June 2008 - Volume 2, Issue 3

THE EFFECT OF AN IRANIAN HERBAL DRUG ON PRIMARY DYSMENORRHOEA (A CLINICAL CONTROLLED TRIAL)

Nahid Khodakrami, MS Shahid Beheshti Medical University, Reproductive Health Research Center Taleghani Hospital Evin,Yaman St Tehran, Iran Tel:0098-2-88076319 Fax:0098-2-22275248 khodakarami@sbmu.ac.ir Moattar, Fariborz (MSc., Dr. rer. nat) Department of Pharmacognosy School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan ,81746-73461, I.R.IRAN Fax: 098-311-6680011 Tel:098-311-7922611 moattar@pharm.mui.ac.ir Ata Ghahiri ,MD,Ob/Gyn OBs & Gyn Department Alzahra University Hospital , Sofeh Street , Esfahan , IRAN. Tel:0098-913-1190117 Fax: +98-311-6684510 ghahiri@med.mui.ac.ir

ABSTRACT Background: To study the effect of an Iranian herbal drug in the treatment of primary dysmenorrhoea: a randomised, double-blind, placebo-controlled pilot trial among 180 female students settled at Isfahan University dormitory aged 18-27 years who suffered from primary dysmenorrhoea. Methodology: Participants randomly divided into three groups (herbal drug, mefenamic acid and placebo). The herbal drug (SCA) group were given 500 mg of SCA (Saffron, Anise and Celery Seed extracts highly purified ) three time a day, for three days starting from the onset of bleeding or pain. Participants were followed with two to three cycles from beginning of menstruation and continued through the whole three days of bleeding. Main outcome measures were the severity and duration of pain, at two and three months. A visual analogue scale (VAS) was used to record pain. Overall-pain was the average pain intensity among days in pain. Results: There were statistically significant reductions in pain score and pain duration in SCA (p<0.001) and mefenamic acid (p<0.01) groups. The decrease in pain score was reflected by a significant reduction in another drug use among the treatment groups compared with placebo The magnitude of the reduction was significantly greater in the SCA group than in mefenamic acid and placebo. Conclusion: Both of the drugs effectively relieved menstrual pain as compared with the placebo .More clinical trials are needed for efficacy of this herbal drug.

BACKGROUND

Primary dysmenorrhoea refers to the occurrence of painful menstrual cramps of uterine origin during menstruation, in the absence of an identifiable pathologic lesion and is a common gynecological complaint. Disturbances of dysmenorrhoea are a major medical problem not only for women but also for their families and health services.

The pain is believed to be related to prostaglandin (PG) (1-4). In the pathogenesis of dysmenorrhoea, prostaglandins and arachinodonic acid metabolites play an important role and women with dysmenorrhoea have a relatively high concentration of PGF2a in menstrual fluid(5). Prostaglandin F2a (PGF2a) and PGE2 stimulate uterine contractions and cervical narrowing and increase vasopressin release, leading to ischemia and pain, and suppression of PG synthesis has become the main treatment(2,4,6 ,7).

Common treatment for dysmenorrhoea is medical therapy such as non-steroidal anti-inflammatories (NSAIDs) or oral contraceptive pills (OCPs) which both work by reducing contractions of the uterus (7, 8). Many consumers are now seeking alternatives to conventional medicine. Research into the menstrual cycle suggest that nutritional intake and metabolism may play an important role in the cause and treatment of menstrual disorders (6,9).

The aim of this clinical trial study was to compare the effect of an Iranian herbal Medicine (SCA) for the treatment of primary dysmenorrhoea.

METHODOLOGY

The study subjects were single female students 17-30 years old at Isfahan Medical University Dormitory, Students who fulfilled the criteria for admission who were willing and able to participate in the trial and had given their informed consent were included in the study.198 students who complained of primary dysmenorrhoea agreed to participate in the present study and responded to a self-administered questionnaire that asked about demographic characteristics, menstrual history, smoking, diet, exercise, and past medical and reproductive histories.

The response rate was 93% (184 subjects). The measured primary outcome was intensity of menstrual pain which was determined by a visual analogue scale (VAS) (0 = no pain, 10= unbearable pain). Eligible students completed the VAS before randomisation. All students with primary dysmenorrhoea had a physical examination by the investigator. Of the remaining 184 students 4 students were excluded due to doubtful evidence of secondary dysmenorrhoea.

Randomisation was determined on a 1:1 :1 basis using random number tables. Stratification was determined according to the severity of the pain (mild 0-3; moderate 3.1-6; severe 6.1-10). Each student was randomly assigned to either the placebo, herbal drug (SCA) or mefenamic acid group ( 60 subjects for every group). Both drugs and also placebo were packed in similar capsules (blue capsules) and packaged in similar wrappings. 27 of the SCA capsule packages in three separate packages contained 9 capsules for one menstruation cycle, each capsule containing 500mg of SCA (Saffron, Anise and Celery Seed extracts) highly purified.

Placebo and mefenamic acid (250 mg) packages contained the same number of tablets of similar color and shape and in similar wrappings. The study was double-blinded and the allocation was known neither to the students, nor to the health centre which administered the medication. The randomisation code was known only to the pharmacologist investigator who made and wrapped the drugs. Each student took three capsules orally daily for three days (from beginning of day 1 until the third day of menstruation).

The students were permitted to consume another drug in addition to the allocated treatment in case of continued pain but finally these students were excluded in data analysis. Changes in the severity and the duration of pain, of clinical trial subjects at two and three months were compared between the groups. Study outcome was a visual analog pain intensity given as mean score and 95% confidence interval.

Statistical comparisons between groups were determined using Mann-Whitney U test, m2 test or unpaired t test, and within-group comparisons were determined with paired t test or Wilcoxon matched pairs rank sum test for paired data as appropriate. m2 and Mann-Whitney U tests were used to analyse differences in categorical data between groups.

This study was undertaken with the approval of the Isfahan Medical University ethics committee, and written consent was obtained from the students and the clinical trial permitted by Iran Ministry of Health, (registration letter no: 5.92,22773 ; 8.10.200).

RESULTS

A total of 198 female students between ages 18-30 (20.6 mean ages) who complained of primary dysmenorrhoea. 180 were randomised (60 in every group). Of the 60 student girls, in the SCA group three subjects were excluded from the study analysis due to withdrawal or lost to follow u. In the mefenamic acid group 5 students were excluded from the study analysis due to the loss of two students girls and 3 discontinuing their medication. In the placebo group 9 subjects were excluded (4 with severe pain) due to discontinuation of medication and 5 lost to follow up of the trial. Finally, the analysis was conducted on the 163 subjects.

There were no significant differences in any variable between the two groups at randomisation (Table 1). Mean duration of menstruation was 6.6+/-1.4 days with the mean cycle days of
29+/-3. The findings observed during menses were as follows: headache in 32.7%, nausea in 54%, vomiting in 21%, diarrhea in 13.6%, fatigue in 92.5% and leaving the daily tasks undone was reported in 63% of the cases. Table 2-3 shows the outcomes at two and three months for SCA and mefenamic acid with placebo.

There were statistically significant reductions in pain score and pain duration in SCA and mefenamic acid medication groups. Also the measure of decrease in pain intensity was greatest in the subgroup with severe dysmenorrhoea treated with SCA.

The decrease in pain score was reflected by a significant reduction in another sedation drug used among the treatment groups compared with placebo (Table 4). The magnitude of the reduction was significantly greater in the SCA group than in the mefenamic acid and placebo groups.

Both of the drugs effectively relieved menstrual pain as compared with the placebo (Tables 2-3). The students taking SCA TDS doses of 500mg decreased the pain intensity in a manner similar to mefenamic acid.

Also the herbal drug (SCA) had a more potent effect than mefenamic acid on severe dysmenorrhoea (Tables 2, 3, 5).

No complication was reported in the SCA treated group, but one case reported nausea due to mefenamic acid.

CONCLUSION

We have shown that the combination of the Saffron, anise and celery seed (SCA) reduced the severity and the duration of pain from primary dysmenorrhoea. All of these effects can be attributed to the reduction of PG synthesis by this SCA acting as an anticolic and anti-PG. There were no side effects and this confirms the report of Gill and Lan Lan Liang Yeh in the folk medicine that the rural people use the plants for dysmenorrhoea(10) .Saffron (Crocus sativus ) is a conventional effective medicine in improving blood circulation, curing bruises and having an anti spasm effect. It has low biochemical toxic effects on animals(11,12). Anise and Celery Seed are able to relax smooth muscle cells and ease the muscle spasms that are the immediate cause of pain of those women who suffer from primary dysmenorrhoea(13).

The most common menstrual disorder is dysmenorrhoea which was reported by over half
of adult menstruating women in moderate to severe intensity, The complaint is associated
with significant levels of disability. The majority of sufferers took analgesics or bed rest to cope with the pain and there was a linear association between severity of pain and its impact(14).

Primary dysmenorrhoea occurs as a result of PG-induced myometrial contractions. The PGs also contributes to uterine ischaemia, and sensitisation of afferent nerve fibres to painful stimuli. NSAIDs are an effective treatment but are contraindicated in some women, and only moderately effective in many women. The combined contraceptive pill (COC) suppresses the progesterone-driven proliferation of the secretory endometrium during the luteal phase, thus resulting in a decrease in PG synthesis and the volume of menstrual fluid. The COC is an accepted treatment for dysmenorrhoea in non-adolescent women, but the efficacy of low dose COC pill in the treatment of adolescent dysmenorrhoea has yet to be determined(8,15,16 ).

We have shown that the SCA and Mefenamic acid both have adequate analgesic effects in dysmenorrhoea. The SCA was found to be more effective than mefenamic acid for severe pain relief in dysmenorrhoea.

The SCA can be used safely and effectively for primary dysmenorrhoeal. It may have a
higher potency than mefenamic acid in the dosages used for this study, especially for
reducing severe dysmenorrhoea. However our results indicate that SCA was three time
superior to placebo and met patient's individual demands much better than mefenamic acid and placebo.

As a conclusion SCA taken at a dose of 500 mg daily for three days from the beginning of menstruation significantly reduces the severity and duration of pain due to primary dysmenorrhoea. These data suggest that SCA represents a safe and effective treatment for primary dysmenorrhoea but more clinical trials are needed.

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