Cephalalgia Diet and nutraceutical interventions for ... · Diet and nutraceutical interventions...
22
Review Article Diet and nutraceutical interventions for headache management: A review of the 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 Reviews—Cochrane 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 Complementary and alternative medicine (CAM) accounts for an ever-increasing portion of health care expenditures. The United States (US) National Institutes of Health (NIH) defines CAM as a ‘‘group of diverse medical and health care systems, practices, and products that are not presently considered to be part of conventional medicine’’ (1). In the US, CAM is a multibillion dollar industry, with spending estimated at $13.9 billion to $33.9 billion annually (2). The use of CAM has become more prevalent over the past decade (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 of CAM use is not unique to the US, with studies in other countries also unveiling prevalent use (5,6). The management of chronic pain has been identified as a priority area for CAM research (7). It also appears that patients with headache commonly turn to CAM for alternatives to traditional allopathic options. In one US headache clinic, a survey revealed that 84% of patients were using CAM interventions, with herbs, vitamins and nutritional supplements accounting for just fewer than 30% of the modalities used in this popu- lation (8). Similarly elevated estimates of CAM use in adult headache patients have been found elsewhere (9–12). A study among pediatric headache patients referred to an Italian tertiary care headache clinic revealed that 76% of the patients were using CAM Children’s Hospital of Eastern Ontario, Canada Corresponding author: Serena Orr, Children’s Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario, K1H 8L1 Canada. Email: [email protected] Cephalalgia 0(0) 1–22 ! International Headache Society 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102415590239 cep.sagepub.com
Transcript of Cephalalgia Diet and nutraceutical interventions for ... · Diet and nutraceutical interventions...
Review Article
Diet and nutraceutical interventions forheadache management: A review of theevidence
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 Reviews—Cochrane 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
Complementary and alternative medicine (CAM)accounts for an ever-increasing portion of health careexpenditures. The United States (US) NationalInstitutes of Health (NIH) defines CAM as a ‘‘groupof diverse medical and health care systems, practices,and products that are not presently considered to bepart of conventional medicine’’ (1). In the US, CAM isa multibillion dollar industry, with spending estimated at$13.9 billion to $33.9 billion annually (2). The use ofCAM has become more prevalent over the past decade(3). Recent estimates have found that more than one-third of US adults and more than 10% of US childrenendorse the use of CAM in the past year (4). This trendof CAM use is not unique to the US, with studies inother countries also unveiling prevalent use (5,6).
The management of chronic pain has been identifiedas a priority area for CAM research (7). It also appears
that patients with headache commonly turn to CAMfor alternatives to traditional allopathic options. In oneUS headache clinic, a survey revealed that 84% ofpatients were using CAM interventions, with herbs,vitamins and nutritional supplements accounting forjust fewer than 30% of the modalities used in this popu-lation (8). Similarly elevated estimates of CAM usein adult headache patients have been found elsewhere(9–12). A study among pediatric headache patientsreferred to an Italian tertiary care headache clinicrevealed that 76% of the patients were using CAM
Children’s Hospital of Eastern Ontario, Canada
Corresponding author:
Serena Orr, Children’s Hospital of Eastern Ontario, 401 Smyth Road,
Ottawa, Ontario, K1H 8L1 Canada.
Email: [email protected]
Cephalalgia
0(0) 1–22
! International Headache Society 2015
Reprints and permissions:
sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/0333102415590239
cep.sagepub.com
therapies for their headaches, with 74% using herbalremedies and 40% using vitamin and mineral supple-ments (13). In a study drawing on data from a nationalsample of children representative of the US population,30% of the children with headaches reported CAM use(14). Therefore, the use of CAM among headachepatients is very prevalent.
There is a significant gap between the prevalence ofCAM use and the degree to which dialogue aboutCAM enters into the typical physician-patient inter-action. In one study carried out in an Italian headacheclinic, 60.9% of the patients using CAM had not toldtheir physician about their CAM use (12). In addition,many physicians lack familiarity with CAM and avoidthe topic during routine clinical encounters. Forpatients interested in exploring CAM, this mutualreluctance to discuss the options may constitute a sig-nificant barrier to trust and optimal care. Given howmany headache patients are resorting to CAM, head-ache practitioners should become well versed in the evi-dence behind current CAM options, so as to enableinformed discussion with their patients.
Within the CAM literature, there has been a focuson nutraceutical interventions for headache. Anotherarea of interest within the non-pharmacologic headacheintervention literature pertains to diet interventions.The present review will provide an overview of thecurrent evidence for dietary and nutraceutical interven-tions for headache in adults and children.
Methods
Two separate literature searches were carried out in orderto identify studies on the efficacy of dietary or nutraceut-ical interviews for primary headache in the pediatric andadult populations. A variety of search term combinationswere used in order to identify the largest possible numberof relevant studies. MEDLINE, Embase and EBMReviews-Cochrane Central Register of ControlledTrials were searched to identify studies. Reference listsof included studies were also scrutinized for pertinent cit-ations. Observational studies, intervention studies andsystematic reviews of dietary or nutraceutical headachetherapies were included.
Dietary interventions for headache
Studies on dietary interventions for primary headachedisorders are summarized in Table 1.
Weight-loss diets for headache
Headache and obesity are comorbid (15). Migraine hasa specific association with obesity (15) and metabolicsyndrome (16,17). Furthermore, obese individuals
appear to be more likely to suffer from chronicmigraine as compared to their peers (18), therebyunveiling a possible relationship between body massindex (BMI) and migraine frequency. There is increas-ing evidence to suggest that migraine and obesity maybe linked through inflammatory mediators released byadipose tissue (19–22). Despite the increasing interest inthe headache-obesity association, there is a lack ofresearch on the use of weight loss as a treatment forheadache disorders. Weight loss has been found to bean efficacious intervention for patients with idiopathicintracranial hypertension (23,24), but little is knownabout its potential for efficacy in the primary head-aches. Two small observational studies have describeda decrease in migraine frequency and disability in obesewomen with migraine following bariatric surgery(25,26). A large retrospective study carried out in sev-eral tertiary care pediatric headache centers uncoveredan association between weight loss and reduction inheadache frequency among overweight children pre-senting with primary headaches (27). Also, an open-label study comparing the ketogenic diet to a standardlow-calorie diet found that both diets yielded a signifi-cant decrease both in BMI and headache frequency(28). The only prospective study assessing a weight-loss diet for migraine recruited obese adolescents withmigraine to undergo a 12-month intervention programinvolving not only a dietary intervention, but also anaerobic exercise program and cognitive-behavioraltraining sessions. In this study, weight loss was asso-ciated with reductions in migraine frequency, intensityand disability (29). However, given the multi-interven-tion approach, it is not known if the dietary interven-tion played a role in the observed effect. A randomizedcontrolled trial (RCT) is currently under way to assessthe efficacy of a behavioral weight-loss treatment pro-gram, involving diet alterations, in a sample of over-weight and obese women with migraine (30). The stateof the current evidence is very limited in regards to theefficacy of weight-loss interventions for primary head-aches. However, the growing interest in the associationof obesity and headache is likely to compel furtherresearch in this area in the years to come.
Low-sodium diets for headache
The potential role for a reduced-sodium diet inheadache has been explored in only one recent study.The theoretical impetus for this study pertained to theassociation between hypertension and headache, andthe role of a low-sodium diet in reducing blood pres-sure. In addition, it is well known that monosodiumglutamate is a headache trigger for some patients withprimary headaches (31). A detailed analysis of head-ache occurrence was carried out on data generated
2 Cephalalgia 0(0)
Tab
le1.
Sum
mar
yof
studie
son
die
tary
inte
rventions
for
head
ache.
Die
tTyp
eof
studie
s
Indiv
idual
studie
s
and
desi
gnN
/pat
ients
Inte
rvention
Com
par
ison
Outc
om
es
Wei
ght
loss
Non-r
andom
ized
Nova
cket
al.,
2011
(25):
pro
spect
ive
obse
rvat
ional
study
29
obese
adult
pat
ients
with
mig
rain
e
Bar
iatr
icsu
rgery
N/A
Aft
er
bar
iatr
icsu
rgery
,
mig
rain
efr
equency
(p<
0.0
001),
dura
tion
(p¼
0.0
2),
medic
atio
nuse
(p¼
0.0
05),
MID
AS
and
HIT
-6sc
ore
sdecr
eas
ed
(p<
0.0
05)
Bond
et
al.,
2011
(26):
pro
spect
ive
obse
rvat
ional
study
57
seve
rely
obese
adult
pat
ients
with
mig
rain
e
Roux-e
n-Y
gast
ric
byp
ass
or
lapar
osc
opic
adju
stab
le
gast
ric
ban
din
g
N/A
Aft
er
surg
ery
,head
ache
frequency
(p¼
0.0
13),
seve
rity
(p¼
0.0
22)
and
dis
abili
ty(p¼
0.0
03)
decr
eas
ed
Hers
hey
et
al.,
2009
(27):
retr
osp
ect
ive
char
tre
view
913
pedia
tric
pat
ients
with
ava
riety
of
head
ache
dis
ord
ers
Routine
care
,ro
utine
die
tary
and
nutr
itio
nal
counse
ling
plu
sdis
cuss
ion
about
heal
thri
sks
of
obesi
tyfo
r
ove
rweig
ht
pat
ients
N/A
Inove
rweig
ht
pat
ients
(BM
Iper-
centile>
85th
),ch
ange
inB
MI
at
follo
w-u
pw
asposi
tive
lyas
so-
ciat
ed
with
chan
gein
head
ache
frequency
(r¼
0.3
2,p¼
0.0
1)
DiLore
nzo
et
al.,
2015
(28):
pro
spect
ive
open-lab
elst
udy
96
adult
pat
ients
with
mig
rain
eas
dia
gnose
d
by
ID-M
igra
ine
who
self-
refe
rred
toa
die
tici
an
for
weig
ht
loss
Keto
genic
die
tw
ith
four-
week
keto
genesi
speri
od,
eig
ht-
week
tran
sitional
peri
od,fo
llow
edby
stan
dar
dlo
w-c
alori
edie
t
(n¼
45).
Die
tch
ose
nbas
ed
on
pat
ient
pre
fere
nce
Stan
dar
dlo
w-c
alori
edie
t
for
six
month
s(n¼
51).
NB
:D
iet
chose
nbas
ed
on
pat
ient
pre
fere
nce
Both
the
keto
genic
and
stan
dar
d
die
tsyi
eld
ed
are
duct
ion
inB
MI
and
both
groups
had
adecr
eas
ein
num
ber
of
head
ache
day
s/m
onth
(p<
0.0
001)
Verr
ott
iet
al.,
2013
(29):
pro
spect
ive
open-lab
elst
udy
135
Cau
casi
anad
ole
scents
with
mig
rain
ean
d
BM
I>97th
perc
entile
12-m
onth
pro
gram
invo
lvin
g
abal
ance
ddie
t,ae
robic
activi
tyan
dco
gnitiv
e-
behav
iora
lth
era
pygr
oup
sess
ions
N/A
Weig
ht,
BM
Ian
dw
aist
circ
um
fere
nce
(p<
0.0
1)
asw
ell
ashead
ache
frequency
(p<
0.0
1),
head
ache
inte
nsi
ty(p<
0.0
1),
use
of
acute
medic
atio
ns
(p<
0.0
5)
and
PedM
IDA
Ssc
ore
s(p<
0.0
5)
were
sign
ifica
ntly
reduce
dat
six
month
s
Low
-sod
ium
diet
RC
TA
mer
et
al.,
2014
(32):
RC
T
390
adult
pat
ients
with
hypert
ensi
on
Die
tary
Appro
aches
toSt
op
Hyp
ert
ensi
on
(DA
SH)
die
t
with
30-d
aycr
oss
-ove
r
peri
ods
of
low
,m
odera
te
and
hig
hso
diu
m(n¼
198)
Contr
oldie
tw
ith
30-d
ay
cross
-ove
rperi
ods
of
low
,m
odera
tean
d
hig
hso
diu
m(n¼
192)
The
low
-sodiu
mcr
oss
-ove
r
peri
od
was
asso
ciat
ed
with
reduce
dhead
ache
occ
urr
ence
asco
mpar
ed
toth
ehig
h-s
odiu
m
peri
od
for
both
groups
(OR¼
0.6
9,
95%
CI¼
0.4
9–0.9
9an
d
OR¼
0.6
9,
95%
CI¼
0.4
9–0.9
8)
(continued)
Orr 3
Tab
le1.
Continued.
Die
tTyp
eof
studie
s
Indiv
idual
studie
s
and
desi
gnN
/pat
ients
Inte
rvention
Com
par
ison
Outc
om
es
Low
-fat
diet
Quas
i-
experi
menta
l
Bic
et
al.,
1999
(34):
quas
i-experi
menta
l
pre
-test
/post
-test
pro
toco
l
54
adults
with
mig
rain
eR
est
rict
ion
of
die
tary
fat
inta
keto
20
g/day
and
advi
seto
limit
caffein
e
inta
kefo
r12-w
eek
inte
r-
vention
peri
od
N/A
Sign
ifica
nt
decr
eas
ein
mig
rain
efr
e-
quency
,in
tensi
ty,head
ache
index
and
frequency
of
medic
atio
nuse
(p<
0.0
001)
RC
TB
unner
et
al.,
2014
(35):
open-lab
el
random
ized
cross
-ove
rst
udy
42
adults
with
mig
rain
eLow
-fat
vega
ndie
tfo
rfo
ur
weeks
follo
wed
by
elim
inat
ion
die
tfo
r
four
weeks
follo
wed
by
rein
troduct
ion
die
t
for
eig
ht
weeks
(n¼
21)
Pla
cebo
(10
mcg
linole
ic
acid
and
10
mcg
vita
min
E)
once
dai
lyfo
r16
weeks
(n¼
21)
Sign
ifica
nt
decr
eas
ein
weig
ht
(p<
0.0
01),
num
ber
of
head
aches
(p¼
0.0
4),
seve
rity
of
wors
tpai
n
(p¼
0.0
3)
and
use
of
medic
atio
ns
(p¼
0.0
04)
ove
rdie
tperi
od
as
com
par
ed
topla
cebo
peri
od
Elim
inat
ion
diet
Non-r
andom
ized
Egg
er
et
al.,
1983
(37):
pro
spect
ive
open-lab
el
study
99
child
ren
with
mig
rain
e
Olig
oan
tige
nic
die
tw
ith
elim
inat
ion
of
multip
le
trig
ger
foods
innon-indi-
vidual
ized
man
ner
with
subse
quent
double
-blin
d
cross
-ove
rperi
od
invo
l-
ving
rein
troduct
ion
of
pro
voca
tive
foods
N/A
93%
impro
ved
great
lyor
reco
vere
dco
mple
tely
on
the
die
t
Wan
tke
et
al.,
1993
(38):
pro
spect
ive
open-lab
elst
udy
28
adults
with
chro
nic
head
aches
and
ahis
tory
of
food
into
lera
nce
His
tam
ine-f
ree
die
tfo
r
four
weeks
N/A
68%
ofpat
ients
had
a50%
or
great
er
reduct
ion
inhead
ache
freq
uency
on
the
die
t,w
ith
adecr
eas
efr
om
3.1�
2.3
to1.1�
1.0
head
aches/
week
(p<
0.0
01)
Arr
oya
veH
ern
andez
et
al.,
2007
(39):
pro
spect
ive
open-lab
elst
udy
with
mat
ched
contr
ols
56
adults
with
mig
rain
e
and
56
age-
and
gender-
mat
ched
contr
ols
IgG
antibodie
sto
food
anti-
gens
were
meas
ure
dan
d
then
culp
rit
foods
rem
ove
dfr
om
the
die
tfo
r
six
month
s
N/A
All
mig
rain
epat
ients
and
15%
of
contr
ols
had
IgG
imm
unore
activ-
ity
(p<
0.0
1);
84%
of
mig
rain
e
pat
ients
had
rem
issi
on
ofm
igra
ine
or
adecr
eas
ein
mig
rain
efr
e-
quency
and
inte
nsi
tyduri
ng
the
die
tperi
od
RC
Ts
Salfi
eld
et
al.,
1987
(36):
RC
T
39
child
ren
with
mig
rain
eFi
ber-
rich
die
tw
ith
excl
usi
on
of
foods
with
vaso
active
amin
es
for
eig
ht
weeks
(n¼
19)
Fiber-
rich
die
tw
ithout
excl
usi
on
of
foods
with
vaso
active
amin
es
for
eig
ht
weeks
(n¼
20)
Both
groups
had
asi
gnifi
cant
reduct
ion
inm
igra
ine
frequency
with
no
diff
ere
nce
betw
een
the
groups
Alp
ayet
al.,
2010
(40):
cross
-ove
rtr
ial
35
adults
with
mig
rain
e
without
aura
IgG
antibodie
sto
food
antige
ns
were
meas
ure
d
and
then
culp
rit
foods
were
elim
inat
ed
for
six
weeks
IgG
antibodie
sto
food
antige
ns
were
meas
ure
d
and
then
culp
rit
foods
were
continued
for
six
weeks
Duri
ng
elim
inat
ion
die
tphas
e,at
tack
count
(p<
0.0
01),
head
ache
day
s
(p<
0.0
01),
use
of
acute
medic
a-
tions
(p<
0.0
01)
and
tota
lm
edi-
cation
inta
ke(p¼
0.0
02)
were
reduce
dsi
gnifi
cantly
(continued)
4 Cephalalgia 0(0)
Tab
le1.
Continued.
Die
tTyp
eof
studie
s
Indiv
idual
studie
s
and
desi
gnN
/pat
ients
Inte
rvention
Com
par
ison
Outc
om
es
Mitch
ell
et
al.,
2011
(41):
singl
e-b
lind,
par
alle
l-gr
oup
RC
T
167
par
tici
pan
tsw
ith
self-
report
ed
mig
rain
e-lik
e
head
aches
IgG
antibodie
sto
food
antige
ns
were
meas
ure
d
and
then
par
tici
pan
tsw
ere
inst
ruct
ed
tore
move
culp
rit
foods
for
12
weeks
(n¼
84)
IgG
antibodie
sto
food
antige
ns
were
meas
ure
d
and
then
par
tici
pan
tsw
ere
inst
ruct
ed
tore
move
a
mat
ched
num
ber
of
non-c
ulp
rit
foods
for
12
weeks
(n¼
83)
No
sign
ifica
nt
diff
ere
nce
inth
efr
e-
quency
of
head
aches,
MID
AS
or
HIT
-6sc
ore
sbetw
een
the
groups
Ket
ogen
icdi
etN
on-r
andom
ized
Schnab
el,
1928
(45):
pro
spect
ive
open-lab
el
study
18
adults
with
mig
rain
eK
eto
genic
die
tN
/A50%
of
pat
ients
had
som
ere
lief
in
their
head
aches
ove
rth
edie
t
peri
od
Bar
bork
a,1930
(46):
pro
spect
ive
open-lab
elst
udy
50
adults
with
mig
rain
e
Keto
genic
die
tfo
r
thre
eto
six
month
s
N/A
78%
of
pat
ients
had
are
sponse
to
the
die
t,w
ith
28%
hav
ing
mig
rain
e
rem
issi
on
on
the
die
t
Koss
off
et
al.,
2010
(50):
pro
spect
ive
open-lab
elst
udy
8ad
ole
scents
with
chro
nic
dai
lyhead
ache
Modifi
ed
Atk
ins
die
tfo
r
thre
em
onth
s.
Only
thre
epar
tici
pan
ts
com
ple
ted
the
thre
e-m
onth
peri
od
N/A
No
par
tici
pan
thad
any
reduct
ion
in
head
ache
frequency
Fark
aset
al.,
2014
(51):
pro
spect
ive
open-lab
elst
udy
18
adole
scents
with
mig
rain
e
Keto
genic
die
tfo
rth
ree
month
s.
Only
six
par
tici
pan
tsco
m-
ple
ted
the
thre
e-m
onth
peri
od
N/A
38%
of
the
ori
ginal
sam
ple
had
som
ere
sponse
to
the
die
t
DiLore
nzo
et
al.,
2013
(52):
pro
spect
ive
open-lab
elst
udy
108
adult
pat
ients
with
mig
rain
e
Keto
genic
die
tfo
rone
month
(n¼
52)
Stan
dar
dlo
w-c
alori
edie
t
for
one
month
(n¼
56)
90%
of
pat
ients
inth
e
keto
genic
die
tgr
oup
had
are
sponse
inte
rms
of
mig
rain
efr
equency
and
reduct
ion
inm
edic
atio
nuse
with
no
resp
onders
inth
est
andar
ddie
t
group
DiLore
nzo
et
al.,
2015
(28):
pro
spect
ive
open-lab
elst
udy
96
adult
pat
ients
with
mig
rain
eas
dia
gnose
d
by
ID-M
igra
ine
who
self-
refe
rred
toa
die
tici
an
for
weig
ht
loss
Keto
genic
die
tw
ith
four-
week
keto
genesi
s
peri
od,eig
ht-
week
tran
sitional
peri
od,
follo
wed
by
stan
dar
dlo
w-
calo
rie
die
t(n¼
45).
Die
tch
ose
nbas
ed
on
pat
ient
pre
fere
nce
Stan
dar
dlo
w-c
alori
edie
t
for
six
month
s(n¼
51).
Die
tch
ose
nbas
ed
on
pat
ient
pre
fere
nce
There
was
asi
gnifi
cant
tim
eby
treat
ment
inte
ract
ion
favo
ring
the
keto
genic
die
tgr
oup
for
clin
ical
head
ache
vari
able
s(p<
0.0
001),
with
the
keto
genic
die
tgr
oup
hav
ing
impro
vem
ent
inal
lhead
-
ache
vari
able
sduri
ng
the
keto
-
genesi
sphas
e(p<
0.0
001)
(continued)
Orr 5
Tab
le1.
Continued.
Die
tTyp
eof
studie
s
Indiv
idual
studie
s
and
desi
gnN
/pat
ients
Inte
rvention
Com
par
ison
Outc
om
es
Misce
llane
ous
Non-r
andom
ized
Dexte
ret
al.,
1978
(53):
pro
spect
ive
open-lab
el
study
74
adult
pat
ients
with
mig
rain
eas
soci
ated
with
fast
ing
stat
es
Low
-sucr
ose
,si
x-m
eal
die
t
plu
ste
stin
gfo
rdia
bete
s
with
afiv
e-h
our
100
gora
l
gluco
seto
lera
nce
test
N/A
All
pat
ients
with
dia
betic
test
resu
lts
had
a75%
or
great
er
impro
ve-
ment
inth
eir
head
aches;
63%
of
those
with
reac
tive
hypogl
ycem
ia
had
a75%
or
great
er
impro
ve-
ment
and
27%
of
them
had
a
50–75%
impro
vem
ent
inth
eir
head
aches
Unge
et
al.,
1983
(54):
pro
spect
ive
open-lab
elst
udy
10
wom
en
with
mig
rain
e
and
cuta
neous
sym
pto
ms
Try
pto
phan
-reduce
ddie
tfo
r
am
inim
um
of
one
month
N/A
90%
had
are
duct
ion
inm
igra
ine
atta
cks
duri
ng
the
die
t
RC
TSp
igt
et
al.,
2012
(55):
RC
T
Adults
with
recu
rrent
head
aches
Life
styl
eco
unse
ling
and
incr
eas
ed
die
tary
wat
er
inta
ke:1.5
lad
ditio
nal
liters
of
wat
er
per
day
for
thre
em
onth
s(n¼
52)
Life
styl
eco
unse
ling
only
(n¼
50)
No
diff
ere
nce
betw
een
the
groups
in
term
sof
head
ache
frequency
or
medic
atio
nusa
ge,
but
great
er
impro
vem
ents
inM
igra
ine-S
peci
fic
Qual
ity
of
Life
score
sw
ere
seen
for
the
inte
rvention
group
(p¼
0.0
07)
Ram
sden
et
al.,
2013
(56):
RC
T
67
adults
with
chro
nic
dai
lyhead
ache
Die
tary
inte
rvention
invo
lvin
gre
duct
ion
of
om
ega
-6fa
tty
acid
s
com
bin
ed
with
incr
eas
ed
om
ega
-3fa
tty
acid
sfo
r
12
weeks
(n¼
33)
Die
tary
inte
rvention
invo
lvin
gre
duct
ion
of
om
ega
-6fa
tty
acid
s
alone
for
12
weeks
(n¼
34)
Both
groups
had
sign
ifica
nt
impro
ve-
ment
inth
eir
head
aches,
but
the
reduce
dom
ega
-6-incr
eas
ed
om
ega
-3die
tyi
eld
ed
abett
er
resp
onse
:lo
wer
HIT
-6sc
ore
s
(p<
0.0
001),
few
er
head
ache
day
s
(p¼
0.0
2)
and
few
er
head
ache
hours
(p¼
0.0
1)
RC
T:ra
ndom
ized
contr
olle
dtr
ial;
BM
I:body
mas
sin
dex;M
IDA
S:M
igra
ine
Dis
abili
tyA
ssess
ment;
HIT
-6:H
ead
ache
Impac
tTe
st-6
;Ig
:im
munogl
obulin
;O
R:odds
ratio;C
I:co
nfid
ence
inte
rval
.
6 Cephalalgia 0(0)
from the Dietary Approaches to Stop Hypertension(DASH)-sodium RCT in order to explore the effect ofdietary sodium on headache. In this trial, adult partici-pants with hypertension were randomized to the DASHdiet or a control diet, with each group also having three30-day cross-over periods to low, moderate and highsodium intakes within their assigned diet. The datashowed that the odds of reporting a headache in thelast seven days of the diet were lower while participantswere on the low-sodium diet as compared to the high-sodium diet, with no difference between the DASH dietand the control diet overall (32). This trial was designedto assess blood pressure as a primary outcome, and theascertainment of headache as a secondary outcome wassuboptimal. However, it does provide a foundation forfurther exploration of the role of low-sodium diets forheadache prevention in adults with hypertension.
Low-fat diets for migraine
Altering dietary fat intake could effect changes inmigraine patterns given the role that dietary fat com-position plays in prostaglandin synthesis.Prostaglandins are thought to play a role in migrainepathogenesis through a variety of mechanisms, includ-ing their vasoactive effects on cranial arteries and theirrole in central and peripheral pain sensitization (33).
Two studies have investigated the role of low-fatdiets for migraine prophylaxis. The first studyemployed a quasi-experimental design to assess the effi-cacy of a low-fat diet in a sample of 54 adults withmigraine. Participants were instructed to reduce dietaryfat intake to a maximum of 20 g per day for a 12-weekintervention period and to complete headache diaries.After the intervention, there was a significant decreasenot only in participant weight and dietary fat intake,but also in headache frequency, intensity and use ofabortive headache medications (34). An open-label,randomized cross-over study evaluated the efficacy ofa low-fat vegan diet combined with an eliminationprotocol to remove trigger foods as compared to pla-cebo over a 16-week intervention period in a sample ofadult migraineurs. Only 42 participants were recruited,with no a priori sample size calculations, and the par-ticipants were demographically homogeneous, withmostly Caucasian, highly educated females recruited.Participants lost an average of 3.6 kg over the dietaryintervention period and had improvement in a numberof headache-related outcomes as compared to placebo(35). Given methodological limitations, the lack ofdetail with regards to how these interventions altereddietary fat composition and given the association of thelow-fat diets with weight loss, it is still unclear as towhether a simple reduction in dietary fat is efficaciousfor migraine.
Elimination diets for headache
Dietary triggers are a well-established phenomenon inmigraine. Several studies have assessed a variety ofelimination diets as therapeutic interventions formigraine.
A small randomized trial evaluated the efficacy ofa high-fiber diet alone vs. a high-fiber diet with elim-ination of foods high in vasoactive amines formigraine prophylaxis in a sample of children andfound no difference in headache parametersbetween the groups (36). Another study among chil-dren with migraines assessed the effect of an oligoan-tigenic diet on migraine through elimination of awide variety of common trigger foods in an unse-lected fashion. The vast majority of children (93%)had complete or great improvement on the diet, andof those who were randomly assigned to reintroduc-tion of provocative foods, most had relapse of theirheadaches (37).
A few studies have been carried out to assesselimination diets among adult migraineurs. Asample of 28 patients with chronic headaches wereplaced on a histamine-free diet for four weeks, and68% of the participants had a 50% or greater reduc-tion in their headaches (38). Individualizedapproaches to elimination diets have been employedin a few studies. One open-label study tested adultmigraine patients for food reactivity by measuringimmunoglobulin (Ig)G antibodies to food antigensand then instructed participants to eliminate the cul-prit foods for six months. Complete or partial head-ache response was reported by 84% of theparticipants after the elimination diet (39). TwoRCTs have also taken a targeted approach to elimin-ation diets for migraine by measuring IgG antibodiesto food antigens and then randomly assigning partici-pants to elimination of provocative foods vs. controlconditions. A small cross-over study found a six-weekindividualized elimination diet to be effective in redu-cing migraine frequency and medication use as com-pared to a standard diet (40). These findings were notreplicated in a parallel-group trial carried out amongadults with self-reported migraines, where the indivi-dualized elimination diet was no different from asham diet after 12 weeks (41). The null results fromthis RCT may have been due to methodological prob-lems with the study, namely the suboptimal selection ofmigraine patients, the lack of compliance monitoringand diet education and a high attrition rate. Overall,although evidence is limited in quality and quantity, itappears that targeted elimination diets for patients withconcurrent migraine and food sensitivities may beeffective for migraine prevention, but further evidenceis required.
Orr 7
macbook
Texte surligné
The ketogenic diet for headache
In the past couple of decades, there has been a renewedinterest in exploring the ketogenic diet for neurologicaldiseases. The ketogenic diet yields multiple biochemicalchanges in the brain that could theoretically affectmigraine propensity (42), including a shift in neuronalenergy states and altered neuronal excitability in thecontext of acidosis and ketone body metabolism (43).Interestingly, the ketogenic diet appears to decreasecortical spreading depression in the short-term (44),making it plausible that it could have an effect inmigraine with aura.
The first case series reporting use of the ketogenicdiet for headache was carried out in 1928. A sample of18 migraine patients were treated with an incrementalketogenic diet regimen, and half of those patientshad some relief of their condition (45). In 1930, asample of 50 migraineurs, most of whom had severeand refractory migraines, were followed for aperiod of several months on the ketogenic diet.Interestingly, 78% of the patients benefitted from thediet, with 28% of the sample achieving complete remis-sion from their migraines (46). Since then, a few casereports have indicated promise for the ketogenic diet inmigraine (47–49).
The modified Atkins diet, which is similar to theketogenic diet and also results in a state of ketosis,was administered to a sample of eight adolescentswith chronic daily headache. Compliance was problem-atic with only three of the participants completing the12-week diet, and none of the participants had anyreduction in migraine frequency over the treatmentperiod (50). Another study among adolescents aimedto administer the ketogenic diet to 18 adolescentswith migraine for a three-month treatment period.Only 38% of the patients adhered to the ketogenicdiet for the entire treatment period, and some responseto the diet was observed in only 38% of the originalsample (51). It is therefore difficult to comment on theefficacy of the ketogenic diet in adolescents because oflimited evidence and significant compliance issuesobserved in the published studies.
Two studies have assessed the efficacy of the trad-itional ketogenic diet for adult migraine prophylaxisand have shown encouraging results. The ketogenicdiet was superior to a standard low-calorie diet over afour-week treatment period with a 90% responder ratein a sample of 108 migraine patients (52). A recentopen-label study, during which 96 migraine patientswere assigned to either the ketogenic diet or a standarddiet depending on their preference, uncovered an asso-ciation between migraine relief and ketosis: During theketogenic phase of the intervention diet, a significantimprovement in headache parameters was observed
(28). Based on the case reports and interventionalstudies described above, there is some preliminary evi-dence to support the use of the ketogenic diet as anintervention in the motivated adult migraine patient.Methodologically rigorous studies are needed to con-firm these findings.
Miscellaneous dietary interventions for headache
Several other dietary interventions have been exploredfor headache in isolated studies. A low-sucrose diet wasadministered to migraineurs reporting an associationbetween migraine attacks and fasting states. A favor-able response rate was observed among patients foundto have diabetes or reactive hypoglycemia on an oral-glucose tolerance test (53). A small series of 10 womensuffering from migraine and cutaneous symptoms con-sistent with food allergy demonstrated improvement intheir headaches on a tryptophan-reduced diet (54).Increased dietary water intake was assessed in anRCT carried out among adult patients with recurrentheadaches. Though subjective improvement in head-ache and disability was observed among the groupwith increased water intake compared to the standardintervention group, no differences were seen whenassessing headache frequency and other parameters inparticipants’ headache diaries (55). Finally, based onthe theory that omega-6 fatty acids are pronociceptiveand omega-3 fatty acids are antinociceptive, a group ofadult patients with chronic headaches were randomizedto a dietary intervention involving either reduction ofomega-6 fatty acids alone or reduction of omega-6 fattyacids combined with increased omega-three fatty acids.After 12 weeks of the diet, participants on the highomega-3 and low omega-6 diet had greater improve-ment in their headaches as compared to participantson the reduced omega-6 diet (56).
Nutraceutical interventionsfor headache
Table 2 summarizes the evidence for nutraceuticals inthe treatment of primary headache disorders.
Feverfew (Tanacetum parthenium L.)for migraine
Feverfew, also known as Tanacetum parthenium L., is amedicinal herb that has been used for centuries for avariety of ailments. Parthenolide, a sesquiterpene lac-tone, appears to be feverfew’s active ingredient and hasmultiple actions in the central nervous system. Severalof its properties suggest a potential mechanism ofaction in migraine prevention, including evidence tosuggest that parthenolide inhibits Fos-induced
8 Cephalalgia 0(0)
Tab
le2.
Sum
mar
yof
studie
son
nutr
aceutica
lin
terv
entions
for
head
ache.
Nutr
aceutica
l
Typ
eof
studie
s
Indiv
idual
studie
san
d
desi
gnN
/pat
ients
Inte
rvention
Com
par
ison
Outc
om
es
Feve
rfew
Syst
em
atic
revi
ew
Pittler
and
Ern
st,
2004
(60):
Coch
rane
syst
em
atic
revi
ew
Five
RC
Ts
(tw
opar
alle
l-
group,th
ree
cross
-ove
r)
of
343
pat
ients
Rib
ofla
vin
inva
rious
form
ula
tions
and
dose
s
Pla
cebo
No
convi
nci
ng
evi
dence
to
est
ablis
hfe
verf
ew
’s
effic
acy;
the
two
hig
hest
qual
ity
RC
Ts
did
not
show
benefit
,an
dth
eoth
er
thre
eR
CT
sdid
Non- random
ized
Cad
yet
al.,
2005
(61):
pro
spect
ive
open-lab
elst
udy
30
adults
with
mig
rain
eG
els
tat
Mig
rain
e�
(com
bin
atio
nof
feve
rfew
and
ginge
r)fo
rac
ute
mig
rain
e
N/A
48%
of
pat
ients
achie
ved
two-h
our
pai
nfr
eedom
and
34%
of
par
-
tici
pan
tshad
only
mild
pai
nat
two
hours
Shri
vast
ava
et
al.,
2006
(64):
pro
spect
ive
open-lab
elst
udy
12
adults
with
mig
rain
e
without
aura
Tan
acetu
mpar
theniu
m
(fev
erf
ew
)300
mgþ
Salix
alba
300
mg
bid
for
12
weeks
N/A
70%
ofpat
ients
had
a50%
or
great
er
reduct
ion
inm
igra
ine
frequency
RC
TC
ady
et
al.,
2011
(62):
RC
T
60
adults
with
mig
rain
eG
els
tat
Mig
rain
e�
(com
bin
atio
nof
feve
rfew
and
ginge
r)fo
rac
ute
mig
rain
e(n¼
45)
Pla
cebo
for
acute
mig
rain
e(n¼
15)
32%
of
Gets
tat
Mig
rain
e�
group
vs.
16%
of
pla
cebo
group
were
pai
n
free
attw
ohours
(p¼
0.0
2)
Mai
zels
et
al.,
2004
(63):
RC
T
49
adults
with
mig
rain
eC
apsu
les
of
feve
rfew
100
mg,
mag
nesi
um
300
mg
and
ribofla
vin
400
mg
two
capsu
les
dai
lyfo
rth
ree
month
s(n¼
24)
25
mg
ribofla
vin
two
capsu
les
dai
lyas
pla
cebo
for
thre
em
onth
s(n¼
25)
No
diff
ere
nce
inth
epro
port
ion
of
pat
ients
achie
ving
a50%
or
great
er
reduct
ion
inm
igra
ine
freq
uency
(p¼
0.8
7)
Ferr
oet
al.,
2012
(65):
RC
T
68
wom
en
with
chro
nic
mig
rain
e
Tan
acetu
mpar
theniu
m
(fev
erf
ew
)150
mg
dai
lyan
d20
acupunct
ure
sess
ions
ove
r10
weeks
(n¼
23)
Tan
acetu
mpar
theniu
m
(fev
erf
ew
)150
mg
dai
ly
ove
r10
weeks
(n¼
23)
20
acupunct
ure
sess
ions
ove
r10
weeks
(n¼
22)
Com
bin
ed
feve
rfewþ
acupunct
ure
was
superi
or
inre
duci
ng
SF-3
6
score
s(p<
0.0
5),
MID
AS
score
s
(p<
0.0
5)
and
mean
pai
nsc
ore
s
(p<
0.0
5)
asco
mpar
ed
toeither
treat
ment
alone
Die
ner
et
al.,
2005
(66):
RC
T
218
adults
with
mig
rain
e
Tan
acetu
mpar
theniu
m
(6.2
5m
gfe
verf
ewextr
act)
CO
2extr
act
(MIG
-99)
tid
for
16
weeks
(n¼
108)
Pla
cebo
for
16
weeks
(n¼
110)
Mig
rain
efr
equency
decr
eas
ed
more
inth
ein
terv
ention
group
as
com
par
ed
topla
cebo
(–1.9
vs.–
1.3
atta
cks/
month
,p¼
0.0
148)
(continued)
Tab
le2.
Continued.
Nutr
aceutica
l
Typ
eof
studie
s
Indiv
idual
studie
san
d
desi
gnN
/pat
ients
Inte
rvention
Com
par
ison
Outc
om
es
Rib
ofla
vin
(vita
min
B2)
Non- random
ized
Smith,1946
(84):
case
seri
es
19
adults
with
mig
rain
e
Rib
ofla
vin
5m
g
tid
for
vari
able
dura
tions
N/A
95%
of
the
pat
ients
impro
ved
on
ribofla
vin
Boehnke
et
al.,
2004
(85):
pro
spect
ive
open-lab
elst
udy
23
adults
with
mig
rain
e
Rib
ofla
vin
400
mg
dai
lyfo
rth
ree
tosi
xm
onth
s
N/A
Mig
rain
efr
equency
decr
eas
ed
from
mean
offo
ur
day
s/m
onth
totw
o
day
s/m
onth
(p<
0.0
01)
Schoenen
et
al.,
1994
(86):
pro
spect
ive
open-lab
elst
udy
44
adults
with
mig
rain
e
Rib
ofla
vin
400
mg
dai
ly(2
3
of
the
44
pat
ients
were
also
give
nas
pir
in75
mg
dai
ly)
for
am
inim
um
of
thre
em
onth
s
N/A
Mean
impro
vem
ent
of68.2
%in
their
mig
rain
ese
veri
tysc
ore
s,w
ith
no
diff
ere
nce
betw
een
those
who
rece
ived
ASA
and
those
who
did
n’t
(no
pgi
ven)
Sandor
et
al.,
2000
(88):
pro
spect
ive
open-lab
elst
udy
26
adults
with
mig
rain
e
Rib
ofla
vin
400
mg
dai
ly
for
four
month
s
Bis
opro
lol10
mg
dai
lyor
meto
pro
lol200
mg
dai
lyfo
rfo
ur
month
s
Both
groups
had
asi
gnifi
cant
decr
eas
ein
head
ache
frequency
(p<
0.0
5),
but
no
diff
ere
nce
betw
een
the
groups
Condo
et
al.,
2009
(91):
retr
osp
ect
ive
char
tre
view
41
child
ren
and
adole
scents
with
a
vari
ety
of
head
ache
dis
ord
ers
Rib
ofla
vin
200
mg
or
400
mg
PO
dai
lyfo
r
thre
e,
four
or
six
month
s
N/A
Sign
ifica
nt
reduct
ion
inhead
ache
frequency
afte
rtr
eat
ment
for
thre
eor
four
month
s
(21.7�
13.7
vs.13.2�
11.8
,
p<
0.0
1),
whic
hw
asnot
sus-
tain
ed
atsi
xm
onth
s(1
9.3�
13.4
vs.11.4�
9.6
,p>
0.0
5)
Mar
kle
y,2009
(92):
retr
osp
ect
ive
char
tre
view
32
adole
scents
with
chro
nic
dai
ly
head
ache
Rib
ofla
vin
400
mg
dai
lyfo
rat
leas
t
six
weeks
N/A
73%
of
pat
ients
had
som
ere
sponse
to
ribofla
vin
RC
TSc
hoenen
et
al.,
1998
(89):
RC
T
55
adults
with
mig
rain
e
Rib
ofla
vin
400
mg
dai
lyfo
rfo
ur
month
s
(n¼
28)
Pla
cebo
for
four
month
s(n¼
27)
Rib
ofla
vin
lead
toa
great
er
reduc-
tion
inm
igra
ine
frequency
by
month
4(p¼
0.0
001),
NN
T¼
2.8
Nam
bia
ret
al.,
2011
(90):
open-
labelR
CT
100
adults
with
mig
rain
e
Rib
ofla
vin
100
mg
dai
lyfo
rat
leas
t
thre
em
onth
s(n¼
50)
Pro
pra
nolo
l80
mg
dai
ly
for
atle
ast
thre
em
onth
s(n¼
50)
The
pro
pra
nolo
lgro
up
had
agr
eate
r
reduct
ion
inm
igra
ine
frequency
infir
stm
onth
(p<
0.0
01),
but
there
were
no
group
diff
ere
nce
s
atth
ree
and
six
month
s
Mac
Lennan
et
al.2008
(93):
RC
T
48
child
ren
and
adole
scents
with
mig
rain
e
Rib
ofla
vin
200
mg
dai
lyfo
r12
weeks
(n¼
27)
Pla
cebo
for
12
weeks
(n¼
21)
No
diff
ere
nce
betw
een
the
groups
in
term
sof
the
pro
port
ion
of
par
-
tici
pan
tsw
ith
50%
or
grea
ter
reduct
ion
of
mig
rain
efr
equency
(44.4
%of
the
ribofla
vin
vs66.6
%
of
the
pla
cebo
group,p¼
0.1
25)
Bru
injet
al.,
2010
(94):
cross
-
ove
rR
CT
42
child
ren
with
mig
rain
e
Rib
ofla
vin
50
mg
dai
ly
for
four
month
s
(n¼
20)
Pla
cebo
for
four
month
s(n¼
22)
No
diff
ere
nce
betw
een
groups
in
term
sof
chan
gein
mig
rain
efr
e-
quency
(p¼
0.4
4);
the
ribofla
vin
group
had
agr
eat
er
reduct
ion
in
the
frequency
of
tensi
on-t
ype
head
aches
asco
mpar
ed
topla
-
cebo
(p¼
0.0
4)
(continued)
Tab
le2.
Continued.
Nutr
aceutica
l
Typ
eof
studie
s
Indiv
idual
studie
san
d
desi
gnN
/pat
ients
Inte
rvention
Com
par
ison
Outc
om
es
Intr
aven
ous
mag
nesium
Non- random
ized
Mar
tinez
Car
denas
et
al.,
2012
(97):
retr
osp
ect
ive
char
tre
view
31
refr
acto
ryhead
aches
in
23
adm
itte
dch
ildre
n
and
adole
scents
Intr
avenous
mag
nesi
um
sulfa
te(M
gSO
4)
with
intr
aven
ous
dip
henhy
dra
min
e.
Man
yof
the
pat
ients
rece
ived
seve
raldose
sof
MgS
O4
N/A
51%
of
head
aches
impro
ved
with
trea
tment
Gert
sch
et
al.,
2014
(98):
retr
osp
ect
ive
char
tre
view
20
child
ren
with
acute
head
ache
inth
eED
Intr
avenous
mag
nesi
um
N/A
77%
of
the
pat
ients
trea
ted
inth
e
ED
were
adm
itte
dfo
rfu
rther
head
ache
man
agem
ent
Mau
skop
et
al.,
1996
(99):
pro
spect
ive
open-lab
elst
udy
40
adult
pat
ients
with
a
vari
ety
of
acute
head
ache
dis
ord
ers
Intr
avenous
MgS
O4
1g
N/A
80%
of
pat
ients
had
com
ple
tepai
n
relie
fw
ithin
15
min
ute
s
Mau
skop
et
al.,
1995
(100):
pro
spect
ive
open-lab
elst
udy
22
adult
pat
ients
with
clust
er
head
ache
for
a
tota
lof
38
infu
sions
Intr
avenous
MgS
O4
1or
2g
N/A
60.5
%of
the
infu
sions
resu
lted
in
impro
vem
ent
inth
ehead
aches
(at
leas
ttw
oday
shead
ache
free)
Syst
em
atic
revi
ew
Orr
et
al.,
2014
(101):
syst
em
atic
revi
ew
4R
CT
sof
247
adult
pat
ients
with
acute
mig
rain
e
Intr
avenous
MgS
O4
1or
2g
Pla
cebo
or
meto
clopra
mid
e
Auth
ors
concl
uded
that
MgS
O4
is
likely
not
effect
ive;one
smal
l
RC
Tfo
und
MgS
O4
superi
or
to
pla
cebo,tw
oR
CT
sfo
und
no
diff
ere
nce
betw
een
pla
cebo
and
MgS
O4
and
one
RC
Tfo
und
MgS
O4
infe
rior
topla
cebo
Choian
dPar
mar
,2014
(102):
syst
em
atic
revi
ew
and
meta
-anal
ysis
5R
CT
sof
295
adult
pat
ients
with
acute
mig
rain
e
Intr
avenous
MgS
O4
1or
2g
Pla
cebo,pro
chlo
rpera
zine
or
meto
clopra
mid
e
Auth
ors
concl
uded
that
MgS
O4
show
edno
benefit
ove
rco
m-
par
ators
;7%
few
er
pat
ients
on
MgS
O4
had
head
ache
relie
fas
com
par
ed
toco
mpar
ators
in
meta
-anal
ysis
(95%
CI:
–0.2
3to
0.0
9)
RC
TSh
ahra
miet
al.,
2015
(103):
RC
T
70
adult
pat
ients
with
acute
mig
rain
e
Intr
avenous
MgS
O4
1g
Intr
aven
ous
meto
clopra
mid
e
10
mgþ
dexam
eth
asone
8m
g
MgS
O4
was
more
effect
ive
in
decr
eas
ing
pai
nse
veri
ty20
min
-
ute
s,one
hour
and
two
hours
afte
rtr
eat
ment
than
meto
clo-
pra
mid
ean
ddexam
eth
asone
(p<
0.0
001)
(continued)
Tab
le2.
Continued.
Nutr
aceutica
l
Typ
eof
studie
s
Indiv
idual
studie
san
d
desi
gnN
/pat
ients
Inte
rven
tion
Com
par
ison
Outc
om
es
Ora
l mag
nesium
Non- random
ized
Cas
telli
et
al.,
1993
(109):
pro
spect
ive
open-lab
elst
udy
40
child
ren
with
peri
odic
syndro
mes
(25
mig
rain
e,
12
recu
rrent
abdom
inal
pai
n,th
ree
feve
rof
unknow
nori
gin)
Mag
nesi
um
pid
ola
te,
dose
s
rangi
ng
from
122
to
266
mg
of
ele
menta
l
mag
nesi
um
for
vari
ous
dura
tions
N/A
72.5
%ofpat
ients
had
are
duct
ion
in
mig
rain
efr
equency
to33%
or
less
of
bas
elin
eaf
ter
one
month
of
treat
ment
Gra
zziet
al.,
2005
(112):
pro
spect
ive
open-lab
elst
udy
9ch
ildre
nw
ith
TT
HM
agnesi
um
pid
ola
te2.2
5m
g
bid
for
two
month
s
N/A
Head
ache
frequency
decr
eas
ed
at
one
year
in80%
ofepis
odic
TT
H
par
tici
pan
tsan
d100%
of
chro
nic
TT
Hpar
tici
pan
tsat
12-m
onth
follo
w-u
pan
d100%
of
allpar
-
tici
pan
tshad
are
duct
ion
in
medic
atio
nusa
geby
12
month
s
Gra
zziet
al.,
2007
(113):
pro
spect
ive
open-lab
elst
udy
45
child
ren
and
adole
scents
with
epis
odic
TT
H
Mag
nesi
um
pid
ola
te
2.2
5m
gbid
for
thre
e
month
s.O
nly
49.1
%
com
ple
ted
follo
w-u
pan
d
treat
ment
aspla
nned
N/A
Head
ache
day
s(p¼
0.0
01),
anal
gesi
c
consu
mption
(p¼
0.0
001)
and
MID
AS
score
s(p¼
0.0
01)
decr
eas
ed
sign
ifica
ntly
at12-
month
follo
w-u
p
RC
TFa
cchin
ett
iet
al.,
1991
(104):
RC
T
20
wom
en
with
menst
rual
mig
rain
e
Mag
nesi
um
pyrr
olid
one
carb
oxyl
icac
id
(360
mg/
day
)fo
rtw
o
month
s(n¼
10)
Pla
cebo
for
two
month
s(n¼
10)
Both
groups
had
reduce
dpai
n,w
ith
mag
nesi
um
group
hav
ing
ala
rger
decr
eas
ein
pai
nm
agnitude
(p<
0.0
3);
only
mag
nesi
um
group
had
less
head
ache
day
s
Kose
ogl
uet
al.,
2008
(105):
RC
T
40
adults
with
mig
rain
e
without
aura
Mag
nesi
um
citr
ate
1830
mg
(295.7
mg
ele
menta
l)PO
bid
for
thre
em
onth
s(n¼
30)
Pla
cebo
for
thre
e
month
s(n¼
10)
The
mag
nesi
um
group
had
alo
wer
media
npost
-/pre
-tre
atm
ent
atta
ckfr
equency
ratio
(0.5
5vs
.
1.0
0,p¼
0.0
05)
Esf
anja
niet
al.,
2012
(106):
singl
e-
blin
dR
CT
133
adults
with
mig
rain
e
or
sim
ilar
head
aches
Mag
nesi
um
oxid
e
500
mg
PO
dai
ly
for
thre
e
month
s(n¼
33)
L-c
arnitin
e500
mg
PO
dai
lyfo
rth
ree
month
s(n¼
35)
Mag
nesi
um
oxid
e
500
mg
PO
dai
ly
þL-c
arnitin
e
500
mg
PO
for
thre
em
onth
s
(n¼
30)
No
treat
ment
for
thre
e
month
s
(n¼
35)
Stat
istica
llysi
gnifi
cant
reduct
ion
in
allgr
oups
exce
pt
for
the
no
treat
ment
group
(p<
0.0
01
for
all);af
ter
post
-hoc
anal
yses,
only
the
mag
nesi
um
group
asco
m-
par
ed
toth
eno
trea
tment
group
had
agr
eat
er
reduct
ion
(p<
0.0
06)
Peik
ert
et
al.,
1996
(107):
RC
T
81
adults
with
mig
rain
eTr
i-m
agnesi
um
dic
itra
te
600
mg
dai
lyfo
r
thre
em
onth
s(n¼
43)
Pla
cebo
for
thre
e
month
s(n¼
38)
Gre
ater
reduct
ion
in
mig
rain
efr
equency
in
the
mag
nesi
um
group
asco
mpar
ed
toth
e
pla
cebo
group
(41.6
%vs
.15.8
%,
p¼
0.0
303)
(continued)
Tab
le2.
Continued.
Nutr
aceutica
l
Typ
eof
studie
s
Indiv
idual
studie
san
d
desi
gnN
/pat
ients
Inte
rvention
Com
par
ison
Outc
om
es
Pfa
ffenra
thet
al.,
1996
(108):
RC
T
69
adults
with
mig
rain
e
without
aura
Mag
nesi
um
L-a
spar
tate
-
hydro
chlo
ride-
trih
ydra
te10
mm
ol
(121.5
mg
ele
menta
l)
PO
twic
edai
lyfo
r
thre
em
onth
s(n¼
35)
Pla
cebo
for
thre
e
month
s(n¼
34)
No
diff
ere
nce
inpro
port
ion
of
pat
ients
with
50%
or
great
er
reduct
ion
indura
tion
or
inte
nsi
ty
of
mig
rain
es
(28.6
%of
the
mag
-
nesi
um
group
vs.29.4
%of
the
pla
cebo
group)
Wan
get
al.,
2003
(110):
RC
T
118
child
ren
and
adole
scents
with
head
aches
sugg
est
ive
of
mig
rain
e
Mag
nesi
um
oxid
eco
nta
inin
g
9m
g/kg
of
ele
menta
l
mag
nesi
um
PO
tid
for
four
month
s(n¼
58)
Pla
cebo
for
four
month
s(n¼
60)
Both
groups
had
adow
nw
ard
trend
inhead
ache
day
s,w
ith
only
the
mag
nesi
um
group
sust
ainin
gth
e
trend
pas
tsi
xw
eeks;
no
sign
ifi-
cant
diff
ere
nce
betw
een
groups
afte
rre
gress
ion
anal
yses
(p¼
0.8
8)
Gal
lelli
et
al.,
2014
(111):
singl
e-b
lind
RC
T
160
child
ren
and
adole
scents
with
mig
rain
ew
ithout
aura
Mag
nesi
um
400
mg
dai
lyþ
aceta
min
ophen
15
mg/
kg
tobe
take
n
with
acute
mig
rain
e
epis
odes
for
up
to
18
month
s(n¼
40)
Mag
nesi
um
400
mg
dai
lyþ
ibupro
fen
10
mg/
kg
tobe
take
nw
ith
acute
mig
rain
e
epis
odes
for
up
to18
month
s(n¼
40)A
ceta
min
ophen
15
mg/
kg
tobe
take
nw
ith
acute
mig
rain
eepis
odes
for
up
to18
month
s(n¼
40)
Ibupro
fen
10
mg/
kg
to
be
take
nw
ith
acute
mig
rain
e
epis
odes
for
up
to
18
month
s(n¼
40)
Tre
atm
ent
with
mag
nesi
um
reduce
d
pai
nin
tensi
tyac
ute
lyw
hen
com
bin
ed
with
aceta
min
ophen
or
ibupro
fen
(p<
0.0
1)
and
resu
lted
ina
reduct
ion
of
mig
rain
efr
equency
(p<
0.0
1)
Coe
nzym
eQ
10
Non- random
ized
Roze
net
al.,
2002
(114):
pro
spect
ive
open-
labelst
udy
32
adults
with
mig
rain
e
Coenzy
me
Q10
150
mg
dai
lyfo
rth
ree
month
s
N/A
61.3
%ofpat
ients
had
50%
or
great
er
reduct
ion
inm
igra
ine
atta
ck
freq
uency
Hers
hey
et
al,2007
(116):
pro
spect
ive
open-
labelst
udy
252
child
ren
and
adole
scents
with
mig
rain
ean
d
coenzy
me
Q10
defic
iency
Coenzy
me
Q10
1–3
mg/
kg
dai
lyfo
r
avera
geof
thre
em
onth
s
N/A
Sign
ifica
ntly
less
head
ache
day
s/
month
afte
rtr
eat
ment
peri
od
(19.2�
9.8
vs.12.5�
10.8
,
p<
0.0
1)
RC
TSa
ndor
et
al.,
2005
(115):
RC
T
43
adults
with
mig
rain
e
Coenzy
me
Q10
100
mg
tid
for
four
month
s
(n¼
22)
Pla
cebo
for
four
month
s(n¼
21)
Coenzy
me
Q10
group
had
agr
eate
r
reduct
ion
inm
igra
ine
atta
ckfr
e-
quency
com
par
ed
topla
cebo
(–
1.1
9�
1.9
vs.–0.0
9�
1.9
,
p¼
0.0
5)
Slat
er
et
al.,
2011
(117):
cross
-ove
r,
add-o
nR
CT
120
child
ren
and
adole
scents
with
mig
rain
e
Coenzy
me
Q10
100
mg
dai
lyfo
rfo
ur
month
s
(n¼
60)
Pla
cebo
for
four
month
s(n¼
60)
Sign
ifica
nt
reduct
ion
in
head
ache
frequency
in
both
groups,
but
repeat
ed-
meas
ure
sA
NO
VA
faile
dto
show
atim
e�
conditio
n
inte
ract
ion
(p>
0.0
5)
(continued)
Tab
le2.
Continued.
Nutr
aceutica
l
Typ
eof
studie
s
Indiv
idual
studie
san
d
desi
gnN
/pat
ients
Inte
rven
tion
Com
par
ison
Outc
om
es
Mis
cella
neous
Non- random
ized
Wag
ner
et
al.,
1997
(118):
pro
spect
ive
open-
labelst
udy
168
adults
with
mig
rain
e
W-lin
ole
nic
acidþa-
linole
nic
acid
1800
mgþ
vita
min
B6,nia
cinþ
D-a
-
toco
phero
lþb-
caro
tene
þva
rious
oth
er
lifest
yle
inte
rventions
for
six
month
s
N/A
Sign
ifica
nt
reduct
ion
inm
igra
ine
frequency
in86%
of
pat
ients
D’A
ndre
aet
al.,
2009
(122):
pro
spect
ive
open-lab
elst
udy
50
wom
en
with
mig
rain
e
with
aura
60
mg
ginkgo
bilo
ba
terp
enes
phy
toso
meþ
11
mg
coenzy
me
Q10þ
8.7
mg
vita
min
B2
for
four
month
s
N/A
Mig
rain
efr
equency
decr
eas
ed
sig-
nifi
cantly
from
3.7�
2.2
to
2.0�
1.9
atta
cks
per
month
(p<
0.0
5)
Esp
osi
toan
dC
arote
nuto
,
2011
(123):
pro
spect
ive
open-lab
elst
udy
119
child
ren
with
mig
rain
ew
ithout
aura
Gin
kgo
lide
Bþ
coenzy
me
Q10þ
ribofla
vinþ
mag
nesi
um
bid
for
thre
em
onth
s
(dose
sunsp
eci
fied)
N/A
Mig
rain
efr
equency
decr
eas
ed
from
9.7
1�
4.3
3to
4.5
3�
3.9
6
(p<
0.0
01)
Esp
osi
toet
al.,
2012
(124):
pro
spect
ive
open-
labelst
udy
374
child
ren
with
mig
rain
ew
ithout
aura
Gin
kgo
lide
B80
mg,
coenzy
me
Q10
20
mg,
ribofla
vin
1.6
mgþ
mag
nesi
um
300
mg
for
six
month
s(n¼
187)
L-t
rypto
phan
250
mg,
5-h
ydro
xy-
tryp
tophan
50
mg,
vita
min
PP
9m
gþ
vita
min
B6
1m
gfo
r
six
month
s(n¼
187)
Gre
ater
reduct
ion
inm
igra
ine
fre-
quency
ingi
nkgo
lide
group
com
-
par
ed
tooth
er
group
(9.1
28�
2.8
42
to1.7
34�
1.2
31
vs.8.7
8�
2.5
12
to
3.0
32�
1.0
72)
Usa
iet
al.,
2010
(125):
pro
spect
ive
open-lab
elst
udy
24
child
ren
and
adole
scents
with
mig
rain
e
without
aura
Gin
kgo
lide
B80
mgþ
coenzy
me
Q10
20
mgþ
vita
min
B2
1.6
mgþ
mag
nesi
um
300
mg
for
thre
em
onth
s
N/A
Mig
rain
efr
equency
decr
eas
ed
from
7.4�
5to
2.2�
2.8
atta
cks/
month
(p¼
0.0
015)
RC
TPra
dal
ier
et
al.,
2001
(119):
RC
T
196
adults
with
mig
rain
e
Om
ega
-3poly
unsa
tura
ted
fatt
y
acid
6g
dai
lyfo
r
four
month
s(n¼
100)
Pla
cebo
for
four
month
s(n¼
96)
No
diff
ere
nce
inm
igra
ine
freq
uency
when
com
par
ing
om
ega
-3gr
oup
topla
cebo
(1.2
0�
1.4
vs.
1.2
6�
1.1
1,N
S)
Har
elet
al.,
2002
(120):
cross
-ove
rR
CT
27
adole
scents
with
mig
rain
e
Mar
ine
n3-e
thyl
est
er
conce
ntr
ate
(EPA
378
mg,
DH
A249
mg
and
toco
phera
l2
mg)
1g
two
capsu
les
dai
lyfo
rtw
om
onth
s
Pla
cebo
(ole
icac
id691
mg,
pal
mitic
acid
106
mg,
linole
icac
id
62
mg
and
toco
phero
l2
mg)
1g
two
capsu
les
PO
dai
lyfo
r
two
month
s
Sign
ifica
nt
reduct
ion
inm
igra
ine
frequency
for
both
groups
but
no
sign
ifica
nt
diff
ere
nce
betw
een
the
groups
(mean
num
ber
of
mig
rain
es
duri
ng
treat
ment
4�
1/m
onth
for
both
groups)
MgS
O4:in
trav
enous
mag
nesi
um
sulfa
teA
SA:ac
ety
lsal
icyl
icac
id;PO
:ora
lly;bid
:tw
ice
dai
ly;tid:th
ree
tim
es
dai
ly;ED
:em
erg
ency
depar
tment;
RC
T:ra
ndom
ized
contr
olle
dtr
ial;
EPA
:eic
osa
penta
enoic
acid
;D
HA
:
doco
sahexae
noic
acid
;A
NO
VA
:an
alys
isof
vari
ance
;T
TH
:te
nsi
on-t
ype
head
ache;M
IDA
S:M
igra
ine
Dis
abili
tyA
ssess
ment;
CI:
confid
ence
inte
rval
;N
A:not
avai
lable
;N
S:not
sign
ifica
nt.
activation of the nucleus trigeminalis caudalis (57), anucleus central to migraine pathogenesis, and evidencefor partial agonist activity of parthenolide at TRPA1channels (58), which have been implicated in migrainepathogenesis (59).
Feverfew is one of the best-studied nutraceuticalagents for migraine prophylaxis in adults. A 2004Cochrane review identified five RCTs on this topic.The studies were quite heterogeneous in terms of qualityand methodology, with notable variations in feverfewdosages. Results from the trials were mixed with regardsto the efficacy of feverfew: Whereas the two highestquality trials were negative, the other three trials sug-gested that feverfew is effective in migraine prophylaxis.Feverfew was well tolerated in all five studies. Theauthors concluded that the evidence available wasunconvincing for feverfew’s efficacy in migraine (60).Since the Cochrane review, six new studies have beenpublished. Five of these studies involved combinationsof feverfew with other active interventions: One open-label study and one RCT have suggested that a combin-ation of feverfew and ginger might be effective for acutemigraine relief (61,62), an RCT found no differencebetween placebo and a combination of feverfew, mag-nesium and riboflavin for migraine prophylaxis (63), asmall open-label study demonstrated promise for a com-bination of feverfew and Salix alba in the prevention ofmigraine with aura (64) and finally a randomized trialfound a combination of feverfew and acupuncture to besuperior to either intervention alone for chronicmigraine (65). A methodologically rigorous RCT com-paring a formulation of feverfew to placebo has alsobeen published since the Cochrane review, and sug-gested that feverfew is superior to placebo for migraineprophylaxis in adults (66). In 2012, the AmericanAcademy of Neurology (AAN) concluded that feverfewis probably effective for migraine prevention based onlevel B evidence (67). Based on the state of the evidence,it appears that feverfew might be effective formigraine prophylaxis in adults, but the heterogeneityof the literature, especially with regards to feverfewpreparations and dosages, makes definite conclusionschallenging.
Butterbur (Petasites hybridus) for migraine
Butterbur is a shrub with a long history of use for medi-cinal purposes. It demonstrates a variety of propertiesthat render it a candidate for migraine prophylaxis,including anti-inflammatory action through inhibitionof cyclooxygenase-2 (68) and vasodilatory effectsthrough inhibition of L-type voltage-gated calciumchannels (69).
Although butterbur has been studied for migraineprophylaxis both in adults and children with promising
results reviewed elsewhere (67,70,71), increasing con-cerns about its safety are emerging. Butterbur containshepatotoxic compounds by the name of pyrrolizidinealkaloids. Many of the butterbur formulations avail-able on the market contain detectable and potentiallyhazardous levels of these compounds (72). Petadolex�,a formulation of butterbur that is marketed for itssafety based on undetectable levels of pyrrolizidinealkaloids, has traditionally been the formulation ofbutterbur that is used clinically. Initial data suggestedthat Petadolex� is safe for use in animals and humans(73). However, cases of hepatotoxicity linked toPetadolex� have been reported post-marketing andsome regulatory authorities, namely European autho-rities including the Swiss Agency for TherapeuticProducts and the German Federal Institute ofMedical Devices, have banned its use (74). Therefore,uncertainty about the safety of Petadolex� precludesrecommendations for its use based on recent data.
Riboflavin (vitamin B2) for migraine
Riboflavin is a vitamin that plays an important role incellular energy production through its two active coen-zyme forms that are involved in oxidation-reductionreactions during a variety of cellular processes (75).Given evidence hinting at mitochondrial energy deple-tion in migraine (76–83), riboflavin’s essential role inmitochondrial energy metabolism suggests that itcould be effective in treating migraine.
Riboflavin has demonstrated efficacy and tolerabilityfor migraine prevention in adults based on a case series(84) and several open-label studies (85–88). One smallRCT found riboflavin to be superior to placebo formigraine prophylaxis in a sample of 55 adult migrain-eurs (89). Riboflavin was comparable to propranololafter three months and six months of administrationin an RCT assessing its efficacy for adult migraineprophylaxis (90). Another RCT among adults withmigraine explored the efficacy of high-dose riboflavin,combined with feverfew and magnesium as comparedto low-dose riboflavin and found that both interven-tions yielded modest responder rates (63). All of theavailable studies indicate that riboflavin is welltolerated among adults with migraine. The AAN hasdetermined that riboflavin is probably effective formigraine prophylaxis based on B-level evidence (67).Therefore, studies on the efficacy of riboflavin are con-sistent in their findings and suggest that riboflavin iswell tolerated and efficacious for adult migraineprophylaxis.
Riboflavin has also been studied in the pediatricpopulation, but results are conflicting. A retrospectivecase series among children with a variety of headachedisorders found riboflavin to be effective in the first
Orr 15
three months of treatment, but efficacy appeared towane over time and results were not sustained beyondthree months (91). Another retrospective case seriesthat similarly investigated the role of riboflavin forthe prophylaxis of a variety of headache disordersfound that adolescents with chronic migraine, but notother headache disorders, responded well to riboflavin(92). An underpowered RCT found no differencebetween riboflavin and placebo for pediatric migraineprophylaxis after 12 weeks of treatment (93). A smallcross-over RCT using a lower dose of riboflavin ascompared to previous studies found that children hada reduction in the number of tension-type headaches(TTHs), but not migraines, on riboflavin (94). In thepediatric population, riboflavin lacks adequately pow-ered and methodologically rigorous studies. Althoughpreliminary results are disappointing, further studiesshould explore the efficacy of riboflavin in thispopulation.
Magnesium for migraine
Magnesium is ubiquitous in the human body and plays animportant role in a multitude of biological processes,some of which are linked to migraine pathogenesis (95).There is a large body of evidence, reviewed elsewhere (96),that points to a state of magnesium deficiency amongmigraineurs. There is therefore a plausible biologicalreason to explore magnesium as a migraine intervention.
Intravenous magnesium sulfate (MgSO4) has beenused to treat acute headaches. Two retrospective caseseries among children with acute headaches contra-dicted each other with regards to conclusions on theefficacy of intravenous magnesium for acute headacherelief (97,98). In adults, open-label studies have shownpromise for intravenous MgSO4 in acutely relievingvarious headache types (99) and cluster headache inpatients with low magnesium levels (100). A recent sys-tematic review of published trials identified four eligibleRCTs on the efficacy of MgSO4 for migraine relief inadults, and results were heterogeneous, with one smalltrial finding MgSO4 superior to placebo, two trials find-ing no difference between placebo and MgSO4 in termsof the primary outcome and one trial finding MgSO4
inferior to placebo. The authors concluded that intra-venous MgSO4 is not likely to be effective for acutemigraine relief (101). Similar conclusions were reachedin a recent meta-analysis on the same topic (102). Sincepublication of these reviews, one further RCT has beenpublished. In this trial, 1 g of intravenous MgSO4 wassuperior to a combination of 10mg of metoclopramideand 8mg of dexamethasone for acute migraine relief inadults (103). Given the relatively low doses of metoclo-pramide and dexamethasone, as well as the small
sample size (N¼ 70) relative to the rest of the literature,this study is unlikely to change conclusions about theefficacy of MgSO4 for acute migraine relief.
Oral magnesium supplementation has been studiedfor adult and pediatric migraine prevention. In asample of women with low magnesium levels, magne-sium was superior to placebo for menstrual migraineprophylaxis (104). Three separates RCTs with varyingmethodologies, comparison groups, magnesiumdosages and formulations have found oral magnesiumto be effective for migraine prophylaxis in adults(105–107). Another RCT contradicted these findingsand found oral magnesium to be no different from pla-cebo on interim analysis in a sample of refractorymigraine patients and thereby halted recruitmentprior to achieving the planned sample size (108). TheAAN guidelines conclude that magnesium is probablyeffective for migraine prophylaxis in adults based onlevel-B evidence (67). Three studies have assessed mag-nesium prophylaxis for pediatric migraine. One open-label study found oral magnesium supplementation tobe beneficial in a variety of childhood periodic syn-dromes (109). A small RCT found a significant down-ward trend in headache frequency for children treatedwith magnesium but not with placebo (110). Finally, anRCT found that daily oral magnesium had a synergisticeffect with acetaminophen or ibuprofen in achievingbetter acute pain relief than either analgesic alone andalso found magnesium to be effective in reducingmigraine frequency (111). These magnesium studieshave consistently uncovered minor gastrointestinalside effects associated with oral magnesium, namelysoft stools and diarrhea, but no major magnesium-associated adverse events. The balance of evidenceseems to be in favor of oral magnesium for migraineprophylaxis, but further research should be carried outin order to confirm these findings and assess differentialefficacy based on baseline magnesium levels, given thatmagnesium-deficient patients would intuitively benefitmore from supplementation or increased dietary intakeof magnesium.
In addition to the evidence for oral magnesiumprophylaxis in migraine, two studies have assessed itsefficacy in pediatric TTH. In a prospective case series ofnine pediatric patients with tension-type headaches,oral magnesium appeared to be quite effective for themajority of the patients (112). The same author grouplater carried out a larger prospective study in 45 pedi-atric TTH patients, and found magnesium to be effect-ive among the patients completing follow-up asprescribed (113). These preliminary results are promis-ing but studies with more rigorous designs should becarried out prior to making recommendations on theuse of magnesium for pediatric TTH.
16 Cephalalgia 0(0)
Coenzyme Q10 for migraine
Coenzyme Q10 acts as an electron carrier in the mito-chondrial electron transport chain and therefore playsan important role in cellular energy metabolism.Hence, similarly to riboflavin, its potential mechanismof action in migraine would relate to the evidencethat migraine results in mitochondrial energy deficiency(76–83).
In a small open-label prospective study, four monthsof treatment with coenzyme Q10 showed promisingresults for the prophylaxis of migraine in adults, withno significant side effects observed (114). An RCT laterfound coenzyme Q10 to be superior to placebo in asmall sample of adults with migraine, with one patientin the coenzyme Q10 group reporting a cutaneousallergy (115), but no other notable side effects. Basedon the adult data, the AAN concludes that coenzymeQ10 is possibly effective for migraine prophylaxis inadults based on level C evidence (67). An open-labelstudy among pediatric migraineurs found a favorableresponse to coenzyme Q10 among patients with lowcoenzyme Q10 levels at baseline (116). The samegroup later carried out a cross-over RCT in a sampleof pediatric patients and did not find any notable dif-ferences between the treatment periods with coenzymeQ10 as compared to placebo (117). The study was lim-ited by a small sample size in the context of a highdrop-out rate, and the authors did not selectivelytreat patients with low baseline coenzyme Q10 levels.Overall, it seems that coenzyme Q10 might be effectiveand safe for migraine prophylaxis, but future high-quality studies that take into consideration baselinecoenzyme Q10 levels should be endeavored.
Miscellaneous nutraceuticals for headache
Although the nutraceuticals described above demon-strate the most promise in headache management,several other agents have been investigated in smallernumbers of studies or with lower-quality evidence.Supplements of polyunsaturated fatty acids (PUFAs)do not appear to be effective for migraine prophylaxis(70). The evidence for their use in migraine derives fromone open-label study finding improvement in adultmigraine with a multi-pronged intervention includingPUFAs (118), two RCTs finding no difference in effi-cacy comparing PUFAs to placebo in adults (119) andadolescents (120) and one RCT, with unblindedpatients, finding that addition of PUFAs to sodiumvalproate resulted in greater reduction in migrainefrequency after one month of treatment, which wasnot sustained after three months (121). Ginkgolide B,in combination with a variety of other nutraceuticalagents, appears to improve migraine status in adults
(122) and children (123–125) based on open-label stu-dies. However, the methodologic limitations and het-erogeneity of the compounds studied make the evidencedifficult to apply to clinical recommendations. Relief ofcluster headache with intranasal capsaicin has beendocumented in several studies, reviewed elsewhere(126). In addition, limited studies have been carriedout to assess the efficacy of a variety of other nutraceut-icals for headache (127), including phytoestrogens formenstrual migraine, caffeine for migraine and a varietyof topical botanical therapies for headache.
Conclusions
Perhaps in response to the growth of the CAMindustry, an increasing number of studies are exploringthe role of CAM for headache. In this review, the cur-rent state of evidence for dietary and nutraceuticalinterventions in headache disorders is described.Several interventions show promise as potentialheadache treatments, although the limited number ofadequately powered studies and low quality of the evi-dence have made it difficult to apply the findings toroutine clinical practice. Because of limited data, cau-tion needs to be taken when considering use of theseinterventions in clinical practice.
When discussing nutraceuticals with patients, severalissues need to be considered. Patients tend to perceiveherbal supplements as safe for a variety of reasons,including their non-prescription availability, and theirnatural properties (128). However, as with pharmaceut-ical agents, physicians must be aware of potentialtoxicities and side effects when counseling patientsabout these interventions. In fact, society would benefitfrom nutraceuticals being conceptualized, scrutinizedand regulated in the same manner as pharmaceuticals,given that they have the potential for both similar effi-cacy and harm. The case of butterbur illustrates theneed for ongoing caution and long-term monitoringof safety data in relation to nutraceuticals.Nonetheless, several of the dietary and nutraceuticalinterventions above warrant further investigationgiven promising preliminary efficacy and safety data.
When considering CAM therapies for patients withheadache disorders, several factors must be weighed.As highlighted above, the quality of the evidence forefficacy and tolerability should be at the forefront of thedecision-making process. In addition, headache practi-tioners should consider patient comorbidities, as someof the CAM therapies have been used in other circum-stances and may therefore offer a twofold benefit.For example, patients with menstrual migraine and pre-menstrual syndrome may experience relief of bothconditions with magnesium, phytoestrogens or ginkgo-lide B (129). In this way, clinicians need to weigh the
Orr 17
risks and benefits from the evidence, and consider indi-vidual patient characteristics and preferences whenprescribing CAM, in the same manner as is currentlythe standard with pharmacological interventions.
Given the prevalence of CAM use among patientswith headaches, it is imperative that practitionersdevelop an understanding of CAM therapies and thestate of evidence for their use. At a minimum, know-ledge of CAM allows the practitioner to engage in edu-cated discussions about the efficacy and safety of CAMand is likely to foster information sharing and shareddecision making between the practitioner and the
patient. In one study, patients seeing general practi-tioners with additional CAM training had lowerhealth care costs and lower mortality as compared topatients seeing general practitioners without additionalCAM training (130). Thus, physicians who are edu-cated about CAM may provide better care to theirpatients. Hence, we owe it to our patients to becomeengaged in this area and to advocate for high-qualityintervention studies, where justified by plausible mech-anisms of action and preliminary data, that will allowus to better comment on the safety and efficacy of theseinterventions.
Clinical implications
. A majority of patients with primary headache disorders have explored complementary and alternativemedicines (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 thenumber of studies and the quality of the evidence.
. Further evidence is required to further explore the safety and efficacy of some of the more promising dietaryand nutraceutical headache interventions.
Funding
This research received no specific grant from any fundingagency in the public, commercial, or not-for-profit sectors.
Conflict of interest
None declared.
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