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Review Article

Cephalalgia
2016, Vol. 36(12) 11121133
Diet and nutraceutical interventions for ! International Headache Society 2015
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DOI: 10.1177/0333102415590239
cep.sagepub.com
evidence

Serena L Orr

Abstract
Background: The use of complementary and alternative medicines (CAM) is common among patients with primary
headaches. In parallel, CAM research is growing. Diet interventions comprise another category of non-pharmacologic
treatment for primary headache that is of increasing clinical and research interest.
Methods: A literature search was carried out to identify studies on the efficacy of diet and nutraceutical interviews for
primary headache in the pediatric and adult populations. MEDLINE, Embase and EBM ReviewsCochrane Central
Register of Controlled Trials were searched to identify studies.
Results: There is a growing body of literature on the potential use of CAM and diet interventions for primary headache
disorders. This review identified literature on the use of a variety of diet and nutraceutical interventions for headache.
Most of the studies assessed the efficacy of these interventions for migraine, though some explored their role in tension-
type headache and cluster headache. The quality of the evidence in this area is generally poor.
Conclusions: CAM is becoming more commonplace in the headache world. Several interventions show promise, but
caution needs to be exercised in using these agents given limited safety and efficacy data. In addition, interest in exploring
diet interventions in the treatment of primary headaches is emerging. Further research into the efficacy of nutraceutical
and diet interventions is warranted.

Keywords
Diet, nutraceuticals, vitamins, herbal medicines, headache, migraine
Date received: 9 February 2015; revised: 18 March 2015; 28 April 2015; accepted: 9 May 2015

Introduction
that patients with headache commonly turn to CAM
Complementary and alternative medicine (CAM) for alternatives to traditional allopathic options. In one
accounts for an ever-increasing portion of health care US headache clinic, a survey revealed that 84% of
expenditures. The United States (US) National patients were using CAM interventions, with herbs,
Institutes of Health (NIH) defines CAM as a group vitamins and nutritional supplements accounting for
of diverse medical and health care systems, practices, just fewer than 30% of the modalities used in this popu-
and products that are not presently considered to be lation (8). Similarly elevated estimates of CAM use
part of conventional medicine (1). In the US, CAM is in adult headache patients have been found elsewhere
a multibillion dollar industry, with spending estimated at (912). A study among pediatric headache patients
$13.9 billion to $33.9 billion annually (2). The use of referred to an Italian tertiary care headache clinic
CAM has become more prevalent over the past decade revealed that 76% of the patients were using CAM
(3). Recent estimates have found that more than one-
third of US adults and more than 10% of US children
endorse the use of CAM in the past year (4). This trend Childrens Hospital of Eastern Ontario, Canada
of CAM use is not unique to the US, with studies in
Corresponding author:
other countries also unveiling prevalent use (5,6). Serena Orr, Childrens Hospital of Eastern Ontario, 401 Smyth Road,
The management of chronic pain has been identified Ottawa, Ontario, K1H 8L1 Canada.
as a priority area for CAM research (7). It also appears Email: sorr@cheo.on.ca
Orr 1113

therapies for their headaches, with 74% using herbal appear to be more likely to suer from chronic
remedies and 40% using vitamin and mineral supple- migraine as compared to their peers (18), thereby
ments (13). In a study drawing on data from a national unveiling a possible relationship between body mass
sample of children representative of the US population, index (BMI) and migraine frequency. There is increas-
30% of the children with headaches reported CAM use ing evidence to suggest that migraine and obesity may
(14). Therefore, the use of CAM among headache be linked through inflammatory mediators released by
patients is very prevalent. adipose tissue (1922). Despite the increasing interest in
There is a significant gap between the prevalence of the headache-obesity association, there is a lack of
CAM use and the degree to which dialogue about research on the use of weight loss as a treatment for
CAM enters into the typical physician-patient inter- headache disorders. Weight loss has been found to be
action. In one study carried out in an Italian headache an ecacious intervention for patients with idiopathic
clinic, 60.9% of the patients using CAM had not told intracranial hypertension (23,24), but little is known
their physician about their CAM use (12). In addition, about its potential for ecacy in the primary head-
many physicians lack familiarity with CAM and avoid aches. Two small observational studies have described
the topic during routine clinical encounters. For a decrease in migraine frequency and disability in obese
patients interested in exploring CAM, this mutual women with migraine following bariatric surgery
reluctance to discuss the options may constitute a sig- (25,26). A large retrospective study carried out in sev-
nificant barrier to trust and optimal care. Given how eral tertiary care pediatric headache centers uncovered
many headache patients are resorting to CAM, head- an association between weight loss and reduction in
ache practitioners should become well versed in the evi- headache frequency among overweight children pre-
dence behind current CAM options, so as to enable senting with primary headaches (27). Also, an open-
informed discussion with their patients. label study comparing the ketogenic diet to a standard
Within the CAM literature, there has been a focus low-calorie diet found that both diets yielded a signifi-
on nutraceutical interventions for headache. Another cant decrease both in BMI and headache frequency
area of interest within the non-pharmacologic headache (28). The only prospective study assessing a weight-
intervention literature pertains to diet interventions. loss diet for migraine recruited obese adolescents with
The present review will provide an overview of the migraine to undergo a 12-month intervention program
current evidence for dietary and nutraceutical interven- involving not only a dietary intervention, but also an
tions for headache in adults and children. aerobic exercise program and cognitive-behavioral
training sessions. In this study, weight loss was asso-
ciated with reductions in migraine frequency, intensity
Methods and disability (29). However, given the multi-interven-
Two separate literature searches were carried out in order tion approach, it is not known if the dietary interven-
to identify studies on the ecacy of dietary or nutraceut- tion played a role in the observed eect. A randomized
ical interviews for primary headache in the pediatric and controlled trial (RCT) is currently under way to assess
adult populations. A variety of search term combinations the ecacy of a behavioral weight-loss treatment pro-
were used in order to identify the largest possible number gram, involving diet alterations, in a sample of over-
of relevant studies. MEDLINE, Embase and EBM weight and obese women with migraine (30). The state
Reviews-Cochrane Central Register of Controlled of the current evidence is very limited in regards to the
Trials were searched to identify studies. Reference lists ecacy of weight-loss interventions for primary head-
of included studies were also scrutinized for pertinent cit- aches. However, the growing interest in the association
ations. Observational studies, intervention studies and of obesity and headache is likely to compel further
systematic reviews of dietary or nutraceutical headache research in this area in the years to come.
therapies were included.
Low-sodium diets for headache
Dietary interventions for headache The potential role for a reduced-sodium diet in
Studies on dietary interventions for primary headache headache has been explored in only one recent study.
disorders are summarized in Table 1. The theoretical impetus for this study pertained to the
association between hypertension and headache, and
the role of a low-sodium diet in reducing blood pres-
Weight-loss diets for headache
sure. In addition, it is well known that monosodium
Headache and obesity are comorbid (15). Migraine has glutamate is a headache trigger for some patients with
a specific association with obesity (15) and metabolic primary headaches (31). A detailed analysis of head-
syndrome (16,17). Furthermore, obese individuals ache occurrence was carried out on data generated
Table 1. Summary of studies on dietary interventions for headache.
1114
Individual studies
Diet Type of studies and design N/patients Intervention Comparison Outcomes

Weight loss Non-randomized Novack et al., 2011 29 obese adult Bariatric surgery N/A After bariatric surgery,
(25): prospective patients with migraine frequency
observational study migraine (p < 0.0001), duration
(p 0.02), medication use
(p 0.005), MIDAS and
HIT-6 scores decreased
(p < 0.005)
Bond et al., 2011 57 severely obese Roux-en-Y gastric bypass or N/A After surgery, headache frequency
(26): prospective adult patients laparoscopic adjustable (p 0.013), severity (p 0.022)
observational study with migraine gastric banding and disability (p 0.003)
decreased
Hershey et al., 2009 913 pediatric patients Routine care, routine dietary N/A In overweight patients (BMI per-
(27): retrospective with a variety of and nutritional counseling centile > 85th), change in BMI at
chart review headache disorders plus discussion about follow-up was positively asso-
health risks of obesity for ciated with change in headache
overweight patients frequency (r 0.32, p 0.01)
Di Lorenzo et al., 2015 96 adult patients with Ketogenic diet with four- Standard low-calorie diet Both the ketogenic and standard
(28): prospective migraine as diagnosed week ketogenesis period, for six months (n 51). diets yielded a reduction in BMI
open-label study by ID-Migraine who eight-week transitional NB: Diet chosen based and both groups had a decrease in
self-referred to a dietician period, followed by on patient preference number of headache days/month
for weight loss standard low-calorie diet (p < 0.0001)
(n 45).
Diet chosen based on patient
preference
Verrotti et al., 2013 135 Caucasian adolescents 12-month program involving N/A Weight, BMI and waist circumference
(29): prospective with migraine and a balanced diet, aerobic (p < 0.01) as well as headache
open-label study BMI > 97th percentile activity and cognitive- frequency (p < 0.01), headache
behavioral therapy group intensity (p < 0.01), use of acute
sessions medications (p < 0.05) and
PedMIDAS scores (p < 0.05) were
significantly reduced at six months
Low-sodium diet RCT Amer et al., 2014 (32): 390 adult patients Dietary Approaches to Stop Control diet with 30-day The low-sodium cross-over
RCT with hypertension Hypertension (DASH) diet cross-over periods of period was associated with
with 30-day cross-over low, moderate and reduced headache occurrence
periods of low, moderate high sodium (n 192) as compared to the high-sodium
and high sodium (n 198) period for both groups
(OR 0.69,
95% CI 0.490.99 and
OR 0.69,
95% CI 0.490.98)
(continued)
Cephalalgia 36(12)
Table 1. Continued.
Orr

Individual studies
Diet Type of studies and design N/patients Intervention Comparison Outcomes

Low-fat diet Quasi- Bic et al., 1999 54 adults with migraine Restriction of dietary fat N/A Significant decrease in migraine fre-
experimental (34): quasi-experimental intake to 20 g/day and quency, intensity, headache index
pre-test/post-test advise to limit caffeine and frequency of medication use
protocol intake for 12-week inter- (p < 0.0001)
vention period
RCT Bunner et al., 2014 42 adults with migraine Low-fat vegan diet for four Placebo (10 mcg linoleic Significant decrease in weight
(35): open-label weeks followed by acid and 10 mcg vitamin E) (p < 0.001), number of headaches
randomized elimination diet for once daily for 16 weeks (p 0.04), severity of worst pain
cross-over study four weeks followed (n 21) (p 0.03) and use of medications
by reintroduction diet (p 0.004) over diet period as
for eight weeks (n 21) compared to placebo period
Elimination diet Non-randomized Egger et al., 1983 (37): 99 children with Oligoantigenic diet with N/A 93% improved greatly or
prospective open-label migraine elimination of multiple recovered completely
study trigger foods in non-indi- on the diet
vidualized manner with
subsequent double-blind
cross-over period invol-
ving reintroduction of
provocative foods
Wantke et al., 1993 28 adults with chronic Histamine-free diet for N/A 68% of patients had a 50% or greater
(38): prospective headaches and a history four weeks reduction in headache frequency
open-label study of food intolerance on the diet, with a decrease from
3.1 " 2.3 to 1.1 " 1.0 headaches/
week (p < 0.001)
Arroyave Hernandez et al., 56 adults with migraine IgG antibodies to food anti- N/A All migraine patients and 15% of
2007 (39): prospective and 56 age- and gens were measured and controls had IgG immunoreactiv-
open-label study gender-matched then culprit foods ity (p < 0.01); 84% of migraine
with matched controls removed from the diet for patients had remission of migraine
controls six months or a decrease in migraine fre-
quency and intensity during the
diet period
RCTs Salfield et al., 1987 39 children with migraine Fiber-rich diet with Fiber-rich diet without Both groups had a significant
(36): RCT exclusion of foods exclusion of foods with reduction in migraine
with vasoactive amines vasoactive amines for eight frequency with no
for eight weeks (n 19) weeks (n 20) difference between
the groups
Alpay et al., 2010 35 adults with migraine IgG antibodies to food IgG antibodies to food During elimination diet phase, attack
(40): cross-over trial without aura antigens were measured antigens were measured count (p < 0.001), headache days
and then culprit foods and then culprit foods (p < 0.001), use of acute medica-
were eliminated for were continued for tions (p < 0.001) and total medi-
six weeks six weeks cation intake (p 0.002) were
reduced significantly
1115

(continued)
Table 1. Continued. 1116
Individual studies
Diet Type of studies and design N/patients Intervention Comparison Outcomes

Mitchell et al., 2011 167 participants with self- IgG antibodies to food IgG antibodies to food No significant difference in the fre-
(41): single-blind, reported migraine-like antigens were measured antigens were measured quency of headaches, MIDAS or
parallel-group RCT headaches and then participants were and then participants were HIT-6 scores between the groups
instructed to remove instructed to remove a
culprit foods for matched number of
12 weeks (n 84) non-culprit foods for
12 weeks (n 83)
Ketogenic diet Non-randomized Schnabel, 1928 (45): 18 adults with migraine Ketogenic diet N/A 50% of patients had some relief in
prospective open-label their headaches over the diet
study period
Barborka, 1930 50 adults with Ketogenic diet for N/A 78% of patients had a response to
(46): prospective migraine three to six months the diet, with 28% having migraine
open-label study remission on the diet
Kossoff et al., 2010 8 adolescents with Modified Atkins diet for N/A No participant had any reduction in
(50): prospective chronic daily headache three months. headache frequency
open-label study Only three participants
completed the
three-month period
Farkas et al., 2014 18 adolescents Ketogenic diet for three N/A 38% of the original sample
(51): prospective with migraine months. had some response to
open-label study Only six participants com- the diet
pleted
the three-month period
Di Lorenzo et al., 2013 108 adult patients Ketogenic diet for one Standard low-calorie diet 90% of patients in the
(52): prospective with migraine month (n 52) for one month (n 56) ketogenic diet group had
open-label study a response in terms of
migraine frequency and reduction
in medication use with no
responders in the standard diet
group
Di Lorenzo et al., 2015 96 adult patients Ketogenic diet with Standard low-calorie diet There was a significant time by
(28): prospective with migraine as diagnosed four-week ketogenesis for six months (n 51). treatment interaction favoring the
open-label study by ID-Migraine who period, eight-week Diet chosen based on ketogenic diet group for clinical
self-referred to a dietician transitional period, patient preference headache variables (p < 0.0001),
for weight loss followed by standard low- with the ketogenic diet group
calorie diet (n 45). having improvement in all head-
Diet chosen based ache variables during the keto-
on patient preference genesis phase (p < 0.0001)
(continued)
Cephalalgia 36(12)
Orr

Table 1. Continued.
Individual studies
Diet Type of studies and design N/patients Intervention Comparison Outcomes

Miscellaneous Non-randomized Dexter et al., 1978 (53): 74 adult patients with Low-sucrose, six-meal diet N/A All patients with diabetic test results
prospective open-label migraine associated plus testing for diabetes had a 75% or greater improve-
study with fasting states with a five-hour 100 g oral ment in their headaches; 63% of
glucose tolerance test those with reactive hypoglycemia
had a 75% or greater improve-
ment and 27% of them had a
5075% improvement in their
headaches
Unge et al., 1983 10 women with migraine Tryptophan-reduced diet for N/A 90% had a reduction in migraine
(54): prospective and cutaneous symptoms a minimum of one month attacks during the diet
open-label study
RCT Spigt et al., 2012 (55): Adults with recurrent Lifestyle counseling and Lifestyle counseling No difference between the groups in
RCT headaches increased dietary water only (n 50) terms of headache frequency or
intake: 1.5 l additional medication usage, but greater
liters of water per day for improvements in Migraine-Specific
three months (n 52) Quality of Life scores were seen
for the intervention group
(p 0.007)
Ramsden et al., 2013 67 adults with chronic Dietary intervention Dietary intervention Both groups had significant improve-
(56): RCT daily headache involving reduction of involving reduction ment in their headaches, but the
omega-6 fatty acids of omega-6 fatty acids reduced omega-6-increased
combined with increased alone for 12 weeks omega-3 diet yielded a better
omega-3 fatty acids for (n 34) response: lower HIT-6 scores
12 weeks (n 33) (p < 0.0001), fewer headache days
(p 0.02) and fewer headache
hours (p 0.01)

RCT: randomized controlled trial; BMI: body mass index; MIDAS: Migraine Disability Assessment; HIT-6: Headache Impact Test-6; Ig: immunoglobulin; OR: odds ratio; CI: confidence interval.
1117
1118 Cephalalgia 36(12)

from the Dietary Approaches to Stop Hypertension


(DASH)-sodium RCT in order to explore the eect of
Elimination diets for headache
dietary sodium on headache. In this trial, adult partici- Dietary triggers are a well-established phenomenon in
pants with hypertension were randomized to the DASH migraine. Several studies have assessed a variety of
diet or a control diet, with each group also having three elimination diets as therapeutic interventions for
30-day cross-over periods to low, moderate and high migraine.
sodium intakes within their assigned diet. The data A small randomized trial evaluated the ecacy of
showed that the odds of reporting a headache in the a high-fiber diet alone vs. a high-fiber diet with elim-
last seven days of the diet were lower while participants ination of foods high in vasoactive amines for
were on the low-sodium diet as compared to the high- migraine prophylaxis in a sample of children and
sodium diet, with no dierence between the DASH diet found no dierence in headache parameters
and the control diet overall (32). This trial was designed between the groups (36). Another study among chil-
to assess blood pressure as a primary outcome, and the dren with migraines assessed the eect of an oligoan-
ascertainment of headache as a secondary outcome was tigenic diet on migraine through elimination of a
suboptimal. However, it does provide a foundation for wide variety of common trigger foods in an unse-
further exploration of the role of low-sodium diets for lected fashion. The vast majority of children (93%)
headache prevention in adults with hypertension. had complete or great improvement on the diet, and
of those who were randomly assigned to reintroduc-
tion of provocative foods, most had relapse of their
Low-fat diets for migraine
headaches (37).
Altering dietary fat intake could eect changes in A few studies have been carried out to assess
migraine patterns given the role that dietary fat com- elimination diets among adult migraineurs. A
position plays in prostaglandin synthesis. sample of 28 patients with chronic headaches were
Prostaglandins are thought to play a role in migraine placed on a histamine-free diet for four weeks, and
pathogenesis through a variety of mechanisms, includ- 68% of the participants had a 50% or greater reduc-
ing their vasoactive eects on cranial arteries and their tion in their headaches (38). Individualized
role in central and peripheral pain sensitization (33). approaches to elimination diets have been employed
Two studies have investigated the role of low-fat in a few studies. One open-label study tested adult
diets for migraine prophylaxis. The first study migraine patients for food reactivity by measuring
employed a quasi-experimental design to assess the e- immunoglobulin (Ig)G antibodies to food antigens
cacy of a low-fat diet in a sample of 54 adults with and then instructed participants to eliminate the cul-
migraine. Participants were instructed to reduce dietary prit foods for six months. Complete or partial head-
fat intake to a maximum of 20 g per day for a 12-week ache response was reported by 84% of the
intervention period and to complete headache diaries. participants after the elimination diet (39). Two
After the intervention, there was a significant decrease RCTs have also taken a targeted approach to elimin-
not only in participant weight and dietary fat intake, ation diets for migraine by measuring IgG antibodies
but also in headache frequency, intensity and use of to food antigens and then randomly assigning partici-
abortive headache medications (34). An open-label, pants to elimination of provocative foods vs. control
randomized cross-over study evaluated the ecacy of conditions. A small cross-over study found a six-week
a low-fat vegan diet combined with an elimination individualized elimination diet to be eective in redu-
protocol to remove trigger foods as compared to pla- cing migraine frequency and medication use as com-
cebo over a 16-week intervention period in a sample of pared to a standard diet (40). These findings were not
adult migraineurs. Only 42 participants were recruited, replicated in a parallel-group trial carried out among
with no a priori sample size calculations, and the par- adults with self-reported migraines, where the indivi-
ticipants were demographically homogeneous, with dualized elimination diet was no dierent from a
mostly Caucasian, highly educated females recruited. sham diet after 12 weeks (41). The null results from
Participants lost an average of 3.6 kg over the dietary this RCT may have been due to methodological prob-
intervention period and had improvement in a number lems with the study, namely the suboptimal selection of
of headache-related outcomes as compared to placebo migraine patients, the lack of compliance monitoring
(35). Given methodological limitations, the lack of and diet education and a high attrition rate. Overall,
detail with regards to how these interventions altered although evidence is limited in quality and quantity, it
dietary fat composition and given the association of the appears that targeted elimination diets for patients with
low-fat diets with weight loss, it is still unclear as to concurrent migraine and food sensitivities may be
whether a simple reduction in dietary fat is ecacious eective for migraine prevention, but further evidence
for migraine. is required.
Orr 1119

(28). Based on the case reports and interventional


The ketogenic diet for headache studies described above, there is some preliminary evi-
In the past couple of decades, there has been a renewed dence to support the use of the ketogenic diet as an
interest in exploring the ketogenic diet for neurological intervention in the motivated adult migraine patient.
diseases. The ketogenic diet yields multiple biochemical Methodologically rigorous studies are needed to con-
changes in the brain that could theoretically aect firm these findings.
migraine propensity (42), including a shift in neuronal
energy states and altered neuronal excitability in the
context of acidosis and ketone body metabolism (43).
Miscellaneous dietary interventions for headache
Interestingly, the ketogenic diet appears to decrease Several other dietary interventions have been explored
cortical spreading depression in the short-term (44), for headache in isolated studies. A low-sucrose diet was
making it plausible that it could have an eect in administered to migraineurs reporting an association
migraine with aura. between migraine attacks and fasting states. A favor-
The first case series reporting use of the ketogenic able response rate was observed among patients found
diet for headache was carried out in 1928. A sample of to have diabetes or reactive hypoglycemia on an oral-
18 migraine patients were treated with an incremental glucose tolerance test (53). A small series of 10 women
ketogenic diet regimen, and half of those patients suering from migraine and cutaneous symptoms con-
had some relief of their condition (45). In 1930, a sistent with food allergy demonstrated improvement in
sample of 50 migraineurs, most of whom had severe their headaches on a tryptophan-reduced diet (54).
and refractory migraines, were followed for a Increased dietary water intake was assessed in an
period of several months on the ketogenic diet. RCT carried out among adult patients with recurrent
Interestingly, 78% of the patients benefitted from the headaches. Though subjective improvement in head-
diet, with 28% of the sample achieving complete remis- ache and disability was observed among the group
sion from their migraines (46). Since then, a few case with increased water intake compared to the standard
reports have indicated promise for the ketogenic diet in intervention group, no dierences were seen when
migraine (4749). assessing headache frequency and other parameters in
The modified Atkins diet, which is similar to the participants headache diaries (55). Finally, based on
ketogenic diet and also results in a state of ketosis, the theory that omega-6 fatty acids are pronociceptive
was administered to a sample of eight adolescents and omega-3 fatty acids are antinociceptive, a group of
with chronic daily headache. Compliance was problem- adult patients with chronic headaches were randomized
atic with only three of the participants completing the to a dietary intervention involving either reduction of
12-week diet, and none of the participants had any omega-6 fatty acids alone or reduction of omega-6 fatty
reduction in migraine frequency over the treatment acids combined with increased omega-three fatty acids.
period (50). Another study among adolescents aimed After 12 weeks of the diet, participants on the high
to administer the ketogenic diet to 18 adolescents omega-3 and low omega-6 diet had greater improve-
with migraine for a three-month treatment period. ment in their headaches as compared to participants
Only 38% of the patients adhered to the ketogenic on the reduced omega-6 diet (56).
diet for the entire treatment period, and some response
to the diet was observed in only 38% of the original Nutraceutical interventions
sample (51). It is therefore dicult to comment on the
ecacy of the ketogenic diet in adolescents because of
for headache
limited evidence and significant compliance issues Table 2 summarizes the evidence for nutraceuticals in
observed in the published studies. the treatment of primary headache disorders.
Two studies have assessed the ecacy of the trad-
itional ketogenic diet for adult migraine prophylaxis Feverfew (Tanacetum parthenium L.)
and have shown encouraging results. The ketogenic
diet was superior to a standard low-calorie diet over a
for migraine
four-week treatment period with a 90% responder rate Feverfew, also known as Tanacetum parthenium L., is a
in a sample of 108 migraine patients (52). A recent medicinal herb that has been used for centuries for a
open-label study, during which 96 migraine patients variety of ailments. Parthenolide, a sesquiterpene lac-
were assigned to either the ketogenic diet or a standard tone, appears to be feverfews active ingredient and has
diet depending on their preference, uncovered an asso- multiple actions in the central nervous system. Several
ciation between migraine relief and ketosis: During the of its properties suggest a potential mechanism of
ketogenic phase of the intervention diet, a significant action in migraine prevention, including evidence to
improvement in headache parameters was observed suggest that parthenolide inhibits Fos-induced
Table 2. Summary of studies on nutraceutical interventions for headache.
Individual
Type of studies and
Nutraceutical studies design N/patients Intervention Comparison Outcomes

Feverfew Systematic Pittler and Ernst, Five RCTs (two parallel- Riboflavin in various Placebo No convincing evidence to
review 2004 (60): Cochrane group, three cross-over) formulations and doses establish feverfews
systematic review of 343 patients efficacy; the two highest
quality RCTs did not show
benefit, and the other
three RCTs did
Non- Cady et al., 2005 30 adults with migraine Gelstat Migraine! N/A 48% of patients achieved two-hour
randomized (61): prospective (combination of feverfew pain freedom and 34% of par-
open-label study and ginger) for acute migraine ticipants had only mild pain at
two hours
Shrivastava et al., 2006 12 adults with migraine Tanacetum parthenium N/A 70% of patients had a 50% or greater
(64): prospective without aura (feverfew) 300 mg reduction in migraine frequency
open-label study Salix alba 300 mg bid
for 12 weeks
RCT Cady et al., 2011 60 adults with migraine Gelstat Migraine! Placebo for acute 32% of Getstat
(62): RCT (combination of feverfew migraine (n 15) Migraine! group vs.
and ginger) for acute 16% of placebo
migraine (n 45) group were pain
free at two hours
(p 0.02)
Maizels et al., 2004 49 adults with migraine Capsules of feverfew 25 mg riboflavin two No difference in the proportion of
(63): RCT 100 mg, magnesium capsules daily as placebo patients achieving a 50% or
300 mg and riboflavin for three months (n 25) greater reduction in migraine
400 mg two capsules frequency (p 0.87)
daily for three
months (n 24)
Ferro et al., 2012 68 women with Tanacetum parthenium Tanacetum parthenium 20 acupuncture sessions Combined feverfew acupuncture
(65): RCT chronic migraine (feverfew) 150 mg (feverfew) 150 mg daily over 10 weeks (n 22) was superior in reducing SF-36
daily and 20 over 10 weeks (n 23) scores (p < 0.05), MIDAS scores
acupuncture sessions (p < 0.05) and mean pain scores
over 10 weeks (n 23) (p < 0.05) as compared to either
treatment alone
Diener et al., 2005 218 adults with Tanacetum parthenium Placebo for 16 Migraine frequency decreased more
(66): RCT migraine (6.25 mg feverfew extract) weeks (n 110) in the intervention group as
CO2 extract (MIG-99) tid compared to placebo (1.9 vs.
for 16 weeks (n 108) 1.3 attacks/month, p 0.0148)

(continued)
Table 2. Continued.
Individual
Type of studies and
Nutraceutical studies design N/patients Intervention Comparison Outcomes

Riboflavin Non- Smith, 1946 (84): 19 adults Riboflavin 5 mg N/A 95% of the patients improved
(vitamin B2) randomized case series with migraine tid for variable on riboflavin
durations
Boehnke et al., 23 adults with Riboflavin 400 mg N/A Migraine frequency decreased from
2004 (85): migraine daily for three mean of four days/month to two
prospective to six months days/month (p < 0.001)
open-label study
Schoenen et al., 44 adults with Riboflavin 400 mg daily (23 N/A Mean improvement of 68.2% in their
1994 (86): migraine of the 44 patients were migraine severity scores, with no
prospective also given aspirin 75 mg difference between those who
open-label study daily) for a minimum of received ASA and those who
three months didnt (no p given)
Sandor et al., 26 adults with Riboflavin 400 mg daily Bisoprolol 10 mg daily or Both groups had a significant
2000 (88): migraine for four months metoprolol 200 mg decrease in headache frequency
prospective daily for four months (p < 0.05), but no difference
open-label study between the groups
Condo et al., 41 children and Riboflavin 200 mg or N/A Significant reduction in headache
2009 (91): adolescents with a 400 mg PO daily for frequency after treatment for
retrospective variety of headache three, four or three or four months
chart review disorders six months (21.7 " 13.7 vs. 13.2 " 11.8,
p < 0.01), which was not sus-
tained at six months (19.3 " 13.4
vs. 11.4 " 9.6, p > 0.05)
Markley, 2009 (92): 32 adolescents with Riboflavin 400 mg N/A 73% of patients had
retrospective chronic daily daily for at least some response to
chart review headache six weeks riboflavin
RCT Schoenen et al., 1998 55 adults with Riboflavin 400 mg Placebo for four Riboflavin lead to a greater reduc-
(89): RCT migraine daily for four months months (n 27) tion in migraine frequency by
(n 28) month 4 (p 0.0001),
NNT 2.8
Nambiar et al., 100 adults with Riboflavin 100 mg Propranolol 80 mg daily The propranolol group had a greater
2011 (90): open- migraine daily for at least for at least reduction in migraine frequency
label RCT three months (n 50) three months (n 50) in first month (p < 0.001), but
there were no group differences
at three and six months
MacLennan et al. 2008 48 children and Riboflavin 200 mg Placebo for 12 No difference between the groups in
(93): RCT adolescents daily for 12 weeks weeks (n 21) terms of the proportion of par-
with migraine (n 27) ticipants with 50% or greater
reduction of migraine frequency
(44.4% of the riboflavin vs 66.6%
of the placebo group, p 0.125)
Bruinj et al., 42 children with Riboflavin 50 mg daily Placebo for four No difference between groups in
2010 (94): cross- migraine for four months months (n 22) terms of change in migraine fre-
over RCT (n 20) quency (p 0.44); the riboflavin
group had a greater reduction in
the frequency of tension-type
headaches as compared to pla-
cebo (p 0.04)

(continued)
Table 2. Continued.
Individual
Type of studies and
Nutraceutical studies design N/patients Intervention Comparison Outcomes

Intravenous magnesium Non- Martinez Cardenas et al., 31 refractory headaches in Intravenous magnesium N/A 51% of headaches improved with
randomized 2012 (97): retrospective 23 admitted children sulfate (MgSO4) with treatment
chart review and adolescents intravenous
diphenhydramine.
Many of the patients received
several doses of MgSO4
Gertsch et al., 20 children with acute Intravenous N/A 77% of the patients treated in the
2014 (98): headache in the ED magnesium ED were admitted for further
retrospective headache management
chart review
Mauskop et al., 1996 40 adult patients with a Intravenous N/A 80% of patients had complete pain
(99): prospective variety of acute MgSO4 1 g relief within 15 minutes
open-label study headache disorders
Mauskop et al., 1995 22 adult patients with Intravenous N/A 60.5% of the infusions resulted in
(100): prospective cluster headache for a MgSO4 1 or 2 g improvement in the headaches
open-label study total of 38 infusions (at least two days headache free)
Systematic Orr et al., 2014 4 RCTs of 247 adult Intravenous MgSO4 1 or 2 g Placebo or Authors concluded that MgSO4 is
review (101): systematic patients with acute metoclopramide likely not effective; one small
review migraine RCT found MgSO4 superior to
placebo, two RCTs found no
difference between placebo and
MgSO4 and one RCT found
MgSO4 inferior to placebo
Choi and Parmar, 2014 5 RCTs of 295 adult Intravenous MgSO4 1 or 2 g Placebo, prochlorperazine Authors concluded that MgSO4
(102): systematic patients with acute or metoclopramide showed no benefit over com-
review and meta-analysis migraine parators; 7% fewer patients on
MgSO4 had headache relief as
compared to comparators in
meta-analysis (95% CI: 0.23 to
0.09)
RCT Shahrami et al., 2015 70 adult patients with Intravenous MgSO4 1 g Intravenous metoclopramide MgSO4 was more effective in
(103): RCT acute migraine 10 mg dexamethasone 8 mg decreasing pain severity 20 min-
utes, one hour and two hours
after treatment than metoclo-
pramide and dexamethasone
(p < 0.0001)

(continued)
Table 2. Continued.
Individual
Type of studies and
Nutraceutical studies design N/patients Intervention Comparison Outcomes

Oral Non- Castelli et al., 40 children with periodic Magnesium pidolate, doses N/A 72.5% of patients had a reduction in
magnesium randomized 1993 (109): syndromes (25 migraine, ranging from 122 to migraine frequency to 33% or
prospective 12 recurrent abdominal 266 mg of elemental less of baseline after one month
open-label study pain, three fever of magnesium for various of treatment
unknown origin) durations
Grazzi et al., 2005 9 children with TTH Magnesium pidolate 2.25 mg N/A Headache frequency decreased at
(112): prospective bid for two months one year in 80% of episodic TTH
open-label study participants and 100% of chronic
TTH participants at 12-month
follow-up and 100% of all par-
ticipants had a reduction in
medication usage by 12 months
Grazzi et al., 2007 45 children and adolescents Magnesium pidolate N/A Headache days (p 0.001), analgesic
(113): prospective with episodic TTH 2.25 mg bid for three consumption (p 0.0001) and
open-label study months. Only 49.1% MIDAS scores (p 0.001)
completed follow-up and decreased significantly at 12-
treatment as planned month follow-up
RCT Facchinetti et al., 1991 20 women with Magnesium pyrrolidone Placebo for two Both groups had reduced pain, with
(104): RCT menstrual migraine carboxylic acid months (n 10) magnesium group having a larger
(360 mg/day) for two decrease in pain magnitude
months (n 10) (p < 0.03); only magnesium
group had less headache days
Koseoglu et al., 2008 40 adults with migraine Magnesium citrate Placebo for three The magnesium group had a lower
(105): RCT without aura 1830 mg (295.7 mg months (n 10) median post-/pre-treatment
elemental) PO bid for attack frequency ratio (0.55 vs.
three months (n 30) 1.00, p 0.005)
Esfanjani et al., 2012 133 adults with Magnesium oxide L-carnitine 500 mg Magnesium oxide No treatment Statistically significant reduction in
(106): single- migraine 500 mg PO daily PO daily for three 500 mg PO daily for three all groups except for the no
blind RCT or similar for three months (n 35) L-carnitine months treatment group (p < 0.001 for
headaches months (n 33) 500 mg PO for (n 35) all); after post-hoc analyses, only
three months the magnesium group as com-
(n 30) pared to the no treatment group
had a greater reduction
(p < 0.006)
Peikert et al., 1996 81 adults with migraine Tri-magnesium dicitrate Placebo for three Greater reduction in
(107): RCT 600 mg daily for months (n 38) migraine frequency in
three months (n 43) the magnesium group
as compared to the
placebo group
(41.6% vs. 15.8%,
p 0.0303)

(continued)
Table 2. Continued.
Individual
Type of studies and
Nutraceutical studies design N/patients Intervention Comparison Outcomes

Pfaffenrath et al., 1996 69 adults with migraine Magnesium L-aspartate- Placebo for three No difference in proportion of
(108): RCT without aura hydrochloride- months (n 34) patients with 50% or greater
trihydrate 10 mmol reduction in duration or intensity
(121.5 mg elemental) of migraines (28.6% of the mag-
PO twice daily for nesium group vs. 29.4% of the
three months (n 35) placebo group)
Wang et al., 2003 118 children and adolescents Magnesium oxide containing Placebo for four Both groups had a downward trend
(110): RCT with headaches 9 mg/kg of elemental months (n 60) in headache days, with only the
suggestive of migraine magnesium PO tid for magnesium group sustaining the
four months (n 58) trend past six weeks; no signifi-
cant difference between groups
after regression analyses
(p 0.88)
Gallelli et al., 2014 160 children and Magnesium 400 mg Magnesium 400 mg Acetaminophen 15 mg/kg Ibuprofen 10 mg/kg to Treatment with magnesium reduced
(111): single-blind RCT adolescents with daily acetaminophen daily ibuprofen to be taken with acute be taken with acute migraine pain intensity acutely when
migraine without aura 15 mg/kg to be taken 10 mg/kg migraine episodes for up episodes for up to combined with acetaminophen
with acute migraine to be taken with to 18 months (n 40) 18 months (n 40) or ibuprofen (p < 0.01) and
episodes for up to acute migraine resulted in a reduction of
18 months (n 40) episodes for up migraine frequency (p < 0.01)
to 18 months (n 40)
Coenzyme Q10 Non- Rozen et al., 2002 32 adults with Coenzyme Q10 150 mg N/A 61.3% of patients had 50% or greater
randomized (114): prospective open- migraine daily for three months reduction in migraine attack
label study frequency
Hershey et al, 2007 252 children and Coenzyme Q10 N/A Significantly less headache days/
(116): prospective open- adolescents with 13 mg/kg daily for month after treatment period
label study migraine and average of three months (19.2 " 9.8 vs. 12.5 " 10.8,
coenzyme Q10 p < 0.01)
deficiency
RCT Sandor et al., 2005 43 adults with Coenzyme Q10 100 mg Placebo for four Coenzyme Q10 group had a greater
(115): RCT migraine tid for four months months (n 21) reduction in migraine attack fre-
(n 22) quency compared to placebo (
1.19 " 1.9 vs. 0.09 " 1.9,
p 0.05)
Slater et al., 2011 120 children and Coenzyme Q10 100 mg Placebo for four Significant reduction in
(117): cross-over, adolescents with daily for four months months (n 60) headache frequency in
add-on RCT migraine (n 60) both groups, but repeated-
measures ANOVA failed to
show a time $ condition
interaction (p > 0.05)

(continued)
Table 2. Continued.
Individual
Type of studies and
Nutraceutical studies design N/patients Intervention Comparison Outcomes

Miscellaneous Non- Wagner et al., 1997 168 adults with W-linolenic acid a- N/A Significant reduction in migraine
randomized (118): prospective open- migraine linolenic acid 1800 mg frequency in 86% of patients
label study vitamin B6, niacin D-a-
tocopherol b-carotene
various other lifestyle
interventions for six months
DAndrea et al., 2009 50 women with migraine 60 mg ginkgo biloba N/A Migraine frequency decreased sig-
(122): prospective with aura terpenes phytosome 11 mg nificantly from 3.7 " 2.2 to
open-label study coenzyme Q10 8.7 mg vitamin 2.0 " 1.9 attacks per month
B2 for four months (p < 0.05)
Esposito and Carotenuto, 119 children with Ginkgolide B coenzyme N/A Migraine frequency decreased from
2011 (123): prospective migraine without aura Q10 riboflavin magnesium 9.71 " 4.33 to 4.53 " 3.96
open-label study bid for three months (p < 0.001)
(doses unspecified)
Esposito et al., 2012 374 children with Ginkgolide B 80 mg, L-tryptophan 250 mg, Greater reduction in migraine fre-
(124): prospective open- migraine without aura coenzyme Q10 20 mg, 5-hydroxy-tryptophan 50 mg, quency in ginkgolide group com-
label study riboflavin 1.6 mg magnesium vitamin PP 9 mg vitamin pared to other group
300 mg for six months (n 187) B6 1 mg for (9.128 " 2.842 to 1.734 " 1.231
six months (n 187) vs. 8.78 " 2.512 to
3.032 " 1.072)
Usai et al., 2010 24 children and Ginkgolide B 80 mg coenzyme N/A Migraine frequency decreased from
(125): prospective adolescents with migraine Q10 20 mg vitamin B2 7.4 " 5 to 2.2 " 2.8 attacks/
open-label study without aura 1.6 mg magnesium month (p 0.0015)
300 mg for three months
RCT Pradalier et al., 2001 196 adults with Omega-3 polyunsaturated fatty Placebo for four No difference in migraine frequency
(119): RCT migraine acid 6 g daily for months (n 96) when comparing omega-3 group
four months (n 100) to placebo (1.20 " 1.4 vs.
1.26 " 1.11, NS)
Harel et al., 2002 27 adolescents Marine n3-ethyl ester concentrate Placebo (oleic acid 691 mg, Significant reduction in migraine
(120): cross-over RCT with migraine (EPA 378 mg, DHA 249 mg and palmitic acid 106 mg, linoleic acid frequency for both groups but no
tocopheral 2 mg) 1 g two capsules 62 mg and tocopherol 2 mg) significant difference between
daily for two months 1 g two capsules PO daily for the groups (mean number of
two months migraines during treatment
4 " 1/month for both groups)

MgSO4: intravenous magnesium sulfate ASA: acetylsalicylic acid; PO: orally; bid: twice daily; tid: three times daily; ED: emergency department; RCT: randomized controlled trial; EPA: eicosapentaenoic acid; DHA:
docosahexaenoic acid; ANOVA: analysis of variance; TTH: tension-type headache; MIDAS: Migraine Disability Assessment; CI: confidence interval; NA: not available; NS: not significant.
1126 Cephalalgia 36(12)

activation of the nucleus trigeminalis caudalis (57), a results reviewed elsewhere (67,70,71), increasing con-
nucleus central to migraine pathogenesis, and evidence cerns about its safety are emerging. Butterbur contains
for partial agonist activity of parthenolide at TRPA1 hepatotoxic compounds by the name of pyrrolizidine
channels (58), which have been implicated in migraine alkaloids. Many of the butterbur formulations avail-
pathogenesis (59). able on the market contain detectable and potentially
Feverfew is one of the best-studied nutraceutical hazardous levels of these compounds (72). Petadolex! ,
agents for migraine prophylaxis in adults. A 2004 a formulation of butterbur that is marketed for its
Cochrane review identified five RCTs on this topic. safety based on undetectable levels of pyrrolizidine
The studies were quite heterogeneous in terms of quality alkaloids, has traditionally been the formulation of
and methodology, with notable variations in feverfew butterbur that is used clinically. Initial data suggested
dosages. Results from the trials were mixed with regards that Petadolex! is safe for use in animals and humans
to the ecacy of feverfew: Whereas the two highest (73). However, cases of hepatotoxicity linked to
quality trials were negative, the other three trials sug- Petadolex! have been reported post-marketing and
gested that feverfew is eective in migraine prophylaxis. some regulatory authorities, namely European autho-
Feverfew was well tolerated in all five studies. The rities including the Swiss Agency for Therapeutic
authors concluded that the evidence available was Products and the German Federal Institute of
unconvincing for feverfews ecacy in migraine (60). Medical Devices, have banned its use (74). Therefore,
Since the Cochrane review, six new studies have been uncertainty about the safety of Petadolex! precludes
published. Five of these studies involved combinations recommendations for its use based on recent data.
of feverfew with other active interventions: One open-
label study and one RCT have suggested that a combin-
Riboflavin (vitamin B2) for migraine
ation of feverfew and ginger might be eective for acute
migraine relief (61,62), an RCT found no dierence Riboflavin is a vitamin that plays an important role in
between placebo and a combination of feverfew, mag- cellular energy production through its two active coen-
nesium and riboflavin for migraine prophylaxis (63), a zyme forms that are involved in oxidation-reduction
small open-label study demonstrated promise for a com- reactions during a variety of cellular processes (75).
bination of feverfew and Salix alba in the prevention of Given evidence hinting at mitochondrial energy deple-
migraine with aura (64) and finally a randomized trial tion in migraine (7683), riboflavins essential role in
found a combination of feverfew and acupuncture to be mitochondrial energy metabolism suggests that it
superior to either intervention alone for chronic could be eective in treating migraine.
migraine (65). A methodologically rigorous RCT com- Riboflavin has demonstrated ecacy and tolerability
paring a formulation of feverfew to placebo has also for migraine prevention in adults based on a case series
been published since the Cochrane review, and sug- (84) and several open-label studies (8588). One small
gested that feverfew is superior to placebo for migraine RCT found riboflavin to be superior to placebo for
prophylaxis in adults (66). In 2012, the American migraine prophylaxis in a sample of 55 adult migrain-
Academy of Neurology (AAN) concluded that feverfew eurs (89). Riboflavin was comparable to propranolol
is probably eective for migraine prevention based on after three months and six months of administration
level B evidence (67). Based on the state of the evidence, in an RCT assessing its ecacy for adult migraine
it appears that feverfew might be eective for prophylaxis (90). Another RCT among adults with
migraine prophylaxis in adults, but the heterogeneity migraine explored the ecacy of high-dose riboflavin,
of the literature, especially with regards to feverfew combined with feverfew and magnesium as compared
preparations and dosages, makes definite conclusions to low-dose riboflavin and found that both interven-
challenging. tions yielded modest responder rates (63). All of the
available studies indicate that riboflavin is well
tolerated among adults with migraine. The AAN has
Butterbur (Petasites hybridus) for migraine
determined that riboflavin is probably eective for
Butterbur is a shrub with a long history of use for medi- migraine prophylaxis based on B-level evidence (67).
cinal purposes. It demonstrates a variety of properties Therefore, studies on the ecacy of riboflavin are con-
that render it a candidate for migraine prophylaxis, sistent in their findings and suggest that riboflavin is
including anti-inflammatory action through inhibition well tolerated and ecacious for adult migraine
of cyclooxygenase-2 (68) and vasodilatory eects prophylaxis.
through inhibition of L-type voltage-gated calcium Riboflavin has also been studied in the pediatric
channels (69). population, but results are conflicting. A retrospective
Although butterbur has been studied for migraine case series among children with a variety of headache
prophylaxis both in adults and children with promising disorders found riboflavin to be eective in the first
Orr 1127

three months of treatment, but ecacy appeared to sample size (N 70) relative to the rest of the literature,
wane over time and results were not sustained beyond this study is unlikely to change conclusions about the
three months (91). Another retrospective case series ecacy of MgSO4 for acute migraine relief.
that similarly investigated the role of riboflavin for Oral magnesium supplementation has been studied
the prophylaxis of a variety of headache disorders for adult and pediatric migraine prevention. In a
found that adolescents with chronic migraine, but not sample of women with low magnesium levels, magne-
other headache disorders, responded well to riboflavin sium was superior to placebo for menstrual migraine
(92). An underpowered RCT found no dierence prophylaxis (104). Three separates RCTs with varying
between riboflavin and placebo for pediatric migraine methodologies, comparison groups, magnesium
prophylaxis after 12 weeks of treatment (93). A small dosages and formulations have found oral magnesium
cross-over RCT using a lower dose of riboflavin as to be eective for migraine prophylaxis in adults
compared to previous studies found that children had (105107). Another RCT contradicted these findings
a reduction in the number of tension-type headaches and found oral magnesium to be no dierent from pla-
(TTHs), but not migraines, on riboflavin (94). In the cebo on interim analysis in a sample of refractory
pediatric population, riboflavin lacks adequately pow- migraine patients and thereby halted recruitment
ered and methodologically rigorous studies. Although prior to achieving the planned sample size (108). The
preliminary results are disappointing, further studies AAN guidelines conclude that magnesium is probably
should explore the ecacy of riboflavin in this eective for migraine prophylaxis in adults based on
population. level-B evidence (67). Three studies have assessed mag-
nesium prophylaxis for pediatric migraine. One open-
label study found oral magnesium supplementation to
Magnesium for migraine
be beneficial in a variety of childhood periodic syn-
Magnesium is ubiquitous in the human body and plays an dromes (109). A small RCT found a significant down-
important role in a multitude of biological processes, ward trend in headache frequency for children treated
some of which are linked to migraine pathogenesis (95). with magnesium but not with placebo (110). Finally, an
There is a large body of evidence, reviewed elsewhere (96), RCT found that daily oral magnesium had a synergistic
that points to a state of magnesium deficiency among eect with acetaminophen or ibuprofen in achieving
migraineurs. There is therefore a plausible biological better acute pain relief than either analgesic alone and
reason to explore magnesium as a migraine intervention. also found magnesium to be eective in reducing
Intravenous magnesium sulfate (MgSO4) has been migraine frequency (111). These magnesium studies
used to treat acute headaches. Two retrospective case have consistently uncovered minor gastrointestinal
series among children with acute headaches contra- side eects associated with oral magnesium, namely
dicted each other with regards to conclusions on the soft stools and diarrhea, but no major magnesium-
ecacy of intravenous magnesium for acute headache associated adverse events. The balance of evidence
relief (97,98). In adults, open-label studies have shown seems to be in favor of oral magnesium for migraine
promise for intravenous MgSO4 in acutely relieving prophylaxis, but further research should be carried out
various headache types (99) and cluster headache in in order to confirm these findings and assess dierential
patients with low magnesium levels (100). A recent sys- ecacy based on baseline magnesium levels, given that
tematic review of published trials identified four eligible magnesium-deficient patients would intuitively benefit
RCTs on the ecacy of MgSO4 for migraine relief in more from supplementation or increased dietary intake
adults, and results were heterogeneous, with one small of magnesium.
trial finding MgSO4 superior to placebo, two trials find- In addition to the evidence for oral magnesium
ing no dierence between placebo and MgSO4 in terms prophylaxis in migraine, two studies have assessed its
of the primary outcome and one trial finding MgSO4 ecacy in pediatric TTH. In a prospective case series of
inferior to placebo. The authors concluded that intra- nine pediatric patients with tension-type headaches,
venous MgSO4 is not likely to be eective for acute oral magnesium appeared to be quite eective for the
migraine relief (101). Similar conclusions were reached majority of the patients (112). The same author group
in a recent meta-analysis on the same topic (102). Since later carried out a larger prospective study in 45 pedi-
publication of these reviews, one further RCT has been atric TTH patients, and found magnesium to be eect-
published. In this trial, 1 g of intravenous MgSO4 was ive among the patients completing follow-up as
superior to a combination of 10 mg of metoclopramide prescribed (113). These preliminary results are promis-
and 8 mg of dexamethasone for acute migraine relief in ing but studies with more rigorous designs should be
adults (103). Given the relatively low doses of metoclo- carried out prior to making recommendations on the
pramide and dexamethasone, as well as the small use of magnesium for pediatric TTH.
1128 Cephalalgia 36(12)

(122) and children (123125) based on open-label stu-


Coenzyme Q10 for migraine dies. However, the methodologic limitations and het-
Coenzyme Q10 acts as an electron carrier in the mito- erogeneity of the compounds studied make the evidence
chondrial electron transport chain and therefore plays dicult to apply to clinical recommendations. Relief of
an important role in cellular energy metabolism. cluster headache with intranasal capsaicin has been
Hence, similarly to riboflavin, its potential mechanism documented in several studies, reviewed elsewhere
of action in migraine would relate to the evidence (126). In addition, limited studies have been carried
that migraine results in mitochondrial energy deficiency out to assess the ecacy of a variety of other nutraceut-
(7683). icals for headache (127), including phytoestrogens for
In a small open-label prospective study, four months menstrual migraine, caeine for migraine and a variety
of treatment with coenzyme Q10 showed promising of topical botanical therapies for headache.
results for the prophylaxis of migraine in adults, with
no significant side eects observed (114). An RCT later
Conclusions
found coenzyme Q10 to be superior to placebo in a
small sample of adults with migraine, with one patient Perhaps in response to the growth of the CAM
in the coenzyme Q10 group reporting a cutaneous industry, an increasing number of studies are exploring
allergy (115), but no other notable side eects. Based the role of CAM for headache. In this review, the cur-
on the adult data, the AAN concludes that coenzyme rent state of evidence for dietary and nutraceutical
Q10 is possibly eective for migraine prophylaxis in interventions in headache disorders is described.
adults based on level C evidence (67). An open-label Several interventions show promise as potential
study among pediatric migraineurs found a favorable headache treatments, although the limited number of
response to coenzyme Q10 among patients with low adequately powered studies and low quality of the evi-
coenzyme Q10 levels at baseline (116). The same dence have made it dicult to apply the findings to
group later carried out a cross-over RCT in a sample routine clinical practice. Because of limited data, cau-
of pediatric patients and did not find any notable dif- tion needs to be taken when considering use of these
ferences between the treatment periods with coenzyme interventions in clinical practice.
Q10 as compared to placebo (117). The study was lim- When discussing nutraceuticals with patients, several
ited by a small sample size in the context of a high issues need to be considered. Patients tend to perceive
drop-out rate, and the authors did not selectively herbal supplements as safe for a variety of reasons,
treat patients with low baseline coenzyme Q10 levels. including their non-prescription availability, and their
Overall, it seems that coenzyme Q10 might be eective natural properties (128). However, as with pharmaceut-
and safe for migraine prophylaxis, but future high- ical agents, physicians must be aware of potential
quality studies that take into consideration baseline toxicities and side eects when counseling patients
coenzyme Q10 levels should be endeavored. about these interventions. In fact, society would benefit
from nutraceuticals being conceptualized, scrutinized
and regulated in the same manner as pharmaceuticals,
Miscellaneous nutraceuticals for headache
given that they have the potential for both similar e-
Although the nutraceuticals described above demon- cacy and harm. The case of butterbur illustrates the
strate the most promise in headache management, need for ongoing caution and long-term monitoring
several other agents have been investigated in smaller of safety data in relation to nutraceuticals.
numbers of studies or with lower-quality evidence. Nonetheless, several of the dietary and nutraceutical
Supplements of polyunsaturated fatty acids (PUFAs) interventions above warrant further investigation
do not appear to be eective for migraine prophylaxis given promising preliminary ecacy and safety data.
(70). The evidence for their use in migraine derives from When considering CAM therapies for patients with
one open-label study finding improvement in adult headache disorders, several factors must be weighed.
migraine with a multi-pronged intervention including As highlighted above, the quality of the evidence for
PUFAs (118), two RCTs finding no dierence in e- ecacy and tolerability should be at the forefront of the
cacy comparing PUFAs to placebo in adults (119) and decision-making process. In addition, headache practi-
adolescents (120) and one RCT, with unblinded tioners should consider patient comorbidities, as some
patients, finding that addition of PUFAs to sodium of the CAM therapies have been used in other circum-
valproate resulted in greater reduction in migraine stances and may therefore oer a twofold benefit.
frequency after one month of treatment, which was For example, patients with menstrual migraine and pre-
not sustained after three months (121). Ginkgolide B, menstrual syndrome may experience relief of both
in combination with a variety of other nutraceutical conditions with magnesium, phytoestrogens or ginkgo-
agents, appears to improve migraine status in adults lide B (129). In this way, clinicians need to weigh the
Orr 1129

risks and benefits from the evidence, and consider indi- patient. In one study, patients seeing general practi-
vidual patient characteristics and preferences when tioners with additional CAM training had lower
prescribing CAM, in the same manner as is currently health care costs and lower mortality as compared to
the standard with pharmacological interventions. patients seeing general practitioners without additional
Given the prevalence of CAM use among patients CAM training (130). Thus, physicians who are edu-
with headaches, it is imperative that practitioners cated about CAM may provide better care to their
develop an understanding of CAM therapies and the patients. Hence, we owe it to our patients to become
state of evidence for their use. At a minimum, know- engaged in this area and to advocate for high-quality
ledge of CAM allows the practitioner to engage in edu- intervention studies, where justified by plausible mech-
cated discussions about the ecacy and safety of CAM anisms of action and preliminary data, that will allow
and is likely to foster information sharing and shared us to better comment on the safety and ecacy of these
decision making between the practitioner and the interventions.

Clinical implications
. A majority of patients with primary headache disorders have explored complementary and alternative
medicines (CAM) for headache relief.
. In this article, an overview of the evidence for dietary and nutraceutical headache interventions is provided.
. A growing number of studies are assessing nutraceutical and diet interventions for headache.
. Several dietary and nutraceutical interventions have been studied for headache, with limitations in the
number of studies and the quality of the evidence.
. Further evidence is required to further explore the safety and ecacy of some of the more promising dietary
and nutraceutical headache interventions.

Declaration of conflicting interests medicine: Guidelines for future research. BMC


The authors declared no potential conflicts of interest with Complement Altern Med 2014; 14: 46.
respect to the research, authorship, and/or publication of this 7. Briggs J and Killen J. Perspectives on complementary
article. and alternative medicine research. JAMA 2013; 310:
6913692.
8. von Peter S, Ting W, Scrivani S, et al. Survey on the use of
Funding complementary and alternative medicine among patients
The authors received no financial support for the research, with headache syndromes. Cephalalgia 2002; 22: 395400.
authorship and/or publication of this article. 9. Karakurum Goksel B, Coskun O, Ucler S, et al. Use of
complementary and alternative medicine by a sample of
Turkish primary headache patients. Agri 2014; 26: 107.
References
10. Kristoffersen ES, Aaseth K, Grande RB, et al. Self-
1. US National Library of Medicine. Complementary reported efficacy of complementary and alternative
and Alternative Medicine, http://www.nlm.nih.gov/tsd/ medicine: The Akershus study of chronic headache.
acquisitions/cdm/subjects24.html (2010, accessed 28 J Headache Pain 2013; 14: 36.
March 2015). 11. Gaul C, Schmidt T, Czaja E, et al. Attitudes towards
2. Nahin RL, Barnes P, Stussman B, et al. Costs of comple- complementary and alternative medicine in chronic pain
mentary and alternative medicine (CAM) and frequency of syndromes: A questionnaire-based comparison between
visits to CAM practitioners: United States, 2007. Natl primary headache and low back pain. BMC
Health Stat Report 2009; 114. Complement Altern Med 2011; 11: 18.
3. Su D and Li L. Trends in the use of complementary and 12. Rossi P, Di Lorenzo G, Malpezzi MG, et al. Prevalence,
alternative medicine in the United States: 20022007. pattern and predictors of use of complementary and
J Health Care Poor Underserved 2011; 22: 296301. alternative medicine (CAM) in migraine patients attend-
4. Barnes PM, Bloom B and Nahin R. Complementary ing a headache clinic in Italy. Cephalalgia 2005; 25:
and alternative medicine use among adults and 493506.
children: United States, 2007. Natl Health Stat Report 13. Dalla Libera D, Colombo B, Pavan G, et al. Complemen-
2008; 12: 123. tary and alternative medicine (CAM) use in an Italian
5. Shmueli A and Shuval J. Use of complementary and alter- cohort of pediatric headache patients: The tip of the ice-
native medicine in Israel: 2000 vs. 1993. Isr Med Assoc J berg. Neurol Sci 2014; 35(Suppl 1): 145148.
2004; 6: 38. 14. Bethell C, Kemper KJ, Gombojav N, et al. Complemen-
6. Fischer FH, Lewith G, Witt CM, et al. High prevalence tary and conventional medicine use among youth with
but limited evidence in complementary and alternative recurrent headaches. Pediatrics 2013; 132: e1173e1183.
1130 Cephalalgia 36(12)

15. Chai NC, Scher AI, Moghekar A, et al. Obesity and 34. Bic Z, Blix G, Hopp H, et al. The influence of a
headache: Part IA systematic review of the epidemi- low-fat diet on incidence and severity of migraine head-
ology of obesity and headache. Headache 2014; 54: aches. J Womens Health Gend Based Med 1999; 8:
219234. 623630.
16. Winsvold BS, Sandven I, Hagen K, et al. Migraine, head- 35. Bunner AE, Agarwal U, Gonzales JF, et al. Nutrition
ache and development of metabolic syndrome: An 11- intervention for migraine: A randomized crossover trial.
year follow-up in the Nord-Trndelag Health Study J Headache Pain 2014; 15: 19.
(HUNT). Pain 2013; 154: 13051311. 36. Salfield S, Wardley B, Houlsby W, et al. Controlled study
17. Guldiken B, Guldiken S, Taskiran B, et al. Migraine in of exclusion of dietary vasoactive amines in migraine.
metabolic syndrome. Neurologist 2009; 15: 5558. Arch Dis Child 1987; 62: 458460.
18. Bigal ME, Liberman JN and Lipton RB. Obesity and 37. Egger J, Carter C, Wilson J, et al. Is migraine food
migraine: A population study. Neurology 2006; 66: 545550. allergy? A double-blind controlled trial of oligoantigenic
19. Peterlin BL, Tietjen GE, Gower BA, et al. Ictal adiponec- diet treatment. Lancet 1983; 15: 865869.
tin levels in episodic migraineurs: A randomized pilot 38. Wantke F, Gotz M and Jarisch R. Histamine-free diet:
trial. Headache 2013; 53: 474490. Treatment of choice for histamine-induced food intoler-
20. Peterlin BL, Alexander G, Tabby D, et al. Oligomeriza- ance and supporting treatment for chronical headaches.
tion state-dependent elevations of adiponectin in chronic Clin Exp Allergy 1993; 23: 982985.
daily headache. Neurology 2008; 70: 19051911. 39. Arroyave Hernandez C, Echavarra Pinto M and
21. Dearborn JL, Schneider ALC, Gottesman RF, et al. Adi- Hernandez Montiel HL. Food allergy mediated by IgG
ponectin and leptin levels in migraineurs in the Athero- antibodies associated with migraine in adults. Rev Allerg
sclerosis Risk in Communities Study. Neurology 2014; 83: Mex 2007; 54: 162168.
22112218. 40. Alpay K, Ertas M, Orhan EK, et al. Diet restriction in
22. Chai N, Bond D, Moghekar A, et al. Obesity and head- migraine, based on IgG against foods: A clinical double-
ache: Part IIPotential mechanism and treatment con- blind, randomised, cross-over trial. Cephalalgia 2010; 30:
siderations. Headache 2014; 54: 459471. 829837.
23. Sinclair AJ, Burdon MA, Nightingale PG, et al. Low 41. Mitchell N, Hewitt CE, Jayakody S, et al. Randomised
energy diet and intracranial pressure in women with idio- controlled trial of food elimination diet based on IgG
pathic intracranial hypertension: Prospective cohort antibodies for the prevention of migraine like headaches.
study. BMJ 2010; 340: c2701. Nutr J 2011; 10: 85.
24. Newborg B. Pseudotumor cerebri treated by rice-reduc- 42. Maggioni F, Margoni M and Zanchin G. Ketogenic diet
tion diet. Arch Intern Med 1974; 133: 802. in migraine treatment: A brief but ancient history.
25. Novack V, Fuchs L, Lantsberg L, et al. Changes in head- Cephalalgia 2011; 31: 11501151.
ache frequency in premenopausal obese women with 43. Sinha SR and Kossoff EH. The ketogenic diet.
migraine after bariatric surgery: A case series. Neurologist 2005; 11: 161170.
Cephalalgia 2011; 31: 13361342. 44. de Almeida Rabello Oliveira M, da Rocha Atade T, de
26. Bond DS, Vithiananthan S, Nash JM, et al. Improvement Oliveira SL, et al. Effects of short-term and long-term
of migraine headaches in severely obese patients after treatment with medium- and long-chain triglycerides
bariatric surgery. Neurology 2011; 76: 11351138. ketogenic diet on cortical spreading depression in young
27. Hershey AD, Powers SW, Nelson TD, et al. Obesity in rats. Neurosci Lett 2008; 434: 6670.
the pediatric headache population: A multicenter study. 45. Schnabel T. An experience with a ketogenic dietary in
Headache 2009; 49: 170177. migraine. Ann Intern Med 1928; 2: 3412347.
28. Di Lorenzo C, Coppola G, Sirianni G, et al. Migraine 46. Barborka CJ. Migraine: Results of treatment by keto-
improvement during short lasting ketogenesis: A proof- genic diet in fifty cases. JAMA 1930; 95: 18251828.
of-concept study. Eur J Neurol 2015; 22: 170177. 47. Strahlman R. Can ketosis help migraine sufferers? A case
29. Verrotti A, Agostinelli S, Dinelli SD, et al. Impact of a report. Headache 2006; 46: 182.
weight loss program on migraine in obese adolescents. 48. Di Lorenzo C, Curra A, Sirianni G, et al. Diet transiently
Eur J Neurol 2013; 20: 394397. improves migraine in two twin sistersse Possible role of
30. Bond DS, Leary KCO, Thomas JG, et al. Can weight loss ketogenesis? Funct Neurol 2013; 28: 305308.
improve migraine headaches in obese women? Rationale 49. Urbizu A, Cuenca-Le0n E, Raspall-Chaure M, et al. Par-
and design of the WHAM randomized controlled trial. oxysmal exercise-induced dyskinesia, writers cramp,
Contemp Clin Trials 2014; 35: 133144. migraine with aura and absence epilepsy in twin brothers
31. Scopp AL. MSG and hydrolyzed vegetable protein with a novel SLC2A1 missense mutation. J Neurol Sci
induced headache: Review and case studies. Headache 2010; 295: 110113.
1991; 31: 107110. 50. Kossoff EH, Huffman J, Turner Z, et al. Use of the
32. Amer M, Woodward M and Appel LJ. Effects of dietary modified Atkins diet for adolescents with chronic daily
sodium and the DASH diet on the occurrence of head- headache. Cephalalgia 2010; 30: 10141016.
aches: Results from randomised multicentre DASH- 51. Farkas M, Mak E, Richter E, et al. EHMTI-0336. Meta-
Sodium clinical trial. BMJ Open 2014; 4: 17. bolic diet therapy in the prophylactic treatment of
33. Antonova M, Wienecke T, Olesen J, et al. Prostaglandins migraine headache in adolescents by using ketogenic
in migraine: Update. Curr Opin Neurol 2013; 26: 269275. diet. J Headache Pain 2014; 15(Suppl 1): 12.
Orr 1131

52. Di Lorenzo C, Coppola G, Sirianni G, et al. Short adults: Report of the Quality Standards Subcommittee
term improvement of migraine headaches during ketogenic of the American Academy of Neurology and the Ameri-
diet: A prospective observational study in a dietician clin- can Headache Society. Neurology 2012; 78: 13461353.
ical setting. J Headache Pain 2013; 14(Suppl 1): P219. 68. Fiebich B, Grozdeva M, Hess S, et al. Petasites hybridus
53. Dexter J, Roberts J and Byer J. The five hour glucose extracts in vitro inhibit COX-2 and PGE2 release by
tolerance test and effect of low sucrose diet in migraine. direct interaction with the enzyme and by preventing
Headache 1978; 18: 9194. p42/44 MAP kinase activation in rat primary microglial
54. Unge G, Malmgren R, Olsson P, et al. Effects of dietary cells. Planta Med 2005; 71: 1219.
protein-tryptophan restriction upon 5-HT uptake by 69. Wang G, Shum A, Lin Y, et al. Calcium channel block-
platelets and clinical symptoms in migraine-like head- ade in vascular smooth muscle cells: Major hypotensive
ache. Cephalalgia 1983; 3: 213218. mechanism of S-petasin, a hypotensive sesquiterpene
55. Spigt M, Weerkamp N, Troost J, et al. A from Petasites formosanus. J Pharmacol Exp Ther 2001;
randomized trial on the effects of regular water intake 297: 240246.
in patients with recurrent headaches. Fam Pract 2012; 70. Orr SL and Venkateswaran S. Nutraceuticals in the
29: 370375. prophylaxis of pediatric migraine: Evidence-based
56. Ramsden C, Faurot K, Zamora D, et al. Targeted alter- review and recommendations. Cephalalgia 2014; 34:
ation of dietary n-3 and n-6 fatty acids for the treatment 568583.
of chronic headaches: A randomized trial. Pain 2013; 154: 71. Pringsheim T, Davenport W, Mackie G, et al. Canadian
122. Headache Society guideline for migraine prophylaxis.
57. Tassorelli C, Greco R, Morazzoni P, et al. Parthenolide is Can J Neurol Sci 2012; 39(2 Suppl 2): 162.
the component of tanacetum parthenium that inhibits 72. Avula B, Wang YH, Wang M, et al. Simultaneous deter-
nitroglycerin-induced Fos activation: Studies in an mination of sesquiterpenes and pyrrolizidine alkaloids
animal model of migraine. Cephalalgia 2005; 25: 612621. from the rhizomes of Petasites hybridus (L.) G.M. et
58. Materazzi S, Benemei S, Fusi C, et al. Parthenolide inhi- Sch. and dietary supplements using UPLC-UV and
bits nociception and neurogenic vasodilatation in the tri- HPLC-TOF-MS methods. J Pharm Biomed Anal 2012;
geminovascular system by targeting TRPA1 channel. 7053:2;rm.
Pain 2013; 154: 120. 73. Danesch U and Rittinghausen R. Safety of a patented
59. Benemei S, Fusi C, Trevisan G, et al. The TRPA1 special butterbur root extract for migraine prevention.
channel in migraine mechanism and treatment. Br J Headache 2003; 43: 7678.
Pharmacol 2014; 171: 25522567. 74. Prieto JM. Update on the efficacy and safety of
60. Pittler M and Ernst E. Feverfew for preventing migraine. Petadolex! , a butterbur extract for migraine prophylaxis.
Cochrane Database Syst Rev 2004; CD002286. Bot Targets Ther 2014; 4: 19.
61. Cady RK, Schreiber CP, Beach ME, et al. Gelstat Migraine 75. Riboflavin. Monograph. Altern Med Rev 2008; 13:
(sublingually administered feverfew and ginger compound) 334340.
for acute treatment of migraine when administered during 76. Montagna P, Sacquegna T, Martinelli P, et al. Mitochon-
the mild pain phase. Med Sci Monit 2005; 11: 6570. drial abnormalities in migraine. Preliminary findings.
62. Cady RK, Goldstein J, Nett R, et al. A double-blind Headache 1988; 28: 477480.
placebo-controlled pilot study of sublingual feverfew 77. Lodi R, Lotti S, Cortelli P, et al. Deficient energy metab-
and ginger (LipiGesicTM M) in the treatment of migraine. olism is associated with low free magnesium in the brains
Headache 2011; 51: 10781086. of patients with migraine and cluster headache. Brain Res
63. Maizels M, Blumenfeld A and Burchette R. A combin- Bull 2001; 54: 437441.
ation of riboflavin, magnesium, and feverfew for 78. Okada H, Araga S, Takeshima T, et al. Plasma lactic acid
migraine prophylaxis: A randomized trial. Headache and pyruvic acid levels in migraine and tension-type
2004; 44: 885890. headache. Headache 1998; 38: 3942.
64. Shrivastava R, Pechadre JC and John GW. Tanacetum 79. Lodi R, Kemp GJ, Montagna P, et al. Quantitative ana-
parthenium and Salix alba (Mig-RL) combination in lysis of skeletal muscle bioenergetics and proton efflux in
migraine prophylaxis: A prospective, open-label study. migraine and cluster headache. J Neurol Sci 1997; 146:
Clin Drug Investig 2006; 26: 287296. 7380.
65. Ferro EC, Biagini AP, da Silva IE, et al. The combined 80. Lodi R, Motagna P, Soriani S, et al. Deficit of brain
effect of acupuncture and Tanacetum parthenium on qual- and skeletal muscle bioenergetics and low brain magne-
ity of life in women with headache: Randomised study. sium in juvenile migraine: An in vivo 31P magnetic reson-
Acupunct Med 2012; 30: 252257. ance spectroscopy interictal study. Pediatr Res 1997; 42:
66. Diener HC, Pfaffenrath V, Schnitker J, et al. Efficacy and 866871.
safety of 6.25 mg t.i.d. feverfew CO2-extract (MIG-99) in 81. Reyngoudt H, Paemeleire K, Descamps B, et al. 31P-
migraine preventiona randomized, double-blind, multi- MRS demonstrates a reduction in high-energy phos-
centre, placebo-controlled study. Cephalalgia 2005; 25: phates in the occipital lobe of migraine without aura
10311041. patients. Cephalalgia 2011; 31: 12431253.
67. Holland S, Silberstein SD, Freitag F, et al. Evidence- 82. Sangiorgi S, Mochi M, Riva R, et al. Abnormal platelet
based guideline update: NSAIDs and other complemen- mitochondrial function in patients affected by migraine
tary treatments for episodic migraine prevention in with and without aura. Cephalalgia 1994; 14: 2123.
1132 Cephalalgia 36(12)

83. Barbiroli B, Montagna P, Cortelli P, et al. Abnormal 99. Mauskop A, Altura BT, Cracco RQ, et al. Intravenous
brain and muscle energy metabolism shown by 31P mag- magnesium sulfate rapidly alleviates headaches of vari-
netic resonance spectroscopy in patients affected by ous types. Headache 1996; 36: 154160.
migraine with aura. Neurology 1992; 42: 12091214. 100. Mauskop A, Altura BT, Cracco RQ, et al. Intravenous
84. Smith C. The role of riboflavin in migraine. Can Med magnesium sulfate relieves cluster headaches in patients
Assoc J 1946; 54: 589591. with low serum ionized magnesium levels. Headache
85. Boehnke C, Reuter U, Flach U, et al. High-dose ribofla- 1995; 35: 597600.
vin treatment is efficacious in migraine prophylaxis: An 101. Orr SL, Aube A, Becker WJ, et al. Canadian Headache
open study in a tertiary care centre. Eur J Neurol 2004; Society systematic review and recommendations on the
11: 4750477. treatment of migraine pain in emergency settings.
86. Schoenen J, Lenaerts M and Bastings E. High-dose Cephalalgia 2015; 35: 271284.
riboflavin as a prophylactic treatment of migraine: 102. Choi H and Parmar N. The use of intravenous magne-
Results of an open pilot study. Cephalalgia 1994; 14: sium sulphate for acute migraine: Meta-analysis of ran-
328329. domized controlled trials. Eur J Emerg Med 2014; 21:
87. Di Lorenzo C, Pierelli F, Coppola G, et al. Mitochon- 29.
drial DNA haplogroups influence the therapeutic 103. Shahrami A, Assarzadegan F, Hatamabadi HR, et al.
response to riboflavin in migraineurs. Neurology 2009; Comparison of therapeutic effects of magnesium sulfate
72: 158891594. vs. dexamethasone/metoclopramide on alleviating acute
88. Sandor PS, Afra J, Ambrosini A, et al. Prophylactic migraine headache. J Emerg Med 2015; 48: 6976.
treatment of migraine with beta-blockers and riboflavin: 104. Facchinetti F, Sances G, Borella P, et al. Magnesium
Differential effects on the intensity dependence of audi- prophylaxis of menstrual migraine: Effects on intracel-
tory evoked cortical potentials. Headache 2000; 40: lular magnesium. Headache 1991; 31: 298301.
3035. 105. Koseoglu E, Talaslioglu A, Gonul AS, et al. The effects
89. Schoenen J, Jacquy J and Lenaerts M. Effectiveness of magnesium prophylaxis in migraine without aura.
of high-dose riboflavin in migraine prophylaxis: Magnes Res 2008; 21: 101108.
A randomized controlled trial. Neurology 1998; 50: 106. Esfanjani A, Mahdavi R, Ebrahimi Mameghani M,
466470. et al. The effects of magnesium, L-carnitine, and con-
90. Nambiar N, Aiyappa C and Srinivasa R. Oral riboflavin current magnesium-L-carnitine supplementation in
versus oral propranolol in migraine prophylaxis: An open migraine prophylaxis. Biol Trace Elem Res 2012; 150:
label randomized controlled trial. Neurol Asia 2011; 16: 42048.
223229. 107. Peikert A, Wilimzig C and Kohne-Volland R. Prophy-
91. Condo M, Posar A, Arbizzani A, et al. Riboflavin laxis of migraine with oral magnesium: Results from a
prophylaxis in pediatric and adolescent migraine. J prospective, multi-center, placebo-controlled and
Headache Pain 2009; 10: 361365. double-blind randomized study. Cephalalgia 1996; 16:
92. Markley HG. Prophylactic treatment of headaches in 257263.
adolescents with riboflavin. Cephalalgia 2009; 29(Suppl 108. Pfaffenrath V, Wessely P, Meyer C, et al. Magnesium in
1): 100. the prophylaxis of migrainea double-blind, placebo-
93. MacLennan SC, Wade FM, Forrest KML, et al. High- controlled study. Cephalalgia 1996; 16: 4369440.
dose riboflavin for migraine prophylaxis in children: 109. Castelli S, Meossi C, Domenici R, et al. Magnesium in
A double-blind, randomized, placebo-controlled trial. J the prophylaxis of primary headache and other periodic
Child Neurol 2008; 23: 13001304. disorders in children [article in Italian]. Pediatr Med
94. Bruijn J, Duivenvoorden H, Passchier J, et al. Medium- Chir 1993; 15: 481488.
dose riboflavin as a prophylactic agent in children with 110. Wang F, Van Den Eeden SK, Ackerson L, et al.
migraine: A preliminary placebo-controlled, randomised, Oral magnesium oxide prophylaxis of frequent
double-blind, cross-over trial. Cephalalgia 2010; 30: migrainous headache in children: A randomized,
14261434. double-blind, placebo-controlled trial. Headache 2003;
95. Taylor FR. Nutraceuticals and headache: The biological 43: 601610.
basis. Headache 2011; 5148411;hea. 111. Gallelli L, Avenoso T, Falcone D, et al. Effects of acet-
96. Teigen L and Boes CJ. An evidence-based review of oral aminophen and ibuprofen in children with migraine
magnesium supplementation in the preventive treatment receiving preventive treatment with magnesium.
of migraine. Cephalalgia 2015; 35: 912922. Headache 2014; 54: 313324.
97. Martinez Cardenas V, Rodriguez M, Burke M, et al. Effi- 112. Grazzi L, Andrasik F, Usai S, et al. Magnesium as
cacy and safety of intravenous magnesium sulfate treat- a treatment for paediatric tension-type headache: A
ment in pediatric patients with headaches. Headache clinical replication series. Neurol Sci 2005; 25:
2012; 52: 896. 338341.
98. Gertsch E, Loharuka S, Wolter-Warmerdam K, et al. 113. Grazzi L, Andrasik F, Usai S, et al. Magnesium as a
Intravenous magnesium as acute treatment for head- preventive treatment for paediatric episodic tension-type
aches: A pediatric case series. J Emerg Med 2014; 46: headache: Results at 1-year follow-up. Neurol Sci 2007;
308312. 28: 148150.
Orr 1133

114. Rozen TD, Oshinsky ML, Gebeline CA, et al. Open 122. DAndrea G, Bussone G, Allais G, et al. Efficacy of
label trial of coenzyme Q10 as a migraine preventive. Ginkgolide B in the prophylaxis of migraine with
Cephalalgia 2002; 22: 1370141. aura. Neurol Sci 2009; 30(Suppl 1): S121S124.
115. Sandor PS, DiClemente L, Coppola G, et al. Efficacy of 123. Esposito M and Carotenuto M. Ginkgolide B complex
coenzyme Q10 in migraine prophylaxis: A randomized efficacy for brief prophylaxis of migraine in school-aged
controlled trial. Neurology 2005; 64: 713715. children: An open-label study. Neurol Sci 2011; 32:
116. Hershey AD, Powers SW, Vockell AL, et al. Coenzyme 7981.
Q10 deficiency and response to supplementation in pedi- 124. Esposito M, Ruberto M, Pascotto A, et al. Nutraceuti-
atric and adolescent migraine. Headache 2007; 47: cal preparations in childhood migraine prophylaxis:
7380. Effects on headache outcomes including disability and
117. Slater SK, Nelson TD, Kabbouche MA, et al. A rando- behaviour. Neurol Sci 2012; 33: 13651368.
mized, double-blinded, placebo-controlled, crossover, 125. Usai S, Grazzi L, Andrasik F, et al. An innovative
add-on study of coenzyme Q10 in the prevention of approach for migraine prevention in young age: A pre-
pediatric and adolescent migraine. Cephalalgia 2011; liminary study. Neurol Sci 2010; 31(Suppl 1):
31: 897905. S181S183.
118. Wagner W and Nootbaar-Wagner U. Prophylactic 126. Markley HG. Topical agents in the treatment of cluster
treatment of migraine with gamma-linolenic and headache. Curr Pain Headache Rep 2003; 7: 1390143.
alpha-linolenic acids. Cephalalgia 1997; 17: 127130. 127. Levin M. Herbal treatment of headache. Headache 2012;
119. Pradalier A, Bakouche P, Baudesson G, et al. Failure of 52(Suppl 2): 7680.
omega-3 polyunsaturated fatty acids in prevention of 128. Snyder FJ, Dundas ML, Kirkpatrick C, et al. Use and
migraine: A double-blind study versus placebo. safety perceptions regarding herbal supplements: A
Cephalalgia 2001; 21: 818822. study of older persons in southeast Idaho. J Nurt
120. Harel Z, Gascon G, Riggs S, et al. Supplementation Elder 2009; 28: 8195.
with omega-3 polyunsaturated fatty acids in the man- 129. Allais G, Castagnoli Gabellari I, Burzio C, et al. Pre-
agement of recurrent migraines in adolescents. J Adolesc menstrual syndrome and migraine. Neurol Sci 2012;
Health 2002; 31: 154161. 33(Suppl 1): S111S115.
121. Tajmirriahi M, Sohelipour M and Basiri K. The effects 130. Kooreman P and Baars EW. Patients whose GP knows
of sodium valproate with fish oil supplementation or complementary medicine tend to have lower costs and
alone in migraine prevention: A randomized single- live longer. Eur J Heal Econ 2012; 13: 769776.
blind clinical trial. Iran J Neurol 2012; 11: 2124.