Efficacy endpoints in migraine clinical trials: the importance of assessing freedom from pain

Abstract

Many efficacy endpoints have been used in clinical trials of acute migraine pharmacotherapy. Headache response or headache relief (i.e., moderate/severe pain reduced to mild/no pain) at a single, specified time-point, traditionally the primary endpoint, and headache recurrence (i.e., return of pain after initial postdose relief) are inadequate. Headache relief does not provide information about pain-free response and counts a partial response as a treatment success. Headache recurrence can reflect sustained efficacy but is confounded by initial response to treatment, because ineffective drugs have low recurrence rates. The International Headache Society (IHS) guidelines state that 2 hour pain-free response and sustained pain-free response (i.e., freedom from pain with no recurrence or use of rescue or study medication 2–24 hours postdose) provide the most clinically relevant information about the efficacy of migraine pharmacotherapy. The pain-free criterion counts partial responses as failures and thus is a more rigorous test of therapeutic benefit than headache relief, and the two endpoints together incorporate the main treatment attributes that determine patient satisfaction. As an example, consider needle-free subcutaneous sumatriptan and oral triptan tablets. An open-label study of needle-free subcutaneous sumatriptan by Cady and colleagues found that 2 hour pain-free response and sustained pain-free response were 64% and 42% respectively. For oral triptan tablets, the 2001 metaanalysis by Ferrari and colleagues reported 2 hour pain-free response rates ranging from 23% to 38% and sustained pain-free response rates ranging from 11% to 26%. The measures of pain-free response 2 hours postdose and sustained pain-free response can differentiate among treatments and be used to guide therapeutic choices.

Keywords::

• Headache response
• Migraine
• Pain-free response
• Recurrence
• Sustained response
• Triptan

Transparency

Declaration of funding

Editorial assistance for this commentary is funded by Medical Leverage and Zogenix Inc.

Declaration of financial/other relationships

S.D.S. is on the advisory panel of and receives honoraria from Allergan, Amgen, Capnia, Coherex, GlaxoSmithKline, Iroko Pharmaceuticals, Lilly, MAP, Medtronic, Merck, Neuralieve, NINDS, NuPathe, Pfizer, and St. Jude Medical. He serves as a consultant for and receives honoraria from Amgen, MAP, Nautilus, Novartis, Opti-Nose, and Zogenix. His employer receives research support from Allergan, BMS, Cumberland, ElectroCore, Lilly, Merck, Opti-Nose, St. Jude Medical, and Troy Healthcare. M.J.M. has received grants for clinical research from Merck. S.J.N. has served as a consultant to Allergan, Zogenix, and MAP. L.C.N. is a member of advisory boards and/or speakers bureaus for Allergan, MAP, Merck, Nautalis, and Zogenix and receives royalties from the Oxford University Press. S.J.F. is employed by Zogenix.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgments

The authors acknowledge Jane Saiers PhD (The WriteMedicine Inc.) and Edward K. Baldwin PhD (Medical Leverage, a Communications Company), for assistance with writing the manuscript. Dr. Saiers’ and Dr. Baldwin’s work was funded by Medical Leverage, a Communications Company, and by Zogenix Inc.

Previous presentation: Much of the material discussed in this article was presented as a poster at the 54th American Headache Society Annual Scientific Meeting in Los Angeles, June 21–24, 2012.