Evaluating the effectiveness of topical application of natural honey and benzydamine hydrochloride in the management of radiation mucositis
Background: Radiation mucositis is an early effect of head and neck radiotherapy. Mucositis can cause ulcers, and patients may experience pain and dysphagia which need proper management. This study was conducted in 60 patients with oral malignancy.
Keywords: Benzydamine hydrochloride, Natural honey, Oral malignancy, Radiation mucositis
Radiotherapy (RT) is the treatment of cancer and other diseases with ionizing radiation. Radiation damages both cancer cells and normal cells. The normal cells are able to repair themselves and function properly. RT is indicated for majority of head and neck cancer patients. 
Mucositis is the painful inflammation and ulceration of the mucous membranes lining the alimentary tract, usually as an adverse effect of chemotherapy and radiotherapy treatment for cancer. Mucositis can occur anywhere along the alimentary tract, but oral mucositis refers to the inflammation and ulceration that occurs in the oral cavity. Oral mucositis is a common and often debilitating complication of cancer treatment. 
At present, mucositis is recognized as an epithelial and sub epithelial injury that develops in five phases (Initiation, Primary damage response, Signal amplification, Ulceration, Healing).  Prevention of mucositis is still limited to reduction of its severity by relief of pain and discomfort, oral health care programs, and/or strategies to eliminate microbes that are thought to be involved in the development or promotion of radiation mucositis.  Honey is a by-product of flower nectar and secretion of the upper aero-digestive tract of the honeybee, which is then concentrated through a dehydration process inside the bee hive. Honey is an age-old remedy from the time of Egyptian civilization, but only very recently it has found a place in modern medicine.  Because of its high viscosity, hygroscopic nature, rich nutritional properties, acidic PH, hydrogen peroxide and high osmolarity, honey can inhibit bacterial growth and enhance healing.  Also, honey has been used to manage burns, infected surgical wounds, post operative wound infections, pressure ulcers. ,,, Biswal  used topical honey to manage radiation mucositis successfully for the first time. The aim of this study is to evaluate the effect of natural honey and 0.15% benzydamine hydrochloride on onset and severity of radiation mucositis and to compare it with control.
This study was conducted in the Department of Oral Medicine and Radiology, Tamilnadu Government Dental College and Hospital, Chennai-3, and the Department of Radiation Oncology, Government General Hospital, Chennai-3 from April 2010 to December 2010. The study was approved by the institutional ethical committee.
Sixty patients (42 males and 18 females) diagnosed with oral malignancy clinically and histopathologically were selected for the study. Informed consent was obtained from all participants. Selected patients had no history of previous radiotherapy/chemotherapy or other systemic diseases. Conventional fractionated radiation was delivered to the tumor volume at a dose rate of 2 Gray per fraction, treating five fractions per week to a total period of 6-7 weeks, at the Department of Radiation Oncology, Government General Hospital, Chennai. The weekly dosage was 10 Gray. The total dosage given varied from 60 to 70 Gray (6000 to 7000 centi Gray).
The patients were assigned into three groups by random sampling. Each group consisted of 20 patients. Group 1 comprised of 11 males and 9 females. Group II comprised of 15 males and 5 females. Group III (Control) comprised of 15 males and 5 females.
The materials used in our study were Pure Natural Honey (Dabur honey), 0.15% Benzydamine hydrochloride (Tantum oral rinse), 0.9% normal saline.
In the group I, the patients were instructed to take 20 ml of natural honey 15 minutes before RT. They were instructed to slowly rinse the honey in their mouths, swish it around for 5 minutes duration, so as to make the honey in contact with the oral mucosa and slowly swallow so as to make better contact with the pharyngeal mucosa. The patients were exposed to therapeutic radiation. After 15 minutes and 6 hours after RT, the patients were instructed to slowly rinse the honey in their mouths, swish it around for 5 minutes duration and then swallow.
In group II, Patients were instructed to rinse with 15 ml of 0.15% benzydamine Hydrochloride without dilution for 5 minutes duration, 15 minutes before RT. The patient should be instructed to keep the rinse in contact with the oral mucosa for at least 5 minutes duration, and then spit it out. The patients were exposed to therapeutic radiation.
After 15 minutes and 6 hours after RT, the patients were instructed to rinse with 15 ml of 0.15% benzydamine hydrochloride, for 5 minutes duration and then spit it out.
In group III (control group), Patients were instructed to rinse with 20 ml of 0.9% normal saline, for 5 minutes duration,15 minutes before RT. The patient should be instructed to keep the saline rinse in contact with the oral mucosa for at least 5 minutes duration, and then spit it out. The patients were exposed to therapeutic radiation. After 15 minutes and 6 hours after RT, the patients were instructed to rinse with 20 ml of 0.9% normal saline, for 5 minutes duration and then spit it out.
The clinical grading of mucositis in the three groups were done according to WHO Mucositis Grading.  The days of onset of mucositis (grade 1) and progression to different grades were noted.
The study was started in April 2010 and completed in December 2010, and all cases received RT as planned. The patient details like age, sex, the localization of the primary tumor, TNM staging of the malignancy are presented in [Table 1]. All the patients were clinically examined from day 1 of RT, throughout the RT regimen and two weeks after completion of RT for development of oral mucositis.
The complete oral examinations were done every day for the patients in the three groups. The day of onset (Grade 1) of mucositis [Figure 1] and the progression to grades 2, 3 and 4 [[Figure 2],[Figure 3] and [Figure 4] respectively] were noted in all the three groups [[Table 2] ,Graph 1[Additional file 1]]. The grading of mucositis in the three groups was recorded at the end of 1 st and 2 nd weeks after RT.
The onset of mucositis (Grade 1) was on 14 th day in group I compared to 12 th day in group II and group III.
The grade 2 was observed only on 19 th day in group 1, compared to 16 th day in both groups II and III.
The grade 3 was observed only on the 25 th day in group 1, compared to 21 st day in groups II and III.
The grade 4 was observed only on the 34 th day in group 1, compared to 27 th day in groups II and 26 th day in group III.
The results revealed that patients in Group I had a late onset of Grades 1, 2, 3 and 4 mucositis, compared to Group II and Group III [Table 3] and the difference was statistically significant.
Only 30% of patients developed more debilitating grade 4 mucositis in group I, compared to group II whereby 95% of patients developed grade 4 mucositis and group III, whereby 100% of patients developed grade 4 mucositis.
Hence, pure natural honey prevents more debilitating Grade IV mucositis and also delays the onset of grade IV of radiation-induced mucositis.
At the end of 1 st week after RT, out of 20 patients in the Group 1, only 10% of patients were with grade 3 mucositis, compared to 50% of patients in the group 2 and 55% of patients in group 3. This shows the low incidence of grade III in the group 1 compared to groups 2 and 3 [Table 4].
At the end of 2 nd week after RT, out of 20 patients in the Group 1, no patients were with grade 3 (0% of patients), compared to 5% of patients in the group 2 and 30% of patients in group 3.This shows the low incidence of grade III in the group 1 compared to groups 2 and 3 [Table 5].
Another finding is that at the end of two weeks after completing RT, 15% of patients in group I, had recovered completely without any signs or symptoms of mucositis (Grade 0), compared to none of the patients in groups II and III [Table 5].
This result shows that the oral mucosa enters a healing phase, more faster in the group 1 more than the groups 2 and 3.
The results reveal that pure natural honey delays the onset of grade 1 of radiation induced mucositis. The severity of radiation mucositis, assessed by the number of patients with symptomatic grade 4, is also reduced by the use of pure natural honey. Thus, topical application of natural honey is a simple and cost-effective treatment in radiation mucositis.
Oral complications arising from radiotherapy are a result of radiation injury to the oral mucosa, tongue, salivary glands, oral musculature and alveolar bone. Radiation mucositis is a complication of radiotherapy for the management of malignancy pertaining to the head and neck region. Normally, the oral mucosa has a relatively high mitotic rate. Exposure to ionizing radiation leads to mucosal erythema, small whitish patches  and ultimately results in confluent mucositis. In the later stages, oral ulceration and bleeding become a dose-limiting toxicity. Mucositis is a result of imbalance between cell death and cell division. The intensity of mucositis can be altered by new fractionation schedules, concurrent chemo-radiotherapy and co-morbid medical conditions. Bacterial colonization in the oral mucosa can aggravate and worsen the pre-existing mucositis. Endotoxins released from the gram-negative bacilli are potent mediators of the inflammatory process in the oral mucosa. Oropharyngeal flora too contributes to the radiation mucositis. 
Other factors like poor oral hygiene and tobacco chewing and smoking habits can contribute to radiation induced mucositis . Various agents have been tried for management of radiation mucositis. The agents recommended or tested for the prevention and management of radiation mucositis, have targeted specific pathways and they include mucosal coating agents, anti-inflammatory agents, antimicrobials, subcutaneous or topical granulocyte macrophage colony stimulating factor, anesthetics and analgesics, and other agents that are difficult to classify. These locally applied as well as systemically taken agents have been supportive at most, consisting of measures to reduce pain and improve discomfort, support adequate hydration and, in some the ability to eliminate secondary infections. ,
Honey forms primarily from the transformation and concentration of nectars from flowers by two processes: The interaction with the upper digestive tract secretion of honeybees and concentration by water loss in the beehives. They contain moisture, fructose, glucose, sucrose, maltose and other compounds, along with trace elements. 
The observation of 70% patients in group I, to not have developed grade 4 mucositis, in our study, also is consistent with the study by Rashad U M et al. in 2006, wherein no patients in the study arm (honey treated) developed grade 4 mucositis.  This observation is consistent with the study by Biswal, Zakaria, Ahmad in 2002,  wherein they reported that there is significant reduction in symptomatic grade 3 and 4 mucositis in honey treated group. In the same study, the mean onset of mucositis both in study and control groups was 3 weeks.
This observation is also consistent with study by B. Khanal, M. Baliga, N. Uppal in 2009, wherein it was observed that the proportion of patients with intolerable oral mucositis was lower in honey group compared with controls. 
M. Motallebnejad et al. in 2004 observed that, in the honey treated group, the mucositis score at the end of each week was significantly lower than the control group. 
In this study, we analyzed the grades of mucositis (WHO mucositis grading) everyday, the day of onset of mucositis (grade 1) and the days of onset of grade 2, 3 and 4.
The results reveal that pure natural honey delays the onset of radiation induced mucositis. The severity of radiation mucositis, assessed by the number of patients with symptomatic grades 3 and 4, is also reduced by the use of pure natural honey.
At the end of post RT 1 st and 2 nd weeks there was low occurrence of Grade 3 in the honey group compared to 0.15% benzydamine and 0.9% saline groups.
The ancient Egyptians and Greeks used honey for wound care, and a broad spectrum of wounds are treated all over the world with natural unprocessed honey from different sources. 
The philosophy of using honey in radiation mucositis was derived from the basic research and clinical observation of rapid epithelization in tissue injuries. , Coating a wound with honey retards tissue oxygenation by sealing the damaged mucosa from air (oxygen). This could dampen pain within 30 seconds after application. 
Important factors that influence the effectiveness of honey are (1) Its hygroscopic nature, (2) Acidic pH prevents bacteria growth when applied to the mucosa; (3) Inhibin (hydrogen peroxide) converted from glucose oxydase and gluconic acid; (4) Enzymes (growth factors) and tissue-nutritive minerals and vitamins help repair tissue directly. The reduction of radiation-induced mucositis in honey-treated patients might be due to the bacteriostatic effect of viscid honey. Pure honey is acidic, with a pH of around 3.9. The solubility reducing factor present in honey can activate in absence of saliva. Honey applied on radiation-induced xerotic mucosa increases the micro-hardness of enamel, thereby preventing caries. Hence, it has been postulated that honey is less cariogenic in dry mouth patients. 
In a report of the Russian academy of Medical Science, patients treated with honey laminolact in uterine cancer patients undergoing radiotherapy showed significant decrease in the severity of radiation-induced intestinal morbidity. 
Pure honey is natural, and exhibits analgesic, antibacterial and tissue nutritive factors to stimulate re-epithelisation in the damaged oral mucosa, and is thereby a justified agent to use in radiation mucositis.
From the study, we conclude that pure natural honey can be an effective agent in managing radiation induced oral mucositis. Honey could be a simple, potent and inexpensive agent, which is easily available, especially in the present Indian scenario for the management of this morbidity. However, further randomized studies are essential to validate our findings.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]