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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL FRONTIERS - 14th Congress of the International Headache Society

Philadelphia, Pennsylvania / September 10-13, 2009

The worldwide undertreatment of migraine, as recognized by the World Health Organization, is accompanied by a relative scarcity of treatment options. However, according to Dr. David W. Dodick, Professor of Neurology, Mayo Clinic, Scottsdale, Arizona, clinicians can have a substantial impact on the efficacy of existing therapies.

Triptans are most effective when used early in the course of a migraine attack, and by counselling patients to treat early, “You can increase headache response rates from 55% or 60% up to 80%, and increase pain-free rates from 30% up to 50%,” Dr. Dodick remarked. “This does not happen with everyone but in individual patients, the results can sometimes be dramatic.”

Dr. Dodick speculated on why triptan therapy could have uneven results. “Dose, timing, route of administration—all these can affect the robustness of the effect,” he suggested. “It may be the triptan only has partial efficacy, and maybe two or three drugs with different mechanisms of action are necessary. It all comes down to genetic heterogeneity in the receptor. The receptor is the lock and the drug is the key. We are never going to find the key that fits everybody’s lock. But if we have enough keys, i.e. drugs, then hopefully, for an individual patient, we are going to be able to jiggle the lock with at least one of the keys that we have.”

Maximizing Results

Dr. Roger Cady, Director, Headache Care Center, Springfield, Missouri, presented findings that lend insight into possible “keys” to triptan response or lack thereof. This was a study showing that elevated saliva calcitonin gene-related peptide (CGRP) levels during acute migraine predict a therapeutic response to rizatriptan (Abstract PO19).

CGRP is a potent neuropeptide implicated in the underlying pathophysiology of migraine; it is believed to act both centrally and in the periphery. Previous research has shown that CGRP is expressed in 40% of trigeminal neurons and there is a marked increase in plasma levels of CGRP in patients undergoing migraine attack. In addition to its known function as a vasodilator in the periphery, CGRP appears to play a role within the central nervous system as a neuromodulator and, acting through receptors in the brainstem and trigeminal ganglion, may contribute to the induction of a pronociceptive state.

Dr. Cady’s group collected saliva samples from 22 participants (20 women and two men) at five different intervals. A total of 14 individuals responded to triptan therapy and response correlated with statistically significant elevations of CGRP in the premonitory, mild and moderate-to-severe phases of headache compared to baseline. Among rizatriptan nonresponders, there was no significant change in saliva CGRP levels at any phase of the migraine attack. “We were looking for a biological marker that could say when migraine started,” Dr. Cady explained. “Quite honestly, we were surprised by our results. I think in the future, CGRP and maybe other markers could assist with therapy.”

Data also revealed that the subset of rizatriptan responders with CGRP elevations during the premonitory period were better able to predict moderate migraine than those whose highest elevations occurred during the moderate attack phase or those without any CGRP elevations during any phase of the attack. Thus, in a subset of patients, there may be potential for pre-headache intervention based on saliva CGRP elevations. “There is the potential to develop a commercial assay,” Dr. Cady suggested, adding that such a prospect is still a long way away.

Dr. Cady is a leader in recognizing that symptom management and early treatment leads to better outcomes with triptan therapy. Earlier this year, he published results of his trial assessing the efficacy of rizatriptan 10 mg prescribed with and without employing a standardized patient-specific migraine education format (Headache 2009;49(5):687-96). When taken early during a migraine attack while pain is mild, the triptan was more efficacious than placebo at providing pain freedom at two hours and sustained pain freedom from two to 24 hours’ post-dose, with treatment also reducing migraine-associated symptoms and functional disability.

A greater proportion of participants in the early treatment plus education arm reported pain freedom at two hours than those receiving treatment without education (71.7% vs. 60.9%). This difference did not reach statistical difference, however, because the study was not sufficiently powered to detect a difference in a population of this size. In the treatment plus education arm, more patients also reported satisfaction with treatment than in the treatment without education arm (80% vs. 59%).

Triptan Use: Pharmacy Claims Database

Still, under the best of circumstances including early treatment, an estimated 30% of migraine attacks are unresponsive to triptan therapy. Dr. Tony Ho, North Wales, Pennsylvania, discussed the clinical significance of treatment failure. With Bozena J. Katic, MPH, MPA, he conducted a study reviewing pharmacy claims for 41,000 patients receiving a new triptan prescription (Abstract PO15). Results showed that the majority (53.8%) received no refill of their initial index triptan over the two-year follow-up period and by the seventh refill, only 10% of patients remained loyal to their index triptan prescription.

“If you look at what happened to the people who did not renew, it turned out that some 68% turned to opiates, a large percentage turned to NSAIDs and 7% or 8% turned to a barbiturate,” Dr. Ho reported. The database also revealed that 7.4% of patients switched to a different triptan while 25.5% stopped using prescription migraine therapy altogether.

Greater Risks Associated with Migraine with Aura: Findings Reviewed

In another presentation, Dr. Sheena Aurora, Assistant Professor and Director, Swedish Pain and Headache Center, University of Washington, Seattle, reviewed a number of studies showing that migraineurs with aura (MA) have an increased long-term risk of developing CV conditions relative to the non-migraine population.

In AMPP (American Migraine Prevalence and Prevention)-II, a recent follow-up to the AMPP study, the largest migraine study ever conducted, researchers analyzed cross-sectional data and found a range of CV comorbidities associated with long-term migraine. The relative risk of later-life CVD was considerably higher with chronic vs. episodic migraine sufferers (Figure 1).

Figure 1.

Earlier work was carried out by Dr. Ann I. Scher, Uniformed Services University, Bethesda, Maryland, in the GEM (Genealogical and Epidemiologic Migraine) study, a cross-sectional analysis conducted among 5755 migraineurs and 5135 non-migraine controls in the Netherlands (Neurology 2005;64(4):614-20). Whereas migraine without aura (MO) did not seem to be accompanied by increased CV risk, MA was associated with an increase in CV risk factors over time.

Dr. Aurora also pointed to data from investigator Dr. Warren Becker, University of Calgary, Alberta, who estimated that in oral contraceptive (OC) users aged 25 to 34 years, the background risk of stroke with MA (28 per 100,000 per year) was three times that
e 2).

Figure 2.

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More recently, there has been physiologic evidence linking MA with late-life presence of cerebellar infarct-like lesions on magnetic resonance imaging. Dr. Aurora described a new study by Dr. Scher and colleagues, this time using data from the Reykjavik Study, a population cohort followed for nearly 26 years. It showed that MA in midlife is significantly associated with white matter lesions (WMLs) but that MO is not (Scher et al. JAMA 2009;301(24):2594-5).

Dr. Aurora was cautious in her interpretation of these and similar findings. “I do not think we should call them ‘infarcts’ because that actually is a clinical syndrome, whereas we do not know the underlying etiology,” she warned. “Clinically, there is no difference in how we treat these patients.” Nonetheless, “There does seem to be a distinction between those who have MA and those who do not,” she added.

More evidence surfaced here at the IHC when Dr. Michael Ferrari, Leiden University Medical Centre, The Netherlands, presented data from the CAMERA (Cerebral Abnormalities in Migraine, an Epidemiologic Risk Analysis)-II study. Preliminary results from that study, an MRI follow-up to the 2004 migraine cohort study based in Leiden, The Netherlands, again suggest that WMLs are more prevalent with MA “and are associated with increased attack frequency of greater than one per month,” Dr. Aurora reported. In their ongoing analysis, the CAMERA-II investigators will attempt to correlate progression of deep and preventricular WML to migraine diagnosis, subtype and evolution over time, and the multivariate analysis will control for CV risk factors (Abstract LB0R5). “When we look at all those data, they seem to be overwhelming... It is important to remember that while the relative risk seems to be high, the absolute risk still is low,” Dr. Aurora suggested. “The absolute risk is only a little bit higher than in the average population, and only for migraine with aura,” she reiterated.

New Therapies for Migraine Prevention and Treatment Under Development

Research into migraine pathophysiology has spawned a promising new field of experimental therapies, with several novel agents in phase III development. One of these is botulinum toxin type A for prevention of chronic migraine, believed to affect one-sixth of the estimated 36 million migraine sufferers in the US.

For treatment, CGRP receptor antagonism has also reached an advanced stage. This neuropeptide is found in every location thought to be involved in migraine genesis and processing. “We think it is working centrally in the brain and modulating transmission of pain from trigeminal nerve,” revealed Dr. Dodick. “We believe that CGRP is working centrally, and not at the peripheral nerve, because the dose [of receptor antagonist] necessary to be effective is orders of magnitude beyond that needed to saturate nerves at the periphery.”

Dr. Ho presented new data from the latest studies of telcagepant, an oral CGRP receptor antagonist. One of these, a multiple attack study in an advanced stage of clinical investigation, showed that telcagepant 140 and 280 mg are effective against placebo in all the migraine end points across four attacks (Abstract LBP003).

The other study evaluated telcagepant for treatment of multiple episodic migraine attacks (Abstract PO03). Results showed that telcagepant 300 mg (n=712) was as effective as rizatriptan 10 mg (n=356) for treatment of episodic migraine. It was found to be safe and well tolerated when used to treat up to eight acute episodic migraine attacks per month, for a cumulative mean average of 31 treated attacks overall vs. 35.1 in controls. Compared with controls, there was no significant difference in the two efficacy end points (pain freedom at two hours’ post-dose and two- to 24-hour sustained freedom). With regard to tolerability, the CGRP receptor antagonist at the higher dose was associated with significantly fewer triptan-related adverse events than the triptan at 10 mg (P<0.001). As a class, CGRP blockers are believed to lack vasoconstrictive properties. New direct evidence in this regard was presented by researcher Dr. Lars Edvinsson, Lund University, Sweden. Laboratory results from a study he co-authored showed telcagepant to be devoid of any contractile or relaxant effects per se in both cerebral and meningeal arteries where CGRP receptors have been found to be located (Abstract PO311). This is important because a substantial number of patients continue to suffer from migraine after menopause, when CVD comorbidities begin to rise and triptans may be contraindicated.

Questions and Answers

Q: Why does the presence of aura increase migraineurs’ relative risk of CVD?

Dr. Aurora: I do not think we have got enough research; at this point we can just hypothesize. In MA, the focal neurological deficit is an electrical phenomenon that looks like cortical-spreading depression, which in itself leads to increases in some inflammatory neuropeptides. Thus it does seem that underlying cortical depression may ensue from some sort of inflammatory response.

Q: Do the findings about the increased relative risk of CVD affect the choice of a triptan or is it only with frank CVD that you would make that call?

Dr. Aurora: I would not think triptans are contraindicated in anyone with migraines, based on this data, unless they had a clinical form of CVD or stroke.

Q: The TEEM study showed an increased response to rizatriptan therapy when combined with personalized patient education, but that finding was not statistically significant. Why not and are the results still instructive?

Dr. Cady: We were concerned that we were going to increase the placebo rate by spending time with patients, so we set up the primary objective to be early intervention—teaching people to treat early—and built the statistical model around that. The education part was set up as an exploratory analysis. The interaction was critical. We asked patients initially how they knew migraine was starting and then gave them a checklist of symptoms. The information provided by both parties was synthesized into a personalized prescription for when to treat, whereas controls without education were told to treat early and given a card with instructions for treatment. We boosted the efficacy of the drug by 11% in the education arm without altering the placebo rate. That was probably one of the highest therapeutic gains of any placebo-controlled early-intervention study in the US.

Q: How do you explain those results? Is it because migraine symptoms are so individualistic?

Dr. Cady: Absolutely, that is the case. One of the limitations of our traditional medical model is that we are structured to have physicians be “the captain of the ship” whereas here we were modelling collaborative care. The person living with migraine is the expert on her own attacks; the physician is an expert on the subject. By putting together their two perspectives, we were able to come back with this individualized “prescription.” We have to assume it is what made the drug work better.