Abstract
An important issue in the management of migraine is the advice given to patients as to when to take their treatment in the course of the attack. While it seems common sense almost to take treatment early in the attack, the evidence base for that advice is not as robust as could be expected. The ‘Act when Mild’ (AwM) Study was a randomized, four-arm, multicentre, multinational, double-blind, placebo-controlled trial of almotriptan (12.5 mg) to compare outcomes after administration of treatment when pain intensity was mild and within 1 h of headache onset (mild/early) with outcomes when pain had become moderate or severe. Of 491 migraineurs enrolled, 403 were evaluable with an intention-to-treat population (ITT) of 404. At the primary end-point, 2 h pain free, on the ITT analysis 49% of patients in the almotriptan 12.5 mg treat early/mild group and 40% in the treat moderate/severe group had responded (P = 0.21). Of these patients, 43 did not take medication according to their randomly allocated baseline pain intensity (mild or moderate/severe) and were subsequently reassigned, prior to study unblinding, to the appropriate group (AwM population) for re-analysis of the primary outcome measure: 2-h pain-free rates. In the almotriptan arms, 53% of the mild/early group and 37.5% of the moderate/severe group were pain free at 2 h (P = 0.02; AwM population). The corresponding proportions in the placebo groups were 24.7% and 17.5% (significantly lower than the respective almotriptan arms; P ≤ 0.01). Considering the ITT population, secondary end-points were also significantly in favour of treatment with almotriptan in the mild/early vs. the moderate/severe stage, including: sustained pain-free, 45.6% vs. 30.5% (P = 0.02); headache recurrence at 24 h, 6% vs. 24% (P = 0.0124). Adverse events were reported in < 5% of patients, with no significant differences between almotriptan and placebo and no serious events in any group. Treatment with almotriptan while migraine pain is still mild and within 1 h of onset provides statistically significant and clinically relevant enhancements in efficacy compared with waiting until pain has reached higher severity levels.
Keywords
Introduction
The development of the serotonin, 5-HT1B/1D receptor agonists (‘triptans’) has revolutionized acute migraine therapy, and these agents have become the mainstay of migraine-specific therapy (1). As their use in a routine clinical setting has evolved, it has become apparent that the timing of their administration in relation to the onset of acute symptoms is an important issue in optimizing their therapeutic benefit (2). While early clinical trials required that patients wait until their headache intensity had become moderate–severe (3), later studies have provided some evidence that treatment with triptans at an early stage of the acute migraine attack can result in better outcomes.
The clinical rationale for treating attacks in their early phase seems almost common sense—indeed, it is how ergotamines have been used for decades (4). A more recent rationale for early dosing with triptans is to abort the development of central sensitization, which is manifest clinically as cutaneous allodynia. This has been reported to be associated with a poor outcome for triptans in open-label studies (5), although this does not seem clear in controlled trials (6). An important issue in this context is to distinguish between ‘mild pain’ and the ‘early phase of an attack’; these may not be equal.
Here, the results of a robustly designed study that overcomes many of the limitations of earlier studies are reviewed. This study—the Act when Mild (AwM) Study—was designed to investigate the relative effects of almotriptan 12.5 mg taken when pain is still mild and within 1 h of migraine onset (mild/early group) vs. almotriptan 12.5 mg taken at any time after pain had become moderate–severe (moderate/severe group) (7).
Methods
Patients aged 18–65 years with a diagnosis of migraine with or without aura (8) for at least 1 year were included in the study. To be eligible, patients had to have experienced two to six migraine attacks per month, and attacks during the preceding year had to be of at least moderate severity. In addition, untreated attacks had to last > 4 h. This was a single-attack, randomized, double-blind, placebo-controlled, parallel group, multicentre, multinational study in which patients were randomized to four treatment groups (Fig. 1). Patients were asked to treat their next migraine attack according to this schedule.
Study flowchart.
The comparisons of principal interest in this study were between the almotriptan groups; placebo was included for reference. The primary end-point of the study was the proportion of patients who were pain free at 2 h in the almotriptan mild/early group vs. the almotriptan moderate/severe group. Secondary end-points included: the proportion of patients who remained pain free at 24 h [sustained pain-free (SPF)], the duration of the migraine attack, time lost in daily activities to the attack, migraine-associated symptoms, and tolerability and safety. The presence of cutaneous allodynia at baseline and 2 h post dose was also assessed using the following questions (9):
Would you describe your headache as ‘throbbing’?
Was your headache worse if you changed position or moved?
Did you have soreness or achy pain in the shoulder or neck areas?
Did you have head or face pain or scalp tenderness in response to touch or pressure that usually does not cause pain?
Analysis populations
Data were analysed for the intention-to-treat (ITT) population as randomized, and the AwM population. The AwM population was a post hoc pre-unblinding reassignment of protocol violators who did not comply with instructions to take medication at the specified severity (Fig. 2). The AwM analysis was subsequently conducted according to the pain severity that study subjects actually treated in accordance with the objectives of the study. The primary end-point was analysed using a logistic regression model with centre and treatment as covariates.
Patient disposition.
Results
Patients
Of 491 patients that were randomized to treatment, 404 constituted the ITT and safety populations (Fig. 2). The mean (
Efficacy
Comparison with placebo
In this study comparisons with placebo were made for reference only and were not the primary outcome comparisons of interest. Nevertheless, a significantly greater proportion of patients (ITT) treated with almotriptan 12.5 mg were pain free at 2 h compared with placebo; 49 vs. 25%, respectively, in the mild/early groups, and 40 vs. 15%, respectively, in the moderate/severe groups (P < 0.001 vs. placebo in both severity groups).
Primary end-point
In the ITT population, the proportion of patients who were pain free at 2 h in the almotriptan mild/early group was not statistically significantly different from that in the almotriptan moderate/severe group (49 vs. 40%, P = 0.21). These findings do not take into account that 21 of 198 (11%) patients randomized to receive almotriptan did not treat attacks at the severity they were randomly assigned to treat. When this correction is made (the AwM population), significantly more patients were pain free at 2 h post dose in the almotriptan mild/early group than in the almotriptan moderate/severe group (53 vs. 37.5%, P = 0.02; Fig. 3).
Two-hour pain-free data in the AwM population.
Secondary end-points
SPF: In the ITT population the proportion of patients who remained pain free at 2–24 h post dose without the use of rescue medication was significantly higher for almotriptan-treated patients in the mild/early group than in those in the moderate/severe almotriptan-treatment group (46 vs. 30%; P = 0.024) (Fig. 4a).
(a) Sustained pain-free 2–24 h. (b) Headache recurrence at 24 h. (c) Duration of migraine attack in the ITT population.
Headache recurrence: Consistent with the sustained pain-free findings in the ITT population, fewer patients taking almotriptan when pain was mild/early had a recurrence of the migraine attack within 24 h than patients taking almotriptan when pain was moderate/severe. Only 6% of patients had headache recurrence within 24 h of dosing in the almotriptan mild/early group compared with 24% of patients in the almotriptan moderate/severe group (P = 0.0124; Fig. 4b).
Duration of headache: The median duration of the migraine attack in patients receiving almotriptan in the mild/early group was 2.0 h compared with 5.0 h in the moderate/severe almotriptan group (P = 0.0005; ITT). When expressed in terms of a Kaplan–Meier plot of pain presence over time (Fig. 4c), the lower overall pain burden in patients taking almotriptan when migraine pain was still mild and within 1 h of onset is clearly evident compared with waiting until pain had become moderate/severe. This had a positive impact on patients' ability to resume daily activities within 48 h after dosing; the median time lost was significantly lower in the almotriptan mild/early group than the almotriptan moderate/severe group (0 vs. 2 h, respectively, P = 0.0015).
Allodynia
The proportion of patients who answered ‘yes’ to at least one of the allodynia questions (9) at baseline in the almotriptan mild/early group and the moderate/severe group was 92% and 96%, respectively. The proportions in the corresponding placebo groups were 91% and 98%. Based on these findings, the apparent presence of allodynia at baseline did not appear to predict outcome of the 2-h pain-free status, whereas others did not.
Safety and tolerability
The incidence of adverse events (AEs) was similar in the four treatment groups (4.7% of patients in the placebo mild/early group; 4.9% in the almotriptan mild/early group; 4% in the placebo moderate/severe group; and 4% in the almotriptan moderate/severe group). All AEs were mild to moderate in severity and resolved by the end of the study. There was no indication of a difference in the nature or incidence of AEs when treating mild/early migraine with almotriptan vs. treating when moderate/severe.
Clinical implications
The AwM Study confirms the high level of efficacy and placebo-like tolerability of almotriptan 12.5 mg in the treatment of migraine found in earlier studies (10, 11). This study further suggests that if patients take almotriptan 12.5 mg while pain is still mild and within 1 h of onset, the outcome is significantly better than waiting until the pain intensity has become moderate or severe. The new findings are consistent with retrospective studies of the almotriptan development database (12), and with studies of other triptans (13–15). Moreover, the outcome is consistent with the bedside experience of both clinicians and patients, who have observed that treating migraine before the attack has fully developed is more effective (16, 17, this Supplement). The benefit to patients of this treatment approach is a lower burden of pain and less time lost in daily activities with no AE penalty, consistent with patient expectations of migraine therapy (18). It is reasonable, therefore, to advise migraine patients prescribed almotriptan in a routine clinical setting to take the medication without delay following the first signs of a migraine attack. Objections to the concept of treating migraine attacks early are derived from concerns that patients who treat attacks that are still mild in intensity might be treating non-migraine headaches or that such an approach may promote medication overuse (2). Careful clinical monitoring is always wise and, along with patient education, will militate against such complications.
The post hoc reassignment of patients in this study is open to criticism, although this is clearly indicated to be a secondary analysis and the re-allocation was done while the blind was unbroken. It could be noted that in practice patients will do as they wish, so that the re-analysed data perhaps more closely inform the reader as to the outcome to be expected, albeit with the usual caveats of controlled trials (16, this Supplement). Furthermore, although statistical significance for the primary outcome measure was found in the AwM population but not the ITT population, the SPF rate showed the significant benefit of taking almotriptan during the mild/early stage compared with the almotriptan moderate/severe group in the ITT population. The relevance of this finding is not trivial, because SPF is a more robust composite measurement of the initial pain-free response at 2 h and the absence of recurrence of migraine during the following 24 h without the use of rescue medication.
The allodynia findings in this study are intriguing. The fact that the great majority of patients in each of the four randomized groups had signs of allodynia at baseline, and this did not alter the responses rates substantially, confounds the hypothesis that the presence of allodynia predicts a poorer outcome to triptans and its obverse, that patients who are treated with triptans before allodynia has become established increase the probability of a pain-free outcome (5). However, the finding in the present study that 91–98% of patients exhibited signs of allodynia at baseline is higher than that reported in previous patient series, which has generally been about two-thirds (19–21). One explanation is that the instrument used to evaluate allodynia in the present study was insufficiently sensitive to distinguish between allodynia symptoms and other manifestations of headache severity. Alternatively, some previous studies may have underestimated the presence of the symptom, or patients entering controlled trials are in some way self-selected for this symptom. Much work is to be done to understand these issues.
Conclusions
Treatment of migraine attacks with almotriptan within 1 h of pain onset and while pain is still mild provides statistically significant benefits to patients in terms of pain-free outcomes and reduced risk of recurrence compared with treating later when pain is more severe. As the severity of pain at initiation of treatment is a key predictor of outcome, patients should be encouraged to treat their migraine attack early while pain is still mild.
Footnotes
Conflicts of interest
P.J.G. has consulted for and lectured at meetings sponsored by Almirall. Stuart Donovan PhD, from Complete Medical Communications, provided support for manuscript preparation, particularly with respect to figure production, and was funded by Amirall.