R osa damascena, popularly known as damask rose, is a medicinal herb belonging to the Rosaceae family.1 This herb is cultivated in Iran, Bulgaria, Pakistan, Turkey, Morocco, and India.2 R damascena is traditionally considered as the king of flowers and is often associated with purity, inspiration, love, happiness, and beauty.3 R damascena is also called Gole-Mohammadi by Iranian people because its fragrance reminds them of Prophet Muhammad.4

R damascena is currently used worldwide in food, perfume, cosmetic, and pharmacological industries.3,5 The pharmacological properties of this herb are attributed to a high percentage of glycosides, terpenes, flavonoids, and anthocyanins.2,6 Traditionally, different products of R damascena have been used for managing conditions as varied as erectile dysfunction, arthritis, hepatitis, cardiovascular disorders, respiratory tract infections, and digestive disorders.3,6,7 R damascena preparations are also suggested to alleviate pain by traditional physicians in Iran and elsewhere and some modern medical practitioners.2,5,6,8–10 In recent years, several in vivo and in vitro studies have assessed the pain-alleviating properties of R damascena in aromatherapy, oral intake, and topical application.11–40

Recent reviews have suggested positive effects of R damascena in aromatherapy form on reducing pain severity.5,6,8,41,42 However, the potential pain-alleviating effects of this herb in oral and topical forms have not yet been addressed in a comprehensive review. Based on the recent randomized controlled trials (RCTs), either topical application or oral intake of R damascena could alleviate different types of pain (e.g., pregnancy-related low back pain, menstrual-related pain, postoperative pain, and aphthous stomatitis-induced pain).24,30,31,35,36,43 On the contrary, two RCTs found no significant difference in sexual-related pain among women who received R damascena capsule compared to those who received placebo capsule.27,28 Similarly, no significant difference was reported between students’ menstrual-related abdominal pain when they received R damascena and mefenamic acid capsules in a cross-over design.25 In addition, oral intake of R damascena had a non-significant alleviating effect on menstrual-related abdominal pain and headache among females with primary dysmenorrhea (PD) and premenstrual syndrome (PMS).26,29 Moreover, topical application of this herbal medicine had no significant effect on pain induced by migraine headaches and aphthous ulcers.32,34

Although the results of recent RCTs are inconclusive on the pain-alleviating effects of R damascena in topical and oral administration forms, to the best of our knowledge, no review has analyzed the conflicting findings of these RCTs. Therefore, we aimed to systematically identify and summarize the results of recent RCTs regarding the effects of topical application and oral intake of R damascena on acute pain severity in adults and also to pool the obtained findings in a meta-analysis.

Methods

This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42020205071). The review was also reported based on the statements presented by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).44

Search strategy

A systematic search was performed on the Cochrane Central Register of Controlled Trials, PubMed, Scopus, Web of Science Core Collection, Embase, Cumulative Index to Nursing and Allied Health Literature, Scientific Information Database (http://www.sid.ir/), and Magiran (http://www.magiran.com). All the searches were conducted by two researchers independently. The searches were conducted in respect of two time periods: (a) from the inception date of the database till 30 October 2020; and (b) from 30 October 2020 to 20 March 2021. Additionally, the Iranian Registry of Clinical Trials and the World Health Organization International Clinical Trials Registry Platform were searched for any records of clinical trials involving R damascena. The corresponding authors of the retrieved trials were contacted via email to get additional information on their trials. Likewise, the reference lists of the eligible trials were checked to avoid missing related studies.

A combination of the following keywords was used in the systematic search: (‘Rosa’ OR ‘Rose’ OR ‘Rosaceae’ OR ‘Rosewater’ OR ‘Rose water’ OR ‘Rose oil’ OR ‘R damascena’ OR ‘R damascena’ OR ‘R X damascena’ OR ‘Damask rose’ OR ‘Rose damask’ OR ‘Damascus rose’ OR ‘Gole Mohammadi’ OR ‘Gol-E-Muhammadi’ OR ‘Gol-E-Mohammadi’) AND (Oral OR Supplement* OR Syrup OR Suspension* OR Emulsion OR Linctus OR Drop* OR Solution OR Extract* OR Oil* OR Capsule* OR Tablet OR Spray OR Ointment* OR Gel* Or Cream OR Lotion OR Massage OR Topical) AND (Pain OR Analgesi*OR Antinocicepti*).

To ensure that none of the related studies were missed, no restrictions were applied with regard to studies’ participants, clinical conditions, language, or publication date in the
literature search.

Eligibility criteria and studies selection

The studies were included based on the elements of the participants, intervention, comparison, outcomes, and study design (PICOS), as per the criteria in Table 1.

Studies were excluded if they: (a) did not have English abstract; (b) were conference papers, theses, letters, comments, short communications, reviews, meta-analyses, and animal studies; (c) administered R damascena in aromatherapy form; (d) administered R damascena in combination with other herbal products; (e) administered other species of Rosa; (f) recruited individuals who experienced chronic pain; and (g) recruited individuals > 60 years of age. Redundant studies with limited data were also excluded.

The screening and selection of the studies were performed by two researchers independently.

A total of 1429 records were found from the electronic search. Based on the screening of title and abstract of 953 records, 938 were removed and full-texts of the 15 remaining studies were assessed for compliance with the inclusion criteria. Of these, four were excluded: two were redundant publications,43,45 one had a single-group study,39 and one study recruited individuals > 60 years of age.34 Finally, 11 studies were considered eligible for this review [Figure 1].24–32,34,36

Data extraction

The following data were extracted for each study by two independent researchers: (a) study details, (b) participants’ characteristics, (c) intervention details, and (d) mean or mean changes and SD, as well as number and percentage for the measured outcomes. In four studies with multiple intervention groups, data were extracted from the R damascena and control groups.26,29,35,36 Of these, one considered both placebo and non-treated groups; hence, data were extracted from the placebo group for comparison.36 If the studies contained unclear or insufficient information, the corresponding authors were contacted via email or phone call to get additional information on their studies. Any disagreement in data extraction between the researchers was resolved by discussion.

Assessment of risk of bias

The risk of bias for each included study was assessed by two independent researchers using the Cochrane Risk of Bias Assessment Tool, which consists of seven items: (a) random sequence generation (selection bias), (b) allocation concealment (selection bias), (c) blinding of participants and personnel (performance bias), (d) blinding of outcome assessment (detection bias), (e) incomplete outcome data (attrition bias), (f) selective reporting (reporting bias), and (g) other biases.46 Disagreements between the researchers were resolved by discussing with a third researcher and reaching a consensus.

Data analysis

Various studies recorded pain at different post-treatment times; hence, we calculated the changes of mean and SD in each study group by comparing the baseline and the end-of-trial values, using standard methods.42,47 In a cross-over trial, the effect sizes of the first and second phases were pooled.25 Also, the effect sizes of one study over the same participants were pooled before conducting the meta-analysis.26

All effect sizes were reported as standardized mean difference (SMD) of outcomes with their 95% CI, using a random-effect model to take between-study heterogeneity into account. To assess heterogeneity, the I2 statistic value of ≥ 50% and Cochran’s Q test value of < 0.05 were considered as significant heterogeneity. Subgroup analysis was performed to determine probable sources of heterogeneity and investigate any possible differences between studies about clinical condition, R damascena total administration dosage and duration as well as administration form, study tool, and study quality. To conduct a subgroup analysis based on total administration dosage, we converted R damascena products to a similar product or unit if possible. According to the administration dosage reported in the majority of included studies, 10 drops of R damascena was estimated as 1 mL. Also, we considered 1 mg of R damascena as equal to 0.001 mL. To find the dependency of the overall estimate on the effect size from a single study, a sensitivity analysis was conducted. The Begg’s and Egger’s tests and also a visual inspection of funnel plots were used to assess potential publication bias. All statistical analyses were performed using Stata, version 11.2 (Stata Corp, College Station, TX). P-values were considered significant at the level of < 0.05.

Results

General characteristics

Out of the 1429 records found from our electronic search, only 11 studies were eligible to be included in this study. All the included studies were conducted in Iran, and three were published in Farsi.24,29,32 These studies were conducted on individuals in the age range 18–40 years who experienced different types of acute pain. All studies recorded only pain severity, except one which recorded frequency and dosage of administrated analgesics in addition to pain severity.30 One study suggested an association of mild allergic rhinitis with R damascena therapy [Table 2].35

Topical application of R damascena

Of the four studies that administered R damascena in topical form, three used 0.5–1 mL topical drop,32,35,36 and the other one administered 5 mL mouthwash.31 The total administration duration of R damascena products varied from 2 to 28 days. The products were self-administered without massage in all studies, except one which applied abdomen massage with R damascena essential oil.36 All studies had a parallel-group design and two recruited only females.35,36 The total sample size of the placebo group (i.e., Diphenhydramine syrup and almond oil) and the R damascena group were 137 and 138, respectively [Table 2].

Based on the combined effect sizes of the four RCTs, topical application of R damascena had no pain-alleviating effect (SMD = 0.10, 95% CI: -0.75–0.96; p = 0.814). Heterogeneity was significant between studies in the overall analysis (I2 = 91.3%, p < 0.001) [Figure 2]. After excluding one study which applied R damascena using massage,36 a non-significant reducing effect of treatment was observed (SMD = -0.06, 95% CI: -1.13–1.00; p = 0.906).

Oral intake of R damascena

Of the seven studies that investigated R damascena in oral form, five administered soft or hard gelatin capsule containing either 200–800 mg extract25,26,30 or 2 mL essential oil.27,28 Two remaining studies used 1 mL or 1.5 mL oral drop.24,29 The total administration duration of R damascena products varied from one day to 60 days. All oral intake studies recruited only females. Six studies had parallel-group design, while one adopted cross-over design.25 The total sample sizes of the placebo/conventional treatment groups (i.e., mefenamic acid capsule) was 262 and that of the R damascena groups was 264 [Table 2].

Based on the combined effect sizes of seven RCTs, oral intake of R damascena reduced pain severity non-significantly compared to the placebo or conventional treatment (SMD = -0.55, 95% CI: -1.27–0.17; p = 0.132). Significant heterogeneity (I2) was found among the included studies for main analysis (I2 = 94.3, p < 0.001) [Figure 3]. After excluding one cross-over study,25 the results of primary meta-analysis did not change (SMD = -0.68, 95% CI: -1.55–0.20; p = 0.129). Based on subgroup analysis, pain severity was significantly reduced when R damascena was administered using oral drop (p = 0.024) [Table 3].

Assessment of the risk of bias

From the perspective of risk of bias, three out of 11 studies had good quality (low risk of bias for all items),25,27,28 while two had poor quality (high risk of bias in one item and unclear risk of bias in more than two items).30,32 The remaining six studies had fair quality (high risk of bias in one item or unclear risk of bias in one item or two items) [Figures 4 and 5, Table 4].24,26,29,31,35,36

Publication bias and sensitivity analysis

With regard to topical application, no evidence of publication bias was found based on the visual inspection of the funnel plot as well as the Begg’s test (p = 0.734) and Egger’s test (p = 0.527). Such findings were also obtained for oral intake based on the funnel plot and also the Begg’s test (p = 0.230) and Egger’s test (p = 0.236) [Figure 6].

Sensitivity analysis showed that the pooled effect sizes obtained for topical application (lower CI limit: -1.17–-0.06; upper CI limit: 0.73–1.48) and oral intake (lower CI limit: -1.55–-0.79; upper CI limit: 0.01–0.34) did not depend on a particular study or group of studies [Figure 7].

Discussion

In Asian countries, herbs have been important in traditional and complementary medicine for alleviating various painful conditions.48,49 Currently, different products of R damascena are being used in Asian countries for their pain-alleviating properties; however, there is a paucity of comprehensive evidence to support their applications.3,7,42 Accordingly, we performed this review to summarize the effects of topical application and oral intake of this herbal medicine on treating acute pain in adults.

Based on the meta-analysis findings, administration of oral intake of R damascena reduced pain severity non-significantly. However, the topical application of this herbal medicine had no pain-alleviating effect, which might be due to the limited number of included studies and also their suboptimal methodological quality. It also might be due to the participants' gender as all the oral medications were administered to females mostly, and that too, for gender-specific pains; only two topical-application studies recruited both sexes. Also, it seems that our findings obtained for topical application studies were affected by one study which applied R damascena by massaging it.36 After excluding that study, pain severity reduction of topical application method was non-significant.

The findings of this review update the available reviews regarding the analgesic effect of R damascena. In a recent meta-analysis by Koohpayeh et al,47 the pooled analysis of five RCTs on the effects of oral intake and aromatherapy of R damascena reduced the menstruation-related pain non-significantly (weighted mean difference (WMD) = –1.39; 95% CI: -3.21–0.43; p = 0.133). Also, in a systematic review of herbal medications for postoperative pain, Arruda et al,50 found no significant reduction in the need for analgesics after oral intake of R damascena in combination with gingeRosa. However, Nayebi et al,2 reported the analgesic effects and safety of R damascena in the forms of inhalation aromatherapy, topical treatment, or massage application on pain induced by surgery, PD, pregnancy, and aphthous ulcer. In another systematic review, Mohebitabar et al,8 found promising evidence for the effectiveness of inhalation use of R damascena on pain of menstruation, renal colic, and surgery. Moreover, Mahboubi et al,5 and Boskabady et al,6 reported the analgesic activities of R damascena based on the results of both in vivo and in vitro studies.

Differences in study objectives might be the main reason for the differences observed in the findings of previously mentioned reviews and in the current review. In this meta-analysis, we included only RCTs that addressed pain-alleviating effects of R damascena using oral or topical administration routes, while the above-mentioned systematic or narrative reviews neither focused specifically on the analgesic properties of R damascena nor they stratified the administration routes of this treatment. However, Nasiri et al,42 pooled 15 RCTs on the effect of aromatherapy with R damascena on adults’ acute pain severity and found a promising pain-alleviating effect of treatment (WMD = -2.12; 95% CI: -2.85–1.40; p < 0.001). Also, they included studies that evaluated the effect of R damascena in form of aromatherapy; whereas, we considered oral intake or topical application of R damascena which can justify the differences in the obtained findings.

The analgesic effects of R damascena induced by oral intake or topical application have been attributed to chemical components in this herbal medicine. Hongratanaworakit has reported the analgesic effects of R damascena oil without olfactory stimulation, and she presumed that molecules of R damascena could enter the bloodstream by dermal absorption.51 In a recent animal study, the non-water soluble ingredients of R damascena oil such as quercetin and kaempferol were reported as responsible for its analgesic effect.33 Likewise, 2-phenylethanol found in R damascena might be a pain signal inhibitor that could block pain receptors.17 Moreover, the topical effects of R damascena on reducing pain might be explained by the high tannin content of the extract of this herbal medicine.31 Further studies are recommended to determine the biochemical mechanisms responsible for analgesic activities of oral intake and topical application of R damascena.

Implications of findings

The findings of the present review can increase our understanding of the value of R damascena as a holistic care approach and non-pharmacological agent. We found that oral intake of R damascena led to a 0.55 unit reduction in pain severity. Also, the administration of R damascena was reported to be free of side effects in most included RCTs. However, we confirmed a paucity of well-designed trials in this area as most included studies had a fair or poor methodological quality. Considering the low-cost and simple application of R damascena, future studies with improved methodological quality are suggested to evaluate the pain-alleviating potencies of this herbal medicine to reach an evidence-based conclusion.

Although we used subgroup analysis, we could not find a source of between-study heterogeneity or a significant difference within subgroups in most cases, which might be due to the limited number of included studies. Based on studies that evaluated the oral intake of R damascena, it seems that pain severity reduced more when the treatment was administrated in the form of oral drops, at higher dosages, and for longer duration. On the contrary, for topical applications of R damascena, it seems that lower dosage and shorter administration duration may have been more beneficial. Further studies are suggested to compare the effects of oral intake and topical application of R damascena on pain severity in different groups of participants with different administration durations, dosages, and forms.

Limitations

Initially, we did not receive any response or feedback from corresponding authors of the published studies in some cases when we requested further information via email. In the following, contact was made with the authors via phone call and the required details were obtained. Regarding one study,30 where the contact number of the author was not available, estimations were made based on our internal discussion and consensus. Secondly, according to pool data using meta-analysis, we compared the changes in baseline and end-of-trial values due to a minor variation in assessment time of pain severity after treatment. Hence, different choices of an endpoint might have led to different effect sizes or heterogeneities. Thirdly, the results obtained by subgroup analysis might be affected by the limited number of studies in each subgroup. Fourthly, we could not perform a dose-response analysis due to the limited number of included studies and the low variations of R damascena administration dosages and durations. Finally, all studies were conducted in Iran and nearly all (except two studies on topical application of the herb) recruited female participants only; hence, the findings may not be generalizable to men, or those outside Iran.

Conclusion

Although the growing trend of recent RCTs about pain-alleviating effects of topical application and oral intake of R damascena provides a scientific rationale for its clinical properties, the present meta-analysis indicated that oral intake of this herbal medicine had a non-significant alleviating effect on adults’ acute pain severity. Also, the topical application of R damascena had no pain-alleviating effect. Therefore, further robust RCTs are needed to elicit reliable conclusions in this regard.

Disclosures

The authors declared no conflicts of interest. No funding was received for this study.

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