Honey

• FINAL NUMBER STUDIES INCLUDED = 9
• TOTAL PATIENTS INCLUDED IN REVIEW = 476 
• SAMPLE RANGE ACROSS STUDIES: 19–127 patients
• KEY SAMPLE CHARACTERISTICS:
  • Comparisons: Honey (manuka honey) vs placebo,  Honey (manuka honey) vs. placebo (sugar-free placebo), Honey (Western Ghats forests) vs. placebo (lignocaine), Honey (Dabur honey) vs. placebo (Tantum), Honey (manuka and kanuka honey) vs. placebo (sterile water) or no gargle, Honey (Egypt honey) vs. placebo (Tantum), Honey (thyme and astragale) vs. placebo (saline), Honey (manuka honey) vs. no gargle, Honey (tea plant) vs. placebo (Tantum)
  • Treatments: Radiotherapy plus chemoradiotherapy, radiotherapy alone, and chemoradiotherapy alone

PHASE OF CARE: Active antitumor treatment 
 
APPLICATIONS: None stated

• The incidence of moderate to severe mucositis was significantly lower in patients receiving honey versus those who received a placebo or no treatment (control group) (p < 0.0001).
• A subanalysis of honey efficacy pertaining to type of regimen demonstrate that honey administration had significantly greater effect in preventing moderate to severe mucositis in patients receiving radiotherapy alone than those receiving chemotherapy (p < 0.0001).
• The onset of mucositis was significantly later in the honey group versus the control group (p = 0.0036).
• The mean mucositis grade for first three weeks of radiotherapy or chemotherapy was significantly lower in the honey group than in the control group (p = 0.0114).

Administration of Honey Versus Control (Mucositis-Related Adverse Effects)

• No statistically significant differences between honey and control groups were found regarding incidences of bacterial or fungal colonization and pain experience (p = 0.3804, p = 0.1831, and p = 0.2903, respectively).
• There was a statistically significant difference for the incidence of weight loss in patients in the honey group versus the placebo group (p < 0.0001).

This study demonstrated the potential efficacy of honey administration in the prevention of oral mucositis and weight loss during radiotherapy and chemotherapy in patients with head and neck cancer. 

• Only two studies that analyzed the incidence of bacterial and fungal colonization were included. 
• Small sample sizes
• Different types of honey and anticancer regimens were used.
• The heterogeneity of the incidence of moderate to severe mucositis in patients receiving chemoradiotherapy could not be decreased in this analysis.

• This study indicated potential prevention interventions for oral mucositis in patients with head and neck cancer.
• Its findings pointed to areas for future nursing research.
• The honey interventions used were low-cost with easy administration and accessibility, which will assist nursing interventions if future studies support their use.   

STUDY PURPOSE: To synthesize the available literature to determine the role of honey in reducing oral mucositis, time to onset of mucositis, weight loss, and treatment interruptions among patients with head and neck cancers undergoing radiation with or without concomitant chemotherapy

TYPE OF STUDY: Meta analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 5 for meta-analysis and 8 for systematic review 
• TOTAL PATIENTS INCLUDED IN REVIEW = 244 (according to the authors)
• SAMPLE RANGE ACROSS STUDIES: Author did not report each sample size, but some numbers were found in the report and a figure. According to the figure, each study had 20–33 participants per group, and it was assumed that each study had approximately 40–60 participants. However, one study used in systematic review seemed to have 131 patients in the study. Sample sizes were not reported well in this study. 
• KEY SAMPLE CHARACTERISTICS: The authors included only randomized controlled trials with a honey intervention for patients with head and neck cancer who were receiving radiation therapy. The authors took appropriate screening procedures to select articles that met the criteria. This shrunk the sample size but resulted in more reliable results for meta-analysis.

PHASE OF CARE: Active antitumor treatment

Honey was significantly better in lowering the risk for treatment interruptions and probably less weight loss but did not decrease the rate of the peak mucositis score. The results for prolonged onset of mucositis is favorable with the honey intervention in two studies, but one study did not show a significant difference.

• Limited number of studies included
• No quality evaluation
• High heterogeneity
• Low sample sizes

The results showed that the honey intervention is effective in reducing treatment interruption. Other measures (weight loss, peak mucositis score, time to mucositis) need further meta-analysis to establish. Further well-designed research is needed to confirm the usefulness of honey preparations.

To investigate whether the use of honey provides protection from the effects of radiation-induced mucositis

Databases searched were PubMed, MEDLINE via OVID, EMBASE, CINAHAL via EBSCO, and Cochrane.

Keywords searched were honey and mucositis or stomatitis.

Studies were included in the review if they

• Were randomized controlled trials that investigated protective effects of honey in patients with head and neck cancer undergoing radiation therapy.
• Used Radiation Therapy Oncology Group (RTOG) or World Health Organization (WHO) criteria to evaluate the severity of radiation mucositis.

Studies were excluded if they

• Were nonhuman clinical trials.
• Were nonrandomized controlled trials.
• Involved patients without diagnoses of head and neck cancer.
• Were trials in which the protective effects of honey were not studied.

A total of 15 references were retrieved. Four trials reported on the protective effects of honey. One of these was nonblinded. The remaining three were randomized examiner-blinded, and these three trials were assessed for overall risk of bias using the Cochrane method. Three of the four studies met the inclusion and exclusion criteria for the meta-analysis.

• The final number of studies included was four human trials, but one trial was excluded because it reported only on pain relief, not the protective effects of honey.   
• The total sample across all studies was 120 patients with 40 in each study.
• Studies involved adults with head and neck cancer receiving radiation therapy. In one study, patients were receiving concurrent chemotherapy and radiation. I all studies, patients with systemic illness or prior chemotherapy were excluded.

All patients were undergoing the active treatment phase of care.

Meta-analysis of the of the three trials reported that honey appeared to have protective effects against radiation-induced mucositis by 80% compared to the control group. Overall relative risk of developing mucositis was almost 80% lower (risk ratio, 0.19; 95% confidence interval, 0.098–0.371) in the honey treatment group than in the control group.

Trials were fairly homogeneous (I² = 0%, p = 0.39), so meta-analysis used a fixed-effects model (Mantel-Haenszel method) to calculate a pooled risk ratio.

• A limited number of trials met the criteria for meta-analysis. Individual studies were weak.
• Two of the studies included had a high risk of bias because of plausible bias in several criteria.
• Patients were not blinded because of the taste of honey. 
• Grade 3 or 4 on the RTOG scale was used as the outcome measure of interest.

Further research is needed to strengthen the current evidence prior to any clinical recommendations for practice. They suggested blinding the assessor in future studies.

To evaluate the evidence for prophylactic agents in management of oral mucositis in patients with cancer receiving treatment

Databases searched were MEDLINE, CANCERLIT, Embase, CINAHL, Latin American and Caribbean Health Sciences Literature (LILACS), System for Information on Grey Literature in Europe (SIGLE), and the Cochrane Database.

An extensive list of search terms and strategies used per database was provided in the article.

Studies were included in the review if they

• Were randomized controlled trials (RCTs).
• Compared an intervention to a placebo or no treatment.

A total of 383 references were retrieved. Risk of bias was evaluated according to the Cochrane Handbook for Systematic Reviews of Interventions. Studies were categorized as low, unclear, or high risk of bias. Studies were labeled using the GRADES system for evaluating quality of evidence.

• The final number of studies included in the review was 131.
• The total sample size across all studies was 10,514 with an across-study sample range of 12–301. 
• Studies involved a variety of cancers and patients receiving chemotherapy, radiation therapy, or both.

• Patients were in the active antitumor treatment phase of care.
• This study has clinical applicability to pediatrics.

• Only 8% of studies included were seen to have a low risk of bias. 
• Studies included a variety of treatments such as acyclovir, allopurinol rinse, aloe vera, amifostine, antibiotic paste, systemic antibiotics, axulene, benzydamine, beta carotene, chamomile, chewing gum, Chinese herbs, chlorhezidine, cryotherapy, epidermal growth factor, glutamine, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), histamine gel, honey, hydrolytic enymes, indigo wood root, intestinal trefoil factor, keratinocyte growth factor, laser, anti-inflammatory drugs, oral care, pentoxifylline, pilocarpine, polymixin/tobramycin/amphotericin (PTA), traumeel, sucralfate, zinc sulphate, and povidone iodine. 
• From all analyses, at least moderately strong evidence of benefit was found for cryotherapy (RR = 0.74, 95% confidence interval [CI] 0.57–0.95, p = 0.02) for any mucositis and for keratinocyte growth factor (RR = 0.82, 95% CI 0.71–0.94, p = .0005) for any mucositis. 
• Weak and unreliable evidence for potential benefit was found with aloe vera, amifostine, glutamine, G-CSF, honey, laser, polymixin/tobramycin, amphotericin lozenges, and sucralfate.
• A substantial body of evidence showed no benefit of chlorhexidine.

Findings support the benefits of cryotherapy and keratinocyte growth factor. The low quality of evidence in most of the other interventions points to the need for ongoing, well-designed research in this area. The presentation of findings in many publications made meta-analysis impossible.

The rationale for the authors' summaries of findings was not entirely clear. Similar RR ratio results with similar evidence quality levels were identified differently in terms of potential benefit. Although the review was inclusive and extensive, interpretation of results was inconsistent. High heterogeneity existed in most interventions, and most studies were either at high or unclear risk of bias with low GRADES scoring. Studies did not always differentiate between mucositis and candidiasis, which would affect recommendations.

This article suggests strong support for use of cryotherapy and keratinocyte growth factor for mucositis prevention. It suggests possible benefit from aloe vera, amifostine, IV glutamine, G-CSF, honey, laser, and antibiotic lozenges. Sucralfate may reduce the severity of mucositis. These findings should be interpreted with caution, given the relatively low quality of overall evidence and high heterogeneity across studies included in meta-analysis, as well as the fact that treatments and sample characteristics were highly varied.

STUDY PURPOSE: To determine the prophylactic effects of honey on radiation- and chemotherapy-induced mucositis

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 7
• TOTAL PATIENTS INCLUDED IN REVIEW = 190 test groups, 191 control groups
• SAMPLE RANGE ACROSS STUDIES: 13–127
• KEY SAMPLE CHARACTERISTICS: In five studies, patient received radiation therapy (260 patients, two studies radiation therapy and chemotherapy [121]). Only three studies mentioned age range (13–89 years).

PHASE OF CARE: Active antitumor treatment

Honey treatment reduced the incidence of oral mucositis in the honey group by 65% compared to the control group. The type of radiation therapy (source, dose) may have influenced the results.

Mostly low quality/high risk of bias studies

Honey prevents the incidence of mucositis compared to no intervention. However, more randomized, controlled trials are needed to determine the prophylactic effects of honey on patients receiving radiation or radiation and chemotherapy.

To evaluate the effect of topical use of honey and a mixture of honey, olive oil-propolis extract, and beeswax (HOPE) as natural products in the treatment of chemotherapy-related oral mucositis

Patients were randomly assigned to one of three groups, with 30 patients in each group. All patients used routine oral care, which included toothbrushing with a soft brush and normal saline rinses three times daily before topical treatment. All treatments were done three times daily to affected oral mucosa until healing or for 10 days, whichever came first. Topical treatments in each group were performed by the resident or nursing staff under researcher supervision.    

• Group 1 (Honey group) applied 0.5 g honey/kg (maximum 15 g) topically to affected oral mucosa.            
• Group 2 (HOPE group) used 0.25 g/kg (maximum 5 g) of a 4:2:1 mixture of honey, olive oil-propolis extract, and beeswax.                                                                 
• Group 3 (control group) received benzocaine 7.5% gel.

• The group consisted of 90 patients, ranging in age from 2–18 years old.
• Mean patient age was 6.9 years. Mean patient age was 9 years (SD = 3.8 years).
• The sample was 63% male and 37% female.
• Patients were included in the study if they
  • Had an acute lymphoblastic leukemia (ALL) diagnosis.
  • Were undergoing the consolidation phase of treatment with methotrexate.
  • Had chemotherapy-related oral mucositis grades 2 and 3 based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC).
• Patients were excluded if they
  • Were diagnosed with diabetes mellitus.
  • Had received antiviral/antifungal therapy or any other treatment for oral mucositis before enrollment.
  • Were experiencing neutropenia with absolute neutrophil count (ANC) of more than 1,500.
  • Had advanced or severe periodontitis (periodontal pockets of 6 mm or greater).

The study was conducted at a single site, inpatient setting at Hematology-Oncology of Children's Hospital of Ain Shams University in Egypt.

• Patients were undergoing the active treatment phase of care.
• This study has clinical applicability for pediatrics.

This was a randomized, non-blinded, controlled, clinical phase II trial.

• The primary outcome measure was recovery time, defined as number of days from initiation of treatment to when complete healing of all ulcers occurred.    
• The NCI-CTC was used.

• In patients with grade 2 mucositis, recovery time was reduced in the honey group as compared with either the HOPE or control groups (p < 0.05).
• In patients with grade 3 mucositis, recovery time did not differ significantly between honey and HOPE (p = 0.6).
• Compared to controls, both the honey and HOPE groups had significantly faster healing (p < 0.01).
• Comparing both grades, honey produced faster healing as compared with either control (p = 0.005; statistical power of 96.2%) or HOPE (p = 0.0056; statistical power of 81.9%).

The superiority of topical honey alone may be related to the amount of honey used as well as better distribution in the oral cavity.

• The sample size was small with fewer than 100 patients.
• The study was not blinded to both researcher and patient.
• The study only involved a select group (pediatrics).
• The authors have a pending patent application for the mixture of honey, beeswax, and olive oil-propolis extract.
• No description was provided regarding the management of mucositis in the control group.
• No information was provided about other treatments for mucositis-related pain.

Mucositis is a significant debilitating side effect of cancer therapy. Effective interventions to reduce or eliminate the severity of this symptom are needed. Further research is needed in all patient populations.

To evaluate the effects of honey on severe oral mucositis

Patients were randomized to the honey or control group. The experimental group was given a topical application of honey before the development of mucositis. Both groups received routine oral hygiene with lidocaine, mycostatin, daktarin mouth gel, and mouthwash.

• N = 40   
• MEAN AGE = 8 years (SD = 4.2 years)
• MALES: 52.5%, FEMALES: 47.5%
• CURRENT TREATMENT: Combination radiation and chemotherapy
• KEY DISEASE CHARACTERISTICS: Hematologic tumors were most common.

• SITE: Single site   
• SETTING TYPE: Inpatient    
• LOCATION: Saudi Arabia

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Pediatrics

Open-label, randomized, controlled trial

• World Health Organization (WHO) mucositis grading
• Oral cultures

Analysis showed an absolute risk reduction for the development of grade 3–4 mucositis of 35% among those using honey (p = 0.02). Less Candida colonization (p = 0.003) and bacterial colonization (p = 0.003) were seen in the honey group.

Honey may have some benefit in the management of oral mucositis.

• Small sample (< 100)
• Risk of bias (no blinding)
• Unintended interventions or applicable interventions not described that would influence results
• Frequency of use of honey not clearly described
• Frequency of oral care not clearly described

There may be some benefit from the use of honey to coat oral mucosa in the management of chemotherapy-induced oral mucositis. This study had several limitations.

To assess the effect of active manuka honey on the grade and duration of mucositis

Patients were randomly allocated by a computer-generated list of random numbers to be given active manuka honey or placebo (golden syrup) mixed with 2% sodium alginate, which increased the contact time by ensuring that the substance adhered sufficiently to the oral and oropharyngeal mucosa. They were shown the technique and given verbal and written instructions to rinse the mouth with 20 ml of the allocated substance and to swallow it slowly, 4 times per day for the duration of the radiotherapy (4 weeks) and for 2 weeks after treatment (42 days in total). To assess compliance, they were also asked to record daily on a card when they took the substance.

The patients were all to receive 4 weeks (20 fractions) of accelerated radiotherapy at a dose between 50 and 55 Gy. Synchronous or induction chemotherapy, or both, was permitted.

Since both substances in the study are known to be cariogenic in patients being treated by radiotherapy, all patients were seen by the hospital dentist before beginning treatment and were provided with fluoride toothpaste and a soft toothbrush and given written and verbal dental hygiene instructions. 

Inter-rater reliability was measured between assessors and found to be higher using the modified scale.

Weekly assessments of mucositis were undertaken during radiotherapy (four weeks) and every two weeks thereafter until the mucositis resolved. Weight was assessed at each assessment.

Swabs were taken from the throat to assess for bacterial and fungal infections. These were taken at baseline and during and after radiotherapy, and the process was overseen by a microbiologist consultant.

• The sample consisted of 131 patients, with 64 in the experimental arm and 63 in the control arm.
• The experimental arm was 83% male and 17% female. The control arm was 92% male and 8% female. 
• The mean age patients in the experimental arm was 59 years old. The mean age of patients in the control arm was 58 years.
• Patients were drawn from a consecutive sample who had either oral or oropharyngeal cancer.

Patients were recruited from an outpatient clinic at a cancer center in northwest England.

Patients were undergoing the active treatment phase of care.

This was a double-blind, randomized, controlled study. The treatment allocation was by minimization with an allocation probability of 2/3 to the arm that would yield a lower imbalance score.

A modified acute radiation toxicity scale of mucositis by the Radiation Therapy Oncology Group was used.

Primary analysis revealed no significant differences in the incidence of grade 3 mucositis or severity or duration of mucositis between the two groups. 

Ninety-eight percent of the patients managed at least 1 week of the intervention, and 67 patients managed more than 2 weeks. Median compliance was 2 weeks for both groups.

The incidence of pathogenic bacteria in both arms was similar to reported baseline values, which indicated that the levels of bacterial colonization were similar to those of an unirradiated mouth. It also confirms the previous findings that honey has a bacteriostatic effect, which might be the result of its hyperosmolar properties, as golden syrup had a similar effect.

No significant differences were found in either the primary or the secondary outcome measures when honey was compared with placebo. The results of the study did not agree with the findings of other trials.

• Poor compliance affected the potential impact of the intervention. Patients reported problems with the taste and texture of the product and cited the effort required to take them as reason for discontinuation.
• Compliance might have been hampered by the use of the carrier agent (sodium alginate).
• The intervention required too much volume and was too sweet for the subjects to be expected to use it daily.
• A different formulation of honey should be used for future studies, using only the active ingredient and using a more liquid formulation.
• This was a single institution study.
• No measurement for or discussion of the use of opioids for pain control in the results and discussion segment of the report, even though this topic was listed as a secondary outcome.
• The article was poorly written with several grammatical errors that hampered understanding.
• The authors did not specify if chemotherapy was given, and, if so, which drugs, amounts, and durations, all of which can influence the development of mucositis.
• Further research is needed to determine methods that are successful in treating grade 3-4 mucositis during radiotherapy.
• The study was not very practical if the median compliance was only half of the study treatment duration. The patients were to swallow 20 ml of honey 4 times a day for the duration of the study, which was too difficult for the participants to accomplish. This intervention is unlikely to be used in clinical practice.

Well-documented bacteriostatic properties of honey exist; further research needs to be done to determine feasibility in the realm of preventing oral mucositis.

To test the effectiveness of the application of a mixture of turmeric and honey on treatment-induced oral mucositis in patients receiving chemotherapy and radiation therapy

Patients were randomly assigned to receive the mixture of turmeric and honey or to a control group that did not receive the intervention. The mixture was applied for five minutes before treatment and again five minutes after treatment. Study measures were obtained on days 2, 4, and 6 of treatment.

• N = 60
• AGE = 50% were between 50–60 years
• MALES: Not provided, FEMALES: Not provided
• KEY DISEASE CHARACTERISTICS: Not provided
• OTHER KEY SAMPLE CHARACTERISTICS: Fifty-five percent were rinsing their mouth after eating, 56.7% were using toothpaste, and 51.7% were brushing their teeth once a day.

• SITE: Single site  
• SETTING TYPE: Not specified  
• LOCATION: India

• PHASE OF CARE: Active antitumor treatment

• Randomized, controlled trial

• World Health Organization Oral Mucositis Scale

The mucositis score was significantly lower at all post measurements in the experimental group (p < 0.05). Scores were similar between groups at baseline, but subsequent measures were lower in the experimental group.

The combination of turmeric and honey may provide some protection against the development of oral mucositis and may provide benefit for treatment.

• Small sample (< 100)
• Risk of bias (no blinding)
• Questionable protocol fidelity
• Not all patients were performing mouth care, and the differences in this aspect between groups is unknown. The method of randomization was not stated. Treatment and disease type information were not provided.

The results of this study suggest that turmeric and honey may have some promise in the management of oral mucositis, but this study has several substantial limitations. Further well-designed research is needed. One of the basic needs for preventing and managing oral mucositis is regular mouth care, the foundation of any intervention.

To determine if honey swished, held, and swallowed reduced the severity of radiation-induced oral mucositis (ROM)

Honey and placebo gel were provided in 5 mL packets to be taken after salt/bicarbonate oral rinses four times a day after meals and after radiotherapy or approximately the same time on non-treatment days. Participants were to pour the product into their mouth, circulate it for 30 seconds, and swallow. Subjects were instructed not to eat, drink, or rinse their mouth for 30 minutes following swallowing the honey or placebo. Treatment started on the first day of radiation and continued for seven days following the last radiation treatment. Visits to the oral oncology/dentistry department were scheduled weekly until mucositis was resolved. During each visit, an oral examination was done for mucositis severity rating, a brief questionnaire was conducted, and weight was obtained. Unused treatment medication was collected at the last visit to measure compliance.

• N = 81  
• MEAN AGE: Honey arm: 56.8 years, placebo arm: 59.5 years
• MALES: Honey arm: 81%, placebo arm: 84%; FEMALES: Honey arm: 19%, placebo arm: 16%
• KEY DISEASE CHARACTERISTICS: Head and neck cancer—hypopharynx, larynx, nasopharynx, oral cavity, oropharynx
• OTHER KEY SAMPLE CHARACTERISTICS: Radiation therapy of ≥ 50 Gy; 62% had concurrent chemotherapy; Caucasian

• SITE: Multi-site 
• SETTING TYPE: Outpatient 
• LOCATION: Vancouver and Sudbury, Canada

• PHASE OF CARE: Active antitumor treatment

• Double-blind, randomized, placebo-controlled, investigator-initiated

• Sialometry and mucositis severity scales from the Radiation Therapy Oncology Group (RTOG)
• World Health Organization (WHO) Oral Mucositis Scale

There were no differences found between the treatment and placebo arms for any of the three outcome assessment scales of mucositis for quality of life, symptom scores, or sialometry. Both the honey (35%) and placebo (43%) groups had lower than expected rates of ≥ grade 3 mucositis.

The honey, when used as directed in this study, did not significantly decrease the severity of ROM. The treatment and placebo groups were well matched, and the blinding was effective. The dropout rate was high (honey: 57%, placebo: 52%, those receiving concurrent chemotherapy: 59%). Most of the dropouts were related to nausea. Patients receiving radiation only had a dropout rate of 48%. Only 48 patients had complete weekly mucositis assessments.

• Small sample (< 100)
• Subject withdrawals ≥ 10%
• Other limitations/explanation: The initial plan for the study was to enroll 180 subjects. The study was terminated at planned interim analysis when 106 patients had been recruited.

There have been varied outcomes in studies of honey for the treatment of mucositis. Differences in methodology could explain at least part of the variability. In this study, the subjects tolerated the honey poorly because of nausea and gagging, and a couple patients experienced a burning sensation. The authors referenced a study from New Zealand in which a honey mouthwash was used because undiluted honey caused extreme nausea, vomiting, and stinging sensations. Potential reasons for the lack of efficacy seen could be that the mucositis tools may not have had adequate sensitivity to reveal any clinical difference between or the osmotic effect of the honey and placebo. Also, Christian areas like Canada, New Zealand, and Great Britain, where honey does not have any special significance, may differ from Muslim areas that have the Koran’s references to honey’s healing powers.

To evaluate the effect of honey and 0.15% benzydamine hydrochloride on the onset and severity of radiation mucositis when compared to 0.9% normal saline

• Patients in group I were instructed to rinse their mouths and swish 20 mL of honey for 5 minutes and slowly swallow. This was to be done 15 minutes before, 15 minutes during, and 6 hours following radiation therapy (RT).
• Group II was instructed to rinse and then spit with 15 mL of 0.15% benzydamine hydrochloride for 5 minutes. This was to be done 15 minutes before, 15 minutes during, and 6 hours following RT.
• Group III (control group) was instructed to rinse with 20 mL of 0.9% normal saline for five minutes and then spit. This was to be done 15 minutes before, 15 minutes during, and 6 hours following RT.  
• The clinical grading of mucositis followed the World Health Organization (WHO) mucositis grading scale on day 1 of RT, daily during treatment, and weekly for two weeks following completion of RT.

• The study reported on 60 patients with an age range of 49–55 years.
• The sample was 70% male and 30% female.
• All patients had oral malignancies and were being treated with RT.

This was a single site, outpatient study conducted in Chennai, India.

Patients were undergoing the active antitumor treatment phase of care.

 This was a three-group, randomized, controlled trial.

Patients were assess via clinical exam.

The onset of mucositis and progression to grades 2, 3, and 4 were noted for each group. Group I had a later onset of grades 1, 2, 3, and 4 mucositis compared to Groups II and III. The difference was statistically significant (p < 0.001).

Honey can be an effective agent in managing radiation-induced oral mucositis. It is simple, inexpensive, and readily available. Further randomized studies are essential to validate the findings.

• The sample size was small with fewer than 100 patients.
• A risk of bias exists because of the lack of blinding.
• A risk of bias exists because of the variations in sample characteristics. For example, the duration of RT varied from 6000-7000 centiGray, and this variation was explained by time not the total dose. The authors did not describe if this difference between groups was statistically significant.
• Although the authors acknowledged that the intensity of mucositis can be altered by fractionation schedules, concurrent chemoradiotherapy, and comorbid medical conditions, including bacterial colonization of the oral mucosa, the study did not address these variables.
• The authors did not discuss how well the patients tolerated the honey.
• Subject withdrawal was not addressed. 
• Pain measurement was not addressed.

Mucositis during RT for oral malignancy is a continuing challenge for patients. Further testing of honey is needed. The availability and cost are benefits. The treatment is not complex or impractical.

To evaluate the use of natural honey for treatment of radiation mucositis

Patients were randomly assigned to the honey treatment or control group. Patients in the intervention group were instructed to take 20 ml of honey 15 minutes before radiation therapy, 15 minutes after radiation therapy, and at bedtime. On days when they had no radiation treatment, they were to take the same amount of honey 3 times per day. Patients were evaluated at baseline, weekly during treatment, and at 3 and 6 weeks after completion of radiation therapy.

• The study reported on 55 patients with head and neck cancer.
• The mean age of patients was 47.5 years with a range of 35–65 years.
• The sample was 78% male and 22% female.

The study was conducted at a single outpatient site in India.

Patients were undergoing the active antitumor treatment phase of care.

This was a randomized controlled trial.

• The World Health Organization (WHO) mucositis scale was used.
• Body weight was recorded.

The authors reported that honey delayed the onset of severe mucositis in about 80% of the intervention group, while 63% of the control group developed severe mucositis.  Grade 3 mucositis developed in 11 patients in the control group and 5 patients in the study group. No statistical analysis was done.

This study suggests that honey may help to delay the onset of mucositis in patients with head and neck cancer during radiation therapy; however, multiple limitations in this report make it impossible to draw firm conclusions.

• The sample size was small with fewer than 100 patients.
• A risk of bias exists because of the lack of blinding and an appropriate attentional control condition.
• Although the authors reported that patients were receiving chemotherapy and radiation therapy, no information was provided regarding the chemotherapy agents used, any treatment delays, or radiation dose at which mucositis developed. 
• No statistical analysis was done.

 Findings as reported from this study are inconclusive regarding any effect of honey on the development of mucositis.

Patients received 20 mL pure, natural honey 14 minutes before radiotherapy, then 20 mL 15 minutes and six hours after radiotherapy. Honey was rinsed and gradually swallowed to coat the oral and pharyngeal mucosa.

• N (honey group) = 20
• N (control group [20 mL NS]) = 20
• KEY DISEASE CHARACTERISTICS: Patients with head and neck cancer received radiation to a total dose of 50–60 Gy.
   

• RCT
  • Single-blind (examiner only)

• Mucositis severity was scored each week of radiation by one clinician blinded to groups.
• Oral Mucositis Assessment Scale (OMAS)

OMAS scores were significantly lower for the honey group than the control group for all weeks (p = 0.000). Significant differences were noted during week six of therapy. Mean weight loss was significantly higher in the control group (p = 0.000).

• Small study

To draw a comparison between the therapeutic effects of treatment modalities (topical steroid, honey, honey plus coffee) in patients with oral mucositis

Patients were randomized to one of three groups that each received a 600 g syrup solution. The solution in the steroid group (S) contained 20, 8 mg Betamethasone solution ampoules. The solution in the honey plus coffee group (HC) contained 300 g of honey plus 20 g of instant coffee. The solution in the honey group (H) contained 300 g of honey. Every three hours for one week, patients were instructed to sip 10 ml of their solution and swallow it. Data were collected prior to the initiation of the intervention and one week later. Patients were not allowed to use any other anti-inflammatory agents during the study. Patients and providers were blinded to the groups.

• N = 75
• AVERAGE AGE = 55.2 years
• MALES: 48%, FEMALES: 52%
• KEY DISEASE CHARACTERISTICS: None presented
• OTHER KEY SAMPLE CHARACTERISTICS: Participants who presented with oral mucositis after chemotherapy during a period of three years at the hospital site; patients with oral mucositis after chemotherapy between 15 and 80 years old

• SITE: Single-site    
• SETTING TYPE: Inpatient    
• LOCATION: Baqiyatallah University Hospital, Tehran, Iran

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Pediatrics, elder care, palliative care 

Double-blinded, randomized clinical trial

• The World Health Organization (WHO) oral toxicity scale was used to grade oral mucositis.
• A physician-rated questionnaire was created and validated for this study (questions not available).

All three regimens significantly reduced oral mucositis at the end of the intervention week (p < .05).

A steroid solution, honey plus coffee solution, or honey only solution reduced the severity of oral mucositis after one week of treatment.

• Small sample (< 100)
• Risk of bias (no control group)
• Risk of bias (no appropriate attentional control condition)
• Unintended interventions or applicable interventions not described that would influence results
• Key sample group differences that could influence results
• Findings not generalizable
• Other limitations/explanation: The study did not take into account what chemotherapy regimens the participants received or the point in the treatment regimens at which mucositis developed. The study also did not report which disease characteristics the participants had prior to treatment. The study did discuss in great length how each solution was prepared. There was no control group.

Further investigation is needed on this intervention taking into account participants' diseases and chemotherapy regimens received.

Patients smeared 20 mL of pure, natural honey (acidic with a pH of about 3.9) on the inside of their mouths 15 minutes before, 15 minutes after, and six hours after radiation. Patients rinsed honey on oral mucosa and then swallowed it slowly. Patients were randomized to the treatment or control group. Patients also used benzydamine HCL plus supportive oral care measures. A solubility-reducing factor present in honey can activate in the absence of saliva.

• N (experimental group) = 20
• N (control group) = 20
• KEY DISEASE CHARACTERISTICS: Patients with head and neck cancer receiving chemotherapy and radiotherapy
• OTHER KEY SAMPLE CHARACTERISTICS: Radiation dose of 60–66 Gy; chemotherapy: cisplatin 20 mg/m² once a week before radiotherapy

• April 2005–July 2006

• World Health Organization

• Treatment group: No patients developed grade 4 mucositis, and only three (15%) developed grade 3 mucositis.
• Control group: Three patients (15%) developed grade 4 mucositis, and nine (45%) developed grade 3 mucositis.
• Stated as significant, but value not given
• Five patients in the control group had therapy interrupted.
   

• Small sample
• Did not give p values for differences in mucositis
   

• Easy to use
• Cost-effective
• Pleasant

PURPOSE: Review evidence and provide guidelines for use of natural agents in the prevention and management of oral mucositis in cancer

TYPES OF PATIENTS ADDRESSED: Patients receiving chemotherapy, radiation therapy, or stem cell transplant

RESOURCE TYPE: Evidence-based guideline

PROCESS OF DEVELOPMENT: Systematic review of evidence, quality rating using Hadorn criteria, and level of evidence classified via Somerfield criteria

DATABASES USED: MEDLINE

KEYWORDS: Alternative, complementary, homeopathic, aloe vera, beta carotene, chamomile, chines herbal, folic acid, and numerous other specific natural agents

INCLUSION CRITERIA: Not specified, other than use of a natural agent

EXCLUSION CRITERIA: Not specified

PHASE OF CARE: Active antitumor treatment

APPLICATIONS: Pediatrics

Ninety-nine papers were identified, and, of these, 49 papers were included in the review.

• Glutamine (20 studies)—not recommended for prevention in patients undergoing hematopoietic cell transplantation. For other situations, no guideline was deemed possible.
• Vitamins A  or E (eight studies)—no guideline possible
• Honey (four studies)—no guideline possible. Each study used a different type of honey.
• Zinc (four studies)—no clear recommendation is given, but the committee suggested it may be of benefit for prevention in patients with oral cancer during radiation or chemoradiation therapy.
• Twelve studies of various other agents were reviewed. No guidelines were possible in any of these.

• Many studies were of low quality, and some were more than 10 years old. 
• Hadorn criteria reliability is questionable. 
• For many products, only one study was found.

Findings do not support efficacy of currently studied natural herbal agents and other agents for prevention of oral mucositis. Systemic zinc supplementation may be helpful for patients with oral cancer receiving treatment. Glutamine is not recommended in patients undergoing cell transplant. Further, well-designed research in this area continues to be needed.