Eryngium caucasicum Improves Primary Dysmenorrhea

A double-blind, randomized, placebo-controlled trial

By Paul Richard Saunders, PhD, ND, DHANP, CCH

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Reference

Behmanesh E, Delavar MA, Kamalinejad M, Khafri S, Shirafkan H, Mozaffarpur SA. Effect of eryngo (Eryngium caucasicum Trautv) on primary dysmenorrhea: a randomized, double-blind, placebo-controlled trial. Taiwan J Obstet Gynecol. 2019;58:227-233.

Study Objectives

To examine the effect of an Iranian traditional herbal medicine, Eryngo (Eryngium caucasicum), for primary dysmenorrhea, compared to ibuprofen and placebo, for primary dysmenorrhea within 1-2 years of menarche

Design

Three-arm, double-blind, placebo-controlled trial

Participants

One hundred sixty-nine women with confirmed primary dysmenorrhea

Inclusion Criteria

Females 15-30 years old, not pregnant, regular menstruation (21- to 35-day cycles), menstrual flow of 3-7 days for the last 6 months, dysmenorrhea lasting 8-72 hours that was rated at grade 1 or moderate to severe on the verbal multidimensional scoring system (VMSS)

Exclusion Criteria

Secondary dysmenorrhea; pregnancy; being a professional athlete; mild dysmenorrhea; irregular menstruation; severe causes of stress (family disputes, death of parents); medication use; abnormal pelvic and/or abdominal findings on ultrasound; history of pelvic surgery

Instruments

VMSS, baseline questionnaire regarding age, menstrual cycle, degree of dysmenorrhea, visual analogue scale (VAS) to measure dysmenorrhea, use of acetaminophen for dysmenorrhea

Treatment

There were 3 treatment groups: Eryngo simple syrup, 5 mL TID; ibuprofen syrup, 200 mg TID; and placebo simple syrup, 5 mL TID. Each treatment began on day 1 of menstruation and continued for 5 days for 2 menstrual cycles.

Analysis

SPSS (version 21) for descriptive statistics, repeated measure analysis of variance, and number needed to treat (NNT). Significance was set at P≤0.05.

Key Findings

The mean age of the study participants was 19.5±5 years; mean BMI was 21.6±3.8 kg/m2. Mean age of menarche was 12.6±1.2 years, mean duration of menstruation was 6.9±1.3 days, and mean menstrual cycle length was 29.1±5.4 days. These are normal findings for this age group.

Peak-pain based on the VAS was significantly reduced at the first and second menstrual cycles compared to the pretreatment cycle (P<0.0001): 4.2 for Eryngo, 4.3 for ibuprofen, and 0.9 for placebo (P<0.0001). This decrease in pain intensity continued for the follow-up menstrual cycle when treatment was withheld; however, pain increased in the placebo group.

In this study, Eryngo was shown to be effective for relief of primary dysmenorrhea after 2 cycles.

Based on the pain level in the second treated menstrual cycle, the NNT was 1.5 for Eryngo and 2.0 for ibuprofen. The NNT for Eryngo combined with ibuprofen was approximately 6.0, according to the authors, although the calculation of the combined NNT value was not described.

No serious side effects were reported in any of the 3 groups. Five of the 136 subjects reported gastric reflux, nausea, vomiting, and menorrhagia, but differences between the treatment groups were not statistically significant. Treatment satisfaction was 70.2%, 39.4%, and 7.0% in the Eryngo, ibuprofen, and placebo groups, respectively; 89.4%, 84.7%, and 37.2%, respectively, would recommend their treatment to others (P=0.0001). Dissatisfaction was 8.5%, 4.3%, and 79.0%, respectively (P=0.0001).

The total phenol content of Eryngo syrup was 35 μg/mL (9.72% of herbal extract); total flavonoid content was 27 μg/mL (7.5% of herbal extract). Thus, a 100-mL bottle of syrup contained 9.72 mg of phenols and 7.5 mg of flavonoids, equating to nearly 525 μg of phenols and 135 μg of flavonoids per daily treatment. The Eryngo was derived from a grower in Babol, Mazandaran, Iran; the placebo and ibuprofen syrups were prepared by Soha Pharmaceutical Company. A professor of pharmacognosy at Shahid Beheshti University of Medical Sciences, Iran, confirmed the identity of the Eryngo specimens before they were prepared.

Practice Implications

Eryngo is a traditional herb used in northern Iran. It is served with fish and chicken and used to flavor pickles and other foods. Its flavor is distinct and somewhat like coriander.

In this study, Eryngo was shown to be effective for relief of primary dysmenorrhea after 2 cycles. The plant is typically used for asthma, bronchitis, and epigastric pain. These indications suggest it is anti-inflammatory, especially given its phenol and flavonoid content, and may have beneficial effects on spastic smooth muscles. Unfortunately, the study authors did not identify its constituents in any detail, nor did they state if they tried to mask its flavor or adjust the placebo and ibuprofen syrups to mimic the flavor of Eryngo.

The genus Eryngium contains 250-300 species and is considered the largest and most complex in the Apiaceae family.1 The various plant species contain flavonoids, tannins, saponins, and triterpenoids. Eryngial is an essential oil common to this genus and has known antibacterial effects in the presence of Staphylococcus aureus, Klebsiella pneumoniae, Proteus mirabilis, and the third stage larvae of Strongyloides stercoralis.2,3E caucasicum also contains 4(5)-acetyl-1H-imidazole, thymol, sesquiphellandrene, limonene, and trans-β-farnesene essential oils.1 The flavonoid content includes quercetin at 12.5-100 μg/mL, but the remaining flavonoids have not been identified. Thus, the plant has good antioxidant properties.4

A systematic review of all clinical trials of herbs for primary dysmenorrhea was published in 2014.5 Exclusion criteria included mild dysmenorrhea, irregular menstruation, and obligation to use a drug as treatment.5 All included trials were required to have a Jadad score ≥3. Twenty-five trials were submitted to intense scrutiny. The top botanicals and number of articles were Foeniculum vulgare (8), Mentha piperita (1), Zataria multiflora (1), Valeriana officinalis (2), Cinnamomum zeylanicum (1), Zingiber officinale (2), Matricaria chamomilla (1), Stachys lavandulifolia (2), Echinophora platyloba (1), Vitex agnus-castus (1), Menstrogol® (2), Menastil® (1), and Achillea wilhelmsii (1).5

In all trials, F vulgare (Apiaceae)—likely its essential oils—was comparable to mefenamic acid in effectiveness.5Z officinale (Zingiberaceae), which inhibits cyclooxygenase, was as effective as ibuprofen and mefenamic acid. Menastil®, which contains Calendula officinalis (Asteraceae) and M piperita (Lamiaceae) essential oil, prevents nerve signal transmission, and was more effective than placebo in decreasing menstrual bleeding. Cumminum cyminum (Apiaceae) was as effective as mefenamic acid, but no mechanism of action was described. Menstrogol® (saffron, celery, and aniseed) was superior to mefenamic acid; essential oils may be its mechanism of action. M chamomilla (Asteraceae) alone reduced menstrual anxiety and was superior to mefenamic acid for pain control; when combined with F vulgare, it reduced pelvic and abdominal pain, depression, and anger. Mechanism of action was not described. V officinalis (Caprifoliaceae) is antispasmodic on smooth muscles, inhibits contractions of cell depolarization, and blocks calcium channels. It was comparable to mefenamic acid in 1 trial, but was only equal to placebo in another trial. C zeylanicum (Lauraceae) has essential oils that are antispasmodic and inhibit biosynthesis of inflammatory prostaglandins; its effects were significantly better than placebo. S lavandulifolia (Lamiaceae), which inhibits prostaglandins, reduced muscle spasms and was comparable to placebo; in another study it reduced duration and severity of dysmenorrhea pain. Z multiflora (Lamiaceae) contains essential oils and flavonoids that inhibit contractions and block calcium channels. The best effect was with 2% essential oil; use of its leaves was comparable to mefenamic acid. M piperita (Lamiaceae) essential oil reduces smooth muscle contractions and was comparable to ibuprofen. Vitex agnus-castus (Lamiaceae) has dopaminergic effects that make it more effective than placebo. E platyloba (Apiaceae) reduced muscle contractions more than placebo; when compared to F vulgare, the latter was more effective. A wilhemsii (Asteraceae) flavonoids have antiprostaglandin effects and inhibit arachidonic acid metabolism, which reduced dysmenorrhea pain.5

Few botanicals have been assessed in more than 1 or 2 trials for primary dysmenorrhea or against conventional pharmaceutical treatments. Eryngium is no exception. It is interesting to note that the Apiaceae, Asteraceae, and Lamiaceae are the most common plant families from which effective botanicals have been identified; probable mechanisms of action may be primarily 3 or 4 in number. This author has experience with about two-thirds of the herbs trialed, although not always for dysmenorrhea, and would be willing to try Eryngium if a reliable source could be found. That said, exercise, diet, stress reduction, and hormonal balancing also are important for treatment of primary dysmenorrhea. This study adds another traditional botanical to the list of those that can address primary dysmenorrhea.

The article was well written, but I was disappointed that the constituents of Eryngium caucasicum in the treatment syrup were not characterized in more detail. The calculation of constituents in the paper is not fully explained, but I provide daily dose phenol and flavonoid totals based on the authors’ initial constituent calculation. Constituent characterization would help us better understand possible mechanisms of action.

The somewhat favorable reaction to the placebo of simple syrup may be due in part to its sweet flavor rather than its clinical effect as it was made according to the United States Pharmacopeia rather than to match the flavor of the syrups in the other 2 treatment arms.

The calculation of phenols and flavonoids per daily dose and the calculation of NNT were not shown and do not agree with my calculations of the same. Finally, while the effect of the herb endured into 1 untreated menstrual cycle, one would like to know from a clinical perspective how much longer that effect lasted as this can help with prescribing for patients.

Summary

E caucasicum, a traditional Iranian and Middle Eastern botanical prepared as syrup, was compared to ibuprofen syrup and placebo syrup in primary dysmenorrhea. It significantly reduced the pain of primary dysmenorrhea after 2 menstrual cycles and was effective for the third cycle without treatment. It was as effective as ibuprofen.

About the Author

Paul Richard Saunders, PhD, ND, DHANP, CCH, completed his PhD in forest ecology at Duke University, his naturopathic degree at Canadian College of Naturopathic Medicine, and his homeopathic residency at National University of Naturopathic Medicine, where he also earned a second naturopathic degree. He is professor of materia medica and clinical medicine at the Canadian College of Naturopathic Medicine; senior naturopathic doctor, Beaumont Health System, Troy Hospital, Michigan; and adjunct professor of integrative medicine, Oakland University William Beaumont Medical School and has a private practice in Dundas, Ontario. Saunders was a member of the transition team that formed the Office of Natural Health Products, served as a natural health expert to the Directorate, and has served on several expert panels for Health Canada. He has conducted clinical research, supervised students and residents, and published widely.

References

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  2. Matejic JS. Stojanovic-Radic ZZ, Ristic MS, et al. Chemical characterization, in vitro biological activity of essential oils and extracts of three Eryngium L. species and molecular docking of selected major compounds. J Food Sci Technol. 2018;55(8):2910-2925.
  3. Forbes WM, Gallimore WA, Mansingh A, Reese PB, Robinson RD. Eryngial (trans-2-dodecenal), a bioactive compound from Eryngium foetidum: its identification, chemical isolation, characterization and comparison with ivermictin in vitro. Parasitology. 2014;141(2):269-278.
  4. Motallebi Riekandeh S, Mazandarani M, Ebrahimzadeh MA, Zargari M. Antioxidant activities of Eryngium caucasicum inflorescence. Eur Rev Med Pharmacol Sci. 2016;20(5):946-949.
  5. Mirabi P, Alamolhoda SH, Esmaeilzadeh S, Mojab F. Effect of medicinal herbs on primary dysmenorrhea- a systematic review. Iran J Pharm Res. 2014;13(3):757-767.