Tuesday, September 6, 2011

Is Aspirin a First-Line Therapy for Headache?

Headache Recently reported research proposes that simple aspirin should be favored over triptan-class drugs as first-line therapy for both migraine and tension-type headaches, regardless of pretreatment pain intensity. While this may make sense for certain patients, there are some concerns with this particular research that merit closer inspection.

Stepped care in migraine management generally relies on treatments targeting symptoms as first-line therapy, reserving triptan-class agents for patients in whom this proves ineffective. Alternatively, stratified care of migraine chooses equally between symptomatic therapy (eg, with aspirin) and triptans on an individualized basis, according to perceived illness severity. A team of European researchers [Lampl et al. 2011] examined whether pain severity — moderate or severe — would (or should) make a difference in recommending aspirin as a first-line therapy for symptomatic relief of migraine or acute episodic tension-type headache (ETTH).

The investigators retrospectively examined individual patient data from 6 randomized, placebo-controlled, double-blind, single-dose clinical trials of aspirin 1000 mg in migraine (N = 2079; 1165 moderate headache, 914 severe) and one of aspirin, either 500 and 1000 mg, in ETTH (N = 325; 180 moderate, 145 severe). In all cases, aspirin therapy was more beneficial than placebo, but the researchers were primarily interested in how pretreatment headache intensity might have affected two outcomes: 1) headache pain relief at 2 hours — that is, a reduction to mild or no pain; 2) pain freedom at 2 hours — ie, a reduction to no pain.

Writing in a prepublication online edition of the journal Headache, they report the following:

  • Migraine — for headache pain relief, a small but non-significant risk difference (RD) in therapeutic gain favored aspirin (1000 mg) for moderate rather than severe pain. For the endpoint of pain freedom, therapeutic gains were almost identical for persons having either moderate or serve pretreatment migraine pain.

  • Episodic tension-type headache (ETTH) — for headache relief, RDs for both aspirin 500 mg and 1000 mg favored severe rather than moderate pain, but the differences were not statistically significant. For pain freedom, the RDs again favored severe pain but not significantly so.

The authors conclude that pretreatment headache intensity — whether moderate or severe — does not affect the success or failure of aspirin as symptomatic, pain-relief therapy. Therefore, in both migraine and ETTH, they recommend aspirin over triptans as first-line treatment regardless of headache intensity.

COMMENTARY: Only 2 of the 6 trials of aspirin for migraine had comparator agents (sumatriptan and ibuprofen), but these alternative treatments were not part of the analyses in this current study. Rather, the authors focused on aspirin compared with placebo and, in that regard, due to substantial placebo responses aspirin did not seem to produce particularly stellar results.

For example, looking closely at study data for complete freedom from migraine pain, the number-needed-to-treat (NNT, calculated by us not the authors) for aspirin was roughly 10 for either moderate or severe pain. That is, for every 10 patients treated with aspirin, only one additional person would be pain-free than if they were all taking a placebo sugar pill instead. Outcomes for headache relief (ie, pain reduction) were somewhat better, with NNT≈5 for moderate pain and NNT≈7 for severe pretreatment migraine pain. (One benchmark of a clinically significant analgesic effect is that roughly half of treated patients [NNT≈2] will achieve at least 50% pain relief. However, it is difficult to convert to this 50% pain-relief measure from the pain freedom and relief endpoints used the aspirin trials.)

Very similar NNTs can be calculated for aspirin in the symptomatic relief of moderate or severe episodic tension-type headache (ETTH). Overall, however, aspirin at the lower 500 mg dose demonstrates statistically non-significant benefits; in fact, the NNT at this lower dose for complete freedom from moderate ETTH pain is very large (=71). So, aspirin at the higher 1000 mg dose seems most beneficial for ETTH.

Generally, the data appear to support the researchers’ premise that the intensity of pretreatment headache pain, whether moderate or severe, does not seem to affect aspirin’s efficacy — such as it is. However, the authors concede that their investigation does not make head-to-head comparisons of aspirin with triptans, and that the latter can be effective in migraine treatment.

At the same time, they observe, triptans are a more expensive alternative to aspirin and are not always reimbursed by healthcare plans, these drugs have some adverse effects and contraindications, and they are not universally effective (particularly for severe pretreatment headache intensity); therefore, triptans are recommended by some stepped-care guidelines and by the study authors only as second-line therapy.

Even without direct aspirin versus triptan comparisons being available, the researchers conclude that there is essentially no reason for preferring a triptan over aspirin as first-line therapy on the basis of pretreatment headache intensity. The only rationale for favoring triptan therapy, they note, would be if aspirin were tried and determined to be ineffective for the individual patient; however, they do not include a discussion of potential and serious adverse effects associated with aspirin (eg, gastrointestinal complications, Reye’s disease in children, etc.) that could preclude its use in select patients.

Readers are advised that there also is a strong possibility this study was commercially biased in favor of aspirin therapy, and the researchers acknowledge that this weakness might be a point of contention. All 3 authors are connected in some fashion with Bayer HealthCare, a manufacturer of aspirin products: one is an employee of the firm (Voelker) and the other two have received consulting fees and/or research funding from Bayer. The 6 trials of aspirin for acute migraine from which data were gathered for this study were all sponsored by Bayer. While these factors may or may not completely override the validity of this particular study, it does raise some concerns, and this is not the first time that we have detected such potential bias in the Headache journal (see NOTE below).

REFERENCE: Lampl C, Voelker M, Steiner TJ. Aspirin is First-Line Treatment for Migraine and Episodic Tension-Type Headache Regardless of Headache Intensity. Headache. 2011(Aug), online ahead of print [abstract here].

*NOTE: We recently reported on another study from the journal Headache [here], which examined a feverfew/ginger product for the relief of migraine headache. This study was funded by PuraMed Bioscience, which makes the feverfew/ginger product, the lead researcher had received research grants from the company, and one of the other named authors is the Chairman/CEO of the company. It is uncertain from these two studies, as examples, whether commercial biases are endemic in the journal or if this was a rare coincidence; however, it emphasizes why readers should always closely examine author affiliation and conflict of interest statements that are included in journal articles.