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Efficacy of Anise (Pimpinella anisum L.) oil for migraine headache: A pilot randomized placebo-controlled clinical trial

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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.
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Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jethpharm
Ecacy of Anise (Pimpinella anisum L.) oil for migraine headache: A pilot
randomized placebo-controlled clinical trial
Seyed Hamdollah Mosavat
a
, Abbas Rahimi Jaberi
b,∗∗
, Zahra Sobhani
c
,
Maryam Mosaa-Jahromi
a
, Aida Iraji
d
, Amin Moayedfard
e,
a
Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
b
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
ABSTRACT
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 Mosaa-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 nal manuscript.
1. Introduction
Migraine is an episodic severe headache, which is generally asso-
ciated 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 aects 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 activ-
ities (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 eects on diseases like
diabetes, hyperlipidemia, dysmenorrhea, hot ash 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 re-
sources, such as Liber continens of Rhazes (865925 AD) (Hashempur
et al., 2017), Canon of Medicine by Avicenna (9801037 AD) (Mosavat
et al., 2017), and the Storehouse of Medicaments written by Aghili
Shirazi (16701747 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 eects (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 eects in current studies, we decided to design a
double blind, randomized, placebo-controlled clinical trial to evaluate
the safety and ecacy 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, placebo-
controlled clinical trial. In this trial, we evaluated the safety and e-
cacy of topical anise essential oil in management of patients with mi-
graine headache. No changes occurred in the methods after trial com-
mencement.
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
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: rahimeia@sums.ac.ir (A.R. Jaberi), mosavath@sums.ac.ir (A. Moayedfard).
Journal of Ethnopharmacology 236 (2019) 155–160
Available online 07 March 2019
0378-8741/ © 2019 Elsevier B.V. All rights reserved.
T
2.2. Participants
Inclusion criteria for the participants enrolled in this study were
men and women aged 1865 years with migraine headache according
to International Classication 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 aliated to
Shiraz University of Medical Sciences, Shiraz, Iran) from July 2017 to
May 2018.
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 pre-
paration of Anise oil are presented in these studies (Mosaa-Jahromi
et al., 2016,2017).
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 es-
sential 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.
2.5. Drug analysis
The analyses were performed on a 7890A gas chromatography
coupled to a 7100 mass detector (Agilent Technologies, CA, USA) for
constituent identication. 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 identied by comparing the
mass spectra fragmentation patterns with those of a computer library,
and linear retention indices (RI), based on a C
8
eC
26
n-alkanes, with
those of products included in the database and literature.
2.6. Intervention
After diagnosis of migraine headache by a neurologist, eligible pa-
tients were divided into two parallel groups. Patients were randomly
assigned to receive either a 6 week Anise essential oil cream (2cc for the
rst 2 migraine attacks) as the intervention group, or placebo cream
(2cc for the rst 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-inammatory
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
in the form. Patients in both groups continued their previous preventive
migraine medications (including propranolol, amitriptyline, and antic-
onvulsants) with a xed dose during the study period.
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 ques-
tionnaire consists of 6 questions that measure the severity of headache,
emotional distress, role functioning, social functioning, cognitive
functioning, and vitality. Each question has ve 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.
2.8. Sample size
Based on the expected dierence 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 signicance
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).
2.9. Safety assessment
We followed all the patients by physicians every two weeks with the
aim of distinguishing the patientspossible complaints. All patients
were asked to report any drug side eects, especially skin redness and
allergic reactions.
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
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.
2.12. Statistical methods
All data were described by mean ± standard deviation or number
(percentage). MannWhitney U tests were used for statistical compar-
ison 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 signicant. All the data were analyzed
using Statistical Package for the Social Sciences software, version 15
(SPSS Inc., Chicago, IL, USA).
S.H. Mosavat, et al. Journal of Ethnopharmacology 236 (2019) 155–160
156
3. Results
3.1. Chemical composition of the anise essential oil
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 identication of 99.95% of the com-
pounds. Anethole (E) (89.3%) is the highest component in anise es-
sential oil.
3.2. Patientsenrollment
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
ve patients were assigned into the drug group and twenty ve to the
placebo group. Fig. 2 is the CONSORT owchart of the groups' re-
cruitment, 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, respec-
tively. This did not show any signicant dierence between the drug
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
signicant dierence between the two groups of the study (P= 0.680).
3.4. Clinical response
As we are shown in Table 2, in the anise oil group, HIT-6 score
showed a signicant decrease from 64.77 ± 5.02 to 58.05 ( ± 6.76)
(P= 0.001), but in the placebo group, there was no signicant dier-
ence 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 signicant (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 signicant (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 signicantly 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 sig-
nicant compared to placebo group (P= 0.220).
3.5. Safety reports
Anise oil was relatively well tolerated by the participants and they
did not report any systemic or dermal side eects. However, two pa-
tients discontinued to take medication due to the sharp smell of anise
cream.
4. Discussion
Ecacy and safety of the anise oil cream on the migraine headache
were evaluated in this study via a randomized, double blind, placebo-
controlled clinical trial. Anise oil cream is demonstrated to have sig-
nicant positive eects on reducing frequency and duration of migraine
attacks as compared to the placebo.
Medicinal herbs are one the most used option amongst com-
plementary and alternative medicines. They can be introduced as new
therapeutics, potentially. However, there are trace evidences for their
use in clinical practice. Although, ecacy of several herbal remedies
such as lavender essential oil, butterbur, feverfew, ginger, and rose oil
were evaluated in previous studies (Diener et al., 2018;Rae 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 rst clinical trial on
topical application of anise oil for migraine headache, and making
Fig. 1. GC-MS chromatograms of anise essential oil.
Table 1
Chemical composition of anise essential oil.
Peak Component RI
a
Area %
1 Phellandrene (α-) 1002 0.045
2 limonene 1024 1.251
3 Dihydrocarvone (cis) 1171 0.143
4 Methyl chavicol 1176 0.849
5 Carvone 1217 3.985
6 Anethole (Z-) 1228 0.107
7 Anethole (E) 1273 89.342
8 Elemene (δ-) 1333 0.045
9 Anisyl methyl ketone 1340 0.125
10 Caryophyllene (E) 1413 0.098
11 Himachalene (α-) 1441 0.134
12 Humulene (α-) 1446 0.054
13 Unknown 1457 0.080
14 Himachalene (γ-) 1470 2.010
15 Zingiberene (α-) 1485 0.420
16 Himachalene (β-) 1492 0.071
17 Bisabolene (β-) 1500 0.107
18 Sesquiphellandrene (β-) 1512 0.080
19 Dill apiole 1586 0.116
20 Unknown 1604 0.045
21 Pseudoisoeugenyl 2-methylbutyrste (E) 1813 0.608
22 Nonadecane (n-) 1900 0.116
23 Heneicosane (n-) 2099 0.116
24 Tricosane (n-) 2301 0.054
a
Retention index determined on a DB-1 fused silica column relative to a
series of n-alkanes (C
8
eC
26
).
S.H. Mosavat, et al. Journal of Ethnopharmacology 236 (2019) 155–160
157
comparison with earlier studies is not possible. The most similar study
to ours is the ecacy 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 sig-
nicantly dierent in patients with migraine when taking rose oil or
placebo. Although various pharmacological eects, such as neuro-pro-
tective, anti-inammatory and analgesic properties, have been attrib-
uted to rose essential oil, this study failed to demonstrate the eects of
these properties in migraine.
Major constituents of anise essential oil are anethole, γ-himacha-
lene, 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 an-
tagonist 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 mi-
graine attack is not detectable, but after this phase, its level increases,
one of the hypotheses proposed to stop the migraine attacks is
Fig. 2. Flow diagram of the groups' allocation, enrolment, intervention, follow-up, and the analysis in both groups of the study.
Table 2
Mean HIT-6 score between the two groups of the study during study period.
Outcome measure Groups Pvalue
Anise oil Placebo
Mean HIT-6 score ± SD Baseline 64.77 ± 5.02 63.06 ± 6.51 0.680
3 weeks 63.13 ± 6.18 63.73 ± 6.32 0.843
6 weeks 55.05 ± 6.76 64.41 ± 5.51 0.012
Pvalue 0.001 0.090
Fig. 3. Trend of the changes of frequency and duration of headache attacks during the study period in each group.
S.H. Mosavat, et al. Journal of Ethnopharmacology 236 (2019) 155–160
158
activation of GABA e pathway. (Welch et al., 1975). Considering pre-
vious 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 phe-
nomenon 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 be-
tween 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 eectiveness of
Anise oil in migraine attacks, perhaps, analgesic and anti-inammatory
eects of this plant is the simplest mechanism of action. Previous stu-
dies showed that the extracts of Pimpinella anisum exhibited signicant
analgesic activities versus benzoquinone-induced writing and in
thermal tests (Shojaii and Abdollahi Fard, 2012;Tas, 2009;Samojlik
et al., 2016). Moreover, analgesic eect of Anise essential oil was re-
ported similar to morphine and aspirin. Also, the ndings demonstrated
that the anise oil has anti-inammatory eect as strong as in-
domethacin and has analgesic eect 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
eects on the patient, the use of topical medications can be helpful.
However, our study had some limitations. Using the minimum ac-
ceptable sample size in this study was one of its main limitations. Of
course, given that our study is the rst clinical trial on the ecacy of
topical anise essential oil in management of patients with migraine
headache, perhaps the small sample size is justied. 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.
5. Conclusion
This randomized, double blind, placebo-controlled clinical trial
demonstrated that Anise (Pimpinella anisum L.) oil has signicant po-
sitive eects on reducing the frequency and duration of migraine at-
tacks as compared to the placebo and could help to reduce the patient's
analgesics consumption as a complementary treatment. However,
larger-scale qualied methodological trials with longer duration of the
intervention are needed to replicate and expand our preliminary nd-
ings in this trial.
Acknowledgements
This study was a MD thesis by Dr. Amin Moayedfard that was ap-
proved by the Ethics Committee (code IR.SUMS.MED.REC.1396.55);
they are all appreciated. The authors thank the research vice chancel-
lery of Shiraz University of Medical Sciences for funding supports.
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Table 3
Mean number of analgesic consumption per week and mean of headache se-
verity between the two groups of the study during study period.
Outcome measure Groups Pvalue
Anise oil Placebo
Mean number of analgesic
consumption ± SD
1 weeks 3.13 ± 5.31 2.66 ± 3.59 0.891
2 weeks 3.45 ± 6.76 1.60 ± 1.40 0.891
3weeks 2.18 ± 3.23 2.21 ± 1.80 0.432
4 weeks 2.10 ± 2.91 2.50 ± 2.02 0.307
5weeks 1.80 ± 4.31 2.25 ± 2.09 0.099
6 weeks 1.85 ± 4.65 2.33 ± 1.87 0.044
Pvalue 0.013 0.090
Mean of headache severity 1 weeks 6.55 ± 1.79 6.06 ± 2.68 0.772
2 weeks 6.19 ± 2.17 6.30 ± 3.53 0.304
3weeks 6.15 ± 1.81 6.54 ± 3.33 0.343
4 weeks 4.39 ± 3.38 5.64 ± 3.59 0.207
5weeks 5.06 ± 2.78 6.50 ± 3.34 0.064
6 weeks 4.63 ± 3.25 5.86 ± 3.50 0.220
Pvalue 0.028 0.753
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