Using Patient-friendly Composite Endpoints to Measure the Success of Acute Migraine Medications: 4th Annual Migraine Meeting, Budapest, October 2004: Proceedings

Using Patient-Friendly Composite Endpoints to Measure the Success of Acute Migraine Medications Proceedings from the 4th Annual Migraine Meeting Budapest, Hungary, October 15–17, 2004

Guest Editor

J. Pascual, Santander

26 figures and 4 tables, 2005

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Vol. 53, Suppl. 1, 2005

Contents

1 Introduction Pascual, J. (Santander) 3 What Do Patients Want from Their Acute Migraine Therapy? Lantéri-Minet, M. (Nice) 10 Migraine, Allodynia, Sensitisation and All of That … Goadsby, P.J. (London) 17 Should We Advise Patients to Treat Migraine Attacks Early:

Methodologic Issues Ferrari, M.D. (Leiden) 22 Defining Response in Migraine: Which Endpoints Are Important? Edmeads, J. (Toronto) 29 Efficacy and Tolerability of Almotriptan in Controlled Clinical Trials Mathew, N.T. (Houston, Tex.) 34 Efficacy and Tolerability of Almotriptan in Postmarketing Surveillance

Studies Pascual, J. (Santander) 41 Almotriptan in Migraine Patients Who Respond Poorly to

Oral Sumatriptan: A Double-Blind, Randomized Trial Diener, H.-C.; Gendolla, A. (Essen); Gebert, I.; Beneke, M. (Leverkusen)

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Eur Neurol 2005;53(suppl 1):1–2 DOI: 10.1159/000085035

Published online: May 3, 2005

Introduction Julio Pascual Service of Neurology, University Hospital Marques de Valdecilla, Santander, Spain

In 1999, my colleagues and I performed a study in 7 hospitals in different regions throughout Spain where 305 patients were questioned about their use of antimigraine medications [1]. The patients reported previous use of the following acute agents: analgesics (99%), nonsteroidal antiinflammatory drugs (NSAIDs, 69%), ergotamines (54%), and sumatriptan (40%). When questioned about their satisfaction with these agents, a subjective good response was reported by 9% of those who had taken analgesics, 23% of those who had taken NSAIDs, 39% of those who had taken ergotamines, and 63% of those who had taken sumatriptan. Now, 5 years and many second-generation triptans later, how have things changed in the treatment of acute migraine? The articles in this supplement, based on presentations at the 4th Annual Migraine Meeting, October 15–17, 2004, in Budapest, Hungary, report on advances made in the management of acute migraine. Dr. Lantéri-Minet describes what patients want from their acute migraine medication, that is, complete freedom from pain, rapid onset of action, no recurrence, and absence of side effects, but explains that, with the underuse of triptans, many patients are not receiving the type of medication that will meet these expectations and leave them satisfied. In addition, many individuals with migraine are still unrecognized and do not have a physician’s diagnosis. Professors Goadsby and Ferrari discuss the important topic of early intervention with acute agents and the impact of this management strategy on migraine outcomes.

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Professor Goadsby presents the pathophysiologic evidence, explaining that to achieve maximal response, triptans may need to be taken early in the progression of a migraine attack, before the establishment of central sensitization and development of cutaneous allodynia. Professor Ferrari, while acknowledging that early treatment seems intuitively very reasonable, and recommending that patients should be advised to take their medication as soon as they are sure they are developing a migraine headache (but not during the aura phase), cautions that because of trial methodology, conclusive evidence in support of early intervention is still required. Dr. Edmeads explains that to improve patients’ satisfaction with therapy, the endpoints used to measure and compare the efficacy of acute treatments should include the attributes that patients value the most. Composite endpoints such as sustained pain free and sustained pain free with no adverse events provide a better representation of patients’ expectations, and the use of agents which achieve high response rates on these endpoints will be associated with higher levels of success and patient satisfaction. Dr. Mathew and I report on clinical trial data of almotriptan, which has been investigated in approximately 3,500 patients enrolled in short-term clinical trials and 1,500 patients enrolled in long-term open-label trials. Dr. Mathew conveys the results of a meta-analysis of placebo-controlled almotriptan trials (n = 2,294), which found a 2-hour pain-relief rate of 63.7%, a 2-hour painfree rate of 36.4%, and 30-minute pain-relief and pain-

Julio Pascual, MD, PhD Service of Neurology University Hospital Marques de Valdecilla ES–39008 Santander (Spain) Tel. +34 942 202507, Fax +34 942 202655, E-Mail [email protected]

free rates that are significantly better than placebo (p ! 0.05). Dr. Mathew also describes post hoc analyses of these studies showing the enhanced efficacy of almotriptan when used early in the progression of a migraine attack. I present the results of postmarketing surveillance studies of almotriptan carried out in Spain and in Germany, which show that the excellent efficacy and tolerability profile of almotriptan seen in controlled clinical trials is achieved, and even surpassed, in real-world clinical settings. Finally, Professor Diener presents a study on the use of almotriptan in patients who were poor responders to sumatriptan. His results show that this difficult-to-treat cohort of migraine patients can be successfully treated with almotriptan. While many things have changed in the past 5 years, others have remained the same. In spite of the availabil-

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ity of effective acute agents, migraine is still underdiagnosed and undertreated. For those patients who are receiving therapy, many remain unsatisfied. Perhaps by treating patients early and using agents that are successful in attaining endpoints that are important to patients (sustained pain free, sustained pain free with no adverse events), more migraine sufferers will achieve results that meet their expectations. Agents such as almotriptan, which offer a combination of high efficacy and placebolike tolerability, are more likely to be associated with satisfactory outcomes.

Reference

1 Pascual J, Leira R, Lainez JM, Alberca R, Titus F, Morales F, Diez-Tejedor E, Garcia de Polavieja J: [Spanish study of quality of life in migraine (ii). Profile of medication consumption and subjective efficacy]. Neurologia 1999; 14: 204–209.

Pascual

Eur Neurol 2005;53(suppl 1):3–9 DOI: 10.1159/000085036

Published online: May 3, 2005

What Do Patients Want from Their Acute Migraine Therapy? Michel Lantéri-Minet Department of Evaluation and Treatment of Pain, Hôpital Pasteur, CHU de Nice, Nice, France

Key Words Pain free
Migraine
Migraine-related quality of life
Patient satisfaction
Sustained pain free
Tolerability
Triptan

Abstract A minority of migraine sufferers are diagnosed and treated and medical consultation rates are low even among those aware of their condition. Despite guidelines recommending the use of triptans, there are high rates of usage of nonspecific treatments, mainly simple analgesics, coupled with low prevalence of triptan use. Consequently, many individuals with migraine are not receiving the kind of treatment that would meet their expectations and leave them satisfied. For patients, the most important attributes of acute migraine treatment are complete freedom from pain, rapid onset of action, no recurrence and absence of side effects. More widespread use of triptans would have the potential to improve outcomes and increase patient satisfaction, leading to a better migraine-related quality of life. In choosing among triptans, physicians need to match individual patients’ needs and wants with the attributes of the particular triptans, taking into account a medication’s complete profile of efficacy, consistency and tolerability, and using information from meta-analyses and modelling to ensure evidenced-based, patient-oriented decision-making.

Introduction

Patients’ expectations with regard to medical care and treatment have been extensively studied in conditions such as cardiovascular disease, arthritis, asthma, and diabetes. Although there are extensive data on epidemiology and healthcare use for migraine, there has been relatively little research into the expectations and experiences of patients with migraine [1]. The two main expectations that patients are likely to have are that their condition will be correctly diagnosed and that it will be well managed, providing them with the outcomes they desire and value. Available evidence, however, indicates that these expectations are too often not achieved and that migraine is underrecognized and far from optimally managed.

Recognition and Management of Migraine

A recent study carried out in France has demonstrated the underrecognition and undertreatment of migraine [2]. Patients presenting to 49 general practitioners (GPs) during their outpatient visiting hours on one day were invited to complete a questionnaire designed to identify individuals suffering from headache and those meeting International Headache Society (IHS) criteria for migraine [3]. While blinded with respect to the patients’ re-

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Michel Lantéri-Minet, MD Department of Evaluation and Treatment of Pain Hôpital Pasteur, CHU de Nice FR–06002 Nice (France) Tel. +33 492 038 474, Fax +33 492 038 481, E-Mail [email protected]

sponses, the GPs completed a questionnaire for each patient to indicate whether they considered the patient to be a migraine sufferer or managed the patient for migraine. A total of 696 patients were included in the study, 289 of whom (42%) reported episodic headache; of these, 176 (25% of the total patient sample) met the IHS criteria for migraine. The GPs identified only 71 (40%) of the 176 patients meeting IHS criteria for migraine as migraine sufferers, and were providing migraine management for only 50 (28%) of them. So, in this study sample, less than a third of patients with migraine were being managed for the condition. Surveys of consultation patterns among the general population reveal a similar picture of underdiagnosis and undertreatment. A population-based telephone survey carried out in France in 2000 (FRAMIG 2000) identified 312 individuals meeting IHS criteria out of a representative sample of 4,689 adults (6.7%). Although 80% of these migraine sufferers were aware of their migrainous state, the majority, 82%, had no medical follow-up for migraine: 23% had never discussed the subject of migraine with a physician and 59% had consulted previously for migraine but had lapsed consulting [4]. Around half of those who had never consulted a physician considered that doing so was useless (56%) or that there was no definite treatment for migraine (45%); most of these patients (93%) thought that they could cope with their migraine on their own. Around half of those who had lapsed from consulting (58%) considered that consulting with a physician made no difference, but 48% had lapsed because the treatment recommended by their last physician had suited them well; again, most (82%) considered they could cope alone. These findings are similar to those in other countries. In Sweden, for example, a randomized population-based survey revealed that only 27% of migraine sufferers were currently consulting a physician, 6% regularly and 21% occasionally, although the majority reported that the most important aspects of their lives were affected by the condition and 57% were quite or very interested in testing other treatments for migraine within the preceding year [5]. Of those who had consulted a physician, 55% thought their physician’s knowledge of migraine was good or very good, but only 39% considered that their physician offered good or very good information on different migraine treatments. An international survey carried out in France, Germany, Italy, the United Kingdom and the United States (the MAZE survey) involving a total of 5553 adults found that 5–12% of the population in these countries were classified as suffering from migraine (ac-

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cording to IHS criteria), but only half of these individuals sought medical advice [6]. The deficits in migraine management suggested by these data are reinforced by studies of triptan use. GRIM 2000 was a large epidemiologic survey of headache characteristics and healthcare resource utilization in the French population [7]. Of more than 25,000 individuals screened, 3,434 subjects with headache were identified (13.4%), of whom 1,721 were interviewed; a total of 290 triptan users were identified. Only 7.5% of the migraine sufferers identified were using triptans; 80% of the triptan users had headache characteristics typical of migraine. Triptan users had more frequent headaches, more severe headaches, more nausea and vomiting and higher migraine disability assessment (MIDAS) scores than nonusers. The principal determinant of triptan use was consultation with a general practitioner (which may in turn have been related to headache severity). In FRAMIG 2000, most patients took nonspecific treatments, with only 8% using triptans [4]. Similar patterns of underuse of triptans have been found in other countries. In the MAZE survey, for example, the percentage of migraine sufferers consulting a physician who were prescribed triptans ranged from 3 to13% in the European countries and was 19% in the United States. In all countries surveyed the most commonly used current treatment was simple analgesics (22– 54%) (fig. 1) [6]. This low prevalence of triptan use is not in accordance with patients’ expectations in terms of acute migraine treatment.

What Are Patients’ Expectations of Migraine Management?

There are few systematically collected data on what patients want from their healthcare providers and migraine medication. A telephone survey of US households carried out in 1998 identified 688 individuals meeting IHS criteria for migraine and indicated that complete pain relief, no recurrence, and rapid onset of action were the attributes of migraine medication that patients rated as important or very important [1]. More than 70% of the respondents were not completely satisfied with their current medication; reasons for dissatisfaction were that pain relief took too long (87%), was incomplete (84%) or inconsistent (84%), that their headache recurred (71%), or that there were too many side effects (35%).

Lantéri-Minet

Migraine treatment patterns: MAZE study France 60

Germany

Italy

UK

USA

54

Population surveyed (%)

47 43 40

35 30

22 19

20

16

14 12

16

14

13

10

5

10

7

5 2

0

Simple analgesics

NSAIDs

4

Antiemetics

3

5

7

4

Ergots

3

Triptans

Medication prescribed at most recent physician consultation

Fig. 1. Patterns of treatment of migraine in an international survey in 4 European countries and the United States. In all countries, the medication prescribed most commonly was simple analgesics [6].

An alternative approach to the type of survey carried out by Lipton and Stewart [1] is to determine the relationship between measures of treatment response and patient satisfaction in a prospective clinical trial. Satisfaction with therapy 2 h after initial treatment (of moderate to severe pain) and before the use of rescue medication was assessed in two clinical trials of rizatriptan in a total of 1,506 migraine sufferers [8]. Subjects who were pain free at 2 hours were somewhat, very, or completely satisfied with their treatment in greater than 90% of attacks (fig. 2). Levels of satisfaction were lower (59– 69%) in those who experienced only pain relief (i.e., who experienced mild pain at 2 h). Subjects who still experienced moderate to severe pain at 2 h were at least somewhat satisfied with treatment in only 9–11% of attacks. Absence of associated symptoms at 2 h was also important in determining patients’ satisfaction with treatment (fig. 2). Among the patients with mild pain at 2 h, those who reported severe pain at baseline, absence of associated symptoms at 2 h and pain relief within the first 90 min had a probability of at least 76% of being at least somewhat satisfied with treatment. The probability of

satisfaction decreased with the presence of associated symptoms, slower pain relief and moderate baseline pain intensity. A similar pattern of satisfaction was seen with regard to functional status, with greater levels of functional ability being related to increased probability of satisfaction. Patients with normal functional ability at 2 h were at least somewhat satisfied in at least 85% of attacks, whereas those who experienced severe impairment were at least somewhat satisfied in only 10–15% of attacks [8]. Further analyses of the data from these trials showed that patients’ migraine-specific quality of life (as assessed by a self-completed questionnaire 24 h after the onset of each treated attack) was better in all five domains (symptoms, feelings/concerns, work function, social function, energy/vitality) if treatment resulted in sustained pain-free status. Patients who were pain free at 2 h with no recurrence had the highest migraine-specific quality-of-life scores, typically 5–6 points (on a scale with a possible score of 3–30 points) higher than patients with no relief (i.e., who still had moderate or severe pain) at 2 h (fig. 3) [9]. Within each domain, outcomes were associated with increasing migraine-specific quality-oflife scores in the same order: no relief at 2 h, headache relief at 2 h with recurrence, headache relief at 2 h with

What Migraine Patients Want

Eur Neurol 2005;53(suppl 1):3–9

Which Treatment Outcomes Are Associated with Satisfaction?

5

Clinical trials: levels of satisfaction by symptom status at 2 h Study 1

Study 2 92

Pain free

98 59

Pain relief

Fig. 2. Levels of satisfaction with acute mi-

69 11 9

Persistent pain

graine treatment in relation to symptom status 2 h postdose in a post hoc analysis of data from two clinical trials of rizatriptan. Subjects rated their level of satisfaction as completely, very, or somewhat satisfied, neither satisfied nor dissatisfied, or somewhat, very, or completely dissatisfied. Percentages shown are those at least somewhat satisfied with treatment [8].

76

Associated symptoms absent

87 30

Associated symptoms present

38 0

20

40 60 Patients satisfied (%)

80

100

Relationship between 2-h pain status and 24-h migraine quality of life No relief

Pain free/recurrence

Headache relief/recurrence

Pain free/no recurrence

Headache relief/no recurrence 15.6

16

14.0

Mean 24-h mqol score

13.4 12

14.9

14.8

14.0 12.2 11.5

11.0

14.1 13.4

11.0 10.0

9.2

9.1

14.9

13.5 12.9

12.6

12.9

10.8 10.1 9.2

8.5

7.8 8

4

0

Symptoms

Feelings/ concerns

Work function

Social function

Energy/ vitality

Domains

Fig. 3. The relationship between pain status 2 h after treatment and 24-hour migraine-related quality of life in a post hoc analysis of data from two clinical trials. Migraine-specific quality of life (MQoL) in 5 domains was assessed by self-completed questionnaires 24 h after the onset of a migraine attack treated with rizatriptan. Adapted with permission [9].

no recurrence, pain free at 2 h with recurrence, pain free at 2 h with no recurrence. Similarly, in all five domains, there was a clear relationship between functional impairment and lower migraine-specific quality of life: patients who rated themselves as having no impairment in func-

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tional ability at 2 h had higher migraine-specific qualityof-life scores than those with slight impairment, who in turn had higher scores than those with severe impairment.

Lantéri-Minet

Taken together, these studies suggest that treatments offering rapid and complete pain relief with no recurrence are most likely to meet patients’ expectations and leave them satisfied. Absence of associated symptoms and adverse events is also important to patients [1, 8].

Given patients’ evident lack of satisfaction with treatment at present, how can management be improved? The evidence about low levels of triptan use suggests that more widespread use of triptans could have the potential to improve patient satisfaction and migraine-related quality of life. In the United States, guidelines produced by the US Headache Consortium propose that patients with moderate to severe migraine without contraindications should be given initial treatment with triptans, and that a triptan should also be prescribed for patients with migraine of any severity when nonspecific medications failed to provide adequate relief in the past [10]. The guidelines produced in France for the management of migraine are perhaps more pragmatic, taking patients’ experiences with their usual medication into consideration.[11] Under these guidelines, patients previously treated with nonspecific agents are asked four questions: whether they have significant relief within 2 h of taking the medication, if the medication is well tolerated, if they take only one dose, and whether 2 h after taking the medication they can resume normal occupational, social, and family activities. It is recommended that patients answering yes to all of these questions remain on their current regimen, while those answering no to at least one question should be prescribed a nonsteroidal anti-inflammatory drug (NSAID) and a triptan together, with the instruction that the patient should start with the NSAID and take the triptan only if relief is not obtained within 2 h. If the NSAID is ineffective or poorly tolerated (after a trial of three attacks), a triptan should be prescribed as first-line agent. In FRAMIG 3 [12], a recent French population-based survey, analysis of the responses to these four questions identified more than 1,000 patients who had treated their most recent attack with nonspecific agents, and 50% of these patients had answered no to at least one of the four questions. The two nonspecific agents most commonly used in France are paracetamol and opioids. The main reasons for dissatisfaction with these medications given by the patients screened were no significant relief of pain at 2 h, the need to take several doses and the lack of rap-

id return of functional ability. Making recommendations according to the guidelines at the patient’s first consultation is one of the variables associated with continued consultation; 44% of current consulters surveyed (n = 335) had been prescribed the recommended acute treatment at their first consultation in comparison with only 33% of lapsed consulters (n = 628, p ! 0.01). How can the physician make the best choice of NSAID or triptan from among those available? One possibility is to base the selection on patients’ preferences as observed in comparative trials. In an open-label, randomized, cross-over trial comparing rizatriptan and sumatriptan, rapid onset of action was the most important determinant of patient preference; among those expressing a preference, 51% of patients selected the option ‘relieved my head pain faster’ as the most important reason for preferring one medication over the other, whereas other options available (e.g., recurrence with one medication and not the other, ease of use) were selected as the most important basis of preference by only 8% of patients or fewer [13]. In an open-label cross-over trial comparing zolmitriptan and sumatriptan, speed of onset of pain relief was also the most common reason for preferring one medication over another among those who expressed a preference, cited by 73% of patients; other reasons given were longer duration of action (39%) and better tolerability (35%) [14]. Unfortunately, there are few direct comparative studies of triptans, and it is unlikely that they will ever all be compared with one another, especially as therapeutic options continue to multiply. Meta-analysis provides another means of comparing the triptans and has provided valuable information about their relative efficacy and tolerability. In a meta-analysis of 53 trials involving more than 24,000 patients, almotriptan 12.5 mg, rizatriptan 10 mg and eletriptan 80 mg were found to provide the highest likelihood of consistently successful treatment of acute migraine on the basis of treatment outcomes such as pain relief, sustained pain free, consistency of response, and tolerability [15, 16]. Although data such as these provide guidance regarding the attributes of medication that may have the greatest influence over patient preference and satisfaction, it must be borne in mind that evidence-based comparisons of triptans can be accomplished only for individual endpoints, and that preference and satisfaction are complex outcomes to which numerous treatment attributes may contribute. The relative importance of particular attributes may differ among and between patients and prescribers, and may also vary within individual patients over time. A model has been developed as an initial at-

What Migraine Patients Want

Eur Neurol 2005;53(suppl 1):3–9

How Can Patients’ Expectations Be Met?

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Similarity to hypothetical ideal triptan in mild migraine Efficacy, consistency, and tolerability only

All criteria (includes worldwide exposure)

% 100

90 80 70 65

65 60

60

60

60

55

55

50

50

50

45

45

45

45

40 40 30

25 20

20

0

n

m

o

m

Al

an

m

El

ri et

an

m

80

pt

pt

ta

p tri

40

ri et

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g

g

g

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. 12

5

an

2.

n

ar

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ta

t iza

R

an

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z

ri at

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an

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pt

rip

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5

g

g

g

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ri at

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ta

a

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an

2.

m

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n

lm

Zo

5

m

ta

ip

pt

p tri

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g

g

m

0 10

itr

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Triptan and Dose

Fig. 4. Similarity of triptans to a hypothetical ideal triptan in mild migraine according to the Tripstar model, combining data from a meta-analysis of clinical trial data and ratings of the relative importance of clinically relevant medication attributes. Adapted with permission [16].

tempt to provide an overall scoring system for triptans that assesses and weighs various attributes of medication to facilitate evidence-based, patient-oriented selection [16]. The concept behind this model, the TRIPSTAR system, was investigated among a sample of 200 physicians attending a major conference, primarily neurologists, who treated patients with migraine. These physicians were asked to rank and weigh attributes of acute migraine therapy for patients with mild or severe migraine. For patients with mild migraine, pain free and sustained pain free (pain free at 2 h with no recurrence within 24 h and no use of rescue medication) were weighted slightly higher than consistency and tolerability; worldwide clinical exposure was the least important attribute. The results for severe migraine were similar, with the endpoints pain free and sustained pain free being weighted marginally higher than consistency and tolerability. Data on the rankings of these attributes were combined in a multiattribute decision-analytic model (the Technique for Ordering Preferences by Similarity to an Ideal Solution [TOPSIS]) with information on the relative performance of the oral triptans derived from a meta-analysis [15, 16] and the scores

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for the individual triptans were compared against a hypothetical ‘ideal’ agent (i.e., a composite of the highest-ranking criteria) [16]. For both mild and severe migraine, if worldwide clinical exposure was included, sumatriptan 50 mg and 100 mg were closest to the ideal triptan (fig. 4). When worldwide clinical exposure was excluded from the model, almotriptan 12.5 mg most closely resembled the ideal triptan, scoring 90% (in comparison with 25–70% for other triptans); the large margin between almotriptan and the other triptans resulted principally from almotriptan’s combination of good tolerability and efficacy. That tolerability is an important factor in optimizing migraine management is demonstrated by the results of a study carried out on behalf of the US National Headache Foundation [17]. The study population was selected from a representative prescreened sample of severe headache and migraine sufferers using the National Family Opinion household panel. Self-completed questionnaires returned by 1,160 individuals meeting IHS criteria for migraine and reporting use of prescription medication indicated that approximately 70% had reported adverse events to their healthcare provider or discussed them,

Lantéri-Minet

and that more than 40% considered lack of adverse events to be an important product attribute. Significantly, twothirds had avoided or delayed taking their prescription medication owing to concerns about adverse events. These concerns led to a delay in taking medication in 37% of treated migraine episodes and to medication avoidance in 44% of untreated attacks during the preceding 6 months. The impact of such delay and avoidance was more intense pain, extended duration of headache, and negative impacts on functional ability (e.g., needing to lie down, suboptimal performance at or absence from school or work, curtailing of social activities).

Conclusions

Migraine is an underdiagnosed and suboptimally managed pathology. Most migraine patients are dissatisfied with their current migraine therapy, largely because of slow onset of efficacy, incomplete pain relief, incon-

sistent relief, recurrence, and side effects. Attributes patients want from their migraine therapy are complete pain relief (i.e., pain free), absence of recurrence, fast onset of action, and no side effects. Extensive and exclusive use of nonprescription medication and underuse of triptans may be responsible for patients’ dissatisfaction; despite guidelines recommending their use, triptans are used by a minority of patients. More widespread use of specific migraine medication would improve outcomes and increase patient satisfaction; treating patients with triptans is most likely to achieve the treatment outcomes that patients desire. When making the choice among triptans, physicians should attempt to match individual patients’ wants and needs with the attributes of the particular triptans, taking into account a medication’s complete profile of efficacy, consistency and tolerability, and using information from meta-analyses and modelling to inform the decision-making processes.

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What Migraine Patients Want

7 Lucas C, Auray JP, Gaudin AF, Dartigues JF, Duru G, Henry P, Lanteri-Minet M, Pradalier A, Chazot G, El Hasnaoui A: Use and misuse of triptans in France: Data from the GRIM2000 population survey. Cephalalgia 2004;24: 197– 205. 8 Davies GM, Santanello N, Lipton R: Determinants of patient satisfaction with migraine therapy. Cephalalgia 2000;20:554–560. 9 Santanello NC, Davies G, Allen C, Kramer M, Lipton R: Determinants of migraine-specific quality of life. Cephalalgia 2002;22: 680–685. 10 Silberstein SD: Practice parameter: Evidencebased guidelines for migraine headache (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000; 55: 754–762. 11 Geraud G, Lanteri-Minet M, Lucas C, Valade D: French guidelines for the diagnosis and management of migraine in adults and children. Clin Ther 2004; 26:1305–1318. 12 Lanteri-Minet M, Valade D, Geraud G, Chautard MH, Lucas C: Migraine and probable migraine – results of FRAMIG 3, a French nation-wide survey carried out according to the 2004 IHS classification. Cephalalgia 2005;In press.

13 Loder E, Brandes JL, Silberstein S, Skobieranda F, Bohidar N, Wang L, Boyle D, Kolodny A, Guerra F, Santanello N, Johnson-Pratt L: Preference comparison of rizatriptan ODT 10-mg and sumatriptan 50-mg tablet in migraine. Headache 2001;41: 745–753. 14 Pascual J, Munoz R, Leira R: An open preference study with sumatriptan 50 mg and zolmitriptan 2.5 mg in 100 migraine patients. Cephalalgia 2001;21: 680–684. 15 Ferrari MD, Roon KI, Lipton RB, Goadsby PJ: Oral triptans (serotonin 5-HT1B/1D agonists) in acute migraine treatment: A meta-analysis of 53 trials. Lancet 2001;358:1668–1675. 16 Ferrari MD, Goadsby PJ, Roon KI, Lipton RB: Triptans (serotonin, 5-HT1B/1D agonists) in migraine: Detailed results and methods of a metaanalysis of 53 trials. Cephalalgia 2002;22:633– 658. 17 Gallagher RM, Kunkel R: Migraine medication attributes important for patient compliance: Concerns about side effects may delay treatment. Headache 2003; 43:36–44.

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Eur Neurol 2005;53(suppl 1):10–16 DOI: 10.1159/000085060

Published online: May 3, 2005

Migraine, Allodynia, Sensitisation and All of That … Peter J. Goadsby Headache Group, Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK

Key Words Migraine
Sensitisation
Triptans
Brainstem

Abstract Migraine is the most common form of disabling primary headache. One common and often troublesome feature of the disorder is an abnormal sensory state where normally innocuous stimuli are felt as painful: allodynia. This occurs in about two-thirds of patients and manifests as common complaints, such as pain when touching the hair. The neurophysiological correlate of allodynia is sensitisation, an increased afferent barrage for an unchanged peripheral stimulus. Sensitisation may be peripheral, central or disinhibitory. The potential mechanisms of each of these and their possible manipulation by treatments of the acute attack are considered. Copyright © 2005 S. Karger AG, Basel

Introduction

Migraine is a complex disorder of the central nervous system characterised by head pain, nausea and sensitivity for sensory input, such as light (photophobia), sound (phonophobia) or head movement [1]. In recent years its therapy has been dramatically improved with the introduction and widespread use of serotonin, 5-HT1B/1D reThis article was written entirely in all respects by the author without editorial input or assistance from the sponsors or their agents.

© 2005 S. Karger AG, Basel 0014–3022/05/0535–0010$22.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/ene

ceptor agonists, triptans [2]. These medicines are highly efficacious in the acute treatment of the disorder [3, 4]. Interest surrounding the mechanism of action of these medicines has fuelled interest in the disorder in general [5]. It remains a substantially clinical question as to how to use the triptans optimally, although some matters have been clarified by clinical trials, such as their reduced efficacy when used in the aura phase of the attack [6–8]. Allodynia, pain from non-noxious heat, cold or pressure stimulus to the skin, has recently been suggested as a marker for likelihood of good outcome from treatment [9], and this has led to considerable interest in the mechanism of that allodynia.

Migraine and Allodynia – the Clinical Picture

Allodynia in migraine is remarkably common. Selby and Lance noted it in two-thirds of their considerable series of 500 patients [10]. Patients thus commonly mention that even common tasks, such as touching the head or combing the hair are painful during or even after an attack. Lance often remarked clinically when hearing patients describe limb or torso allodynia that this must implicate a higher order (than trigeminal nucleus) disturbance, and cited the thalamus as a likely target (personal communication). This consideration led directly to studies of thalamic processing of trigeminovascular transmission in experimental animals [11–13]. Most recently, allodynia in migraine has been studied in a systematic fashion using quantitative sensory testing and again was

Prof. P.J. Goadsby Institute of Neurology, Queen Square London WC1N 3BG (UK) Tel. +44 20 7829 8749, Fax +44 20 7813 0349 E-Mail [email protected]

noted in 79% of patients [14]. In one carefully followed patient their development again suggested extra-trigeminal involvement [15]. A number of common clinical observations in migraine may be considered as allodynic. As an example, neck stiffness that is a very common premonitory symptom [16] may be simply a form of allodynia in combination with subtle over-activity of muscles associated with segmental nocifensive activation. Patients may report old scars that become uncomfortable when touched during the attack – again this seems likely to be a form of allodynia. Given that there is little convincing evidence for vasodilation as a consistent feature of migraine, throbbing may represent a form of allodynia, i.e., pain from normal vascular distension. Similarly, sensitivity to head movement, or indeed pain with coughing, bending or sometimes just with lying down flat, may all represent allodynic reports of pain from otherwise innocuous mechanical stimulation. What then is the basis of allodynia if it is such a common phenomenon?

Sensitisation and Allodynia

If patients report allodynia, neurons are said to be sensitised. Sensitisation is increased afferent activity for an unchanged stimulus. Sensitisation may occur in three primary ways: – Peripheral sensitisation – Central sensitisation – Disinhibitory sensitisation It must be said that while it is not clear which of these is the main pathophysiological substrate in migraine, it at least seems extremely unlikely that peripheral sensitisation is crucial. Given that photophobia, phonophobia and osmophobia do not need any peripheral change to be horribly disabling and distressing, it seems likely that, by Occam’s Razor, a central nervous system sensitisation process would be the most parsimonious explanation for the disorder.

es protons or activates heat sensitive receptors, such as the TRPV1 (previously VR1) class receptor [17]. These latter capsaicin sensitive receptors are located on C fibres and can be found in human trigeminal ganglion neurons using immunohistochemical methods [18]. There is now recognised a family of these Transient Receptor Potential (TRP) receptors that are responsive to heat [19]. The action of capsaicin at the TRPV1 receptor can be blocked by the antagonist capsazepine [20]. It can be shown that TRPV1 receptors are present in the dura mater of the rat although their actions seem minor [21]. Local chemical release can sensitise afferents, such as with application of the so-called inflammatory soup [22]. This mixture includes prostaglandin E2, bradykinin and serotonin. The concept that ecosanoids produce sensitisation is not particular to trigeminal neurons [23]. While such a local process may explain head pain, it certainly has no hope to explain limb discomfort, or indeed photophobia in migraine. So we must look more centrally for a complete explanation.

Central Sensitisation

Peripheral sensitisation implies increased primary afferent activity from an unchanged stimulus due to some local activating process. Activation of C fibres by, for example, heat or chemical stimulation, would produce sensitisation. The most familiar form of this to most would be sunburn. In that process, solar damage perhaps releas-

Central sensitisation can be defined as altered behaviour of neurons characterised by enlarged receptive field, increased spontaneous firing, or evoked firing rate, or appearance of firing to novel stimuli not previously eliciting activation [24]. It was recognised by Woolf and Wall [25] as a potentially important mechanism in post-injury pain states and has been the subject of study since. Central sensitisation may be promoted by local dural stimulation with the inflammatory soup [26], or by specific stimulation with prostaglandin E2 [27, 28]. Glutamate NDMA receptor mediated activation is pivotal in induction of central sensitisation in dural neurons [29]. Triptans can block the development of central sensitisation [9] by an effect at the second order synapse [30]. Recently it has been recognised that cranial parasympathetic activation, that may be a rather frequent sub-clinical accompaniment of migraine [31], may be important in the induction of sensitisation in trigeminovascular neurons [32]. Wind-up. Wind-up is a feature of certain dorsal horn neurons first described by Mendell and Wall [33]. Windup and central sensitisation are not equal [34]. Wind-up (fig. 1) very specifically refers to an increase in neuronal responses with subsequent stimuli to A
or C fibre afferents that has a hyperbolic function with a typical plateau after approximately twenty stimuli. Interestingly we have recently been able to record typical wind-up in trigeminal

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Peripheral Sensitisation

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DHE [42] and the mixed cyclooxygenase I and II inhibitor ketorolac can reverse the sensitisation process associated with dural inflammation [43], while sumatriptan alone cannot [36]. Both ketorolac and aspirin inhibit trigeminocervical nociceptive afferents by a mechanism that is naloxone independent [44].

Central Sensitisation and the Trigeminocervical Complex – Explaining Neck Pain

A+C

A

Fig. 1. Wind-up in dorsal horn neurons. Recordings from a single

neuron responding to A fibre stimulation only (right) or A and C fibre stimulation (left). The stimulus was repeated every 1–3 ms; markings on the vertical scale represent 100-ms intervals. Stimulation of A and C fibres elicits a discharge that increases with successive stimuli [33].

neurons with responses to electrical stimulation of facial receptive fields but not in any trigeminal neurons we studied with electrical stimulation to the dura mater, either for A
or C fibre inputs [35]. One must be cautious in a negative study but it is curious that intracranial nociceptive afferents do not easily exhibit wind-up. Central Sensitisation and Triptans. Studies employing a model of trigeminovascular nociceptive activation by application of an inflammatory soup, containing bradykinin, serotonin and substance P, have been used to study mechanisms of sensitisation in the trigeminal nucleus caudalis [26]. The sensitisation thus produced is robust and difficult to terminate after 30 min or so [36]. It has been shown that it can be prevented with early use of triptans [36] Just as it has been shown that triptan [37, 38] and ergot-derivatives, such as dihydroergotamine (DHE) [39] and ergometrine [40, 41], can inhibit second order neuronal traffic in the trigeminocervical complex, similarly triptans disrupt second order communication after a dural inflammatory stimulus [30]. Interestingly,

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For the clinician, pain presentations in the headache patient are frequently a diagnostic challenge as the localization and time course does not allow a single and immediate diagnosis. The pain may be diffuse with a dull, burning quality and in due course may move, radiate or spread throughout different innervation territories so that an exact topographical attribution is difficult. Patients with migraine mostly report pain that involves the front of the head, in the cutaneous distribution of the first (ophthalmic) division of the trigeminal nerve. However, the pain in due course frequently exceeds the trigeminal territory as pain from the back of the head, innervated by the greater occipital nerve (GON) which is a branch of the C2 spinal root, is also described [10, 45]. A mechanism that could explain these clinical presentations is a trigeminocervical interaction with a convergence of trigeminal and cervical afferents onto the same neurons in the brainstem. Evidence from animal models supports the view that convergence is an important component in the clinical phenomena of spread and referred pain whereby pain originating from an affected tissue is perceived as originating from a distant not directly innervated receptive field [46]. A second component, a central sensitization of these central neurons may lead to clinical correlates such as hypersensitivity and allodynia, and is necessary to fully account for the phenotypes seen in practice. These mechanisms could also participate in the transition and maintenance from acute to chronic migraine states. Nociceptive information from the dura mater to second-order neurons in the brainstem is transmitted via small-diameter A and C fibre afferents in the ophthalmic division of the trigeminal nerve via the trigeminal ganglion to second-order neurons in the superficial and deep layers of the medullary dorsal horn of the trigeminocervical complex [47]. The trigeminocervical complex extends from the trigeminal nucleus caudalis to the dorsal horns of the C1/2 segments of the cervical spinal cord in rat [48], cat [49] and

Goadsby

b

ms

the convergence principle in the trigeminocervical complex (TCC). The supratentorial dura mater (A) or greater occipital nerve (B) were electrically stimulated and neural responses were recorded in second-order neurons in the dorsal horn of the TNC (C). b Recordings from units in the trigeminocervical complex with A and C fibre inputs showing sensitisation of dural afferents with peri-middle meningeal input after stimulation of the greater occipital nerve [47].

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A-fibre evoked responses

Fig. 2. a Experimental set-up for analysing

C-fibre evoked responses

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–30 –20 –10 –1 el. stim GON

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180 300 min

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monkey [50]. Ascending nociceptive pathways project in the spinothalamic tract to supraspinal relay sites such as the thalamus and higher cortices [12, 13]. Structures of the posterior fossa, the occiput and the upper cervical spinal cord are innervated by the upper three cervical spinal nerves. The major afferent contribution is mediated by the C2 spinal root that is peripherally represented by the greater occipital nerve (GON) [51, 52]. Kerr and Olafson [53] were the first to suggest a convergence between trigeminal and cervical afferents; however, a direct coupling between meningeal afferents and cervical afferents was not described in an animal model until recently [47, 54] and further extended to human data [55]. It was shown that a population of nociceptive second-order neurons in the C2 dorsal horn receive convergent synaptic input from the trigeminallyinnervated supratentorial dura mater and from cervical afferents running in the GON. Remarkably, quite often

GON afferents not only converge on the ipsilateral second-order neuron, but these neurons also receive input from the contralateral GON [47] possibly contributing to the dull and poorly localized quality of head and neck pain [56]. This anatomical arrangement of trigeminal and cervical afferents also has functional implications as nociceptive spinal cord neurons can be sensitized to a strong afferent stimulation by small-fibre afferents. This hyperexcitability is reflected in a reduction of the activation threshold, an increased responsiveness to afferent stimulation, an enlargement of receptive fields or the emergence of new receptive fields and the recruitment of ‘silent’ nociceptive afferents. The clinical correlates of this central hypersensitivity in migraine patients include the development of spontaneous pain, hyperalgesia and allodynia [15]. The hypersensitivity of the afferent synaptic input in the spinal cord is thought to be due to the

Migraine and Allodynia

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Disinhibitory Sensitisation – Disordered Modulation of Trigeminovascular Afferent Signals

It is well established that dura-sensitive neurons in the trigeminal nucleus are subject to a modulation from various levels of the central nervous system. One plausible explanation for sensitisation in migraine would be dysfunction of known sub-cortical trigeminal modulatory nuclei, i.e., disinhibitory sensitisation rather than sensitisation due to abnormal afferent traffic [58]. Most prominent among these inhibitory systems are projections from brainstem structures, such as the periaqueductal gray (PAG), nucleus raphe magnus (NRM) and the rostroventral medulla (RVM), which have a profound antinociceptive effect on these neurons [59], but other structures such as the hypothalamus [60], thalamus [61] and cortical regions seem also to be involved. Recent findings emphasize the role of the ventrolateral division of the PAG (vlPAG) in trigeminal nociception as stimulation of

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10

2h

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Pain (VAS score)

stimulation-induced release of various neuropeptides, such as calcitonin gene-related peptide (CGRP), or to glutamate release and action at the NMDA receptor, but may also be due to decrease of local segmental spinal inhibition in response to the afferent stimulation [24]. It was tested whether these changes occur in neurons in the trigeminal nucleus caudalis that receive convergent synaptic input from the dura mater and the GON (fig. 2). Each afferent source at a time was stimulated using a strong noxious input either stimulating the dura mater or the GON, respectively. Indeed, noxious stimulation of the dura mater elicited facilitated GON responses that were reflected in increased responses to electrical stimulation, enlarged cervical cutaneous receptive fields and increased sensitivity of deep paraspinal muscles to noxious mechanical stimulation [54]. Stimulation of the GON also elicited a central sensitization with increased responses to dural stimulation [47]. This shows that dural afferents and GON afferents do not just represent an anatomical connection, but that these connections are functionally relevant in terms of mutual changes of excitability. The above described mechanisms of convergence and central sensitization are important to understand the clinical phenomena of spread and referral of pain by which pain originating from an affected tissue is perceived as originating from a distant receptive field that does not necessarily involve a peripheral pathology [46, 57].

6 4 2 0 Early-1 h Rx

Late- 4 h Rx

Allodynia (–)

Early-1 h Rx

Late-4 h Rx

Allodynia (+)

Fig. 3. Pain (VAS score ordinate) at baseline and 2 h after early

(with 1 h) and late (4 h into an attack) treatment with a triptan presented as a cohort without allodynia (n = 27) and with allodynia (n = 34). The patients without allodynia did better at 2 h than those with allodynia irrespective of time to treatment [9].

the vlPAG modulates dural nociception and receives input from trigeminovascular afferent [62–64]. We recently described a model of PAG-mediated dural nociception and facilitation of dural nociceptive input after local blockade of P/Q-type voltage-gated calcium channels in the vlPAG [64]. Mis-sense mutations of P/Q-type voltage gated calcium channels seem to be involved in some subforms of migraine [65]. The role of the PAG is also further corroborated by the observation that 5-HT1B/1D receptor activation to naratriptan injection in the midbrain periaqueductal gray matter evokes a selective anti-nociceptive effect of descending pain-modulatory projections on dural nociception [62]. The involvement of the PAG in migraine finds its correlate in functional imaging studies in patients with spontaneous attacks of migraine without aura that point to a specific role of the PAG in migraine pathophysiology [66]. Dura-sensitive neurons in the trigeminal nucleus are also subject to a modulation of hypothalamic projections as it recently has been shown that these neurons can be inhibited or facilitated depending on the type of peptidergic transmission [67]. These electrophysiological findings may link clinical observations of hypothalamic involvement in primary headache syndromes, such as migraine [68] and cluster headache [69], and the pain phenotypes in these syndromes [67] supporting the view that the regulation of autonomic and neuroendocrine functions as well as nociceptive processing are closely coupled in the hypothalamus.

Goadsby

Implications for the Treatment of Migraine

It has been suggested that the result of acute treatment of migraine may improve with triptans if patients are treated before allodynia develops [9]. It has been shown in an open-label study that the presence of allodynia predicts a poor outcome from acute treatment (fig. 3). If this is a general phenomenon it is extremely important since two-thirds of patients probably experience allodynia during an attack [10]. However, it needs to be recalled that this study was unblended. There has been considerable discussion in the literature and admixture of ‘early’ with ‘mild’ in terms of treatment. Unsurprisingly, treatment of migraine when it is mild yields better outcomes [70, 71]. Remarkably, the pain-free response after treatment with oral eletriptan is correlated with pain severity not

time to dosing with relationship to onset of headache [72]. However, studies have been plagued by patient selection issues and retrospective analyses [73–75]. The issue of whether allodynia predicts outcome in a placebo-controlled trial is unresolved and certainly important from a mechanistic viewpoint. It will not change practice since few physicians suggest that patients wait to suffer before treating once the patients recognise they have a migraine. Indeed if allodynia is predictive of treatment outcome this will not prove at all that there is central sensitisation of second-order trigeminal neurons, since the triptans may be targeting either those neurons, thirdorder thalamic neurons [76], or even PAG matter modulatory neurons [62]. It is an exciting time to be thinking about the pathophysiology of migraine.

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30 Levy D, Jakubowski M, Burstein R: Disruption of communication between peripheral and central trigeminovascular neurons mediates the antimigraine action of 5ht 1b/1d receptor agonists. Proc Natl Acad Sci USA 2004; 101:4274–4279. 31 May A, Goadsby PJ: The trigeminovascular system in humans: Pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab 1999;19: 115–127. 32 Yarnitsky D, Goor-Aryeh I, Bajwa ZH, Ransil BI, Cutrer FM, Sottile A, Burstein R: 2003 Wolff award: Possible parasympathetic contributions to peripheral and central sensitization during migraine. Headache 2003;43:704–714. 33 Mendell LM, Wall PD: Responses of single dorsal cord cells to peripheral cutaneous unmyelinated fibres. Nature 1965;206:97–99. 34 Woolf CJ: Windup and central sensitization are not equivalent. Pain 1996;66:105–108. 35 Bolton SC, O’Shaughnessy CT, Goadsby PJ: Properties of neurons in the trigeminal nucleus caudalis responding to noxious dural and facial stimulation. Brain Res 2005;in press. 36 Burstein R, Jakubowski M: Analgesic triptan action in an animal model of intracranial pain: A race against the development of central sensitization. Ann Neurol 2004;55: 27–36. 37 Cumberbatch MJ, Hill RG, Hargreaves RJ: Rizatriptan has central antinociceptive effects against durally evoked responses. Eur J Pharmacol 1997;328:37–40. 38 Kaube H, Hoskin KL, Goadsby PJ: Inhibition by sumatriptan of central trigeminal neurones only after blood-brain barrier disruption. Br J Pharmacol 1993;109:788–792. 39 Hoskin KL, Kaube H, Goadsby PJ: Central activation of the trigeminovascular pathway in the cat is inhibited by dihydroergotamine. A c-fos and electrophysiological study. Brain 1996;119(Pt 1):249–256. 40 Lambert GA, Lowy AJ, Boers PM, Angus-Leppan H, Zagami AS: The spinal cord processing of input from the superior sagittal sinus: Pathway and modulation by ergot alkaloids. Brain Res 1992;597:321–330. 41 Storer RJ, Goadsby PJ: Microiontophoretic application of serotonin (5ht)1b/1d agonists inhibits trigeminal cell firing in the cat. Brain 1997;120(Pt 12):2171–2177. 42 Pozo-Rosich P, Oshinsky M: Effect of dihydroergotamine (dhe) on central sensitisation of neruons in the trigeminal nucleus caudalis. Neurology 2005;64:A151. 43 Burstein R, Levy D, Collins B, Jakubowski M: Therapeutic approach to migraine with allodynia. Neurology 2005;64:A151. 44 Kaube H, Hoskin KL, Goadsby PJ: Intravenous acetylsalicylic acid inhibits central trigeminal neurons in the dorsal horn of the upper cervical spinal cord in the cat. Headache 1993; 33:541–544. 45 Bogduk N: The clinical anatomy of the cervical dorsal rami. Spine 1982;7:319–330. 46 Ruch TC: Pathophysiology of pain; in Ruch TC, Patton HD (eds): Physiology and Biophysics. Philadelphia, Saunders, 1965, pp 345–363.

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47 Bartsch T, Goadsby PJ: Stimulation of the greater occipital nerve induces increased central excitability of dural afferent input. Brain 2002;125:1496–1509. 48 Strassman AM, Mineta Y, Vos BP: Distribution of fos-like immunoreactivity in the medullary and upper cervical dorsal horn produced by stimulation of dural blood vessels in the rat. J Neurosci 1994; 14:3725–3735. 49 Kaube H, Keay KA, Hoskin KL, Bandler R, Goadsby PJ: Expression of c-fos-like immunoreactivity in the caudal medulla and upper cervical spinal cord following stimulation of the superior sagittal sinus in the cat. Brain Res 1993;629:95–102. 50 Goadsby PJ, Hoskin KL: The distribution of trigeminovascular afferents in the nonhuman primate brain macaca nemestrina: A c-fos immunocytochemical study. J Anat 1997;190(Pt 3):367–375. 51 Becser N, Bovim G, Sjaastad O: Extracranial nerves in the posterior part of the head. Anatomic variations and their possible clinical significance. Spine 1998;23: 1435–1441. 52 Poletti CE: C2 and c3 pain dermatomes in man. Cephalalgia 1991;11: 155–159. 53 Kerr FW, Olafson RA: Trigeminal and cervical volleys. Convergence on single units in the spinal gray at c-1 and c-2. Arch Neurol 1961; 5: 171–178. 54 Bartsch T, Goadsby PJ: Increased responses in trigeminocervical nociceptive neurons to cervical input after stimulation of the dura mater. Brain 2003;126:1801–1813. 55 Piovesan EJ, Kowacs PA, Tatsui CE, Lange MC, Ribas LC, Werneck LC: Referred pain after painful stimulation of the greater occipital nerve in humans: Evidence of convergence of cervical afferences on trigeminal nuclei. Cephalalgia 2001;21:107–109. 56 Linderoth B, Brodin E: ‘mirror pain’ and indications of bilateral dorsal horn activation in response to unilateral nociception. Pain 1994; 58:277–278. 57 Arendt-Nielsen L, Laursen RJ, Drewes AM: Referred pain as an indicator for neural plasticity. Prog Brain Res 2000;129:343–356. 58 Goadsby PJ: Migraine pathophysiology: The brainstem governs the cortex. Cephalalgia 2003;23: 565–566. 59 Behbehani MM: Functional characteristics of the midbrain periaqueductal gray. Prog Neurobiol 1995;46:575–605. 60 Benjamin L, Levy MJ, Lasalandra MP, Knight YE, Akerman S, Classey JD, Goadsby PJ: Hypothalamic activation after stimulation of the superior sagittal sinus in the cat: A fos study. Neurobiol Dis 2004;16:500–505. 61 Matharu MS, Bartsch T, Ward N, Frackowiak RS, Weiner R, Goadsby PJ: Central neuromodulation in chronic migraine patients with suboccipital stimulators: A pet study. Brain 2004;127:220–230. 62 Bartsch T, Knight YE, Goadsby PJ: Activation of 5-ht(1b/1d) receptor in the periaqueductal gray inhibits nociception. Ann Neurol 2004; 56:371–381.

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63 Keay KA, Bandler R: Vascular head pain selectively activates ventrolateral periaqueductal gray in the cat. Neurosci Lett 1998; 245: 58– 60. 64 Knight YE, Bartsch T, Kaube H, Goadsby PJ: P/Q-type calcium-channel blockade in the periaqueductal gray facilitates trigeminal nociception: A functional genetic link for migraine? J Neurosci 2002;22:RC213. 65 Ferrari MD, Haan J, Palotie A: Genetics of migraine, in Olesen J, Tfelt-Hansen P, Welch KMA (eds): The Headaches. Philadelphia, Lippincott Williams and Wilkins, 2003. 66 Weiller C, May A, Limmroth V, Juptner M, Kaube H, Schayck RV, Coenen HH, Diener HC: Brain stem activation in spontaneous human migraine attacks. Nat Med 1995; 1:658– 660. 67 Bartsch T, Levy MJ, Knight YE, Goadsby PJ: Differential modulation of nociceptive dural input to [hypocretin] orexin a and b receptor activation in the posterior hypothalamic area. Pain 2004; 109:367–378. 68 Peres MF, Sanchez del Rio M, Seabra ML, Tufik S, Abucham J, Cipolla-Neto J, Silberstein SD, Zukerman E: Hypothalamic involvement in chronic migraine. J Neurol Neurosurg Psychiatry 2001; 71:747–751. 69 Goadsby PJ: Pathophysiology of cluster headache: A trigeminal autonomic cephalgia. Lancet Neurol 2002;1:251–257. 70 Cady RK, Sheftell F, Lipton RB, O’Quinn S, Pharmd, Jones M, Putnam DG, Crisp A, Metz A, McNeal S: Effect of early intervention with sumatriptan on migraine pain: Retrospective analyses of data from three clinical trials. Clin Ther 2000;22:1035–1048. 71 Klapper JA, Rosjo O, Charlesworth B, Jergensen AP, Soisson T: Treatment of mild migraine with oral zolmitriptan 2.5 mg provides high pain-free response rates in patients with significant migraine-related disability. Neurology 2002;58:A416. 72 Diener HC, Dodick D, Goadsby PJ, Almas M, Tiseo P: Eletriptan in migraine: Is pain-free response more correlated with pain severity or time from headache onset to dosing? Neurology 2005;64:A151. 73 Pascual J, Cabarrocas X: Within-patient early versus delayed treatment of migraine attacks with almotriptan: The sooner the better. Headache 2002;42: 28–31. 74 Ryan RE, Diamond S, Giammarco RAM, Aurora SK, Reed RC, Fletcher PE: Efficacy of zolmitriptan at early time points for acute treatment of migraine and treatment of recurrence. CNS Drugs 2000;13: 215–226. 75 Winner P, Mannix LK, Putnam DG, McNeal S, Kwong J, O’Quinn S, Richardson MS: Painfree results with sumatriptan taken at the first sign of migraine pain: 2 randomized, doubleblind, placebo-controlled studies. Mayo Clin Proc 2003;78: 1214–1222. 76 Shields KG, Goadsby PJ: Naratriptan modulates trigeminovascular nociceptive transmission in the ventroposteromedial (vpm) thalamic nucleus of the rat. Cephalalgia 2004; 24: 1098.

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Eur Neurol 2005;53(suppl 1):17–21 DOI: 10.1159/000085037

Published online: May 3, 2005

Should We Advise Patients to Treat Migraine Attacks Early: Methodologic Issues Michel D. Ferrari Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands

Key Words Clinical trial methodology
Early migraine therapy
Migraine
Triptan

Abstract In clinical trials of triptans in acute migraine, patients have traditionally been required to take their medication only when their pain reached moderate or severe intensity. This methodology better ensured that migraine attacks rather than nonmigraine headaches were treated, minimized the placebo response and simplified comparison of improvement as all patients start from the same baseline pain level. In clinical practice, patients do not take medication in this way, and there is some theoretical evidence that early treatment might be beneficial. There are increasing numbers of reports claiming advantages of ‘early’ treatment, when the pain is mild, over ‘late’ treatment, when pain is moderate or severe, but these studies raise significant methodologic issues. Treating ‘early’ may equate with treating ‘mild’ in slowly progressing attacks only but this may not always be the case in rapidly progressing attacks; these two types of migraine attacks should be distinguished carefully and investigated separately. Trials should be placebo-controlled, blinded, assess the therapeutic gain versus placebo rather than the absolute rates, and use the sus-

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tained pain-free endpoint. Early treatment may also increase the risk of medication overuse headaches. At present, there is no scientific support to advise patient to treat early. Patients should be advised to take their medication as soon as they are sure they are developing a migraine headache, but not during the aura phase. Copyright © 2005 S. Karger AG, Basel

Introduction

In clinical trials assessing the efficacy of oral triptans in acute migraine, patients have traditionally been required to treat a migraine attack with medication only when their headache pain reached moderate or severe intensity on a 4-point scale of severity ranging from no pain (0), through mild (1) and moderate (2), to severe (3) (fig. 1) [1]. Although this strategy is somewhat artificial, there are many good methodologic reasons underlying it. If patients wait until a moderate or severe pain level has been reached, they are more likely to be treating a true migraine rather than a nonmigraine (tension-type) headache [1]. Delayed treatment should also minimize the placebo response, allowing for spontaneous resolution of possible short, nonmigraine headaches. The strategy additionally means that the assessment of improvement is always made from the same baseline pain severity rather

Prof. Michel D. Ferrari, MD, PhD Department of Neurology, Leiden University Medical Centre P.O. Box 9600 NL–2300 RC Leiden (The Netherlands) Tel. +31 71 5262895, Fax +31 71 5248253, E-Mail [email protected]

Definition of efficacy endpoints Pain relief

3 Severe

Pre-dose

2 Moderate

1 Mild

Pain free

0 None

Post-dose

Fig. 1. Migraine pain intensity is assessed on a 4-point scale where 0 = no pain, 1 = mild, 2 = moderate and 3 = severe pain.

than from different levels: Improvement from severe to moderate pain is not the same as improvement from mild to no pain. This is not, however, how patients treat their migraines in clinical practice. Clinicians are searching for trial designs that better reflect clinical reality, and are attempting to establish whether early treatment of an acute migraine attack with triptans, while the pain is still mild, might afford improved efficacy. Intuitively, early treatment would seem to be an attractive approach, but how can we demonstrate conclusively that it results in clinically relevant improved efficacy? Is early treatment superior to delayed treatment, so that we should be advising patients to treat their attacks early, or does this still remain to be proven [2]?

The Neurobiologic Rationale for Early Treatment

It seems intuitively obvious that treating a migraine attack early in its course is preferable to delaying therapy, and there is some neurobiologic evidence for a mechanistic basis to support the approach. In a series of elegant studies, Burstein and colleagues [3, 4] have provided evidence to support their theory that the development of throbbing pain in the initial phase of a migraine attack is mediated by sensitization of peripheral trigeminovascular neurons, whereas the development and maintenance of cutaneous allodynia (pain resulting from a normally nonnoxious stimulus, thought to occur in the majority of

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patients) in the later stages of the attack is mediated by sensitization of central trigeminovascular neurons. They have described the process of therapy with triptans as a race against the development of central sensitization, and have shown in animal models that early application of triptans blocks the development of central sensitization, whereas late application of triptans is insufficient to counteract established central sensitisation[4]. In addition, by conducting a small study in 31 patients with 34 migraine attacks that were associated with allodynia at the time of treatment and 27 attacks that were not, they have found that triptan therapy is more likely to be effective if administered before rather than after the development of cutaneous allodynia. Patients were pain free 2 h after triptan therapy in 15% of allodynic attacks in comparison with 93% of nonallodynic attacks [3]. Treating the attack 1 or 4 h after the onset of pain was equally ineffective in providing freedom from pain in the presence of allodynia, but equally effective in the absence of allodynia. Patients who did not develop allodynia were highly likely to achieve freedom from pain after triptan therapy at any time after the onset of pain. Although the difference between response in allodynic and nonallodynic attacks is marked, and the work is significant, there are some methodologic limitations that prevent extrapolation of these results to the wider clinical world [2]. The study in migraine sufferers involved a small number of selected patients. The assessments of cutaneous allodynia and triptan efficacy were open, i.e., not blinded, and the study lacked a placebo control. The effect needs to be confirmed in a large, double-blind, placebo-controlled trial in an unselected study population. In some earlier placebo-controlled studies, late treatment has been shown to result in similar response rates as early treatment [5, 6]; although these older studies did not assess the presence of allodynia, it is highly likely that many of the late-treated patients would have had allodynia. In addition, a recent study has indicated that patients with allodynia are capable of responding well to subcutaneous triptan therapy [7].

Clinical Trial Evidence in Favor of Early Treatment: A Critical Appraisal

There are a growing number of reports in the scientific literature describing clinical trials that purport to demonstrate the benefits of ‘early’ treatment [8–15], taken when the pain is mild, over ‘late’ treatment, when pain is moderate or severe, but the evidence that early treat-

Ferrari

Early Treatment of Migraine: Methodological Issues

Rapidly vs. slowly progressing migraine attacks

Severe Headache severity

ment affords superior efficacy must be carefully examined [2]. Some of the evidence in favor of early treatment is based on post-hoc analyses of protocol violators, patients who failed to comply with instructions and accidentally treated a mild headache. Post-hoc analyses of headaches treated during mild pain in three sumatriptan trials, for example, found that patients who had treated their headache while pain was mild had higher pain-free response rates and lower rates of redosing than those who had treated when their headache pain was moderate to severe [8]. Comparisons of response rates in patients treating mild or early headaches in new trials with response rates from old trials in which patients were instructed to treat moderate or severe headaches are not instructive, as they cannot take into account differences in study designs and patient types, or the possible effect of higher placebo rates in patients treating their headache early. The therapeutic gains in comparison with placebo in the current trials of ‘mild’ migraine can be, owing to possibly higher placebo response rates, in fact similar or even smaller than those in the previous trials of ‘severe’ migraine. An additional complication is the confusion between early treatment and treatment of mild pain, which are not interchangeable. The fundamental basis of a clinical trial is to compare like with like. It is not possible, for example, to compare the effect of one medication in severe disease with the effect of another medication in mild disease. A clinical trial requires a balanced distribution of the baseline characteristics of the study populations, particularly disease severity, duration, and other prognostic factors. This, after all, is the purpose of randomization. Migraine attacks can progress slowly or rapidly (fig. 2). Although the same level of pain intensity may be reached ultimately in the two types of attacks, it will take longer in the slowly progressing type. Treating early may be the same as treating mild pain in a slowly progressing migraine attack, but early treatment may not equate with treatment of mild pain in a rapidly progressing migraine attack. If early and late treatment are to be compared fairly without considering pain intensity, the comparison needs to be made in one type of attack group only, either in those with slowly progressing attacks (in whom early treatment will equate with treatment of mild pain) or in those with rapidly progressing attacks (in whom treating early does not always mean treating mild pain). The effect of placebo is another factor that must be borne in mind in the interpretation of early treatment studies. A patient may improve after taking placebo, or indeed medication, for several reasons. It is important to

Moderate

Rapidly progressing

Mild

Slowly progressing

Time (h)

Fig. 2. The two types of migraine, rapidly progressing and slowly

progressing. Treating ‘early’ (arrow) may be the same as treating ‘mild’ in a patient with slowly progressing migraine, but early treatment may not equate with treatment of mild pain in an individual with rapidly progressing migraine.

remember that migraine attacks are self-limiting. There might be regression to the mean (i.e., patients may seek medical help or take medication at the peak of severity, and the severity would have declined thereafter irrespective of medication) or the attack might follow a short natural course. The diagnosis may also be incorrect; for example, the patient might treat a tension-type headache attack rather than a true migraine attack, so the patient would be treating a condition with a better outcome. Some patients will experience a true placebo effect, a response that may be mediated by endorphins. In studies of early treatment in which patients might have different headache types, they can be instructed to treat a migraine attack early, prior to the onset of associated symptoms such as photophobia, phonophobia, nausea, or vomiting. Under such circumstances, there is a chance of them inadvertently treating a nonmigraine attack or a short migraine, in which case the improvement registered may not result from pharmacologic activity. As part of the informed consent process, information must be provided to patients regarding the reason for a clinical trial. If this information is not neutral and suggests doubts about the equivalence of the treatment regimens, patients may be aware that early treatment is potentially superior to late treatment; the consequent expectation of superior efficacy could bias patients and promote a placebo effect. For these reasons, any comparison of early and late treatment must be placebo controlled. In addition the analysis of the results must involve compar-

Eur Neurol 2005;53(suppl 1):17–21

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ison of the therapeutic gains, the response to medication over and above that to placebo, rather than the comparison of absolute response rates. The therapeutic gain from early treatment must be higher than that from late treatment to demonstrate that early treatment is superior. The outcome measure used in a trial of early versus late treatment of migraine raises further issues. Clinical trials in the past have used reduction of pain from severe or moderate to mild (pain relief) or none (pain free) as primary endpoints (fig. 1). Pain free 2 h post-dose is now recommended as the primary efficacy measure in clinical trials of migraine therapy rather than 2-hour pain relief, the primary endpoint used in most earlier trials [1]. These measures, however, may not be appropriate for a trial of early treatment in which the aim is to prevent progression of pain. In a trial of early treatment, pain free at 2 h can represent an improvement from mild to no pain, which cannot be considered as clinically relevant as improvement from moderate or severe pain to mild or no pain. As discussed earlier by Dr. Lantéri-Minet, migraine sufferers want the attack to be fully blocked, not simply delayed for a few hours. An endpoint that incorporates duration of antimigraine activity in addition to improvement in pain would be more suitable for early treatment studies. Measuring only 2-hour pain free also results in unrealistically high response rates that raise patients’ and doctors’ expectations too high. The danger in this is that, because ‘satisfaction = reality & expectation’ (R.B. Lipton, Florence, April 1999, unpublished data), patients and doctors will become dissatisfied if they are expecting too much from the medication. The sustained pain-free outcome, i.e., freedom from pain at 2 h post-dose, without recurrence during the subsequent 22 h and without the need for additional medication, is a more appropriate endpoint for migraine trials. This endpoint can be used to assess the effect of medication on migraine of any baseline severity and encompasses both improvement and prevention of progression, thus reflecting what patients want from treatment. The sustained pain-free endpoint is both clinically relevant and realistic and patients achieving this outcome measure will have experienced a true blockade of their attack. Treatment success rates in the sustained pain-free parameter will, inevitably, be lower than those in the 2-hour pain-free parameter, but this will lessen the potential for unreasonably high expectations to engender dissatisfaction with treatment outcomes.

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Optimal Design for an Early Treatment Trial

Any trial comparing early treatment with late treatment preferably should be performed in one type of patient, either with slowly progressing or with rapidly progressing attacks, and the trial must be placebo controlled [2]. The design should allocate patients at random to one of four treatment arms: (1) early treatment with placebo, (2) early treatment with active medication, (3) late treatment with placebo or (4) late treatment with active medication. Pain severity should also be considered. An alternative would be a two-arm parallel design in which patients treat two attacks, with one treatment arm allocated to early treatment and the other to late treatment; one of the two attacks would be treated with placebo and the other with active medication, in randomized order. A complete crossover design trial of four attacks would probably be too complicated. The results of early and late treatment must be compared in terms of therapeutic gains rather than absolute rates. Sustained pain free is the appropriate outcome measure to use. Any conclusions drawn will be limited to the type of attacks included. Early treatment equates with treatment of mild pain only if pain at the time of medication intake is still mild, i.e., in slowly progressing attacks only. Finally, any assessment of allodynia should be made in a blinded fashion with respect to treatment (active/placebo).

Conclusions

In deciding whether or not to recommend early treatment of migraine to patients, we must focus critically on the available evidence. Although early treatment intuitively would seem to be a good approach, and there are some promising results in support of early treatment, the evidence base is insufficient as yet. Some of the evidence comes from trials with inadequate designs and insufficient outcome measures, and there is a danger that the unrealistically high success rates being reported will ultimately reduce patient satisfaction because they raise expectations too high. Placebo-controlled, randomized studies within the same attack type, using sustained pain free as the outcome measure, are required. Another danger in advising early medication for all patients is that this may increase the risk of medication overuse headache. Medication overuse headache is a growing problem worldwide. Epidemiologic data suggest that up to 4% of the population overuse analgesics and other drugs for the

Ferrari

treatment of pain conditions like migraine and that about 1% of the general population in Europe, North America, and Asia suffer from medication overuse headache [16]. Treating too early can increase the risk of medication overuse in patients who often have more than one type of headache and are not able to differentiate migraine from other headache types.

On the basis of the currently available evidence, our advice to patients ought to be that they should treat their headache as soon as they are certain that they are developing a migraine headache, but that they should not treat during the aura phase.

References 1 Tfelt-Hansen P, Block G, Dahlöf C, Diener HC, Ferrari MD, Goadsby PJ, Guidetti V, Jones B, Lipton RB, Massiou H, Meinert C, Sandrini G, Steiner T, Winter PB: Guidelines for controlled trials of drugs in migraine: Second edition. Cephalalgia 2000;20: 765–786. 2 Ferrari MD: Should we advise patients to treat migraine attacks early? Cephalalgia 2004; 24: 915–917. 3 Burstein R, Collins B, Jakubowski M: Defeating migraine pain with triptans: A race against the development of cutaneous allodynia. Ann Neurol 2004;55:19–26. 4 Burstein R, Jakubowski M: Analgesic triptan action in an animal model of intracranial pain: A race against the development of central sensitization. Ann Neurol 2004;55: 27–36. 5 Plosker GL, McTavish D: Sumatriptan. A reappraisal of its pharmacology and therapeutic efficacy in the acute treatment of migraine and cluster headache. Drugs 1994;47:622–651.

Early Treatment of Migraine: Methodological Issues

6 The Subcutaneous Sumatriptan International Study Group: Treatment of migraine attacks with sumatriptan. N Engl J Med 1991; 325: 316–321. 7 Diamond S, Freitag FG: Sumatriptan 6 mg subcutaneous as a successful treatment for migraine associated with allodynia. Neurology 2004;62(suppl 5):A149. 8 Cady RK, Sheftell F, Lipton RB, O’Quinn S, Pharmd, Jones M, Putnam DG, Crisp A, Metz A, McNeal S: Effect of early intervention with sumatriptan on migraine pain: Retrospective analyses of data from three clinical trials. Clin Ther 2000; 22:1035–1048. 9 Pascual J, Cabarrocas X: Within-patient early versus delayed treatment of migraine attacks with almotriptan: The sooner the better. Headache 2002;42:28–31. 10 Mathew NT, Kailasam J, Meadors L: Early treatment of migraine with rizatriptan: A placebo-controlled study. Headache 2004; 44: 669–673. 11 Mathew NT: Early intervention with almotriptan improves sustained pain-free response in acute migraine. Headache 2003; 43: 1075– 1079.

12 Dowson AJ, Massiou H, Lainez JM, Cabarrocas X: Almotriptan improves response rates when treatment is within 1 hour of migraine onset. Headache 2004; 44:318–322. 13 Cady R, Elkind A, Goldstein J, Keywood C: Randomized, placebo-controlled comparison of early use of frovatriptan in a migraine attack versus dosing after the headache has become moderate or severe. Curr Med Res Opin 2004; 20: 1465–1472. 14 Scholpp J, Schellenberg R, Moeckesch B, Banik N: Early treatment of a migraine attack while pain is still mild increases the efficacy of sumatriptan. Cephalalgia 2004;24: 925–933. 15 Klapper J, Lucas C, Rosjo O, Charlesworth B: Benefits of treating highly disabled migraine patients with zolmitriptan while pain is mild. Cephalalgia 2004;24:918–924. 16 Diener HC, Limmroth V: Medication-overuse headache: A worldwide problem. Lancet Neurol 2004;3:475–483.

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Eur Neurol 2005;53(suppl 1):22–28 DOI: 10.1159/000085038

Published online: May 3, 2005

Defining Response in Migraine: Which Endpoints Are Important? John Edmeads Sunnybrook and Women’s College Health Sciences Centre, Toronto, Canada

Key Words Almotriptan
Migraine
Sustained pain free
Tolerability
Triptan

Abstract The primary endpoint traditionally measured in clinical trials of triptans for acute migraine therapy has been 2hour pain relief, a decrease in pain intensity from moderate/severe to mild/none. Although harder to achieve, endpoints such as 2-hour pain free and the composite measure sustained pain free are now preferred as they better reflect what patients desire from medication, namely rapid onset of action, and complete and lasting relief of pain. A comprehensive meta-analysis has shown that oral triptans differ in their ability to achieve these endpoints, with almotriptan 12.5 mg, eletriptan 80 mg and rizatriptan 10 mg providing the highest likelihood of success. Although all triptans have simple and consistent pharmacokinetic features, they also have specific differences that may play a part in their differing clinical attributes. Incorporating tolerability to generate a more stringent endpoint, sustained pain free with no adverse events (SNAE), may provide an even better representation of patients’ expectations. Comparison of SNAE rates using data from the meta-analysis of oral triptans indicates that almotriptan 12.5 mg has the best balance of high efficacy and good tolerability.

Introduction

The goals of acute treatment of migraine are to relieve the attack rapidly and consistently, avoid recurrence, minimize the need for rescue medication, restore the ability to function, and allow patients to care for themselves, all while minimizing or avoiding adverse effects and being cost-effective [1]. How can these goals best be met? Evidence-based guidelines for the acute treatment of migraine produced by the US Headache Consortium recommend initial treatment with triptans for moderate to severe migraine in patients without contraindications, and for migraine of any severity when nonspecific medications have failed to provide adequate relief in the past [1]. There are currently seven triptans available, in various doses and formulations, for the treatment of acute migraine in most countries and, although there are guidelines about circumstances in which a triptan is appropriate, presently there are no good guidelines that inform about which particular triptan should be chosen. The ideal way to compare triptans with one another is in direct head-to-head trials, but such direct active comparator trials are available for only a few triptans and it is unlikely that they will ever all be compared [2]. A method of selecting the triptan that is most likely to be satisfactory for each individual patient is needed. A consideration of the various endpoints that can be used to assess the outcome of therapy is an intrinsic part of this process. Which end-

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John Edmeads, MD Sunnybrook and Women’s College Health Sciences Centre #A233-2075 Bayview Avenue Toronto, Ont., M4N 3M5 (Canada) Tel. +1 416 480 5200, Fax +1 416 480 4992, E-Mail [email protected]

points best represent the attributes of therapy that predict patient satisfaction and health-related quality of life, and which triptans are most successful at achieving these endpoints?

Results from Meta Analysis with Different Endpoints

Meta-analysis provides one method of comparing medications that have not been compared directly in clinical trials. A comprehensive meta-analysis of 53 clinical trials in 24,089 patients has provided valuable information that clinicians can use to guide their selection of a triptan providing the greatest likelihood of consistent success [2, 3]. All the trials included in this meta-analysis were randomized, controlled (active or placebo) studies in patients aged 18 to 65 years with moderate to severe migraine treated with oral triptans at a recommended dose within 8 h of onset. Headache pain was assessed on a 4-point scale (0, no pain; 1, mild pain; 2, moderate pain; 3, severe pain), as recommended by the Clinical Trials Subcommittee of the International Headache Society (IHS) [4]. A variety of endpoints had been used in these clinical trials, including pain relief, pain free, complete relief (pain relief coupled with absence of associated symptoms), recurrence rates, use of rescue medication, relief of associated symptoms, quality of life, and disability/functionality. The primary endpoint in most of the studies included in the meta-analysis was the proportion of patients with pain relief at 2 hours, i.e., a reduction in pain from moderate or severe to mild or none on the 4-point scale, despite the IHS recommendation to use 2-hour pain free [4, 5]. In comparison with sumatriptan 100 mg (chosen as the reference triptan primarily because this is the triptan and dose for which most clinical data are available) [2], eletriptan 80 mg (not an approved single dosage in most European countries and the United States) and rizatriptan 10 mg gave higher pain relief rates, and eletriptan 20 mg, frovatriptan 2.5 mg, and naratriptan 2.5 mg gave lower rates; other triptans and doses had confidence intervals overlapping with the reference triptan, and were therefore not significantly different. Although 2-hour pain relief is a useful, statistically powerful outcome measure for establishing the efficacy of a triptan in ameliorating the pain of migraine, it does not provide an ideal representation of what patients want from their migraine therapy. This endpoint treats a change from severe to no pain and a change from moder-

Migraine Response: Which Endpoints Are Important?

ate to mild pain as equivalent, reducing the extent to which different treatments can be discriminated. Patients do not regard a reduction of moderate pain to mild pain as a successful treatment [6], and while they might consider that their migraine attack has been cured even though some mild pain remains, what patients really expect and want from treatment is to be completely free from pain and for this to occur rapidly [7, 8]. Considerations such as these led the IHS to recommend that the percentage of patients pain free at 2 h without any rescue medication should be the primary (though not the only) efficacy measure in clinical trials [4]. Pain free is a more robust measure that is less sensitive to placebo effects [2]. Two hours may not be sufficient time for some drugs to eliminate rather than reduce pain, but this is a time beyond which patients should be permitted to take rescue medication [4]. Pain free at 2 h was a secondary efficacy measure in most of the trials in the meta-analysis of oral triptans. Treatment with almotriptan 12.5 mg, eletriptan 80 mg, and rizatriptan 10 mg resulted in higher percentages of patients pain free at 2 h than sumatriptan 100 mg, whereas eletriptan 20 mg, naratriptan 2.5 mg, and sumatriptan 25 mg were less effective than sumatriptan 100 mg (fig. 1) [2, 3]. It is also possible to discriminate among the triptans on the basis of their ability to prevent recurrence of pain, another attribute that is important to patients [7]. Recurrence is inconvenient to patients, and the extra medication that it necessitates imposes extra costs and may lead to medication overuse headaches [2]. Isolated comparison of recurrence rates, without taking into account differences in initial relief rates and use of rescue medication, may be misleading, so comparison of sustained pain-free rates is preferred [2]. Sustained pain free is a composite measure defined as the percentage of patients with moderate or severe initial pain who are pain free by 2 h postdose with no recurrence of moderate or severe headache and no use of rescue medication from 2 to 24 h [2] or 2 to 48 hours postdose [4]. This outcome measure includes the elements patients say they want from treatment and that predict satisfaction with treatment and improvement in health-related quality of life [7–9]. Sustained pain free is regarded by the IHS as the ideal response to a drug for the treatment of a migraine attack, the ultimate goal in drug development, but is recommended as a secondary efficacy measure as the lower rates inevitably achieved in comparison with pain free at 2 h do not reflect the enormous clinical impact of the triptans on migraine treatment [4].

Eur Neurol 2005;53(suppl 1):22–28

23

Meta-analysis: pain free at 2 h Better 0 Sumatriptan

25 mg 50 mg 100 mg

Zolmitriptan

2.5 mg 5 mg

Naratriptan

2.5 mg

Rizatriptan

5 mg 10 mg

Eletriptan

20 mg 40 mg 80 mg

10

20

30

40

50

Fig. 1. Mean (and 95% confidence interval)

percentages of patients pain free at 2 h after treatment with various triptans derived by meta-analysis of clinical trial data. The vertical bar represents the rate and 95% confidence interval envelope for sumatriptan 100 mg (the reference triptan). Three treatments are superior to the reference triptan: almotriptan 12.5 mg, eletriptan 80 mg, and rizatriptan 10 mg [2, 3].

Almotriptan

12.5 mg

Meta-analysis: sustained pain free Better

0

Fig. 2. Mean (and 95% confidence interval) sustained pain-free rates (the percentage of patients with moderate or severe initial pain who are pain free by 2 h postdose with no recurrence of moderate or severe headache and no use of rescue medication 2– 24 h postdose) for various triptans derived by meta-analysis. The vertical bar represents the rate and 95% confidence interval envelope for sumatriptan 100 mg (the reference triptan). Three treatments are superior to the reference triptan: almotriptan 12.5 mg, eletriptan 80 mg, and rizatriptan 10 mg [2, 3].

Sumatriptan

25 mg 50 mg 100 mg

Zolmitriptan

2.5 mg 5 mg

Naratriptan

2.5 mg

Rizatriptan

5 mg 10 mg

Eletriptan

20 mg 40 mg 80 mg

Almotriptan

Comparison of sustained pain-free rates in the metaanalysis of oral triptans indicated that almotriptan 12.5 mg, eletriptan 80 mg, and rizatriptan 10 mg were superior to sumatriptan 100 mg, whereas eletriptan 20 mg yielded lower rates than sumatriptan 100 mg (fig. 2). Other triptans/doses did not differ significantly from sumatriptan 100 mg [2, 3].

24

Eur Neurol 2005;53(suppl 1):22–28

10

20

30

12.5 mg

The evolution from pain relief at 2 h through pain free at 2 h to sustained pain free manifests as increasing patient satisfaction, but the clinical reality is that response becomes increasingly difficult to achieve. Broadly speaking, treatment with an oral triptan will provide 2-hour pain relief in approximately 60% of patients and 2-hour pain free in approximately 30%, but sustained pain-free

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Meta-analysis: range of response rates✽ Response rate decreases with more stringent endpoints

Nara 2.5 mg 15.9%

SPF

Nara 2.5 mg 22.4%

Almo 12.5 mg 25.9%

2-h PF

Riza 10 mg 40.1%

Frova 2.5 mg 41.5%

Riza 10 mg 68.6%

2-h PR

Fig. 3. Decreasing rates of response to trip-

tan therapy with increasing stringency of outcome measure. Response rates are derived by meta-analysis of clinical trial data [2, 3]. PR, pain relief; PF, pain free; SPF, sustained pain free.

0

20

✽Commonly

60

80

used doses.

rates center around 20% (fig. 3). Data from the metaanalysis can be used to guide therapeutic choice so that patients can be offered the triptan demonstrating the best response rates in clinical trials, therefore being the most likely to achieve optimal response. According to the meta-analysis, rizatriptan 10 mg is the triptan and dose that provides the highest 2-hour pain-relief and 2-hour pain-free rates, but almotriptan 12.5 mg offers the best results in terms of the more stringent sustained pain-free endpoint. The reason underlying the shift from rizatriptan to almotriptan as the most effective triptan for achieving the more demanding outcome measure (sustained pain free) is the markedly higher recurrence rate seen with rizatriptan 10 mg. Rizatriptan (10 and 5 mg) was the only triptan with a higher recurrence rate than the reference triptan (sumatriptan 100 mg) in the meta-analysis [2, 3].

Incorporating Tolerability with Efficacy: Sustained Pain Free with No Adverse Events

The idea of a composite outcome measure like sustained pain free can be developed further to incorporate another aspect of therapy that is important to patients, namely absence of adverse events. That patients are concerned about tolerability and adverse events was demonstrated in a survey of 1,160 individuals meeting IHS criteria for migraine among the US National Family Opinion household panel; 67% of the respondents had delayed

Migraine Response: Which Endpoints Are Important?

40 Absolute response rate (%)

or avoided taking a current prescription medication because of concerns about adverse effects [10]. These concerns had led to a delay in taking medication in 37% of treated attacks and to medication avoidance in 44% of untreated attacks during the preceding 6 months. In an era when the emphasis of treatment is shifting to early dosing, delay in taking medication because of apprehension about side effects is unacceptable. Ferrari et al. attempted to make an overall comparison among triptans in relation to the reference triptan, sumatriptan 100 mg, in terms of efficacy, consistency, and tolerability using data from their meta-analysis and direct comparator studies [2, 3]. They rated individual triptans as inferior to, possibly inferior to, no different from, better, possibly much better, or much better than sumatriptan 100 mg for pain relief at 2 h, sustained pain free, consistency of effect, and tolerability. The resulting pattern enabled them to conclude that three triptans showed favorable results and would provide the highest likelihood of consistent success: almotriptan 12.5 mg (better sustained pain free and better consistency, and much better tolerability than sumatriptan 100 mg), eletriptan 80 mg (better efficacy, slightly inferior tolerability, though not an approved single dose in most countries), and rizatriptan 10 mg (better efficacy and consistency, similar tolerability). In a move to capture both efficacy and tolerability in a more well-defined and statistical way, a new endpoint has been proposed: sustained pain free with no adverse events (SNAE) [11, 12]. This composite endpoint may

Eur Neurol 2005;53(suppl 1):22–28

25

Table 1. Calculation of SNAE (sustained pain free [SPF] with no Endpoints as measures of patient satisfaction No adverse events

Increasing patient satisfaction

No No recurrence recurrence 2–24 h 2–24 h No assoc No use of No use of symptoms rescue med rescue med at 2 h 2–24 h 2–24 h

Pain relief at 2 h 2-h pain relief

Pain free at 2 h

Pain free at 2 h

Pain free at 2 h

Pain free at 2 h

2-h pain free

Complete relief

SPF

SNAE

adverse events [AE]) from meta-analysis of clinical trials of oral triptans. %SNAE = %SPF ! [(100 4 %AE)/100]. Triptan, dose (mg)

SPF, %*

AE, %*

SNAE, %

Almotriptan 12.5 Rizatriptan 10 Sumatriptan 50 Sumatriptan 100 Eletriptan 40 Zolmitriptan 2.5 Eletriptan 80 Zolmitriptan 5 Naratriptan 2.5

25.9 25.3 19.8 20.0 20.9 19.0 25.0 21.9 15.9

14.2 40.8 28.2 33.6 42.4 39.2 53.9 47.8 31.4

22.2 15.0 14.2 13.3 12.1 11.6 11.5 11.4 10.9

* [2, 3].

Increasing challenge

Fig. 4. The relationship between endpoints in trials of acute mi-

graine medication and patient satisfaction. SPF, sustained pain free; SNAE, sustained pain free with no adverse events.

represent even better what patients want from their migraine treatment. Yet, as before, the increased degree of patient satisfaction carries with it a corresponding increase in the challenge of achieving the endpoint (fig. 4). Only two triptans, almotriptan 12.5 mg and naratriptan 2.5 mg, were found to have a significantly lower placebo-subtracted adverse event rate than sumatriptan 100 mg on meta-analysis [2, 3]. In fact, the adverse event rate with almotriptan was essentially the same as placebo. The SNAE endpoint can be calculated from data from the meta-analysis by adding the placebo adverse event rate back onto the placebo-subtracted rate and assuming that the proportion of adverse events in the total population is similar to the proportion of adverse events in the sustained pain-free subgroup, i.e., that sustained pain free and adverse events are independent. The SNAE rate is obtained by multiplying the sustained pain-free rate by the percentage of patients with no adverse events (% SNAE = % patients sustained pain free ! [(100 – % patients with adverse events)/100]). Data from the metaanalysis for 9 triptans/doses [2, 3] can be used to calculate SNAE rates ranging from 22.2% for almotriptan 12.5 mg down to 10.9% for naratriptan 2.5 mg (table 1). The endpoint can be used to identify triptans with a good balance between efficacy and tolerability. Eletriptan 80 mg, for example, although showing good efficacy, with the third

26

Eur Neurol 2005;53(suppl 1):22–28

highest sustained pain-free rate (25.0%), had the highest absolute adverse event rate (53.9%), giving it the third lowest SNAE rate. With eletriptan 80 mg, the patient would have a high likelihood of experiencing a good therapeutic effect but would be at increased risk of adverse events. Conversely, naratriptan 2.5 mg had a relatively low adverse event rate (31.4%), but it was coupled with a low efficacy (sustained pain-free rate of 15.9%); this combination produced the lowest SNAE value, 10.9%. A patient treated with naratriptan 2.5 mg would be at a relatively low risk of experiencing adverse events but might be less likely to achieve a good therapeutic effect. Almotriptan appears to have the best combination of high efficacy and good tolerability.

The Basis of Differences between Triptans

Although at marketed doses all oral triptans are effective and well tolerated, tools such as meta-analysis and comparison of composite endpoints such as SNAE facilitate discrimination among the triptans. At present, almotriptan 12.5 mg, eletriptan 80 mg, and rizatriptan 10 mg provide the best likelihood of consistent success, and almotriptan 12.5 mg provides the best combination of efficacy and tolerability. The differences among the triptans are relatively small, but they are nonetheless relevant for individual patients. Why is it that the triptans, which all exert their effect through the same receptor, have differing efficacy and tolerability profiles? Pharmacokinetics probably underlies these differences. The time between ingestion of the drug and maximum

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16

Meta-analysis: placebo-subtracted incidence of CNS adverse events 14.6

11.5

12

Patients ( %)

9.9

9.4 7.5

8 6.3

6.1

3.7

4

2.6 1.9

1.7 0

Fig. 5. Incidence of central nervous system adverse events (placebo-subtracted) in meta-analysis of clinical trials of oral triptans. Rates of adverse events vary according to triptan and dose [2, 3].

–4

25

50

100

Suma

2.5 Zolmi

5

2.5 Nara

5

10 Riza

20

40 Ele

80

–1.5 12.5 Almo

therapeutic concentration, Tmax, for example, varies from 2–3 h for sumatriptan to 1–2 h for some of the newer triptans [13]. In theory, a shorter Tmax is associated with a quicker onset of action. Triptans also vary in the length of time they persist in the circulation, with t½ values ranging from 2 h for sumatriptan and rizatriptan to 26 h for frovatriptan [13]. The t½ value may relate to duration of action and therefore may influence recurrence rates [2]. Bioavailability is another parameter that may affect efficacy or tolerability. Sumatriptan has low oral bioavailability, 14%, whereas some of the newer triptans have bioavailability of approximately 70% (almotriptan, naratriptan) [13]. Higher bioavailability may predict more consistent efficacy over multiple attacks [2]. Most of the triptans are metabolized via only one enzymatic pathway (most commonly monoamine oxidase), but almotriptan and naratriptan can be degraded via several metabolic pathways, almotriptan by monoamine oxidase, cytochrome P3A4, cytochrome P2D6, and flavin monoxygenase, and naratriptan by various cytochrome P450 isoforms. Monoamine oxidase-mediated metabolism is a common pathway for the breakdown of drugs; it may not be possible to use a triptan that is metabolized only by monoamine oxidase in combination with another medication that relies on this same pathway for its metabolism. Zolmitriptan concentration, for example, can be affected by cimetidine. Also, monoamine oxidase inhibitors are contraindicated with sumatriptan, rizatriptan, and zolmitriptan as these triptans are degraded

only by the monoamine oxidase pathway. Eletriptan, which relies solely on cytochrome 3A4 for its metabolism, is contraindicated for use with potent inhibitors of this pathway (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir). Drug–drug interactions may be less likely with a triptan that has multiple metabolic pathways, since if one is inhibited, another may be utilized. For example, no drugs are contraindicated for use with either almotriptan or naratriptan, agents with several metabolic routes. Differences in central nervous system (CNS) adverse event rates among the triptans are particularly interesting, as CNS side effects are related to factors such as ease of entry of the triptan into the brain, concentration achieved by the triptan in the brain, and the length of time the triptan exerts its action. Improved understanding of the physiologic basis of the CNS side effects of triptans may lead to improvement in migraine management [13]. The incidence of CNS adverse events of triptans (eg, drowsiness) is dose related [13] and higher with some triptans (eg, eletriptan 80 mg) than others (eg, with almotriptan, the placebo-subtracted CNS adverse event rate is not statistically different from 0, i.e., it is no different from placebo) (fig. 5) [2, 3]. The incidence of CNS adverse events is related to the lipophilicity of the triptan, possibly because highly lipophilic triptans penetrate the blood– brain barrier more easily (although lipophilicity may be less important at low doses) [13]. Triptans with low lipo-

Migraine Response: Which Endpoints Are Important?

Eur Neurol 2005;53(suppl 1):22–28

27

philicity, such as almotriptan, have relatively few CNS adverse events whereas those with high lipophilicity, such as eletriptan, are associated with a high incidence of CNS adverse events [13]. In addition, some of the triptans are broken down into active, lipophilic, desmethyl metabolites, and those that are (frovatriptan, rizatriptan, zolmitriptan, and eletriptan) have more CNS side effects than those that are not (almotriptan, naratriptan, sumatriptan). It is possible that the desmethyl metabolite binds to 5-HT receptors that are associated with triptan-related side effects or that the increased lipophilicity of the metabolite means that it achieves a higher concentration in the brain and is therefore more likely to cause CNS adverse events [13]. An understanding of the particular pharmacokinetic features of individual agents may help to inform triptan choice for a particular patient.

Conclusions

Although triptans all have the same mechanism of action, they are different in ways that are clinically relevant to individual patients with migraine. Physicians should select the treatment that offers the best chance of achieving patient satisfaction. To do this, it is necessary to compare triptans’ abilities to achieve the endpoints that reflect the attributes patients value in their treatment. Clinical trials have traditionally measured pain relief at 2 h, but this endpoint does not take into account patients’ desire for rapid, consistent, and lasting freedom from pain. Composite endpoints encompassing the range of attributes patients desire from their medication facilitate this process of discriminating among triptans. The SNAE endpoint, which captures both efficacy and tolerability, may best represent what patients want from their acute migraine treatment.

References 1 Silberstein SD: Practice parameter: Evidencebased guidelines for migraine headache (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000; 55: 754–762. 2 Ferrari MD, Goadsby PJ, Roon KI, Lipton RB: Triptans (serotonin, 5-HT1B/1D agonists) in migraine: Detailed results and methods of a metaanalysis of 53 trials. Cephalalgia 2002;22:633– 658. 3 Ferrari MD, Roon KI, Lipton RB, Goadsby PJ: Oral triptans (serotonin 5-HT1B/1D agonists) in acute migraine treatment: A meta-analysis of 53 trials. Lancet 2001;358:1668–1675. 4 Tfelt-Hansen P, Block G, Dahlöf C, Diener HC, Ferrari MD, Goadsby PJ, Guidetti V, Jones B, Lipton RB, Massiou H, Meinert C, Sandrini G, Steiner T, Winter PB: Guidelines for controlled trials of drugs in migraine: Second edition. Cephalalgia 2000;20: 765–786.

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5 International Headache society committee on clinical trials in migraine: Guidelines for controlled trials of drugs in migraine; First edition. Cephalalgia 1991;11:1–12. 6 Massiou H, Tzourio C, el Amrani M, Bousser MG: Verbal scales in the acute treatment of migraine: Semantic categories and clinical relevance. Cephalalgia 1997; 17: 37–39; discussion 32. 7 Lipton RB, Stewart WF: Acute migraine therapy: Do doctors understand what patients with migraine want from therapy? Headache 1999; 39(suppl 2):S20–S26. 8 Davies GM, Santanello N, Lipton R: Determinants of patient satisfaction with migraine therapy. Cephalalgia 2000; 20:554–560.

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9 Santanello NC, Davies G, Allen C, Kramer M, Lipton R: Determinants of migraine-specific quality of life. Cephalalgia 2002;22:680–685. 10 Gallagher RM, Kunkel R: Migraine medication attributes important for patient compliance: Concerns about side effects may delay treatment. Headache 2003;43:36–44. 11 Williams P, Reeder CE: A comparison of the cost-effectiveness of almotriptan and sumatriptan in the treatment of acute migraine using a composite efficacy/tolerability end point. J Manag Care Pharm 2004; 10:259–265. 12 Williams P, Reeder CE: Cost-effectiveness of almotriptan and rizatriptan in the treatment of acute migraine. Clin Ther 2003; 25: 2903– 2919. 13 Dodick D, Martin V: Triptans and CNS sideeffects: Pharmacokinetic and metabolic mechanisms. Cephalalgia 2004;24: 417–424.

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Published online: May 3, 2005

Eur Neurol 2005;53(suppl 1):29–33 DOI: 10.1159/000085039

Efficacy and Tolerability of Almotriptan in Controlled Clinical Trials Ninan T. Mathew Department of Neurology, University of Texas Houston Medical School, Houston, Tex., USA

Key Words Almotriptan
Migraine
Efficacy
Tolerability
Early intervention

Abstract Seven triptans are now available for the acute treatment of migraine. While all of these agents have been shown to be safe and more or less well tolerated, they differ in ways that are clinically relevant to individual patients. Almotriptan has been investigated in approximately 3,500 patients enrolled in short-term clinical trials and 1,500 patients enrolled in long-term open-label trials. In a meta-analysis of placebo-controlled almotriptan trials (n = 2,294), treatment with almotriptan 12.5 mg results in a 2-hour pain-relief rate of 63.7% and a 2-hour painfree rate of 36.4%. Almotriptan is associated with a rapid onset of action, with 30-min pain-relief and pain-free rates significantly better than placebo (p ! 0.05). Direct comparator studies show the efficacy of almotriptan 12.5 mg to be comparable to that of sumatriptan but almotriptan is associated with superior tolerability. Trials assessing the efficacy of almotriptan over multiple attacks show that this agent is associated with a consistent and persistent response, not differing from the first to the last attack, an important property for a medication used to treat a chronic condition such as migraine. Early intervention with almotriptan enhances the activity of this agent. Treatment of mild pain with almotriptan has resulted in 2-hour pain-free rates of 84 and 77% and

© 2005 S. Karger AG, Basel 0014–3022/05/0535–0029$22.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/ene

a sustained pain-free rate of 67%. Early treatment (within 1 h) of moderate to severe headaches with almotriptan also improves outcomes. In conclusion, clinical trials and post hoc analyses of such trials have shown almotriptan to be effective and well tolerated for the acute treatment of migraine. Its placebo-like tolerability makes it a good choice for early intervention, a strategy associated with better patient outcomes. Copyright © 2005 S. Karger AG, Basel

Introduction

The development of the triptans, which are 5-hydroxytryptamine (5-HT)1B/1D receptor agonists, has been a major advance in the field of acute pharmacotherapy for migraine. All of the available triptans have been shown to be safe and generally well tolerated. However, a metaanalysis of 53 controlled trials that compared almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, and zolmitriptan with sumatriptan showed that these agents differ with respect to efficacy in providing rapid, complete, and consistent pain relief and association with adverse events (AEs), characteristics that are clinically relevant to individual patients [1, 2]. Almotriptan 12.5 mg, eletriptan 80 mg (not an approved single dosage in most countries), and rizatriptan 10 mg emerged from this meta-analysis as the agents most likely to successfully and consistently treat migraine in the acute setting.

Ninan T. Mathew, MD Department of Neurology, University of Texas Houston Medical School 1213 Hermann Drive, Houston, TX 77004 (USA) Tel. +1 713 528 1916, Fax +1 713 528 6369 E-Mail [email protected]

Placebo 70

Placebo

Almotriptan 12.5 mg

a

Almotriptan 12.5 mg 30

✽

25.8 ✽

✽

50

Patients (%)

Patients (%)

60

✽

40 30 ✽

20

20 11.1 10

10 0 30

60

90

120

0 Sustained pain free

Time (min) 40

b

✽

Patients (%)

30

term, placebo-controlled trials of almotriptan 12.5 mg achieving sustained pain free. * p ! 0.0001 vs. placebo (Almirall, data on file).

✽

20 ✽

10 ✽ 0

30

60 90 Time (min)

120

Fig. 1. Proportion of patients achieving pain relief (a) and pain free (b) after dosing with almotriptan 12.5 mg and placebo from a meta-

analysis of placebo-controlled almotriptan trials. * p ! 0.05 vs. placebo [7].

The clinical database for almotriptan includes findings from approximately 3,500 patients enrolled in short-term placebo- and active-controlled clinical trials and 1,500 patients enrolled in long-term open-label trials [3]. This article will provide a comprehensive review of efficacy and safety data from the almotriptan clinical development program.

Short-Term Controlled Clinical Trials

Three pivotal studies of almotriptan for acute migraine therapy were conducted [4–6]. All three trials were randomized, double-blind, placebo-controlled, multicenter, dose-ranging studies that enrolled more than 2,000 patients in total. Two of the trials gathered data for one attack per patient; in the other trial, three attacks per patient were included in the analysis.

30

Fig. 2. Proportion of patients in three short-

Eur Neurol 2005;53(suppl 1):29–33

A pooled analysis of data from those placebo-controlled trials showed that almotriptan 12.5 mg was significantly better than placebo for providing pain relief and complete pain freedom [7]. Significant differences between data points for the almotriptan and placebo arms for both of these measures were observed starting at 30 min after dosing (fig. 1a, b). The pooled analysis also showed that almotriptan 12.5 mg was associated with a significantly greater rate for sustained pain free (SPF; pain free at 2 h after dosing and no headache recurrence or use of rescue medication for 24 h after dosing) (fig. 2) (Almirall, data on file). Data from direct comparisons of almotriptan with other triptans can be found in two clinical trials, one that used sumatriptan 100 mg as the comparator [8] and another that used sumatriptan 50 mg as the comparator [9]. More information is provided by the meta-analysis of Ferrari et al. that compared all the available oral triptans and doses with sumatriptan 100 mg. This meta-analysis included three placebo-controlled trials of almotriptan, one of which also used sumatriptan 100 mg as an active comparator [1, 2]. The results showed that almotriptan 12.5 mg was associated with significantly better rates for 2-hour pain free and SPF compared to sumatriptan 100 mg. Consistency across attacks for 2-hour pain relief was assessed in the placebo-controlled clinical trial that collected data on three attacks [6]. In the assessment of individual attacks in that study, the 2-hour pain-relief rates

Mathew

Long-Term Open-Label Clinical Trials

Results from long-term open-label studies of almotriptan are available from two trials, a 6-month trial that enrolled 611 patients and a 12-month trial that enrolled 805 patients [11, 12]. Both trials collected data from an average of 18 attacks per patient. The 2-hour pain relief and 2-hour pain-free rates were 76.2 and 48.9%, respectively, for the 6-month trial and 84.2 and 58.2% for the 12month trial. The rates for 2-hour pain relief and 2-hour pain free were similarly high when dosing was done when pain was moderate and when it was severe (fig. 3a, b). Consistency of response was assessed in the 12-month open-label study [12]. Two-hour pain relief was obtained by 61.8% of patients for 680% of their attacks during the trial, by 77.7% of patients for 660% of their attacks, and

Almotriptan in Controlled Clinical Trials

a

100

2-h PR

2-h PF 85.7

76.2

Attacks (%)

80

54.3

60

60.6

48.9

40 27.0 20

0 All attacks 100

b

Moderate

Severe

88.9

84.2

76.6

80 64.5 Attacks (%)

for patients receiving almotriptan 12.5 mg ranged from 65 to 69% compared with 33–37% for patients receiving placebo (p ! 0.001). Assessment of 2-hour pain relief across all three attacks showed that 75% of patients in the almotriptan 12.5-mg group achieved 2-hour pain relief for 62 attacks compared with 36% of patients in the placebo group (p ! 0.001), and the proportion of patients achieving 2-hour pain relief for all three attacks was 50% for the almotriptan 12.5-mg group and 16% for the placebo group (p ! 0.001). The efficacy findings from the controlled trials of almotriptan and the meta-analysis of oral tripans indicate that almotriptan provided rapid, complete, sustained, and consistent pain relief in controlled clinical trials. The tolerability of almotriptan is also of note. In the three placebo-controlled clinical trials, AEs reported by a greater proportion of the almotriptan group than the placebo group that occurred in 61% of patients receiving almotriptan were nausea (almotriptan, 2%; placebo, 1%), dry mouth (almotriptan, 1%; placebo, 0.5%), and paresthesia (almotriptan, 1%; placebo, 0.5%) [10]. In the metaanalysis, the placebo-subtracted incidence of any AE, central nervous system (CNS) AEs, and chest AEs was significantly less for almotriptan 12.5 mg than for sumatriptan 100 mg [1, 2]. These results compare favorably with those for the other oral triptans. The only other triptan associated with a significantly lower rate of any AE than sumatriptan 100 mg was naratriptan 2.5 mg; no triptan had a significantly lower rate of CNS or chest AEs compared with sumatriptan 100 mg. These findings show that almotriptan is particularly well-tolerated in the acute treatment of migraine.

58.2 60 42.9 40

20

0 All attacks

Moderate

Severe

Fig. 3. Proportion of attacks in which 2-hour pain relief and 2-hour pain free were achieved by patients dosing with almotriptan 12.5 mg from a 6-month (a) and a 12-month (b) open-label extension trial. PR, pain relief; PF, pain free. Adapted with permission from Pascual [11, 12].

86.7% of patients for 640% of their attacks. Consistency of 2-hour pain relief among patients for whom data were collected for 630 attacks each (n = 97) was also analyzed. The rate for 2-hour pain relief was consistently high (ranging from 87.4 to 91.2%) after the first, fifth, fifteenth, and thirtieth attack. Although these long-term trials were not controlled and the patient population included only those for whom almotriptan had been efficacious in a previous short-term controlled trial, the findings add to our knowledge of almotriptan in the clinical trial setting. These trials showed that almotriptan continued to be efficacious and well tolerated for the acute treatment of migraine, an important finding because of the chronic, recurrent nature of migraine.

Eur Neurol 2005;53(suppl 1):29–33

31

Moderate/severe

Mild

100

76.9 ✽

80 Attacks (%)

66.6 ✽

Fig. 4. Proportion of attacks with 2-hour

pain free, sustained pain free, recurrence, and use of rescue medication in patients dosing with almotriptan 12.5 mg for attacks of mild or moderate/severe pain at baseline. * p ! 0.001 for mild vs moderate/severe [13].

60 43.9 36.6

40

25.0 20

2-h pain free

Sustained pain free

Recurrence

Almotriptan 12.5 mg 37.9 ✽

40

35.7 ✽

34.7 ✽ 29.6

Patients (%)

29% 20

17.0

20%

0

The benefits of early intervention with almotriptan were assessed retrospectively from data obtained from the two long-term open-label trials. In these post hoc analyses efficacy was evaluated according to pain intensity at time of dosing [13, 14]. In the 6-month trial, administration of almotriptan 12.5 mg when pain was mild was associated with significantly higher rates for 2-hour pain free and SPF compared with administration when pain was moderate to severe (76.9 vs. 43.9% for 2-hour pain free, p ! 0.001; 66.6 vs. 36.6% for SPF, p ! 0.001) (fig. 4) [13]. Dosing with almotriptan 12.5 mg when pain was mild was also associated with a significantly lower rate of headache recurrence and need for rescue medication compared with dosing when pain was moderate to severe (12.9 vs. 25.0% for recurrence, p ! 0.001; 9.4 vs.

Eur Neurol 2005;53(suppl 1):29–33

18.9

10

Early Intervention post hoc Analyses

32

Need rescue medication

Sumatriptan 100 mg

30

hour pain free and sustained pain free after taking almotriptan 12.5 mg, sumatriptan 100 mg, or placebo within 1 h of moderateto-severe pain. The dotted line represents the median rates for 2-hour pain free and sustained pain free reported in the metaanalysis of Ferrari et al. * p ! 0.05 vs. placebo. Adapted with permission from Dowson [2, 15].

9.4 ✽

0

Placebo

Fig. 5. Proportion of patients achieving 2-

17.2

12.9 ✽

2-h pain free

Sustained pain free

17.2% for use of rescue medication, p ! 0.001) (fig. 4) [13]. Comparison of outcomes for almotriptan dosing when pain was mild vs. moderate to severe in a post hoc analysis of the 12-month open-label trial also favored dosing when pain was mild [14]. This analysis examined a subgroup of 118 migraine sufferers who had treated at least 6 attacks, with the stipulation that at least three of the treated attacks were mild and at least three were moderate or severe. This comparison demonstrated significant differences within patients between dosing mild pain vs. moderate to severe pain for 2-hour pain free (84 vs. 53%, p ! 0.001), headache recurrence (28 vs. 33%, p = 0.01), and need for rescue medication (8 vs. 13%, p ! 0.01) [14]. A retrospective analysis of data from a short-term, randomized, double-blind, placebo- and active-controlled trial demonstrated the benefits of almotriptan dosing

Mathew

within 1 h of onset of moderate-to-severe migraine pain. The 2-hour pain-free rate for dosing with almotriptan 12.5 mg within 1 h after migraine onset was higher than that for sumatriptan 100 mg (37.9 vs. 35.7%), and both of these rates were significantly higher than that for placebo (18.9%; p ! 0.05) (fig. 5) [15]. Analysis of the SPF rate after dosing within 1 h of onset of moderate-to-severe pain showed that the rate for patients using almotriptan 12.5 mg was higher than that for sumatriptan 100 mg (34.7 vs. 29.6%) and was significantly greater than that for placebo (17.0%; p ! 0.05). The rates for 2-hour pain free and SPF shown by patients using almotriptan 12.5 mg or sumatriptan 100 mg within 1 h of onset of migraine pain are higher than those seen in the meta-analysis of oral triptans, in which an average of 29% of patients achieved 2-hour pain free and 20% achieved SPF after treating moderate to severe pain. Therefore, in addition to the benefits seen from treating mild pain, this analysis demonstrates that early treatment (within 1 h) of moderate-to-severe pain can also enhance the efficacy rates achieved by triptans. The benefits of early intervention in acute migraine therapy are multiple. Early intervention was associated

with higher pain-free and SPF rates, lower recurrence, and less need for rescue medication. Caution should be used with early intervention to guard against medication overuse and prevent development of rebound headaches. However, these findings suggest that early intervention can prevent progression of the migraine attack, lessen disability, and restore function more rapidly.

Conclusion

Data from the almotriptan clinical development database demonstrate that this agent is efficacious and well tolerated for the acute treatment of migraine. Almotriptan was associated with rapid, complete, and sustained pain relief. The high level of efficacy and low incidence of AEs associated with almotriptan make it a good choice for a first-line triptan and for use as an early intervention. The efficacy of almotriptan was shown to be consistent over multiple attacks during long-term treatment. Finally, the efficacy of almotriptan was enhanced when it was used early in the attack (defined by both pain intensity and by time to treatment).

References 1 Ferrari MD, Roon KI, Lipton RB, Goadsby PJ: Oral triptans (serotonin 5-HT1B/1D agonists) in acute migraine treatment: A meta-analysis of 53 trials. Lancet 2001;358:1668–1675. 2 Ferrari MD, Goadsby PJ, Roon KI, Lipton RB: Triptans (serotonin, 5-HT1B/1D agonists) in migraine: Detailed results and methods of a metaanalysis of 53 trials. Cephalalgia 2002;22:633– 658. 3 Dodick DW: A review of the clinical efficacy and tolerability of almotriptan in acute migraine. Expert Opin Pharmacother 2003; 4: 1157–1163. 4 Cabarrocas X: Efficacy data on oral almotriptan, a novel 5HT1D agonist. Cephalalgia 1997; 17:421. 5 Dahlof C, Tfelt-Hansen P, Massiou H, Fazekas A: Dose finding, placebo-controlled study of oral almotriptan in the acute treatment of migraine. Neurology 2001;57:1811–1817.

Almotriptan in Controlled Clinical Trials

6 Pascual J, Falk RM, Piessens F, Prusinski A, Docekal P, Robert M, Ferrer P, Luria X, Segarra R, Zayas JM: Consistent efficacy and tolerability of almotriptan in the acute treatment of multiple migraine attacks: Results of a large, randomized, double-blind, placebo-controlled study. Cephalalgia 2000;20:588–596. 7 Martinez E, Peris F, Cabarrocas X, Luria X: Efficacy and safety of almotriptan in the treatment of migraine: A meta-analysis. Cephalagia 2000;20: 310. 8 Dowson AJ, Massiou H, Lainez JM, Cabarrocas X: Almotriptan is an effective and well-tolerated treatment for migraine pain: Results of a randomized, double-blind, placebo-controlled clinical trial. Cephalalgia 2002;22:453– 461. 9 Spierings EL, Gomez-Mancilla B, Grosz DE, Rowland CR, Whaley FS, Jirgens KJ: Oral almotriptan vs. oral sumatriptan in the abortive treatment of migraine: A double-blind, randomized, parallel-group, optimum-dose comparison. Arch Neurol 2001;58:944–950.

10 Axert (almotriptan malate) tablets – prescribing information. Ortho-McNeil Pharmaceuticals, Inc. 2003. 11 Mathew N: A long-term open-label study of oral almotriptan 12.5 mg for the treatment of acute migraine attacks. Headache 2002; 42:32–40. 12 Pascual J, Falk R, Docekal R, Prusinski A, Jelencsik J, Cabarrocas X, Segarra X, Luria X, Ferrer P: Tolerability and efficacy of almotriptan in the long-term treatment of migraine. Eur Neurol 2001;45:206–213. 13 Mathew NT: Early intervention with almotriptan improves sustained pain-free response in acute migraine. Headache 2003; 43: 1075– 1079. 14 Pascual J, Cabarrocas X: Within-patient early vs delayed treatment of migraine attacks with almotriptan: The sooner the better. Headache 2002;42:28–31. 15 Dowson AJ, Massiou H, Lainez JM, Cabarrocas X: Almotriptan improves response rates when treatment is within 1 h of migraine onset. Headache 2004;44:318–322.

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Published online: May 3, 2005

Eur Neurol 2005;53(suppl 1):34–40 DOI: 10.1159/000085040

Efficacy and Tolerability of Almotriptan in Postmarketing Surveillance Studies Julio Pascual Service of Neurology, University Hospital Marques de Valdecilla, Santander, Spain

Key Words Migraine
Triptan
Randomized controlled trial
Postmarketing surveillance study
Early intervention
Primary care
Neurologist
2-hour pain-free
Sustained pain-free

Abstract While randomized, double-blind, placebo-controlled trials are considered the gold standard of clinical evidence, they are limited by patient numbers, duration of patient exposure, and restricted patient populations. Data from controlled trials may not be generalizable to all individuals likely to take the drug under investigation. Postmarketing surveillance studies are designed to measure efficacy and safety in larger and more diverse populations, allowing them to detect less common and delayed adverse events. However, postmarketing surveillance studies are limited by their lack of randomization, open-label design that can result in patient and physician bias, incomplete follow-up, less than rigorous outcome measurement, and lack of a contemporaneous control group. With regard to acute treatment of migraine, clinical trials using per protocol primary endpoints do not reflect the more favorable experience with triptans in general practice. Postmarketing surveillance studies have been performed to determine whether the high levels of efficacy

© 2005 S. Karger AG, Basel 0014–3022/05/0535–0034$22.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

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and tolerability of almotriptan reported in controlled clinical trials can been reproduced in routine practice. An observational study conducted in Spain with 2,074 migraine sufferers (4,183 attacks) reported a 2-hour painrelief rate of 86.9%, a 2-hour pain-free rate of 51.5%, and a sustained pain-free rate of 46.0%; 1.1% of patients reported adverse reactions. A German postmarketing study in 899 patients (2,131 attacks) with acute migraine treated with almotriptan 12.5 mg reported 2-hour pain relief in 84.5% of attacks and 2-hour pain free in 41.4%; 1.1% of patients reported adverse reactions. The consistency of response (at least two out of three attacks successfully treated) with almotriptan 12.5 mg was 87.3%. Regarding satisfaction, 88.5% of patients were satisfied or very satisfied and 80.3% of patients stated that almotriptan was better compared to their prior therapy; 92% of physicians indicated that they would continue treating their patients’ migraines with almotriptan. The results of these studies demonstrate that the high levels of efficacy and tolerability seen with almotriptan in controlled clinical trials are achieved in real-world clinical settings. In conclusion, a combination of controlled clinical trials, postmarketing surveillance studies, and physician’s experience in the general population can give us a better understanding of the efficacy and tolerability of acute migraine agents. Copyright © 2005 S. Karger AG, Basel

Julio Pascual, MD, PhD Service of Neurology University Hospital Marques de Valdecilla ES–39008 Santander (Spain) Tel. +34 942 202507, Fax +34 942 202655, E-Mail [email protected]

Introduction

Migraine is a highly prevalent neurologic disorder, with an estimated 1-year prevalence of 10–12% of the population of the western world [1]. Although migraine affects more women than men, is more prevalent among young and middle-aged adults than other age groups, and appears to affect a greater proportion of caucasians than those of other races [1, 2], the sheer number of migraineurs affected reflects the impact of this condition on a wide variety of patients. Another factor adding to the diversity of the population of migraineurs is its association with a large number of comorbid conditions including other neurologic diseases, mood disorders, and rheumatologic diseases [3–5]. Triptans are considered the gold standard for acute therapy of migraine. The efficacy and safety of these agents have been demonstrated in a large number of clinical trials, including placebo- and active comparator-controlled studies and long-term safety and outcome studies [6–8]. Despite this large body of scientific literature on the use of triptans for the acute treatment of migraine, there is little published data on the use of triptans in routine clinical practice. This article will explore the value of postmarketing surveillance studies for providing data on real-world clinical practice experience with triptans in acute migraine therapy and will describe postmarketing surveillance studies of almotriptan conducted in Spain and Germany.

Randomized Controlled Trials vs. Postmarketing Surveillance Studies

Evidence-based clinical reviews employ a hierarchical system of classifying data from various sources according to their perceived strength and value. For example, the American Academy of Family Physicians distinguishes 3 levels of evidence. The highest level, Level A, consists of high-quality randomized controlled trials (RCTs) and meta-analyses. The next highest level, Level B, includes other trial evidence such as lower-quality RCTs, clinical cohort studies, case-controlled studies, high-quality epidemiologic studies, and well-designed nonrandomized clinical trials, along with nonquantitative systemic reviews. The lowest level, Level C, consists of consensus viewpoints and expert opinions [9]. Randomized controlled trials consistently receive the highest ranking in these types of classification systems. The protocols for RCTs aim to prevent bias through ran-

Almotriptan in Postmarketing Surveillance Studies

Table 1. Randomized Controlled Trials vs. Postmarketing Surveillance Studies

Parameter

RCT

PS

Randomization Blinding Control Follow-up Outcome measurement Patients Number Population Exposure

Yes Double-blind Placebo or Active Rigorous Predefined

No Open-label None Incomplete No predefinition

Limited Restricted Limited

Large Diverse Large

domization, blinding, use of controls, and predefined outcome measurements, and rigorous follow-up enables a more complete data set from each patient. Randomized controlled trials are designed to have high internal validity, that is, the ability to assess whether treatment A is better than treatment B or placebo within that trial [10]. This internal validity is maintained when several requirements are met, including randomization that results in well-balanced treatment arms, maintenance of blinding (which can be endangered by the emergence of adverse events [AEs] characteristic of a particular study drug), and sufficient statistical power. Data from RCTs, including high-quality RCTs, have limitations because of the rigid study design, particularly with respect to patient selection. Table 1 lists several parameters of RCTs and postmarketing surveillance (PS) protocol design that highlight the relative strengths and weaknesses of each type of study. Randomized clinical trials are generally smaller than PS studies. The patients in RCTs have less exposure to the study drug, particularly when the study drug is a rescue medication or acute treatment. Finally, patient populations in RCTs tend to exhibit less diversity than those in PS studies. Patients frequently excluded from RCTs include children and the elderly, those with coexistent disorders and those using other medications, and those who, for various other reasons, may have an increased risk for an AE. For these reasons, it may not be possible to generalize data from RCTs to all patients who may use the medication. Postmarketing surveillance studies provide certain types of data that are less likely to be captured in RCTs. The diverse patient populations found in PS studies makes it possible to ascertain individual differences in drug efficacy, tolerability, and safety. Owing to the larger

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35

number of patients, rare AEs are more likely to be detected, and because the duration of follow-up can be longer, it may be possible to detect delayed AEs. The value of PS studies lies in their potential for greater external validity, that is, the ability to apply the results of the study to the general population of individuals with the disorder. This is possible because patients included in PS studies are more representative of the general population. These studies provide data on a wider range of patients with respect to demographic characteristics such as age, race, and medical history.

Randomized Controlled Trials vs. Postmarketing Surveillance Studies of Triptans

Factors specific to migraine trials which pose challenges to the external validity of RCTs include the extent of triptan experience and level of migraine-associated disability of the patients included in the trial. For migraineurs, previous experience with triptans appears to be relevant to response to therapy. Patients who have used a particular triptan may be biased in favor of or against that particular triptan, and post hoc analysis is necessary to see if these biases were balanced within and across treatment arms [10]. For example, post hoc analysis of two studies that included sumatriptan-experienced patients observed a higher sumatriptan 2-hour pain-relief rate for sumatriptan-experienced patients compared with sumatriptan-naïve patients [11]. Level of migraine-associated disability is also relevant to the outcome of triptan studies. The Disability in Strategies of Care Study found that patients with more severe headache pain as classified using the Migraine Disability Assessment Scale had a lower rate of response to acute treatment than those with less severe headache pain [12]. Patients who seek or are referred for sophisticated help for migraine from neurologists and/or from headache specialty centers usually have more difficult-to-treat headaches than those who are satisfied with therapy provided by primary care physicians, and it is believed that these two types of patients may respond differently to therapy [10]. The results of a review of nine RCTs that compare an oral triptan and a nontriptan agent for acute migraine therapy highlight how RCT findings do not always agree with real-world clinical experience [13]. Sumatriptan was used in six of the trials, zolmitriptan in two trials, and eletriptan in one trial. Nontriptan comparators included

36

Eur Neurol 2005;53(suppl 1):34–40

ergotamine tartrate plus caffeine, lysine acetyl salicylate plus metoclopromide, tolfenamic acid, diclofenac-potassium, ketoptofen, aspirin plus metoclopromide, isometheptene mucate plus dichloralphenazone plus acetaminophen, and acetyl salicylic acid plus metoclopramide. Outcomes of these clinical trials tended to favor the triptans over the nonspecific agents, and in some cases the differences were significant, however, in contrast to clinical practice experience, differences in outcomes between the two types of agents were not remarkable. The authors of this review of clinical trials of triptans versus nonspecific agents provided four potential explanations for the discrepancy between the RCT results and clinical experience studies, which show the superior efficacy of triptans. Three of these explanations point to study design: (1) the primary outcome of these RCTs, 2hour pain relief, may not be stringent enough to capture the benefits of triptans relative to these other agents; (2) having the patients wait until headache pain is moderate to severe as required in these RCTs may not be optimal for triptan efficacy; (3) these RCTs may have lacked the statistical power to fully distinguish the effects of the two types of agents. The fourth point is regarding patient selection: those receiving triptans in clinical practice may respond more robustly to triptans than to nonspecific agents compared with patients in clinical trials. The first two explanations require further discussion. The first point has already been covered by John Edmeads earlier in this supplement [14]. Two-hour pain relief, the primary endpoint generally used in earlier RCTs may not be the best endpoint to compare acute migraine treatments as it does not represent what patients want from their therapy. Two-hour pain free, sustained pain free (SPF), and SPF with no AEs are better endpoints to use and may have revealed a more dramatic difference between triptans and nontriptans, closer to that seen in clinical experience. The second point, the timing of dosing, has been discussed by Michel Ferrari [15] and Ninan Mathew [16] earlier in this supplement. Post hoc analyses of RCT data from almotriptan studies indicate that dosing when pain is mild was more efficacious than dosing when pain had become moderate or severe [17, 18]. Whereas RCTs generally require patients to wait until their pain is moderate to severe before taking their acute migraine medication, in real-world situations patients are dosing earlier, when the pain is still mild, resulting in higher efficacy rates in PS studies than in RCTs. The requirement to treat moderate to severe headaches in RCTs may have been a disadvantage to the triptans and accounted for smaller ben-

Pascual

% 100

a

ITT

% 100

PP

b 88.0

80

80 70.2

60

60

52.8 46.5

40

40

Fig. 1. Results from the Spanish PS study:

2-hour pain-relief, 2-hour pain-free, and sustained pain-free rates for patients receiving treatment with almotriptan 12.5 mg from neurologists (a) and primary care physicians (b). ITT, intention-to-treat analysis; PP, per protocol analysis; 2-h PR, 2-hour pain relief; 2-h PF, 2-hour pain free; SPF, sustained pain free [19, 20].

29.2 22.9 20

20 65.5

26.6

0

86.6

50.5

44.8

2-h PR

2-h PF PCP study

SPF

0 2-h PR

2-h PF SPF Neurologist study

efit of these agents over nontriptans compared to that seen in clinical experience (or PS) trials. Owing to the diverse medical histories of migraine sufferers who seek therapy in real-world clinical practice settings, a variety of different types of studies and analyses are needed to achieve a complete picture of the efficacy, safety, and tolerability of agents used to treat this disorder. Along with RCTs, other needed data sources include meta-analyses, preference trials, and PS studies.

Spanish and German Postmarketing Surveillance Studies

Two multicenter, open-label observational PS studies of the efficacy and tolerability of almotriptan 12.5 mg in the acute treatment of migraine have been conducted in Spain [19, 20]. The first study recruited patients receiving headache treatment from neurologists, and approximately 1,000 were analyzed for efficacy (intent-to-treat analysis). The second study recruited patients receiving headache therapy from primary care physicians (PCPs), and approximately 2,000 were analyzed for efficacy. With the exception of the recruiting sites, the protocols of the two studies were identical. Comparison of findings from the two studies showed that response rates for 2-hour pain relief, 2-hour pain free and SPF were higher for the patients receiving treatment from the PCPs than those treated by the neurologists (fig. 1) [19, 20]. These results suggest that the patients re-

Almotriptan in Postmarketing Surveillance Studies

18.6

ceiving therapy from the neurologists are more difficult to treat than those who are seen by the PCPs. Yet in spite of this status, greater than 70% of patients treated by neurologists achieved 2-hour pain relief. Comparison of response rates according to severity of pain at dosing shows consistently better outcomes for 2-hour pain relief, 2hour pain free, and SPF when almotriptan was taken when headache pain was mild compared with dosing when pain was moderate/severe (fig. 2) [19, 20]. The overall incidence of AEs was 3.9% in the neurologist study and 1.1% in the PCP study. The incidence of AEs per migraine attack was 2.0% in the neurologist study and 0.8% in the PCP study. Most AEs were mild to moderate in intensity. The most common AEs were somnolence (0.9%), nausea (0.8%), and dizziness (0.7%) in the neurologist study and nausea (0.4%), abdominal pain (0.2%), and somnolence (0.2%) in the PCP study. The German PS study was a multicenter (1300 sites), open-label observational study that included almost 900 patients receiving almotriptan 12.5 mg for the acute treatment of migraine from neurologists and PCPs [21, 22]. Data were analyzed from 12,000 attacks (1–3 attacks per patient). Figure 3 depicts 2-hour pain relief and 2-hour pain free rates according to severity of headache pain at dosing. Most patients achieved pain relief at 2 h regardless of severity of headache pain. Two-hour pain-free rates differed according to baseline headache severity: the 89.3% rate for patients dosing when pain was mild was particularly impressive, especially compared with that for pa-

Eur Neurol 2005;53(suppl 1):34–40

37

ITT

PP

a

80

80

b

65.4 55.2

60

SPF (%)

2-h PF (%)

60

40

40

26.2 20.4 20

20 59.7

43.9

23.3

16.1

0

0

Mild Mod/severe Pain intensity at baseline

Mild Mod/severe Pain intensity at baseline

c

100

100

d

83.9

Fig. 2. Findings from the Spanish PS studies: 2-hour pain-free and SPF rates among patients receiving almotriptan 12.5 mg from neurologists (a, b) and primary care physicians (c, d) according to headache intensity at time of dosing. ITT, intention-totreat analysis; PP, per protocol analysis; 2-h PF, 2-hour pain free; SPF, sustained pain free [19, 20].

80

60

SPF (%)

2-h PF (%)

80

50.8

40

20

73.7

60 44.9 40

20 80.5

48.5

70.9

0

43.0

0 Mild Mod/severe Pain intensity at baseline

100

a 96.3

Mild Mod/severe Pain intensity at baseline

100 b

89.3

84.5 80

74.0 2-h PF (%)

2-h PR (%)

80

60

40

60

55.3 41.5

40 22.1 20

20

Fig. 3. Findings from the German PS study: 2-hour pain-relief and 2-hour pain-free rates according to headache pain intensity at time of dosing with almotriptan 12.5 mg. 2-h PR, 2-hour pain relief; 2-h PF, 2-hour pain free [21].

38

Eur Neurol 2005;53(suppl 1):34–40

0

0 Moderate

Severe All attacks

Mild

Pain intensity at baseline

Moderate

Severe All attacks

Pain intensity at baseline

Pascual

a

Sufficient

b

Sufficient Insufficient

Insufficient

32.3% good 37.3% good

50.3% very good

Tolerability

Efficacy

c

64% very good

d

Sufficient Insufficient

Worse Not reported

13% Unchanged

Fig. 4. Global assessments from the Ger-

33.8% satisfied

man PS study: Physicians’ global assessment of efficacy (a) and tolerability (b) of almotriptan 12.5 mg; patients’ satisfaction with treatment using almotriptan 12.5 mg (c); physicians’ assessment of patients’ satisfaction with almotriptan 12.5 mg (d) [22].

54.7% very satisfied 80.3% better

Patient satisfaction

Physician assessment

tients with headache of moderate (55.3%) and severe (22.1%) intensity [21]. Analysis of the emergence of severe pain and migraine-associated symptoms (nausea, vomiting, and photophobia) during three successive attacks showed that the proportion of patients experiencing these symptoms decreased from attack 1 to 2 to 3. This finding suggests that the patients learned to treat their migraines earlier in the progression of the attack. Global assessments were also obtained in the German PS study (fig. 4) [22]. Physicians rated the efficacy and tolerability of almotriptan highly, with 88% rating efficacy as very good or good and 96% rating tolerability as very good or good. Most patients held favorable views of almotriptan therapy, with 88% being very satisfied or satisfied. Physicians’ perceptions of patient satisfaction were in agreement with patient’s reports, with greater than 80% reporting that patients were satisfied with their treatment.

A total of 29 AEs were reported for the 2,131 attacks included in the study; this corresponds to an incidence of 1.1% of patients reporting an AE. Adverse events reported by 10.1% of patients were fatigue (0.3%) and nausea (0.2%). Chest tightness occurred in 0.1% of patients.

Almotriptan in Postmarketing Surveillance Studies

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Conclusion

High-quality RCTs are considered the most reliable source of unbiased data for medical therapies. However, a variety of different types of studies and analyses are needed to get a complete picture of the efficacy, safety, and tolerability of drugs, including meta-analyses, preference trials, and PS studies. Valuable data that is not readily attainable in RCTs can be obtained from PS studies. Because there are fewer restrictions on the number and type of patients enrolled, PS study patient populations are more diverse and more representative of those who

39

use the medication in routine clinical practice than RCT patient populations. The results of the Spanish and German PS studies demonstrated that the high levels of efficacy (indicated by 2-hour pain-free and SPF rates) and tolerability of almotriptan in the acute treatment of migraine observed in RCTs could be achieved and even surpassed in routine clinical practice. The Spanish studies observed this efficacy and tolerability in patients treated

by PCPs and the more difficult-to-treat patients seen in neurology practices. Both the Spanish and German study results indicated that early intervention with almotriptan when headache pain is mild was associated with improved outcomes, consistent with retrospective analyses of data from clinical trials [17, 18]. In conclusion, almotriptan has been shown to be highly efficacious and well tolerated in both RCT and real-world PS study settings.

References 1 Breslau N, Rasmussen BK: The impact of migraine: Epidemiology, risk factors, and co-morbidities. Neurology 2001; 56:S4–S12. 2 Lipton RB, Stewart WF: Migraine headaches: Epidemiology and comorbidity. Clin Neurosci 1998;5:2–9. 3 Breslau N, Merikangas K, Bowden CL: Comorbidity of migraine and major affective disorders. Neurology 1994;44:S17–S22. 4 Joish VV, Cady P, Bennett D, Harris R: An epidemiological case-control study of migraine and its associated comorbid conditions. Ann Epidemiol 2000;10:460. 5 Shechter AL, Lipton RB, Silberstein SD. Migraine comorbidity; in: Silberstein SD, Lipton RD, Dalessio DJ (eds): Wolff’s Headache and Other Headache Pain. New York, Oxford University Press, 2001, pp 108–118. 6 Tfelt-Hansen P, De Vries P, Saxena PR: Triptans in migraine: A comparative review of pharmacology, pharmacokinetics and efficacy. Drugs 2000;60:1259–1287. 7 Dodick DW, Martin VT, Smith T, Silberstein S: Cardiovascular tolerability and safety of triptans: A review of clinical data. Headache 2004; 44(Suppl 1):S20–30. 8 Dodick D, Martin V: Triptans and CNS sideeffects: Pharmacokinetic and metabolic mechanisms. Cephalalgia 2004;24:417–424.

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9 Levels of evidence in AFP. American Academy of Family Physicians. Available at: http:// www.aafp.org/x17444.xml. Accessed September 26, 2004. 10 Lipton RB: Studying the migraine studies: Methodological issues in comparative trials of acute medications. Am J Clin Proc 2001;1:51– 57. 11 Tfelt-Hansen P, Goldstein J, Malbecq W, Lines C: Comparison of rizatriptan and sumatriptan: A reply to O’Quinn et al. Headache 1999;39: 340–341. 12 Lipton RB, Stewart WF, Stone AM, Lainez MJ, Sawyer JP: Stratified care vs step care strategies for migraine: The disability in strategies of care (DISC) study: A randomized trial. JAMA 2000;284:2599–2605. 13 Lipton RB, Bigal ME, Goadsby PJ: Doubleblind clinical trials of oral triptans vs other classes of acute migraine medication – a review. Cephalalgia 2004; 24:321–332. 14 Edmeads J: Defining response in migraine: which endpoints are important? Eur Neurol 2005;53(suppl 1):22–28. 15 Ferrari MD: Should we advise patients to treat migraine attacks early: methodological issues. Eur Neurol 2005;53(suppl 1):17–21.

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16 Mathew NT: Efficacy and tolerability of almotriptan in controlled clinical trials. Eur Neurol 2005;53(suppl 1):29–33. 17 Pascual J, Cabarrocas X: Within-patient early versus delayed treatment of migraine attacks with almotriptan: The sooner the better. Headache 2002;42: 28–31. 18 Mathew NT: Early intervention with almotriptan improves sustained pain-free response in acute migraine. Headache 2003; 43: 1075– 1079. 19 Pascual J, Lainez JM, Leira R, Titus F, Mateos V, Galvan J: [almotriptan in the treatment of migraine attacks in clinical practice: Results of the TEA 2000 observational study]. Neurologia 2003; 18:7–17. 20 Pascual J, Tranche S, Leira R, Lainez JM, Mateos V, Galvan J: Almotriptan in clinical practice: Experience in primary care vs. neurology setting. Headache 2003;43: 525. 21 Diener HC: Consistency of almotriptan 12.5 mg tablets across multiple migraine attacks when used in routine clinical settings in Germany. Headache 2004;44:471. 22 Diener HC: Satisfaction with almotriptan 12.5 mg for treating multiple migraine attacks: An observational study in routine clinical settings in Germany. Headache 2004; 44: 470– 471.

Pascual

Eur Neurol 2005;53(suppl 1):41–48 DOI: 10.1159/000085061

Published online: May 3, 2005

Preprint from Headache, July, 2005. Online April, 2005.

Almotriptan in Migraine Patients Who Respond Poorly to Oral Sumatriptan: A Double-Blind, Randomized Trial Hans-Christoph Dienera Astrid Gendollaa Irmingard Gebertb Manfred Benekeb a

Department of Neurology, University Essen, and b Bayer HealthCare, Leverkusen, Germany

Key Words Almotriptan
Migraine
Nonresponder
Sumatriptan
Switch

Abstract Objective: To investigate the efficacy and tolerability of almotriptan 12.5 mg in migraine patients who respond poorly to sumatriptan 50 mg. Background: Poor response to sumatriptan therapy for acute migraine attacks has been documented in the literature, but few controlled trials have investigated the efficacy of an alternative triptan in this subgroup of patients. Methods: Patients with an International Headache Society diagnosis of migraine who self-described as experiencing at least two unsatisfactory responses to sumatriptan treated their first migraine attack with open-label sumatriptan 50 mg. Patients who did not achieve 2-hour pain relief (improvement of headache from moderate/severe to mild/no headache) were then randomized to treat their second attack with almotriptan 12.5 mg or placebo under double-blind conditions. Results: In the first attack, 221 of 302 participants (73%) did not achieve 2hour pain relief with sumatriptan and were randomized to treatment of their second attack with almotriptan 12.5 mg or placebo. Of the 198 sumatriptan nonre-

© 2005 S. Karger AG, Basel 0014–3022/05/0535–0041$22.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

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sponders who treated their second attack (99 almotriptan; 99 placebo), 70% had severe headache pain at baseline. Two-hour pain-relief rates were significantly higher with almotriptan compared to placebo (47.5 vs. 23.2%; p ! 0.001). A significant treatment effect for almotriptan was also seen in pain-free rates at 2 h (33.3 vs. 14.1%; p ! 0.005) and sustained freedom from pain (20.9 vs. 9.0%; p ! 0.05). In the second attack, 7.1% of patients in the almotriptan group experienced adverse events compared to 5.1% in the placebo group (p = 0.77). Conclusions: Almotriptan 12.5 mg is an effective and well-tolerated alternative for patients who respond poorly to sumatriptan 50 mg. A poor response to one triptan does not predict a poor response to other agents in that class. Copyright © 2005 S. Karger AG, Basel

Introduction

Migraine is a chronic, disabling disorder affecting approximately 300 million individuals worldwide [1]. Triptans (5-HT1B/1D receptor agonists) are effective and generally well-tolerated agents for acute migraine therapy [2–4], and are recommended by the American Academy of Neurology as first-line agents for moderate to severe

Dr. Hans-Christoph Diener, MD, PhD Department of Neurology, University Essen Hufelandstrasse 55 DE–45122 Essen (Germany) Tel. +49 201 723 2460, Fax +49 201 723 5901, E-Mail [email protected]

Sumatriptan responders n = 57

Almotriptan 12.5 mg

Fig. 1. Patient disposition. ITT pop = in-

tent-to-treat population, any patient with baseline and postrandomization efficacy criteria for the primary variable and who was randomized and treated with test medication for Attack 2; PP addl = per protocol sample excluding any patient taking the second dose of study drug within 2 h of the first dose; PP pop = PP population, excluded those patients presenting serious violations of the protocol.

Enrolled patients

Received sumatriptan 50mg

Sumatriptan nonresponders

n = 302

n = 221

n = 328

migraine headaches or headaches of any severity when nonspecific medications did not provide adequate relief in the past [5]. Although direct head-to-head trials have not been performed between all seven available triptans, a meta-analysis of 53 trials of oral triptans, involving more than 24,000 patients, found clinically meaningful differences in efficacy and side effects among the triptans across a range of treatment attributes [3]. Migraine patients represent a heterogeneous population, and response to a triptan cannot be predicted in any individual [6]. Clinical trials of sumatriptan, the first triptan to be developed, have shown that between 50 and 68% of patients respond to treatment, as measured by the 2-hour pain-relief variable [7, 8]. Typically, in a single attack, at least 50% of migraine sufferers respond to at least one of the triptans; however, 30–40% do not [9]. Within an individual, responsiveness to a particular triptan is likely to be consistent from attack to attack [10]. However, lack of response to one triptan does not translate to lack of response to another triptan, and in the event of a poor response, switching to an alternative triptan is common in clinical practice. The objective of this study was to evaluate the efficacy and tolerability of almotriptan 12.5 mg in migraine patients shown to be poor responders to sumatriptan 50 mg.

Patients and Methods Ethical Conduct The trial was conducted according to the declaration of Helsinki, local laws, and regulations and was approved by independent ethics committees. Patients gave their written informed consent to participate.

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Others not randomized

Attack 1

n = 24

n = 108

Placebo n = 113

Attack 2

Received almotriptan ITT pop = 99 PP pop = 93 PP addl = 71

Received placebo ITT pop = 99 PP pop = 94 PP addl = 73

Study Population This study, conducted in 60 outpatient centers in Germany, recruited adults aged 18 to 65 years who had suffered from migraine with or without aura (International Headache Society categories 1.1 or 1.2) for at least 1 year, and had experienced unsatisfactory responses to sumatriptan on at least two occasions. All patients must have experienced at least one moderate or severe migraine attack in each of the 2 months preceding study entry. Female patients were required to be adequately protected against pregnancy. Patients with a complex form of migraine, a history of tension-type headache at least 15 days per month, or an inability to distinguish migraine from nonmigraine headaches were excluded. Other exclusion criteria included ischemic heart disease (myocardial infarction, angina pectoris, documented silent ischemia, Prinzmetal angina), severe hypertension, or mild to moderate uncontrolled hypertension, pregnancy or breastfeeding, history of migraine medication abuse, allergy or sensitivity to sulfonamides or triptans, and concurrent physical or psychiatric illness. Concurrent use of monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, other triptans, lithium, or other investigational drugs was not allowed during the study. Patients were permitted to continue prophylactic migraine medications. Ergotcontaining medications were not permitted within 24 h before or 6 h after the study medication. Study Design At Visit 1, inclusion and exclusion criteria were reviewed to determine patients’ eligibility. Eligible patients were given one dose of oral sumatriptan 50 mg, the more commonly used sumatriptan dosage form in Europe [11] and the United States, with efficacy equivalent to sumatriptan 100 mg [3], and instructed to take the medication for the next migraine attack that resulted in moderate or severe pain. This first migraine attack was referred to as ‘Attack 1’ and treatment was on an open-label basis (fig. 1). Patients were provided with diaries and asked to document: when treatment was administered; pain intensity before and 0.5, 1, and 2 h after treatment (using a four-point scoring system where 0 = no pain, 1 = mild pain, 2 = moderate pain, and 3 = severe pain) for Attack 1; adverse events; and use of concomitant medication within 24 h of study medication.

Diener/Gendolla/Gebert/Beneke

At Visit 2 (1–7 days after treatment of Attack 1), the response to sumatriptan 50 mg was evaluated by reviewing the diary cards. Nonresponse was defined as moderate or severe pain persisting 2 h after drug intake. Responders were excluded from further involvement in the study. Nonresponders were reassessed against the inclusion and exclusion criteria, and those eligible to continue were allocated a number in ascending order. This code was used to randomly and equally assign them to receive, under double-blind conditions, two oral doses of either almotriptan 12.5 mg or placebo for treatment of their next migraine attack, ‘Attack 2.’ Patients were instructed to take the first dose of study medication as soon as possible (i.e., within 1 h after onset of the headache phase of the migraine attack) for the next attack that resulted in moderate or severe pain. Patients were permitted to take the second dose if they had initially responded to the first dose, but the pain reappeared within 2–24 h. Escape medication was permitted if pain remained moderate or severe 2 h after the administration of study medication. The form of escape medication was chosen by the investigator, according to patient characteristics and preferences; however, neither ergot derivatives nor triptans were permitted. Patients were provided with new diaries to record: treatment administration; pain intensity before and 0.5, 1, and 2 h after medication; adverse events; and use of concomitant or escape medication within 24 h of study treatment. At Visit 3 (1–7 days after treatment of Attack 2), diaries documenting the patients’ responses to treatment of Attack 2 were collected. Outcome Measures Efficacy The primary efficacy variable was pain relief at 2 h after doubleblind treatment of Attack 2. As with the assessment of response for Attack 1, response was defined as conversion from moderate or severe pain to mild or no pain (score of 2 or 3 reducing to 1 or 0). Patients with irregular drug ingestion (ie, taking a second dose of medication without a rebound attack, concomitant medication within 2 h of study medication) and those with no reported relief within 2 h after administration of study medication were classified as nonresponders. Secondary efficacy endpoints for Attack 2 included pain-free efficacy at 2 h (score of 2 or 3 reducing to 0); sustained pain-free efficacy (i.e., pain free at 2 h after taking medication with no recurrence of moderate or severe headache and no rescue headache medication 2–24 h postdose); and use of rescue medication within 24 h. Safety and Tolerability Laboratory evaluations (hematology and blood chemistry) and a standard EKG were carried out at Visit 1. Physical examination and an assessment of vital signs (blood pressure and heart rate) were undertaken at each visit. Medical history was taken at all visits, with Visits 2 and 3 recording incidence of adverse events (noting the seriousness, intensity, and relationship to study drug) and use of concomitant medication since the previous visit. Power Calculation and Statistical Analysis The primary efficacy endpoint was headache response 2 h after administration of study medication (almotriptan 12.5 mg or placebo). Assuming a 65% response rate for almotriptan 12.5 mg and a 40% response rate for placebo, 92 patients were required in each

Almotriptan in Patients Who Respond Poorly to Sumatriptan

treatment group (almotriptan and placebo) in order to analyze the primary endpoint with at least 90% power to detect a difference between almotriptan and placebo on a two-sided test at the 0.05 level of significance. The same test would have 97% power to detect a difference if the actual responder rates were 60 and 30% for almotriptan and placebo, respectively. The proportion of nonresponders to sumatriptan 50 mg was not known at the start of the study. However, assuming a response rate of 35%, it was estimated that 526 patients were required for enrollment to obtain the required number of patients to be treated for Attack 2. The statistical method for primary endpoint analysis was Fisher’s exact test. Efficacy evaluation was based on the last observation carried forward method of pain scores for headache relief at 2 h (pain score 0 or 1 from 2 or 3) of the intent-to-treat (ITT) population. The ITT population for the evaluation of the primary endpoint was composed of any patient with baseline and postrandomization efficacy criteria for the primary variable and who was randomized and treated with test medication for Attack 2. A per protocol analysis of the primary efficacy endpoint excluded those patients presenting serious violations of the protocol. An additional primary endpoint analysis was carried out on the per protocol sample excluding any patient taking the second dose of study drug within 2 h of the first dose. Evaluation of secondary endpoints was restricted to the ITT population. Safety and tolerability analyses were carried out on all patients taking at least one dose of study medication (sumatriptan, almotriptan, or placebo) and providing follow-up data. The incidence of adverse events was summarized descriptively and categorized by body system (COSTART). The analysis of adverse events included two study periods: prerandomization (Attack 1 treated with sumatriptan 50 mg) and postrandomization (Attack 2 treated with almotriptan 12.5 mg or placebo). Fisher’s exact test was used to explore any difference among the three treatment groups, although this test was not sufficiently powered to identify statistically significant treatment differences.

Results

Patients A total of 328 patients were enrolled into the study; 26 patients were subsequently withdrawn before taking any medication due to protocol violations. Of the remaining 302 patients treated with sumatriptan 50 mg for Attack 1 (fig. 1), 221 (73%) did not respond to sumatriptan (i.e., they still had moderate or severe pain at 2 h) and were, therefore, considered for inclusion in the double-blind comparison of almotriptan and placebo. Of the 81 patients not randomized, 57 were sumatriptan responders (achieved 2-hour pain relief); reasons for nonrandomization of the remaining patients included loss to follow-up, withdrawal from study, protocol violations, and withdrawal of consent. A total of 221 patients were randomized to doubleblind treatment with almotriptan 12.5 mg (n = 108) or

Eur Neurol 2005;53(suppl 1):41–48

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Table 1. Patient demographics at

baselinea

Characteristics

Sumatriptan 50 mg

n 81 Age, years Mean (SD) 41.1 (14.2) Range 19–81 Sex, n (%) Male 11 (13.6) Female 70 (86.4) Race, n (%) White 81 (100) Asian 0 Height, cm, mean (range) 169 (148–186) Weight, kg, mean (range) 71.5 (45–124) Years with migraine attacks Mean (SD) 16.1 (11.8) Range 0–49 Baseline headache intensity, n (%)b Severe Moderate

Almotriptan 12.5 mg

Placebo

108

113

41.1 (11.4) 19–65

41.4 (12.0) 19–69

13 (12.0) 95 (88.0)

16 (14.2) 97 (85.8)

107 (99.1) 1 (0.9) 167.6 (150–190) 70.6 (45–115)

112 (99.1) 1 (0.9) 168.1 (148–189) 70.4 (49–120)

16.8 (11.4) 0–47

18.2 (13.4) 0–56

69 (69.7%) 30 (30.3%)

71 (71.7%) 28 (28.3%)

a

Demographics of 302 patients in total: 81 who received only sumatriptan and were not randomized; 108 who received sumatriptan and were randomized to almotriptan; and 113 who received sumatriptan and were randomized to placebo. b Based on 99 patients in the almotriptan group and 99 patients in the placebo group who received study medication.

placebo (n = 113), but 23 patients did not receive doubleblind study medication (9 almotriptan, 14 placebo) for reasons including missing or invalid data, violation of protocol, and no second migraine attack. A total of 198 patients who did not achieve 2-hour pain relief with sumatriptan in Attack 1 received almotriptan 12.5 mg or placebo for treatment of Attack 2 (99 in each group). The safety population was composed of 302 patients in total: 81 who received only sumatriptan and were not randomized, 108 who received sumatriptan and were randomized to almotriptan, and 113 who received sumatriptan and were randomized to placebo. The baseline characteristics of the patients were similar among the treatment groups (table 1). The mean age was 41 years and the patients were predominantly white and female. Approximately 70% of randomized patients treating their headache in Attack 2 with almotriptan 12.5 mg or placebo had severe pain at baseline. Primary Efficacy Endpoint: Response Rates in Sumatriptan Nonresponders In Attack 2, 47.5% of patients who did not respond to treatment of their prerandomization migraine attack

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Eur Neurol 2005;53(suppl 1):41–48

with sumatriptan 50 mg achieved pain relief at 2 h after treatment with almotriptan 12.5 mg. The headache response rate associated with almotriptan treatment was significantly higher than with placebo (23.2%) on an ITT basis (fig. 2). The per protocol analyses confirmed this significant treatment response. Pain relief rates at 2 h were significantly higher with almotriptan compared with placebo in the standard per protocol analysis, excluding serious protocol violators (47.3 vs. 24.5%; p = 0.001), and in the additional per protocol analysis, which also excluded patients taking a second dose of study drug within 2 h of taking the first dose (60.6 vs. 31.5%; p ! 0.001). Secondary Efficacy Endpoints A favorable response to almotriptan was also demonstrated in the secondary measures of efficacy in this group of patients who previously failed to achieve 2-hour pain relief with sumatriptan. A significantly greater number of patients treated with almotriptan 12.5 mg achieved painfree status at 2 h, compared with placebo (33.3 vs. 14.1%, p ! 0.005) (fig. 3). Furthermore, almotriptan provided significantly better sustained pain-free efficacy than pla-

Diener/Gendolla/Gebert/Beneke

47.5✽

50

Placebo

30

30

25

Patients (%)

Patients (%)

40

23.2

20 10

Almotriptan 12.5 mg Pain relief at 2 h

Placebo < 0.001

20.9✝

20 14.1

15

9

10 5

0 ✽p

Almotriptan 12.5 mg 33.3✽

35

0 Pain free at 2 h ✽p

Sustained pain free

< 0.005; ✝p < 0.05

Fig. 2. Rates of pain relief at 2 h with almotriptan versus placebo in sumatriptan nonresponders. Pain relief defined as proportion of patients converting from moderate or severe to mild or no pain at 2 h after taking medication (intent-to-treat population).

Fig. 3. Efficacy of almotriptan versus placebo in sumatriptan non-

Table 2. Number and type of adverse events

cebo (20.9 vs. 9.0%, respectively; p ! 0.05) (fig. 3). Significantly fewer patients in the almotriptan group required rescue medication, compared with the placebo group (26.6 vs. 46.9%; p ! 0.005).

in Attack 2 Related to treatment Almotriptan 12.5 mg (n = 99) Seven TEAEs reported by 7 patients Bitter taste Yes Chest tightness Yes Feeling of warmth Yes Pain in muscles Yes Pruritus, face Yes Cystitis No Weakness No Placebo (n = 99) Nine TEAEs reported by 5 patients Dizziness Yes Giddiness Yes Nausea (n = 2) Yes Nervousness Yes Trembling Yes Desire to urinate No Flickering eyes No Tiredness No TEAE = treatment-emergent adverse events.

Almotriptan in Patients Who Respond Poorly to Sumatriptan

responders. Pain free defined as proportion of patients converting from moderate or severe to no pain at 2 h after taking medication. Sustained pain free defined as pain free at 2 h after taking medication with no recurrence of moderate or severe headache and no rescue headache medication 2–24 h postdose (intent-to-treat population).

Safety and Tolerability After treatment of Attack 1 with sumatriptan 50 mg, 49 of 302 patients (16.2%) reported 70 treatment-emergent adverse events. The most commonly reported adverse events associated with sumatriptan were dizziness and nausea. For Attack 2, the proportion of patients with treatment-emergent adverse events in the almotriptan group was not statistically different from that in the placebo group (7.1 vs. 5.1%, respectively, p = 0.77). Seven treatment-emergent adverse events were reported by 7/99 patients receiving almotriptan and nine treatment-emergent adverse events were reported by 5/99 patients receiving placebo (table 2). Five treatment-emergent adverse events reported by 5 patients in the almotriptan group were considered related to treatment compared to six treatment-emergent adverse events reported by 3 patients in the placebo group. In all treatment groups, the majority of adverse events reported were of mild to moderate intensity, and transient in nature.

Eur Neurol 2005;53(suppl 1):41–48

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Discussion

While much is known about the efficacy and tolerability of the triptans, and switching triptans in cases of nonresponse is an acknowledged practice, few controlled studies have measured treatment efficacy in patients who have failed to respond to a previous triptan. The inclusion criteria for the double-blind, placebo-controlled study described here required that enrolled patients experienced at least two previous unsatisfactory responses to sumatriptan. The 73% nonresponse rate seen with sumatriptan 50-mg treatment in Attack 1 suggests that this patient inclusion criterion did result in a greater number of individuals who were poor responders to sumatriptan. It also shows that the statement of nonresponse has to be verified in a controlled fashion. The elimination of patients who achieved 2-hour pain relief with sumatriptan in Attack 1 further increased the proportion of nonresponders in the study cohort prior to randomization. The trial demonstrates that almotriptan 12.5 mg is effective in patients who previously did not achieve 2-hour pain relief when treated with sumatriptan 50 mg. In addition to providing 2-hour pain relief to these sumatriptan nonresponders, almotriptan also provides significantly better 2-hour pain-free, and sustained pain-free rates, compared with placebo. The efficacy of almotriptan in the present study is of particular note considering the challenging nature of this population; at baseline, approximately 70% of patients had severe pain intensity. The requirement of no pain relief with sumatriptan in Attack 1 is most likely responsible for this enriched population of patients with severe migraine. Three other studies have investigated the efficacy of switching triptan therapy in patients who were poor responders to sumatriptan [10, 12, 13]. The efficacy of zolmitriptan 5 mg and rizatriptan 10 mg, each taken for five attacks, was investigated in 56 patients with a history of nonresponse to sumatriptan 50 mg in three or more of five previous attacks, using an open-label, crossover design [12]. Nonresponse to sumatriptan was not confirmed prospectively. Favorable painrelief and pain-free rates were seen with both triptan treatments although, due to the small sample size, no statistical conclusions could be drawn. A more recent double-blind, parallel-group study evaluated eletriptan 40 and 80 mg (80-mg arm is not discussed in this article as it is not an approved single dosage in Germany, the United States, and many other countries) versus placebo across three migraine attacks in patients who had ceased treatment with sumatriptan due to unsatisfac-

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tory efficacy or tolerability [13]. It is of interest that only 49% of study participants had described insufficient clinical response as the reason they had stopped taking sumatriptan; 30% had discontinued sumatriptan because of adverse events. Patients were instructed to take the medication as soon as possible after onset of moderate or severe migraine. In the first attack, 59% of patients treated with eletriptan 40 mg achieved pain-relief at 2 h compared with 30% in the placebo group. A limitation of this study is that the design did not include a prerandomization migraine attack to confirm prospectively the lack of 2-hour pain relief with sumatriptan 50 mg. Perhaps because of the less rigorous definition of sumatriptan nonresponder required for entry into this trial, only 30% of the participants were found to have severe headache pain at baseline (compared to 70% in the almotriptan trial described here). In a trial of similar design to the present study, Stark et al. [10] examined the efficacy and tolerability of naratriptan 2.5 mg in patients describing themselves as experiencing an unsatisfactory response to sumatriptan. Of the 347 enrolled patients with moderate or severe migraine prospectively screened for response to sumatriptan 50 mg, 206 did not respond (response defined as reduction from moderate or severe to mild or no pain at 4 h) in the prerandomization phase and were thus included in the randomized, double-blind, placebo-controlled, parallel-group evaluation. Forty-six percent of patients entering the second phase of the trial had severe headache pain at baseline, a level intermediate between the eletriptan (30%) and almotriptan (70%) trials. Naratriptan was associated with a significantly better 2-hour pain-relief rate compared with placebo (25 vs. 10%; p = 0.005); the 2hour pain-free response was not statistically significant compared to placebo (6 vs. 3%). The limitations of the current and previous trials described here are that the designs included either no or only one prospective prerandomization attack to screen out patients who achieved 2-hour pain relief with sumatriptan, the lack of a placebo arm in the trials that did include this screening attack, and the absence of a sumatriptan arm in the randomized attack used to investigate the efficacy of the alternative triptan compared to placebo. Subjecting enrolled patients to treatment of three prerandomization attacks with sumatriptan would have further enriched the randomized population with patients more certain to be sumatriptan nonresponders. The inclusion of a placebo arm in the prerandomization attack would have controlled for patient bias against sumatriptan, which may have led to a higher nonresponder rate. The addition of a sumatriptan arm to the randomized, placebo-controlled attack

Diener/Gendolla/Gebert/Beneke

would also confirm the response to alternative triptans in patients who were consistently nonresponsive to sumatriptan. The design of such a study, however, would require a much larger number of patients to be treated over a longer period of time, and it has been shown that response to a particular triptan is associated with a high rate of intrapatient consistency [14]. In addition, the design of the study described here more closely resembles situations physicians are more likely to encounter in real-world settings. The response rates achieved here with almotriptan cannot be compared directly with those achieved in the trials discussed above [10, 12, 13]. Although all of the trials recruited patients with a history of poor response to sumatriptan, their study designs were different. The almotriptan and naratriptan trials were conducted according to similar protocols (double-blind, placebo-controlled, prerandomization attack to screen out sumatriptan responders), but the zolmitriptan/rizatriptan (open-label, no prerandomization attack) and eletriptan (doubleblind, placebo-controlled, no prerandomization attack) trials followed different protocols. In addition, the baseline pain intensity varied among the attacks from 30% severe in the eletriptan trial [13] to 46% severe in the naratriptan trial [10] and 70% severe in the almotriptan trial described here. Baseline pain intensity was not reported in the zolmitriptan/rizatriptan trial [12]. However, the overall evidence from these trials in patients who responded poorly to sumatriptan reveals that failure to respond to one triptan does not translate to failure to respond to all members of this class. This is not surprising in light of the fact that migraine patients are not all the same, migraine headaches are not all the same, and triptans are not all the same. Patients with migraine are a heterogeneous population, and it may be that the differences among patients and their responses to triptans are at least as important as the differences among the triptans [6, 9]. Clinical trials of oral triptans have shown intrapatient consistency of response with, for example, almotriptan 12.5 mg providing pain relief in at least two attacks in 75% of the patients who treated three attacks [14, 15]. These results suggest that lack of response is also consistent [10]. Triptans vary in their pharmacokinetic properties, such as bioavailability, onset of action, half-life, and drug–drug interactions, and in their tolerability [16–18]. For example, naratriptan has the slowest onset of action of the available triptans, frovatriptan has the longest halflife, and almotriptan has the highest (oral) bioavailability [18]. Almotriptan and naratriptan have the most favorable adverse event profiles [18]. A meta-analysis of dou-

ble-blind studies comparing triptans reported that although all oral triptans are effective and well tolerated, they differ in ways that are clinically significant for individual patients [3]. The authors suggested that trial and error may be needed to find the best therapy, such that if the first triptan fails the patient can be successfully switched to another. They concluded that rizatriptan 10 mg, eletriptan 80 mg, and almotriptan 12.5 mg provide the highest likelihood of consistent success. The results of this trial suggest that when migraine patients present to their physician with a history of poor response to a previous triptan, the physician should switch these patients to a different triptan. To avoid a second triptan failure in this group of patients, who may be more likely to refuse treatment after repeated treatment failures, the physician should select a triptan with a high probability of success, that is, one with excellent efficacy and placebo-like tolerability. Controlled clinical trials and long-term open-label studies have shown almotriptan to have a favorable pharmacokinetic, efficacy, and tolerability profile [19]. The efficacy of almotriptan 12.5 mg is comparable to that of sumatriptan 50 and 100 mg [20, 21], but almotriptan is associated with a placebo-like tolerability [20–23]. When considered together with the results presented here, almotriptan 12.5 mg represents a logical choice for the treatment of migraine sufferers who failed to respond to their previous triptan therapy.

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Conclusions

The data reported here and in other studies suggest that when migraine patients respond poorly to sumatriptan or other triptan treatment, another agent in this class should be attempted. Almotriptan 12.5 mg provides an effective and well-tolerated option for this switch. Acknowledgments Additional participating investigators from Germany include Drs. Arnold (Berlin), Backhaus (Hildesheim), Baudet (Aachen), Beckmann-Reinholdt (Königstein), Derbot (Isselburg), Gendolla (Essen), Gudden (Windach), Husstedt (Münster), Kukowski (Göttingen), Mantwill (Bornheim), Mattern (Bochum), May (Regensburg), Mey (Dortmund), Müller-Schwefe (Göppingen), Nolte (Wiesbaden), Schellenberg (Hüttenberg), Schumann (Bochum), Seifert (Bitterfeld), Siever (Oldenburg), Steinberg (Hamburg), Straube (München), Wassermann (Rimpar), and Wiedeking (Essen). Dr. Diener received grant support from AstraZeneca, GlaxoSmithKline, Johnson & Johnson, Bayer, Pfizer, Allergan, and Böhringer. Funding for this trial was provided by Bayer HealthCare.

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Diener/Gendolla/Gebert/Beneke