CME

Pharmacologic treatment of migraine

Comparison of guidelines
A. Schuurmans, MD C. van Weel, FRCGP

ABSTRACT
OBJECTIVE To compare guidelines (not the primary studies) for pharmacologic treatment of migraine as to methods of
guideline development; recommendations, particularly on triptans; and quality of supporting evidence (with emphasis on
comparative studies of triptans versus ergot alkaloids and nonsteroidal anti-inammatory drugs [NSAIDs]).
DATA SOURCES We searched MEDLINE via PubMed for guidelines on migraine management published since 1990 in any
language; in addition, we browsed the Internet for information.
STUDY SELECTION We found nine clinical guidelines on migraine; one guideline, not supported by references, was excluded.
SYNTHESIS Preference for triptans is not well founded and is largely based on comparisons with placebo. Too few studies
compared new drugs with established ones (NSAIDs or dihydroergotamine). Guidelines that propose a hierarchy for selection
of drugs are opinion-based rather than evidence-based.
CONCLUSION The current lack of evidence from comparative studies seriously limits development of evidence-based clinical
practice guidelines for pharmacologic treatment of migraine.
RSUM
OBJECTIF Comparer les directives (et non les tudes primaires) concernant le traitement pharmacologique de la migraine, sous
laspect particulier des mthodes de dveloppement de ces directives, des recommandations mises, notamment pour les
triptans, et de la qualit des preuves lappui (notamment pour les tudes comparant les triptans aux alcalodes de lergot et
aux anti-inammatoires non strodiens [AINS]).
SOURCES DES DONNES On a utilis PubMed pour identier dans MEDLINE les directives publies dans toutes les langues
depuis 1990 sur le traitement de la migraine; on a galement consult Internet.
CHOIX DES TUDES Neuf lignes directrices de pratique sur la migraine ont t repres; une directive sans support
bibliographique a t exclue.
SYNTHSE La prfrence pour les triptans nest pas bien fonde, reposant principalement sur des comparaisons avec placebo.
Trop peu dtudes ont compar les nouveaux mdicaments aux mdicaments traditionnels (AINS ou dihydroergotamine). Les
directives prconisant un ordre de prfrence pour les mdicaments reposent sur des opinions plutt que sur des preuves.
CONCLUSION lheure actuelle, il ny a pas assez dtudes comparatives sur le traitement pharmacologique de la migraine
pour permettre lmission de lignes directrices de pratique fondes sur des preuves.

This article has been peer reviewed.

Cet article a fait lobjet dune rvision par des pairs.
Can Fam Physician 2005;51:838-843.

838 Canadian Family Physician Le Mdecin de famille canadien d VOL 5: JUNE JUIN 2005

S
everal guidelines on diagnosis and treatment of
migraine headache have been developed since
the introduction of sumatriptan, the rst drug
in its class, around 1990. Until that time, ergot alka-
loids were known to be eective against migraine,
and nonsteroidal anti-inammatory drugs (NSAIDs)
and acetaminophen were often prescribed.
Sumatriptan seemed to mark the beginning of
a new period in migraine treatment. The ecacy
of sumatriptan was self-evident, but by the time it
was introduced, the essential question was whether
the much more expensive sumatriptan was cost-
eective compared with simple analgesics, such
as acetaminophen, NSAIDs, or ergot alkaloids.
Another issue was sumatriptans safety for chronic
use. This required studies that compared sumatrip-
tan with available (reference) medications, a general
problem 1 in introducing new drugs. In compar-
ing migraine treatment guidelines published since
1990, we were particularly interested in the role
these guidelines dened for triptans and the evi-
dence to support this role (particularly in compar-
ing triptans with reference medications).
One problem for family physicians is that dif-
ferent guidelines deal with the same clinical topic.
This can lead to information overload or even con-
icting guidance. This is why we decided to com-
pare guidelines on migraine management.
Sources of information
In our systematic search for published guidelines
on migraine treatment, we used MEDLINE through
PubMed. The point of departure for the search was
the occurrence of the word migraine in the title.
In keeping with this, we specied that publications
should include the key terms guideline, guidelines,
or consensus and that the key terms pharmaco-
therapy or drug therapy had to occur. In view of the
small number of publications, no limitations were
Dr Schuurmans is a clinical pharmacologist at the
Dutch Institute for Eective Use of Medicine in Utrecht,
The Netherlands. Professor van Weel teaches in the
Department of Family Medicine at the University
Medical Centre in Nijmegen, The Netherlands.
VOL 5: JUNE JUIN 2005 d Canadian Family Physician Le Mdecin de famille canadien
Pharmacologic treatment of migraine CME
applied with regard to the target group (rst line)
of the guidelines. As we were particularly inter-
ested in the position of triptans, we restricted the
search to guidelines published after 1990.
In addition, we browsed the Internet via
AltaVista using the terms clinical guidelines, prac-
tice guidelines, and medical guidelines. The web-
sites of institutes known to participate in guideline
development were also searched. We also looked in
a few relevant and recent reviews for references to
other guidelines.
We summarized and subdivided recommenda-
tions found in the guidelines into rst-, second-, and
third-choice medications according to the guide-
lines or to our best judgment. Special emphasis
was placed on the role of triptans and their posi-
tion in comparison with acetaminophen, NSAIDs,
and ergot alkaloids.
Results
The search produced 32 articles; nine were clin-
ical guidelines for migraine management.2-10 We
could not use one guideline because the recom-
mendations were not supported by references.2 A
summary of recommendations from the guidelines
investigated is shown in Table 1.2-10 Some guide-
lines3,4,6,9 recommend a stepwise approach: acute
attacks are treated initially with the safest, least
expensive therapies with a switch to migraine-
specic medication only if initial treatment fails.
Stratied management, on the other hand, speci-
es migraine severity and recommends migraine-
specic agents for severe attacks.7
The remaining guidelines,5,7,10 which do not make
recommendations in order of preference, give each
investigated drug a place based on all references.
Table 12-10 shows medications in order of preference,
partly as stated by the guidelines,3,4,6,7,9 and partly (a
somewhat arbitrary arrangement) according to our
best judgment.5,8,10 Table 22-4,6-22 summarizes the
position of triptans and (dihydro-)ergotamine in
relation to NSAIDs and ergot alkaloids (only key
studies are presented). There are few comparative
studies; most recommendations mention the eec-
tiveness of sumatriptan among other triptans. Most
839
CME Pharmacologic treatment of migraine

guidelines, however, emphasize the lack of research not enable users to grade the quality of guide-
on ergotamine and, to a lesser degree, dihydroer- lines. The guidelines we studied ranged from the
gotamine. American guideline, which gives each investigated
drug a place based on all published studies, to the
German guideline, which recommends a stepwise
Discussion approach with conventional medication but has
The guidelines we investigated differ greatly in only weak support for this recommendation. Use
thoroughness and content. The AGREE instru- of levels of evidence is relatively common. The
ment 23 is an internationally accepted tool for guidelines that make no use of them 3,9,10 mostly
assessing guidelines, but unfortunately it does discuss and evaluate the references they cite.3,10

Table 1. Summary of recommendations from investigated guidelines: Where no evidence is listed in the Table, none had been
presented in the guideline.
FIRST-CHOICE TREATMENT (LEVEL OF SECOND-CHOICE TREATMENT (LEVEL OF THIRD-CHOICE TREATMENT (LEVEL OF
GUIDELINE EVIDENCE) EVIDENCE) EVIDENCE)

The Netherlands. NHG.3 (1999)
Stepwise approach
The Netherlands. Quality-control
committee of the Netherlands Society
for Neurology.4 (1997)
Stepwise approach
United States. American Academy of
Family Physicians and American
College of PhysiciansAmerican
Society of Internal Medicine.6 (2002)
Stepwise approach
Germany. German Migraine and
Headache Society.9 (1998)
Stepwise approach
Canada. Canadian Headache Society.7
(1997)
Stratied approach
United States. US Headache
Consortium.5 (2000)
Without ranking
Canada. Canadian Association of
Emergency Physicians.8 (1999)
(Only serious migraine emergency)
Without ranking
Canada. Therapeutics Initiative.10
(1997)
Without ranking
ASAacetylsalicylic acid, DHEdihydroergotamine, NHGNetherlands College of General Practitioners, NSAIDnonsteroidal anti-inammatory drug.
Levels of evidence: IAt least one properly conducted randomized controlled trial, systematic review, or meta-analysis; IIOther comparison trials or non-randomized cohort, case-control, or
epidemiologic studies, preferably with more than one study; IIIExpert opinion or consensus statements.
* Not as an antiemetic.
Antiemetic combined with
acetaminophen or ASA
Acetaminophen, ASA, or NSAID
combined with an antiemetic if
necessary
(I-III)
NSAIDs (ASA, ibuprofen, naproxen,
tolfenamic acid, or a combination)
(I, II)
Antiemetic combined with ASA,
acetaminophen, or NSAID
ASA (I), acetaminophen (III); NSAID
(ibuprofen, naproxen) (I);
antiemetic (III)
Intravenous antiemetic (II),
acetaminophen (II), NSAID (I, II) (ASA,
ibuprofen, naproxen, tolfenamic acid),
phenothiazine (II),* intranasal or
subcutaneous DHE (I, II), sumatriptan
(I), naratriptan (I), rizatriptan (I),
zolmitriptan (I)
Intravenous antiemetic (I),
intravenous phenothiazine (I),* NSAID
(I), sumatriptan (I), DHE (II)
Acetaminophen, ASA, NSAID
(ibuprofen, naproxen, diclofenac)
combined with an antiemetic, oral
sumatriptan
Antiemetic combined with NSAID
Sumatriptan (I)
Intranasal DHE (I) eg, naratriptan,
sumatriptan,
rizatriptan,
zolmitriptan
Ergotamine,
DHE
NSAID (ibuprofen, naproxen,
mefenamic acid) (I), sumatriptan (I),
DHE (I), ergotamine (II)
Ergotamine (II), NSAID (intramuscular
ketorolac) (II)
Haloperidol (III), intranasal lidocaine
(I), intranasal opiate (I), corticosteroid
(II)
Intravenous antiemetic,
phenothiazine,* DHE, NSAID
(ketorolac), subcutaneous
sumatriptan, opiate
Sumatriptan,
ergotamine
Ergotamine (I, III)
Intranasal opiate (I) or intravenous
antiemetic (II)
Sumatriptan
Intravenous antiemetic (I), NSAID
(ketorolac) (I), intravenous
phenothiazine (I),* sumatriptan (I),
DHE (I), intranasal opiate (I),
corticosteroid (II)
Barbiturate (II, III), opiate (I),
corticosteroid (III)
DHE, opiate, intranasal sumatriptan

840 Canadian Family Physician Le Mdecin de famille canadien d VOL 5: JUNE JUIN 2005
 Pharmacologic treatment of migraine CME

Orders of preference in guidelines3,4,9 are opinion-
based, but this is not always mentioned.3,9 One
guideline 7 classifies migraine headache on the
basis of its severity without mentioning that this
classication is not based on the reference stud-
ies. Another guideline6 mentions that the question
of which approach is best (stepwise or stratied
management) is still unresolved.24,25
The place of triptans varies enormously
(Table 12-10). This is at least remarkable, given the
sparse international literature and the fact that all
guidelines were based on (systematic) searches of

Table 2. Role of triptans: Comparative studies with NSAIDs and ergot alkaloids, and the role of (dihydro-)ergotamine.

GUIDELINE RESULTS OF TRIALS (LEVEL OF EVIDENCE, WHERE GIVEN)

The Netherlands. NHG. 3

Sumatriptan compared with:
(1999) NSAIDs: equally eective11,12
Stepwise approach Ergotamine: sumatriptan more eective, but headaches recurred sooner13
DHE: sumatriptan works somewhat faster, but headaches recurred sooner14
Ergotamine: eectiveness demonstrated15,16

The Netherlands. Quality- Sumatriptan compared with other medications: records the small number of studies, not the conclusions12,13 (I)
control committee of the Ergotamine and DHE: conclusions based mainly on clinical experience16,17 (II)
Netherlands Society for
Neurology.4 (1997)
Stepwise approach

United States. American Oral sumatriptan compared with:

Academy of Family
Physicians and American
College of Physicians
American Society of Internal
Medicine.6 (2002)
Stepwise approach
NSAIDs: equally eective11,12,18 (I)
Ergot or caeine: sumatriptan more eective13 (I)
Subcutaneous sumatriptan compared with subcutaneous and intranasal DHE: sumatriptan more eective, but headaches recurred sooner14,19 (I)
Intramuscular sumatriptan compared with intravenous chlorpromazine: equally eective20 (III)
Ergotamine: inconsistent results17 (III)
Subcutaneous, intravenous, and intramuscular DHE: no studies demonstrate eectiveness as monotherapy21 (III)
Intranasal DHE: less eective than subcutaneous sumatriptan19 (II)
Subcutaneous DHE: after 3 hours equally eective as subcutaneous sumatriptan14 (I)

Germany. German Migraine Oral sumatriptan compared with NSAIDs: not reviewed12
and Headache Society.9 (1998) Ergotamine and DHE: eectiveness mentioned but not supported22
Stepwise approach

Canada. Canadian Headache Oral and subcutaneous sumatriptan compared with:

Society.7 (1997) NSAID: equally eective11 (I)
Stratied approach DHE: sumatriptan more eective14 (I)
Ergotamine: eectiveness not demonstrated17,22 (I)
Subcutaneous, intravenous, intramuscular, and intranasal DHE: eective14 (I)

Canada. Canadian Oral sumatriptan compared with ergotamine and caeine: eective13 (I)
Association of Emergency Subcutaneous sumatriptan compared with:
Physicians.8 (1999) Subcutaneous DHE: sumatriptan faster, but more recurrence of headaches14 (I)
(Only serious migraine Intranasal DHE: sumatriptan more eective, but shorter acting19 (II)
emergency) DHE: few studies, no conclusions21 (III)
Without ranking Intranasal DHE: eective19 (II)

Canada. Therapeutics Oral sumatriptan compared with ergotamine with caeine and ASA: no visible dierence11-13
Initiative.10 (1997) Subcutaneous sumatriptan compared with:
Without ranking Subcutaneous DHE: equally eective14
Intranasal DHE: sumatriptan more eective19
Ergotamine: eectiveness not demonstrated22
Intranasal DHE: eective19
ASAacetylsalicylic acid, DHEdihydroergotamine, NHGNetherlands College of General Practitioners, NSAIDnonsteroidal anti-inammatory drug.
Levels of evidence: IAt least one properly conducted randomized controlled trial, systematic review, or meta-analysis; IIOther comparison trials or non-randomized cohort, case-control,
or epidemiologic studies, preferably with more than one study; IIIExpert opinion or consensus statements.

VOL 5: JUNE JUIN 2005 d Canadian Family Physician Le Mdecin de famille canadien 841
CME Pharmacologic treatment of migraine
this literature. National medicopolitical dierences
might have a role here, as only a few guidelines
consider costs in their recommendations.3,9 Given
the many assumptions in the articles focusing on
costs, it seems that cost-eectiveness calculations
are somewhat theoretical.26,27
A factor that hampers development of high-
quality guidelines for migraine treatment is that
recently developed drugs, such as the triptans, have
been the subject of more studies and more pub-
lications than old ones. Consequently, all guide-
lines list sumatriptan with supporting evidence.
This, however, is evidence against placebo because
there are only few comparisons with other eective
drugs (Table 22-4,6-22). Recommendations on ergot
alkaloids are, to a large extent, based on opinion or
consensus.
Although the side eects of ergotamine (particu-
larly vasoconstriction, nausea, and vomiting) are
well known,16 triptans also have side eects (such
as chest pain).28,29 Lack of data on the relative long-
term safety of triptans has led to the conclusion
that they are equal to the older drugs in terms of
side eects. Again this is opinion, rather than evi-
dence-based information.
Limitations
This study was limited by the time frame chosen for
selecting guidelines, but more information from
recent reviews28-32 and results of studies compar-
ing sumatriptan and NSAIDs33,34 do not essentially
change the ndings of this study.
Conclusion
Guidelines should support medical practitioners in
pursuing the highest quality of care for their patients.
But family physicians who turn to the guidelines on
migraine for support for pharmacotherapy will prob-
ably not nd much help. Dierent guidelines recom-
mend dierent approaches, even when they are written
for the same clinical care setting, such as primary care.
Actual guideline-prescribed care will depend to a large
extent on which guideline has been used. This intro-
duces an unsatisfactory element of chance.
842 Canadian Family Physician Le Mdecin de famille canadien d VOL 5: JUNE JUIN 2005
EDITORS KEY POINTS
Family doctors frequently treat migraine headache, and there are
numerous guidelines with recommendations for best care. The intro-
duction of triptans added a new but expensive alternative.
Some guidelines are based on an evaluation of the evidence, but
ranking of treatments is somewhat arbitrary and based on con-
sensus. This is because there are few trials comparing older treat-
ments with triptans.
Family doctors need to be aware of the lack of convincing evidence
that triptans are more eective than older treatments.
POINTS DE REPRE DU RDACTEUR
Le mdecin de famille doit souvent traiter des cphales
migraineuses et il existe du nombreuses directives prconi-
sant un traitement de prfrence un autre. Lintroduction
des triptans reprsente une option nouvelle, quoique
dispendieuse.
Certaines directives reposent sur une valuation des preuves,
mais ltablissement dun ordre de prfrence pour les traite-
ments est plutt arbitraire et relve du consensus. La raison
en est quil y a peu dtudes comparant les agents tradition-
nels aux triptans.
Le mdecin de famille doit savoir quil y a peu de preuves convain-
cantes que les triptans sont suprieurs aux traitements traditionnels.
A comparison of the effectiveness and safety
of all available migraine drugs, over all stages of
migraine severity, would benet family physicians.
As long as these data are unavailable, guidelines
will have little to oer. As long as new drugs are
not tested before they are introduced in studies
that compare their therapeutic value in the prac-
tical settings in which patients are usually treated,
important information is unavailable to those who
have to design guidelines. We would welcome a
policy in which new medicines are accepted only
when they have an evidence-based value over exist-
ing standard therapy.
Competing interests
None declared
Correspondence to: A. Schuurmans, MD, clinical
pharmacologist, Tijinkweg 6, 7421 ED Deventer, The
Netherlands; or Professor C. van Weel, Department
of Family Medicine, University Medical Centre
Nijmegen, PO Box 9101, 6500 HB Nijmegen, The
Netherlands

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