The Effect of Topical Application of Pure Honey on Radiation-induced Mucositis: A Randomized Clinical Trial

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The Effect of Topical Application of Pure Honey on Radiation-induced Mucositis:

A Randomized Clinical Trial

Aim: Radiation-induced mucositis is an early effect of head and neck radiotherapy. Mucositis can cause ulcers, and patients may experience pain and dysphasia which need treatment. The aim of this study is to evaluate the effect of pure natural honey on radiation induced mucositis.

Methods and Materials: In this randomized single blind (examiner blind) clinical trial 40 patients with head and neck cancer requiring radiation to the oropharyngeal mucosa were randomly assigned to two groups. Twenty patients assigned to the study group received honey, while both the study and control groups received standard head and neck radiation therapy based on a standard protocol. In the study group patients were instructed to take 20 ml of honey 15 minutes before radiation therapy, then again at intervals of 15 minutes and six hours after radiation. In the control group patients were instructed to rinse with 20 ml of saline before and after

radiation. Patients were evaluated weekly for progression of mucositis using the Oral Mucositis Assessing Scale (OMAS). Data were analyzed using the independent t-test, Mann-Whitney, and Friedman tests.

Results: A significant reduction in mucositis among honey-received patients compared with controls (p=0.000) occurred.

Conclusion: Within the limits of this study the results showed the application of natural honey is effective in managing radiation induced mucositis.

Abstract

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Introduction

Cancer is one of the major threats to public health in the developed world and increasingly in the developing countries. In developed countries cancer is the second most common cause of death.1 When deaths are aggregated by age, cancer has surpassed heart disease as the leading cause of death for persons younger than 85 since 1999.2 According to the World Health Report 2004 cancer accounted for 7.1 million 4 deaths in 2003, and it is estimated the overall number of new cases will rise by 50% in the next 20 years.3 Oropharyngeal cancer is more common in developing countries.4,5

Radiotherapy plays an important role in the management of head and neck cancer. The majority of new cases with invasive head and neck cancer will require radiotherapy as a primary treatment, as an adjunct to surgery, in combination with chemotherapy, or as palliation.6 Most patients with head and neck carcinomas, treated with curative intent, receive a dose

between 50 and 70 Gy. This dose is usually given in 2 Gy fractions once a day for five days a week over a five to seven week period. In addition to an anti-tumor effect, ionizing radiation causes damage to normal tissues located in the radiation portals. The most common acute complication of radiotherapy in the head and neck region is oral mucositis.7Radiation mucositis is considered to be an inevitable but transient side effect of therapeutic head and neck irradiation and is

strongly related to radiation dose, fraction size, volume of irradiated tissue, fractionation scheme, and the type of ionizing irradiation.8At present, mucositis is recognized as an epithelial and subepithelial injury that develops in five phases:9

1. Initiation

2. Primary damage response 3. Signal amplification 4. Ulceration

5. Healing

The Consensus Development Panel of the National Institutes of Health10 has stated no drugs can prevent mucositis, an opinion that still holds true to date.8,11,12 Consequently, prevention of mucositis is still limited to reduction of its severity by oral care programs, relief of pain and discomfort, and/or strategies to eliminate microorganisms that are thought to be involved in the development or promotion of radiation mucositis.6

Honey is a by-product of flower nectar and the upper aero-digestive tract of the honeybee, which is concentrated through a dehydration process inside the bee hive. Though honey is an age-old remedy from the time of Egyptian

civilization, very recently it has found a place in modern medicine.13 Because of its high viscosity, acidic PH, hydrogen peroxide, high osmolarity, and rich nutritional properties honey can inhibit bacterial growth and enhance healing.14-16 Also, honey has been used to manage burns, oral infections, surgical wounds, and pressure wounds.15-19 Biswall13used topical honey to manage radiation mucositis successfully for the first time.

Clinical Significance: Natural honey is a product with rich nutritional qualities that could be a pleasant, simple, and economic modality for the management of radiation mucositis.

Keywords: Mucositis, honey, cancer, radiotherapy, Oral Mucositis Assessing Scale, OMAS

Citation: Motallebnejad M, Akram S, Moghadamnia A, Moulana Z, Omidi S. The Effect of Topical Application of Pure Honey on Radiation-induced Mucositis: A Randomized Clinical Trial. J Contemp Dent Pract 2008 March;

(9)3:040-047.

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an appropriate and similar material to use as a placebo was impossible because all materials similar to honey may have some effects on mucositis because of the high viscosity or high carbohydrate concentration. As a result, the 20 patients in the control group were advised to rinse their mouths with 20 ml of normal saline (0.09%) before and after each radiotherapy session. The patients in this control group were matched to the study group by sex, age, the localization of the primary tumor, radiation dose, and general health status.

Both groups were provided instruction on adequate fluid intake, supplementation with a high protein diet, and oro-dental care. The weight of patients was measured at the beginning and at the end of treatment. During the course of treatment, patients with a severe burning sensation in the mouth, pain, or with a WBC count less than 3000/mm3 were excluded from the study.

Examinations of the oral mucosa were performed on all patients at the beginning of treatment and continued weekly up to the end of radiotherapy by an evaluator who was blinded to the group assignments of the participants. The Oral Mucositis Assessing Scale (OMAS) was used to score the ulceration or pseudo membranous areas from 0 to 3 and erythema with scores ranging from 0 to 2 in nine distinct areas of the mouth.11A score of ‘0’ is without erythema or ulceration (pseudo membranous area), and a score of 3 is an ulceration more than 3 cm in diameter or severe erythema. The final score could range from 0 to 45.

In this study pure natural honey from Thymus and Astragale in the Alborz mountains in northern Iran was used. The organoleptic, microbial, and physicochemical analysis of the honey sample was evaluated by authorized Drug and Food Control Laboratory of the Ministry of Health of Iran. A microbiological assay was done against pathogenic organisms at pure, 1:2, 1:4, and 1:8 dilutions, respectively. Cultures of Pseudomonas aeruginosa, Streptococcus pyogenes,

Staphylococcus aureus, and Escherichia coli were i plated on BHI agar and a filter disc was placed on the medium. A volume of 30 μl of pure and 1:2, 1:4, and 1:8 diluted honey was placed on the The aim of this study is to evaluate the effect of

topical pure honey on radiation mucositis.

Methods and Materials

This double blind randomized clinical trial was conducted in the Babolsar Center for Cancer from March, 2003 to August, 2004.

Forty patients (18 females and 22 males with a mean age of 57.05±9.43 and 56.95±14.5, respectively) with head and neck cancer who underwent radiotherapy of the head and neck were selected. Informed consent was obtained from all participants. This project was approved by the Ethics Committee of the Babol University of Medical Sciences. Selected patients had no history of previous radio chemotherapy or other systemic diseases. All patients’ blood sugar levels were checked, and those with a FBS > 150 mg/

dl were not selected. All patients were advised to avoid alcohol, spicy and acidic foods, smoking, and to maintain good oral hygiene during the course of radiotherapy.

Radiotherapy was administered using Cobalt 60 at a dose of 1.8 to 2 Gy per day, five times a week up to total dose of 50 to 60 Gy (in five to six weeks).

Patients were divided into two groups. The study group of 20 patients took 20 ml pure natural honey 15 minutes before then 20 ml doses again at 15 minutes and six hours after radiotherapy.

They were instructed to rinse the honey around in their mouths and swallow gradually in order to coat the oral and pharyngeal mucosa. Finding

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In the study group four patients (20%) showed no evidence of mucositis during the radiotherapy course leading to refusal of treatment or taking of medication.

The mean rank of OMAS at the end of each week in two groups was estimated (Table 1).

The mucositis score of OMAS at the end of each week in the study group was significantly lower than the control group (Mann-Whitney test) (p=0.000) (Figure1).

The mucositis score changes for the two groups during the six weeks were compared using the Friedman test and showed significant differences in the OMAS during the six weeks (p=0.000) (Figure 2).

Weight loss was measured in both groups. In the study group the mean weight loss was 1±0.35 (0 to 7 kg). Ten patients showed no weight loss in this group. In the control group the mean weight loss was 6.3±0.53 (2 to 11 kg). The mean weight loss in both groups was analyzed using the independent Sample t-test which was significantly higher in the control group (p=0.000).

Discussion

This study showed honey had a remarkable effect on radiation mucositis which confirms the Biswal’s study of the effect of honey on radiation mucositis.13

Radiation mucositis develops early during radiotherapy. The acute mucositis response to radiotherapy is a result of mitotic death of epithelial cells, since the cell cycle time of the discs. In another plate 100 μl of pure and 1:2, 1:4,

and 1:8 diluted honey was placed in the wells.

The plates were incubated for 24 hours at 37°C and the inhibition zone was measured.

The weights of all patients were checked before and after the radiotherapy courses. Data were analyzed using the Independent Sample t-test and the Mann-Whitney and Friedman tests by means of SPSS software (SPSS Inc., Chicago, IL, USA) with p<0.05 considered significant.

Results

The study was completed in August 2004, and all cases received radiotherapy as planned. The distribution of primary tumors was as follows:

• Nasopharynx (20 cases)

• Oral cavity (10 cases)

• Salivary glands (3 cases)

• Hypopharynx (4 cases)

• Tonsils (3 cases)

The pH of the honey was 3.3 and its density was 1.202 g/ml. The organoleptic properties and microbial tests were compatible with standard criteria. The fructose/glucose ratio was 0.7.

Antibacterial activity was negative in each dilution for all four organisms.

The 40 patients evaluated were 18 females and 22 males with a mean age of 57.05±9.43 and 56.95±14.5, respectively. In the control group three patients in the fourth week and three patients in the fifth week took medication because of severe mucositis. In addition, two patients in the fourth week and one in the fifth week of radiotherapy temporarily refused to continue the treatment.

Table 1. Mean rank (95% Confidence Interval) of OMAS at the end of each week during radiation therapy in the two groups.

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the mucositis and endotoxins released from gram-negative bacilli are potent mediators of thei inflammatory process in the oral cavity.21,22 A major difficulty to interventional and

epidemiologic mucositis research has been the lack of an acceptable, validated, and objective scoring system for mucositis. Many researchers have developed different scoring systems, often with different objectives. These systems have attempted either to eliminate subjective findings basal keratinocytes is about four days.8Radiation

mucositis is defined as a reactive inflammation of the mucous membrane during radiotherapy.

It is characterized by atrophy of squamous epithelial tissue, absence of vascular damage, and an inflammatory infiltrate concentrated at the basement region.20The early radiation reaction causes discomfort as well as difficulties in drinking, eating, swallowing, and speech, which gives rise to nutritional problems. Bacterial colonization in the oral mucosa can aggravate

Figure 1. Comparison of the median of mucositis (OMAS) in two groups.

Figure 2. Mucositis changes (OMAS) during six weeks of treatment in two groups.

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wound infections.30,31Important factors which influence the effectiveness of honey are as follows:13

• Its hygroscopic properties

• Its acidic pH

• The conversion of hydrogen peroxide from glucose oxydase and gluconic acid

• Its enzymes and tissue nutrition minerals and vitamins that help repair tissue directly

The antibacterial effects of honey are divided into physical and chemical effects. The physical effect is based on high osmotic properties so it can extract water from bacterial cells and cause them to die.14The chemical effect of honey is related to elements having antibacterial properties such as the glucose oxidase enzyme which produces hydrogen peroxide and prorolis.14,17

The effect of honey on infection is not only related to antibacterial agents but also to its effect on the proliferation of B and T lymphocytes.32 Furthermore, 1% honey in a tissue culture can release TNF, IL-1, and IL-6 from monocytes.33 The comparison of the results of the present study to the Biswall13 study shows the effect of honey on mucositis is not only due to its antibacterial properties since the honey used had no effect against the same microorganisms studied by Biswall. However, the honey used in the present study had a similar effect on radiation- induced mucositis.

Conclusion

Within the limits of the Biswall and present study, it seems the effect of honey is not only based on antibacterial effects or geographic location and source of pollens but due to the combination of all useful properties in natural honey. However, further studies are needed to confirm these results.

Clinical Significance

Natural honey is a product with rich nutritional qualities that could be a pleasant, simple, and economic modality for the management of radiation mucositis.

completely or to evaluate them independent of objective findings and then integrate them into a comprehensive score. The OMAS was first suggested by Sonis11who showed the scale was easy to use and had a high interobserver reproducibility. The OMAS was responsive over time and measured those elements deemed to be associated with mucositis. It also showed the use of concomitant symptomatic measurements by VAS and questionnaires are likely unnecessary.11 Because of these findings the OMAS was used for scoring of radiation mucositis in the present study.

Prevention of mucositis is still limited to reduction of its severity by oral care programs, relief of pain and discomfort, and/or choosing strategies to eliminate microorganisms that are thought to be involved in the development or promotion of radiation mucositis. Currently, most oral care programs target the following:8

• Removal of mucosal irritation factors

• Cleansing of the oral mucosa

• Maintaining moisture of the lips and the oral cavity

• Relief of mucosal pain and inflammation

• Prevention or treatment of infection There are many different modalities for management of mucositis such as using transforming growth factor ß3,23 keratinocyte growth factor,24 chemical protection of mucosa such as amifostine,25 G-CSF,26 anti inflammatory agents,27and local antibiotic lozenges.28These treatments are not easy to use and produce inconsistent results.

Honey is flower nectar which is transformed and concentrated within the upper digestive tract and secreted by honey bees. Honey contains moisture, fructose, glucose, sucrose, maltase and other compounds, along with trace elements.29 The quality of honey basically depends upon its source and dilution. In the present study honey obtained mainly from Thymus and Astragale in northern Iran was used.

In the recent past honey has been used for the treatment of burn wounds,16 infected surgical wounds,18 pressure ulcers,19 and postoperative

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About the Authors

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Aknowledgement

The authors would like to express their appreciation to Mr. Hadjian and all the staff of Shahid Rejaie Center of Radiotherapy in Babolsar, Iran for their assistance with this study.

This project was supported by the Research Council of Babol University of Medical Sciences.

We also appreciate Dr. Sabetha for useful advices.

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