In 1991 the Clinical Trials Subcommittee of the
International Headache Society (IHS) published its
first edition of the Guidelines on controlled trials of
drugs in migraine (1). The Guidelines’ overarching
goal was to improve ‘the quality of controlled clinical
trials in migraine’, which could be achieved by using
scientifically robust methods of clinical research. The
report highlighted the complex nature of migraine clinical
trial methodologies and offered a road map to clinical
investigators who were interested in the field. The
Migraine Guidelines were adopted widely (2–7),
although – for a variety of reasons, including regulatory
restrictions – not universally (8–11), and this was
the impetus for the development of similar guidelines for tension-type headache (12,13) and for cluster headache
The second edition of the guidelines was published in
2000 (15) and, based on the second edition, the
European Medicines Agency published in 2007
‘Guidelines on Clinical Investigation of Medicinal
Products for the Treatment of Migraine’ (16).
Have investigators then followed the recommendations
in these guidelines for randomized controlled
trials (RCTs)? Unlike the case of RCTs for migraine
prevention where the recommended primary efficacy
measure of migraine attack frequency was used in
72% of 52 RCTs (17), adherence to the recommendations
in the guidelines for acute migraine treatment has
not been overwhelming. Indeed, the recommended
measure of freedom from pain after 2 h was the primary
efficacy measure in 31% of 145 acute RCTs between
2002 and 2008 (17). Instead, headache relief after 2 h
(a decrease from moderate or severe to none or mild)
was used in 39% of such trials. Notwithstanding, the
proportion of RCTs using pain freedom as the primary
efficacy measure has continued to increase over time
(17), and is even used in recent large clinical trials
Following the publication of the IHS Clinical Trials
Guidelines, several clinical drug development programmes
emerged, notably for acute migraine (e.g. 5-
HT1B/D agonists, triptans) and for prevention (e.g.
topiramate). The majority of these RCTs were performed
mainly for registration purposes (16). This
exponential increase in migraine clinical research, the
accumulating experience of clinical researchers and the
pharmaceutical industry alike, and the trend towards
large multi-centre and multi-national studies, call for
a timely revisit and a refresh of the original guidelines
and their second edition.
The third edition of Migraine Clinical Trials
Guidelines is a consensus summary that was developed
by experts in the field, and its purpose is to recommend
a contemporary, standardized, and evidence-based
approach to the conduct and reporting of migraine
Broader discussions of clinical trials methodologies
can be found elsewhere (22–30). Also, ethical considerations
in migraine clinical research have been published
separately (31). Finally, it should be noted that the
revised Guidelines represent Research Practice
Parameters and are the highest level in the hierarchy
of Evidence-Based Recommendations in the absence of
published Standards of Research Practice. Therefore,
the IHS endorses the adherence to the Guidelines
unless there is scientific justification for deviations
from the recommendations.
The Third Edition of The Migraine Clinical Trials
Guidelines is organized similarly to the previous two
editions. Notably, RCTs for acute attacks of migraine
are addressed in the first section of these guidelines and
are followed by discussions and recommendations
relating to RCTs for migraine prevention, including
short-term prophylaxis or ‘mini-prophylaxis’ for predictable
migraine attacks, such as those associated
with menses (32). Sub-sections include: patient selection,
trial design, evaluation of results and statistics.
A toolbox for each type of trial (acute and prevention)
is provided at the end.
1. IHS. Guidelines for controlled trials of drugs in
migraine. First edition. International Headache Society
Committee on Clinical Trials in Migraine. Cephalalgia
1991; 11: 1–12.
2. Schoenen J and Sawyer J. Zolmitriptan (Zomig, 311C90),
a novel dual central and peripheral 5HT1B/1D agonist: an
overview of efficacy. Cephalalgia 1997; 17(Suppl 18):
3. Rolan PE and Martin GR. Zolmitriptan: a new acute
treatment for migraine. Expert Opin Investig Drugs 1998;
4. Dahlof C and Lines C. Rizatriptan: a new 5-HT1B/1D
receptor agonist for the treatment of migraine. Expert
Opin Investig Drugs 1999; 8: 671–685.
5. Dooley M and Faulds D. Rizatriptan: a review of its efficacy
in the management of migraine. Drugs 1999; 58:
6. Spencer CM, Gunasekara NS and Hills C. Zolmitriptan: a
review of its use in migraine. Drugs 1999; 58: 347–374.
7. Saxena P and Tfelt-Hansen P. Triptans, 5HT1B/1D
agonists in the acute treatment of migraine. In: Olesen J,
Goadsby PJ, Ramadan NM, Tfelt-Hansen P, Welch KMA
(eds) The headaches. Vol. 3, Philadelphia: Lippincott Williams
& Wilkins, 2006, pp.469–503.
8. Pilgrim AJ. Methodology of clinical trials of sumatriptan
in migraine and cluster headache. Eur Neurol 1991; 31:
9. Dechant KL and Clissold SP. Sumatriptan. A review of
its pharmacodynamic and pharmacokinetic properties,
and therapeutic efficacy in the acute treatment of
migraine and cluster headache. Drugs 1992; 43: 776–798.
10. Plosker GL and McTavish D. Sumatriptan. A reappraisal
of its pharmacology and therapeutic efficacy in the acute
treatment of migraine and cluster headache. Drugs 1994;
11. Perry CM and Markham A. Sumatriptan. An updated
review of its use in migraine. Drugs 1998; 55: 889–922.
12. IHS. Guidelines for trials of drug treatments in tensiontype
headache. First edition: International Headache
Society Committee on Clinical Trials. Cephalalgia 1995;
13. Bendtsen L, Bigal ME, Cerbo R, et al. Guidelines for
controlled trials of drugs in tension-type headache:
second edition. Cephalalgia 2010; 30: 1–16.
14. Lipton RB, Micieli G, Russell D, et al. Guidelines for
controlled trials of drugs in cluster headache.
Cephalalgia 1995; 15: 452–462.
15. Tfelt-Hansen P, Block G, Dahlof C, et al. Guidelines for
controlled trials of drugs in migraine: second edition.
Cephalalgia 2000; 20: 765–786.
16. EMEA CFMPFHU. Guideline on clinical investigation
of medicinal products for the treatment of migraine. Vol
2011. London, 2007.
17. Hougaard A and Tfelt-Hansen P. Are the current IHS
guidelines for migraine drug trials being followed?
J Headache Pain 2010; 11: 457–468.
18. Ho TW, Mannix LK, Fan X, et al. Randomized controlled
trial of an oral CGRP receptor antagonist, MK-
0974, in acute treatment of migraine. Neurology 2008; 70:
19. Ho TW, Ferrari MD, Dodick DW, et al. Efficacy and
tolerability of MK-0974 (telcagepant), a new oral antagonist
of calcitonin gene-related peptide receptor, compared
with zolmitriptan for acute migraine: a
randomised, placebo-controlled, parallel-treatment trial.
Lancet 2008; 372: 2115–2123.
20. Connor KM, Shapiro RE, Diener HC, et al. Randomized,
controlled trial of telcagepant for the acute treatment
of migraine. Neurology 2009; 73: 970–977.
21. Tfelt-Hansen P. Pain freedom at 2 hours in migraine after
telcagepant 300 mg. CNS Drugs 2011; 25: 269–270.
22. Good C. The principles and practice of clinical trials.
Edinburgh: Churchill Livingstone, 1976.
23. Pocock S. Clinical trials. A practical approach.
Chichester: John Wiley & Sons, 1984.
24. Meinert C. Clinical trials: design, conduct, and analysis.
Oxford: Oxford University Press, 1986.
25. Spilker B. Guide to clinical trials. New York: Raven Press,
26. Olesen J, Krabbe AA and Tfelt-Hansen P. Methodological
aspects of prophylactic drug trials in migraine.
Cephalalgia 1981; 1: 127–141.
27. Gerber WD, Soyka D, Niederberger U and Haag G.
[Problems in and approaches to the design and evaluation
of therapeutic studies in patients with headache.].
Schmerz 1987; 1: 81–91.
28. Tfelt-Hansen P and Olesen J. Methodological aspects of
drug trials in migraine. Neuroepidemiology 1985; 4:
29. Olesen J and Tfelt-Hansen P. Methodology of migraine
trials. In: Orgogozo J-M, Capildeo R (eds) Methods in
clinical trials in neurology. Vascular and degenerative
brain disease. London: Macmillan, 1988, pp.85–109.
30. Lipton RB. Methodologic issues in acute migraine clinical
trials. Neurology 2000; 55: S3–S7.
31. IHS. Ethical issues in headache research and management:
report and recommendations of the ethics subcommittee
of the International Headache Society. Cephalalgia
1998; 18: 505–529.
32. MacGregor EA. "Menstrual" migraine: towards a definition.
Cephalalgia 1996; 16: 11–21.