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Efficacy of Anise (Pimpinella anisum L.) oil for migraine headache: A pilot randomized placebo-controlled clinical trial
Journal of Ethnopharmacology 236 (2019) 155–160
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Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jethpharm
Efficacy of Anise (Pimpinella anisum L.) oil for migraine headache: A pilot randomized placebo-controlled clinical trial
T
Seyed Hamdollah Mosavata, Abbas Rahimi Jaberib,∗∗, Zahra Sobhanic, Maryam Mosaffa-Jahromia, Aida Irajid, Amin Moayedfarde,∗ a
Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran c Quality Control Department, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran d Central Research Laboratory, Shiraz University of Medical Sciences, Shiraz, Iran e Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran b
A B S T R A C T
Seyed Hamdollah Mosavat has made substantial contributions in conception, designing, acquisition of data and preformed clinical trial., Amin Moayedfard and Abbas Rahimi Jaberi had contribution in designing and preformed clinical trial. Zahra Sobhani and Maryam Mosaffa-Jahromi designed and prepared drugs of study. Aida Iraji has made drug biochemical assay. Seyed Hamdollah Mosavat had contribution in designing and revised the manuscript critically for important intellectual content and had contribution in designing and analyzing of data. Seyed Hamdollah Mosavat, Amin Moayedfard and Abbas Rahimi Jaberi had contribution in conception and designing and revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.
1. Introduction Migraine is an episodic severe headache, which is generally associated with nausea or/and sound and light sensitivity (Sadeghi et al., 2015). It is one of the frequent complaints encountered by neurologists in daily practice. Previous reports showed migraine affects up to 12 percent of the general population (Lipton et al., 2001). Although several treatments have been proposed for the treatment of migraine, it is still not completely manageable. Hence, patients are usually looking for herbal remedies to control migraines (Jivad et al., 2016). Anise (Pimpinella anisum L.) which belongs to the Apiaceae family is one of the oldest medicinal herbs and widely used spice plants. Anise components are used in perfumery, food and cosmetic industries. Previous studies showed that Anise have a variety of biological activities (Miething et al., 1990). Aniseeds have a variety of properties such as antifungal, antiviral, antimicrobial, antioxidant, muscle relaxant, anticonvulsant and analgesic. It also has good effects on diseases like diabetes, hyperlipidemia, dysmenorrhea, hot flash and gastrointestinal diseases (Shojaii and Abdollahi Fard, 2012). In traditional medicine, Anise has been used as analgesic, appetizer, sedative, expectorant, carminative hepatoprotective, galactagogue, and disinfectant (Aiswarya et al., 2018). Moreover in several Persian medicine resources, such as Liber continens of Rhazes (865–925 AD) (Hashempur
et al., 2017), Canon of Medicine by Avicenna (980–1037 AD) (Mosavat et al., 2017), and the Storehouse of Medicaments written by Aghili Shirazi (1670–1747 AD) (Shakeri et al., 2018), Anise oil has been used for management of various neurological diseases, including headache and; it is also believed to have neuroprotective effects (Gorji and Khaleghi Ghadiri, 2001; Zargari, 1995; Shojaii and Abdollahi Fard, 2012). Regarding the traditional use of Anise (Pimpinella anisum L.) as well as its known favorable effects in current studies, we decided to design a double blind, randomized, placebo-controlled clinical trial to evaluate the safety and efficacy of topical anise essential oil in management of patients with migraine headache. 2. Materials and methods 2.1. Trial design We designed a double blind, double arm, randomized, placebocontrolled clinical trial. In this trial, we evaluated the safety and efficacy of topical anise essential oil in management of patients with migraine headache. No changes occurred in the methods after trial commencement.
∗
Corresponding author. Research Center for Traditional Medicine and History of Medicine, Shiraz University of Medical Sciences, Shiraz, P.O Box: 71356-44144, Iran. ∗∗ Corresponding author. Department of Neurology, Nemazi Hospital, Shiraz, P.O Box: 71356-44144, Iran. E-mail addresses: [email protected] (A.R. Jaberi), [email protected] (A. Moayedfard). https://doi.org/10.1016/j.jep.2019.01.047 Received 14 July 2018; Received in revised form 2 January 2019; Accepted 21 January 2019 Available online 07 March 2019 0378-8741/ © 2019 Elsevier B.V. All rights reserved.
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in the form. Patients in both groups continued their previous preventive migraine medications (including propranolol, amitriptyline, and anticonvulsants) with a fixed dose during the study period.
2.2. Participants Inclusion criteria for the participants enrolled in this study were men and women aged 18–65 years with migraine headache according to International Classification of Headache Disorders by the International Headache Society (3rd edition − beta version) (Society, 2013). They have had at least two headache attacks per month over the past three months. All participants signed the informed consent form to enroll in the study. The exclusion criteria were pregnancy, lactation, any other neurological disorder, and known allergy to Anise and/or related products. This study was carried out in outpatient neurologic clinic of Shahid Faghihi and Emam Reza polyclinics (two academic clinics affiliated to Shiraz University of Medical Sciences, Shiraz, Iran) from July 2017 to May 2018.
2.7. Outcome measures Headache Impact Test (HIT-6) score was set as the primary outcome measure. We used validated Persian HIT-6 questionnaire. This questionnaire consists of 6 questions that measure the severity of headache, emotional distress, role functioning, social functioning, cognitive functioning, and vitality. Each question has five obtainable answers: always, very often, sometimes, rarely and never. The total score could range between 36 and 78, and a higher total score represents more negative impact of headache on the quality of life (Zandifar et al., 2014). Frequency, severity, duration of migraine attacks and analgesic consumption rate were the other outcome measures. Any observed adverse event was also considered as the secondary outcome. No changes were made to trial outcomes after the trial commenced.
2.3. Plant material Anise essential oil was purchased from the School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. This is exactly the oil used in two previous studies. Details of the method for the preparation of Anise oil are presented in these studies (Mosaffa-Jahromi et al., 2016, 2017).
2.8. Sample size Based on the expected difference of severity of headache, as one of the outcome measures, between the two groups of the trial according to a previous study, and by taking into account two-sided significance level of 0.05, power of 80%, the sample size was calculated 25 patients in each group to be totally 50 patients (Niazi et al., 2017).
2.4. Preparation of drugs Anise essential oil was added to the cold cream base gradually under mechanical mixing at ambient temperature. The concentration of essential oil was 7% (w/w). The ingredient of cold cream base is borax, bees wax and mineral oil. After adding all amounts of oil, the cream was mixed 5 min and then packaged in suitable jars. Placebo creams were cold cream base and packaged in the similar jars.
2.9. Safety assessment We followed all the patients by physicians every two weeks with the aim of distinguishing the patients’ possible complaints. All patients were asked to report any drug side effects, especially skin redness and allergic reactions.
2.5. Drug analysis The analyses were performed on a 7890A gas chromatography coupled to a 7100 mass detector (Agilent Technologies, CA, USA) for constituent identification. The injection was performed in the split mode adjusted to 1:30. The GC system was equipped with a DB-1 column (30 m × 0.25 mm × 0.25 μm). The carrier gas was helium at 1.2 ml/min. Injector, transfer line, and source temperatures were set at 250, 280, and 230 °C, respectively. The following temperature program was used: from 70 °C to 280 °C at a rate of 3 °C min−1 and then held at 280 °C for 4 min (Salehpour et al., 2018; Abbaszadegan et al., 2016). The mass detector was operated with an electron impact system at 70 eV. Constituents of the samples were identified by comparing the mass spectra fragmentation patterns with those of a computer library, and linear retention indices (RI), based on a C8eC26 n-alkanes, with those of products included in the database and literature.
2.10. Randomization and blinding Fifty eligible patients were randomized in two parallel groups. A statistician generated a randomized list by using NCSS (statistical software) with simple block randomization method. Then, the eligible patients were assigned into two groups by a researcher according to the randomized list. All participants and investigators were blind to the allocation of the patients. Because placebo cream was similar to anise cream in the same size, weight, shape and color, the physician, drug deliverer, and data analyst were blinded to the type of medicine. 2.11. Ethical issues
2.6. Intervention
The trial was in compliance with the Declaration of Helsinki, and also reviewed, approved, and monitored by the ethics committee of Shiraz University of Medical Sciences (License number: IR.SUMS.MED.REC.1396.55). All the participants signed an informed consent form prior to their enrollment in the study.
After diagnosis of migraine headache by a neurologist, eligible patients were divided into two parallel groups. Patients were randomly assigned to receive either a 6 week Anise essential oil cream (2cc for the first 2 migraine attacks) as the intervention group, or placebo cream (2cc for the first 2 migraine attacks) as the control group. Participants were instructed to spread 2cc of their creams on the temporal and forehead zones at the onset of migraine attacks. Also, they were instructed to use the study drug in migraine attacks and if 30 min after taking the study drugs, the headache has not been controlled, they were told to use other medications that the neurologist has prescribed for them (including non-steroid anti-inflammatory drugs, acetaminophen, triptans, or ergotamines). They were asked to record the frequency and duration of headache attacks in a daily form. They were requested to record the dose and type of their analgesic use
2.12. Statistical methods All data were described by mean ± standard deviation or number (percentage). Mann–Whitney U tests were used for statistical comparison of baseline characteristics. Friedman test was used to determine the changes in outcomes between the two groups of the study. P values less than 0.05 were considered significant. All the data were analyzed using Statistical Package for the Social Sciences software, version 15 (SPSS Inc., Chicago, IL, USA). 156
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Fig. 1. GC-MS chromatograms of anise essential oil.
and placebo groups of the study (P = 0.819). The mean baseline HIT-6 score of the participants was 64.77 ± 5.02 and 63.06 ± 6.51 points in Anise oil and placebo groups, respectively. This also did not show any significant difference between the two groups of the study (P = 0.680).
Table 1 Chemical composition of anise essential oil. a
Peak
Component
RI
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Phellandrene (α-) limonene Dihydrocarvone (cis) Methyl chavicol Carvone Anethole (Z-) Anethole (E−) Elemene (δ-) Anisyl methyl ketone Caryophyllene (E−) Himachalene (α-) Humulene (α-) Unknown Himachalene (γ-) Zingiberene (α-) Himachalene (β-) Bisabolene (β-) Sesquiphellandrene (β-) Dill apiole Unknown Pseudoisoeugenyl 2-methylbutyrste (E) Nonadecane (n-) Heneicosane (n-) Tricosane (n-)
1002 1024 1171 1176 1217 1228 1273 1333 1340 1413 1441 1446 1457 1470 1485 1492 1500 1512 1586 1604 1813 1900 2099 2301
Area % 0.045 1.251 0.143 0.849 3.985 0.107 89.342 0.045 0.125 0.098 0.134 0.054 0.080 2.010 0.420 0.071 0.107 0.080 0.116 0.045 0.608 0.116 0.116 0.054
3.4. Clinical response As we are shown in Table 2, in the anise oil group, HIT-6 score showed a significant decrease from 64.77 ± 5.02 to 58.05 ( ± 6.76) (P = 0.001), but in the placebo group, there was no significant difference from 63.06 ± (6.51) to 64.41 ( ± 5.51) (P = 0.090). Also in the anise oil group, frequency of migraine attacks decreased from 3.45 ( ± 1.89) attack/week to 1.89 ( ± 1.94) (P = 0.001), while in the control group, it slightly increased from 2.40 ( ± 1.72) attack/ week to 2.41 ( ± 1.83) (P = 0.315). In addition, in the anise oil group, the mean duration of migraine attacks decreased from 17.38 ( ± 29.22) hours to 5.18 ( ± 7.72) which was statistically significant (P < 0.001), and in the control group, it decreased from 16.46 ( ± 25.95) hours to 10.41 ( ± 10.09) that was not statistically significant (P = 0.083). Fig. 3 represents the trend of the changes of frequency and duration of headache attacks during the study period in each group. As shown in Table 3, the mean number of analgesic consumption per week significantly decreased in the anise oil group compared to placebo group after 6 weeks. Moreover severity of headache decreased more in anise oil group, but this decrease was not statistically significant compared to placebo group (P = 0.220).
a Retention index determined on a DB-1 fused silica column relative to a series of n-alkanes (C8eC26).
3. Results
3.5. Safety reports
3.1. Chemical composition of the anise essential oil
Anise oil was relatively well tolerated by the participants and they did not report any systemic or dermal side effects. However, two patients discontinued to take medication due to the sharp smell of anise cream.
Fig. 1 depicted the chromatographic analysis of anise essential oil and the relative amounts of chemical composition of EO are presented in Table 1 which enabled the identification of 99.95% of the compounds. Anethole (E−) (89.3%) is the highest component in anise essential oil.
4. Discussion Efficacy and safety of the anise oil cream on the migraine headache were evaluated in this study via a randomized, double blind, placebocontrolled clinical trial. Anise oil cream is demonstrated to have significant positive effects on reducing frequency and duration of migraine attacks as compared to the placebo. Medicinal herbs are one the most used option amongst complementary and alternative medicines. They can be introduced as new therapeutics, potentially. However, there are trace evidences for their use in clinical practice. Although, efficacy of several herbal remedies such as lavender essential oil, butterbur, feverfew, ginger, and rose oil were evaluated in previous studies (Diener et al., 2018; Rafie et al., 2016; Martins et al., 2018; Vogler et al., 1998). Of course, most of these herbal drugs have been evaluated in a systemic dosage form. To the best of our knowledge, this trial is the first clinical trial on topical application of anise oil for migraine headache, and making
3.2. Patients’ enrollment From July 2017 to May 2018, eighty two volunteers were assessed for eligibility. Fifty participants who had the inclusion criteria and tended to participate in the study were divided into two groups. Twenty five patients were assigned into the drug group and twenty five to the placebo group. Fig. 2 is the CONSORT flowchart of the groups' recruitment, allocation, intervention, follow up, and analysis. 3.3. Baseline clinical characteristics The mean age of the participants in the trial was 39.95 ( ± 9.60) and 41.53 ( ± 12.85) years in Anise oil and placebo groups, respectively. This did not show any significant difference between the drug 157
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Fig. 2. Flow diagram of the groups' allocation, enrolment, intervention, follow-up, and the analysis in both groups of the study.
placebo. Although various pharmacological effects, such as neuro-protective, anti-inflammatory and analgesic properties, have been attributed to rose essential oil, this study failed to demonstrate the effects of these properties in migraine. Major constituents of anise essential oil are anethole, γ-himachalene, cis-isoeugenol and linalool (Samojlik et al., 2012). It seems that among the compounds of anise oil, anethole has the most important role in treatment of migraine attacks. Because anethole has a similar structure to dopamine, so it is possible that anethole acts as an antagonist of dopamine in binding to the dopamine receptor. Due to the role of dopamine in inducing migraine attacks, it is proposed that the use of a dopamine antagonist could also block the chain of migraine attack cascade (Pourgholami et al., 1999). Since the plasma levels of y-aminobutyric acid (GABA) during migraine attack is not detectable, but after this phase, its level increases, one of the hypotheses proposed to stop the migraine attacks is
Table 2 Mean HIT-6 score between the two groups of the study during study period. Outcome measure
Groups
Mean HIT-6 score ± SD
Baseline 3 weeks 6 weeks P value
P value
Anise oil
Placebo
64.77 ± 5.02 63.13 ± 6.18 55.05 ± 6.76 0.001
63.06 ± 6.51 63.73 ± 6.32 64.41 ± 5.51 0.090
0.680 0.843 0.012
comparison with earlier studies is not possible. The most similar study to ours is the efficacy of topical rose oil for migraine headache that is done via a randomized double-blinded placebo-controlled cross-over trial (Niazi et al., 2017). In this study, overall results were not significantly different in patients with migraine when taking rose oil or
Fig. 3. Trend of the changes of frequency and duration of headache attacks during the study period in each group. 158
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5. Conclusion
Table 3 Mean number of analgesic consumption per week and mean of headache severity between the two groups of the study during study period. Outcome measure
Mean number of analgesic consumption ± SD
Mean of headache severity
Groups
1 weeks 2 weeks 3weeks 4 weeks 5weeks 6 weeks P value 1 weeks 2 weeks 3weeks 4 weeks 5weeks 6 weeks P value
This randomized, double blind, placebo-controlled clinical trial demonstrated that Anise (Pimpinella anisum L.) oil has significant positive effects on reducing the frequency and duration of migraine attacks as compared to the placebo and could help to reduce the patient's analgesics consumption as a complementary treatment. However, larger-scale qualified methodological trials with longer duration of the intervention are needed to replicate and expand our preliminary findings in this trial.
P value
Anise oil
Placebo
3.13 ± 3.45 ± 2.18 ± 2.10 ± 1.80 ± 1.85 ± 0.013 6.55 ± 6.19 ± 6.15 ± 4.39 ± 5.06 ± 4.63 ± 0.028
2.66 ± 1.60 ± 2.21 ± 2.50 ± 2.25 ± 2.33 ± 0.090 6.06 ± 6.30 ± 6.54 ± 5.64 ± 6.50 ± 5.86 ± 0.753
5.31 6.76 3.23 2.91 4.31 4.65 1.79 2.17 1.81 3.38 2.78 3.25
3.59 1.40 1.80 2.02 2.09 1.87
0.891 0.891 0.432 0.307 0.099 0.044
2.68 3.53 3.33 3.59 3.34 3.50
0.772 0.304 0.343 0.207 0.064 0.220
Acknowledgements This study was a MD thesis by Dr. Amin Moayedfard that was approved by the Ethics Committee (code IR.SUMS.MED.REC.1396.55); they are all appreciated. The authors thank the research vice chancellery of Shiraz University of Medical Sciences for funding supports. References
activation of GABA e pathway. (Welch et al., 1975). Considering previous studies that reported that anise oil may cause activation of GABA receptors, GABA pathway activation may be another mechanism of action of anise oil (Karimzadeh et al., 2012). Evidence has shown that cortical spreading depolarization (CSD) is involved in causing pain in migraine attacks. CSD describes a phenomenon characterized by the development of depolarization neurons waves and neuroglia that spreads across the cortex. An animal study claimed theoretically that anise oil could suppress CSD phenomenon as the underlying mechanism of migraine with aura (Haghir et al., 2010). Other compounds of Anise oil, such as eugenol and estragole, also have anesthetic, muscle relaxant and anti-epileptic properties which could help relieve migraine headaches (Calabresi et al., 2007; Haghir et al., 2010). Because there are neuro-physiological similarities between migraine and epilepsy, some antiepileptic therapies are also used to treat migraines. Previous studies well demonstrated anticonvulsant activity of eugenol and estragole in Anise oil (Dallmeier and Carlini, 1981). In addition to all the proposed mechanisms for the effectiveness of Anise oil in migraine attacks, perhaps, analgesic and anti-inflammatory effects of this plant is the simplest mechanism of action. Previous studies showed that the extracts of Pimpinella anisum exhibited significant analgesic activities versus benzoquinone-induced writing and in thermal tests (Shojaii and Abdollahi Fard, 2012; Tas, 2009; Samojlik et al., 2016). Moreover, analgesic effect of Anise essential oil was reported similar to morphine and aspirin. Also, the findings demonstrated that the anise oil has anti-inflammatory effect as strong as indomethacin and has analgesic effect comparable to that of 100 mg/kg aspirin and 10 mg/kg morphine (Dallmeier and Carlini, 1981; Tas et al., 2006). One of the strengths of this study was the presentation of a topical dosage form for migraine control. Since many oral analgesic drugs used for migraine have gastrointestinal complications with long-term side effects on the patient, the use of topical medications can be helpful. However, our study had some limitations. Using the minimum acceptable sample size in this study was one of its main limitations. Of course, given that our study is the first clinical trial on the efficacy of topical anise essential oil in management of patients with migraine headache, perhaps the small sample size is justified. Short-term follow up of the participants was another limitation of the study. Although, by extending the study period, we could also evaluate the recurrence of migraine or may reveal adverse events, but by prolongation of the study period, increase in the patients' drop-out rate could be predicted.
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Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jethpharm
Efficacy of Anise (Pimpinella anisum L.) oil for migraine headache: A pilot randomized placebo-controlled clinical trial
T
Seyed Hamdollah Mosavata, Abbas Rahimi Jaberib,∗∗, Zahra Sobhanic, Maryam Mosaffa-Jahromia, Aida Irajid, Amin Moayedfarde,∗ a
Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran c Quality Control Department, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran d Central Research Laboratory, Shiraz University of Medical Sciences, Shiraz, Iran e Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran b
A B S T R A C T
Seyed Hamdollah Mosavat has made substantial contributions in conception, designing, acquisition of data and preformed clinical trial., Amin Moayedfard and Abbas Rahimi Jaberi had contribution in designing and preformed clinical trial. Zahra Sobhani and Maryam Mosaffa-Jahromi designed and prepared drugs of study. Aida Iraji has made drug biochemical assay. Seyed Hamdollah Mosavat had contribution in designing and revised the manuscript critically for important intellectual content and had contribution in designing and analyzing of data. Seyed Hamdollah Mosavat, Amin Moayedfard and Abbas Rahimi Jaberi had contribution in conception and designing and revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.
1. Introduction Migraine is an episodic severe headache, which is generally associated with nausea or/and sound and light sensitivity (Sadeghi et al., 2015). It is one of the frequent complaints encountered by neurologists in daily practice. Previous reports showed migraine affects up to 12 percent of the general population (Lipton et al., 2001). Although several treatments have been proposed for the treatment of migraine, it is still not completely manageable. Hence, patients are usually looking for herbal remedies to control migraines (Jivad et al., 2016). Anise (Pimpinella anisum L.) which belongs to the Apiaceae family is one of the oldest medicinal herbs and widely used spice plants. Anise components are used in perfumery, food and cosmetic industries. Previous studies showed that Anise have a variety of biological activities (Miething et al., 1990). Aniseeds have a variety of properties such as antifungal, antiviral, antimicrobial, antioxidant, muscle relaxant, anticonvulsant and analgesic. It also has good effects on diseases like diabetes, hyperlipidemia, dysmenorrhea, hot flash and gastrointestinal diseases (Shojaii and Abdollahi Fard, 2012). In traditional medicine, Anise has been used as analgesic, appetizer, sedative, expectorant, carminative hepatoprotective, galactagogue, and disinfectant (Aiswarya et al., 2018). Moreover in several Persian medicine resources, such as Liber continens of Rhazes (865–925 AD) (Hashempur
et al., 2017), Canon of Medicine by Avicenna (980–1037 AD) (Mosavat et al., 2017), and the Storehouse of Medicaments written by Aghili Shirazi (1670–1747 AD) (Shakeri et al., 2018), Anise oil has been used for management of various neurological diseases, including headache and; it is also believed to have neuroprotective effects (Gorji and Khaleghi Ghadiri, 2001; Zargari, 1995; Shojaii and Abdollahi Fard, 2012). Regarding the traditional use of Anise (Pimpinella anisum L.) as well as its known favorable effects in current studies, we decided to design a double blind, randomized, placebo-controlled clinical trial to evaluate the safety and efficacy of topical anise essential oil in management of patients with migraine headache. 2. Materials and methods 2.1. Trial design We designed a double blind, double arm, randomized, placebocontrolled clinical trial. In this trial, we evaluated the safety and efficacy of topical anise essential oil in management of patients with migraine headache. No changes occurred in the methods after trial commencement.
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Corresponding author. Research Center for Traditional Medicine and History of Medicine, Shiraz University of Medical Sciences, Shiraz, P.O Box: 71356-44144, Iran. ∗∗ Corresponding author. Department of Neurology, Nemazi Hospital, Shiraz, P.O Box: 71356-44144, Iran. E-mail addresses: [email protected] (A.R. Jaberi), [email protected] (A. Moayedfard). https://doi.org/10.1016/j.jep.2019.01.047 Received 14 July 2018; Received in revised form 2 January 2019; Accepted 21 January 2019 Available online 07 March 2019 0378-8741/ © 2019 Elsevier B.V. All rights reserved.
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in the form. Patients in both groups continued their previous preventive migraine medications (including propranolol, amitriptyline, and anticonvulsants) with a fixed dose during the study period.
2.2. Participants Inclusion criteria for the participants enrolled in this study were men and women aged 18–65 years with migraine headache according to International Classification of Headache Disorders by the International Headache Society (3rd edition − beta version) (Society, 2013). They have had at least two headache attacks per month over the past three months. All participants signed the informed consent form to enroll in the study. The exclusion criteria were pregnancy, lactation, any other neurological disorder, and known allergy to Anise and/or related products. This study was carried out in outpatient neurologic clinic of Shahid Faghihi and Emam Reza polyclinics (two academic clinics affiliated to Shiraz University of Medical Sciences, Shiraz, Iran) from July 2017 to May 2018.
2.7. Outcome measures Headache Impact Test (HIT-6) score was set as the primary outcome measure. We used validated Persian HIT-6 questionnaire. This questionnaire consists of 6 questions that measure the severity of headache, emotional distress, role functioning, social functioning, cognitive functioning, and vitality. Each question has five obtainable answers: always, very often, sometimes, rarely and never. The total score could range between 36 and 78, and a higher total score represents more negative impact of headache on the quality of life (Zandifar et al., 2014). Frequency, severity, duration of migraine attacks and analgesic consumption rate were the other outcome measures. Any observed adverse event was also considered as the secondary outcome. No changes were made to trial outcomes after the trial commenced.
2.3. Plant material Anise essential oil was purchased from the School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. This is exactly the oil used in two previous studies. Details of the method for the preparation of Anise oil are presented in these studies (Mosaffa-Jahromi et al., 2016, 2017).
2.8. Sample size Based on the expected difference of severity of headache, as one of the outcome measures, between the two groups of the trial according to a previous study, and by taking into account two-sided significance level of 0.05, power of 80%, the sample size was calculated 25 patients in each group to be totally 50 patients (Niazi et al., 2017).
2.4. Preparation of drugs Anise essential oil was added to the cold cream base gradually under mechanical mixing at ambient temperature. The concentration of essential oil was 7% (w/w). The ingredient of cold cream base is borax, bees wax and mineral oil. After adding all amounts of oil, the cream was mixed 5 min and then packaged in suitable jars. Placebo creams were cold cream base and packaged in the similar jars.
2.9. Safety assessment We followed all the patients by physicians every two weeks with the aim of distinguishing the patients’ possible complaints. All patients were asked to report any drug side effects, especially skin redness and allergic reactions.
2.5. Drug analysis The analyses were performed on a 7890A gas chromatography coupled to a 7100 mass detector (Agilent Technologies, CA, USA) for constituent identification. The injection was performed in the split mode adjusted to 1:30. The GC system was equipped with a DB-1 column (30 m × 0.25 mm × 0.25 μm). The carrier gas was helium at 1.2 ml/min. Injector, transfer line, and source temperatures were set at 250, 280, and 230 °C, respectively. The following temperature program was used: from 70 °C to 280 °C at a rate of 3 °C min−1 and then held at 280 °C for 4 min (Salehpour et al., 2018; Abbaszadegan et al., 2016). The mass detector was operated with an electron impact system at 70 eV. Constituents of the samples were identified by comparing the mass spectra fragmentation patterns with those of a computer library, and linear retention indices (RI), based on a C8eC26 n-alkanes, with those of products included in the database and literature.
2.10. Randomization and blinding Fifty eligible patients were randomized in two parallel groups. A statistician generated a randomized list by using NCSS (statistical software) with simple block randomization method. Then, the eligible patients were assigned into two groups by a researcher according to the randomized list. All participants and investigators were blind to the allocation of the patients. Because placebo cream was similar to anise cream in the same size, weight, shape and color, the physician, drug deliverer, and data analyst were blinded to the type of medicine. 2.11. Ethical issues
2.6. Intervention
The trial was in compliance with the Declaration of Helsinki, and also reviewed, approved, and monitored by the ethics committee of Shiraz University of Medical Sciences (License number: IR.SUMS.MED.REC.1396.55). All the participants signed an informed consent form prior to their enrollment in the study.
After diagnosis of migraine headache by a neurologist, eligible patients were divided into two parallel groups. Patients were randomly assigned to receive either a 6 week Anise essential oil cream (2cc for the first 2 migraine attacks) as the intervention group, or placebo cream (2cc for the first 2 migraine attacks) as the control group. Participants were instructed to spread 2cc of their creams on the temporal and forehead zones at the onset of migraine attacks. Also, they were instructed to use the study drug in migraine attacks and if 30 min after taking the study drugs, the headache has not been controlled, they were told to use other medications that the neurologist has prescribed for them (including non-steroid anti-inflammatory drugs, acetaminophen, triptans, or ergotamines). They were asked to record the frequency and duration of headache attacks in a daily form. They were requested to record the dose and type of their analgesic use
2.12. Statistical methods All data were described by mean ± standard deviation or number (percentage). Mann–Whitney U tests were used for statistical comparison of baseline characteristics. Friedman test was used to determine the changes in outcomes between the two groups of the study. P values less than 0.05 were considered significant. All the data were analyzed using Statistical Package for the Social Sciences software, version 15 (SPSS Inc., Chicago, IL, USA). 156
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Fig. 1. GC-MS chromatograms of anise essential oil.
and placebo groups of the study (P = 0.819). The mean baseline HIT-6 score of the participants was 64.77 ± 5.02 and 63.06 ± 6.51 points in Anise oil and placebo groups, respectively. This also did not show any significant difference between the two groups of the study (P = 0.680).
Table 1 Chemical composition of anise essential oil. a
Peak
Component
RI
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Phellandrene (α-) limonene Dihydrocarvone (cis) Methyl chavicol Carvone Anethole (Z-) Anethole (E−) Elemene (δ-) Anisyl methyl ketone Caryophyllene (E−) Himachalene (α-) Humulene (α-) Unknown Himachalene (γ-) Zingiberene (α-) Himachalene (β-) Bisabolene (β-) Sesquiphellandrene (β-) Dill apiole Unknown Pseudoisoeugenyl 2-methylbutyrste (E) Nonadecane (n-) Heneicosane (n-) Tricosane (n-)
1002 1024 1171 1176 1217 1228 1273 1333 1340 1413 1441 1446 1457 1470 1485 1492 1500 1512 1586 1604 1813 1900 2099 2301
Area % 0.045 1.251 0.143 0.849 3.985 0.107 89.342 0.045 0.125 0.098 0.134 0.054 0.080 2.010 0.420 0.071 0.107 0.080 0.116 0.045 0.608 0.116 0.116 0.054
3.4. Clinical response As we are shown in Table 2, in the anise oil group, HIT-6 score showed a significant decrease from 64.77 ± 5.02 to 58.05 ( ± 6.76) (P = 0.001), but in the placebo group, there was no significant difference from 63.06 ± (6.51) to 64.41 ( ± 5.51) (P = 0.090). Also in the anise oil group, frequency of migraine attacks decreased from 3.45 ( ± 1.89) attack/week to 1.89 ( ± 1.94) (P = 0.001), while in the control group, it slightly increased from 2.40 ( ± 1.72) attack/ week to 2.41 ( ± 1.83) (P = 0.315). In addition, in the anise oil group, the mean duration of migraine attacks decreased from 17.38 ( ± 29.22) hours to 5.18 ( ± 7.72) which was statistically significant (P < 0.001), and in the control group, it decreased from 16.46 ( ± 25.95) hours to 10.41 ( ± 10.09) that was not statistically significant (P = 0.083). Fig. 3 represents the trend of the changes of frequency and duration of headache attacks during the study period in each group. As shown in Table 3, the mean number of analgesic consumption per week significantly decreased in the anise oil group compared to placebo group after 6 weeks. Moreover severity of headache decreased more in anise oil group, but this decrease was not statistically significant compared to placebo group (P = 0.220).
a Retention index determined on a DB-1 fused silica column relative to a series of n-alkanes (C8eC26).
3. Results
3.5. Safety reports
3.1. Chemical composition of the anise essential oil
Anise oil was relatively well tolerated by the participants and they did not report any systemic or dermal side effects. However, two patients discontinued to take medication due to the sharp smell of anise cream.
Fig. 1 depicted the chromatographic analysis of anise essential oil and the relative amounts of chemical composition of EO are presented in Table 1 which enabled the identification of 99.95% of the compounds. Anethole (E−) (89.3%) is the highest component in anise essential oil.
4. Discussion Efficacy and safety of the anise oil cream on the migraine headache were evaluated in this study via a randomized, double blind, placebocontrolled clinical trial. Anise oil cream is demonstrated to have significant positive effects on reducing frequency and duration of migraine attacks as compared to the placebo. Medicinal herbs are one the most used option amongst complementary and alternative medicines. They can be introduced as new therapeutics, potentially. However, there are trace evidences for their use in clinical practice. Although, efficacy of several herbal remedies such as lavender essential oil, butterbur, feverfew, ginger, and rose oil were evaluated in previous studies (Diener et al., 2018; Rafie et al., 2016; Martins et al., 2018; Vogler et al., 1998). Of course, most of these herbal drugs have been evaluated in a systemic dosage form. To the best of our knowledge, this trial is the first clinical trial on topical application of anise oil for migraine headache, and making
3.2. Patients’ enrollment From July 2017 to May 2018, eighty two volunteers were assessed for eligibility. Fifty participants who had the inclusion criteria and tended to participate in the study were divided into two groups. Twenty five patients were assigned into the drug group and twenty five to the placebo group. Fig. 2 is the CONSORT flowchart of the groups' recruitment, allocation, intervention, follow up, and analysis. 3.3. Baseline clinical characteristics The mean age of the participants in the trial was 39.95 ( ± 9.60) and 41.53 ( ± 12.85) years in Anise oil and placebo groups, respectively. This did not show any significant difference between the drug 157
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Fig. 2. Flow diagram of the groups' allocation, enrolment, intervention, follow-up, and the analysis in both groups of the study.
placebo. Although various pharmacological effects, such as neuro-protective, anti-inflammatory and analgesic properties, have been attributed to rose essential oil, this study failed to demonstrate the effects of these properties in migraine. Major constituents of anise essential oil are anethole, γ-himachalene, cis-isoeugenol and linalool (Samojlik et al., 2012). It seems that among the compounds of anise oil, anethole has the most important role in treatment of migraine attacks. Because anethole has a similar structure to dopamine, so it is possible that anethole acts as an antagonist of dopamine in binding to the dopamine receptor. Due to the role of dopamine in inducing migraine attacks, it is proposed that the use of a dopamine antagonist could also block the chain of migraine attack cascade (Pourgholami et al., 1999). Since the plasma levels of y-aminobutyric acid (GABA) during migraine attack is not detectable, but after this phase, its level increases, one of the hypotheses proposed to stop the migraine attacks is
Table 2 Mean HIT-6 score between the two groups of the study during study period. Outcome measure
Groups
Mean HIT-6 score ± SD
Baseline 3 weeks 6 weeks P value
P value
Anise oil
Placebo
64.77 ± 5.02 63.13 ± 6.18 55.05 ± 6.76 0.001
63.06 ± 6.51 63.73 ± 6.32 64.41 ± 5.51 0.090
0.680 0.843 0.012
comparison with earlier studies is not possible. The most similar study to ours is the efficacy of topical rose oil for migraine headache that is done via a randomized double-blinded placebo-controlled cross-over trial (Niazi et al., 2017). In this study, overall results were not significantly different in patients with migraine when taking rose oil or
Fig. 3. Trend of the changes of frequency and duration of headache attacks during the study period in each group. 158
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5. Conclusion
Table 3 Mean number of analgesic consumption per week and mean of headache severity between the two groups of the study during study period. Outcome measure
Mean number of analgesic consumption ± SD
Mean of headache severity
Groups
1 weeks 2 weeks 3weeks 4 weeks 5weeks 6 weeks P value 1 weeks 2 weeks 3weeks 4 weeks 5weeks 6 weeks P value
This randomized, double blind, placebo-controlled clinical trial demonstrated that Anise (Pimpinella anisum L.) oil has significant positive effects on reducing the frequency and duration of migraine attacks as compared to the placebo and could help to reduce the patient's analgesics consumption as a complementary treatment. However, larger-scale qualified methodological trials with longer duration of the intervention are needed to replicate and expand our preliminary findings in this trial.
P value
Anise oil
Placebo
3.13 ± 3.45 ± 2.18 ± 2.10 ± 1.80 ± 1.85 ± 0.013 6.55 ± 6.19 ± 6.15 ± 4.39 ± 5.06 ± 4.63 ± 0.028
2.66 ± 1.60 ± 2.21 ± 2.50 ± 2.25 ± 2.33 ± 0.090 6.06 ± 6.30 ± 6.54 ± 5.64 ± 6.50 ± 5.86 ± 0.753
5.31 6.76 3.23 2.91 4.31 4.65 1.79 2.17 1.81 3.38 2.78 3.25
3.59 1.40 1.80 2.02 2.09 1.87
0.891 0.891 0.432 0.307 0.099 0.044
2.68 3.53 3.33 3.59 3.34 3.50
0.772 0.304 0.343 0.207 0.064 0.220
Acknowledgements This study was a MD thesis by Dr. Amin Moayedfard that was approved by the Ethics Committee (code IR.SUMS.MED.REC.1396.55); they are all appreciated. The authors thank the research vice chancellery of Shiraz University of Medical Sciences for funding supports. References
activation of GABA e pathway. (Welch et al., 1975). Considering previous studies that reported that anise oil may cause activation of GABA receptors, GABA pathway activation may be another mechanism of action of anise oil (Karimzadeh et al., 2012). Evidence has shown that cortical spreading depolarization (CSD) is involved in causing pain in migraine attacks. CSD describes a phenomenon characterized by the development of depolarization neurons waves and neuroglia that spreads across the cortex. An animal study claimed theoretically that anise oil could suppress CSD phenomenon as the underlying mechanism of migraine with aura (Haghir et al., 2010). Other compounds of Anise oil, such as eugenol and estragole, also have anesthetic, muscle relaxant and anti-epileptic properties which could help relieve migraine headaches (Calabresi et al., 2007; Haghir et al., 2010). Because there are neuro-physiological similarities between migraine and epilepsy, some antiepileptic therapies are also used to treat migraines. Previous studies well demonstrated anticonvulsant activity of eugenol and estragole in Anise oil (Dallmeier and Carlini, 1981). In addition to all the proposed mechanisms for the effectiveness of Anise oil in migraine attacks, perhaps, analgesic and anti-inflammatory effects of this plant is the simplest mechanism of action. Previous studies showed that the extracts of Pimpinella anisum exhibited significant analgesic activities versus benzoquinone-induced writing and in thermal tests (Shojaii and Abdollahi Fard, 2012; Tas, 2009; Samojlik et al., 2016). Moreover, analgesic effect of Anise essential oil was reported similar to morphine and aspirin. Also, the findings demonstrated that the anise oil has anti-inflammatory effect as strong as indomethacin and has analgesic effect comparable to that of 100 mg/kg aspirin and 10 mg/kg morphine (Dallmeier and Carlini, 1981; Tas et al., 2006). One of the strengths of this study was the presentation of a topical dosage form for migraine control. Since many oral analgesic drugs used for migraine have gastrointestinal complications with long-term side effects on the patient, the use of topical medications can be helpful. However, our study had some limitations. Using the minimum acceptable sample size in this study was one of its main limitations. Of course, given that our study is the first clinical trial on the efficacy of topical anise essential oil in management of patients with migraine headache, perhaps the small sample size is justified. Short-term follow up of the participants was another limitation of the study. Although, by extending the study period, we could also evaluate the recurrence of migraine or may reveal adverse events, but by prolongation of the study period, increase in the patients' drop-out rate could be predicted.
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