The Effect of Fennel on Pain Relief in Primary Dysmenorrhea: A Systematic Review of Clinical Trials

Background and aims: Fennel is often advocated for primary dysmenorrhea. Whether this herb has a real effect on pain relief is still a matter of debate in medicine. Therefore, this study was conducted to evaluate the effect of fennel on primary dysmenorrhea. Methods: This systematic review was conducted on clinical trials (non-randomized, randomized, historical study with concurrent control) published in PubMed (MEDLINE), Web of Science, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), ProQuest, and Persian databases (Magiran, IranMedex, SID, Irandoc) regarding the effect of fennel on pain intensity in primary dysmenorrhea from 1990 to 2019. Nine studies met all inclusion criteria. Any clinical trials on young women with primary dysmenorrhea were included in the study. Studies that used fennel plus other products investigated fennel effect on premenstrual syndrome (PMS) and bleeding; studies without a control group and nonclinical trials were excluded. In all studies, participants were young female university or high school students. All of them had moderate to severe primary dysmenorrhea. Results: In all of the studies except for one, fennel had been more effective than placebo in pain relief (P < 0.01). Non-steroidal drugs had the same result as fennel for pain relief. However, in one study, the difference between non-steroidal anti-inflammatory drugs (NSAIDs) and fennel in pain relief was observed. Only one study reported increasing vaginal bleeding after fennel consumption in some cases. Conclusion: Collectively, these studies favored fennel over NSAID, other herbal drugs, and placebo. But more investigation is needed to draw a firm conclusion. Registration: PROSPERO 42015023725


Introduction
Primary dysmenorrhea is one of the most important public health problems among young females worldwide, which interfere with their social responsibility and quality of life. Primary dysmenorrhea is defined as painful menstrual cramps of the uterus without any obvious gynecological problem. 1 The elevated level of Prostaglandins E 2 and F 2 α (PG E 2 and F 2 α) has been known as a cause of primary dysmenorrhea. Ischemia and pain were induced by increasing vasopressin, and uterine contraction was induced by PG E 2 and F 2 Α. Foeniculum vulgare (Fennel) is used as foodstuff and also an herbal drug in traditional medicine. It is an anti-inflammatory and anti-spasmodic substance. 2 In a study, Ostad et al. reported a decrease in the frequency and intensity of uterine contraction in rats after using fennel. 3 The standard treatment to relieve pain is medical therapy by oral contraceptive or non-steroidal anti-inflammatory drugs (NSAIDs) such as mefenamic acid or ibuprofen. 4,5 The treatment with NSAID S still has 20% to 25% failure rates. 1 Moreover, due to the side effects of medical treatment, many women are currently seeking conservative treatment. Considering the side effects of chemical therapy, it seems that some herbal drugs may be a good substitute. Fennel is known as an anti-inflammatory and estrogenic substance. It has demonstrated beneficial effects in the treatment of primary dysmenorrhea. 6 The authors' search showed that there are several clinical trials that compare different types of fennel with other herbs, NSAIDs, and placebo for pain relief in young women. Therefore, this study aimed to review the effect of fennel on primary dysmenorrhea since this product has fewer side effects compared to NSAID.

Materials and Methods
The authors summarized the evidence from several bibliographies and scientific databases including CENTRAL, MEDLINE via PubMed, Scopus, Web of Science, ProQuest, and Persian databases (MagIran, IranMedex, SID, Irandoc) regarding the effect of fennel on primary dysmenorrhea. We did not find any article in Grey literature from Scopus and Google Scholar for conference proceedings (www.greylit.org). Search terms used were as follows: TITLE-ABS-KEY (fennel OR "Foeniculum Vulgare") AND TITLE-ABS-KEY (dysmenorrhea OR menstrua*) AND TITLE-ABS-KEY (trial* OR intervention* or comparative OR clinical trial* OR randomized controlled trial) AND DOCTYPE (ar OR re) and PUBYEAR from 1989 to 2019. All articles retrieved in the search were screened by title and abstract for relevance. The full-text articles that have been potentially relevant were included in this study. Articles that fulfilled all of the inclusion criteria were included. The inclusion criteria were as follows: Any clinical trials (nonrandomized, randomized, historical study with concurrent control) on young women with primary dysmenorrhea were included in this study. Studies which used any type and dose of fennel in the form of a soft capsule, extract, or essence were included. Studies with any types of control groups such as standard treatment (NSAIDs [mefenamic acid and ibuprofen] and vitamin E), placebo, no treatment, or other herbal drugs were included. Studies that measured pain relief by any scale such as visual analogue scale (VAS), checklist, or questionnaire were included. Studies that assessed secondary dysmenorrhea were excluded.
The data extraction and quality assessment were independently carried out by two authors using a predefined data extraction form. Disagreements were solved through discussion. To assess the risk of bias, two reviewers independently evaluated the included studies using a modified CONSORT 2010 checklist. The inclusion criteria were random sequence generation, blinding procedure (single, double, triples), allocation concealment, completeness of outcome, and reporting of outcome and other sources of bias. Primary studies that used fennel plus other products investigated the effect of fennel on premenstrual syndrome (PMS) and bleeding; studies without a control group and nonclinical trials were excluded.
The qualities of the included trials were assessed by two authors. Due to the sensitivity of this part, any disagreement between the two authors was discussed. Studies that were duplicated with identical data were considered one study. Figure 1 shows the flow chart of the screening and selection process of articles. Initially, 418 publications were identified by systematic search. Nine studies met   No side effect Both of the two groups reported a decrease in pain, but it was not significant (P > 0.05).

Study Inclusion
our defined criteria and were reviewed. 5,[7][8][9][10][11][12][13][14] The quality assessment revealed a score of at least equal or higher than 12 in all of studies using the CONSORT checklist. Most of the studies had been done on female university students and only one study had been done on high school students. In addition, in one study, both high school and university students were selected.

Study Characteristics and Findings
In all of the studies except one, fennel had been more effective than placebo in pain relief (P ≤ 0.001 for most of them, and with P > 0.006 for one). NSAIDs such as mefenamic acid or gelofen had the same result as fennel for pain relief. However, the difference between NSAIDs and fennel in pain relief was observed in one study. The decrease in clinical signs was implied in two studies and there were no significant differences between NSAIDs and fennel. In one study, fennel had reduced menstrual bleeding better than non-steroidal drugs on the third day of menstruation after the second cycle (P > 0.04), and there were no differences in nausea, headache, and other somatic signs between three groups (P > 0.05). Table 1 shows the summarized key data.
In one study, nausea intensity and weakness decreased during the menstrual period, and a significant difference was found after two and three months of use. Moreover, difference in the quality of well-being after one and three months was significant. The pain relief was observed after using fennel and continued considerably over time. In another study, there was no pain in 80% of the fennel group and 73% of the mefenamic acid group. In regard to the limitation of activities, 83% in the fennel group and 71% in the mefenamic acid group had no rest after treatment.
Only in one study, three cycles of menstruation were compared with each other. These cycles were compared day by day for the effect, potency, time of initiation of effect, and drug complications using a self-scoring system. Both of the drugs (fennel and mefenamic acid) effectively relieved menstrual pain as compared with no medication as the control cycles (P < 0.001). The mean duration of initiation of effect was 67.5 ± 46.06 minutes for mefenamic acid and 75 ± 48.9 minutes for fennel after using them; however, the difference was not statistically significant (P > 0.57). In another study, mefenamic acid had a more potent effect than fennel on the second and third menstrual days (P < 0.05); however, the difference on the other days was not significant. One study found that fennel had similar effects as Vitagnus for treatment of dysmenorrhea and mefenamic acid was less effective than both of the mentioned drugs (P < 0.05).

Discussion
The aim of this study was to evaluate the efficacy of different types of fennel on primary dysmenorrhea. The quality assessment revealed a score of at least equal or higher than 12 in the majority of studies using the CONSORT checklist. For all systematic reviews, publication bias is a major concern that may lead to a false-positive result and negative studies might remain unpublished.
Different types of fennel consisting of extract, drop, and soft capsule have been compared with NSAIDs, other herbal drugs, and placebo for relieving pain. The majority of the studies reported that fennel (extract, drop, and capsule) is more effective than NSAIDs and other herbal drugs or placebo. In one study, the researchers reported that the effectiveness of fennel was not as strong as the mefenamic acid. The difference between the positive outcome and negative result from other RCT is not readily explicable, but the researcher stated that the dose of the drop may not be sufficient for pain relief. 8 Fennel is generally used as foodstuff and spice in pickles, so it is assumed that it is free of serious adverse effects. However, it can be an unsafe substance. For example, it may be safe when used in low doses as a spice, but it may be harmful when it is taken in higher doses as a drug.
There were no reports of the side effects of fennel in some studies. 9,13,14 The other studies did not mention any adverse effects of fennel. 7,8,[10][11][12] In one study, the researchers stated that one subject was reported to have increased menstrual bleeding after consuming fennel drop. 5 It seems that more studies are needed to assess the side effects of fennel. Because of the diversity of the dose and duration of fennel administration in various studies, it is not possible to summarize the results of the studies, which is the limitation of this study.

Conclusion
In summary, we found that fennel is a promising herbal drug with pain-relieving properties, but it seems that the clinical investigation is not sufficient to draw a firm conclusion because all of the presented studies had a small sample size. Further rigorous studies are needed to establish whether fennel is the most effective herbal drug for primary dysmenorrhea.