Strong placebo response key to adolescent migraine trial failures

Jan 31 2013

By Helen Albert, Senior medwireNews Reporter

A strong response to placebo is the main reason drug trials in the treatment of adolescent migraine have so far failed, say researchers.

They note that attempts to minimize the placebo effect, such as reducing the time to pain relief measurement from 2 hours to 1 hour after treatment, have not made much difference. But the team believes that similar, innovative approaches could yet improve the chance for success.

For example, one of the few successful adolescent migraine trials of rizatriptan, conducted in 2011, excluded patients who reacted strongly to an initial placebo given in response to a single attack of migraine. Remaining participants were then randomly assigned in a standard fashion.

Other approaches that could increase the chance of seeing an effect are the use of formulations that can reduce the time to peak plasma exposure, ensuring that patient reporting is unbiased and that negative results get reported as often as positive results, and carrying out more research into the physiology of adolescent migraine.

Based on the failure of the majority of previous trials of migraine drugs in adolescents, William Rodriguez, from the US Food and Drug Administration in Silver Spring, Maryland, and colleagues systematically reviewed the findings and methods of seven such studies (pooled cohort of 3732 participants; mean age 14 years) to identify possible reasons for failure or success.

Of the seven studies, two assessed rizatriptan benzoate (2011 and 1999), one almotriptan malate (2008), two sumatriptan succinate (2000 and 2003), one zolmitriptan (2003), and one eletriptan hydrobromide (2003).

Placebo responses were moderate to high in all seven studies, ranging from 22.0% in the rizatriptan 2011 study to 57.5% in the zolmitriptan study.

Only two of the studies, the one testing almotriptan and the rizatriptan 2011 study, showed a significantly beneficial effect of the drug versus placebo, with pain relief responses 2 hours after treatment of 71.8% versus 55.3% and 30.6% versus 22.0%, respectively.

The success of the second rizatriptan study could be at least partly explained by the design, and by the fact that the researchers used weight-based dosing, say the researchers. However, this would not explain the success of almotriptan, which had the highest drug response of all the trials and was also higher in adolescents than in adults given the drug, at 71.8% versus an average of 55.5% in adults.

"The reason almotriptan showed a high rate of drug response needs to be further explored," write Rodriguez and team in JAMA Pediatrics.

"In general, a better understanding of the underlying physiological and genotypic differences would decrease the variability now seen in the phenotypic expression of the disease," they conclude.

"Increased diagnostic precision in clinical practice based on such studies could then enhance the likelihood of more successful management of migraine and avoid the 'therapeutic futility' of using targeted medicines in patients who are unlikely to respond."

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