HEADACHE CURRENTS

Headache Currents

Nutraceuticals in Migraine: A Summary of Existing

Guidelines for Use
Thilinie Rajapakse, MD; Tamara Pringsheim, MD, MSc

Background.—The use of nutraceuticals or food/herbal fortable to disclose this information. It is imperative that clear
products for health benefits is expanding in adults with communication regarding the use of CAM exists especially in
migraine as they seek relief from pain in an effective and toler- light of potentially dangerous drug-herb interactions.
able manner not always afforded by current conventional phar- Guidelines from the American Academy of Neurology
macologic therapies. Guidelines from the American Academy (AAN)/American Headache Society (AHS), the Canadian
of Neurology/American Headache Society, Canadian Headache Headache Society (CHS), and the European Federation of
Society, and European Federation of Neurological Societies Neurological Societies (EFNS) have all discussed nutraceutical
have discussed nutraceuticals in varying degrees of detail with agents in migraine prophylaxis to varying degrees, sometimes
at times conflicting recommendations.
with conflicting recommendations. The purpose of this review
Conclusion.—This review serves to provide a summary of
is to translate existing AAN/AHS, CHS, and EFNS guidelines
existing guidelines for the use of certain nutraceuticals includ-
ing riboflavin, coenzyme Q10, magnesium, butterbur, fever- for use for the clinical practitioner and highlight the random-
few, and omega-3 polyunsaturated fatty acids. The review will ized controlled trial evidence for use of the following nutra-
also discuss the regulation of nutraceuticals in North America ceuticals: riboflavin, coenzyme Q10, magnesium, butterbur,
and the current controversy regarding butterbur and its safety. feverfew, and omega-3 polyunsaturated fatty acids (OPFA). A
brief discussion of the regulatory processes of natural medi-
Key words: migraine, nutraceutical, supplement, herbal, prophylaxis
cines in Canada and the USA will also cover some points in
the hotly debated issue of butterbur safety.

INTRODUCTION REGULATION OF NUTRACEUTICALS IN

Patients frustrated with the frequent lack of efficacy, cost, NORTH AMERICA
and side effects of conventional pharmacologic agents are In Canada, nutraceuticals and all natural health products
turning to nutraceuticals for migraine relief. The term must adhere to the Natural Health Products Regulations insti-
“nutraceutical” was coined by DeFelice in 1979 and is derived tuted in 2004 stipulating product licensing based on manufac-
from the “nutrition” and “pharmaceutical” industries. It is turer provision of proper safety and efficacy evidence to
defined as a “food, or parts of food, that provide medicinal or Health Canada, Canada’s federal health department.3 Informa-
health benefits, including the prevention and treatment of tion provided to Health Canada from the manufacturer must
disease.”1 disclose medicinal ingredients, source, dose, potency, and non-
Patients with migraine are turning to complementary and medicinal ingredients as well as a recommended dose. A
alternative medicine (CAM), of which nutraceuticals are con- license is issued along with a Natural Product Number (NPN;
sidered biological based therapies,2 in increasing numbers as which must be present on the product label) if Health Canada
reported from the 2007 National Health Interview Study. In deems a product to be safe, effective, and of high quality.
adults with migraine/severe headache, 49.5% reported using Similarly, any sites in Canada involved in marketing/packag-
CAM, compared with 33.9% who did not have migraine/ ing/labeling/importing natural medicines must also have a site
headache.2 Interestingly, most adults with migraine do not dis- license and follow good manufacturing practices outlined by
cuss their use of CAM with their health care providers. Clini- Health Canada.
cians should make an effort to enquire about CAM use in In the United States of America, the U.S. Food and Drug
their patients; similarly, patients should be made to feel com- Administration (FDA) regulates dietary supplements, which
include nutraceuticals. The FDA regulates dietary supplements
under a different set of regulations than those covering
From the Section of Neurology, Department of Pediatrics, Alberta Children’s Hospital, Uni- “conventional” foods and drug products under the Dietary
versity of Calgary, Calgary, Alberta, Canada (T. Rajapakse); Departments of Clinical Neuro-
sciences, Psychiatry, Pediatrics and Community Health Sciences, University of Calgary, Supplement Health and Education Act of 1994 (DSHEA).4
Calgary, Alberta, Canada (T. Pringsheim) In contrast to Canadian regulations, research studies in
Address all correspondence to T. Pringsheim, 3280 Hospital Drive NW, Calgary, AB, T2N
humans to prove dietary supplement safety/efficacy are not
4Z6, Canada
Accepted for publication February 8, 2016.
............. .............
Headache Conflict of Interest: Thilinie Rajapakse has no conflicts of interest to disclose. Tamara Pring-
C 2016 American Headache Society
V sheim has received travel support to attend a scientific meeting from Allergan Canada.

808
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required by the FDA prior to marketing. However, there is a group (19%). The treatment was well tolerated with minor
responsibility of the manufacturers and distributors to ensure adverse reactions of diarrhea and polyuria reported.
the product marketed is safe and that claims made on the Maizels et al8 conducted a randomized, double-blind pla-
label are accurate and truthful. Health claims made must be cebo controlled trial rated as fair (CHS) Class II (AAN/AHS)
followed by the statement, “This statement has not been eval- quality in 49 patients over a 3 month period following a one
uated by the Food and Drug Administration. This product is month baseline run-in period. This study received a “fair”
not intended to diagnose, treat, cure, or prevent any disease.” quality rating in part due to failure to state the method of
If the FDA subsequently finds a supplement to be unsafe, randomization in the methods section.9 A compound of daily
adulterated, or misbranded, they may take action against the riboflavin 400 mg with magnesium 300 mg and feverfew
manufacturer or distributor through issuance of a warning or 100 mg was compared to a “placebo” of 25 mg of riboflavin.
requiring the product be removed from the market. The In the primary outcome measure of 50% or greater reduction
FDA’s postmarketing responsibilities include monitoring of migraines, there was no significant difference between active
safety, for example, voluntary dietary supplement adverse and “placebo” groups.
event reporting, and product information, such as labeling, Guideline Recommendations
claims, package inserts, and accompanying literature. The CHS guidelines9 gave riboflavin a strong recommenda-
In 2015, the New York State Attorney’s office accused four tion based on low quality evidence for benefit, and minimal
major U.S. retailers of selling fraudulent and potentially dan- side effects. The CHS guidelines recommended riboflavin
gerous herbal supplements and demanded that these products 400 mg daily to eligible patients for migraine prophylaxis.
be removed from store shelves. At one popular retail chain, 3 The AAN/AHS guidelines10 give riboflavin a Level B rec-
out of 6 products tested negative for the herbs on their ommendation, stating it is probably effective and should be
labels.5 This recent story highlights the current significant considered for migraine prevention. The EFNS guidelines11
issues regarding safety and regulation of nutraceuticals. give riboflavin a Level C recommendation, stating it is possi-
bly useful for migraine prevention.
Coenzyme Q10
NUTRACEUTICALS IN MIGRAINE REVIEW Coenzyme Q10 (coQ10) is an essential cofactor of the elec-
tron transport chain and protects against mitochondrial col-
Riboflavin
lapse or degeneration by maintaining mitochondrial energy
The name for this member of the vitamin B (B2) family
output through proper electron transport down the respiratory
comes from “ribitol,” the reduced sugar form creating part of
chain.6,12 CoQ10 prevents mitochondrial membrane transi-
its structure, and the “flavin” ring-moiety which, when oxi-
tion pore opening, thus preventing the translocation of large
dized, imparts the characteristic yellow color seen in the urine
molecules that can lead to mitochondrial functional demise.13
of patients taking this vitamin. Riboflavin itself functions as a
CoQ10 also counteracts endothelial dysfunction by stimulat-
cofactor for flavoprotein enzyme function in the electron ing endothelial release of nitric oxide14 and exerts anti-
transport chain of the Kreb’s cycle as well as membrane stabi- inflammatory effects as well.15 Using magnetic resonance spec-
lization and maintenance of energy-related cellular functions.6 troscopy, researchers found evidence of interictal mitochon-
Evidence Review drial dysfunction in the occipital lobes of patients with
Two randomized controlled trials examined efficacy of ribo- migraine, with a correlation seen between severity of findings
flavin in adult patients with migraine. Schonen et al7 con- and intensity of clinical phenotype.16
ducted a trial rated as good (CHS) or Class I (AAN/AHS), Evidence Review
which compared riboflavin 400 mg daily to placebo (please There is one randomized control trial of coenzyme Q10 as
see Table 1 for description of the AHS/AAN, CHS, and a migraine prophylactic agent. Sandor et al17 conducted a fair
EFNS rating systems). After a one month placebo phase, (CHS) or Class II (AAN/AHS) quality double blind, random-
patients were randomized to riboflavin 400 mg daily or pla- ized, placebo-controlled trial in 43 patients with migraine.
cebo for 12 weeks. The primary outcome assessed was the The quality criteria unfulfilled by this study included minor
change in attack frequency in month 4 compared with base- differences between treatment and placebo groups, although
line month 1. A significantly greater responder rate was seen they were deemed generally comparable.9 After a one month
in the riboflavin group with 2 fewer attacks per month versus placebo baseline phase, patients received either coenzyme Q10
no change in the placebo group (P 5.0001) after 3 months. 100 mg po TID or placebo for a 3 month period. The pri-
The responder rate, defined as the percentage of patients mary outcome variable was change of attack frequency in
achieving 50% reduction in migraine frequency, was signifi- month 4 compared with baseline, and results showed a signifi-
cantly higher in the riboflavin group (56%) versus the placebo cant reduction in the coQ10 group of 21.19 migraine attacks
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Headache Currents

Table 1.—Description of the AHS/AAN, CHS, and EFNS Guideline Rating Systems

Organization Description of Rating System for Guideline Recommendations

Canadian Headache Study Quality:

Society Studies are rated “good” if all of the following criteria are met: assembly of comparable groups, adequate random-
ization, allocation concealment, confounders distributed equally, maintenance of comparable groups, absence of
overall high or important differential loss to follow-up, measurement instruments are acceptable and applied
equally, masking of outcome assessment, clear definition of interventions, all important outcomes considered, and
intention to treat analysis performed.
A “fair” study does not meet all criteria but has no fatal flaw that invalidates its results.
A “poor” study contains a fatal flaw. Fatal flaws include the assembly of noncomparable groups, the use of unac-
ceptable or unequally applied measurements, lack of blinding of outcome assessment, failure to address key con-
founders, and lack of intention to treat analysis.
Recommendation Grades:
Strong – high quality evidence: Benefits clearly outweigh risks and burdens for most patients, can apply to most
patients in most circumstances
Strong – moderate quality evidence: Benefits clearly outweigh risks and burdens for most patients, can apply to
most patients, but there is a chance the recommendation may change with more research
Strong – low quality evidence: Benefits clearly outweigh risks and burdens for most patients, can apply to most
patients, but there is a good chance the recommendation could change with more research
Weak – high quality evidence: Benefits are more closely balanced with risks and burdens for many patients;
whether a medication is used will depend upon patient circumstances
Weak – moderate quality evidence: Benefits are more closely balanced with risks and burdens for many patients;
whether a medication is used will depend on patient circumstances, but there is less certainly about when it
should be used
Weak – low quality evidence: Benefits are more closely balanced with risks and burdens; there is considerable
uncertainty about when to use this medication
American Headache Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome
Society/American assessment, in a representative population. Relevant baseline characteristics are presented and substantially equiva-
Academy of lent among treatment groups or there is appropriate statistical adjustment for differences.
Neurology The following are also required:
a. concealed allocation
b. primary outcome(s) clearly defined
c. exclusion/inclusion criteria clearly defined
d. adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers
with numbers sufficiently low to have minimal potential for bias.
e. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also
required*:
1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for
equivalence or noninferiority.
2. The standard treatment used in the study is substantially similar to that used in previous studies establishing
efficacy of the standard treatment (eg, for a drug, the mode of administration, dose and dosage adjustments are
similar to those previously shown to be effective).
3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treat-
ment are comparable to those of previous studies establishing efficacy of the standard treatment.
4. The interpretation of the results of the study is based on a per protocol analysis that takes into account drop-
outs or crossovers.
Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with
masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study
with masked or objective outcome assessment in a representative population that meets b–e above. Relevant base-
line characteristics are presented and substantially equivalent among treatment groups or there is appropriate sta-
tistical adjustment for differences.
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own
controls) in a representative population, where outcome is independently assessed, or independently derived by
objective outcome measurement.**
Class IV: Studies not meeting Class I, II, or III criteria including consensus or expert opinion.
*Note that numbers 1–3 in Class Ie are required for Class II in equivalence trials. If any one of the three is miss-
ing, the class is automatically downgraded to Class III.
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Table 1.—Continued
Organization Description of Rating System for Guideline Recommendations

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient,
treating physician, investigator) expectation or bias (eg, blood tests, administrative outcome data).
Classification of recommendations
A 5 Established as effective, ineffective, or harmful (or established as useful/predictive or not useful/predictive) for
the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)*
B 5 Probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given
condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II
studies.)
C 5 Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given
condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class
III studies.)
U 5 Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.
*In exceptional cases, one convincing Class I study may suffice for an “A” recommendation if 1) all criteria are
met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence
interval is >2).
European Federation Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assess-
of Neurological ment in a representative population or an adequately powered systematic review of prospective randomized con-
Sciences trolled clinical trials with masked outcome assessment in representative populations. The following are required:
(1) randomization concealment (2) primary outcome(s) is/are clearly defined (3) exclusion/inclusion criteria are
clearly defined (4) adequate accounting for dropouts and crossovers with numbers sufficiently low to have mini-
mal potential for bias (5) relevant baseline characteristics are presented and substantially equivalent among treat-
ment groups or there is appropriate statistical adjustment for differences
Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment
that meets a–e above or a randomized, controlled trial in a representative population that lacks one criteria a–e
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own
controls) in a representative population, where outcome assessment is independent of patient treatment
Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion
Rating of recommendations
Level A rating (established as effective, ineffective, or harmful) requires at least one convincing class I study or at
least two consistent, convincing class II studies
Level B rating (probably effective, ineffective, or harmful) requires at least one convincing class II study or over-
whelming class III evidence
Level C (possibly effective, ineffective, or harmful) rating requires at least two convincing class III studies

per month versus 20.09 in the placebo group. The 50% and disability in those supplemented with coQ10. Clinicians
responder rate for the coQ10 was significantly higher at may want to consider serum coQ10 level testing in patients
47.6% versus 14.3% in the placebo group. Authors found the prior to supplementation.
coQ10 effect appeared after the first month and was maximal Guideline Recommendations
after 3 months of treatment and calculated a number needed The CHS guidelines gave coQ10 a strong recommendation
to treat of 3 for coQ10 use in the prophylaxis of migraine. based on low quality evidence for the prophylaxis of migraine.
The coQ10 was well tolerated with only one patient with- It was recommended that a 300 mg daily dose of coenzyme
drawing due to cutaneous allergy. Q10 be given 100 mg po TID.
An interesting study in adolescents by Hershey et al18 sug- The AAN/AHS and EFNS guidelines gave coQ10 a Level
gests that coQ10 deficiency may be common in children and C recommendation, stating it is possibly effective and may be
adolescents with migraine, and that determination of defi- considered for migraine prevention.
ciency and subsequent supplementation may result in clinical Magnesium
improvement. In 1,550 patients tested, 32.9% were deficient Magnesium has been postulated to play a role in establish-
in coQ10. Deficient patients were treated with doses ranging ment of a threshold for migraine attacks.19 Important patho-
from 1-3 mg/kg/day. In this adolescent population, there was physiological mechanisms by which this is achieved include
evidence of significant (P <.001) reduced headache frequency neuroinflammatory blockade, calcium channel blocking
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Headache Currents

effects, N-methyl-D-aspartate (NMDA)-glutamate receptor 30 patients receiving magnesium and only 10 patients receiv-
blockade and effects on glutamate and nitric oxide synthesis, ing placebo.
release and activity, serotonin receptor affinities and activities, A recent review23 of oral magnesium supplementation in
and endogenous hormone regulation. Through these methods, migraine prevention suggests that regardless of the various
magnesium is thought to regulate various vascular and neuro- magnesium measurement techniques used, low magnesium
nal mechanisms.6 levels and migraine generally remain associated. However, due
Evidence Review to the limited evidence, the authors suggested increasing die-
Two fair (CHS) quality randomized controlled trials20,21 tary magnesium intake as a form of supplementation. Similar
were performed comparing magnesium to placebo for the pro- to coenzyme Q10, clinicians may want to consider doing
phylaxis of migraine. serum magnesium testing prior to supplementation in the pro-
Peikert et al20 randomized 81 patients to 24 mmol elemental phylaxis of migraine. In addition, it has been suggested that
magnesium (600 mg elemental magnesium as trimagnesium the mixed results of current randomized controlled trials of
dicitrate) or placebo daily for 12 weeks. Patients treated with magnesium supplementation in migraine prevention are
magnesium had a significantly higher reduction in attack fre- related to the inclusion of both magnesium deficient and non-
quency (21.51 in magnesium group, 20.58 in placebo group, deficient patients in these trials.24 Future trials may benefit
P 5.03) in the final month of treatment compared with base- from studying an exclusively magnesium deficient population.
line versus the placebo group. The responder rate of a 50% or Guideline Recommendations
greater reduction in number of attacks from baseline was The CHS makes a strong recommendation based on low
52.8% in the magnesium group and 34.4% in the placebo quality evidence to support the use of magnesium in the pro-
group (P 5.15) in the final month of treatment. Adverse events phylaxis of migraine, in light of some evidence for benefit and
included diarrhea in 18.6%, which led to treatment discontinu- minimal side effects. Due to contradictory evidence in various
ation in 2 patients, as well as gastric irritation in 4.7% of par- trials, they suggest a dose of 24 mmol (600 mg) or elemental
magnesium as magnesium citrate be used daily as a positive
ticipants. This study was rated only as “fair” due to the
result was only obtained with this particular compound. The
unfulfilled quality criteria including allocation concealment
AAN/AHS guideline gave magnesium a Level B recommenda-
method not stated and inadequate description of randomization
tion, and the EFNS gave a Level C. The EFNS supported use
procedures.9
of the same dose of magnesium as the Canadian guidelines.
Pfaffenrath et al21 randomized 69 patients to 10 mmol ele-
Butterbur
mental magnesium twice daily (243 mg elemental magnesium
Petasites hybridus, commonly known as butterbur, is a
twice daily as magnesium-L-aspartate-hydrochloride trihy-
perennial shrub with a history of use in the prevention of
drate) to placebo for 12 weeks following a 4 week baseline
migraine. The name butterbur is attributed to the traditional
period. There was no significant difference (28.6% magne- use of its large leaves to wrap butter in warm weather.25 The
sium, 29.4% placebo) seen in the percentage of patients leaves, rhizomes (underground stems), and roots of the Peta-
achieving the primary outcome of 50% reduction of migraine sites plant are all used to make solid extracts sold in tablet
duration (in hours) or the intensity of migraine at the end of form.
the third month of treatment. The main side effect experi- Its use has recently been surrounded in controversy, how-
enced was soft stools or diarrhea. This study was rated as ever, with safety concerns regarding the Petadolex formulation
“fair” quality due to the lack of consideration of all important and other Petasites hybridus butterbur formulations, and 40
outcomes, inadequate statement of randomization, and alloca- reported cases of hepatotoxicity26 (2 requiring liver transplant)
tion concealment.9 reported through the World Health Organization’s pharmaco-
Koseoglu et al22 conducted a poor (CHS) quality study in vigilance database VigiBase. In addition, a recent study testing
40 patients comparing magnesium citrate (600 mg elemental 21 commercially available supplements claiming to contain
magnesium daily) to a placebo control. The randomization P. hybridus in the USA demonstrated that only 7 of the 21
was 4:1 with 30 patients receiving magnesium and only 10 compounds contained the amount of petasins labeled on the
receiving placebo. After a baseline 4 week period, patients package and, more concerningly, hepatotoxic pyrrolizidine
were randomized to either magnesium or placebo, and alkaloids were detected in 7 of the 21 analyzed supplements.27
migraine attack frequency was found to be significantly In Canada, there are 10 licensed butterbur products com-
reduced (P 5.005) in the group receiving treatment with mag- mercially available with an NPN and, thus, certified by Health
nesium (21 attack monthly) when compared with placebo Canada to be safe, effective, and of high quality. To date,
(20.5 attacks monthly). The study was rated as poor quality, there have been no Health Canada warnings for removal of
however, as there was very unequal treatment group size with butterbur from the commercial market due to safety concerns.
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Headache Currents

In the United States, the number of available butterbur sup- tory requirements in light of a number of shortcomings in the
plements is unknown, and to date there have been no FDA original protocol and analysis.9 Compared with a baseline 4
warnings for removal of butterbur products from the commer- week period, patients in the butterbur group had a significant
cial market. decrease in the number of migraine attacks per month at
In the United Kingdom, Petadolex was sold as a section 12 week 12 compared with placebo. Mean attack frequency
traditional herbal product. Concerns with the safety of its use decreased from 3.4 at baseline to 1.8 at week 12 (P 5.0024).
in light of the above mentioned cases of hepatotoxicity, as There was no significant difference in mean attack frequency
well as concerns regarding mass market retail sector use with- from baseline to week 12 in the placebo group. The percent-
out doctor supervision, led to rejection of the license applica- age of treatment responders was 45% in the butterbur group
tion by the UK Medicines and Healthcare products and 15% in the placebo group.
Regulatory Agency (MRHA).28 Meta-analysis of the two above studies for the 50 mg twice
In Germany, where the Petadolex formulation is manufac- daily dose of butterbur versus placebo gives an odds ratio of
tured and exported, marketing authorization was withdrawn 2.24 for achieving a 50% reduction in migraine attack fre-
in 2008.29 While the manufacturers of Petadolex previously quency at week 12.9
extracted harmful pyrrolidizine alkaloids using a methylene Guideline Recommendations
chloride solvent extraction process, in 1988 the solvent was Although the reports of hepatotoxicity may lead to changes
changed to carbon dioxide (CO2), which was thought to be in the near future with respect to the use of butterbur in
superior for the removal of harmful alkaloids. However, when migraine prevention, current Canadian Headache Society guide-
resubmitted for registration, the extraction method was viewed lines give butterbur a strong recommendation for use based on
as a change in the active ingredient, and therefore, the prod- moderate quality evidence for migraine prophylaxis at a dose of
uct marketed was considered different from the one submitted 75 mg twice daily. Consumers are cautioned that only commer-
for license, and the application was denied. cially prepared products in which plant carcinogens and hepato-
Due to this on-going controversy, this picture regarding the toxic alkaloids have been removed and which have been
use of butterbur is conflicted and unclear. Clinicians are standardized to contain a minimum of 15% petasins are recom-
advised to follow the regulations of their national health agen- mended. Patients are cautioned against consuming the plant in
cies and when regulations are unclear or unavailable, to exer- any other form.9 In Canada, the 10 commercially available
cise caution until clear guidelines or regulatory statements are licensed butterbur compounds have all passed Health Canada
made by federal agencies regarding the use of butterbur in inspection for absence of pyrrolizidine alkaloids.
migraine prophylaxis. Although the American Headache Society has not published
Evidence Review any revisions to its recommendation, a recent editorial high-
Safety concerns aside, the efficacy of butterbur in migraine lights ongoing debate regarding this controversial issue.32
prophylaxis has been assessed in two randomized controlled Based on the 2012 guidelines and two above mentioned good
trials30,31 rated as good (CHS) or Class I (AHS/AAN) quality. quality/class I trials, the AHS gave a Level A indication and
Lipton et al30 compared butterbur 50 mg twice daily, but- deemed butterbur as an effective therapy that should be
terbur 75 mg twice daily, and placebo in a 16 week trial fol- offered to patients for migraine prevention.
lowing a 4 week baseline period. The primary outcome The EFNS has not made any official statements or retractions
assessed was the change in frequency of migraine attacks per regarding butterbur use in migraine prophylaxis following its rat-
month over the entire treatment period calculated as a per- ing of butterbur as Level B or “possibly useful for migraine pre-
centage change from baseline. The butterbur 75 mg group vention” in its 2009 guidelines; however, the UK’s MRHA
had a significantly greater percent change from baseline of advised consumers not to take unlicensed butterbur products.28
245% compared with the 50 mg group (232%) and placebo Clinicians should be aware that official statements from the
(228%). The 4 month responder rate was significantly higher CHS, AAN/AHS, and EFNS on the use of butterbur for
in the 75 mg group (68%) compared with the placebo group migraine prophylaxis and potential retractions of previous rec-
(49%, P <.05). Butterbur 50 mg was not significantly better ommendations for use may be made once there is a more com-
than placebo. Significant differences were seen in the rates of plete understanding of the risks of serious harm. Clinicians
adverse events only with respect to burping in the butterbur should therefore consider not recommending butterbur for
group. migraine prophylaxis until these statements are published.
Diener et al31 performed an independent analysis of a trial Feverfew
by Grossman and Schmidramsl comparing butterbur 50 mg Tanacetum parthenium, commonly known as feverfew, is a daisy-
twice daily for 12 weeks to placebo in 33 patients. The inde- like perennial plant whose name stems from the Latin word febrifu-
pendent reanalysis of the data was performed to follow regula- gia or “fever reducer.” The first-century Greek physician
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Headache Currents

Dioscorides prescribed feverfew for “all hot inflammations,”33 As then, it has been postulated that OPFAs act by various
however, its antimigraine properties are attributed to its principally mechanisms in cardiovascular disorders, including decreased
known bioactive ingredient, parthenolide, a sesquiterpene lactone platelet aggregation, vasodilation, anti-inflammatory effects
which acts to prevent migraine largely via antiplatelet, vascular and improved endothelial function.40 The exact mechanism of
smooth muscle relaxation, and anti-inflammatory mechanisms.6 action of OPFAs in migraine is unknown.
Evidence Review Evidence Review
There have been four studies on feverfew use for migraine One “good” quality class I randomized controlled trial41
prophylaxis, two parallel group studies34,35 and two crossover examined the role of OPFAs in 196 patients with migraine.
studies.36,37 There were differences between the CHS and the After a 4 week single blind placebo run in period, patients
AHS/AAN in how the methodological quality of these studies were randomized to either 6 g of OPFA daily versus placebo
were rated, leading to major differences in recommendations for 16 weeks. No difference was seen in the mean number of
for the use of feverfew for migraine prophylaxis. attacks during the last 4 weeks of the study. A significant dif-
Pfaffenrath et al34 compared feverfew at doses of 2.08, ference between groups was seen in per protocol analysis.
6.25, and 18.75 mg three times daily to placebo for 12 weeks There were no OPFA related adverse events in the study.
in a parallel group study of good (CHS) quality. There was Guideline Recommendations
no difference between the treatment or placebo groups in the Only the AAN/AHS guidelines discuss OPFAs and gave
primary outcome of total number of migraines during the last them a level U indication, citing inadequate evidence to sup-
28 days of treatment compared with baseline. While the CHS port or refute their use in migraine prophylaxis.
concluded that this was a negative study, the AHS/AAN
assessment of this study was that it was positive, as a subanaly-
sis evaluating only patients who had at least four migraine CONCLUSIONS
attacks during the baseline period showed a significant benefit Complementary and alternative medicine use is expanding
with feverfew compared to placebo. worldwide, and headache is among the most common ail-
Of the three remaining studies, two of which found a benefi- ments associated with utilization. Users tend to be women, in
cial effect of feverfew,35,36 and the other which found no differ- middle age, with more education.42 Due to the great interest
ence between feverfew and placebo37 were of poor quality due to and widespread use of nutraceuticals, clinicians must be aware
a failure to include an intention to treat analysis.9 No differences of the limited amount and quality of evidence available in
were reported in the rate of adverse events between placebo and favor of and against their use in migraine prophylaxis.
feverfew groups. One of the positive studies rated as poor quality In what type of patients should nutraceuticals be recom-
by the CHS32 was rated as class I by the AHS/AAN. mended for migraine prevention? A survey of patients with pri-
A Cochrane Review of five trials covering 343 patients mary headache disorders found that patients rate efficacy as the
yielded mixed results and did not convincingly establish that most important aspect in choosing a migraine preventive drug,
feverfew is efficacious for preventing migraine. No major followed by speed of onset, and absence of side effects.43 Cur-
safety problems with feverfew were found in the review, with rently, there are no head to head trials or network meta-
only mild and transient adverse effects reported.38 analyses comparing nutraceuticals to pharmacological agents for
Guideline Recommendations migraine prevention. Most nutraceutical trials however show
The CHS made a strong recommendation based on moder- very low rates of adverse effects. Patients should, therefore, be
ate quality evidence against offering feverfew for the prophylaxis counseled that the relative efficacy of nutraceuticals to pharma-
of migraine, citing the evidence indicating feverfew is no better cological agents is unknown. Those patients for whom adverse
than placebo for the prophylaxis of migraine. Due to the differ- effects are the most important aspect in choosing a preventive
ences in rating study quality from the CHS, the AAN/AHS has treatment may consider trying a nutraceutical for migraine pre-
recommended feverfew as probably effective and should be vention before pharmacological agents are prescribed.
offered for prevention (level B). The EFNS stated that feverfew Clinicians must inquire about the use of nutraceuticals from
is possibly useful for migraine prevention (level C). all patients with migraine, as there are risks for potential dan-
Omega-3 Polyunsaturated Fatty Acids gerous drug-herbal interactions that can occur from concurrent
The health benefits of dietary OPFA were highlighted by the use of conventional pharmacologic therapies and nutraceuticals.
1979 epidemiological study of Greenland Eskimos, who were Regulations for nutraceutical use vary across nations and com-
found to have a rare incidence of death by cardiovascular dis- plicate care for patients in an age where, for better or for worse,
ease despite a known high fat diet.39 Dietary sources of OPFAs the internet is informing many patients regarding indications
include fatty fish including salmon, mackerel, and tuna, and and safety of nutraceutical use. Nutraceuticals require continued
some nuts and seeds, including walnuts and flaxseed. dedicated, rigorous testing in well designed, randomized
815 | Headache | April 2016
Headache Currents

controlled trials, so that clinicians can offer evidence based rec- 15. Schmelzer C, Lindner I, Vock C, Fujii K, D€oring F. Functional
ommendations to patients with migraine who are significantly connections and pathways of coenzyme Q10-inducible genes: An
affected and yearning for effective and safe therapies. in-silico study. IUBMB Life. 2007;59:628-633.
16. Lodi R, Iotti S, Cortelli P, et al. Deficient energy metabolism is
Acknowledgment: The authors would like to thank Mr. associated with low free magnesium in the brains of patients with
Curtis Claassen and Ms. Ashley Dunstan for their assis- migraine and cluster headache. Brain Res Bull. 2001;54:437-441.
17. Sandor PS, Di Clemente L, Coppola G, et al. Efficacy of coen-
tance with research for the manuscript.
zyme Q10 in migraine prophylaxis: A randomized controlled
trial. Neurology. 2005;64:713-715.
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