Financial support: P. R. acknowledges the generous support of Mr. Charles Ledley, who underwrote the preparation of this manuscript.
Tolerance to the Beneficial Effects of Prophylactic Migraine Drugs: A Systematic Review of Causes and Mechanisms
Article first published online: 1 SEP 2011
© 2011 American Headache Society
Headache: The Journal of Head and Face Pain
Volume 51, Issue 8, pages 1323–1335, September 2011
How to Cite
Rizzoli, P. and Loder, E. W. (2011), Tolerance to the Beneficial Effects of Prophylactic Migraine Drugs: A Systematic Review of Causes and Mechanisms. Headache: The Journal of Head and Face Pain, 51: 1323–1335. doi: 10.1111/j.1526-4610.2011.01985.x
Conflict of Interest: None
- Issue published online: 1 SEP 2011
- Article first published online: 1 SEP 2011
- Accepted for publication June 7, 2011.
- migraine prevention;
- chronic migraine;
- medication overuse headache
Loss of benefit of a previously effective treatment regimen, also known as tolerance, can be an important barrier to the successful preventive treatment of migraine. We undertook a systematic review of the literature to identify the prevalence and possible mechanisms of drug tolerance in migraine prophylaxis. Results demonstrate that the frequency of tolerance to prophylactic migraine treatment is unknown, but available data support an estimate that it occurs in 1-8% of patients receiving prophylaxis. Four broad types of tolerance were identified that are likely to be relevant to migraine prophylaxis. These are pharmacokinetic, pharmacodynamic, behavioral, and cross tolerance. The mechanisms that underlie these types of tolerance determine whether their effects can be overcome or minimized. For example, certain forms of tolerance may be affected by manipulation of environmental cues associated with drug administration, by the order in which drugs are used, and by the concomitant use of other medications. Many medications used for migraine prophylaxis exert their effects through the endogenous opioid system. The implications of this finding are explored, particularly the parallels between medication overuse headache and tolerance to migraine prophylaxis. Given the many ways in which tolerance to migraine medications may develop, in some ways it is not surprising that migraine-preventive drugs stop working; it is more surprising that in many cases they do not.