Early treatment in migraine: how strong is the current evidence?

Authors


Dr Astrid Gendolla, Klinik für Neurologie, Universitätsklinik Essen, Essen, Germany. Tel. + 49 020 1436 9610, fax + 49 020 1436 9633, e-mail astrid.gendolla@uni-due.de

Abstract

Gendolla A. Early treatment in migraine: how strong is the current evidence? Cephalalgia 2008; 28:28–35. London. ISSN 0333-1024

Over the last 10 years, triptans (serotonin 5-HT1B/1D receptor agonists) have proved to be efficacious in treating migraine pain. However, recent evidence suggests that patients are still not receiving optimal pain management, particularly in clinical trials, where triptan treatment is generally not initiated until pain has reached moderate intensity. Pathophysiological evidence indicates that if treatment is initiated at an early stage, while pain is still mild and before the onset of central sensitization, outcomes for patients may be improved. In addition, a small number of clinical trials have been reported in which triptans were taken early (within 1 h of pain onset) or while pain was still mild; although constraints of trial design and data analysis limit definite conclusions, overall the results suggest that this early/mild approach results in more rapid and sustained pain relief. New studies are therefore needed to clarify the clinical benefits of early treatment, whilst taking into account potential risks, such as medication overuse. Ultimately, migraine treatment strategies require optimization in order to meet patient expectations and to reduce the current burden of migraine-associated disability.

Introduction

Since their introduction more than a decade ago, the serotonin 5-HT1B/1D receptor agonists, or triptans, have proved to be highly effective in treating migraine pain (1, 2). However, sustained pain-free rates in clinical trials remain comparatively low, indicating that pain management is not optimal under such conditions (3). One possible reason is that treatment with triptans in clinical trials has traditionally been initiated when pain is at least of moderate intensity (4, 5). There are sound methodological reasons for this—it enables migraine pain to be distinguished from non-migraine headache, provides a higher baseline from which to measure change, and minimizes placebo response (5, 6). Clinical practice is different, however: patients treat inter- and intra-individually and the concept of early treatment reflects the real world for most migraineurs. Many patients with disabling headache report that they treat mild pain to prevent its progression and to minimize migraine-related disability. Unsurprisingly, therefore, clinicians have been searching for trial designs that better reflect the situation in the general population (7).

Here, the rationale for early treatment in migraine will be examined, including the underlying scientific principles for treating migraine within 1 h of pain onset and while pain is still mild, patient expectations of their migraine treatment, and the clinical evidence to date.

Evolution of migraine pain

When examining the evolution of migraine pain and the opportunities for optimizing the timing of treatment, it is important to distinguish between the terms ‘early’ and ‘mild’. Between 81% and 90% of migraine attacks are believed to begin with a phase of mild pain (8) (Fig. 1), although the duration of this phase varies between patients and may even differ between different attacks in the same patient. Depending on whether the attack evolves quickly or slowly, the interval of mild pain experienced by a migraineur may last from just a few minutes to > 1 h (8). Equally, pain intensity at an early stage of a migraine attack (within 1 h of onset) may have already progressed to a moderate or severe level (Fig. 1) (8). ‘Early’ and ‘mild’ are not, therefore, interchangeable terms, and this must be considered when assessing the efficacy of treatment at different time points after pain onset. While the evidence suggests that early treatment after migraine onset may be beneficial in a clinical practice setting, taking triptans while pain intensity is still mild seems to be the driving factor for achieving better efficacy rates (6, 9). This is probably because the central sensitization cascade, which usually establishes within 1 h of pain onset, is avoided (10).

Figure 1.

Evolution of migraine pain: distinguishing between ‘early’ and ‘mild’.

Migraine attacks may be triggered by stress, food or drugs, odours, hormonal fluctuations or changes in sleep habits. These triggers activate the peripheral trigeminovascular system, inducing vasodilation and the release of vasoactive neuropeptides, resulting in neurogenic inflammation of the meningeal blood vessels and, consequently, throbbing pain (11). As an acute attack progresses, sensory neurons in the trigeminal nucleus caudalis become sensitized (12). It is postulated that this central sensitization produces the phenomenon of cutaneous allodynia and muscle tenderness (10). Triptans are believed to act at several different points during the progression of a migraine attack, inhibiting neurogenic inflammation, acting as vasoconstrictors of the cerebral blood vessels, and blocking the transmission of pain from the peripheral trigeminal nerves to the brainstem (11). However, if treatment is initiated once central sensitization has occurred, response to triptan therapy is likely to be poor (12).

The early treatment of migraine is therefore a race against central sensitization (13, 14) and, in support of this, data from a pivotal open-label study have indicated that triptan therapy may be more efficacious if initiated before the onset of cutaneous allodynia (10). In this study, 53 migraineurs treated their pain either early (1 h after pain onset) or late (4 h after pain onset) on in the attack, with the presence or absence of cutaneous allodynia recorded at the time of treatment. Of those patients who recorded allodynia, only 6% achieved the end-point of sustained pain-free at 2 h. In comparison, when allodynia was absent, 94% of patients were sustained pain-free at 2 h (10). Waiting to treat migraine until pain is severe may significantly restrict the efficacy of antimigraine drugs and substantially reduce the chances of a positive outcome for patients.

Changing patient behaviour to meet treatment expectations

During the past few years, multiple surveys and analyses have been carried out to determine what patients expect from their migraine treatment, resulting in an ever-increasing ‘shopping list’ of ideal attributes (15). Unsurprisingly, the most important determinants for treatment satisfaction are efficacy, tolerability, and consistency of effect (16). Patients require rapid onset of action and fast resolution/complete relief from their migraine pain, allowing a quick return to normal functioning (15, 17–19). Sustained pain relief, with less frequent or no pain recurrence, and a reduction in migraine-associated symptoms (such as nausea, vomiting, and phono-, photo- and osmophobia) are also important (16, 19, 20). In addition, patients prefer migraine treatments that do not produce side-effects but provide pain relief that is consistent across attacks (7, 16, 18).

Unfortunately, although patients are often very clear about the outcomes they expect from their migraine medication, their behaviour may conflict with these expectations (21). Although migraineurs often expect rapid results from treatment, many patients delay taking their medication. Reasons for this include: waiting to see if the headache is really migraine; using medication for only the severest migraine attacks; and concerns about tolerability, tolerance and addiction (9, 22). In addition, quantity limits imposed on triptan therapy by health plans can hinder the optimal acute treatment of migraine in some countries (23). Clearly, further education of migraine patients is required, to enable them to differentiate between headache types and to assess when and how to use their acute migraine medication most effectively. Positive physician–patient communication to improve patient compliance is key to successful treatment outcomes (24, 25).

The Triptans: Efficacy in Migraine after Precocious Oriented (TEMPO) dosing study, a French prospective, cross-over, open-label trial, has shown conclusively that changing patient behaviour can improve the results of migraine treatment (26). TEMPO was a within-patient comparison of pain-free status at 2 h in migraineurs who changed from ‘late’ (> 1 h after pain onset) to ‘early’ (< 1 h after pain onset) triptan dosing. Initially, patients treated three attacks in their usual manner (Phase I). Patients who treated at least two of these three attacks > 1 h after pain onset were instructed to treat their next three attacks < 1 h after pain onset (Phase II). The results showed that changing patient behaviour can improve outcomes, with pain-free status statistically associated with early intake of a triptan (odds ratio 0.432; 95% confidence interval 0.309, 0.605) (Fig. 2) (26).

Figure 2.

Within-patient comparison of pain-free rates in patients in TEMPO who treated at least two of three migraine attacks > 1 h after pain onset in Phase I, and switched to an early dosing time (< 1 h after pain onset) in Phase II (26) (reproduced by kind permission of Dr Michel Lantéri-Minet, Pôle Neurosciences Cliniques, Nice, France).

‘Early’/‘mild’ studies in migraine

Traditionally, triptan trials have required patients to treat migraine attacks only when their pain is moderate or severe (27). A limited number of studies have used trial designs that attempted to examine the outcome of treating migraines early, while pain is still mild. However, the overall picture from such studies is a confused mix of differing trial designs, and a failure to distinguish between ‘early’ and ‘mild’(6, 28). In order for early/mild triptan trials to produce accurate, scientifically robust data, they should fulfil several key requirements in their design. These include: an adequate number of patients for sufficient statistical power; a randomized, double-blind, parallel-group design for patient homogeneity; placebo control to establish therapeutic gain; randomized early vs. late treatment for good statistical analysis; definitions of both mild pain and early treatment; prospective trial design; patient ability to differentiate migraine from non-migraine headache; and appropriate outcome measures.

A review of published mild pain/early treatment trials with individual triptans has revealed 14 studies between 2000 and 2006 (four sumatriptan studies; three studies for zolmitriptan; two each for almotriptan and rizatriptan; and one each for frovatriptan and eletriptan) (Table 1) (7, 29–41). Collectively, this historical evidence tends to show that there are potential benefits to starting treatment at an early/mild stage of pain. However, all of these previous triptan studies are constrained by limitations of study design and data analysis that, in turn, limit the conclusions that can be drawn about their use early in the course of acute migraine (Table 2) (29–42). Double-blind randomization enables data to be collected without the risk of therapeutic bias on the part of the patient or investigator, whereas due to high levels of placebo response in studies involving migraine medication, a placebo control is necessary in order to calculate the true therapeutic gain. In addition, for trials purporting to examine the effects of taking medication early or mild, it is essential that the terms ‘early’ and ‘mild’ are clearly defined from the outset. Of the four sumatriptan studies published, two were based on post-hoc analyses of protocol violators from larger clinical trials (32, 33), one was based on pooled data analysis from six trials with some methodological heterogeneity (41), and one was an open-label study that did not include a placebo control (39). Both almotriptan studies were post hoc and were additionally open-label analyses with no placebo control (36, 38). None of the three zolmitriptan studies was designed to compare early vs. late treatment, and although all of these studies were prospective, one was open label without placebo control (34, 35, 40). The data for rizatriptan are similar: both studies were prospectively designed, but neither was set up to compare early with late treatment, and although the protocols specified early treatment, the data indicated that treatment delays may have occurred in some patients (31, 37). In general, the frovatriptan study was well conceived, being a prospective, placebo-controlled, cross-over study, but no timings for dosage were specified, and there was no attempt to check the compliance of patients who were instructed to treat migraine when pain was mild (30). Finally, the single eletriptan study was a post-hoc analysis and was also limited by the fact that the study design did not require patients to take their medication at any particular time or pain intensity, resulting in a heterogeneous patient population (29).

Table 1.  ‘Mild’ pain/‘early treatment’ studies with triptans (2000–2006): design issues. Adapted from Dowson et al. 2006 (7)
TriptanAuthorsDose2-h pain-free rates according to headache severity at time of dosing (% patients)Limitations of trial design
MildModerateSevereNumber of patients (attacks)DesignPlacebo controlledRandomized ‘early’ vs. ‘late’Analysis
  1. D-B, double blind; P-G, parallel group; R, randomized; OL, open label; LT, long term; ODF, oral disintegrating formulation; X-O, crossover. aP < 0.05 vs. placebo.bP < 0.05 vs. moderate–severe pain.cP < 0.0001 vs. placebo.dP < 0.001 vs. moderate–severe pain.eP < 0.01 vs. placebo.fP < 0.001 vs. placebo.

SumatriptanCady et al. (2000) (32)50 mg502726 (212)D-B, P-GYesNoPost hoc
Placebo06
Cady et al. (2000) (33)100 mg67a3692 (118)D-B, P-GYesNoPost hoc
50 mg51b31
Placebo287
Winner et al. (2005) (41)100 mg58c2 297D-B, P-GYesNoPooled
50 mg49c
Placebo24
Scholpp et al. (2004) (39)100 mg71b53153R, OLNoYesProspective
AlmotriptanPascual et al. (2002) (38)12.5 mg84d53118 (708)LT, OLNoNoPost hoc
Mathew (2003) (36)12.5 mg77d44 582 (10 645)LT, OLNoNoPost hoc
Zolmitriptan311C90 Study Gp (1998) (40)5 mg8057352 058 (31 579)LT, OLNoNoProspective
Klapper et al. (2004) (34)2.5 mg43c280D-B, P-GYesNoProspective
Placebo18
Loder et al. (2005) (35)2.5 mg ODF483731565D-B, P-GYesNoProspective
Placebo241527
RizatriptanMathew et al. (2004) (37)10 mg72e42112 (235)D-B, P-GYesNoProspective
Placebo2516
Cady et al. (2006) (31)10 mg58f1 030D-B, P-GYesNoPooled
Placebo31
FrovatriptanCady et al. (2004) (30)2.5 mg28a241 (248)D-B, X-OYesYesProspective
Placebo20
EletriptanBrandes et al. (2005) (29)40 mg68c39e565D-B, P-GYesNoPost hoc
20 mg3635e
Placebo2521
Table 2.  Overview of design characteristics of studies in ‘early/mild’ migraine (2000–2006)
StudyS1S2S3S4A1A2Z1Z2Z3R1R2F1E1AwM
  1. ✓, yes; ✗, no; ?, unclear. S = sumatriptan: S1, Cady et al. (2000) (32); S2, Cady et al. (2000) (33); S3, Winner et al. (2005) (41); S4, Scholpp et al. (2004) (39). A = Almotriptan: A1, Pascual et al. (2002) (38); A2, Mathew (2003) (36). Z = zolmitriptan: Z1, 311C90 Study Group (1998) (40); Z2, Klapper et al. (2004) (34); Z3, Loder et al. (2005) (35). R = Rizatriptan: R1, Mathew et al. (2004) (37); R2, Cady et al. (2006) (31). F = frovatriptan: F1, Cady et al. (2004) (30). E = eletriptan: E1, Brandes et al. (2005) (29). AwM = Act when Mild Study with almotriptan: Goadsby et al. (2006) (42).

Prospective
Single trial
Placebo
Double-blind??
Randomized?
Sample size
‘Early’ defined
‘Early’ vs. ‘late’
‘Mild’ defined

All of these studies suggest that early treatment with triptans may be the best approach to maximize the likelihood of achieving the patient's top priorities (rapid pain-free results and sustained freedom from pain, facilitating a speedy return to normal daily activities) (Table 1) (7, 29–41). However, overall, the methodologies used in all of these studies limit the robustness of interpretation of results in terms of benefit or early and/or mild treatment (Table 2) (29–42).

Aims of new studies

Since this analysis of historical early/mild treatment was presented, the results of two further prospective almotriptan trials have been reported (43, 44), both of which appear to support the benefits of treating migraine pain early (Table 3). However, definitive evidence in favour of early triptan treatment can be provided only by trials such as the Act when Mild (AwM) Study, also with almotriptan (42). With a more sophisticated trial design, incorporating all of the elements required for robust analysis of the data, AwM was specifically conceived to examine prospectively the issue of treatment initiation (42). Key attributes of the AwM Study include a double-blind, randomized, placebo-controlled design to preclude the possibility of patient bias, whereas a prospective design ensures that the trial is powered correctly for significant statistical analysis and that all of the data required are identified for collection. In addition, AwM differs from all previous studies by examining patients whose pain was still mild and who were treated early—patients were instructed to take almotriptan 12.5 mg or placebo when migraine pain was still mild and within 1 h of pain onset, or to wait until pain intensity had become moderate to severe. Baseline pain intensity and timing of treatment are, therefore, covariates in this study, allowing accurate assessments of the effects of the timing of treatment on pain outcomes, and enabling definite conclusions to be drawn (42).

Table 3.  Results of the recent AIMS and AEGIS studies with almotriptan (43, 44)
AuthorsDose2-h pain-free rates according to headache severity at time of dosing (% patients)Trial design
MildModerateSevereNumber of patients (attacks)DesignPlacebo controlledRandomized ‘early’ vs. ‘late’Analysis
  1. AIMS, AXERT® 12.5 mg time vs. intensity migraine study; AEGIS, AXERT® early migraine intervention study; R, randomized; OL, open label; D-B, double blind; P-G, parallel group. aP < 0.05 vs. severe pain.bP = 0.01 vs. placebo.

Freitag et al. (2007) (43)12.5 mg43.4a43.8a31.01450R, OLNoYesProspective
Mathew et al. (2007) (44)12.5 mg37.0b317D-B, P-GYesNoProspective
Placebo23.9

Conclusions

Although, historically, guidelines for clinical trials have advised that patients should wait until migraine pain is moderate/severe before taking a triptan, the pathophysiological evidence indicates that optimal results may be achieved if treatment begins early, while pain is still mild and before central sensitization has occurred. The evidence currently available for using triptans in an early/mild setting suggests that this approach may improve outcomes such as rapid pain relief and sustained freedom from pain, although methodological limitations hinder more definite conclusions. Studies such as AwM aim to clarify the clinical benefits of early treatment, whilst concurrently evaluating potential risks, such as medication overuse. Ultimately, it is hoped that the data on early/mild treatment of migraine with triptans will be conclusive enough to update treatment guidelines to drive optimal treatment strategies.

Competing interests

A.G. has received fees for speaking from Almirall, GlaxoSmithKline, Merck, Sharpe and Dhome, Böringer Ingelheim, AstraZeneca, Johnson & Johnson and consultancy fees from MSD and Pfizer.

Acknowledgements

The author would like to thank Sally Mitchell PhD, from Complete Medical Communications, who provided medical writing support funded by Almirall.