Reports

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16th Migraine Trust International Symposium

London, UK / September 18-20, 2006

According to Dr. Hans-Christoph Diener, Chairman, Department of Neurology, University of Essen, Germany, all studies of single agents for pain therapy should be placebo-controlled. This allows indirect comparisons between trials and is needed to identify adverse effects attributable to the medications, bearing in mind that a placebo commonly causes a certain number of adverse events. It is obviously second-best to direct comparisons between different medications when feasible, but better than having no placebo in single-agent trials.

On the other hand, Dr. Diener advised physicians who treat migraine to read the results of preference trials extremely carefully. “I consider preference trials to be highly dependent on design. You cannot use placebo, it is very difficult to blind them and they depend heavily on patient selection and choice of end points. Preference trials treating mild headache generally do not reflect clinical reality.”

Value of Meta-Analysis

Dr. Diener is also a strong believer in meta-analyses of trials to guide migraine management. Since the different selective serotonin 5-HT1B/1D receptor agonists have small but notable differences in clinical efficacy and adverse event profiles, meta-analyses provide superior predictive power, narrower confidence limits and potential for differentiating drug characteristics when direct comparisons have not been carried out.

In a classic meta-analysis of 53 clinical trials comparing an assortment of seven oral triptans to placebo or other anti-migraine compounds in more than 24,000 patients, investigators in The Netherlands, UK and US found the 5-HT1B/1D receptor agonists to be consistently well tolerated and more effective than placebo. The investigators reported that in relation to the prime comparator sumatriptan, rizatriptan 10 mg provided a 17% greater response at two hours, provided 38% more pain freedom and 25% better sustained pain-free performance over 24 hours in at least one of three migraine attacks. When including consistency over all three attacks, rizatriptan performed even better, at 67% for response and 58% for pain freedom, researchers reported. It offered rapid and consistent freedom from pain when tested in double-blind direct comparisons, meta-analyses and real-world studies, Dr. Diener told delegates.

Complete Pain Relief Above All

A recent survey has shown that migraine patients’ expectations from acute treatment consist of complete pain relief in 87%, no recurrence in 86%, rapid onset in 83%, no side effects in 79% and relief of associated symptoms in 76%.

Dr. Michel D. Ferrari, Leiden University Medical Centre, The Netherlands, and lead investigator of the 53-trial meta-analysis, described another emerging concept during the scientific sessions in which a triptan that provides the lowest recurrence rate may not necessarily be the most advantageous.

Since recurrence occurs in responders only, high recurrence rates can only occur in groups which initially achieved high response rates. Given a choice between administering a triptan with a high rate of pain relief but a higher rate of recurrence vs. one with lower rates of pain relief and low recurrence, it may seem logical to administer the agent with the proven ability to avert a recurrence. However, with a more efficacious record of pain relief efficacy in the first instance, the agent with the highest percentage of recurrences may still offer the greatest likelihood of successful treatment. Dr. Ferrari suggested that it might be necessary to consider sustained pain-free rates and not be misled by low recurrence rates.

He therefore recommended sustained freedom from pain as the most salient primary end point in clinical trials. Dr. Ferrari believes the proportion of patients who are pain-free by two hours, who do not have a recurrence of moderate or severe migraine or use rescue medication within 24 hours represent the ideal efficacy end point, although it is the most difficult one to achieve.

The intrapatient consistency rates of efficacy of rizatriptan 10 mg over multiple attacks were the greatest of the six triptans studied in the 53 clinical trials, Dr. Ferrari reported (Ferrari et al. Lancet 2001;358:1668-75). Response and pain-free rates were 96% and 77%, respectively, in at least one of three migraine attacks, 86% and 48% in at least two of three attacks, and 60% and 20% in all three actively-treated attacks.

Dr. Andrew Moore, Pain Research, Oxford University, UK, suggested clinicians should not be surprised at the wide variability of results from small trials. “If you read the results of 10,000 randomized, small, controlled clinical trials, do not be surprised to see some in which placebo out-performs the active drug. If you study large trials of at least 400 patients, they are much more likely to provide reproducible results. When you include large numbers of randomized trials and good meta-analyses of them, you can put together information of use in clinical practice. You get results you can trust.”

Pre-emptive Care

Findings from trials of early treatment with triptans result in more pain-free and sustained pain-free responses than treatment given after the attack has evolved into a moderate or severe phase. Typically, rizatriptan was significantly more likely than placebo to produce pain-free responses when both were given within two hours from the onset of an attack (Mathew et al. Headache 2004:44(7):669-73). When medication was taken at the earliest sign of headache, pain-free response at two hours was reported by 70% of 112 migraineurs given active treatment vs. 22% of those given placebo. Sustained pain-free response for at least 24 hours was also significantly greater among patients in the active treatment cohort.

Dr. Rami Burstein, Beth Israel Deaconess Medical Center, Boston, Massachusetts, suggested this is because pain pathways in migraineurs appear to be sensitized sequentially from the peripheral neurons of the trigeminal ganglion to the central pathways originating in the dorsal horn of the spinal cord. The first of these appear to cause the mild pain of headache onset and the latter are associated with the brutal pain of a full-blown migraine attack. Triptan administration immediately after the onset of mild pain can prevent central pain pathway sensitization and development of moderate or severe pain by acting in succession on different receptors in the cranial vasculature and meningeal pain fibres. He noted that triptans could prevent, but not reverse, established central sensitization and cutaneous allodynia, which supports the scientific rationale for early intervention.

Dr. Carl Dahlöf, Institute of Neuroscience and Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden, added that the gastrointestinal dysmotility induced by migraine attacks which may obstruct drug absorption can be circumvented with early treatment with a triptan when the attack is still mild.