Search methods and key words

A comprehensive search was performed in PubMed, the Cochrane Library, Elsevier Science Direct, China National Knowledge Infrastructure (CNKI), VIP database (Chinese scientific journal database), and China Biology Medicine (CBM) to collect relevant published studies on the use of honey for the prevention and treatment of radio/chemotherapy-induced mucositis. Furthermore, a manual search and screening of the references reported in the studies identified was also performed. The following search terms were used: ‘honey’, ‘oral mucositis’, ‘mucositis’, ‘randomised’, and ‘randomized’. An upper date limit of 30 September 2015 was applied; there was no lower date limit. There was no language restriction. The search strategy used in PubMed was as follows:

• #1 honey [Title/Abstract];

• #2 oral mucositis [Title/Abstract];

• #3 mucositis [Title/Abstract];

• #4 (#2 OR #3);

• #5 randomised [Title/Abstract];

• #6 randomized [Title/Abstract];

• #7 (#5 OR #6);

• #8 (#1 AND #4 AND #7).

Inclusion and exclusion criteria

Inclusion criteria were the following: (1) randomized controlled trials, whether or not blinding methods were applied; (2) head and neck cancer patients undergoing radiotherapy and/or chemotherapy; (3) test group receiving honey treatment and control group receiving no other treatment (blank control) or receiving another single factor intervention (lidocaine or golden syrup); other treatments or other potential factors had to be consistent between the two groups; (4) outcome measure being the incidence of oral mucositis within 1 week after radio/chemotherapy (World Health Organization (WHO), Radiation Therapy Oncology Group (RTOG), or Oral Mucositis Assessment (OMA) scale scores of oral mucositis ≥3 were defined as clinical symptoms).

Exclusion criteria were as follows: (1) review articles or letters to the editor; (2) animal or laboratory studies; (3) case reports; (4) technical reports.

Data extraction

The data from all eligible articles were extracted independently by two reviews (JLX and ZHS) using predefined data abstraction forms. The following information was extracted from each study (when available): first author, publication year, study design, single-centre or multi-centre study, population characteristics, intervention characteristics, the source of the honey, the administration of honey, assessment scale types, and mucositis scores.

Assessment of the methodological quality

Two reviewers (JLX and ZHS) evaluated the quality of all included studies independently, according to the risk of bias assessment scale for randomized controlled trials recommended in the Cochrane handbook for systematic reviews, and these were cross-checked. Disagreements between the two reviewers were resolved by consensus with a third reviewer (RX). The classification of the risk of bias potential for each study was based on the following criteria: random sequence generation, allocation concealment, blinding of participants, blinding of implementers, incomplete outcome data handled appropriately, absence of selective reporting, and absence of other sources of bias. If all assessment items are reported as ‘yes’, the study is judged to be at low risk of bias. If one or more items are reported as ‘unclear’, the study is considered to be at moderate risk of bias. If one or more items are reported as ‘no’, the study is regarded as being at high risk of bias.

Statistical analysis

To evaluate the prophylactic effect of honey use on the management of radio/chemotherapy-induced mucositis, a pooled risk ratio (RR) with the 95% confidence interval (CI) was calculated. All effect sizes and 95% CI were calculated on the basis of fixed- or random-effects models. A test of heterogeneity of combined RRs was carried out using Cochran’s Q test and Higgins’s I ² statistic. Heterogeneity was defined as P < 0.05 or I ² > 50%. If there was no statistical difference for heterogeneity ( P > 0.05 or I ² ≤ 50%), a fixed-effects model was to be used to analyse the data (the Mantel–Haenszel method); in the opposite case, a random-effects model was to be applied (the DerSimonian–Laird method). Publication bias among the studies included was evaluated using Egger’s linear regression test and Begg’s funnel plot. In the case of publication bias, the funnel plot will be asymmetric, or the P -value will be <0.05 by Egger’s test. All P -values were two-sided. All analyses were performed using Stata 11.0 (StataCorp LP, College Station, TX, USA).

Literature search

Based on the data collection method and search strategy, a total of 113 articles were identified through the initial comprehensive database search. Using professional document management software EndNote, 51 articles were excluded as they were cited in more than one research of terms. The two reviewers then screened the abstracts of the remaining articles for relevance, resulting in the exclusion of 46 articles; the reasons for exclusion were as follows: no full text available, no data could be extracted for analysis, and other influencing factors introduced into the test group. The full texts of the remaining 16 articles were then screened against the inclusion criteria. In addition, a manual search was performed and the references lists of the identified studies were screened for further studies; one additional article was identified in this way. Finally, seven articles were included in the meta-analysis ( Fig. 1 ).

Flow chart showing the search, screening, and selection process.

Description of the studies

Details of the studies included in the final meta-analysis are given in Table 1 . A total of 190 patients were included in the test groups and 191 in the control groups, and these were ultimately included in the meta-analysis. All seven articles were published in English. The patients in five studies underwent radiotherapy and the others underwent radio/chemotherapy. All test groups received honey only as the intervention. The control groups in five studies received no honey treatment (blank control); one study control group was given lidocaine treatment and another was given golden syrup treatment.

Table 1

Basic characteristics of the studies included.

First author	Publication year	Study design	No. of mucositis in test group	No. of mucositis in control group	Patient age range (average), years	Intervention: test group vs. control group	Source of honey	Administration of honey	Type of assessment scale	Radio/chemotherapy strategy a
Biswal et al.	2003	RCT (single centre)	4/20	15/20	14–89 (58.50)	Radiotherapy + honey vs. radiotherapy	Camellia sinensis near the Cameron Highland of peninsular Malaysia	Rinse the mouth with 20 ml, 15 min before, 15 min after, and 6 h after radiation therapy	RTOG scale	Using a 6-MV linear accelerator, 60–70 Gy in a total period of 6–7 weeks
Motallebnejad et al.	2008	RCT (single centre)	4/20	16/20	NM (56.995)	Radiotherapy + honey vs. radiotherapy	Thymus and Astragalus in the Alborz mountains in northern Iran	Rinse the mouth with 20 ml, 15 min before, 15 min after, and 6 h after radiation therapy	OMA scale	Using Cobalt-60, total radiation dose of 50–60 Gy over 5–6 weeks
Maddocks-Jennings et al.	2009	RCT (single-centre)	0/6	1/7	45–75 (NM)	Radiotherapy + honey vs. radiotherapy	Leptospermum scoparium and Kunzea ericoides in the north of the South Island of New Zealand	Gargle in the mouth for 30 min before and after radiotherapy, to continue for a week after the completion of radiotherapy, 2 drops per treatment, 3 and 5 times per day	RTOG scale	NM b
Rashad et al.	2009	RCT (single centre)	3/20	12/20	NM (48.20)	Radio-chemotherapy + honey vs. radio-chemotherapy	Trifolium alexandrinum	Smear 20 ml in the mouth, 15 min before, 15 min after, and 6 h after radiation therapy	WHO scale	Using a 6-MV linear accelerator or Cobalt-60, up to a dose of 60–66 Gy, infusion of 20 mg/m 2 cisplatin once a week before radiotherapy
Khanal et al.	2010	RCT (single centre)	1/20	15/20	NM (NM)	Radiotherapy + honey vs. radiotherapy + lidocaine	Beehives of the Western Ghats forests in India	Swish in the mouth for 2 min and expectorate, 20 ml before and 20 ml at 15 min after radiation	RTOG scale	NM c , 60 Gy of radiation over the course of 6 weeks
Bardy et al.	2012	RCT (single centre)	51/64	47/63	38–85 (58.50)	Radiotherapy + honey vs. radiotherapy + syrup	Canterbury area of New Zealand	Rinse the mouth and then swallow honey slowly, 5 ml one time, 4 times a day for the duration of the radiotherapy (4 weeks) and for 2 weeks after treatment (42 days in total)	RTOG scale	NM c , 4 weeks of accelerated radiotherapy at a dose between 50 and 55 Gy
Hawley et al.	2014	RCT (single centre)	14/40	18/41	NM (NM)	Radio-chemotherapy + honey vs. radio-chemotherapy	Preston Pharmaceuticals	Pour the honey into the mouth, circulate the honey gel in the mouth for ≥30 s, and then swallow; treatment to start at the beginning of radiation and to continue to 7 days following the last radiation treatment	RTOG scale	NM c , radiation therapy of 50 Gy or greater

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