Efficacy of combination of Viola odorata, Rosa damascena and Coriandrum sativum in prevention of migraine attacks: a randomized, double blind, placebo-controlled clinical trial

1. Introduction

Headache disorders are a major public-health problem. They are common and give rise to widespread ill-health (1). In classification of headache, migraine is the second most common after tension headaches (2). Migraine is a disorder that affects more than 10% of the adult population in the world. In the United States, 14.2% of adults have migraine or severe headaches (3). Although migraine can begin at any age, the initial attack occurs most commonly during adolescence, by the age of 40 (4) or in the productive period of life (5). Migraine is the chronic periodic headache that is among the ten disabling factors throughout the world (6). Migraine also affects people’s quality of life at home, in addition to having a negative impact on work and school. Also, migraine is associated with increased healthcare costs (7). Several prophylactic treatments have been used for decreasing the frequency and severity of migraine attacks. Antiepileptics, three-cyclic antidepressants and beta blockers are medicines that are frequently prescribed (8), but their side effects including constipation (9), tremor, weight gain, somnolence (10), polycystic ovarian and orthostatic hypotension (11), are inevitable. A great number of patients cannot tolerate side effects and some patients mention drug resistance against the prophylactic effects of medicines in long-term use (12). These side effects and drug resistances are the main and inevitable complication in migraine prophylactic treatment (13). The limitations of drug therapy in migraine, can justify the good acceptance of complementary and alternative therapies among patients with this disease (14). Migraine has two common types. Migraine without aura is a clinical syndrome, which is actually a headache with specific characteristics, and migraine with aura, which is mainly associated with neurological transient symptoms include hyperactivity, hypoactivity, depression, cravings for particular foods, repetitive yawning, fatigue and neck stiffness and/or pain, and usually preceded or accompanied by symptoms of the patient (15). According to the World Health Organization (WHO), health systems around the world face increase of chronic diseases and health care costs. Patients and health care providers want improvement of health care services with more emphasize on individual-based care, this includes development of traditional and complementary medicine (16). Complementary medicine, according to the WHO, has a long history in maintaining health and prevention and treatment of diseases, especially chronic diseases. One of the most productive branches of complementary medicine is Iranian traditional medicine, with a ten thousand-year history. Traditional and complementary medicines have always been considered as a valid source for novel treatment findings (17). Headache, like medicine, has a history as long as the existence of human beings, and special approaches have been invented for its relief in each historical period including Iranian traditional medicine (18), for example, use of herbal drugs for the treatment of headache by Iranian physicians goes back to the 6th century. Iranian physicians were well aware of specific therapeutic effects of herbal drugs as analgesics or sedatives and their prophylactic effects in special diseases such as headache. Therefore, they used several herbal drugs for the treatment of headache (19). Included among these medicinal plants that were used for headache which are mentioned in the valid books of Iranian traditional medicine are violet (Viola odorata L. (V. odorata)), rose (Rosa damascena L. (R. damascena)) and coriander (Coriandrum sativum L. (C. sativum)), in isolation (20, 21) and in the form of a combination (22–24). Also, several studies have investigated the analgesic, sedative, and pre-anesthetic effects of V. odorata in rats (25, 26), analgesic effects of R. damascene on migraine in human studies and animal studies (27–29), and hypnotic effects of this plant in mice (30), and analgesic effects of C. sativum on migraine in human studies (31) in isolation, oral or topical (25–31). There are also overviews that examine the effects of medicinal plants, which have shown the analgesic effect of these three herbs (32, 33). But there is no clinical evidence showing the efficacy of a herbal medicine combination of V. odorata, R. damascena and C. sativum on pain or migraine. This is the first study to be done on such a combination that is derived from authentic texts of traditional medicine. Therefore, we aimed to investigate the effect of an herbal medicine combination of V. odorata flowers, R. damascene flowers and C. sativum fruits on migraine assuming the possibility of decreasing severity, duration and frequency of headaches in a clinical trial.

2. Material and Methods

3. Results

In the present study, 88 patients who had migraine headache, were divided into two groups. One of the patients in the intervention group, was not followed because of inappropriate use of prescription drugs, and one of them in the control group was excluded from the study because of positive pregnancy test. Therefore 43 patients in each group were able to finish the study. There was no significant difference between the two groups in terms of age, sex, marital status, and type of migraine (without aura and with aura) (Table 1). There was no significant difference between the two groups of herbal medicine and placebo in the zero week in terms of duration (hour) of headaches (p=0.594). The behavior of the two protocols was changed over time (p<0.001). During the 4 weeks, the time and drug interactions, were significant (p<0.001). In other words, the pattern of changes to the two protocols over time, was different. Also, at the end of the 4th week, there was a significant difference between the two groups (p<0.001) (Figure 2). There were no significant differences between the two groups of herbal medicine and placebo in the zero week in terms of frequency (per week) of headaches (p=0.944). The behavior of the two protocols was changed over time (p<0.001). During the 4 weeks, the time and drug interactions, were significant (p <0.001). In other words, the pattern of changes to the two protocols over time was different. Also, at the end of the 4th week, there was a significant difference between the two groups (p<0.001) (Figure 3). There were no significant differences in the severity (VAS score) of attacks between the two groups of herbal medicine and placebo in the zero week (p=0.886). The behavior of the two protocols was changed over time (p<0.001). During the 4 weeks, the time and drug interactions, were significant (p<0.001). In other words, the pattern of changes to the two protocols over time, was different. Also, at the end of 4th week, there was a significant difference between the two groups (p<0.001) (Figure 4).

4. Discussion

The obtained findings show that the Iranian traditional medicine combination of V. odorata flower, R damascene flower and C. sativum fruit is effective in improving frequency, duration and severity of migraine attacks. This is the first study to investigate the clinical efficacy of this combined herbal medicine in patients with migraine. Hence, we are not able to compare the results we faced here with other studies. With regard to each individual herbal plant, which this herbal product contains, some evidence exists about their analgesic, sedative, anti-inflammatory and hypnotic effects, on headache in human or animal models. Feizabadi et al. studied efficacy of V. odorata in the treatment of chronic insomnia in this study, in which violet oil was used. The authors believe that violet oil is an effective medication for insomnia in Iranian traditional medicine. In this study, the effect of violet oil on chronic insomnia was evaluated in pre-test and post-test in 50 patients referred to the Iranian Traditional Medicine Clinic of Mashhad University of Medical Sciences. The treatment consisted of the use of violet oil in the form of an intranasal, two drops in each nostril, each night, before bedtime for one month. Insomnia intensity index (ISI) was completed for all patients before and after one month of treatment. The results indicated that sleep deprivation had decreased scores in patients after one month of use of violet intranasal oil (p<0.05). In this study, there was no evidence of severe side effects due to the use of violet oil. According to these results, the authors suggest that violet oil can be a tolerable and effective drug for chronic insomnia (36). Vishal Antil et al. performed a study aiming to evaluate, experimentally, the analgesic effect of n-hexane, butanolic, methanolic, and aqueous extracts of the aerial part of V. odorata at a dose level of 200 and 400 mg/kg, p.o. in rats. In this study, the analgesic effect of aqueous (p<0.01) and methanolic extract (p<0.05) of Viola odorata at a dose of 400 mg/kg, p.o., in the peripheral and central models of pain (tail immersion and hot plate) was significant, but the n-hexane and butanolic extract did not show significant analgesic effects (P > 0.05) (25). Alireza Monadi et al. evaluated the sedative and pre-anesthetic effects of V. odorata extract compared with diazepam in rats. Diazepam is a long-acting benzodiazepine. This study mentions that V. odorata contains alkaloid, glycoside, saponins, methyl slicylate, mucilage and vitamin C. In this experimental study, 30 Wistar male rats weighing 300±10g and about 3 months old were used. The rats were divided into six groups of five. In order to investigate the effects of sedative and pre-anesthetic violet flower extract in comparison with diazepam, in the first group of mice, 100 mg/kg of extract, in the second group, 200 mg/kg of extract, in the third group, 400 mg/kg, in the fourth group, 1.2 mg/kg diazepam, in the fifth group, 1.2 mg/kg placebo (dimethyl sulfoxide), was injected intra peritoneal. No drug was given to the sixth group. The results indicated that there was no significant difference between the sedative and pre-anesthetic effects of 100 and 200 mg/kg BW doses of violet flower extract compared to diazepam. But the dose of 400 mg/kg BW was a better sedative and had pre-anesthetic effects. The authors of this paper suggest that violet flower extract has better sedative and pre-anesthetic effects than diazepam. But the effects are dose dependent (26).

Hossein Delavar Kasmaei et al. compared the effects of C. sativum syrup on migraine in a clinical trial with placebo. In this study, 68 patients were equally divided between the intervention and placebo groups. The intervention group received 500 mg of sodium valproate daily with C. sativum syrup three times a day. But, the placebo group received sodium valproate 500 mg tablets daily with placebo syrup three times a day. Both groups were treated for one month. Then, frequency of migraine attacks per week, and the duration and severity of headache attacks were evaluated at weeks 12–3 and 4. They found that the coriander fruit syrup decreased duration, severity and frequency of migraine, in the intervention group (p<0.001), to be more precise, the mean migraine duration, severity and frequency, in the intervention group, were 5.7 hours, 3.65 units and about 50% less than the control group, respectively (31). Hassan Rakhshandah et al. studied analgesic effects of the aqueous, ethanolic and chloroformic extracts of R. damascene in mice. Mice were treated with intraperitoneal injection of 100, 500 and 1000 mg/kg aqueous, ethanolic and chloroformic extract of roses and their antinociceptive effects were evaluated using hot plate and tail flick methods. The results indicated that the ethanolic extract of roses had stronger effects than morphine, but there was no antinociceptive effect with aqueous and chloroformic extracts (29). Maria Niazi et al. studied efficacy of topical rose (R. damascena) oil for migraine headache in a randomized double-blinded placebo-controlled cross-over trial. Forty patients with migraine headache were randomly assigned to 2 groups of this double-blind, placebo-controlled cross-over trial. The patients were treated for the first 2 consecutive migraine headache attacks by topical R. damascena oil or placebo. Then, after one week of washout period, cross-over was done. Pain intensity of the patients’ migraine headache was recorded at the beginning and ten sequence time schedules of attacks up to 24 hours. In addition, photophobia, phonophobia, and nausea and/or vomiting (N/V) of the patients were recorded as secondary outcomes. Finally, gathered data were analyzed in a syndrome differentiation manner to assess the effect of R. damascena oil on Hot and Cold type migraine headache. They found that mean pain intensity of the patients’ migraine headache in the different time points after R. damascene oil or placebo use, was not significantly different. Additionally, regarding mean scores of N/V, photophobia, and phonophobia severity of the patients, no significant differences between the two groups were observed. Finally, applying a syndrome differentiation model, the mean score of migraine headache pain intensity turned out to be significantly lower in patients with “hot” type migraine syndrome at 30, 45, 60, 90, and 120 min after R. damascena oil application compared to “cold” types (p-values: 0.001, 0.001,<0.001,<0.001, and 0.02; respectively). It is suggested that syndrome differentiation can help in selection of patients who may benefit from the topical R. damascena oil in short-term relief of pain intensity in migraine headache. Finally, they mention in this study that, further studies of longer follow-up and larger study population, however, are necessary for more scientifically rigorous judgment on efficacy of R. damascena oil for patients with migraine headache (27).

Valiallah Haj Hashemi et al., in an animal model using rats, investigated the antinociceptive and anti-inflammatory effects of hydroalcoholic extract of R. damascena and its essential oil. The extract was administered in doses of 250, 500 and 1000 mg/kg, and essential oil in doses of 100, 200 and 400 μL/kg orally. To evaluate the analgesic effects, the acetic acid-induced writhing response, formalin-induced paw licking time in the early and late phases and light tail flick test were used in mice. For evaluation of anti-inflammatory effect, carrageenan-induced paw edema, served as a valid animal model in rats, was used. The results showed that the extract significantly reduced the responses stimulated by intraperitoneal injection of acetic acid, and the effect of strong antinociception in both phases of formalin test were shown. Also, the high dose of the extract significantly reduced carrageenan- induced paw edema. Rose essential oil did not have an anti-inflammatory or analgesic effect in any of the prescribed doses (28). Of the possible side effects of V. odorata, is nausea, of the R. damascene, is decrease in libido and thirst, and of the C. sativum, is diarrhea, decrease in libido and forgetfulness (21). One of the limitations of the present study was consumption of this herbal medicine for only one month, that makes it impossible to claim anything about its efficacy in long-term use. Moreover, our patients were not followed-up after the intervention period. Therefore, the results of studying long-term effects with greater sample size can be generalized better. Menstruation of women, which can cause headache or exacerbate headaches, the arbitrary use of herbal medicines or sedative and anti-inflammatory chemical drugs, (although patients were asked not to use any herbal or chemical drugs) were other limitations of this study.

5. Conclusions

The study findings suggest that the Iranian traditional product combination of V. odorata, R. damascena and C. sativum may be effective in improving headaches in patients with migraine. Four weeks administration of this herbal medicine (V. odorata, R. damascena and C. sativum) associated with improved frequency, duration and severity of headache attacks without any serious side effects in patients with migraine. We recommend further studies on human subjects with longer follow-ups and comparison to chemical drugs currently used for migraine, to find any advantage or disadvantage of this herbal medicine.