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Role of honey in preventing radiation-induced oral

Cite this: Food Funct., 2021, 12, 3352
mucositis: a meta-analysis of randomized
controlled trials†
Wei An,‡a,b Shaoqing Li‡a and Lizheng Qin *a

Received 27th October 2020,
Accepted 7th March 2021
DOI: 10.1039/d0fo02808h
rsc.li/food-function
Background: Radiotherapy-induced mucositis easily arouses oral ulceration, pain and xerostomia. Intense
pain, difficulty swallowing and speaking greatly affect the quality of life and the treatment process.
Objective: This study aimed to examine the effects of honey in preventing and treating radiotherapy-
induced mucositis in patients with head and neck cancer using a different analytical strategy. Methods:
Articles published until July 2020 were searched across PubMed, Embase, and Cochrane Library data-
bases. Randomized controlled trials that evaluated honey were assessed by two reviewers. The number of
mucositis incidences was the primary outcome. Weight loss, pain scale and incidence of severe pain were
pooled to be calculated as secondary outcomes. Statistical analyses were conducted using RevMan5.3
software. The funnel plot was used to detect publication bias. Results: Overall, 11/179 records with 715
patients who received radiotherapy were included. Honey significantly reduced the incidence of grade 2
(OR: 0.43, 95%CI: 0.54–0.98, P = 0.03), grade 3 (odds ratio [OR]: 0.24, 95% confidence interval [CI]:
0.16–0.35, P < 0.001) and grade 4 mucositis (OR: 0.17, 95%CI: 0.08–0.36, P < 0.001). In grade 1 (OR: 1.54,
95%CI: 1.15–2.06, P = 0.003), and honey was not significant in preventing radiation-induced mucositis.
The incidence of unbearable pain was lower in the honey group at all grades (OR: −0.20, 95%CI: −0.33 to
−0.07). The effect of honey on weight loss and pain score was not statistically significant. Conclusion:
Honey can prevent and alleviate grade 2–4 mucositis, especially in high grade mucositis. Honey also pro-
vides some relief from severe pain. But, more evidence is required to prove that honey is an effective sub-
stance for relieving pain or minimizing weight loss.

Introduction upregulated, positive feedback loops are stimulated, and sig-

Radiotherapy is one of the most important methods for treat-
ing cancer, although radiation-related toxicities are inevitable
and can result in serious adverse reactions. In head and neck
cancer, up to 70% of patients require radiotherapy and
40–76% of them experience radiation-induced mucositis.1
Mucositis, a form of mucosal barrier injury, is the most
common complication of radiotherapy.2 When the oral cavity
tissue is exposed to radiation, reactive oxygen species are gen-
erated, DNA is directly damaged, and the nuclear factor-kappa
B is activated. Subsequently, pro-inflammatory cytokines are
a
Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing
Stomatological Hospital, Capital Medical University, Tian Tan Xi Li No.4, Beijing,
100050, China. E-mail: qinlizheng@aliyun.com
b
Department of Oral and Maxillofacial Surgery, Shanxi Provincial People’s Hospital,
Shuang Ta Temple Street No. 29, Taiyuan, Shanxi, 300012, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0fo02808h
‡ These authors contributed equally to this work.
nalling is amplified, resulting in prolonged mucosal injury.3–5
Therefore, radiation-induced mucositis is characterized by an
inflammatory response including oral erythema, ulceration,
and pain. Serious reactions include intense pain, difficulty in
swallowing and speaking, and viral and fungal infections,2
which greatly affect the quality of life and the treatment
process.
Honey has a long medical history and is recognized world-
wide for its health-promoting properties. It has been proven to
have anti-inflammatory, antioxidant, antimicrobial, and rapid
tissue-healing properties.6–9 In contemporary medicine, honey
has been successfully used to heal wounds, including skin
ulcers, burns, and infections. Since 2003, several randomized
controlled trials (RCTs) have supported the protective effects
of honey in the treatment of radiation-induced oral muco-
sitis.10 However, its efficacy remains unclear because of some
negative results.11 Previous meta analyses had focused on
assessing the incidence of serious mucositis at the end of
trials. But the impact of honey at different times and on the
grade of mucositis was rarely mentioned. At the same time,

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Food & Function
there has been a high heterogeneity problem in many studies.
This study aimed to analyse the effects of honey on every grade
of oral mucositis as well as on weight loss and pain scores
after radiotherapy. The heterogeneity of the data was also sig-
nificantly reduced by using a new analysis strategy.
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Materials and methods
Ethics committee approval and informed consent were not
required for this study.
Selection criteria
Only RCTs were included, irrespective of the publication
language or status. Patients with oral mucositis were selected
without exclusion based on sex, age, tumor stage, and species
of honey. The trials compared the outcomes of honey with
those of controls ( placebo, alternative medicine, or no preven-
tive intervention) in oral mucositis. Oral mucositis grade was
measured using the World Health Organization (WHO),
Radiation Therapy Oncology Group (RTOG), or Oral Mucositis
Assessment (OMA) scales. Case reports, technical reports, and
laboratory experiments were excluded. Finally, the Cochrane
Collaboration tool was used to assess the methodological
quality of the selected trials by assessing the risk of bias.
Search strategy
This systematic review included articles published in PubMed,
Cochrane Library, Clinical Trials, and Embase databases using
the medical subject headings (MeSH) and free text terms
related to “honey”, “radiotherapy”, “stomatitis”, or “xerosto-
mia”. All articles published on or before July 5, 2020 were
included with no language restrictions. The following search
protocol was used with all databases:
#1 MeSH descriptor: [Honey]
#2 MeSH descriptor: [Radiotherapy]
#3 (radiation or radiotherapy or irradiation or radiotherap*
or irradiat*): ti, ab, kw
#4 MeSH descriptor: [Stomatitis]
#5 MeSH descriptor: [Xerostomia]
#6 Stomatitides or Oromucositi* or Mucositi* or
Oromucositis or Asialia* or xerostomia* or hyposalivation* or
“dry* mouth”
#7 #2 or #3
#8 #4 or #5 or #6
#9 #1 and #7 and #8
Data extraction
Two independent reviewers screened and selected articles
according to the selection criteria. The extracted data included
the author, year of publication, sample size, species of honey,
intervention, outcomes, and mucositis assessment method
(WHO, RTOG, or OMA scale). A third reviewer was consulted to
resolve any inconsistencies through discussion and consensus.
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Outcomes
Primary outcomes were assessed using the WHO and RTOG
scales, which are two similar measurements for mucositis
evaluation. Grades 1 and 2 were considered as mild mucositis,
while grades 3 and 4 were considered as severe mucositis.
Incidences of each grade of oral mucositis were measured after
1 week of radiotherapy and recorded every week until the end
of the treatment.
Weight loss and pain score of the oral cavity were deter-
mined after the completed treatment as secondary outcomes.
Pain was assessed using Likert and visual analog scales, and
the incidence of severe pain was recorded for the analyses.
Risk of bias assessment
Two reviewers independently assessed the risk of bias of the
included trials using the Cochrane Collaboration’s tool
(Handbook for Systematic Reviews of Interventions).12
Disagreements were resolved through consultations with a
third reviewer to reach a consensus.
Statistical analysis
Statistical analysis was performed using Review Manage v5.3
(The Nordic Cochrane Centre, The Cochrane Collaboration,
2014, Copenhagen, Denmark). We calculated the odds ratio
(OR) and standard mean difference (SMD) with 95% confi-
dence intervals (CIs) between groups and evaluated heterogen-
eity using the I2 test. When I2 ≤ 50% or P > 0.05, a fixed-effects
model (Mantel–Haenszel method) was used. When I2 > 50% or
P < 0.05, heterogeneity was considered large and a random-
effects model was used to analyze the data. Subgroup analysis
was conducted to find the reason for high heterogeneity.
Literature publication bias was evaluated using funnel plots.
Sensitivity analysis was carried out by excluding an individual
study each time to assess the stability of our results.
Theory/calculation
The main aim of this study was to investigate the effect of
honey on different grades of radiation-induced mucositis
development at different times and its impact on the quality of
life. A forest plot was used to analyze the incidence of radio-
therapy-induced mucositis and the effect of honey from the 1st
to 6th week of treatment as well as its influence on weight loss,
pain scale, and incidence of severe pain.
Results
The electronic searches identified 179 articles; of these, 90
were excluded after removing duplicates and 66 were ineligible
after title and abstract screening. Additionally, 11 articles were
excluded for the following reasons: conference abstracts (n =
5);10,13–16 full texts of the conference abstracts found in
PubMed or via other methods (n = 4);10,13,14,16 not a real RCT
(n = 1);17 related data were not mentioned (n = 2);18,19 different
form ( proportional terms) to assess results (n = 1);11 and
incomplete data because of failure to connect with the investi-
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Fig. 1 Flow diagram of the study selection process.
gators (n = 2).20,21 Additionally, of the 12 articles selected for
qualitative synthesis, two were combined that were derived
from the same clinical sample.22,23 Therefore, 11 articles were
finally included in the meta-analysis22–33 (Fig. 1).
Participant characteristics
A total of 715 patients were included in the 11 trials that met
the selection criteria, 11 participants discontinued the treat-
ment or lost follow-up during the trial. The characteristics of
the trials and participants are presented in Table 1. Patient age
ranged from 18–89 years. Neither sex nor tumor location was
statistically different between the treatment and control
groups (Table S1†). The tumor sites included the nasopharynx
and larynx, paranasal sinus, thyroid, oral cavity, oropharynx,
hypopharynx, and parotid and mastoid areas. The radiother-
apy dose range was 50–70 Gy, and patients in 9/11 studies
received a dose of 60–70 Gy. Of the 11 trials that used honey in
the intervention group, Ziziphus honey, manuka honey, thyme
honey, and natural honey were used; one trial used a combi-
nation of natural honey and 0.15% benzydamine hydro-
chloride. The control group was treated with normal saline,
salt–soda, gargle, placebo, betadine, or lignocaine gel. The pro-
cedures for administering honey or the control agent were very
similar across all the studies (20 mL of honey or control agent
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swallowed slowly 15 min before and after radiotherapy) except
for two studies (20 mL of honey diluted in 100 mL of purified
water; Table 2). Seven trials used the RTOG scale, three the
WHO scale, and one the OMA scale to evaluate mucositis
severity.
Mucositis
Of the 11 trials, eight reported that honey had prophylactic
effects on mild mucositis and nine reported it in severe muco-
sitis. Firstly, we evaluated mild and severe mucositis after
radiotherapy using the methods as earlier meta-analyses
did.34–36 The results of the meta-analysis comparing the inci-
dence of mucositis after radiotherapy/chemoradiotherapy
revealed high heterogeneity in the grade 1/2 mucositis group
(I2: 78%, P < 0.01) and grade 3/4 mucositis group (I2: 78%, P <
0.01) (Fig. 2 and 3). The high heterogeneity results were
similar to early meta-analyses.34–36 A further subgroup analysis
was performed to analyze the data whether associations by
country, mucositis cause, radiation dose, type of assessment
scale and control arm intervention, but the sources of high
heterogeneity were not found (Tables S2 and S3†). This assess-
ment method also does not know how honey plays a role in
the treatment of mucositis. To make up for the weaknesses of
this method, we use a new strategy to perform the data ana-
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lysis. Instead of collecting total incidence of mild and serious

57.83 ±

57.83 ±
60–78
50–55

60–70

60–70

50–70

62–70

60–66

66–70
Dose mucositis at the end of the experiment, each of the four grades

7.40

7.40
(Gy)

≥50

60
of mucositis was collected and analysed from 1st week to 6th
week separately. Meanwhile, the effect of honey on the devel-
opment of mucositis at different time points was also reflected

Chemoradiotherapy
Chemoradiotherapy

Chemoradiotherapy

Chemoradiotherapy

Chemoradiotherapy

Chemoradiotherapy
Chemoradiotherapy
during the first time.
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In grade 1 mucositis analysis, the OR of 1.54 (95%CI:

Radiotherapy/

Radiotherapy/

Radiotherapy/

Radiotherapy/
Radiotherapy

Radiotherapy
Radiotherapy

Radiotherapy

Radiotherapy
1.15–2.06, P = 0.003, heterogeneity: I2 = 24%, P = 0.17) suggests
Treatment

that the intervention group did not experience a decrease in

the incidence of mucositis within the 6 weeks of treatment. In
the 3rd week (OR: 2.67, 95%CI: 1.31–5.41, P = 0.007) and 5th
metastatic
Metastatic

Metastatic
Metastatic
week (OR: 2.47, 95%CI: 1.16–5.27, P = 0.02), the protective
effects of honey were even less than the control group, while in
Non-

the remaining 4 weeks, the intervention demonstrated no

advantages compared with the control (Fig. 4).
Hypopharynx, larynx nasopharynx, oral cavity, oropharynx

Additionally, honey had no positive effects in preventing

Nasopharynx larynx, paranasal sinus, thyroid, oral cavity,

78 (40/38) 52.58 ± 11.21/54.15 ± 7.92 Oral cavity, oropharynx, hypopharynx, and larynx cancer
40 (20/20) 47.65 ± 13.17/48.18 ± 10.46 Oral cavity, salivary glands, hypopharynx, tonsils cancer

grade 2 mucositis (OR: 0.92, 95%CI: 0.70–1.22, P = 0.57) and

oropharynx + hypopharynx parotid, mastoid cancer

had high heterogeneity (I2 = 52%, P = 0.004) (Fig. S1†). The

40 (20/20) 47.65 ± 13.17/48.18 ± 10.46 Oral cavity, pharynx (nasopharynx, oropharynx or

reason for this heterogeneity was attributed to the study by

Jayachandran et al.28 When their data were excluded from the
H&N cancer (squamous cell carcinoma)

analysis, the heterogeneity decreased (I2 = 2%, P = 0.43; OR =

Oral salivary, pharynx, larynx cancer

0.73, 95%CI: 0.54–0.98) (Fig. 5). In the study of Jayachandran,

the low-quality assessment in selection and performance bias
hypopharynx), larynx cancer

may be the reason for heterogeneity. Finally, we found that

Oral, oropharyngeal cancer

honey has a positive effect in preventing grade 2 mucositis

after the study of Jayachandran was excluded.
cancer, unknown

Evaluations in patients with severe mucositis demonstrated

Oral malignancy
Oral carcinoma

that the intervention had a significant effect in preventing

H&N cancer

H&N cancer
Cancer type

grade 3 (OR: 0.24, 95%CI: 0.16–0.35; I2 = 0%, P = 0.99) and

grade 4 mucositis (OR: 0.17, 95%CI: 0.08–0.36; I2 = 0%, P =
0.97). From the beginning of the treatment, honey effectively
regulated grade 3 mucositis (Fig. 6). With the exception of the
50 (25/25) 58.31 ± 10.69/49.92 ± 9.34
72 (36/36) 59.97 ± 12.7/63.08 ± 14.3
Age (y) mean or median

3rd week (OR = 0.44, 95%CI: 0.18–1.04, P = 0.06), the remaining

82 (41/41) 49.90/50.17 (median)

40 (20/20) 49.5/55.55 (median)

127 (64/ 59 ± 11.5/58 ± 11.25

40 (20/20) 54 ± 11.75/54.5 ± 16

5 weeks of treatments suggested that honey demonstrated pro-

(treatment/control)

106 (54/ 56.8/59.5 (median)

tective effects compared with the control intervention. The

72 (36/36) 61.53 (median)

incidence of grade 3 mucositis in the intervention group in the

4th, 5th, and 6th week was 0.25 (95%CI: 0.12–0.55, P < 0.01),
0.24 (95%CI: 0.10–0.55, P < 0.01), and 0.21 (95%CI: 0.06–0.74,
40 (20/20) —

P = 0.02), respectively.
Characteristics of the randomized controlled trials

The analysis of grade 4 mucositis revealed no protective

Sample

effects in the oral mucosa for the first 3 weeks (1st week, OR:
size

63)

52)

H&N: head and neck; RCT: randomized controlled trial.

0.07, 95%CI: 0.00–1.34, P = 0.08; 2nd week, OR: 0.05, 95%CI:

0.00–1.04, P = 0.05; 3rd week, OR: 0.44, 95%CI: 0.10–2.00, P =
RCT double

RCT double
RCT double

RCT double
Article type

RCT single

RCT single

RCT single

0.29). However, starting from the 4th week after radiotherapy,

blinded

blinded

blinded

blinded

blinded

blinded

blinded

the incidence of grade 4 mucositis was significantly lower in

RCT
RCT

RCT

RCT

RCT

the honey group. The odds ratio was similar in the 4th week
(OR: 0.18, 95%CI: 0.04–0.85, P = 0.03), 5th week (OR: 0.16, 95%
Kingdom
2003 Malaysia
2017 Pakistan

CI: 0.03–0.92, P = 0.04), and 6th week (OR: 0.16, 95%CI:

Year Country

2013 Canada
2018 Cyprus

Charalambous22 2017 Cyprus

2012 United

2009 Egypt
2012 India
2010 India

2017 India

2015 India

0.03–0.94, P = 0.04). The results showed that honey had a posi-

Motallebnejad30 2008 Iran

tive preventive and therapeutic effect on the development of

high grade mucositis. (Fig. 7).
23

28
Charalambous

Pain
Jayachandran

33
Samdariya
Khanal 29
Amanat24

Patients with strong, unbearable pain and those who required

Rashad32
Hawley27
Biswal26
Table 1

Bardy25
Author

opiate analgesics were pooled from three studies (Fig. S2†). In

Rao31

accordance with the study by Samdariya et al.33 a pain score >4

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Table 2 Intervention methods in the experimental and control groups

Author Year Intervention Protocol Control Protocol Scale

24
Amanat 2017 Ziziphus honey Take 20 mL of Ziziphus honey 0.9% of saline Administered as per RTOG
to swallow slowly 15 min before prescribed directives
and after radiotherapy. Advise
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patients to take 20 mL of honey

before sleeping at night.
Bardy25 2012 Manuka honey Take 20 mL of honey to rinse Placebo (golden syrup) Administered as per RTOG
the mouth and swallow it slowly, prescribed directives
four times a day during the
radiotherapy (4 weeks) and 2
weeks after treatment (42 days
in total).
Biswal26 2003 Natural honey Take 20 mL of natural honey to No treatment No treatment RTOG
rinse the mouth and swallow
slowly before and after
radiotherapy and 6 h after
therapy.
Charalambous23 2018 Thyme honey Dilute 20 mL of honey in Normal saline oral Administered as per RTOG
100 mL of purified water, rinse rinses prescribed directives
the mouth 15 min before and
after radiotherapy and 6 h later,
three times a day for 7 weeks
(starting from the first day of
the 4th week of radiotherapy)
Charalambous22 2017 Thyme honey 20 mL of honey diluted in Normal saline oral Administered as per —
100 mL of purified water, rinse rinses prescribed directives
the mouth before and after
radiotherapy and 6 h later.
Hawley27 2014 Manuka honey Take 5 mL of honey gels after A clear yellowish gel Administered as per RTOG
every oral rinse, circulate the gel with a consistency and prescribed directives
in their mouth for at least 30 s, taste similar to natural
and then swallow. Not to eat, honey, but less sweet.
drink, or rinse mouth within
30 min of each application.
Jayachandran28 2012 Natural honey + Take 20 mL of honey to rinse 0.9% normal saline Administered as per WHO
0.15% the mouth and swallow slowly, prescribed directives
benzydamine swish it around for 15 min
hydrochloride before RT, and 15 min and 6 h
after RT.
Khanal29 2010 Honey Take 20 mL of honey to rinse Lignocaine gel Given as per prescribed RTOG
the mouth for 2 min and directives.
expectorate 15 min before
radiation, 15 min after
radiation, and before going to
bed.
Motallebnejad30 2008 Natural honey Take 20 mL of honey to rinse 0.9% of saline Administered as per OMAS
and swallow gradually 15 min prescribed directives
before radiotherapy, and 15 min
and 6 h after radiotherapy.
Rao31 2017 Honey (polyfloral Take 20 mL of honey to rinse Betadine 1 mL of betadine and RTOG
origin) the mouth three times a day 1 h 100 mL of water
before radiation, and 2 and 6 h administered as per
after radiation. Not to eat within prescribed directives
30 min of each application.
Rashad32 2009 Natural honey Take 20 mL of honey to rinse Unclear Unclear WHO
the mouth and swallow slowly
15 min before radiotherapy, and
15 min and 6 h after
radiotherapy.
Samdariya33 2015 Honey Take 20 mL of honey to rinse Salt-soda and Every 3 h by patients —
the mouth and swallow to benzydamine gargle during the course of
smear it on the oral and radiotherapy and up to
pharyngeal mucosa 15 min 3 months post-
before, 15 min after, and 6 h radiotherapy.
after radiotherapy. Along with
the honey, salt-soda and
benzydamine mouth gargles
alternatively were prescribed
every 3 h.

WHO: World Health Organization; RTOG: Radiation Therapy Oncology Group; OMA: Oral Mucositis Assessment Scale.

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Fig. 2 Forest plot of the incidence of radiotherapy-induced mucositis (grade 1–2) (honey vs. control intervention).
Fig. 3 Forest plot of the incidence of radiotherapy-induced mucositis (grade 3–4) (honey vs. control intervention).
was set as the threshold for opiate analgesics in this analysis.
Although two trials revealed that the intervention reduced pain
and the use of pain medications, the results of the meta-ana-
lysis suggested high heterogeneity in pain assessment scores
(I2 = 69%, P = 0.04). The reason for this heterogeneity was
attributed to the study by Bardy et al.25 When their data were
excluded from the analysis, the heterogeneity significantly
decreased (I2 = 0%, P = 0.71). Differences in pain measurement
may account for the heterogeneity. Meanwhile, the results
suggested that the incidence of unbearable pain was lower in
the honey group (OR: −0.20, 95%CI: −0.33 to −0.07) (Fig. 8A).
Pain evaluation scores after 1 month of radiotherapy
showed that the intervention also demonstrated similar preven-
tive advantages to that in the studies by Samdariya et al.33
(SMD: −2.89, 95%CI: −3.57 to −2.20) and Charalambous et al.22
(SMD: −1.23, 95%CI: −1.73 to −0.72). The study suggested that
honey and control groups had no significant difference due to
high heterogeneity (I2 = 93%, P < 0.001) (Fig. 8B). The differ-
ences in the perception of the degree of pain and reporting bias
may be responsible for the high heterogeneity. But the small
number of studies was a limitation for finding the source of
high heterogeneity by subgroup analysis.
Weight loss
Three studies that reported weight loss were included in the
pooled analysis (SMD: −3.80, 95% CI: −6.41 to −1.20); one
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study was excluded due to different outcome measures. High
heterogeneity between the intervention and control groups was
observed between the studies (I2: 97%, P < 0.001). Although all
three trials revealed that the intervention reduced weight loss,
(especially in the study by Motallebnejad et al.30), more trails
are required to certify the honey effect (Fig. 8C).
Quality assessment
The 11 included studies were assessed for risk of bias using
the Cochrane Collaboration tool. In the selection bias assess-
ment, all trials were RCTs and two studies did not mention
the method of random sequence generation; three trials used
a double-blind design; three trials used a single-blind design;
and five trials did not mention the type of design clearly.
Incomplete outcome data and selective reporting were not
mentioned. Two trials did not mention whether there was bias
according to sex. The Cochrane Collaboration results are
shown in Fig. S3 and S4†.
Sensitivity analysis and publication bias
Sensitivity analysis was conducted to assess the stability of our
results. No noticeable changes were exposed when an individ-
ual study was excluded in the study. The results of the funnel
plot asymmetry test showed that no obvious publication bias
was found (Fig. S5†).
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Fig. 4 Forest plot of the incidence of radiotherapy-induced mucositis (grade 1) from the 1st week to the 6th week of treatment (honey vs. control
intervention).
Discussion
In this meta-analysis, preventive and curative effects of honey
in mucositis following radiotherapy were assessed. Previous
meta-analyses have focused more on the effect of honey on
severe mucositis and less on the relationship between the
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development of mucositis and time.36,37 Considering that not
all patients underwent an evaluation at the end of treatment,
we analysed the data from a different perspective to solve the
problem of the inconsistent timing of disease assessment.
This study was novel because it evaluated each grade of muco-
sitis over time to understand the effect of honey on the
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Fig. 5 Forest plot of the incidence of radiotherapy-induced mucositis (grade 2) (honey vs. control intervention).
different grades of mucositis development. Meanwhile, our
study also significantly reduced the heterogeneity of the meta-
analyses.
In grades 3 and 4 mucositis, honey significantly limited
mucosal inflammation compared with the controls. From the 4th
week of treatment, honey protected patients from grade 4 muco-
sitis. The fact that severe mucositis often appears in the later
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stages of radiotherapy could explain why honey is an effective
intervention for grade 4 mucositis within the first 3 weeks.
In grade 2 mucositis, (OR = 0.73, 95%CI: 0.54–0.98), our
research pioneered the demonstration that the intervention
group did experience an incidence decrease in grade 2 muco-
sitis during 6 weeks of treatment. This discovery was also not
mentioned before. But, compared with grade 3 or grade 4, the
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Fig. 6 Forest plot of the incidence of radiotherapy-induced mucositis (grade 3) incidence from the 1st week to the 6th week of treatment (honey vs.
control intervention).
protective effect in grade 2 is small. Due to the limited number
of trails, the preventive role of honey is not to confirmed and
requires more research. The result is promising and worth
further study.
However, treatment with honey demonstrated no difference
in the incidence of grade 1 mucositis, (OR: 1.54, 95%CI:
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1.15–2.06). During 6 weeks of assessment, honey demonstrated
no advantage in lowering the risk of grade 1 mucositis. It is
possible that honey can only relieve radiation-induced severe
mucositis while having no remarkable therapeutic effects on
low grade mucositis. Alternatively, it is possible that honey can
prevent mucositis by transforming high grade mucositis into
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Fig. 7 Forest plot of the incidence of radiotherapy-induced mucositis (grade 4) from the 1st to the 6th week of treatment (honey vs. control
intervention).
low mucositis, suggesting that the true effects of honey on
mild mucositis cannot be determined. However, measurement
bias could also have affected the final analysis. Therefore,
whether honey is valuable in preventing grade 1 and 2 muco-
sitis should be further investigated. We can conclude,
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however, that honey can have a substantial prophylactic effect
on severe mucositis (grades 3 and 4).
Although honey has shown positive effects in radiation-
induced oral mucosal injury, the exact mechanism by which it
inhibits radiation-induced injury is yet to be elucidated. A
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Fig. 8 Forest plot of the incidence of severe pain (A), pain score after 1 month (B), and weight loss (C) after radiotherapy (honey vs. control
intervention).
possible explanation could be that honey, as a type of anti-
oxidant, sequesters free radicals and donates hydrogen to
reduce injury due to oxidative stress.38 Honey could also stimu-
late H2O2 generation and promote the healing of epithelial
cells.39 Simultaneously, it could create an environment of low
water activity, which reduces infections.40
In this study, the incidence of strong pain was evaluated;
however, high heterogeneity limited further analysis of the
effect of honey. The high heterogeneity is due to the different
measure scales. In three experiments, two studies evaluated
the incidence of severe pain with the sore scale and the other
one was designed on the use of acesodyne. It is possible that
patients pretended that the pain was severe to obtain aceso-
3362 | Food Funct., 2021, 12, 3352–3365
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Food & Function
dyne leading to potential reporting bias. After excluding this
experiment, the study showed that honey had positive effects
in preventing pain (OR: −0.20, 95%CI: −0.33 to −0.07).
The pain score after 1 month of radiotherapy was also ana-
lysed. Although both trials revealed that honey could reduce
the pain score separately, the meta-analyses demonstrated that
honey has no statistically significant effect in reducing the
pain score. Therefore, further studies are required with a large
sample size and a uniform standard to clarify the heterogen-
eity and evaluate the relationship between honey and pain.
Since mucositis influences eating and drinking, weight loss
is another factor that can be used to assess the effects of
honey. In this analysis, all three studies suggested that weight
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Food & Function
loss was reduced by the intervention. Another study with
different evaluation methods demonstrated that the weight
decreased by 8% (0–24%) in the treatment group compared
with 9% (0–22%) in the control group.25 Although there is
insufficient evidence to demonstrate that honey can improve
the quality of life (include pain and weight loss), several RCTs
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have revealed that honey can relieve pain and reduce weight
loss, both of which influence the quality of life. In the study by
Charalambous et al.,22 the visual analog scale score for quality
of life was significantly higher in the intervention group than
that in the control group at the end of 1 month (5.19 ± 2.3 vs.
2.66 ± 1.2, respectively, P < 0.001) and 6 months (7.47 ± 1.8 vs.
4.28 ± 1.6, P < 0.001) of radiotherapy. However, because of
insufficient data and different approaches of measurements,
the pooled assessment of quality of life was difficult in this
meta-analysis.
Although only RCTs were included in this meta-analysis,
the limited sample size led to problems of reliability and het-
erogeneity. High-quality multi-centre studies with large sample
sizes are recommended for future research. The differences in
the methods used by the different trials, such as pain and
weight loss measurement, also made the data collection and
analysis difficult. Future studies should aim to achieve lower
statistical heterogeneity by considering the participant charac-
teristics, and measurement approach.
Conclusion
This meta-analysis demonstrated that honey significantly
reduced the severity of grade 3 and 4 mucositis, especially
grade 4 mucositis. The study also suggested that honey has
potential to prevent grade 2 mucositis and has an optimistic
effect in reducing pain. Although honey cannot be shown to
reduce the incidence of grade 1 mucositis, the protective effect
of honey in other grades has been demonstrated, especially in
severe oral mucositis. More RCTs are necessary in the future to
identify the role of honey in low grade mucositis, quality of
life, pain, and weight loss.
Author contributions
WA was responsible for project design, literature search, date
collection, data analysis, and drafting the manuscript. SL co-
ordinated literature search, date collection and extraction, and
statistical analyses. LQ oversaw the data collection and guided
the design of the project and drafting of the manuscript. All
authors have read and approved the final manuscript. WA and
SL contributed equally to this work.
Abbreviations
Medline Medical Literature Analysis and Retrieval System
Online
MeSH Medical Subject Headings
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Review
PubMed Public Medline
RCT Randomized clinical trials
WHO World Health Organization
CI Confidence interval
ORs Odds ratios
RTOG Radiation Therapy Oncology Group
OMA Oral Mucositis Assessment Scale
ti Title
ab Abstract
kw Key word
SMD Standard mean difference
Funding
This work was supported by the National Natural Science
Foundation of China (No. 81570991).
Conflicts of interest
There are no conflicts to declare.
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