. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information.
Search keywords were (neoplasm* OR leukemia OR leukaemia OR lymphoma* OR plasmacytoma OR “histiocytosis malignant” OR reticuloendotherliosis OR “sarcoma mast cell” OR “LettererSiwe disease” OR “immunoproliferative small intestine disease” OR “Hodkin disease” OR “bone marrow transplant*” OR cancer* OR tumor* OR malignan* OR netropeni* OR carino* or Adenocarcinoma* OR radioth* OR radiat* OR radiochemo* OR irradiat* OR chemo*) AND (stomatitis OR “Stevnes Johnson syndrome” OR “candidiasis oral” OR mucositis OR (oral AND (cand* OR mucos* OR fung*)) OR mycosis OR mycotic OR thrush. Extensive appendices are provided with specific search strategies used for each database.
Studies were included in the review if they
- Were randomized controlled trials using placebo, no treatment, or another active intervention.
- Involved patients with cancer receiving chemotherapy or radiotherapy and experiencing oral mucositis.
- Involved any intervention for the treatment of oral mucositis or its associated pain.
- Written in any languages. Papers not in English were translated by members of the Cochrane collaboration.
The final assessment incorporated 32 studies. Out of an initial 95 eligible studies, 64 were excluded because of study design issues, protocol violations, lack of useable data, or no relevant outcomes.
- The final set of studies involved a total of 1,505 patients; 1,023 patients were involved in trials investigating the effectiveness of agents to treat mucositis, and 718 patients were involved in trials evaluating pain relief.
- Sample sizes ranged from 6–71 patients per treatment or control group.
- Twenty-eight trials included only adult patients, and four included only children.
- Trials included patients treated for a combination of leukemia and solid tumors (n = 14), patients with head and neck cancer (n = 8), and patients who had received bone marrow or stem call transplant (n = 11).
Treatment of mucositis
Summary of data from single trials showed the following interventions to demonstrate statistically significant benefit (p < 0.05).
- Allopurinal mouthwash resulted in improvement in mucositis, eradication of mucositis in some cases, and reduction in time to healing.
- Granulocyte macrophage-colony stimulating factor (GM-CSF) demonstrated mixed results, with two trials showing improved time to healing versus use of providone iodine and antimycotic mouthwash and one trial showing improvement in mucositis by the end of radiotherapy.
- Human placental extract demonstrated improvement in mucositis in one trial.
- Phenytoin mouthrinse was associated with better quality of life than placebo in one trial, but no benefit for pain was found and healing was not evaluated.
- Polyvariant intramuscular immunoglobulin was associated with improvement in mucositis versus placebo in one trial.
- Topical vitamin E was associated with improvement in mucositis and eradication of mucositis compared to systemic vitamin E in one trial.
- Debridement was associated with fewer days to clinical resolution and decreased severity of mucositis, when compared to no debridement.
- Laser treatment was beneficial in management of mild to moderate mucositis compared to sham treatment.
Other interventions for treatment of mucositis evaluated included chlorhexadine versus salt and soda, Gelclair verus sucralfate and mucaine,”Magic” mouthwash versus salt and soda, sucralfate versus placebo and versus salt and soda, and tetrachlorodecaoxide.
Management of pain with mucositis
The following interventions demonstrated statistically significant benefit in managing pain (p < 0.05).
- Opiod use was associated with lower average pain scores when compared to antidepressant use.
- Morphine pharmacokinetically patient controlled analgesia (PKPCA) was associated with lower average pain score than morphine standard patient controlled analgesia (PCA).
- When morphine PCA was compared to continuous morphine infusion, meta-analysis showed no difference in mean pain scores; however, mean opiate intake was reduced with PCA, and PCA was associated with fewer days of pain.
- Interventions reviewed that showed no statistical benefit for treatment of mucositis included chlorhexadine, Gelclair, “Magic” mouthwash, and sucralfate.
- Interventions reviewed for management of associated pain that demonstrated no statistical benefit included hydromorphone PCA versus morphine, Alfentanil versus morphine, Dicofenic versus placebo, PCA versus staff controlled, hypnosis, relaxation, and imagery.
- Out of 27 different interventions evaluated for treatment of mucositis, only one comparison was significant for one outcome: low level laser treatment reduced the severity of mucositis.
- No evidence was found to suggest a difference in pain control between continuous infusion and PCA; however, the PCA group required less morphine, and the pain lasted two less days.
- Some evidence exists that low level laser treatment may help reduce severity of mucositis.
- No evidence suggests that PCA is more effective than continuous infusion for controlling pain. Weak evidence is available to support that PCA is associated with less opiate used per hour and that the duration of pain may be reduced.
- No clear benefit appears to be associated with antimicrobial use and GM-CSF for prevention or management of mucositis.
- This review demonstrated weak and unreliable evidence of benefit for interventions for mucositis.
The lack of independent duplication of studies investigating the same intervention limits the strength of evidence and ability to generalize results.
Most studies reviewed had small sample sizes and may have been underpowered to demonstrate significant differences in outcomes.
Different scoring systems for mucositis were used, and, in some studies, the method of scoring was not defined.
The need for further well-designed trials to evaluate the effectiveness of interventions continues.
Adoption of standard clinical outcome measures should be considered, including patient-based measures and inclusion of the cost of interventions.
Kwong, K.K. (2004). Prevention and treatment of oropharyngeal mucositis following cancer therapy: Are there new approaches? Cancer Nursing, 27(3), 183–205.doi: 10.1097/00002820-200405000-00003
Database searched was MEDLINE (1993–2003) for randomized, controlled trials evaluating mucositis interventions.
A total of 50 randomized controlled trials were presented. Other trials and papers were referenced.
- Sample sizes ranged from 10–222.
- Patients were treated with chemotherapy, radiotherapy, and bone marrow transplantation.
The author concluded that most agents require more study.
- Evidence for cryotherapy and bolus 5-fluorouracil was strong.
- Sucralfate studies produced conflicting results and included varying doses and administration frequencies, making comparisons difficult. Most studies indicated no difference in severity or duration. The validity and reliability of the data were questioned because of the measurement scales used.
- Similarly, studies of cytokine-like agents used different doses, making comparisons difficult.
- Moderate evidence suggested that benzydamine is effective in relieving mouth pain caused by radiation-induced mucositis in patients with head and neck cancer. The agent requires additional investigation and study for chemotherapy-induced mucositis.
- Large studies of chlorhexidine mouthwashes have failed to show significant findings; however, the studies may have had inadequate sample sizes, as power analyses were not performed.
- Povidone-iodine showed significant reduction in onset, incidence, total duration, and worst grade of mucositis for patients with head and neck cancer undergoing radiation with carboplatin in two studies. Both studies had sample sizes of 40. Given these sample sizes and specific populations, generalizability of the findings was restricted.
- Oral hygiene protocols were shown to reduce the duration and severity of mucositis; however, the content of the protocols was not proven.
The author noted the problem of variation in study protocols, insufficient sample sizes, and a lack of consensus regarding the scoring system for mucositis.
The author noted the need to include psychotherapeutic interventions and management and pointed out the lack of a quality-of-life tool for mucositis.
Stokman, M.A., Spijkervet, F.K., Boezen, H.M., Schouten, J.P., Roodenburg, J.L., & deVries, E. G. (2006). Preventive intervention possibilities in radiotherapy and chemotherapy-induced oral mucositis: Results of meta-analysis. Journal of Dental Research, 85, 690–700.doi: 10.1177/154405910608500802
Databases searched were MEDLINE, EMBASE, and CINAHL (1966–2004).
Search keywords were [neoplasms] AND [(mucositis OR stomatitis)] AND [limit to (clinical trial OR randomized-controlled trials)].
Studies were included in the review if they were
- Published in English.
- Were aimed at the prevention of mucositis in patients undergoing head and neck radiation, chemotherapy, or chemoradiation.
The search yielded 109 publications. Of these, five were not aimed at prevention, 13 were nonrandomized, and 29 did not contain data in a comprehensive form. Seventeen articles stood alone in terms of intervention, and 45 articles included meta-analyses. Studies with zero or infinite odds ratios were omitted because variances could not be calculated with accuracy. Sample sizes ranged from 14–502.
Patients with various cancer diagnoses receiving chemotherapy, radiation therapy, or combination chemoradiotherapy.
Of the 27 interventions identified for the prevention of oral mucositis, meta-analysis could be performed on eight. Four interventions showed a preventive effect on the development or severity of oral mucositis: PTA (polymyxin E, tobramycine, and amphotericin B) lozenges or paste, systemic administration of granulocyte macrophage–colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF), oral cooling, and amifostine.
Of 14 studies (each on a different intervention type), nine showed some positive results; however, methodological flaws (e.g., small sample sizes, lack of double-blind or placebo-controlled designs) prevented those studies from demonstrating effectiveness. One study of benzydamine (Epstein et al., 2001) showed an improved ulcer-free rate and decreased incidence of ulcer and erythema.
Palifermin demonstrated positive results for the prevention of mucositis in patients with hematologic malignancies undergoing autologous stem cell transplantation.
Worthington, H.V., Clarkson, J.E., & Eden, O.B. (2004). Interventions for treating oral mucositis for patients with cancer receiving treatment. Cochrane Database of Systematic Reviews (Online), 2, CD001973.
Database searched were Cochrane Oral Health Group's Trial Register, CENTRAL, MEDLINE, and EMBASE. Reference lists from relevant articles were searched, and the authors of eligible trials were contacted to identify trials and obtain additional information. Most recent search was conducted in August 2003.
A total of 25 randomized, controlled trials comparing agents prescribed to treat oral mucositis were evaluated.
- A total of 1,292 patients were involved in the 25 studies.
- All patients were receiving chemotherapy, radiotherapy, or both.
In one trial of 44 patients, a mouthwash of 300 mg allopurinol dissolved in water was compared to placebo. Patients rinsed with the mouthwash for one minute, four to six times per day. The study showed improvement but had a moderate risk of bias and weak evidence.
In another study of 80 patients with head and neck cancer and radiation-induced mucositis, patients were given immunoglobulin (10 mL on day 0, 5 mL on day 2, 5 mL on day 4) or placebo of 10% human albumin given at the same dosages and times. Both groups received nystatin. Patients who received immunoglobulin showed improvement; however, evidence was weak.
According to the authors, “There is weak and unreliable evidence that allopurinol mouthwash, vitamin E, immunoglobulin, or human placental extract improve or eradicate mucositis. There is no evidence that patient-controlled analgesia is better than the continuous infusion method for controlling pain; however, less opiate was used per hour, and duration of pain was shorter for patient-controlled analgesia. Further, well-designed, placebo-controlled trials assessing the effectiveness of allopurinol mouthwash, immunoglobulin, human placental extract, other interventions investigated in this review and new interventions for treating mucositis are needed.”
Research Evidence Summaries
Panahi, Y., Ala, S., Saeedi, M., Okhovatian, A., Bazzaz, N., & Naghizadeh, M. (2010). Allopurinol mouth rinse for prophylaxis of fluorouracil-induced mucositis. European Journal of Cancer Care, 19(3), 308–312.10.1111/j.1365-2354.2008.01042.x
To prepare and evaluate an allopurinol mouth rinse for prophylaxis of fluorouracil-induced mucositis
Intervention Characteristics/Basic Study Process:
Allopurinol mouthwash (1 mg/ml) or placebo was administered 1, 2, and 3 hours after chemotherapy and three consecutive nights for 30 seconds. Patients were instructed to neither wash their mouths nor to eat and drink for 15 minutes afterward.
- The study reported on 30 patients, with a mean age of 56.9 years (SD = 10.3 years) for the allopurinol group and 49.5 years (SD = 13.8 years) for the placebo group.
- The percentage of males was not mentioned in the study. The allopurinol group was 60% female and the placebo group was 66.7% female.
- Cancer diagnoses were breast (n = 13), colon (n = 12), rectum (n = 2), gastric (n = 3), pancreas (n = 2), and esophageal (n = 1).
- All patients with malignant disorders, who were going to receive 5-FU-containing chemotherapy in the outpatient setting, were analyzed.
This was a single-site, outpatient study conducted in a clinic in Sari, Iran.
Phase of Care and Clinical Applications:
- All patients were undergoing the active treatment phase of care.
- The study has clinical applicability for end of life and palliative care, elderly care, late effects and survivorship.
This was a placebo-controlled, double-blinded, randomized clinical trial.
An independent physician completed questionnaires consisting of demographic parameters, medical status, quality-of-life survey, and mucosal injury scoring table (based on World Health Organization [WHO] scales for mucositis).
- In the allopurinol arm, 11 of 15 patients (73.3%) did not have mucositis, four (26.6%) had grade 1 (mild), and none had mucositis at a higher grade.
- In the placebo arm, 8 of 15 patients (53.3%) showed no mucositis, five (33.3%) had grade 1, and two (13.3%) developed grade 2 mucositis.
No significant differences were found between the groups with regard to occurrence and severity of mucositis.
- The sample size was small with fewer than 30 patients.
- The time period for treatment and follow up was very short.
- The rationale for timing of the intervention was not clear.
- Substantial differences existed between groups in the type of chemotherapy given, which would be likely to affect mucositis development.
- No information was provided regarding patient compliance with the protocol for oral rinsing.
- The study was not blinded.
Because of compliance issues with the mouth rinse regimen, low concentration of the allopurinol in the rinse, and a small sample size, the treatment was deemed ineffective in prevention and severity of mucositis. Further studies are needed once the limitations are removed.