Elevated Saliva CGRP Levels During Migraine Predict Response to Rizatriptan

Daniel M. Keller, PhD

September 16, 2009

September 16, 2009 (Philadelphia, Pennsylvania) — Elevated levels of calcitonin gene-related peptide (CGRP) in the saliva predict a migraine patient's responsiveness to rizatriptan (Maxalt, Merck), a new study suggests.

For those patients who respond to rizatriptan, CGRP is elevated at all active phases of migraine, and levels returned to near baseline with a positive response to the drug. CGRP is implicated in the underlying pathophysiology of migraine and may act both centrally and in the periphery.

Roger Cady, MD, director of the Headache Care Center in Springfield, Missouri, presented results of this study here during the 14th International Headache Congress.

Predicting Response

The 22 participants comprised 2 men and 20 women, had a history of 1 to 6 migraines per month with or without aura, had at least 15 headache-free days per month in the previous 3 months, and had not used any migraine preventive medications in the past 3 months. They were told to treat a migraine attack with 10 mg rizatriptan when the headache was at moderate intensity.

Participants collected saliva samples during a baseline period when they had been headache-free for at least 48 hours, early in the premonitory period when they could identify a migraine, within 2 hours of the onset of mild headache, before treatment of moderate to severe headache with a triptan, and within 4 hours after resolution of migraine. Samples were stored at −20°C.

The patients ranged in age from 21 to 64 years (mean, 38.9 years) and reported an average of 4.3 migraines per month. Responders were defined as patients who were symptom-free at the time of the final saliva collection and did not need additional rizatriptan or other rescue medication.

Dr. Cady and coworkers found that of the 14 subjects who responded to rizatriptan, 6 had saliva CGRP levels that were significantly elevated in the premonitory, mild, and moderate/severe phases of a migraine compared with the interictal period. The other 8 responders showed a slower elevation of CGRP, with a rise in the level only during the moderate pain phase of the headache. Subjects with elevated saliva levels of CGRP had better responses to rizatriptan. On successful treatment with the drug, saliva CGRP levels returned to near baseline.

"On the other hand, very interestingly, in the 8 people that did not respond to rizatriptan there was no elevation of CGRP at any phase of migraine, and so their levels never went above those of baseline at any phase," Dr. Cady told Medscape Neurology.

He said the implication of these findings is that there may be biologic explanations in some cases of why people respond or not. Even when treated promptly and under the best circumstances, about 30% of migraine attacks do not respond to triptans. People have often assumed that nonresponse resulted from patients waiting too long to treat their headache, using stepwise treatment strategies, or from gastric stasis with oral medications.

"But this would say there are biologic reasons why medicine may not work, or on the other hand, [why] it is working," Dr. Cady explained. He said he is confident that his findings can be generalized to all triptans that are known to block the release of CGRP.

The CGRP assay is not widely available and is not for clinical use, but Dr. Cady predicted that CGRP testing may provide a way to select patients who will be most helped by triptans and to determine who may need other drugs. He postulated that multiple mechanisms may generate migraine symptoms and that, in the future, treatments may be chosen according to underlying mechanisms, "rather than assume because the symptoms are the same the treatments should be the same."

Objective Parameter

Per Gisle Djupesland, MD, PhD, an ear, nose, and throat surgeon and chief scientific officer of OptiNose, a drug delivery devices company in Oslo, Norway, commented on the study. He agreed that it opens up new ways of thinking about mechanisms involved in migraine and that measuring CGRP in saliva could have clinical application.

"The fact that you can easily measure this substance or potentially other substances as well and see if it's related to your treatment, and use it as a parameter that you can look at different types of drugs...I think that's interesting," he said. "You can get kind of an objective parameter maybe that's related to the disease and the degree of disease."

The study was supported by a research grant from Merck & Co, Inc. Dr. Cady has disclosed that he has received research grants from Allergan; Alexza Pharmaceuticals; Amerilab; BioAlliance Pharma; Boston Scientific; Capnia, Inc; GlaxoSmithKline; Merck & Co, Inc; Neuralieve; Quality Metrics; and Wyeth. He has also received honoraria from Endo Pharmaceuticals, Inc; GlaxoSmithKline; KOWA Pharmaceuticals; MAP Pharmaceuticals; Merck & Co, Inc; Minster Pharmaceuticals; NuPathe; Ortho-McNeil Neurologics; and Prometheus Labs. In addition, he is on the advisory boards of Aradigm; Endo Pharmaceuticals, Inc; Jazz Pharmaceuticals, Inc; KOWA Pharmaceuticals; MAP Pharmaceuticals; Merck & Co, Inc; Minster Pharmaceuticals; NuPathe; Ortho-McNeil Neurologics; Prometheus Labs; and Zogenix. He is an assignor on a patent filed by Banyan Group, Inc. Dr. Djupesland is chief scientific officer of OptiNose, a Norwegian drug delivery devices company.

14th International Headache Congress: Abstract PO19. Presented September 11 and 12, 2009.

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