Are the current IHS guidelines for migraine drug trials being followed?

Abstract

In 2000, the Clinical Trials Subcommittee of the International Headache Society (IHS) published the second edition of its guidelines for controlled trials of drugs in migraine. The purpose of this publication was to improve the quality of such trials by increasing the awareness amongst investigators of the methodological issues specific to this particular illness. Until now the adherence to these guidelines has not been systematically assessed. We reviewed all published controlled trials of drugs in migraine from 2002 to 2008. Eligible trials were scored for compliance with the IHS guidelines by using grading scales based on the most essential recommendations of the guidelines. The primary efficacy measure of each trial was also recorded. A total of 145 trials of acute treatment and 52 trials of prophylactic treatment were eligible for review. Of the randomized, double-blind trials, acute trials scored an average of 4.7 out of 7 while prophylactic trials scored an average of 5.6 out of 9 for compliance. Thirty-one percent of acute trials and 72% of prophylactic trials used the recommended primary efficacy measure. Fourteen percent of the reviewed trials were either not randomized or not double-blinded. Adherence to international guidelines like these of IHS is important to ensure that only high-quality trials are performed, and to provide the consensus that is required for meta analyses. The primary efficacy measure for trials of acute treatment should be “pain free” and not “headache relief”. Open-label or non-randomized trials generally have no place in the study of migraine drugs.

Guidelines for controlled trials of drugs in migraine: Third edition. A guide for investigators

“…Instead, headache relief after 2 h (a decrease from moderate or severe to none or mild) was used in 39% of such trials. Notwithstanding, the proportion of RCTs using pain freedom as the primary efficacy measure has continued to increase over time (17), and is even used in recent large clinical trials (18)(19)(20)(21).…”

Diclofenac potassium for oral solution (CAMBIA®) in the acute management of a migraine attack: clinical evidence and practical experience

“…9 Moreover, as pain severity increases over the course of a migraine attack, a treatment initiated later is less effective in terms of pain-free outcomes and risk of recurrence compared with an earlier treatment. 5 The effectiveness of triptans may also be decreased in the presence of central sensitization and cutaneous allodynia (a clinical indicator of central sensitization) as the migraine attack progresses. 11 In this advanced phase of migraine, levels of cyclooxygenases (COXs) in the spinal cord are increased; NSAIDs, such as diclofenac, inhibit the activity of these COXs and may offer benefit to migraineurs with allodynia and central sensitization.…”

“…5 Headache relief was used in 39% of trials, and sustained pain freedom for 48 h (IHS recommendation) was used in 3% of trials, but 47% of the trials modified this efficacy measure to evaluate the pain-free state at 24 hours. 5 Commonly used secondary endpoints include measures of disability, absence of nausea or vomiting, or absence of photophobia or phonophobia. 21 Recently, the US Food and Drug Administration began to require acute migraine treatment trials to use the combined endpoint of 2-h pain freedom and freedom from the most bothersome associated symptom (nausea, photophobia, or phonophobia).…”

“…6 Despite their wide uptake and recommendation as standard care for migraine attacks, triptans do not work for all patients and their use for migraine is relatively low in the United States. 5,7 In the longitudinal American Migraine Prevalence and Prevention (AMPP) study, 18.3% of respondents used triptans; only 21.7% of respondents who were taking triptans were using them as monotherapy, while the remainder combined triptans with nonsteroidal anti-inflammatory drugs (NSAIDs; 43.3%), over-the-counter (OTC) analgesics (34.1%), or other OTC medications (34.8%). 7 This study found that triptan use was associated with higher levels of disability related to headache and higher headache frequency.…”

Placebo response in migraine

“…Finally, there is an increasing tendency to use pain free at 2 h as the primary efficacy measure in RCTs on acute treatment migraine [5], and pain free is what the migraine patients want to be [6].…”