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International Journal of Clinical Trials | January-March 2016 | Vol 3 | Issue 1 Page 24
International Journal of Clinical Trials
Hatef B et al. Int J Clin Trials. 2016 Feb;3(1):24-31
http://www.ijclinicaltrials.com
pISSN 2349-3240 | eISSN 2349-3259
Research Article
The efficiency of pulsed electromagnetic field in refractory
migraine headaches: a randomized, single-blinded,
placebo-controlled, parallel group
Boshra Hatef1, Fahime Hashemirad2, Gholam Hossein Meftahi1, Leila Simorgh3, Soodeh
Razeghi Jahromi4, Forough Rahimi5, Mansoureh Togha4*
INTRODUCTION
Migraine is a serious illness with a spontaneous clinical
evolution that has a tendency to become chronic.1,2 The
International Headache Society introduced refractory
migraine (RM) into the International Classification of
Headache Disorders 3 (ICHD-3 beta and 2 (ICHD-2)
with a prevalence of 5%.3-5 RM characteristics include
chronic migraines or migraines without an aura, that
significantly interfere with the quality of life in spite of
preventive medications.3,4
Many studies suggest that there are various causes behind
migraines such as dysfunction within certain voltage
channels in the CNS, neural regulation of the brain stem
and cerebral circulation.6,7,10 Furthermore electro-
ABSTRACT
Background:
The study attempts to investigate the effect of PEMF therapy on Refractory Migraines (RM), both
those which were related and those which were not related to menstrual cycle, in a randomized, single blind, placebo-
controlled study.
Methods:
The study attempts to investigate the effect of PEMF therapy on Refractory Migraines (RM), both those
which were related and those which were not related to menstrual cycle, in a randomized, single blind, placebo-
controlled study.
Results:
There was a significant improvement for the active group in terms of their headache days, durations and
work-loss hours due to headache compared to the placebo group after 2 weeks. The added results of the assessment of
the active group indicated a significant improvement in the days and duration of headaches, work-loss hours and
number of medications even after a following 4-8-month period. Headache intensity and the amount of medication
used for headache were reduced only in RM patients that had headaches which were not related to their menstrual
cycles.
Conclusions:
PEMF (10 Hz, 4-5mT) can be considered as a beneficial and persistent prophylactic treatment option
for refractory migraine.
Keywords: Refractory migraine, Pulsed electromagnetic field therapy, Randomized clinical trial
1Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
2Monash University, Melbourne, Victoria, Australia
3Department of Rehabilitation Sciences, Shahid Beheshti University of Medical Science, Tehran, Iran
4Department of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
5School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Received: 10 December 2015
Accepted: 27 December 2015
*Correspondence:
Dr. Mansoureh Togha,
E-mail: toghae@sina.tums.ac.ir
Copyright: © the author(s), publisher and licensee Medip Academy. This is an open-access article distributed under
the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial
use, distribution, and reproduction in any medium, provided the original work is properly cited.
DOI: http://dx.doi.org/10.18203/2349-3259.ijct20160475
Hatef B et al. Int J Clin Trials. 2016 Feb;3(1):24-31
International Journal of Clinical Trials | January-March 2016 | Vol 3 | Issue 1 Page 25
physiological and imaging studies have shown that
changes appear in the brain before headache (in the pre-
ictal phase). However, they return to the normal state
after the migraine attack.10-13 Evidence indicates that non-
pharmacologic treatments can play an important role in
controlling RM.14 Pulsed electromagnetic field (PEMF)
has shown promising results in the prophylactic treatment
of migraine. Patients achieved over 70 percent
improvement in their activity after using PEME.15-17
Extremely low-frequency electromagnetic fields may
have a beneficial effect in controlling migraines through
several mechanisms. The exposure of neural and vascular
cells to electromagnetic fields that resonate at 10 Hz can
induce intracellular calcium oscillations and change the
signaling cascades such as calcium-calmodulin-NO.18,19
Electromagnetic fields also enhance vascular tonicity and
velocity.20,21 They stimulate ATP, mitochondrial enzymes
synthesis as well as the anti-inflammatory process.21,22
They also increase the rate of synthesis (turnover) of
dopamine and serotonin, eventually reducing the alpha
band of EEG.23-25 It seems that there is a correlation
between the etiology of migraines and the effects of an
electromagnetic field on the human brain.9 Nevertheless,
there is no strong evidence to support efficiency of this
treatment in migraine sufferers.17 Therefore, the aim of
this study was to investigate the effects of applying the
PEMF to patients experiencing RM headache.
METHODS
Subjects
Thirty patients from the out-patient department of the
Clinic of Neurology participated in this study. They had
been diagnosed as sufferers of migraine or medication-
overuse headaches by the corresponding author, who is
an expert in headaches. The study was approved by the
Ethics Committee of Tehran University of Medical
Sciences and recorded in the www.clinicaltrials.gov
website with the tracking number NCT01670214. The
subjects were informed about the procedures involved in
the study and gave written informed consent according to
the Helsinki convention.
Inclusion criteria required patients in an age range of 18
to 60 years, either male or female, and to have been
diagnosed with migraine or chronic migraine for at least
12 months based on ICH-II with a low quality-of-life
score (MIDAS>11). Exclusion criteria were pregnancy or
lactation, psychiatric, systemic diseases, epilepsy, and
malignancy within the past year. Patients were also
excluded if they had the criteria of concomitant non-
migraine headaches more than three times per month
within the last 3 months, or alcohol or drug addiction
according to the Diagnostic and Statistical Manual of
Mental Disorders-IV. They were also excluded. If they
had received oral contraceptive during or within 3 months
before the study.26,27
The design of the study
This research was a randomized single-blind placebo-
controlled study performed in three phases (Figure 1).
Characteristics of headaches of patient who met the
inclusion and exclusion criteria were recorded in two
weeks before starting the treatment. After this two-week
headache- assessment, patients were randomly assigned
into two groups: active or placebo. In female patients,
menstrual-related migraine was also assessed according
to ICHDIII-beta. They were categorized as menstruation-
related RM, if their symptoms were associated with
menstrual period.28
All patients had an experience of taking of a combination
of propranolol- nortriptyline +/- sodium valproate or
topiramate, as prophylactic drugs. However, the
mentioned medications had not been adequately effective
for the patients. One month before beginning the study,
the patients were asked to stop taking preventive
medicines, alone or in combination. During this period,
they were allowed to take minor pain relief medications
such as Sumatriptan, Ibuprofen or Acetaminophen for
their acute attacks.
The first phase of the study consisted of six sessions
(three sessions per week) of PEMF treatment for both
groups. The electromagnetic instrument was turned on for
both groups, but electromagnetic current was not
employed for the placebo group.8 None of the patients
knew to which group they belonged. In the second phase,
patients in the active PEMF group continued the
treatment for six more sessions (two additional weeks),
and were then followed up for four months in the third
phase. For the subsequent 8 months, participants were
telephoned twice a month and asked about headache
frequency. No other variables were included during this
phase. In the placebo group no further follow up or
additional exposure to the magnetic field were
perfpormed001.
Figure 1: The schematic view of the procedure.
Hatef B et al. Int J Clin Trials. 2016 Feb;3(1):24-31
International Journal of Clinical Trials | January-March 2016 | Vol 3 | Issue 1 Page 26
The pulsed electromagnetic field therapy
Parameters of the pulsed electromagnetic field (generated
by: BTL 5000, made in UK) were rectangular
electromagnetic pulses with 10 Hz frequency (pulse for
3ms, pause for 97 ms) and 4-5 mT intensity. The patients
were exposed to the electromagnetic field for 30 minutes
per session. The solenoid (diameter was 70 cm) was
placed around the patients’ head while they lay supine on
the treatment bed. The lines of electromagnetic field were
paralleled to body. PEMF has been approved by FDA for
fracture treatment.29 The treatment dosage used in this
study was in the safety range of PEMF without any
hazardous effect.11,21,30,31
Outcome measures
All the participants were asked to record their symptoms
in a migraine diary form. This recording began two
weeks prior to the study (baseline measurement) and
continued during the first phase in both groups. Patients
in the active group continued logging their symptoms in
the diary for the second and third phases. The MIDAS
score (Persian version) was employed both at baseline
and at the end of three months of treatment.32
The following parameters were assessed in the diary for
each phase: 1) Frequency of migraine attacks, number of
days per two weeks with migraine or headache, 2)
Intensity of headache rated using Visual Analog Scale
(VAS), 3) Duration of migraine attack, 4) The hours of
impairment in everyday activities or work missed, and 5)
The type and dosage of medications taken.
The patients were allowed to take only simple analgesics,
no triptans or ergot derivatives during the migraine
attacks. Frequency of headache was considered as the
primary outcome measure and was followed for eight
months. Other outcomes were considered as secondary
outcomes.
Statistics
Chi-square and independent sample t-tests were used to
compare the demographic and clinical characteristics in
both active and placebo groups. A two-way mixed model
ANOVA was conducted to evaluate two main factors,
group (active and placebo) and menstrual relationship of
migraine (menstrual RM and non-menstrual RM), and pre
vs. post treatment. A simple mixed-model ANOVA was
used to assess the changes in the outcome measures from
the beginning of the study until the end of the follow-up
period in the active treatment group that was divided to
sub-groups. One group with RM is related to menstrual
cycle and the other one is not related to menstrual cycle.
The MIDAS scores before and after three months of
treatment were evaluated in the active treatment group by
paired sample t-test. The significance level was set at
0.05. All analyses were performed using the IBM SPSS
statistics 21.
RESULTS
A total number of 33 patients were enrolled to participate
in the study. Nineteen patients were randomly assigned to
the active treatment group while the remaining 14
patients were placed in the placebo group. Table 1
presents the demographic and clinical characteristics of
both groups. No significant difference was found between
the groups in terms of gender, age, years and type of
migraine, MIDAS score and menstrual relationship of
migraine and migraine symptoms such as nausea,
vomiting or aura.
Table 1: Demographic and clinical characteristics
of groups.
Active
group
(n=19)
Placebo
group
(n=14)
P-
value
Gender
89.4%
female
78.5%
female
0.38
Age (years)*
35.5 (8)
37.7 (9)
0.52
History of migraine
(years)*
12.7 (6)
16.5 (8)
0.18
RCM / RM
12 / 7
8/ 6
0.72
Nausea or vomiting
68.4 % yes
71.4 %
yes
0.85
Aura
26.3 % yes
28.5 %
yes
0.88
Menstrual related
47.3% yes
50% yes
0.88
MIDAS score*
77.76 (42)
72.33
(39)
0.76
*: the data are mean (standard deviation)
Table 2 represents the means, lower and upper band of
95% CI of headache activity, and relation to menstrual
cycle in both groups before and after two weeks of
treatment.
Table 3 reports the means of outcome measures from
both groups before and after two weeks of treatment.
Results of the two-way mixed model ANOVA test
demonstrated that there is a significant interactional
effect between time and group in three variables of
frequency, duration of headache and work loss due to
headache. Following up the interaction between group
and time in these variables indicated a significant
decrease over time in the active group. However, there
was no change from pre to post treatment in the placebo
group. The findings show that there are significant
interactions between time and menstrual relationship with
respect to the intensity of headache and amount of
medication used. The bonferroni pairwise comparison
evaluated this interaction and showed that these variables
significantly diminished in patients who had migraine not
related to menstrual cycle, after two weeks regardless of
the type of treatment (Table 3).
Hatef B et al. Int J Clin Trials. 2016 Feb;3(1):24-31
International Journal of Clinical Trials | January-March 2016 | Vol 3 | Issue 1 Page 27
Table 2: The means (standard deviation) of number of days, intensity and duration of headache, work-loss and
number of medications because of headache for active and placebo groups.
Outcome
measure
ments
Pre/post
treatment
Relation to
menstrual
cycle
Mean (lower and upper of 95%
CI)
Active group (n=19)
Mean (lower and upper of 95%
CI)
Placebo group (n=14)
Day
Pre
Yes
9.78 (7.2-12.4)
11.4 (8.6-13.6)
No
7.6 (4.8-10.6)
7.5 (3.6-11.8)
Post
Yes
3 (2-4)
11.2 (8.3-14)
No
3.9 (3.1-4.8)
7.1 (3.2-11.8)
Intensity
(VAS)
Pre
Yes
6.6 (4.9-8.3)
7.7 (6.4-9)
No
8.1 (7.2-9)
8 (6.5-9.3)
Post
Yes
6.5 (4.7-8)
8.2 (7.3-9.2)
No
5 (3.5-6.6)
5.8 (4-8)
Duration
(hours)
Pre
Yes
177.11 (99.7-261.5)
210 (144-290)
No
135.2 (69.4-216.6)
108.3 (41.5-220.4)
Post
Yes
41.6 (25.7-60.4)
201 (130-280)
No
34.3 (16.1-54.9)
101.5 (18.3-221.5)
Work-
Loss
(hours)
Pre
Yes
28.11 (13.6-43.8)
48.4 (22.5-74)
No
40.8 (21.2-62.1)
39.8 (11-73)
Post
Yes
9.6 (3-19.5)
42.8 (15.4-69.7)
No
7.4 (2-13.3)
28.5 (1-69.2)
Medicatio
n
(number)
Pre
Yes
5.3 (2.6-8)
8.1 (3.2-15)
No
12.8 (5.6-19.5)
14.8 (5-26.6)
Post
Yes
4.4 (1.7-8.1)
10.5 (4-18.3)
No
1.9 (0.7-3)
11.6 (1.3-24.6)
The 95% CI excludes the value zero. Time frame for baseline and post-intervention is two weeks. Day: the number of days that patient
had headache.
Table 3: Results of two-way mixed ANOVA comparing active and placebo groups in relation to menstruation cycle,
pre and post treatment.
*: Time frame for each variable is two weeks. Significances are bolded. Pre-post: comparison before and after 6 sessions of treatment,
Group: comparison the placebo and active group, RTM: comparison the patients who had migraine related and not related to menstrual
cycle
The results of the remaining active group participants (19
patients) were analyzed using mixed design ANOVA.
The assumption of sphericity was violated so the
Greenhousee Geisser correction was employed for the F-
ratio computations. There was a significant interaction
between times and menstrual relationship. The number of
days with headache (F (3.2, 49.1) =22.4, P <0.0001) was
decreased after the 8 month follow ups (Figure 2). The
durations of headache (F (1.6, 26.1) =18.6, P<0.0001)
and work loss hours (F (1.6, 26) =18.6, P<0.0001)
considerably decreased after 4 months follow up. The
mean intensity of headache (F (10, 160) =1.9, P=0.048),
and the number of medications (F (2.3, 35.8) = 4, P=
0.02) that interacted with the menstrual relationship
decreased after 4 months follow up. This means that the
effect of treatment persisted in the RM without menstrual
relationship in intensity and medications used for
headache. The bonferroni test showed that there was a
significant difference in intensity between groups with
and without menstrual relationship at the 6th, 8th and 10th
week follows ups (Figure 3). A similar result was seen
only in the last time frame for the number of medications
used for headache. The days of headache and work-loss
hours in RM patients that had headaches related to their
Time
Group
RTM
Time × Group
Time × RTM
Group× RTM
Time ×
Group× RTM
Days*
0.0001
.0.016
.0.04
0.0001
0.32
0.121
0.12
Intensity*
0.002
0.14
0.55
0.21
0.0001
0.51
0.77
Duration*
0.0001
0.075
00.029
0.002
0.615
0.159
0.552
Work-Loss*
0.0001
0.071
0.75
0.037
0.20
0.40
0.56
Medications*
0.0007
0.067
0.237
0.151
0.002
0.726
0.811
Hatef B et al. Int J Clin Trials. 2016 Feb;3(1):24-31
International Journal of Clinical Trials | January-March 2016 | Vol 3 | Issue 1 Page 28
menstrual cycles were significantly higher than that of
patients who reported that their headaches were not
related to menstrual cycle.
Figure 2: The mean number of days with headache in
menstrual RM and non-menstrual RM. Each time
frame is two weeks of pre-treatment, 1st-6th session
(phase I), 7th-12th sessions (phase II) of treatment, as
well as the 1st-16th frames of follow up (FU) in the
active PEMF group. The days of FU11&12 until FU15
& 16 was normalized to two weeks (phase III). Results
showed that the number of headache days
significantly decreased in the active group after
treatment and this improvement persisted
after eight-months.
Figure 3: The mean intensity of a migraine episode in
the menstrual RM and non-menstrual RM. Each time
frame is two weeks of pretreatment, 1ts-6th sessions
(phase I), 7th-12th sessions of treatment(phase II), as
well as 1st-8th frames of follow up (FU) after
treatment(phase III) in the active group.
MIDAS scores were obtained three months after active
PEMF treatment which were then compared to the
MIDAS scores prior to treatment initiation. A significant
decrease was obtained (t=7.5, sig<0.0001) (Figure 4).
Figure 4: The bar plots represent the MIDAS score
before and three months after the treatment in the
active group. **: P value <0.0002.
DISCUSSION
Results showed significant beneficial effects of active
PEMF therapy in headache activity for RM patients.
Days and durations of headache and work-loss hours due
to headache were reduced in comparison with the placebo
group. This improvement was consistent in the active
group, even after the 10-week follow up period.
Menstrual relationship with headache had an interactional
effect on both intensity and amount of medication used
for headache. However, the results showed that PEMF
did not have any therapeutic effect on headache linked
with women's hormone fluctuations. The current study
has several strengths in comparison with the previous
studies that were collected by Vincent et al in.17 For
example, the existence of the parallel placebo group in a
randomized clinical trial, assessment of PEMF in RM
patients for whom the routine treatment did not work, and
consideration of menstrual relation to migraine as factors
in a mixed model analysis have not been previously
included in published work.
EEG studies have shown that electromagnetic field has a
dose-dependent effect, being well demonstrated in pain
and EEG studies.25,33,34 Many of the studies from 1985 to
2005, gathered in a review article, illustrated the effect of
the use of large spread spectrum of PEMF doses on
decreasing headache activity.17 Although most of these
research studies had no control or comparison group, or
had very brief follow-up periods and uncompleted reports
of dosimeter. Sherman et al in 1998 revealed a
therapeutic effect of PEMF at 27.12 MHz in their pilot
study of six migraine patients exposed to a PEMF
machine, showing a change in headache activity from
3.32 to 0.58 per week compared to the controls.35 They
also showed that 75% of 42 participants had significant
improvement in their migraine headaches after exposure
for two weeks (10 sessions).16 In another study, 76% of
participants indicated that they were “clear” or “very
clear” of their complaints about headaches, with no side
effects from the treatment (4 weeks PEMF: 16 Hz, 5
Hatef B et al. Int J Clin Trials. 2016 Feb;3(1):24-31
International Journal of Clinical Trials | January-March 2016 | Vol 3 | Issue 1 Page 29
microT), while no improvement was observed in the
control group.15
The effect of menstrual relationship on the intensity of
migraine attacks and medication used for headache, may
demonstrate that PEMF has little effect on the women's
hormonal fluctuations that trigger the headaches in this
group.
There are currently no studies that actually demonstrate
how electromagnetic fields reduce migraines. However,
several explanations can be considered for the therapeutic
effects of PEMFs on headache. These rationales include
electrophysiological, neurochemical, and vascular
phenomena.17 Some animal and human studies support
neurochemical effects of weak electromagnetic fields that
may act on neurotransmitters such as melatonin, cortisol,
serotonergic and dopaminergic systems implicated in the
pathophysiology of migraine.3,23,36 Many electro-
physiological studies in migraines often showed high
power and asymmetry in the low EEG frequency band
due to the reduction of the cholinergic activity of the
brainstem that induces dysrhythmia in the thalamo-
cortical pathway.11,37 On the other hand, an
electromagnetic field with a frequency of 10 Hz reduced
the alpha band of the EEG.25,38,39 There are some
controversies regarding the effect of PEMF due to the
intensity and frequency of exposure on EEG.24,38,39 Then
the electrophysiological rationale of effect of
electromagnetic field on migraine may be supported.
Exposure to PEMF at 10 Hz also stimulates the calcium
oscillation in the cell.19 It causes minimum calcium
leakage from the cell membrane synthesis of ATP and
mitochondrial enzymes, and anti-inflammatory
process.21,22,40,41 Therefore, use of an electromagnetic
field at 10 Hz also increases the rate of synthesis
(turnover) of dopamine and serotonin.23 The cellular
effect of PEMF on calcium oscillation for modulating
Calcium-Calmodulin-NO signaling is a basis for any
response from vascular and neural cells to
PEMF.18,19,21,31,42 Many studies have revealed that
electromagnetic fields at a wide range of frequencies,
activate certain cellular mechanisms, increase blood flow,
and produce vasodilation of the vascular tone.20,43 These
mechanisms may be related to cellular survival activity,
the vascular system, as well as inflammation process
following the use of PEMF. On the other hand, an
abnormal rhythmic activity between thalamus and cortex,
along with a decrease in the velocity of blood flow
through cerebral arteries (especially the middle cerebral
artery), were observed on the affected hemisphere in
migraine.9,13,44 Almost 50% of migraine sufferers have
inter-hemispherical asymmetries in regional cerebral
blood flow (rCBF).9,45 The blood flow in several parts of
the brain, including the anterior cingulate cortex, auditory
and visual association cortices, brainstem (locus
coeruleus and dorsal raphe nuclei), bilateral insula,
bilateral cerebellar hemispheres, prefrontal cortex,
putamen, and rostral medulla, are all increased during a
migraine attack.7 There is also a correlation between
autonomic system dysfunction and migraines, as well as
an increased risk of cardiac ischemia.46,47 Olesen in 2009
revealed that disturbance of the para-sympathetic input to
the cerebrovascular system (especially pial arteries)
initiates migraines without an aura.48 This study also
showed that PEMF is effective in migraine prevention.
One limitation of the current study was the combination
of both episodic and chronic forms of migraine among
participants. Moreover, there was a lack of adequate
control on the use of abortive medications because each
patient was used to taking certain drugs. The short time
frame of baseline and post intervention (two weeks) to
compare placebo and active groups in the first phase was
another limitation of the study. Although the pilot study
and power of analysis showed that the number of subjects
was sufficient, an increased number of subjects would
increase the reliability of the results.
CONCLUSION
In future studies, PEMF can be compared to traditional
migraine therapies to establish comparative efficacy and
safety. Furthermore, longer follow-up periods will be
needed in order to determine whether any therapeutic
benefits, resulting from the use of PEMFs, endure over
time. More clinical trials are suggested to find a dose of
PEMF therapy with the best therapeutic result and the
least amount of side effects.
This randomized single-blinded parallel-placebo
controlled study showed significant improvement of
headache activity in the PEMF active group, while no
changes of headache parameters were seen in the placebo
group in the first phase. The second and third part of the
study showed that improvements in the active group
persisted even after an 8 month follow-up period. The
study also showed that menstrual dependency of
headache diminished the effect of PEMF treatment.
ACKNOWLEDGMENTS
The study was funded by Tehran University of Medical
Sciences. The authors express their sincere thanks to Dr
Soheil Saadat, associate Professor of Sina Trauma and
Surgery Research Center for his help to statistical report.
Funding: No funding sources
Conflict of interest: None declared
Ethical approval: The study was approved by the
Institutional Ethics Committee
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Cite this article as: Hatef B, Hashemirad F, Meftahi
GH, Simorgh L, Jahromi SR, Rahimi F, et al. The
efficiency of pulsed electromagnetic field in refractory
migraine headaches: a randomized, single-blinded,
placebo-controlled, parallel group. Int J Clin Trials
2016;3(1):24-31.
