Propolis, also known as “bee glue,” is a wax-like substance that is collected from local flora by honeybees to protect and repair their hives [
Many researchers have studied propolis in recent decades. The major components extracted from propolis have shown antimicrobial activity [
The external use of propolis is defined by the application of pharmaceutical or natural products on the surface or point of illness [
A recently published systematic review on propolis for oral health reported that it can reduce oral infection and dental plaque and treat stomatitis [
Therefore, we conducted a systematic review and meta-analysis following the PRISMA recommendations [
We searched the following electronic databases up to June 2016 without a language restriction: MEDLINE (OvidSP), EMBASE (OvidSP), the Cochrane Central Register of Controlled Trials (CENTRAL), and CINAHL Plus (EBSCOhost). We also searched six Korean medical databases (Korea Institute of Science and Technology Information, Korean traditional knowledge portal, KoreaMed, OASIS, RISS, and the National Library of Korea) and two Chinese databases (CNKI and Wanfang). Furthermore, we conducted nonelectronic searches of conference proceedings, our own article files and nine traditional Korean medical journals (Journal of Korean Medicine, the Journal of Korean Acupuncture and Moxibustion Society, Korean Journal of Acupuncture, Journal of Acupuncture and Meridian Studies, Journal of Pharmacopuncture, Journal of Oriental Rehabilitation Medicine, the Journal of Korean Chuna Manual Medicine for Spine and Nerves, Korean Journal of Oriental Physiology and Pathology, and the Journal of Korean Oriental Internal Medicine).
The following search terms were used in each database’s language: “propolis” AND “external use OR external application OR external treatment OR topical application OR ointment OR gel OR dressing OR oral OR skin OR genital” AND “randomized controlled trial OR randomized clinical trial”.
We defined EUP interventions as any type of intervention in which propolis ingredients were applied to illness points as a treatment. All RCTs evaluating EUP for various diseases were included. Patients diagnosed with any disease were also included. We classified each disease according to the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) [
Studies on the combined effects of EUP and other interventions (e.g., EUP plus rinsing therapy) were considered for inclusion when the same intervention was applied to both the EUP group and the control group.
Clinical trials comparing EUP with placebo or other active controls were included. Other active control interventions included rinsing therapy, miconazole, oral antiseptics, silver sulfadiazine, honey, Vaseline, pine pollen packs, and metronidazole gel.
Non-RCTs, animal or cell studies, and quasi-RCTs were excluded. Trials including healthy participants were also excluded. We did not include studies on the internal use of propolis (e.g., propolis capsules, tablets, or suspensions) or mouthwash interventions (e.g., mouth rinsing, teeth brushing). Unqualified control interventions (e.g., herbal medicine, acupuncture, and bee venom therapy) were excluded because their efficacy was unable to be investigated.
Three authors (S. H. Sung, G. H. Choi, and N. W. Lee) independently selected the included studies and extracted data using a predefined data extraction form. N. W. Lee, who is a Traditional Chinese Medicine (TCM) practitioner, searched the Chinese databases and screened the Chinese-language trials. For studies with insufficient information, we contacted the corresponding authors to request additional data. Disagreements were resolved by discussion between two authors (G. H. Choi and B. C. Shin) to reach consensus.
We used the Cochrane risk of bias tool [
For meta-analyses, we extracted dichotomous data using risk ratios (RR) for the total effective rate (TER) for pain disappearance. We applied a random-effects model using Review Manager (Revman) software (version 5.3 for windows; the Nordic Cochrane Centre, Copenhagen, Denmark).
Of the 286 potentially relevant records, 221 studies were screened after duplicate trials were removed. Of these 221 studies, 139 were excluded because they were nonclinical trials (reviews, qualitative studies, and animal or in vitro studies) or were not related to propolis. Of the remaining 82 trials, 12 RCTs (English:
Flowchart of the RCT selection process. CCTs: controlled clinical trials; RCTs: randomized controlled trials; EUP: external use of propolis.
Twelve studies were conducted in various countries, including two trials in Brazil and China and one trial in the Democratic Republic of Congo, Iran, Korea, Italy, Macedonia, Poland, Sudan and Ukraine each. We grouped the 12 trials into those addressing three diseases: five trials applied EUP for oral diseases (Table
Characteristics of the included RCTs for oral diseases.
First author, year | Location of propolis production, chemical composition of propolis | Used form of propolis, amount used | Patient’s disease, sample size (randomized/analysed) | Experimental group (intervention, regimen) | Control group (intervention, regimen) | Outcome measures | Main results | AE |
---|---|---|---|---|---|---|---|---|
Ali, 2011 [ |
UAE, n.r. | Paste, n.r. | Recurrent oral aphthae, 120/114 | (A) PP (containing olive oil), |
(B) PP (containing sesame oil), |
(1) TER for pain disappearance |
(1) |
n.r. |
|
||||||||
Atanasovska, 2014 [ |
Macedonia, I 62.5% + B 55% + TP 24.2% + TFF 8% + TFD 49% | Spray, n.r. | Recurrent oral aphthae, 20/20 | (A) PS (Proaftol), |
(B) Placebo spray, |
(1) Lesion size |
(1) On day 3, |
n.r. |
|
||||||||
Capistrano, 2013 [ |
n.r., n.r. | Gel, 1 session 5 mL | Candidal stomatitis, 45/45 | (A) PG, |
(B) Mouthrinse (containing propolis), |
(1) CFU |
(1) Significant difference in |
n.r. |
|
||||||||
Chen, 2009 [ |
n.r., n.r. | Extract, n.r. | Recurrent oral aphthae, 76/76 | (A) PE, |
(B) Placebo (oral antiseptics), |
(1) TER for ROA |
(1) |
n.r. |
|
||||||||
Piredda, 2015 [ |
n.r., n.r. | Extract, 1 session 8–10 mg | Oral mucositis, 60/60 | (A) PE + mouthrinse, |
(B) Mouthrinse, |
(1) NCI-CTCAE version 4.0 | (1) |
Manifested suspected skin reaction |
AE: adverse events; B: balm (extract with 70% ethanol); CFU: colony forming units; I: inhibitor against
Characteristics of the included RCTs for skin diseases.
First author, year | Location of propolis production, chemical composition of propolis | Used form of propolis, amount used | Patient’s disease, sample size (randomized/analysed) | Experimental group (intervention, regimen) | Control group (intervention, regimen) | Outcome measures | Main results | AE |
---|---|---|---|---|---|---|---|---|
Gregroy, 2002 [ |
n.r., n.r. | Cream, n.r. | Second-degree burns, 33/ |
(A) PC, |
(B) SSD, |
(1) CFU |
(1) NS |
n.r. |
|
||||||||
Kucharzewski, 2013 [ |
Poland, n.r. | Ointment, n.r. | Varicose veins of lower extremities with ulcer, 56/56 | (A) PO + rinsing the ulcer with PSCS + compression treatment, |
(B) Rinsing the ulcer with PSCS + compression treatment, |
(1) Duration of treatment for ulcer | (1) |
n.r. |
|
||||||||
Ngatu, 2011 [ |
Japan, n.r. | Extract, n.r. | Tinea capitis and tinea versicolour, 242/188 | (A) PE (50 mg/mL), |
(B) PE (100 mg/mL), |
(1) Pruritus |
(1) |
Itch (1 in group (D)) |
|
||||||||
Park, 2013 [ |
Korea, n.r. | Mask pack, 2 g | Acne, 30/30 | (A) PMP, |
(B) PPMP, |
(1) Skin conditions |
(1) |
n.r. |
|
||||||||
Yin, 2013 [ |
China, n.r. | Ointment, n.r. | Other specified diabetes mellitus with foot ulcer, 60/60 | (A) PO + VT, |
(B) VT, |
(1) TER for ulcer | (1) |
n.r. |
AE: adverse events; CFU: colony forming units; negative: (B) significantly better than (A); n.r.: not reported; NS: no significant difference between groups; PC: propolis cream; PE: propolis extract; PMP: propolis mask pack; PO: propolis ointment; positive: (A) significantly better than (B); PPMP: pine pollen mask pack; PSCS: physiological sodium chloride solution; SSD: silver sulfadiazine; TER: total effective rate; VT: vasodilator therapy; WBC: white blood cell.
Characteristics of the included RCTs for genital diseases.
First author, year | Location of propolis production, chemical composition of propolis | Used form of propolis, amount used | Patient’s disease, sample size (randomized/analysed) | Experimental group (intervention, regimen) | Control group (intervention, regimen) | Outcome measures | Main results | AE |
---|---|---|---|---|---|---|---|---|
Mousavi, 2016 [ |
Iran, n.r. | Cream, 1 session 3 g | Acute vaginitis, 100/100 | (A) PVC, |
(B) MVG, |
(1) Amsel’s criteria |
(1) |
n.r. |
|
||||||||
Vynograd, 2000 [ |
Canada, n.r. | Ointment, n.r. | Herpes viral infection of genitalia and urogenital tract, 90/90 | (A) PO, |
(B) AO, |
(1) Number of patients who were healed |
(1) |
None |
AE: adverse events; AO: acyclovir ointment; MVG: metronidazole vaginal gel; n.r.: not reported; PO: propolis ointment; positive: (A) significantly better than (B); PVC: propolis vaginal cream.
The 12 studies included 862 participants. The sample size per group ranged from 10 to 52 participants. One study reported on 23 patients with two burn areas, one of which received EUP and the other a control intervention [
We classified the 12 RCTs into those addressing oral, skin, and genital diseases because the types of disease were heterogeneous. The five studies included in the oral diseases group consisted of three studies on recurrent oral aphthae (ROA) [
Four studies compared EUP with a placebo intervention that was the same form of EUP [
A total of eight studies described the countries where propolis had been collected, including the UAE [
The chemical composition of propolis was reported in only one study [
Seven forms of EUP were used in 12 RCTs; extract and ointment were utilized in three trials each, and other types of EUP included paste [
The amount of EUP used was reported in only four studies: the amount of EUP for 1 session ranged from 8 mg to 3 g in three trials [
Twelve studies reported on very diverse outcome measures due to the various types of diseases. The duration of treatment for each disease was investigated in three studies [
The included RCTs had a generally low methodological quality (Table
Risk of bias assessment.
First author, year | Selection bias | Performance bias | Detection bias | Attrition bias | Reporting bias | |
---|---|---|---|---|---|---|
Random sequence generation | Allocation concealment | Blinding of participants and personnel | Blinding of outcome assessment | Incomplete outcome data | Selective reporting | |
Ali, 2011 [ |
U | U | H | U | U | U |
Atanasovska, 2014 [ |
U | U | L | U | L | U |
Capistrano, 2013 [ |
U | U | H | L | L | L |
Chen, 2009 [ |
U | U | L | U | L | U |
Piredda, 2015 [ |
U | L | H | U | L | L |
Gregroy, 2002 [ |
U | U | H | U | U | U |
Kucharzewski, 2013 [ |
H | U | H | U | L | U |
Ngatu, 2011 [ |
U | U | H | U | U | L |
Park, 2013 [ |
U | U | L | U | L | U |
Yin, 2013 [ |
U | U | H | U | L | U |
Mousavi, 2016 [ |
U | U | H | U | L | L |
Vynograd, 2000 [ |
U | U | H | U | L | U |
H: high risk; L: low risk; U: unclear risk.
A meta-analysis was not possible because of the heterogeneity in the diseases or outcome measures, with the exception of two trials on ROA [
Of the five studies on oral diseases, a meta-analysis of two studies [
Meta-analysis of the total effective rate (TER) of EUP versus placebo. EUP: external use of propolis; CI: confidence intervals.
Of the five studies on skin disease, one on burns [
Of the two studies on genital diseases, one study comparing propolis vaginal cream with metronidazole vaginal gel reported a significant improvement in Amsel’s criteria and gram stain [
Three studies described adverse events. One trial reported a skin reaction in 2 cases in the EUP group [
The objective of this systematic review and meta-analysis was to provide evidence on EUP for any disease. A total of 12 studies were included in our review. Three studies on ROA [
Most of the included trials had a low methodological quality based on Cochrane’s risk of bias tool. Although the 12 RCTs stated that the participants were randomly assigned, an adequate method of randomization was not described, and only one [
The propolis used in the 12 included RCTs was collected from diverse countries. Eight out of 12 studies [
Four studies used placebo interventions that used the same form of propolis for the control group [
In this review, trials using propolis as a mouthwash were excluded because we focused on assessing the evidence of the efficacy of EUP when its ingredients were applied at the point of illness. There was some evidence in a recent dentistry study that propolis mouthwash protects against oral disease due to its antimicrobial properties [
Although our review indicated the applicability of propolis for external use, few studies on the standardization of EUP have been examined. Therefore, the following factors should be standardized to reduce the heterogeneity of future trials on EUP: (1) type of EUP form based on chemical composition of propolis; (2) effects and safety of EUP considering geographical locations; (3) amount used and number of treatment sessions; and (4) placebo model for EUP.
The strength of our review is that there was no restriction of language or publication status; hence, English, Chinese, Korean, and Persian papers were included in the review. However, there are some limitations to this systematic review. First, although 12 studies on EUP were included in this review, the heterogeneity in the diseases, the types of EUP form, control groups, and outcome measures was high; thus, a statistic pooling of 10 studies could not be assessed. In addition, it is difficult to propose any definitive conclusions regarding the safety of EUP because of the insufficient information on adverse effects. Therefore, researchers should conduct RCTs on EUP considering these limitations. Moreover, the side effects and amount used must be described in future studies to establish clinical practice guidelines for EUP.
As previous publications only investigated propolis for oral diseases [
Our systematic review and meta-analysis suggested that the effectiveness of EUP for the treatment of oral, skin, and genital diseases was inconclusive because of the low methodological qualities and the small sample sizes. Further RCTs, with a high quality and large samples for specific disorders, must be conducted to provide additional clinical evidence on EUP treatment. Furthermore, the standardization of EUP to ensure clinical efficacy and safety is needed.
The authors declare that there is no conflict of interests regarding the publication of this paper.
Soo-Hyun Sung, Byung-Cheul Shin, Nam-Woo Lee, and Gwang-Ho Choi were responsible for the study concept and design. Soo-Hyun Sung, Gwang-Ho Choi, and Nam-Woo Lee searched and selected studies for inclusion. Nam-Woo Lee, trained in Traditional Chinese Medicine, searched and selected studies of Chinese literature. Soo-Hyun Sung and Gwang-Ho Choi evaluated the risk of bias of the included studies. Soo-Hyun Sung and Byung-Cheul Shin performed the data analysis and interpretation. Soo-Hyun Sung, Gwang-Ho Choi, and Lam-Woo Lee wrote the paper. Byung-Cheul Shin revised the manuscript. All authors were involved in the whole process of the study.
This work was supported by a grant to Korean Medical Science Research Centre for Healthy Aging from the National Research Foundation of Korean Government (2014R1A5A2009936).