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European Journal of Integrative Medicine 5 (2013) 217–225

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
b 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 combi-
nation, for head and neck cancers include surgery, chemotherapy
∗ Corresponding author at: Nursing Department, Cyprus University of Tech-
nology, 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.
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 gen-
erally recommended for 30–40% of stage I–II 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 dur-
ing 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

1876-3820/$ – see front matter © 2013 Elsevier GmbH. All rights reserved.
http://dx.doi.org/10.1016/j.eujim.2013.01.003
218 M. Charalambous et al. / European Journal of Integrative Medicine 5 (2013) 217–225
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 multi-
step process. Sonis [6] has described a five phase model to
characterize the theory for the pathogenesis of oral mucosi-
tis. 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 prolifer-
ation and cellular differentiation restoring the lining of the oral
cavity [6].
The development of oral mucositis is an expected accompa-
niment of radiation therapy applied to the head and neck regions.
Severe radiation mucositis leads to ulceration and painful dys-
phagia 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 66–70 Gy radiation are delivered to large
mucosal surfaces in 6–7 weeks with 1.8–2 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 patient’s 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 sialo-
gogues [8–10]. 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 manag-
ing oral mucositis [13–15]. 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 comple-
mentary 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 popula-
tions use CAM as adjunct therapies whether prescribed or not
[17,18]. Despite the increased attention on such methods in dif-
ferent cancer populations there has been a disproportional study
for their use in head and neck cancer patients [19]. The avail-
able preceding studies emphasized the management of various
treatments related side-effects experienced by head and neck
cancer patients through the use of CAM [20–23]. 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 inter-
leukins, 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 bac-
tericidal properties [28,29]. These properties may help phase 4
(ulceration and inflammation) of the biologic process of mucosi-
tis 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 contri-
bution 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 effective-
ness 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 elec-
tronic 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) 217–225
words: “clinical trials”; “honey”; “oral mucositis”; “radiation
therapy” and “head and neck cancer”.
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 interven-
tion or treatment. However, it is common in the literature that the
poorly designed RCTs may suffer from methodological prob-
lems which impact the quality, generalizability and acceptability
of their findings. Furthermore, any variations in their method-
ological 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 ref-
erences from each database. The total number of references
derived from the searched strategy was 528 and included stud-
ies on the general management of radiation-induced mucositis
(Fig. 1). Fifteen articles were retrieved from EMBASE, 18 arti-
cles 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
528 titles
428 studies excluded with
reasons (title)
52 studies removed due to
duplication
48 abstracts
43 studies excluded with
reasons (abstract)
5 full text
(RCT’s)
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 accord-
ing 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 predomi-
nantly 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 RCT’S, only 2 out of the 5
thoroughly discussed how the randomization of the participants

Table 1
List of reviewed studies.
Authors Study design
[39] • 20 patients in study arm –
rinses of 20 ml pure honey before,
after and 6 h after radiotherapy
• 20 patients in control arm
(without intervention)
• The allocation was equally
by computer-generated random
numbers
[37] • 20 patients in study arm –
rinses of 20 ml pure honey before,
after and 6 h after radiotherapy
• 20 patients in control arm
(without intervention)
[38] • A single-blinded,
randomized controlled trial
• 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
220
Scales-tools Type of honey Analysis Results JADAD
score
• Clinical and Tea plant • Demographic, • 16 patients in the s/a showed some form of 3
mirror examination of (Camellia treatment, morbidity radiation mucositis/19 patients in c/a
the mucosa. sinensis) scores – Microsoft-Excel
software difference
between various
parameters was compared
using chi-squared test
M. Charalambous et al. / European Journal of Integrative Medicine 5 (2013) 217–225
• RTOG grading • Difference in grade 3–4 was 20% in the s/a
system scale and 75% in c/a (p < 0.00058)
• Median mucositis grade was grade 2 in c/a
and grade 1 in s/a
• Clinical Clove (Trifolium • Microsoft-Excel • In the s/a no patients developed grade four 2
evaluation every week alexandrinum) software mucositis and 3 developed grade three mucositis
for radiation mucositis (15%)/in the c/a 3 patients developed grade four
mucositis and 9 patients developed grade three
mucositis (45%)
(WHO) • Descriptive analysis • 5 c/a patients (25%) was interrupted as a
and Yates corrected consequence of radiation mucositis, compared
chi-square analysis with none in the treatment group.
• Clinical Forest honey • SPSS Version 11.5 • In the honey group 1 of 20 developed 3–4
evaluation every week was used to performed all mucositis grade and in the lignocaine group 15
for radiation mucositis statistical analysis of 20 patients developed mucositis grade 3–4
• RTOG (Grating • Descriptive analysis • The relative risk of a patient in the test 4
system) was used group developing mucositis grate 3–4 was
0.05/0.75 which is 0.7 or 70%
• To determine whether • The number needed to treat (NNT derived
there was a statistically from the inverse of the risk difference) was 1.43,
significant difference in implying that treating 14 patients would benefit
proportions of patients in 10.
the groups with
intolerable mucositis the
chi-squared test was
applied
• 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)
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] • A single-blinded, • Clinical • Thyme and • T-test • In the study group 4 patients (20%) showed
randomized controlled trial evaluation every week astragale no evidence of mucositis during the radiotherapy
for radiation mucositis (Astragalus course leading to refusal of treatment or taking
membranaceus) the medication
• 20 patients in honey group • (OMAS scale) • Mann–Whitney test • The mucositis score of OMAS at the end of 3

M. Charalambous et al. / European Journal of Integrative Medicine 5 (2013) 217–225

(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
[41] • 130 patients were randomly
allocated by a
computer-generated list of
random numbers
• 66 patients in active manuka
honey group
• 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).
• Friedman test
• Clinical • Manuka • Chi-squared test with
evaluation every week Yates’ correction to assess
for radiation mucositis the significance of
RTOG scale to assess differences in the primary
mucositis was used 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
Wilcoxon’s rank sum test.
week in the study group was significantly lower
than the control group (Mann–Whitney 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 5
(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 1–42 days for
both groups).

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

221
222 M. Charalambous et al. / European Journal of Integrative Medicine 5 (2013) 217–225
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 [38–40] and only one
study scored 5 [41].
Oral mucositis and honey
The main purpose of all RCTs was to evaluate the effective-
ness 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 radi-
ation 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 Radia-
tion 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 differ-
ences 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 reduc-
tion of oral mucositis in the treatment group strengthens the
hypothesis that the prophylactic use of pure honey is effec-
tive 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 sta-
tistically 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 qual-
ity 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 per-
formed 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 car-
rier (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 sys-
tematic 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 pos-
itively 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 effec-
tiveness 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 inter-
vention regarding wound healing, oral pain and oral infections
resulting from radiation therapy [24–28].
Honey was found to promote faster wound healing, mini-
mize scarring tissue, alleviate pain and fight infections [42–45].
 M. Charalambous et al. / European Journal of Integrative Medicine 5 (2013) 217–225
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. thy-
mus honey) have fortified specific qualities that may cause a
greater effect on the amelioration of oral mucositis whilst oth-
ers (i.e. Manuka honey) can be more effective in wound healing.
Although it has been determined that the antimicrobial and heal-
ing activity of each kind of honey varies [47,48] there are not
enough clinical studies that compare or consider the honey’s
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 sub-
jected to a variety of processing methods (i.e. pasteurization),
that determine its classification. Based on these processing meth-
ods, 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 classifica-
tion 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 anal-
ysis in four out of the five studies [37,39–41] in order to verify its
quality. Particularly, three of the studies [37,39,40] mentioned
that honey subjected to chemical analysis, microbial, pH, den-
sity 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 com-
parisons 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 Health’s organization scale (WHO) [49], the National
Cancer Institute’s 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 objec-
tive 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 transplanta-
tion 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 stud-
ies, patients were weekly clinically evaluated in order to detect
the onset or changes in the grade of the developed radiation-
induced mucositis using the RTOG grading system [38,39,41].
Other assessment tools used included the World Health Organi-
zation (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 assess-
ments. 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 dura-
tion 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 actu-
ally 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. How-
ever, 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 radio-
therapy, 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 influ-
ence 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 50–70 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) 217–225
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 [39–41]
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 effec-
tiveness of honey in patients receiving radiotherapy alone.
However, the review stressed the need for more studies to
explore honey’s 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 random-
ized clinical trials especially in head and neck cancer patients
regarding the management of oral complications through com-
plementary 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 fur-
ther investigation through high quality blinded RCTs regarding
honey’s 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 pre-
existing 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.
Conflict of interest
The authors declare that they have no conflicts of interest.
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