Marketed Oral Triptans in the Acute Treatment of Migraine: A Systematic Review on Efficacy and Tolerability

Authors

  • Julio Pascual MD, PhD,

  • Valentin Mateos MD,

  • Carles Roig MD, PhD,

  • Margarita Sanchez-del-Rio MD,

  • Dolores Jiménez MD, PhD


  • From the University Hospital—Neurology, Salamanca, Spain (Dr. Pascual); Hospital General de Asturias, Neurology, Oviedo, Asturias, Spain (Dr. Mateos); Neurology Service, Hospital Sant Pau, Barcelona, Spain (Dr. Roig); Hospital Ruber Internacional—Neurology, Madrid, Spain (Dr. Sanchez-del-Rio); Hospital Virgen del Rocio—Neurology, Sevilla, Spain (Dr. Jiménez).

Address all correspondence to Dr. Julio Pascual, University Hospital—Neurology, Paseo de San Vicente 58-182 Salamanca 37007, Spain.

Abstract

Background.—In the current literature, there is neither a reported systematic review comparing the efficacy of triptans at 30 minutes and 1 hour after the migraine treatment, nor data related to efficacy of new marketed triptans.

Objective.—The main objective of this analysis was to compare the efficacy and tolerability of currently marketed oral, non-reencapsulated triptan formulations vs placebo in the treatment of moderate-to-severe migraine attacks.

Methods.—A systematic review of double-blind, randomized clinical trials reporting data after a single migraine attack was conducted. Efficacy results are shown using relative risk ratios with 95% confidence intervals. A sensitivity analysis was also conducted.

Results.—After reviewing 221 publications, 38 studies were included. All marketed triptans provided significant relief and/or absence of pain at 2 hours, and relief at 1 hour when compared with placebo. After 30 minutes, fast-dissolving sumatriptan 50 and 100 mg, sumatriptan 50 mg, and rizatriptan 10 mg showed significant relief when compared to placebo, whereas the fast-dissolving formulation of sumatriptan 100 mg was the only oral triptan that was superior to placebo in meeting the pain-free endpoint. On the other hand, fast-dissolving sumatriptan 50 and 100 mg and eletriptan 40 mg showed a lower rate of recurrence than placebo, whereas rizatriptan 10 mg was the only triptan with a recurrence rate greater than that of placebo. Adverse events associated with treatment with tablet formulations of sumatriptan and zolmitriptan were significantly more frequent than those of the placebo group.

The inclusion of trials with reencapsulated triptans in the analysis introduced minor specific changes in these results.

Conclusion.—This analysis updates the comparative data available for the 7 currently marketed oral triptans and clearly demonstrates their efficacy when compared to placebo, even with stricter endpoints, such as efficacy at 30 minutes. No triptan exhibited better tolerability than placebo. Results are diverse, depending on the triptan, which probably is a reflection of heterogeneous pharmacokinetics.

Abbreviations: 
NSAIDs

non-steroid anti-inflammatory drugs

RCT

randomized control trial

AEs

adverse events

ITT

intent to treat

RR

relative risk

Migraine is a disorder that affects approximately 15% of the population and adversely influences the quality of life of patients who suffer from it, mostly young or middle-aged women.1 Two pharmacological treatment options exist for migraine: preventive and symptomatic treatment. Symptomatic or acute treatment is necessary for all patients with migraine. The symptomatic treatment options include simple analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), ergotics, and serotonin 5-HT1B/1D receptor agonists (known as “triptans”).2 Except in children or in adult's mild attacks, the effectiveness of simple analgesics is very poor. On the other hand, because of efficacy and tolerability reasons, ergotics are not considered as the standard medication for migrainous patients.3 The symptomatic treatment of migraine lies, therefore, in the wise use of NSAIDs and triptans. In general, NSAIDs are indicated in mild-to-moderate attacks, whereas triptans are the medication of choice in the treatment of moderate-to-severe attacks and in those patients who do not respond to or do not tolerate NSAIDs.2

There are 7 marketed triptans that, despite sharing the same action mechanism (agonism at serotonin 1B/1D receptors), are different in terms of pharmacodynamics and, particularly, in their pharmacokinetic characteristics. Thus, from a theoretical standpoint, the different triptans are expected to exhibit differences regarding their efficacy and tolerability profile. Comparisons among these compounds have generally been conducted by means of comparative trials with sumatriptan, the reference drug within this therapeutic group. Because it is practically impossible to compare all different triptans in the same clinical trial, various systematic reviews have been conducted, wherein data from controlled, randomized trials with these drugs have been analyzed and comparisons between the triptans made.4–8 These reviews are already more than 5 years old, since the authors closed their databases around the year 2000. In the past few years, results have been published for clinical trials performed with the most recently marketed triptan, frovatriptan. Furthermore, new oral formulations have been made available for some of the triptans. Finally, the potential effect of reencapsulation vs non-reencapsulation on the trial results, which has often been the subject of controversy,9 has not been specifically analyzed until now. At least theoretically, encapsulation could, for instance, affect early efficacy time points.

The main objective of this analysis is to compare the efficacy and tolerability of the marketed oral non-reencapsulated triptan formulations (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan) vs placebo in the acute treatment of migraine attacks (severe and/or moderate). This comparison has been performed by a systematic review of double-blind randomized clinical trials (RCTs), which reported data after the first migraine attack. This comparison is the first including data collected in the first hour of the attack as well as data of new marketed triptans.

METHODS

The methodology proposed by the QUOROM Steering Committee10 was followed for this systematic review.

Search Strategy.— The search was conducted using the Pubmed/MEDLINE electronic database and the Cochrane Central Register of Controlled Trials. Furthermore, a search of articles cited in the selected publications was performed. The publication inclusion and exclusion criteria were determined before conducting the search. In order to focus the review on the disorder of interest, the terms acute treatment and migraine were used, limiting the search to the currently marketed triptans.

The search strategy was the following one: (almotriptan OR eletriptan OR frovatriptan OR naratriptan OR rizatriptan OR sumatriptan OR zolmitriptan OR triptan OR triptans) AND (migraine OR migraines) AND (acute treatment OR acute treatments). Limits: All Adult: 19+ years, English, Publication list 2007/02/22, Randomized Controlled Trial, Humans.

Article Selection Criteria.— To be included in the review, an article had to meet the following criteria: (1) describe controlled, double-blind, and RCTs, (2) employ at least 1 single dose of 1 or more of the 7 triptans under consideration, (3) study at least 1 commercially available triptan, (4) study triptans administered orally as tablets or as orally disintegrating formulations, (5) include patients with symptomatic relief of an acute migraine attack, (6) be conducted in adult humans, (7) published in the Pubmed list up until 22 February 2007, (8) be published in English (Fig. 1).

Figure 1.—.

Flow diagram.

Data Analysis.— A pilot study was conducted with 5 selected RCTs in order to decide the data to be extracted in and to design a standardized extraction forms. Four evaluators selected the articles and extracted the data from the original papers. Each article was read, rated, and reviewed by 2 independent evaluators. After reading and reviewing the articles, disagreements were resolved through discussion and the criteria for achieving homogeneity of the data of interest were defined.

Characteristics of the Included Studies.— The studies included were either parallel or crossover with at least 2 arms of active treatment and placebo. Clinical trials with multiple attacks were included, but data were collected for the first attack only, as described in the literature.11,12 Whatever the trial design, parallel or crossover, single or multiple attacks, to avoid data heterogeneity and to homogenize clinical conditions, the trials were only included provided that separate data were available for the first attack treated and for the first treatment administered. On the other hand, in order to evaluate the quality of each clinical trial, the validated Jadad scale was used.13 One point is scored for each positive answer to the 5 following questions: (1) Is the study randomized? (2) Is the study double blinded? (3) Is there a description of withdrawals? (4) Is the randomization adequately described? (5) Is the blindness adequately described? Each trial received a score of 0-5, with higher scores indicating higher quality in the reporting of the study. According to the inclusion criteria, the articles included in this review are RCTs, and all have a minimum value of 2 in the Jadad scale. The patients in the included clinical trials were adults over 18 years of age who presented with a moderate and/or severe acute migraine attack, with or without aura and had been diagnosed according to the International Headache Society (IHS).14 Only full publications with detailed data from at least one of the outcomes were considered. The doses for analysis were selected following the recommendations for clinical practice found in the Summary of Product Characteristics of each commercially available triptan.

Efficacy and Tolerability Assessment Endpoints.— The selected endpoints follow the recommendations of the Cochrane Foundation reviews as relevant, reliable criteria for measuring migrainous manifestations.15 Furthermore, these criteria are defined in the same way by the IHS for clinical trials on migraines,16 with the exception of recurrence, which is assessed, in the present review, using the broader definitions contained in the papers selected. The efficacy endpoints assessed were pain relief (“response”) and pain free at half an hour (30 minutes), at 1 hour and at 2 hours following administration of the treatment. Recurrence representing the reappearance of moderate-to-severe pain before 24 hours elapsed since response at 2 hours was obtained. Also included are those studies that only record a recurrence 24 hours after having obtained a response at 4 hours (this difference will be addressed in the sensitivity analysis, Table 4).

Table 4.—.  Results of the Sensitivity Analysis for Recurrence, Including Only Those Articles That Contain 2-24-Hour Recurrence, Based on the Relative Risk, RR
 2-24 Hour Recurrence
NeNpRR (CI)
  1. Ne = number of articles included in the systematic review's comparison group for each variable; Np = total population studied in each comparison; NA = not applicable; RR = relative risk.

  2. *Statistical significance P < .05.

Sumatriptan 50 mg tablets vs placebo, 2-24-h recurrence12220.88 (0.59, 1.32)
Sumatriptan 100 mg tablets vs placebo, 2-24-h recurrence26311.39 (0.91, 2.11)
Naratriptan 2.5 mg tablets vs placebo, 2-24-h recurrence11270.85 (0.39, 1.87)
Frovatriptan 2.5 mg tablets vs placebo, 2-24-h recurrence1 781.25 (0.47, 3.30)

Overall number of patients experiencing an adverse event (AE), when available, was the endpoint used in order to calculate the relative risks (RR) to assess tolerability. The published categorized incidence of specific AEs was not included in the analysis because there is a significant variability depending on the frequency of their occurrence, which leads to a significant publication bias. Moreover, there is no common criterion for the definition of the AEs in the different studies, which makes it difficult to classify them according to identical or similar terms.

Statistical Analysis.— In this systematic review, an analysis using the efficacy and tolerability endpoints described above was conducted comparing the various oral, non-reencapsulated formulations of triptans to placebo. The studied population is defined by the intent-to-treat (ITT) population, the most common data set employed in the clinical trials under analysis. This population represents those randomized patients who suffered a migraine attack and received active treatment or a placebo. The computer program Review Manager 4.2.9 (SMRKSoft) was used to aggregate data and to perform the analysis. A chi-square was performed to test heterogeneity. In order to conduct this analysis, a random-effects model was selected, being the more restrictive in the determination of the CI. No confounding variables were included as covariates. All the data were aggregated using multiplicative models based on the RR ratio, with 95% confidence intervals (RR, 95% CI).17 If the treatment makes no difference to the rate of events, the RR is 1. Beneficial interventions, except in the case of the recurrence outcome, will have an RR greater than 1. When CI of RR crosses unity, there was no significant difference in the rate of outcomes between treatment and placebo groups.

The robustness of the comparisons was assessed using a sensitivity analysis; the following subgroups were considered:

  • 1Methodological quality of the RCTs (publications with a 2 or 3 Jadad score vs the publications with a 4 or 5 Jadad score). A publication was considered to be of poor quality when the score is 2 or 3 points and of good quality when it is 4 or 5 points;
  • 2Analysis of recurrence for each of the definitions used in the included clinical trials (2-24 h recurrence vs 2-24 h and 4-24 h recurrence);
  • 3Analysis of nonmarketed reencapsulated forms of triptans, generally used to ensure double-blind conditions of the clinical trials.

The statistical methodology used to aggregate the data of the sensitivity analysis was a multiplicative model based on the RR ratio, with 95% confidence intervals (RR, 95% CI).17

RESULTS

Study Selection Flow Diagram.— A total of 221 publication abstracts were reviewed and, as a result, 106 publications were initially discarded. From this publications 45 were excluded to deal with nonoral triptans, 23 not to deal with adequate outcome, 10 to deal with other disease than an acute migraine attack, 8 not to use a placebo arm, 11 not to deal with one of the 7 triptans of interest, 5 to be open label, 2 to deal with no adequate population, 1 not to deal only with first attack data, and another one not to be a full publication. Following a complete, detailed reading of the remaining 115 articles, 3818–54 studies were then chosen to be included in the review and 3 additional ones in the sensitivity analysis. The remaining 74 articles were eliminated following the reasons detailed in the flow diagram (Fig. 1).

Characteristics of the Study.— Thirteen comparisons among placebo groups were made, using 8 different efficacy and tolerability endpoints on the basis of triptan, dose, and drug formulations. The summary of the reviewed papers is shown in Table 1. Figure 2A-C shows the graphs based on the RR. In order to homogenize the results obtained from the different studies (crossover/parallel, multiple/single-attack treatments, etc.), we have only included the efficacy data on the first attack with only the first treatment.

Table 1.—.  Articles Included in the Review: Quality of the Article, Intervention, and Type of Oral Presentation
ArticlesJadadIntervention, Dose, and ITT*Formulations
  1. *Intervention, dose, and ITT of the branches studied in the systematic review (ITT as defined in Methods).

Ahrens184Placebo (N = 185),* rizatriptan 10 mg (N = 188),* rizatriptan 5 mg (N = 182)Orally disintegrating tablets (ODT)
Bomhof194Placebo (N = 107),* rizatriptan 10 mg (N = 201),* naratriptan 2.5 mg (N = 214)*Tablets (T)
Carpay204Placebo (N = 153),* sumatriptan 100 mg (N = 142),* sumatriptan 50 mg (N = 137)*Fast release/rapid disintegrating tablets (FR)
Cutler213Placebo (N = 65),* sumatriptan 100 mg (N = 66),* sumatriptan 50 mg (N = 62),* sumatriptan 25 mg (N = 66)Tablets (T)
Dahlof225Placebo (N = 99),* zolmitriptan 5 mg (N = 213),* zolmitriptan 10 mg (N = 214), zolmitriptan 15 mg (N = 215), zolmitriptan 20 mg (N = 209)Tablets (T)
Dahlof234Placebo (N = 80),* almotriptan 2 mg (N = 170), almotriptan 6.25 mg (N = 167), almotriptan 12.5 (N = 164),* almotriptan 25 mg (N = 161)Tablets (T)
Diener245Placebo (N = 106),* eletriptan 40 mg (N = 210),* eletriptan 80 mg (N = 214), cafergot (N = 203)Tablets (T)
Dowson255Placebo (N = 240),* zolmitriptan 2.5 mg (N = 231)*Orally disintegrating tablets (ODT)
Elkind263Placebo (N = 38),* frovatriptan 2.5 mg (N = 37)*Tablets (T)
Garcia-Ramos274Placebo (N = 92),* eletriptan 40 mg (N = 192),* naratriptan 2.5 mg in capsules (N = 199)Tablets (T)
Geraud285Placebo (N = 56),* sumatriptan 100 mg (N = 504),* zolmitriptan 5 mg (N = 498)*Tablets (T)
Gijsmant293Placebo (N = 67),* rizatriptan 10 mg (N = 145),* rizatriptan 5 mg (N = 130), rizatriptan 2.5 mg (N = 75)Tablets (T)
Goadsby305Placebo (N = 142),* sumatriptan 100 mg in capsules (N = 129), eletriptan 20 mg (N = 144), eletriptan 40 mg (N = 136),* eletriptan 80 mg (N = 141)*Tablets (T)
Goldstein313Placebo (N = 142),* rizatriptan 10 mg (N = 294),* rizatriptan 5 mg (N = 294), sumatriptan 25 mg (N = 297), sumatriptan 50 mg (N = 291)*Tablets (T)
Goldstein323Placebo (N = 118),* frovatriptan 2.5 mg (N = 126)*Tablets (T)
Kaniecki333Placebo (N = 127),* sumatriptan 100 mg (N = 131)*Tablets (T)
Klassen343Placebo (N = 122),* naratriptan 2.5 mg (N = 127)*Tablets (T)
Kolodny352Placebo (N = 288),* rizatriptan 10 mg (N = 296),* rizatriptan 5 mg (N = 288), sumatriptan 25 mg (N = 290), sumatriptan 50 mg (N = 285)*Tablets (T)
Kramer365Placebo (N = 83),* rizatriptan 10 mg (N = 324)*Tablets (T)
Mathew374Placebo (N = 419), eletriptan 40 mg (N = 822),* sumatriptan 100 mg in capsules (N = 831)Tablets (T)
Nappi374Placebo (N = 86),* sumatriptan 100 mg (N = 158)*Tablets (T)
Pascual385Placebo (N = 176),* almotriptan 6.25 mg (N = 360), almotriptan 12.5 (N = 376)*Tablets (T)
Pascual394Placebo (N = 154),* rizatriptan 10 mg (N = 308),* zolmitriptan 2.5 mg (N = 304)*Tablets (T)
Pfaffenrath404Placebo (N = 99),* sumatriptan 25 mg (N = 309), sumatriptan 50 mg (N = 303),* sumatriptan 100 mg (N = 298)*Tablets (T)
Pini412Placebo (N = 151),* sumatriptan 100 mg (N = 87)*Tablets (T)
Pini423Placebo (N = 61),* sumatriptan 50 mg (N = 96)*Tablets (T)
Rapoport434Placebo (N = 199),* frovatriptan 2.5 mg (N = 219)*Tablets (T)
Sakai443Placebo (N = 59),* zolmitriptan 1 mg (N = 52), zolmitriptan 2.5 mg (N = 61),* zolmitriptan 5 mg (N = 57)*Tablets (T)
Sakai453Placebo (N = 84),* eletriptan 40 mg (N = 80),* eletriptan 80 mg (N = 77), eletriptan 20 mg (N = 80)Tablets (T)
Sandrini463Placebo (N = 84),* sumatriptan 50 mg in capsules (N = 181), sumatriptan 100 mg in capsules (N = 170), eletriptan 40 mg (N = 176),* eletriptan 80 mg (N = 184)*Tablets (T)
Sargent472Placebo (N = 47),* sumatriptan 25 mg (N = 48), sumatriptan 50 mg (N = 46),* sumatriptan 100 mg (N = 46)*Tablets (T)
Savani483Sumatriptan 50 mg (N = 123),* sumatriptan 100 mg (N = 108)*Tablets (T)
Sheftell495Placebo (N = 292),* eletriptan 40 mg (N = 296),* eletriptan 80 mg (N = 312), eletriptan 20 mg (N = 290)Tablets (T)
Sheftell504Placebo (N = 989),* sumatriptan 50 mg (N = 990),* sumatriptan 100 mg (N = 973)*Fast release/rapid disintegrating tablets (FR)
Stark515Placebo (N = 304),* eletriptan 40 mg (N = 453),* eletriptan 80 mg (N = 462)*Tablets (T)
Steiner525Placebo (N = 144),* eletriptan 40 mg (N = 392),* eletriptan 80 mg (N = 396), zolmitriptan 2.5 mg (N = 405)*Tablets (T)
Teall533Placebo (N = 238),* rizatriptan 10 mg (N = 456),* rizatriptan 5 mg (N = 458)Tablets (T)
Tfelt-Hansen545Placebo (N = 32),* rizatriptan 10 mg (N = 126),* rizatriptan 5 mg (N = 45), sumatriptan 100 mg (N = 160)*Tablets (T)
Figure 2.—.

(A) Pain relief, (B) pain free, (C) recurrence at 24 hours and overall adverse events, RR.

Efficacy and Tolerability Results.—Table 2 shows the data from which RR, 95% CI were obtained. Table 3 shows the results obtained following analysis of the RR of the active drugs vs placebo.

Table 2.—.  Detailed Data Extracted from the Publications
AuthorPain ReliefPain FreeRecurrenceGlobal Events
DPLDPLDPLDPLDPLDPLDPLDPL
  1. ODT = orally disintegrating tablets; D = drug; PL = placebo; h = hour.

  2. *Crossover trial.

Sumatriptan 50 mg FR vs placebo1/2 h 1 h 2 h 1/2 h 1 h 2 h 
Carpay et al−/−−/−−/−−/−−/−−/−5/1373/15350/13729/15370/13730/ 153−/−−/−14/1378/153
Sheftell et al, study 1 and study 2 pooled171/990125/989397/990259/989603/990376/989−/−−/−−/−−/−358/990137/989162/603173/37698/99042/989
Sumatriptan 50 mg tablets vs placebo1/2 h 1 h 2 h 1/2 h 1 h 2 h 
Goldstein et al*−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−46/29135/142
Kolodny et al*−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−142/287102/288
Savani et al26/3314/15474/33126/154140/33145/154−/−−/−−/−−/−63/3315/15464/17718/44−/−−/−
Sargent et al−/−−/−−/−−/−25/468/47−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−
Cutler et al−/−−/−−/−−/−31/6217/65−/−−/−−/−−/−10/625/65−/−−/−42/6248/65
Pini et al−/−−/−−/−−/−31/968/61−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−
Pfaffenrath et al−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−67/19812/3482/30320/99
Sumatriptan 100 mg FR vs placebo1/2 h 1 h 2 h 1/2 h 1 h 2 h 
Carpay et al−/−−/−−/−−/−−/−−/−15/1423/15363/14229/15388/14230/153−/−−/−24/1428/153
Sheftell et al, study 1 and study 2 pooled198/973125/989442/973259/989650/973376/989−/−−/−−/−−/−426/973137/989188/650173/376151/97342/989
Sumatriptan 100 mg tablets vs placebo1/2 h 1 h 2 h 1/2 h 1 h 2 h 
Geraud et al−/−−/−171/50411/56304/50424/56−/−−/−54/5041/56150/5047/5684/3046/24279/50413/56
Cutler et al−/−−/−−/−−/−37/6617/65−/−−/−−/−−/−15/665/65−/−−/−42/6648/65
Kaniecki et al−/−−/−−/−−/−64/13147/127−/−−/−−/−−/−32/13118/127−/−−/−−/−−/−
Nappi et al−/−−/−−/−−/−73/16225/88−/−−/−−/−−/−34/16210/88−/−−/−24/694/19
Pfaffenrath et al−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−59/19612/34111/29820/99
Pini et al−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−18/1516/87
Sargent et al−/−−/−−/−−/−26/468/47−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−
Tfelt-Hansen et al43/38819/160108/38832/160239/38864/1605/3883/16030/3885/160127/38815/16076/23913/64202/38851/160
Zolmitriptan 2.5 mg ODT vs placebo1/2 h 1 h 2 h 1/2 h 1 h 2 h 
Dowson et al (B)36/23124/240101/23144/240138/23153/240−/−−/−18/2317/24060/23117/240−/−−/−63/23129/240
Zolmitriptan 2.5 mg tablets vs placebo1/2 h 1 h 2 h 1/2 h 1 h 2 h 
Pascual et al43/30413/154102/30426/154193/30443/1542/3041/15430/3047/154103/30414/15456/19311/43119/30432/154
Sakai5/616/5915/6113/5929/6117/59−/−−/−−/−−/−10/617/593/179/2920/618/59
Steiner et al27/4057/14493/4057/144224/40530/144−/−−/−21/4051/14499/4058/14483/21816/31137/40557/144
Zolmitriptan 5 mg tablets vs placebo1/2 h 1 h 2 h 1/2 h 1 h 2 h 
Geraud et al−/−−/−163/49111/56288/49124/56−/−−/−37/4911/56144/4917/5674/2886/24287/49113/56
Sakai7/576/5917/5713/5935/5717/59−/−−/−−/−−/−12/577/5910/359/2925/578/59
Dahlof et al 1998−/−−/−79/21314/99118/21317/99−/−−/−18/2130/9918/2131/9918/7011/17130/21334/99
Rizatriptan 10 mg wafer vs placebo1/2 h 1 h 2 h 1/2 h 1 h 2 h 
Ahrens et al49/18817/18584/18839/185140/18842/1858/1880/18524/1886/18579/18818/18559/14015/42−/−−/−
Rizatriptan 10 mg tablets vs placebo1/2 h 1 h 2 h 1/2 h 1 h 2 h 
Goldstein et al*−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−45/30535/142
Gijsman et al20/1456/6744/14514/6769/14512/67−/−−/−−/−−/−40/1452/6725/694/1221/700/12
Bomhof et al28/2015/10776/20117/107138/20124/1073/2011/10719/2011/10790/2019/10746/1386/2439/20123/107
Kolodny et al*−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−139/294102/288
Kramer et al*81/32415/83176/32425/83246/32430/835/3240/8340/3242/83142/3246/83−/−−/−−/−−/−
Pascual et al41/30813/154124/30826/154206/30843/1548/3081/15437/3087/154126/30814/15458/20611/4395/30832/154
Teall et al109/45654/304209/45682/304323/456106/304−/−−/−−/−−/−19/45630/304152/32342/106170/45671/304
Tfelt-Hansen et al50/38719/160141/38732/160258/38764/1606/3873/16040/3875/160155/38715/160123/25813/64180/38751/160
Almotriptan 12.5 tablets mg vs placebo1/2 h 1 h 2 h 1/2 h 1 h 2 h 
Dahlof et al−/−−/−−/−−/−96/16426/80−/−−/−−/−−/−62/1648/80−/−−/−30/16412/80
Pascual et al−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−144/37627/176−/−−/−−/−−/−
Eletriptan 40 mg tablets vs placebo1/2 h 1 h 2 h 1/2 h 1 h 2 h 
Diener et al−/−−/−60/21013/106111/21021/106−/−−/−−/−−/−58/2105/106−/−−/−−/−−/−
Garcia-Ramos−/−−/−65/19219/92−/−−/−−/−−/−−/−−/−67/19217/92−/−−/−59/19233/92
Goadsby et al4/1368/142−/−−/−76/13631/142−/−−/−−/−−/−34/1368/14226/767/3147/13624/142
Mathew et al−/−−/−279/83546/429551/835109/429−/−−/−58/8350/429296/83521/429171/55151/109259/835146/429
Sakai et al−/−−/−−/−−/−54/8043/84−/−−/−−/−−/−23/8013/849/5211/46−/−−/−
Sandrini et al−/−−/−52/17510/84106/17525/84−/−−/−7/1751/8452/1753/84−/−−/−−/−−/−
Stark et al−/−−/−−/−−/−267/45344/238−/−−/−−/−−/−138/4537/23880/26718/44−/−−/−
Steiner et al−/−−/−101/3927/144229/39230/144−/−−/−21/3921/144115/3928/14465/22516/31117/39257/144
Sheftell et al27/29612/292101/29644/292184/29664/292−/−−/−21/2963/29280/29612/29253/18423/64−/−−/−
Naratriptan 2.5 mg tablets vs placebo1/2 h 1 h 2 h 1/2 h 1 h 2 h 
Bomhof et al23/2145/10759/21417/107103/21424/1072/2141/1077/2141/10744/2149/10722/1036/2429/21423/107
Klassen et al−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−21/7616/4133/9732/93
Frovatriptan 2.5 mg tablets vs placebo1/2 h 1 h 2 h 1/2 h 1 h 2 h 
Elkind et al−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−−/−9/3710/38
Goldstein et al−/−−/−−/−−/−48/12630/118−/−−/−−/−−/−19/1266/11810/485/30−/−−/−
Rapoport et al−/−−/−−/−−/−88/21946/199−/−−/−−/−−/−31/2196/19912/8812/4690/21963/199
Table 3.—.  Results Based on the Relative Risk, RR
 Pain Relief at 2 hPain Relief at 1 hPain Relief at 1/2 hPain Free at 2 hPain Free at 1 hPain Free at 1/2 hRecurrence at 24 hOverall Adverse Events
NeNpRR (CI)Hetero geneity (p)NeNpRR (CI)Hetero geneity (p)NeNpRR (CI)Hetero geneity (p)NeNpRR (CI)Hetero geneity (p)NeNpRR (CI)Hetero geneity (p)NeNpRR (CI)Hetero geneity (p)NeNpRR (CI)Hetero geneity (p)NeNpRR (CI)Hetero geneity (p)
  1. Ne = number of articles included in the systematic review's comparison group for each variable; Np = total population studied in each comparison; NA = not applicable; RR = relative risk. *Statistical significance P≤ .01, **statistical significance P < .05.

  2. Heterogeneity (p): test of heterogeneity, chi square (significance).

Sumatriptan 50 mg FR vs placebo119791.60 (1.46, 1.76)** 119791.53 (1.35, 1.74)** 119791.37 (1.10, 1.69)** 222692.61 (2.23, 3.06)**0.9912901.93 (1.30, 2.86)** 12901.86 (0.45, 7.64) 19790.58 (0.49, 0.69)** 222692.27 (1.64, 3.14)**0.7
Sumatriptan 50 mg T vs placebo48621.95 (1.38, 2.76)**0.1214851.32 (0.88, 1.98) 14853.02 (1.07, 8.51)* 26123.61 (1.27, 10.21)*0.1200NA 00NA 24530.91 (0.67, 1.25)0.8415371.03 (0.74, 1.45)<0.001
Sumatriptan 100 mg FR vs placebo119621.76 (1.60, 1.92)** 119621.73 (1.53, 1.97)** 119621.61 (1.31, 1.98)** 222573.16 (2.71, 3.68)**112952.34 (1.61, 3.41)** 12955.39 (1.59, 18.22)** 110260.63 (0.53, 0.74)** 222573.58 (2.65, 4.86)**0.77
Sumatriptan 100 mg T vs placebo618401.60 (1.34, 1.92)**0.14211081.48 (1.11, 1.99)**0.5115480.93 (0.56, 1.55) 517472.37 (1.76 3.20)**0.33211082.91 (1.26, 6.74)**0.4115480.69 (0.17, 2.84)0.2538611.14 (0.77, 1.67) 619621.57 (1.04, 2.35)*<0.001
Zolmitriptan 2.5 mg ODT vs placebo14712.71 (2.09, 3.51)** 14712.38 (1.76, 3.23)** 14711.56 (0.96, 2.53) 14713.67 (2.21, 6.09)** 14712.67 (1.14, 6.28)* 00NA 00NA 14712.26 (1.51, 3.37)**
Zolmitriptan 2.5 mg T vs placebo311272.26 (1.80, 2.83)**0.27311272.13 (1.05, 4.32)*0.01311271.41 (0.91, 2.19)0.53311273.05 (1.67, 5.58)*0.1210072.90 (1.00, 8.41)0.2414581.01 (0.09, 11.09) 35310.81 (0.60, 1.12)0.36311271.50 (0.76, 2.94)<0.001
Zolmitriptan 5 mg T vs placebo39752.07 (1.22, 3.51)**0.00639751.87 (1.27, 2.75)**0.2411161.21 (0.43, 3.38) 39752.32 (1.34, 4.00)**0.3528596.73 (1.35, 33.63)**0.4100NA 34630.69 (0.36, 1.35)0.0539752.21 (1.57, 3.10)**0.19
Rizatriptan 10 mg ODT vs placebo13733.28 (2.48, 4.33)** 13732.12 (1.54, 2.92)** 13732.84 (1.70, 4.74)** 13734.32 (2.70, 6.91)** 13733.94 (1.65, 9.41)** 137316.73 (0.97, 287.78) 11821.18 (0.75, 1.85) 00NA 
Rizatriptan 10 mg T vs placebo626962.16 (1.83, 2.55)**0.05626961.84 (1.61, 2.11)**0.5626961.39 (1.14, 1.70)**0.57626963.50 (1.39, 8.83)**<0.001417243.44 (2.03, 5.83)**0.58417241.50 (0.57, 3.93)0.6512431.36 (1.01, 1.83)*0.16731881.23 (0.95, 1.57)<0.001
Almotriptan 12.5 mg T vs placebo12441.86 (1.32, 2.61)** 00NA 00NA 27962.77 (1.94, 3.94)**0.2900NA 00NA 00NA 12441.22 (0.66, 2.25) 
Eletriptan 40 mg T vs placebo840962.48 (1.99, 3.11)**<0.001632472.54 (1.95, 3.31)**0.0728661.17 (0.29, 4.80)0.04943804.83 (3.05, 7.66)**<0.001426477.94 (2.88, 21.87**0.300NA 616800.72 (0.59, 0.87)**0.26423621.01 (0.73, 1.38)0.001
Naratriptan 2.5 mg T vs placebo13212.15 (1.47, 3.13)** 13211.74 (1.07, 2.82)* 13212.30 (0.90, 5.88) 13212.44 (1.24, 4.82)** 13213.50 (0.44, 28.08) 13211.00 (0.09, 10.90) 22440.75 (0.48, 1.16)0.725110.81 (0.52, 1.26)0.16
Frovatriptan 2.5 mg T vs placebo26621.64 (1.30, 2.08)**0.5500NA 00NA 26623.76 (2.04, 6.95)**0.4600NA 00NA 22120.76 (0.33, 1.77)0.1624931.26 (0.98, 1.60)0.42

The sensitivity analyses, in relation to recurrence at 24 hours for each of the definitions used, are shown in Table 4. The results of the sensitivity analyses that incorporate the reencapsulated forms are shown in Tables 5 and 6. Regarding the sensitivity analysis in relation to the Jadad score, no differences were observed with respect to the results shown in Table 3.

Table 5.—.  Results of the Sensitivity Analysis Including Nonmarketed Reencapsulated Forms As Opposed to the Same Results in the Absence of These Formulations, Based on the Relative Risk, RR
 Pain Relief at 2 hPain Relief at 1 hPain Relief at 1/2 hPain-Free at 2 hPain-Free at 1 hPain-Free at 1/2 hRecurrence at 24 hOverall Adverse Events
NeNpRR (IC)NeNpRR (IC)NeNpRR (IC)NeNpRR (IC)NeNpRR (IC)NeNpRR (IC)NeNpRR (IC)NeNpRR (IC)
  1. Ne = number of articles included in the systematic review's comparison group for each variable; Np = total population studied in each comparison; NA = not applicable; RR = relative risk.

  2. *Statistical significance P < .05.

 
Sumatriptan 50 mg tablets vs placebo48621.95 (1.38, 2.76)*14851.32 (0.88, 1.98)14853.02 (1.07, 8.51)*26123.61 (1.27, 10.21)*00NA00NA24530.91 (0.67, 1.25)415371.03 (0.74, 1.45)
Sumatriptan 50 mg tablets/capsules vs placebo615971.77 (1.49, 2.10)*312201.65 (1.27, 2.15)*29552.83 (1.46, 5.47)*413473.74 (2.49, 5.61)*27353.72 (1.08, 12.84)*1470NA36290.97 (0.76, 1.23)520071.12 (0.83, 1.52)
Sumatriptan 100 mg tablets vs placebo618401.60 (1.34, 1.92)**211081.48 (1.11, 1.99)**15480.93 (0.56, 1.55)517472.37 (1.76, 3.20)**211082.91 (1.26, 6.74)**15480.69 (0.17, 2.84)38611.14 (0.77, 1.67)619621.57 (1.04, 2.35)*
Sumatriptan 100 mg tablets/capsules vs placebo1140931.80 (1.54, 2.11)*630901.73 (1.33, 2.23)*28191.11 (0.66, 1.86)1040002.98 (2.20, 4.02)*529333.69 (1.39, 9.82)*15480.69 (0.17, 2.84)717711.05 (0.82, 1.35)1039611.59 (1.22, 2.08)*
 
Rizatriptan 10 mg tablets vs placebo626962.16 (1.83, 2.55)**626961.84 (1.61, 2.11)**626961.39 (1.14, 1.70)**626963.50 (1.39, 8.83)**417243.44 (2.03, 5.83)**417241.50 (0.57, 3.93)512431.36 (1.01, 1.83)*731881.23 (0.95, 1.57)
Rizatriptan 10 mg tablets/capsules vs placebo728702.21 (1.89, 2.60)*728701.84 (1.61, 2.10)*626961.39 (1.14, 1.70)*728703.83 (1.64, 8.95)*417243.44 (2.03, 5.83)*417241.50 (0.57, 3.93)613041.34 (1.04, 1.72)*833621.24 (1.00, 1.54)*
 
Almotriptan 12.5 mg tablets vs placebo12441.80 (1.28, 2.53)*00NA00NA27962.77 (1.94, 3.94)**00NA00NA00NA12441.22 (0.66, 2.25)
Almotriptan 12.5 mg tablets/capsules vs placebo25271.52 (1.13, 2.04)*12831.21 (0.84, 1.73)00NA310792.47 (1.75, 3.47)*12830.97 (0.33, 2.81)00NA11460.96 (0.46, 2.02)25272.10 (0.66, 6.65)
 
Naratriptan 2.5 mg tablets vs placebo13212.15 (1.47, 3.13)**13211.74 (1.07, 2.82)*13212.30 (0.90, 5.88)13212.44 (1.24, 4.82)**13213.50 (0.44, 28.08)13211.00 (0.09, 10.90)22440.75 (0.48, 1.16)25110.81 (0.52, 1.26)
Naratriptan 2.5 mg tablets/capsules vs placebo13212.15 (1.47, 3.13)*26121.44 (1.02, 2.04)*13212.30 (0.90, 5.88)26121.51 (0.61, 3.73)13213.50 (0.44, 28.08)13211.00 (0.09, 10.90)22440.75 (0.48, 1.16)38020.81 (0.64, 1.02)
Table 6.—.  Articles That Contain Nonmarketed Reencapsulated Forms Included in the Sensitivity Analysis: Quality of the Article, Intervention, and Type of Oral Presentation
ArticlesJadadIntervention, Dose, and ITT*Formulations
  1. *Reencapsulated active principle.

Garcia-Ramos274Placebo (N = 92); eletriptan 40 mg (N = 192); naratriptan* 2.5 mg (N = 199)Naratriptan in capsules
Goadsby305Placebo (N = 142); sumatriptan* 100 mg (N = 129); eletriptan 20 mg (N = 144); eletriptan 40 mg (N = 136); eletriptan 80 mg (N = 141)Sumatriptan 100 mg in capsules
Mathew374Placebo (N = 419); eletriptan 40 mg (N = 822); sumatriptan* 100 mg (N = 831)Sumatriptan 100 mg in capsules
Sandrini463Placebo (N = 84); sumatriptan* 50 mg (N = 181); sumatriptan* 100 mg (N = 170); eletriptan 40 mg (N = 176); eletriptan 80 mg (N = 184)Sumatriptan 50 mg and sumatriptan 100 mg in capsules
Dowson554Placebo (N = 99); almotriptan 25 mg (N = 191); almotriptan* 12.5 mg (N = 184); sumatriptan* 100 mg (N = 194)Sumatriptan 100 mg and almotriptan 12.5 mg in capsules
Visser563Placebo (N = 85); rizatriptan* 10 mg (N = 89); rizatriptan 20 mg (N = 82); rizatriptan 40 mg (N = 121); sumatriptan* 100 mg (N = 72)Sumatriptan 100 mg and rizatriptan 10 mg in capsules
Simth573Placebo (N = 241); sumatriptan* 50 mg (N = 229)Sumatriptan 50 mg in capsules

Efficacy at 2 Hours Following Treatment.— All the marketed oral triptans exhibited improved results in comparison with placebo. When the efficacy parameters of pain relief or pain free at 2 hours were analyzed, the lower limit of the RR confidence interval was greater than 1 (in all cases, P < .05). Upon inclusion of the studies with reencapsulated forms (Table 5), naratriptan 2.5 mg in tablets does not show any significant difference in comparison to placebo when pain free at 2 hours endpoint is considered (P > .05, [0.61, 3.73]).

Efficacy at 1 Hour Following Treatment.— Sumatriptan 50 mg tablets, almotriptan 12.5 mg tablets, and frovatriptan 2.5 mg tablets did not prove to attain better results than placebo in terms of pain free or pain relief at 1 hour following treatment (P≥ .05). Naratriptan 2.5 mg tablets show better results 1 hour after treatment when compared to placebo with pain relief parameter (P < .01, [1.07, 2.82]) but not pain free (P > .05). It is worth mentioning that only one clinical trial was included in the above triptan formulations, which consider efficacy data at 1 hour following treatment.17 All remaining triptan formulations show better results when compared to placebo after 1 hour following treatment (P < .05).

When taking into consideration the reencapsulated forms (Table 5), the only change observed with respect to the previous analysis is that sumatriptan 50 mg tablets attain significant pain relief after 1 hour following treatment (P < .05, [1.27, 2.15]).

Efficacy at 30 Minutes Following Treatment.— Upon assessing pain free at 30 minutes following initial treatment, fast-disintegrating sumatriptan 100 mg shows better results than placebo (P < .01, [1.59, 18.22]). Rizatriptan 10 mg ODT (orally disintegrating tablets) in one trial of 373 patients obtain an RR of 16.73 with inferior limit just under 1 (CI 0.97, 287.78). For the endpoint of pain relief at half an hour, in comparison to placebo, significance (P < .05) is achieved with fast-disintegrating sumatriptan 50 mg, sumatriptan 50 mg tablets, fast-disintegrating sumatriptan 100 mg, rizatriptan 10 mg tablets, and rizatriptan 10 mg orally disintegrating tablets. No data are available for this specific efficacy endpoint with almotriptan and frovatriptan.

Recurrence at 24 Hours.— Fast-disintegrating sumatriptan 50 or 100 mg and eletriptan 40 mg tablets show a lower recurrence at 24 hours than placebo (upper limit of the RR confidence interval less than 1, P < .01). On the contrary, rizatriptan 10 mg tablets exhibit a greater number of recurrences at 24 hours when compared to placebo (P < .05, [1.01, 1.83]). The remaining drug forms do not show any significant difference when compared to placebo.

While excluding those clinical trials that report improvement in the first 4 hours from the recurrence analysis and taking into consideration only those that show improvement at 2 hours (Table 4), no variations in the results already described were observed in terms of the statistical significance when compared to placebo.

Absolute Adverse Events.— Fast-disintegrating sumatriptan 50 and 100 mg, sumatriptan 100 mg tablets, orally disintegrating zolmitriptan 2.5 mg, and zolmitriptan 5 mg tablets showed a higher incidence of AEs than placebo (P < .05).

When reencapsulated forms are included in the analysis, rizatriptan 10 mg shows a higher overall incidence of AEs than placebo (Table 5, P < .05, [1.00, 1.54]).

COMMENTS

This is the first systematic review conducted in the present decade and the only one that analyses the results by separating non-reencapsulated (those marketed) and reencapsulated forms. Furthermore, this analysis includes only those oral formulations that are marketed in most countries. Other innovative aspects of this study are the use of a multiplicative model based on the RR with confidence intervals in comparison to placebo and the inclusion of efficacy variables at 30 minutes and 1 hour. The inclusion of marketed (non-reencapsulated) forms and very early efficacy endpoints in the main analysis is one of the limitations of the study, because, for some triptans (eg, almotriptan and frovatriptan) it reduced the number of studies available for analysis. Other limitation of this work is the relative heterogeneity of the studies analyzed. Furthermore, as compared with the meta-analysis conducted by Ferrari et al,5,6 this analysis only includes the published data available, but not the raw data submitted by the pharmaceutical companies.

Regarding the standard efficacy endpoints, pain relief or pain free at 2 hours, data show that all the marketed triptans, without exception, are significantly superior to placebo. This result confirms the efficacy of these compounds in the symptomatic treatment of migraine attacks. When the data from the clinical trials with reencapsulated forms were considered in the analysis, the benefit over placebo is maintained, with the sole exception of naratriptan, for which a significant benefit when compared to placebo at 2 hours for pain free was not achieved. Efficacy data at 1 hour and at 30 minutes were not available for frovatriptan 2.5 mg (pain relief and pain free) or for sumatriptan 50 mg (pain free). In addition, there are no published data for zolmitriptan 2.5 mg (lyophilized tablet formulation) and 5 mg, almotriptan 12.5 mg or eletriptan 40 mg up to 30 minutes. Efficacy results recorded earlier than 30 minutes have not been included in the comparison because they have been obtained only in one article.48 In that publication, the combined data from 2 trials, showed that the time to onset of pain relief in patients using sumatriptan 100 mg FR (fast release) was 20 minutes (6% of the patients presented pain relief vs 4% with placebo, P < .05). When considering pain relief at 1 hour, all triptans proved to be superior to placebo with the exception of tablet formulations of sumatriptan 50 mg, although sumatriptan fast-disintegrating tablet was clearly superior to placebo, which probably reflects its improved pharmacokinetics. Sumatriptan 50 mg standard tablet form did show benefit over placebo when clinical trials with reencapsulated formulations were included in the analysis. Very similar results were obtained for pain free endpoint at 1 hour: all triptans were superior to placebo, except naratriptan and almotriptan, although one must take into consideration that the number of patients in the trials with almotriptan was low, as most of the trials included reencapsulated formulations. Pain relief at 30 minutes for sumatriptan 50 mg tablets and fast-disintegrating formulation, fast-disintegrating sumatriptan 100 mg, and rizatriptan 10 mg (conventional and wafer tablets) showed significant improvement when compared to placebo. There are very few trials observing efficacy in triptans in the first half an hour after drug administration, which could result in publication bias. Except in the cases of rizatriptan 10 mg tablets with 6 trials contemplating pain relief and 4 studies considering pain free, zolmitriptan 2.5 mg tablets with 3 trials dealing with pain relief, and eletriptan 40 mg with 2 studies observing pain relief, all the half-an-hour results correspond to only one publication. Sumatriptan 100 mg fast-disintegrating formulation shows efficacy at 30 minutes as defined by pain free when compared to placebo. Nevertheless, rizatriptan 10 mg ODT was very close in the lower CI limit to an RR of 1. More data are necessary to obtain stronger evidence. But even if the number of studies dealing with this outcome is small, it can be concluded that the results are accurate when compared with data shown at 1 hour and 2 hours after treatment. These data did not vary when taking into account those studies wherein the drugs were reencapsulated.

Despite the uncertainties that statistical analysis of the differences in recurrence vs placebo usually create, the rate of recurrence was analyzed. Again, no published data were available for non-reencapsulated almotriptan 12.5 mg. Sumatriptan 50 and 100 mg in the new fast-disintegrating form, along with eletriptan 40 mg, showed a lower rate of recurrence than placebo. On the contrary, rizatriptan 10 mg, conventional tablet formulation, was the only triptan with a greater recurrence rate than placebo. Almotriptan did not differ from placebo when data from the reencapsulated trials were included. The comparative results of recurrence were not changed when this endpoint was analyzed taking into account the response at 2 hours vs 4 hours. These data are perfectly comparable with those from previous systematic reviews, in which rizatriptan showed greater recurrence rates than other triptans while eletriptan exhibit lower rates.5–8 The only marketed triptan that shows significantly better results than placebo in all the efficacy variables analyzed is the new, fast-disintegrating form of sumatriptan 100 mg.

Finally, the absolute occurrence of AEs in triptans vs placebo was analyzed in this study. As expected, none of the triptans showed better tolerability than placebo. The frequency of AEs of the sumatriptan fast-release formulations at 50 and 100 mg, conventional sumatriptan formulations in tablets at 100 mg, and zolmitriptan 2.5 mg lyophilized tablets and 5 mg tablets, was significantly higher than that of placebo. Rizatriptan 10 mg also showed this result when the reencapsulated studies were included. The remaining oral triptans did not show tolerability differences with respect to placebo. It should be noted that most number of significant test of heterogeneity was found in comparative studies of the overall AEs (sumatriptan 50 and 100 mg tablets, zolmitriptan 2.5 mg tablets, rizatriptan 10 mg tablets, and eletriptan 40 mg tablets). Thus, results of overall AEs have to be considered carefully.

In summary, this review updates the comparative data for the 7 different marketed oral triptans and shows their clear efficacy when compared to placebo, even with strict efficacy endpoints, such as efficacy at 30 minutes. Probably due to their pharmacokinetic heterogeneity, the results are different for each of the triptans and their various oral formulations. This information may be of help when prescribing these drugs in everyday clinical practice, wherein direct comparative studies of the seven available triptans are unfeasible. The specific analysis of data obtained from clinical trials with reencapsulated formulations resulted only in occasional differences in the main results. In our opinion, this suggests that the influence of reencapsulation on the effectiveness and tolerability data is small. Although we cannot at all dismiss the possibility that reencapsulation may slightly affect the results, the differences found in this study seem to be primarily due to the increase in the number of patients when the clinical trials that use oral reencapsulated triptans are included.

Acknowledgments

Acknowledgments: This work was supported by a grant from GSK-Spain. We are very grateful to Carles Iglesias, MD, and Karine Fauria, PhD, from SALUTIS RESEARCH, S.L., Barcelona (Spain) for carrying out the statistical analysis.

Conflict of Interest:  All the authors have given paid lectures for the companies launching the triptans analyzed in this paper.

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