Available online at www.sciencedirect.

com

European Journal of Integrative Medicine 5 (2013) 217225

Review article

The effectiveness of honey for the management of radiotherapy-induced oral

mucositis in head and neck cancer patients: A systematic review of clinical
trials
Melanie Charalambous a , Vasilios Raftopoulos b , Ekaterini Lambrinou a , Andreas Charalambous c,
a

Cyprus University of Technology, Nursing Department, Limassol, Cyprus

Cyprus University of Technology, Nursing Department, Mediterranean Research Centre for Public Health and Quality of Care, Limassol, Cyprus1
c Cyprus University of Technology, Nursing Department, Euro-Mediterranean Research Centre for Oncology and Palliative Care, Cyprus2
Received 26 November 2012; received in revised form 16 January 2013; accepted 16 January 2013

Abstract
Aim: To evaluate the effectiveness of honey in the management of oral mucositis in head and neck cancer patients undergoing radiotherapy.
Methods: The review of the literature was based on a keyword strategy and pre-determined inclusion and exclusion criteria. The keywords
head and neck cancer, radiotherapy, oral mucositis, controlled trial and honey were used as search terms in the EMBASE, CINAHL,
COCHRANE and PUBMED databases. The citation and reference list of the eligible articles were also screened for potentially relevant articles.
The methodological quality of the selected trials was assessed by the JADAD scale.
Results: In total, 5 studies met the criteria and were included in the systematic review. Three studies assessed the effectiveness of honey against
other products including golden syrup, lignocaine and saline and two studies assessed the effectiveness of honey against standard treatment regimes.
Four out of the five studies demonstrated significant reduction in the mucositis levels and one study reported that honey had no statistical association
with less severe mucositis. Methodologically the quality of most studies was moderate due to the small sample size, which might impact upon the
significance of the findings.
Conclusions: Although honey appears to be a simple, affordable, available and cost-effective treatment for the management of radiation-induced
oral mucositis, there is a need for further multi-centre randomized trials to validate these findings.
2013 Elsevier GmbH. All rights reserved.
Keywords: Clinical trials; Honey; Oral mucositis; Radiation therapy; Head and neck cancer

Introduction
An estimated 36,500 new cases of and 7900 deaths from oral
cavity and pharyngeal cancers occurred in 2010 in the United
States [1]. Squamous cell carcinoma or a variant is the histologic
type in more than 90% of these tumours [2,3]. The three main
kinds of treatment that may be given independently or in combination, for head and neck cancers include surgery, chemotherapy

Corresponding author at: Nursing Department, Cyprus University of Technology, Cyprus. Tel.: +357 25002011; fax: +357 25002822.
E-mail address: andreas.charalambous@cut.ac.cy (A. Charalambous).
1 www.cut.ac.cy/medyp.
2 http://www.euro-mediterraneancenter.com.
1876-3820/$ see front matter 2013 Elsevier GmbH. All rights reserved.
http://dx.doi.org/10.1016/j.eujim.2013.01.003

and radiation therapy (RT). The treatment plan for an individual

patient depends on a number of factors including the location
of the tumour, the stage and the pathologic findings. These
factors consecutively guide the appropriate radiation protocol,
chemotherapy regime or surgical procedure to be followed [4].
Single-modality treatment with surgery or radiotherapy is generally recommended for 3040% of stage III head and neck
cancer patients [5]. In addition to its desired effect on cancer
cells, radiation therapy often causes acute toxicities although
most of them are temporary. Most side effects occur towards the
middle and the end of the course of treatment and continue during the first couple of weeks after the treatment has finished. The
effects can be mild or severe, depending on the dose of RT and
the length of the treatment. Oral mucositis is one of the most

218

M. Charalambous et al. / European Journal of Integrative Medicine 5 (2013) 217225

common, severe and persistent side effects that patients with

head and neck cancer confronted during and after radiotherapy.
Molecular and cell biology in oral mucositis is a multistep process. Sonis [6] has described a five phase model to
characterize the theory for the pathogenesis of oral mucositis. These phases include initiation, signalling, amplification,
ulceration and healing [6]. According to this theory, reactive
oxygen species generated by exposure to radiation therapy or
chemotherapy result in DNA strand breaks and that causes
damage to the cells, tissues and blood vessels. These damages
activate transcription factors which cause increased production
of pro-inflammatory cytokines like interleukin that lead to tissue
injury and apoptosis. The cytokines cause further tissue damage
which amplifies the signalling cascade that lead to ulceration and
inflammation. A signal send by the submucosal tissue initiates
the healing process which in turn stimulates epithelial proliferation and cellular differentiation restoring the lining of the oral
cavity [6].
The development of oral mucositis is an expected accompaniment of radiation therapy applied to the head and neck regions.
Severe radiation mucositis leads to ulceration and painful dysphagia that can negatively influence the quality of life and
force the discontinuation of treatment. At least 50% of patients
will experience some grade of oral mucositis as well as grade
3 mucositis when 6670 Gy radiation are delivered to large
mucosal surfaces in 67 weeks with 1.82 Gy per fraction [7].
A variety of treatments are used for the prevention and the
management of oral mucositis and the choice of the treatment
depends on the patients condition and needs. The most usual
categories of these agents include topical cytoprotective agents
(e.g. sucralfate), anti-inflammatory agents (e.g. benzydamine
hydrochloride), antibacterial agents (e.g. chlorhexidine) topical
or systemic anti-oxidants (e.g. amifostine, vit. E) and sialogogues [810]. Cryotherapy and low-level laser therapy found
to be helpful in reducing the severity of chemotherapy and
radiation-induced oral mucositis [11,12]. Keratinocyte growth
factor (KGF-1, palifermin), G-CSF and GM-CSF factors and
glutamine (nonessential amino acid) are some of the therapies
which have recently been evaluated for preventing and managing oral mucositis [1315]. Despite the availability of treatment
options for oral mucositis, these do not seem to provide an
effective and comprehensive management method [16].
In the light of the ineffectiveness of these conventional means,
health-care professionals and the public alike turned to complementary and alternative medicine (CAM) in order to find ways
to better manage oral mucositis. However, a dilemma emerged
regarding the use of such methods (i.e. honey) due to the lack
of consistent scientific evidence in relation to their efficacy and
safety. Nevertheless, an increasing number of cancer populations use CAM as adjunct therapies whether prescribed or not
[17,18]. Despite the increased attention on such methods in different cancer populations there has been a disproportional study
for their use in head and neck cancer patients [19]. The available preceding studies emphasized the management of various
treatments related side-effects experienced by head and neck
cancer patients through the use of CAM [2023]. Among these
treatments that have been explored is that of natural honey.

Some studies refer to honey as one of the traditional

medicines that have beneficial properties to health [24,25]
including its ability to facilitate the healing process. Molan,
stressed that honey facilitates an increase in lymphocytes and
phagocytes and aids monocytes to release cytokines and interleukins, thus stimulating the healing process [24]. Hence there
is a reasonable justification that honey can enhance phase 3
of oral mucositis pathogenesis which involves signalling and
amplification.
Honey is acidic with a pH ranging from 3.2 to 4.5, which
serves to inhibit the growth of pathogens as the majority thrives
at a pH between 7.2 and 7.4 [24,25]. High sugar content of
honey draws water from the wound, reducing the availability of
water to the pathogens, which further impedes microbial growth
[26]. It also contains the enzyme glucose-oxidase that stimulates
the release of hydrogen peroxide after contact with body tissue,
which has an antiseptic effect [27,28] and within some types of
honey there are phytochemicals which are known to have bactericidal properties [28,29]. These properties may help phase 4
(ulceration and inflammation) of the biologic process of mucositis and thus minimize more severe mucositis and colonization
by oral bacteria and the risk of sepsis.
Honey contains numerous compounds such as organic
acids, proteins, aminoacids, minerals, polyphenols, vitamins and
aroma compounds [29] and its composition depends greatly
on the botanical origin [30]. Despite the fact that the contribution of honey to the recommended daily intake is small, it can
help head and neck cancer patients undergoing radiation therapy
and chemotherapy who suffer from malnutrition and increased
weight loss [31]. Studies have also shown that honey applied to
wounds reduced and relieved pain, a symptom that accompanies
patients with oral mucositis [21,31,32].
Although several studies explored the effectiveness of honey
in different side-effects, there is a need for further research
looking at the use of honey explicitly for the management of
radiation-induced oral mucositis. This is strengthened by the
fact that to date, there is only one systematic review by Bardy
et al. [31] exploring the use of honey and its potential value
within oncology care, but it does not fully explore its effectiveness in radiotherapy induced-oral mucositis in head and neck
cancer patients.
The aim of this study is to retrieve and review the available
Randomized Control Trials (RCTs) that have a clear focus on
the effectiveness of honey in the management of radiotherapy
induced-oral mucositis in head and neck cancer patients.

Materials and methods

EMBASE, CINAHL, COCHRANE and PUBMED electronic databases were thoroughly searched from 1977 to date.
The search was undertaken from January to March 2012 in
order to identify the articles that met the inclusion and exclusion
criteria.
The search strategy was identical for each of these electronic
databases and was undertaken with the use of the following key

M. Charalambous et al. / European Journal of Integrative Medicine 5 (2013) 217225

words: clinical trials; honey; oral mucositis; radiation

therapy and head and neck cancer.

528 titles
428 studies excluded with
reasons (title)

Inclusion/exclusion criteria
The inclusion criteria were as follows: (a) RCTs that use
honey as a sole intervention (rinses in oral cavity) or as an adjunct
to another standard treatment for the treatment of oral mucositis,
(b) adult participants (>18+ years old), (c) head and/or neck
cancer populations, and (d) written in English or Greek language.
Articles were excluded if: (a) the trials were in progress, (b)
the trials were published in the form of dissertations, abstracts,
single case studies, reviews or meta-analyses, (c) the trials did
not focus solely on head and neck cancer patients, and (d) oral
mucositis was not the side-effect of radiotherapy.
Validity assessment
Walji and Boon [33], state that RCTs are widely recognized
as the gold standard for evaluating the efficacy of a new intervention or treatment. However, it is common in the literature that the
poorly designed RCTs may suffer from methodological problems which impact the quality, generalizability and acceptability
of their findings. Furthermore, any variations in their methodological quality can affect the conclusions about the existing
evidence [34] and this is the reason why their quality assessment
becomes essential.
As part of the current review, all potentially relevant RCTs
were independently read by three authors (MC, AC, VR) and
were scored for methodological quality following the JADAD
scale scoring system [35]. This scale assigns points ranging
from poor (=0) to high (=5) methodological quality. The items
of the JADAD score assess randomization (maximum points:
2), blinding (maximum points: 2) and reporting of withdrawals
and dropouts (maximum points: 1) [35]. The decision to use
the JADAD scoring scale lays on the following reasons: The
JADAD scale has been adapted for use in many health care
areas and it was found to be the most frequently cited and the
most commonly used scale by the health care community [36].
Furthermore, it was tested for construct validity [24], test-retest
reliability in different areas and it presented the best validity
evidence compared to other scales [35].
Search outcome
The literature search was carried out by the three researchers
(MC, AC, VR). The researchers screened independently all references from each database. The total number of references
derived from the searched strategy was 528 and included studies on the general management of radiation-induced mucositis
(Fig. 1). Fifteen articles were retrieved from EMBASE, 18 articles from CINAHL, 70 from COCHRANE and another 425 from
PUBMED.
Following this, a hand search was performed in all articles
and their citation list in order to ensure that no relevant articles
were overlooked or duplicated. During this phase 52 studies
were removed due to duplication. All articles went through

219

52 studies removed due to

duplication
48 abstracts
43 studies excluded with
reasons (abstract)

5 full text
(RCTs)

5 studies included in
systematic review

Fig. 1. Flow diagram of reviewed studies.

a title screening by the three researchers and the titles that

were irrelevant with the aim of the review were excluded. With
this approach 428 articles were removed and 48 articles were
selected. The selected articles were forwarded to the next phase.
Their abstracts were read and checked by the researchers according to the inclusion and exclusion criteria. Forty three studies
were excluded during this phase. The full text of the retrieved
articles was read and examined by the reviewers (MC, AC, VR)
to decide whether the information on the topic of interest was
included, according to the predefined criteria additionally to a
fourth reviewer who acted as a moderator (EL). Five articles
were included in the final review (Table 1).
Results
All five trials were published between 2003 and 2011 and
were conducted in different countries. All studies used oral
assessment scales for research data collection with predominantly that of Radiation Therapy Oncology Group (RTOG) and
the population examined involved only patients with head and
neck cancer. Each study was assessed independently and data
were collected on the clear wording of the purpose, design,
size and characteristics of the sample, the methodology and the
results. One of the methodological weaknesses identified was the
small sample size with the majority being small in both groups
(20 participants in each group). The total number of participants
included in this systematic literature review was 309.
The methodological quality of the majority of the studies
according to JADAD score was moderate ranging from 2 to 5
(Table 1). Although these studies were RCTS, only 2 out of the 5
thoroughly discussed how the randomization of the participants

220

Table 1
List of reviewed studies.
Study design

Scales-tools

Type of honey

Analysis

Results

JADAD
score

[39]

20 patients in study arm

rinses of 20 ml pure honey before,
after and 6 h after radiotherapy

Clinical and
mirror examination of
the mucosa.

Tea plant
(Camellia
sinensis)

Demographic,
treatment, morbidity
scores Microsoft-Excel
software difference
between various
parameters was compared
using chi-squared test

16 patients in the s/a showed some form of

radiation mucositis/19 patients in c/a

20 patients in control arm

(without intervention)
The allocation was equally
by computer-generated random
numbers

RTOG grading
system scale

20 patients in study arm

rinses of 20 ml pure honey before,
after and 6 h after radiotherapy

Clinical
evaluation every week
for radiation mucositis

20 patients in control arm

(without intervention)

(WHO)

A single-blinded,
randomized controlled trial

Clinical
evaluation every week
for radiation mucositis
RTOG (Grating
system)

[37]

[38]

20 patients in honey
group(s/a) rinses of 20 ml pure
honey 15 before and 15 after
radiotherapy and before going to
bed
20 patients in lignocaine
group (c/a) rinses of 20 ml
lignocaine gel 15 before and 15
after radiotherapy and before
going to bed

Difference in grade 34 was 20% in the s/a

and 75% in c/a (p < 0.00058)
Median mucositis grade was grade 2 in c/a
and grade 1 in s/a
Clove (Trifolium
alexandrinum)

Microsoft-Excel
software

Descriptive analysis
and Yates corrected
chi-square analysis
Forest honey

In the s/a no patients developed grade four

mucositis and 3 developed grade three mucositis
(15%)/in the c/a 3 patients developed grade four
mucositis and 9 patients developed grade three
mucositis (45%)
5 c/a patients (25%) was interrupted as a
consequence of radiation mucositis, compared
with none in the treatment group.

SPSS Version 11.5

was used to performed all
statistical analysis
Descriptive analysis
was used

In the honey group 1 of 20 developed 34

mucositis grade and in the lignocaine group 15
of 20 patients developed mucositis grade 34
The relative risk of a patient in the test
group developing mucositis grate 34 was
0.05/0.75 which is 0.7 or 70%

To determine whether
there was a statistically
significant difference in
proportions of patients in
the groups with
intolerable mucositis the
chi-squared test was
applied

The number needed to treat (NNT derived

from the inverse of the risk difference) was 1.43,
implying that treating 14 patients would benefit
10.

A low relative risk of 0.067 and NNT of

1.43 indicated that honey has a strong protective
effect in lessening the severity of
radiation-induced oral mucositis
Honey and lignocaine groups were
compared using the chi-squared test to
determine whether choice of intervention had a
statistically significant association with less
severe mucositis (p = < 0.0001)

M. Charalambous et al. / European Journal of Integrative Medicine 5 (2013) 217225

Authors

Table 1 (Continued)
Authors

Study design

Scales-tools

Type of honey

Analysis

Results

JADAD
score

Honey had a statistically significant

association with less severe mucositis.
[40]

Clinical
evaluation every week
for radiation mucositis

20 patients in honey group

(s/a) rinses of 20 ml pure honey
15 before and 15 after
radiotherapy and 6 h after
radiation
20 patients (c/a) rinses of
20 ml saline 15 before, 15 after
and 6 h after radiotherapy

(OMAS scale)

130 patients were randomly

allocated by a
computer-generated list of
random numbers

Clinical
evaluation every week
for radiation mucositis
RTOG scale to assess
mucositis was used

66 patients in active manuka

honey group

Thyme and
astragale
(Astragalus
membranaceus)

T-test

MannWhitney test

Friedman test

Manuka

Chi-squared test with

Yates correction to assess
the significance of
differences in the primary
outcome (the incidence of
grade 3 or 4 mucositis)
between the two arms of
the trial.
The median areas
under the curve were
compared using
Wilcoxons rank sum test.

In the study group 4 patients (20%) showed

no evidence of mucositis during the radiotherapy
course leading to refusal of treatment or taking
the medication
The mucositis score of OMAS at the end of
week in the study group was significantly lower
than the control group (MannWhitney test)
(p < 0.001)

The mucositis score changes for the two

groups during the 6 weeks were compared using
the Friedman test and showed significant
differences in the OMAS during the 6 weeks
(p < 0.001)
127 patients were available for analysis. The
distribution of oral and oropharyngeal cancers
did not differ significantly between the honey
and the syrup arms, and the diagnostic groups
and treatment regimens were equally
represented between the 2 arms.

The primary analysis revealed no difference

(p = 0.64) in the incidence of grade 3 mucositis
between AMH 51/64 (80%) and placebo 47/63
(75%). There was also no significant difference
(p = 0.79) in the severity or duration of mucositis
in the AMH group and the golden syrup group
Ninety-eight patients managed at least 1
week of the intervention, and 67 patients
managed more than 2 weeks. The median
compliance was 2 weeks (range 142 days for
both groups).

M. Charalambous et al. / European Journal of Integrative Medicine 5 (2013) 217225

[41]

A single-blinded,
randomized controlled trial

64 patients in placebo
(golden syrup) rinses of 20 ml of
the allocated substance, and to
swallow it slowly, 4 times a day
for the duration of the
radiotherapy (4 weeks) and for 2
weeks after treatment (42 days in
total).
221

RTOG, Radiation Therapy Oncology Group; WHO, World Health Organization; OMAS, Oral Mucositis Assessment Scale.

222

M. Charalambous et al. / European Journal of Integrative Medicine 5 (2013) 217225

was done. One of the studies [37] scored 2 points as it only

mentioned some details about randomization and blinding, 3
studies had a score equal to 3 or more [3840] and only one
study scored 5 [41].
Oral mucositis and honey
The main purpose of all RCTs was to evaluate the effectiveness of honey on radiation- induced mucositis. The majority of
the studies except that of Bardy et al. [41], seem to suggest that
honey can provide a distinct benefit by limiting the severity of
mucositis (reduction in grades three and four mucositis) [37,38]
and a delayed onset of mucositis [39,40].
The first single blinded research was conducted by Biswal
et al. [39] in a sample of 40 patients diagnosed with head and
neck cancer requiring radiation to the oropharyngeal mucosal
area. Patients were allocated in two arms to either receive radiation alone or radiation additionally to topical application of
20 ml pure honey three times a day (15 before radiotherapy,
15 after radiotherapy and 6 h from the time of radiotherapy).
The duration of the honey treatment was undertaken throughout
the course of radiation. Patients were assessed weekly for the
development of radiation-induced mucositis using the Radiation Therapy Oncology Group (RTOG). The results showed that
the number of subjects in the control arm who developed some
form of radiation-induced mucositis was higher than the number
in the intervention arm. The two arms also demonstrated differences on the grade of mucositis. These findings were statistically
significant (p < 0.00058).
Motallebnejad et al. [40] assessed the effect of pure natural
honey on radiation-induced mucositis in a sample of 40 patients
divided into two groups. The control group received radiation
plus 20 ml of saline rinses before and after radiation and the
intervention group received radiation and topical application of
pure honey using the same protocol as Biswal et al. [39]. Patients
were evaluated weekly for progression of mucositis using the
Oral Mucositis Assessing Scale (OMAS). The findings pointed
towards a statistically significant reduction in mucositis among
the patients who received honey compared to the control group
(p < 0.001).
Similarly, another RCT study [37] enrolled 40 head and neck
cancer patients who were randomized to either the treatment
group to receive concomitant radio-chemotherapy plus topical
application of honey, or the control group to receive only the
concomitant radio-chemotherapy. The oral cavity was weekly
assessed for the development of radiation-induced mucositis
using the World Health Organization (WHO) oral mucositis
grading. The findings of this study showed that honey can
markedly reduce the incidence of radio-chemotherapy-induced
oral mucositis of grade three and four. The significant reduction of oral mucositis in the treatment group strengthens the
hypothesis that the prophylactic use of pure honey is effective in reducing oral mucositis in head and neck cancer patients
undergoing radio-chemotherapy.
Another single-blinded RCT was carried out by Khanal
et al. [38] and compared the mucositis-limiting qualities of
honey with lignocaine. Subjects were head and neck cancer

patients undergoing radiotherapy and were randomized into two

groups, the intervention group receiving oral rinses of 20 ml
pure honey three times a day and the control group receiving
oral rinses of 20 ml lignocaine three times a day. Assessments
were done according to the RTOG oral assessment scale. The
results showed that the proportion of patients with intolerable
oral mucositis was lower in the honey group and this was statistically significant (p < 0.001). Therefore, these results suggest
that honey appears to provide a distinct benefit by limiting the
severity of oral mucositis in head and neck patients undergoing
radiotherapy.
The last double-blind, placebo-controlled randomized trial
assessed the effectiveness of honey on the grade and duration of
radiation-induced oral mucositis [41]. This trial had a high quality score and was the largest study in terms of the sample used
(131 head and neck cancer patients). Patients were receiving
radiotherapy and were randomly allocated to take either 20 ml
of manuka honey (n = 67) or 20 ml of placebo (n = 64 golden
syrup), 4 times a day. The assessment of oral mucositis was performed weekly during radiotherapy and twice thereafter until the
oral mucositis resolved using the RTOG criteria. The study had
a poor compliance among the patients receiving honey (median
compliance was 2 weeks) which affected the potential impact of
the intervention and any safe conclusions drawn on the results.
According to the researchers, the poor compliance was attributed
to problems with the taste and texture of the products and cited
the effort required to take them as reason for discontinuation.
Compliance might have been hampered by the use of the carrier (sodium alginate). This trial found no statistical differences
between the honey and placebo group, failing to show that honey
can ameliorate radiation-induced oral mucositis. These results
are in contrast with those reported by the other trials in this systematic review which supported that honey had a positive effect
on oral mucositis. However, the results demonstrated a notable
reduction in the incidence of bacterial infections which can positively influence the onset and severity of oral mucositis. This
finding should be read in the light of poor compliance and high
drop-out rate which were found to affect the potential impact of
the intervention.
Although most of the results are in agreement with the
hypothesis that honey can be effective in oral mucositis in head
and neck cancer patients undergoing radiotherapy, most of the
RCTs were pilot studies which failed to provide valid data on
the effectiveness of honey application.
Discussion
The aim of this review was to critically evaluate the effectiveness of honey for the management of oral mucositis. This
systematic review provides encouraging evidence for the role of
honey in the management of oral mucositis for head and neck
cancer patients undergoing radiotherapy. Previous reviews in
other cancer populations support that honey is an effective intervention regarding wound healing, oral pain and oral infections
resulting from radiation therapy [2428].
Honey was found to promote faster wound healing, minimize scarring tissue, alleviate pain and fight infections [4245].

M. Charalambous et al. / European Journal of Integrative Medicine 5 (2013) 217225

Molan [46] and Sela [47] in their studies identified the potential
positive role of explicit properties of honey in oral health. A
common finding in these two studies supports that the supposed
solubility-reducing factor present in honey, which according
to literature, remains active in the absence of saliva, but will
be inactivated by salivary enzymes, gives some support to the
hypothesis that honey is less cariogenic in dry-mouth subjects
[47].
The majority of the studies examined have a small number
of individuals in both arms and as a consequence these findings
must be treated with caution as it might have a negative impact on
their significance (i.e. generalizability). The researchers do not
discuss the rationale underlying the sample sizes and whether
these had sufficient statistical power.
In these studies the researchers have used different types
of honey and therefore this might have biased the findings
reported. The researchers have used Manuka honey [41], forest
honey [40], honey from clover (Trifolium alexandrenum) [37]
and tea honey (Camellia sinsesis) [39]. In the study of Khanal
et al. [38], the authors only mentioned that the honey was pure
without specifying its origin. Different types of honey (i.e. thymus honey) have fortified specific qualities that may cause a
greater effect on the amelioration of oral mucositis whilst others (i.e. Manuka honey) can be more effective in wound healing.
Although it has been determined that the antimicrobial and healing activity of each kind of honey varies [47,48] there are not
enough clinical studies that compare or consider the honeys
source (i.e. plants origin) as an indicator of its effectiveness. In
light of this aspect, findings are comparable only in those cases
where the same type of honey was tested.
In addition to the type, the classification and quality of the
honey must also be taken to consideration. Honey can be subjected to a variety of processing methods (i.e. pasteurization),
that determine its classification. Based on these processing methods, honey can be classified as crystallized, pasteurized, raw,
strained, ultra filtered, ultrasonicated, whipped, dried, comb and
chunk. Only two of the reviewed studies clarified the classification of honey used [37,39]. In both studies the honey used was
classified as raw. This means that the honey was as it existed
in the beehive or as obtained by extraction, settling or straining
without adding heat. The honey was subjected to chemical analysis in four out of the five studies [37,3941] in order to verify its
quality. Particularly, three of the studies [37,39,40] mentioned
that honey subjected to chemical analysis, microbial, pH, density and viscosity measurements while in one was reported that
honey underwent stringent quality control testing [41].
Contrary to the varied types of honey assessed, the protocols
(amount and frequency) used by the researchers in the 5 trials is
rather consistent. This potentially allows for cross-studies comparisons at least on the basis of the amount and the solution
density of the honey used in the intervention groups.
Also, notable were the variety of oral mucositis assessment
scales, the frequency and the duration of assessments used in
each of the reviewed trials. A number of scoring systems have
been defined to assess the severity of oral mucositis including
the World Healths organization scale (WHO) [49], the National
Cancer Institutes Common Toxicity Criteria (NCI CTC version

223

3 and 4) [50], the Oral Mucositis Assessment Scale (OMAS)

which has been proposed by Sonis [52] and a scale devised by
Radiation Therapy Oncology Group (RTOG) [51]. It has become
clear that there is a lack of a definitive technique to appropriately
measure oral mucositis. The WHO scale has integrated objective mucosal changes like redness and ulceration with functional
outcomes like ability to eat. In contrast, NCI CTC scale has
been developed to classify oral mucositis in patients undergoing
chemotherapy, radiation therapy and bone marrow transplantation and has common features with RTOG scale. The OMAS
scale separates objective and subjective findings with primary
and secondary indicators. In the majority of the reviewed studies, patients were weekly clinically evaluated in order to detect
the onset or changes in the grade of the developed radiationinduced mucositis using the RTOG grading system [38,39,41].
Other assessment tools used included the World Health Organization (WHO) oral scale [37] and the OMAS scale [40]. Given
that the assessment scales used in the reviewed studies were not
the same, any conclusions with regards to the correlations of
their results or comparisons between the scales should be made
with caution.
A related aspect to the assessment tools that emerged from the
reviewed studies was the time period of the oral mucosa assessments. The review revealed the variability of the frequency of
the assessments making it difficult to assess the duration or/and
onset of any positive effect deriving from the use of honey. Two
of the studies [37,39] did not mention the frequency and duration of the oral assessments. In the study of Motallebnejad et al.
[40] it was reported that all patients were examined weekly up
to the end of radiotherapy whereas in the study of Bardy et al.
[41] oral assessments were undertaken during radiotherapy (4
weeks in total) and every 2 weeks thereafter until the mucositis
resolved. Khanal et al. [38] reported that the assessment of oral
mucositis was done weekly for 6 weeks. Therefore, based on
the findings from this review the effect (if any) of honey on oral
mucositis is not evident beyond the 6 week period.
There is scarcity regarding the details reported on who actually assessed the patients oral cavities during these studies. In
two studies [37,39] the researchers did not clarify who actually
carried out the assessments while in the other studies [38,40,41]
blinded researchers performed the visuals examinations. However, no detailed explanations (i.e. physician, nurse) about the
background of each evaluator were provided. This may have
influenced the outcome measures and consequently biased the
findings placing a thread on the validity of the results.
An aspect that deserves consideration was the doses of radiotherapy, fraction size, volume of irradiated tissue, fractionation
scheme and the type of ionizing irradiation (depending on TNM
classification) given to the patients and the areas of the body that
were irradiated. This information is important as these can influence the degree of acute radiation morbidities like oral mucositis
[39]. In the studies included in this review, the participants
had oropharynx or oral carcinoma and the radiation protocol
included doses of 5070 Gy in total. To an extent this allows for
the necessary cross-studies comparisons.
The degree and extent of oral mucositis that develops in
each patient appears to depend on factors such as age, gender,

224

M. Charalambous et al. / European Journal of Integrative Medicine 5 (2013) 217225

underlying systemic disease and race, as well as tissue specific

factors [40] Although the effects of patients age, cancer stage
and gender on the oral mucositis of head and neck cancer are
not clear, these are some of the characteristics that have to be
collated to this systematic review. In three of the studies [3941]
the mean age of the participants ranged from 54 to 60 years, in
one study it was 48 years [39] while one study only mentioned
an overall age division which covered > or < 40 years [38]. Apart
from age, the number of male patients seemed outweigh females
in four out of the five studies. In the study of Khanal et al., there
was no mention about gender. Further, the exact type of cancer
of the participants was only reported by Bardy et al. [41] and
whilst there is missing information about the stage of cancer for
most studies, staging is one of the determinants that can affect
the severity of the radiation-induced oral mucositis.
Further to these aspects, most studies investigated the effectiveness of honey in patients receiving radiotherapy alone.
However, the review stressed the need for more studies to
explore honeys effectiveness in head and neck patients also in
cases where patients were treated with chemo-radiotherapy. This
review has highlighted the need for further high quality randomized clinical trials especially in head and neck cancer patients
regarding the management of oral complications through complementary and alternative means. The results of this systematic
review cannot be compared with other reviews as there are no
similar systematic reviews or meta-analyses focused on head
and neck cancer patients and the effect of honey in the treatment
of oral mucositis.
Conclusions
The scarcity of trials in this field and group of patients, the
design, the methodological quality, and the small samples must
be taken into consideration before advocating in favour of or
against honey in the management of radiotherapy-induced oral
mucositis. The sample sizes were relatively small; while their
methodological quality was medium to low affecting the validity
and generalization of the results.
The majority of studies showed that honey can have a positive
effect on the management of radiation-induced oral mucositis.
At the same time though, this review highlights the need for further investigation through high quality blinded RCTs regarding
honeys potential value in oncology, especially in head and neck
cancer patients receiving radiotherapy.
The anti-inflammatory, antimicrobial and healing properties
of honey enhance the potentially positive effective management
of head and neck cancer patients, as this population is prone
to oropharyngeal infections as a result of aggravation of preexisting mucositis. The fact that the conventional therapies have
failed to offer a comprehensive and effective management for
oral complications, calls for studies to support the effectiveness
of honey in various cancer populations receiving radiotherapy
or chemo-radiotherapy.
Conict of interest
The authors declare that they have no conflicts of interest.

References
[1] American Cancer society. Cancer facts & figures Atlanta: American
Cancer Society. Available at: http://www.cancer.org./downloads/STT/
Cancer-Facts-and-Figures-2010 (accessed 12.04.11).
[2] De Vita Jr V, Lawrence T, Rosenberg S. Cancer: principles & practice of
oncology. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.
[3] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics. CA: A Cancer Journal
for Clinicians 2010;60:277300.
[4] Scully C, Epstein JB. Oral health care for the cancer patient. Oral Oncology
European Journal of Cancer 1996;32B:28192.
[5] National Comprehensive Cancer Network. Head and Neck Cancers:
Clinical Practice Guidelines in Oncology 2011;9(6). Available at:
www.NCCN.org
[6] Sonis ST. The pathobiology of mucositis. Nature Reviews of Cancer
2004;4:27784.
[7] Dische S, Saunders M, Barrett A, Harvey A, Gibson D, Parmar M. Accelerated fractionation (AF) compared to conventional fractionation (CF).
Improve loco-regional control in the radiotherapy of advanced head and
neck cancer: results of the EORTC 22851 trial. Radiotherapy and Oncology
1997;44:12336.
[8] McGuire DB, Correa ME, Johnson J, Wienandts P. The role of basic
oral care and good clinical practice principles in the management of oral
mucositis. Support Care Cancer 2006;14:5417.
[9] Shieh SH, Wang ST, Tsai ST, Tseng CC. Mouth care for nasopharyngeal
cancer patients undergoing radiotherapy. Oral Oncology 1997;33:3641.
[10] Lalla RV, Schubert MM, Bensadoun RJ, Keefe D. Anti-inflammatory
agents in themanagement of alimentary mucositis. Support Care Cancer
2006;14(6):55865.
[11] Mahood DJ, Dose AM, Loprinzi CL, Veeder MH, Athmann LM, Therneau
TM, et al. Inhibition of fluorouracil-induced stomatitis by oral cryotherapy.
Journal of Clinical Oncology 1991;9:44952.
[12] Barasch A, Peterson DE, Tanzer JM, DAmbrosio JA, Nuki K, Schubert MM, et al. Heliumneon laser effects on conditioning-induced oral
mucositis in bone marrow transplantation. Cancer 1995 Dec 15;76(12):
25506.
[13] Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T,
et al. Palifermin for oral mucositis after intensive therapy for hematologic
cancers. New England Journal of Medicine 2004;351:25908.
[14] Wyminga AN, van der Graaf WT, Hofstra LS, Spijkervet FKL, Timens W,
Timmer-Bosscha H, et al. Phase I study of transforming growth factor-beta3
mouthwashes for prevention of chemotherapy-induced mucositis. Clinical
Cancer Research 1999;5:13638.
[15] Foncuberta MC, Cagnoni PJ, Brandts CH, Mandanas R, Fields K, Derigs
HG, et al. Topical transforming growth factor-beta3 in the prevention or
alleviation of chemotherapy-induced oral mucositis in patients with lymphomas or solid tumors. Journal of Immunotherapy 2001;24:3848.
[16] Clarkson JE, Worthington HV, Eden OB. Interventions for treating oral
mucositis for patients with cancer receiving treatment. Cochrane Database
of Systematic Reviews 2007:CD001973.
[17] Ernst E. Prevalence of use of complementary/alternative medicine: a systematic review. Bulletin of the World Health Organization 2000;78:3936.
[18] Molassiotis A, Fernadez-Ortega, Pud D, Ozden G, Scott JA, Pandeli V,
et al. Use of complementary and alternative medicine in cancer patients: a
European survey. Annals of Oncology 2005;16:65563.
[19] Simon L, Prebay D, Beretz A, Bagot A, Lobstein A, Rubinstein I, et al.
Complementary and alternative medicines taken by cancer patients. Bulletin du Cancer 2007;94:4838.
[20] Cavanagh D, Beazley J, Ostapowicz F. Radical operation for carcinoma
of the vulva. A new approach to wound healing. Journal of Obstetrics and
Gynaecology of the British Commonwealth 1970;77:103740.
[21] Chiba M, Idobata K, Kobayashi N, Sato Y, Muramatsu Y. Use of honey to
ease the pain of stomatitis during radiotherapy. Kangogaku Zasshi Japanese
Journal of Nursing 1985;49:1716.
[22] Smirnova II, Filatova EI, Suvorov AN, Bylinskaia EN. The use of therapeutic/prophylactic dragee honey laminolact in radiotherapy of uterine
tumors. Voprosy Onkologii 2000;46:74850.

M. Charalambous et al. / European Journal of Integrative Medicine 5 (2013) 217225

[23] Simon A, Sofka K, Wiszniewsky G, Blaser G, Bode U, Fleischhack G.
Wound care with antibacterial honey (Medihoney) in pediatric hematologyoncology. Supportive Care in Cancer 2006;14:917.
[24] Molan PC. Honey as a topical antibacterial agent for the treatment of
effected wounds. Worldwide wounds available at: http://www.world
widewounds.com/2001/november/molan/honey-as-topical-agent.html
(accessed 11/2001).
[25] Stephen-Haynes J. Evaluation of a honey-impregnated tulle dressing
in primary care. British Journal of Community Nursing Supplement
2004;9:S217.
[26] Lusby PE, Coombes A, Wilkinson JM. Honey: a potent agent for
wound healing? Journal of Wound, Ostomy and Continence Nursing
2002;29:295300.
[27] Hyslop PA, Hinshow DB, Scraufstatter IU, Cochrane CG, Kunz S, Vosbeck
K. Hydrogen peroxide as a potent bacteriostatic antibiotic: implications for
host defense. Free Radical Biology and Medicine 1995;19:317.
[28] Anderson I. Honey dressings in wound care. Nursing Times
2006;102:402.
[29] White JW. Composition of honey. In: Crane E, editor. Honey. A comprehensive survey. London: Heinemann Edition; 1975. p. 157206.
[30] Persano Oddo L, Piro R. Main European unifloral honeys: descriptive
sheets. Apidologie 2004;35:S3881.
[31] Bardy J, Slevin JN, Mais LK, Molassiotis A. A systematic review of honey
uses and its potential value within oncology care. Journal of Clinical Nursing 2008;17:260423.
[32] Subrahmanyam M, Sahapure A, Nagane N. Effects of topical application of honey on burn wound healing. Annals of Burns and Fire Disasters
2001;14:1435.
[33] Walji R, Boon H. Redefining the randomized control trial in the context
of acupuncture research. Complementary Therapies in Clinical Practice
2006;12:916.
[34] Verhagen APDE, Vet HC, de Bie RA, Kessels AG, Boers M, Knipschild
PG. Balneotherapy and quality assessment: interobserver reliability of the
Maastricht criteria list and the need for blinded quality assessment. Journal
of Clinical Epidemiology 1998;51:33541.
[35] Jadad AR, Moore RA, Carrol D, Jenkinson C, Reynolds DJM, Gavaghan
DJ, et al. Assessing the quality of reports of randomized clinical trials is
blinding necessary? Controlled Clinical Trials 1996;17:112.
[36] Olivo SA, Macedo LG, Gadotti IC, Fuentes J, Stanton T, Magee DJ. Scales
to assess the quality of randomized controlled trials: a systematic review.
Physical Therapy 2007;88(2):15675.
[37] Rashad UM, Al-Gezawy SM, El-Gezawy E, Azzaz AN. Honey as topical prophylaxis against radiochemotherapy-induced mucositis in head
and neck cancer. The Journal of Laryngology and Otology 2009;123:
2238.
[38] Khanal B, Baliga M, Uppal N. Effect of topical honey on limitation of
radiation-induced oral mucositis: an intervention study. International Journal of Oral and Maxillofacial Surgery 2010;39:11815.

225

[39] Biswal BM, Zakaria A, Ahmad NM. Topical application of honey in the
management of radiation mucositis: a preliminary study. Supportive Care
in Cancer 2003;11:2428.
[40] 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. Journal of Contemporary Dental Practice
2008;9:407.
[41] Bardy J, Molassiotis A, Ryder WD, Kathleen M, Sykes A, Yap P, et al. A
double-blind, placebo-controlled, randomized trial of active manuka honey
and standard oral care for radiation-induced oral mucositis. Journal of Oral
and Maxillofacial Surgery 2011;(3):2216.
[42] English HK, Pack AR, Molan PC. The effects of manuka honey on plaque
and gingivitis: a pilot study. Journal of the International Academy of Periodontology 2004;6:637.
[43] Al-Waili NS. Topical application of natural honey, beeswax and olive
oil mixture for atopic dermatitis or psoriasis: partially controlled, singleblinded study. Complementary Therapies in Medicine 2003;11:22634.
[44] Fox C. Honey as a dressing for chronic wounds in adults. British Journal
of Community Nursing 2002;7:5304.
[45] Tahmaz L, Erdemir F, Kibar Y, Cosar A, Yalcyn O. Fourniers gangrene:
report of thirty-three cases and a review of the literature. International
Journal of Urology 2006;13:9607.
[46] Molan PC. The potential of honey to promote oral wellness. General Dentistry 2001;49:5849.
[47] Sela M, Maroz D, Gedalia L. Streptococcus mutans in saliva of normal
subjects and head and neck irradiated cancer subjects after conception of
honey. Journal of Oral Rehabilitation 2000;27:26970.
[48] Maddocks-Jennings W, Wilkinson JM, Cavanagh HM, Shillington D. Evaluating the effects of the essential oils Leptospermum scoparium [manuka]
and Kunzea ericoides (kanuka) on radiotherapy induced mucositis: a
randomized, placebo controlled feasibility study. European Journal of
Oncology Nursing 2009;13:8793.
[49] World Health Organization. WHO handbook for reporting the results of
cancer treatment. Geneva, Switzerland: WHO Offset Publications; 1979.
p. 1522.
[50] Cox JD, Stetz J, Pajak TF. Toxicity criteria of Radiation Therapy Oncology
Group (RTOG) and European Organization for Research and Treatment of
Cancer (EORTC). International Journal of Radiation Oncology, Biology,
Physics 1995;31:13416.
[51] National Cancer Institute. Common Terminology Criteria for
Adverse Events (CTCAE) Version4.0 Published: May 28, 2009
(v4.03: June 14, 2010) U.S. Department of health and humanservices, National Institutes of Health (NIH) Publication No. 09-5410
http://evs.nci.nih.gov/ftp1/CTCAE/About.html
[52] Sonis ST, Eilers JP, Epstein JB, LeVeque FG, Liggett Jr WH, Mulagha MT,
et al. Validation of a new scoring system for the assessment of clinical trial
research of oral mucositis induced by radiation or chemotherapy. Mucositis
study group. Cancer 1999;85(10):210313.