Randomized Controlled Study to Evaluate Prophylactic Properties of Ayurvedic Treatment Protocol in Refractory and Chronic Migraine Patients

Abstract

Background: Migraine is a disorder marked by recurrent episodes of headache. There is a subset of migraine patients who remain refractory to the conventional prophylactic and abortive therapies. This study aimed to assess the therapeutic role of an ayurvedic treatment protocol in patients who had chronic/ refractory migraine. Methods: This single-center, open label, randomized, controlled clinical trial compared the efficacy of ayurvedic treatment protocol to conventional treatment. Included patients were 18-65 years of age and met the diagnostic criteria for chronic/ refractory migraine. The patients were randomized in a 1:1 ratio to the ayurvedic treatment or conventional therapy at the baseline and were followed at regular intervals for 360 days. The primary outcome was reduction in the number of headache days in the last 3 months and the secondary outcomes were a reduction in the visual analog scale (VAS) score and migraine disability assessment score (MIDAS) as compared to the baseline. Results: Patients (n=154) were randomized to the two treatment groups with similar baseline demographic and clinical characteristics. The patients in ayurvedic treatment group had a greater reduction in the number of headache days, VAS score and MIDAS score at day 360 (p<0.05). Further, there were no reported medication-related adverse effects in either group. Conclusion: Ayurvedic treatment protocol is well tolerated and is associated with significant improvement in symptoms of chronic refractory migraine.

Full text

International Journal of Innovative Research in Medical Science (IJIRMS)
Volume 06, Issue 04, April 2021,
https://doi.org/10.23958/ijirms/vol06-i04/1106
www.ijirms.in
259
Original article
Randomized Controlled Study to Evaluate
Prophylactic Properties of Ayurvedic Treatment
Protocol in Refractory and Chronic Migraine Patients
Vaidya Balendu Prakash *1, Nitin Chandurkar 2, Vaidya Shikha Prakash 1, Shakshi Sharma 1, Sneha Tiwari 1
1VCPC Research Foundation, Uttarakhand, India
2Ipca Laboratories Limited, Maharashtra, India
*Corresponding author: Vaidya Balendu Prakash, VCPC Research Foundation, Prakash Villa, Beside Rave
Cinemas, Danpur, Rudrapur, Uttarakhand, India; balenduprakash@gmail.com
Received 08 March 2021; Accepted 29 March 2021; Published 07 April 2021
Abstract
Background: Migraine is a disorder marked by recurrent episodes of headache. There is a subset of migraine patients who remain refractory to
the conventional prophylactic and abortive therapies. This study aimed to assess the therapeutic role of an ayurvedic treatment protocol in
patients who had chronic/ refractory migraine. Methods: This single-center, open label, randomized, controlled clinical trial compared the
efficacy of ayurvedic treatment protocol to conventional treatment. Included patients were 18-65 years of age and met the diagnostic criteria for
chronic/ refractory migraine. The patients were randomized in a 1:1 ratio to the ayurvedic treatment or conventional therapy at the baseline and
were followed at regular intervals for 360 days. The primary outcome was reduction in the number of headache days in the last 3 months and the
secondary outcomes were a reduction in the visual analog scale (VAS) score and migraine disability assessment score (MIDAS) as compared to
the baseline. Results: Patients (n=154) were randomized to the two treatment groups with similar baseline demographic and clinical
characteristics. The patients in ayurvedic treatment group had a greater reduction in the number of headache days, VAS score and MIDAS score
at day 360 (p<0.05). Further, there were no reported medication-related adverse effects in either group. Conclusion: Ayurvedic treatment
protocol is well tolerated and is associated with significant improvement in symptoms of chronic refractory migraine.
Keywords: Migraine, Refractory, Chronic, Ayurveda, Clinical trial
Introduction
Refractory migraine is a headache that causes significant
interference with functions or quality of life despite modification of
triggers, lifestyle factors and adequate trails of acute and preventive
medicines with established efficacy. The patients fail 3-4 adequate
trials of preventive medicines, alone or in combination, from at
least 2 of 4 drug classes including beta-blockers, anticonvulsants,
tricyclics and calcium channel blockers. Patients should also fail
adequate trials of abortive medicines, including both a triptan and
dihydroergotamine (DHE) intranasal or injectable formulation and
either non-steroidal anti-inflammatory drugs (NSAIDs) or
combination analgesic, unless contraindicated. Refractory migraine
patients must meet the International Classification of Headache
Disorders, Second Edition (ICHD-2) criteria for chronic migraine
or refractory migraine [1].
There is a constant upsurge in the prevalence of migraine
globally. In United States, the incidences rose from 6.54% in 2003
to 9.69% in 2012 [2]. 5-8% migraineurs have chronic migraine and
about 5% suffer from refractory migraine, with overall prevalence
of RM/CM at around 2-3% [3]. The disease adversely affects an
individual‟s personal, professional and social life causing moderate
to severe debility and also substantial agony, frustration and
financial burden [3]. In 2015, $5.4 million were spent on treatment
of CM in the US [4].
The management of RM/CM is complicated and the
conventional treatment causes moderate to severe side effects and
badly affects the psychological state of its sufferers [5]. A North
India based Ayurvedic clinical practice has reported sustainable
and complete relief from migraine in significant number of cases
by using an Ayurvedic Treatment Protocol, comprising of four
herbo-mineral Ayurvedic preparations, Narikel Lavan, Numax,
Rason Vati and Godanti Mishran [6,7].
These formulations are derived from Rasa Shastra in
Ayurveda and have successfully passed through toxicological
studies [8,9]. The present study was carried out under a competent
neurologist to prove the stated prophylactic properties of
Ayurvedic formulations in RM/CM patients.

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Material and Methods
The study was carried at Department of Neurology, All India
Institute of Medical Sciences, New Delhi between 1st April 2012
and 31st May 2016. Ethical clearance was obtained vide reference
no. IEC/NP-276/2011 dated 03-10-2011. A tripartite agreement
was made between investigators, participating institute and
sponsoring body.
Study design and patient population
This is a randomized, open labelled, double arm comparative study
conducted in a single tertiary care centre in India. The study
protocol was approved by the institutional review board and the
trial was registered with the clinical trial registry of India (Protocol
No. Ipca/ATP/P III-10).
Adults aged 18–65 years who met the International
Classification of Headache Disorders – 2nd Edition diagnostic
criteria for migraine or chronic migraine and who remained
refractory to treatment with conventional prophylactic medications
were included in the study. Refractory migraine was defined as
headaches causing significant interference with function or quality
of life despite modification of triggers and lifestyle factors and
refractory to treatment with three or more adequate trials of
preventive medications from at least 2 of the 4 drug classes,
including β blockers, tricyclic antidepressants, calcium channel
blockers and anticonvulsants [1]. Informed consent was obtained
from all patients.
Patients with secondary headaches, concurrent chronic
diseases, and those with a history of substance abuse were
excluded from the study. Additionally, patients who were on any
medications for conditions other than migraine and/or those with a
history of hypersensitivity to any medication were also excluded
from the study.
Visits and Randomization
At the initial screening visit, a detailed clinical history was
obtained and physical examination was performed and the patients
were assessed for the inclusion and exclusion criteria. In addition,
baseline investigations including a complete hemogram, blood urea
nitrogen, serum creatinine, bilirubin, liver transaminases, fasting
blood glucose, and cranial non-contrast computed tomography
scans were performed for all patients.
Eligible patients were randomized in a 1:1 ratio to receive
either ayurvedic treatment protocol or conventional treatment
through selection of sealed opaque envelopes. The ayurvedic
treatment protocol used in this study is shown in Table 1. All
patients were assessed for headache days, pain intensity, headache
frequency, duration and associated symptoms in the seven
subsequent visits on days 30, 60, 90, 120, 150, 180 and 360.
Table 1: Ayurvedic treatment protocol
Name of formulation
Dose
Vehicle
Schedule
Narikela Lavana (powder)
1 gram, 12 hourly
200 grams yoghurt + 50 mL water
Before breakfast and dinner
Numax
500 mg, 12 hourly
Water
During breakfast and dinner
Rasonadi Vati
500 mg, two tablets 8 hourly
Hot water
After breakfast, lunch and dinner
Godanti Mishran
500 mg, 24 hourly
Mishri
At bedtime
Outcomes
The primary outcome was mean change in the number of headache
days in the last three months from the baseline and the secondary
outcome measures were change in the visual analog scale (VAS)
score and migraine disability assessment score (MIDAS) as
compared to the baseline. In addition, we also assessed the
proportion of patients reporting relief from the associated
symptoms of migraine.
Safety measures
Self-reported medication related adverse effects were recorded at
each follow-up visit. Detailed physical examinations were
performed at each visit to screen for any apparent side effects.
Further, all baseline blood investigations were repeated at the final
visit to look for any changes from the baseline.
Sample size calculation and statistical analysis
The sample size was calculated considering a 10% difference in
reduction of migraine frequency between the two groups. Setting
the type 1 error at 0.05 and considering a 20% dropout rate, sample
size in each arm was calculated as 77 patients, providing 80%
statistical power to the study.
Intention to treat analysis was performed and the last
observation was carried forward to impute for the missing values
for patients who were lost to follow up after at least one recorded
post-randomization efficacy measurements. The baseline
characteristics of the two groups were compared using chi square
for categorical variables and independent t-test for continuous
variables. The change in primary and secondary outcome measures
from the baseline was calculated for each group independently and
was compared between the two groups. Further, proportion of
patients reporting relief from migraine associated symptoms were
compared between the two study groups.
Monitoring
The project was well monitored and four periodical progress
reports were submitted by the investigators to the sponsoring body
(data on file).
Results
During the study period, 257 patients were screened for the
eligibility criteria. Ultimately, 154 patients were randomized in a
1:1 ratio to receive either ayurvedic treatment protocol or the
conventional treatment. Of these, 7 patients from the ayurvedic
treatment group discontinued after the baseline visit and 1 patient
from the conventional treatment group discontinued after the first
follow-up visit on day 30. With the intention to treat analysis, last
observations were used to impute the missing values for the one
patient in the conventional treatment group whereas the 7 patients
with no efficacy measurements were excluded from the further
analysis.
The mean ± SD age of the study population was 34.6 ± 9.6
years and 72.1% were females. The mean ± SD duration of
migraine was 4.9 ± 4.6 years and the mean ± SD VAS and MIDAS
scores at baseline were 8.2 ± 0.77 and 41.5 ± 9.2, respectively. The
two treatment groups were similar in the demographic and clinical
characteristics at baseline except for significantly higher MIDAS
score in the ayurvedic treatment group (Table 2).

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Table 2: Baseline demographics and clinical characteristics
Conventional Treatment (n=77)
Ayurvedic treatment (n=77)
p-value
Age (years)
34.74 (9.33)
34.53 (10.00)
0.894
Female
59 (76.62)
52 (67.53)
0.209
History of migraine (years)
4.51 (3.83)
5.33 (5.22)
0.266
Migraine days in 3 months
56.48 (16.45)
55.19 (18.48)
0.649
Nausea
63 (81.82)
63 (81.82)
1.000
Vomiting
53 (68.83)
51 (66.23)
0.731
Photophobia
69 (89.61)
68 (88.31)
0.797
Phonophobia
60 (77.92)
59 (76.62)
0.848
VAS score
8.21 (0.80)
8.19 (0.74)
0.917
MIDAS score
38.79 (8.58)
44.22 (9.02)
<0.001
All categorical variables are represented as n (%), all continuous variables are represented as mean (SD) VAS- Visual Analog Scale,
MIDAS- Migraine Disability Assessment
Outcome measures
The difference in the primary and secondary outcomes from the
baseline and between the two treatment groups is shown in Table
3. The primary outcome measure, that is, the reduction in the
number of headache days from baseline was 44.0 days for the
ayurvedic treatment group and 36.5 days for the conventional
treatment group with an average of 7.5 days greater reduction (95%
CI = 2.1 – 13.0) in the ayurvedic treatment group (p<0.01).
The secondary outcome measures, that is, the reduction in the VAS
score at day 360 was 6.0 for the ayurvedic treatment group and 5.4
for the conventional treatment group. Similarly, the reduction in
the MIDAS score at day 360 was 36.7 for the ayurvedic treatment
group and 27.7 for the conventional treatment group. The
ayurvedic treatment group had a significantly greater reduction in
both the scores when compared to the conventional treatment
group (p<0.01) (Figure 1 and 2).
Table 3: Change in primary and secondary end-points from the baseline
Conventional
Treatment* (n=77)
Ayurvedic
treatment* (n=70)
Difference in
Means** (95% CI)
β Coefficient
(95% CI)
p-value***
Primary endpoint
Migraine days in 3 months
-36.45 (1.68)
-43.99 (2.24)
-7.53 (-13.00 – -2.07)
-0.01 (-0.01 – 0.00)
0.007
Secondary endpoints
VAS
Day 90
-2.32 (0.08)
-2.49 (0.11)
-0.16 (-0.10 – 0.42)
-0.06 (-0.17 – 0.04)
0.219
Day 180
-4.49 (0.12)
-4.84 (0.11)
-0.35 (-0.67 – -0.03)
-0.09 (-0.17 – -0.01)
0.035
Day 360
-5.35 (0.15)
-5.99 (0.13)
-0.64 (-1.02 – -0.25)
-0.11 (-0.17 – -0.04)
0.002
MIDAS
Day 90
-10.68 (0.81)
-17.71 (0.69)
-7.04 (-9.17 – -4.91)
-0.03 (-0.04 – -0.02)
<0.001
Day 180
-19.99 (1.22)
-29.43 (0.96)
-9.44 (-12.54 – -6.34)
-0.02 (-0.03 – -0.01)
<0.001
Day 360
-27.66 (1.32)
-36.66 (0.94)
-9.00 (-12.25 – -5.75)
-0.02 (-0.03 – -0.01)
<0.001
* Difference in means (SE) from baseline. ** Difference in mean reduction between ayurvedic and conventional treatment groups. *** p
values are for ayurvedic treatment group vs conventional treatment group. VAS- Visual Analog Scale, MIDAS- Migraine Disability
Assessment
Figure 1: Effect of conventional and ayurvedic treatment on Visual Analog Score (VAS)
030 60 90 180 360
Conventional treatment 8.21 7.32 6.55 5.88 3.71 2.86
Ayurvedic treatment 8.19 7.23 6.53 5.73 3.37 2.23
0
1
2
3
4
5
6
7
8
9
VAS Score
Days
Conventional treatment Ayurvedic treatment

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Figure 2: Effect of conventional and ayurvedic treatment on Migraine Induced Disability Assessment Scale (MIDAS)
Associated symptoms
A greater proportion of patients reported relief from all associated
symptoms of migraine in ayurvedic treatment group as compared
to the conventional treatment group. However, the difference was
statistically significant for nausea, photophobia, phonophobia and
fatigue (p<0.05) (Table 4).
Safety assessment
No serious adverse effects were reported at any of the follow-up
visits in either treatment group. Additionally, the physical exams
and blood investigations of all patients remained unchanged from
the baseline.
Table 4: Percentage of subjects in ayurvedic and conventional treatment groups reporting relief from symptoms associated with
migraine
Conventional treatment (%)
Ayurvedic treatment (%)
p value
Nausea
37.31
63.93
0.003
Vomiting
85.19
95.65
0.101
Photophobia
40.58
59.38
0.031
Phonophobia
63.33
84.62
0.013
Fatigue
44.44
68.63
0.014
Blurring of vision
77.78
89.29
0.258
Otalgia
86.36
86.96
0.953
Tinnitus
83.33
100.00
-
Perspiration
56.52
63.64
0.491
Heartburn
88.00
95.83
0.338
Belching
82.22
88.57
0.433
Flatus
91.30
100.00
-
Constipation
79.59
80.00
0.962
Discussion
This study demonstrates the safety and efficacy of ayurvedic
treatment protocol in patients with chronic refractory migraine. As
compared to the conventional treatment, ayurvedic treatment was
associated with greater reduction in the number of headache days,
VAS scores, MIDAS scores as well as the associated symptoms of
migraine. Further, ayurvedic treatment protocol had no serious
adverse effects noted in the first 360 days of it use.
Chronic refractory migraine is a difficult-to-treat complex
disorder. As a result, patients suffering from it often seek novel
approaches to treatment. A variety of herbal medications like
Tenacetum Parthenium, Petasites Hybridus, have been studied for
the treatment of headaches [10,11]. In addition, alternate medicinal
systems such as, yoga, relaxation, and meditation have also shown
efficacy in the treatment of headaches. In general, chronic pain is
among the most common indications for the use of complementary
and alternative therapies and their use in chronic migraine is
particularly increased due to the fear of adverse effects and lack of
efficacy of the conventional medications [12]. The results shown in
our study are highly encouraging for the use of ayurvedic treatment
protocol in patients who are refractory to the conventional
prophylactic medications. The four Ayurvedic formulations used in
this study are classical Ayurvedic formulations which have shown
cumulative prophylactic properties in RM/CM patients. These
formulations have also undergone pharmacological studies. The
data of the study shows that these formulations have no analgesic,
anti-inflammatory, anti-histamine, anti-5HTeffects or effects on
general CNS activity, or behavioural and hemodynamic
parameters, alone or in combination (data on file).
This randomized controlled clinical trial was carried on an
adequate sample size and could be termed as preliminary „proof of
efficacy‟ study to verify the reported therapeutics of Ayurvedic
treatment protocol. Further pharmacological and multicentre open
label/ double blind clinical trials should be carried to understand
phenomenal nature of Ayurvedic treatment.
090 180 360
Conventional treatment 38.79 28.12 18.83 11.16
Ayurvedic treatment 44.22 26.9 15.19 7.96
0
5
10
15
20
25
30
35
40
45
50
MIDAS score
Days
Conventional treatment Ayurvedic treatment

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In conclusion, ayurvedic treatment protocol is well
tolerated and is associated with significant improvement of
symptoms in patients with chronic refractory migraine. There is a
need for more carefully conducted large prospective studies to
clearly define the therapeutic role and assess the safety of
ayurvedic treatment in patients with migraine.
Funding
The study was sponsored by Ipca Laboratories Limited, Mumbai.
Conflict of interest
Authors declare no conflict of interest.
Acknowledgement
We are thankful to Prof Dr Manjari Tripathi, Prinicipal
Investigator, Department of Neurology and Prof Dr A. K.
Mahapatra, Co-investigator, Dept of Neurology for conducting this
study. We also acknowledge the role of Ms Bharti, Ms Sangita and
Mr Ramesh for logistic support. We are grateful to Ipca
Laboratories, especially its Managing Director, Mr Premchand
Godha for sponsoring the study.
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