Abstract
Background
Migraine is a highly disabling condition for the individual and also has wide‐reaching implications for society, healthcare services, and the economy. Sumatriptan is an abortive medication for migraine attacks, belonging to the triptan family. Intranasal administration may be preferable to oral for individuals experiencing nausea and/or vomiting, although it is primarily absorbed in the gut, not the nasal mucosa.
Objectives
To determine the efficacy and tolerability of intranasal sumatriptan compared to placebo and other active interventions in the treatment of acute migraine attacks in adults.
Search methods
We searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, online databases, and reference lists for studies through 13 October 2011.
Selection criteria
We included randomised, double‐blind, placebo‐ and/or active‐controlled studies using intranasal sumatriptan to treat a migraine headache episode, with at least 10 participants per treatment arm.
Data collection and analysis
Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate relative risk (or 'risk ratio') and numbers needed to treat to benefit (NNT) or harm (NNH) compared to placebo or a different active treatment.
Main results
Twelve studies (4755 participants) compared intranasal sumatriptan with placebo or an active comparator. Most of the data were for the 10 mg and 20 mg doses. Sumatriptan surpassed placebo for all efficacy outcomes. For sumatriptan 10 mg versus placebo the NNTs were 7.3, 7.4, and 5.5 for pain‐free at two hours, and headache relief at one and two hours, respectively. For sumatriptan 20 mg versus placebo the NNTs were 4.7, 4.9, and 3.5, respectively, for the same outcomes. The 20 mg dose was significantly better than the 10 mg dose for each of these three primary efficacy outcomes.
Relief of headache‐associated symptoms, including nausea, photophobia, and phonophobia, was greater with sumatriptan than with placebo, and use of rescue medication was lower with sumatriptan than placebo. For the most part, adverse events were transient and mild and were more common with sumatriptan than placebo.
Direct comparison of sumatriptan with active treatments was limited to two studies, one comparing sumatriptan 20 mg and dihydroergotamine (DHE) 1 mg, and one comparing sumatriptan 20 mg with rizatriptan 10 mg.
Authors' conclusions
Intranasal sumatriptan is effective as an abortive treatment for acute migraine attacks, relieving pain, nausea, photophobia, phonophobia, and functional disability, but is associated with increased adverse events compared with placebo.
Plain language summary
Sumatriptan (intranasal route of administration) for acute migraine attacks in adults
Sumatriptan is one of the triptan family of drugs used to treat migraine attacks. It is available as a nasal spray, and this route of administration may be preferable for individuals experiencing nausea and/or vomiting, although absorption of the drug occurs primarily in the gut rather than the nasal mucosa. This review found that a single intranasal dose was effective in relieving migraine headache pain and associated symptoms of nausea, sensitivity to light, and sensitivity to sound. Pain was reduced from moderate or severe to no pain by two hours in approximately 2 in 10 people (24%) taking sumatriptan 10 mg, compared with about 1 in 10 (10%) taking placebo. Pain was reduced from moderate or severe to no worse than mild pain by two hours in 5 in 10 people (50%) taking sumatriptan 10 mg, compared with approximately 3 in 10 (32%) taking placebo. In addition to relieving headache pain, sumatriptan also relieved symptoms of nausea and sensitivity to light and sound by two hours in about half of those who took it, compared with about one‐third of those who took placebo. The 20 mg dose had greater efficacy, but may be associated with more adverse events, most of which were of short duration and mild or moderate in severity.
Background
Description of the condition
Migraine is a common, disabling headache disorder, with considerable social and economic impact (Hazard 2009). Recent reviews found a one‐year prevalence of 15% for adults in European countries (Stovner 2010) and 13% for all ages in the US (Victor 2010). Migraine is more prevalent in women than in men (by a factor of two to three), and in the age range 30 to 50 years.
The International Headache Society (IHS) classifies two major subtypes. Migraine without aura is the most common subtype. It is characterised by attacks lasting 4 to 72 hours that are typically of moderate to severe pain intensity, unilateral, pulsating, aggravated by normal physical activity, and associated with nausea and/or photophobia and phonophobia. Migraine with aura is characterised by reversible focal neurological symptoms that develop over a period of 5 to 20 minutes and last for less than 60 minutes, followed by headache with the features of migraine without aura. In some cases the headache may lack migrainous features or be absent altogether (IHS 2004).
A recent large prevalence study in the US found that over half of migraineurs had severe impairment or required bed rest during attacks. Despite this high level of disability and a strong desire for successful treatment, only a proportion of migraine sufferers seek professional advice for the treatment of attacks. The majority were not taking any preventive medication, although one‐third met guideline criteria for offering or considering it. Nearly all (98%) migraineurs used acute treatments for attacks, with 49% using over‐the‐counter (OTC) medication only, 20% using prescription medication, and 29% using both. OTC medication included aspirin, other non‐steroidal anti‐inflammatory drugs (NSAIDs), paracetamol (acetaminophen), and paracetamol with caffeine (Bigal 2008; Diamond 2007; Lipton 2007). Similar findings have been reported from other large studies in France and Germany (Lucas 2006; Radtke 2009).
The significant impact of migraine with regard to pain, disability, social functioning, quality of relationships, emotional well‐being, and general health (Edmeads 1993; Osterhaus 1994; Solomon 1997) results in a huge burden for the individual, health services, and society (Clarke 1996; Ferrari 1998; Hazard 2009; Hu 1999; Solomon 1997). The annual US economic burden relating to migraine, including missed days of work and lost productivity, is USD 14 billion (Hu 1999). Thus successful treatment of acute migraine attacks not only benefits patients by reducing their disability and improving health‐related quality of life, but also reduces the need for healthcare resources and increases economic productivity (Jhingran 1996; Lofland 1999).
Description of the intervention
The symptomatic treatment of migraine advanced significantly with the development of the triptan class of drugs, of which sumatriptan was the first, in 1991. It is available as a standard oral tablet, a nasal spray, subcutaneous injection, and rectal suppository. The nasal spray is available only by prescription. This formulation may be particularly useful for individuals who experience severe nausea or vomiting with their attacks. However, although the drug is taken intranasally, sumatriptan is poorly absorbed through the nasal mucosa and requires ingestion to be bioavailable. It is therefore likely to have similar absorption rate and onset of action to oral formulations, and may be similarly affected by vomiting and gastric stasis. In the UK in 2010 there were over 910,000 prescriptions for sumatriptan, of which approximately 52,000 were for the intranasal formulation (PCA 2011).
In order to establish whether sumatriptan is an effective treatment at a specified dose in acute migraine attacks, it is necessary to study its effects in circumstances that permit detection of pain relief. Such studies are carried out in individuals with established pain of moderate to severe intensity, using single doses of the interventions. Participants who experience an inadequate response with either placebo or active treatment are permitted to use rescue medication, and the intervention is considered to have failed in those individuals. In clinical practice, however, individuals would not normally wait until pain is of at least moderate severity, and may take a second dose of medication if the first dose does not provide adequate relief. Once efficacy is established in studies using single doses in established pain, further studies may investigate different treatment strategies and patient preferences. These are likely to include treating the migraine attack early while pain is mild, and using a low dose initially, with a second dose if response is inadequate.
How the intervention might work
Sumatriptan is a 5‐HT1 agonist, selectively targeting the 5‐HT (serotonin) 1B and 1D receptors. It has three putative mechanisms of therapeutic action (Ferrari 2002; Goadsby 2007):
vasoconstriction of dilated meningeal blood vessels;
inhibition of the release of vasoactive neuropeptides from perivascular trigeminal sensory neurons;
reduction of pain signal transmission in the trigeminal dorsal horn.
It is used for acute treatment, having no efficacy in preventing future attacks.
Why it is important to do this review
Sumatriptan was the first marketed triptan, is the most used triptan worldwide, and has become the standard against which new acute migraine treatments are compared. An earlier Cochrane review of oral sumatriptan for acute migraine headaches searched for studies to the end of 2001 (McCrory 2003) and included comparisons with placebo, no intervention, other drug treatments, and behavioural or physical therapies. More studies have been published since that time, and an update is needed to include and evaluate the data from these. We decided to include all routes of administration in the update, and to limit comparators to placebo and other pharmacological interventions. Owing to the very large amount of information now available, particularly for the oral formulation, we carried out separate reviews for each route of administration (Derry 2012a; Derry 2012b; Derry 2012c; Derry 2012d), together with an overview of all routes of administration (Derry (forthcoming)). These sumatriptan reviews form part of a larger series of reviews planned for acute treatments for migraine attacks.
Objectives
The objective of this review is to determine the efficacy and tolerability of intranasal sumatriptan compared to placebo and other active interventions in the treatment of acute migraine attacks in adults.
Methods
Criteria for considering studies for this review
Types of studies
We included randomised, double‐blind, placebo‐ and/or active‐controlled studies using intranasal sumatriptan to treat a migraine headache episode. Studies had to have a minimum of 10 participants per treatment arm and report dichotomous data for at least one of the outcomes specified below. We accepted studies reporting treatment of consecutive headache episodes if outcomes for the first, or each, episode were reported separately. Cross‐over studies were accepted if there was adequate washout (≥ 48 hours) between treatments.
Types of participants
Studies enrolled adults (at least 18 years of age) with migraine. We used the definition of migraine specified by the International Headache Society (IHS 1988; IHS 2004). There were no restrictions on migraine frequency, duration, or type (with or without aura). Participants taking stable prophylactic therapy to reduce migraine frequency were accepted; where reported, details on the prophylactic therapy prescribed or allowed are provided in the Characteristics of included studies table.
Types of interventions
We included studies in which self administered intranasal sumatriptan was used to treat a migraine headache episode. There were no restrictions on dose, dosing regimen (e.g. single dose versus optional second dose) or timing of the first dose in relation to headache intensity (e.g. taking the first dose when pain was of moderate or severe intensity versus when pain was only mild).
A placebo comparator is essential to demonstrate that sumatriptan is effective in this condition. We considered active‐controlled trials without a placebo as secondary evidence. We excluded studies designed to demonstrate prophylactic efficacy in reducing the number or frequency of migraine headaches.
Types of outcome measures
Primary outcomes
In selecting the main outcome measures for this review, we considered scientific rigour, availability of data, and patient preferences (Lipton 1999). Patients with acute migraine headaches have rated complete pain relief, no headache recurrence, rapid onset of pain relief, and no side effects as the four most important outcomes (Lipton 1999).
In view of these patient preferences, and in line with the guidelines for controlled trials of drugs in migraine issued by the IHS (IHS 2000), we considered the following primary outcomes:
pain‐free at one and two hours, without the use of rescue medication;
reduction in headache pain ('headache relief') at one and two hours (pain reduced from moderate or severe to none or mild without the use of rescue medication);
sustained pain‐free during the 24 hours postdose (pain‐free within two hours, with no use of rescue medication or recurrence of moderate to severe pain within 24 hours);
sustained headache relief during the 24 hours postdose (headache relief at two hours, sustained for 24 hours, with no use of rescue medication or a second dose of study medication).
Pain intensity or pain relief had to be measured by the patient (not the investigator or carer). Pain measures accepted for the primary outcomes are:
pain intensity: four‐point categorical scale, with wording equivalent to none, mild, moderate, severe; or 100 mm visual analogue scale (VAS);
pain relief: five‐point categorical scale, with wording equivalent to none, a little, some, a lot, complete; or 100 mm VAS.
All included studies used one or more of these standard scales and reported outcomes as defined above. We considered only data obtained directly from the patient.
Secondary outcomes
Secondary outcomes considered were:
use of rescue medication;
participants with any adverse event during the 24 hours postdose;
participants with particular adverse events during the 24 hours postdose;
withdrawals due to adverse events;
headache‐associated symptoms: relief and/or presence at two hours;
functional disability: relief and/or presence at two hours.
Although recurrence of headache is perceived to be a problem with triptan medication, we chose not to analyse this outcome because of variation in the definition of 'recurrence' and poor reporting, such that it is often unclear whether the result is reported as a proportion of the whole treatment group or only of those who experienced headache relief at two hours. Furthermore, because recurrence is dependent upon first experiencing headache relief at two hours ‐ an outcome that varies across different treatment groups ‐ interpretation of the result is difficult. We believe that the outcome of sustained headache relief at 24 hours qualitatively provides the same information to patients, but in a more rigorous and intuitive way.
Definitions of important terms, including all measured outcomes, are provided in Appendix 1.
Search methods for identification of studies
Electronic searches
We searched the following databases:
the Cochrane Central Register of Controlled Trials (CENTRA) (2011, Issue 1);
MEDLINE (via OVID) (to 1 February 2011);
EMBASE (via OVID) (to 1 February 2011);
Oxford Pain Relief Database (Jadad 1996a).
See Appendix 2, Appendix 3, and Appendix 4 for the search strategies for MEDLINE, EMBASE, and CENTRAL, respectively. There were no language restrictions.
Searching other resources
We searched reference lists of retrieved studies and review articles for additional studies. We also searched online clinical trials databases (www.gsk‐clinicalstudyregister.com and http://www.clinicaltrials.gov). We made a written request to the manufacturer of sumatriptan (GlaxoSmithKline) for information about both published and unpublished data, but no additional studies were identified. We did not search grey literature and abstracts.
Data collection and analysis
Selection of studies
Two review authors independently carried out the searches and selected studies for inclusion. We viewed titles and abstracts of all studies identified by electronic searches on screen and excluded any that clearly did not satisfy the inclusion criteria. We read full copies of the remaining studies to identify those suitable for inclusion. Disagreements were settled by discussion with a third review author.
Data extraction and management
Two review authors independently extracted data from included studies using a standard data extraction form. Disagreements were settled by discussion with a third review author. One author entered data into RevMan 5.1 (RevMan 2011).
Assessment of risk of bias in included studies
We assessed methodological quality using the Oxford Quality Score (Jadad 1996b).
The scale is used as follows:
Is the study randomised? If yes, give one point.
Is the randomisation procedure reported and is it appropriate? If yes, add one point; if no, deduct one point.
Is the study double‐blind? If yes, add one point.
Is the double‐blind method reported and is it appropriate? If yes, add one point; if no, deduct one point.
Are the reasons for patient withdrawals and dropouts described? If yes, add one point.
The scores for each study are reported in the Characteristics of included studies table.
We also completed a 'Risk of bias' table for each study, using assessments of random sequence generation, allocation concealment, blinding, and study size.
Measures of treatment effect
We used relative risk (or 'risk ratio', RR) to establish statistical difference. We used numbers needed to treat (NNT) and pooled percentages as absolute measures of benefit or harm.
We used the following terms to describe adverse outcomes in terms of harm or prevention of harm:
When significantly fewer adverse outcomes occurred with sumatriptan than with control (placebo or active) we used the term the number needed to treat to prevent one event (NNTp).
When significantly more adverse outcomes occurred with sumatriptan compared with control (placebo or active) we used the term the number needed to harm or cause one event (NNH).
Unit of analysis issues
We accepted randomisation at the individual patient level only.
Dealing with missing data
The most likely source of missing data was in cross‐over studies. Where this might be problematic (e.g. where data were missing for > 10% of participants), we used only first‐period data where available. In all cases (cross‐over or parallel‐group) we proposed to comment if there were substantial missing data and perform sensitivity analysis if possible.
Assessment of heterogeneity
We assessed heterogeneity of response rates using L'Abbé plots, a visual method for assessing differences in results of individual studies (L'Abbé 1987).
Assessment of reporting biases
We assessed publication bias by examining the number of participants in trials with zero effect (relative risk of 1.0) needed for the point estimate of the NNT to increase beyond a clinically useful level (Moore 2008). In this case, we specified a clinically useful level as a NNT of ≥ 8 for pain‐free at two hours, and ≥ 6 for headache relief at two hours.
Data synthesis
We analysed studies using a single dose of sumatriptan in established pain of at least moderate intensity separately from studies in which medication was taken before pain became well established or in which a second dose of medication was permitted.
We calculated effect sizes and combined data for analysis only for comparisons and outcomes where there were at least two studies and 200 participants (Moore 1998). We calculated relative risk of benefit or harm with 95% confidence intervals (CIs) using a fixed‐effect model (Morris 1995). We calculated NNT, NNTp, and NNH with 95% CIs using the pooled number of events by the method of Cook and Sackett (Cook 1995). A statistically significant difference from control is assumed when the 95% CI of the relative risk of benefit or harm does not include the number one.
We determined significant differences between NNT, NNTp, and NNH for different doses of active treatment, or between groups in the sensitivity analyses, using the z test (Tramer 1997).
We describe data from comparisons and outcomes with only one study or fewer than 200 participants in the summary tables and text where appropriate for information and comparison, but we did not analyse these data quantitatively.
Subgroup analysis and investigation of heterogeneity
We analysed different doses separately. We planned no further subgroup analysis.
Sensitivity analysis
We planned sensitivity analysis for study quality (Oxford Quality Score of 2 versus 3 or more) and for migraine type (with aura versus without aura). A minimum of two studies and 200 participants were required for any sensitivity analysis.
Results
Description of studies
Included studies
Twelve studies (10 publications) met the inclusion criteria for this review; 10 were published in full peer‐reviewed journals (Boureau 2000; Diamond 1998; Djupesland 2010; Peikert 1999; Ryan 1997 (Study 1 and Study 2); Salonen 1991; Salonen 1994 (One Nostril Study and Two Nostril Study); Wang 2007), and two were available as a Results Summary on the manufacturer's website (S2BT50; SUM40031). These studies provided data on 4755 participants.
All of the included studies recruited adult participants only, with the majority (11/12) recruiting participants between 18 and 65 years of age (mean ages ranged from 37 to 43 years), and the other recruiting participants aged 18 to 60. The majority of participants were female (78% to 88%) and had a diagnosis of migraine without aura (70% to 91%). Most studies (10/12) required participants to have had at least a one‐year history of migraine attacks prior to screening, and all required treated attacks to meet IHS diagnostic criteria (IHS 1988; IHS 2004). Four studies required participants to discontinue any prophylactic medication before receiving study medication, while three studies allowed stable prophylactic medications (often excluding monoamine oxidase inhibitors, methysergide, propanolol, and ergotamine or ergotamine‐containing medications); the remaining five studies did not report on prophylaxis. Seven studies restricted participants from taking study medication within a defined time period of other acute migraine medications. This was most often 24 hours for any opiate, ergotamine, or triptan use; and six hours for any simple analgesics or antiemetics.
Participants were generally excluded for: pregnancy or breast‐feeding; inadequate contraception; confirmed or suspected cardiovascular or cerebrovascular disease (particularly history of ischaemic heart disease); uncontrolled hypertension (diastolic ≥ 95 mmHg or systolic ≥ 160 mmHg); current or past drug abuse; psychiatric illness; epilepsy; hepatic disease; Raynaud's syndrome; and/or basilar, hemiplegic, or opthalmoplegic migraine. In addition, one study excluded participants if they had previously used 5HT1 agonists in the treatment of acute migraine, and one study excluded participants specifically if they had previously used either intranasal or the dispersible (i.e. disintegrating) tablet formulation of sumatriptan.
The majority of included studies (9/12) stated that migraine headache pain had to be of moderate or severe intensity before study medication could be administered. The remaining studies did not report the baseline headache intensity at which study medication was administered, but were dominated by participants treating attacks with moderate or severe pain, and provided data based specifically on this population. None of the included studies provided data for participants who treated attacks when pain was still mild.
Nearly all studies used a parallel‐group design (11/12), treating a single migraine attack (10/12). Those studies treating multiple attacks treated up to two, or three, attacks each. The response of headaches to study treatment was measured using a standard four‐point pain intensity scale in all 12 studies. The majority of the studies (11/12) reported at least one IHS preferred outcome (IHS 2000); one study failed to provide any useable data for any efficacy outcome (Boureau 2000). Half of the studies (6/12) offered participants the option of a second dose of study medication if either the initial response had been inadequate, or if the participant experienced recurrence (defined as a relapse of moderate or severe intensity headache after an initial response) (one study); or to treat recurrence alone (five studies). All studies reported allowing rescue medication if the response to study treatment was insufficient after a defined time period. Ten studies allowed some form of rescue medication after two hours, and two studies allowed it after three hours. In some cases rescue medication was available to treat recurrence as well as inadequate response, but most studies did not address this question specifically.
The 12 studies reported on eight different treatment comparisons. Ten studies used only a placebo comparator and the remaining two studies used only active comparators.
Sumatriptan 1 mg versus placebo (Salonen 1994 One Nostril Study and Two Nostril Study).
Sumatriptan 2.5 mg versus placebo (Peikert 1999).
Sumatriptan 5 mg versus placebo (Diamond 1998; Peikert 1999; Salonen 1994 One Nostril Study and Two Nostril Study).
Sumatriptan 10 mg versus placebo (Diamond 1998; Djupesland 2010; Peikert 1999; Ryan 1997 Study 1 and Study 2; S2BT50; Salonen 1994 One Nostril Study and Two Nostril Study).
Sumatriptan 20 mg versus placebo (Boureau 2000; Diamond 1998; Djupesland 2010; Peikert 1999; Ryan 1997 Study 1 and Study 2; S2BT50; Salonen 1994 One Nostril Study and Two Nostril Study; SUM40031; Wang 2007).
Sumatriptan 20 mg versus dihydroergotamine (DHE) 1 mg intranasal (Boureau 2000).
Sumatriptan 20 mg versus rizatriptan 10 mg oral wafer (SUM40031).
Sumatriptan 40 mg versus placebo (Salonen 1991; Salonen 1994 One Nostril Study and Two Nostril Study).
In total, 74 participants were treated with sumatriptan 1 mg, 123 with sumatriptan 2.5 mg, 496 with sumatriptan 5 mg, 1046 with sumatriptan 10 mg, 1695 with sumatriptan 20 mg, 114 with sumatriptan 40 mg, 809 with placebo, 198 with intranasal DHE 1 mg, and 200 with rizatriptan wafer 10 mg.
Full details of included studies are provided in the Characteristics of included studies table.
Excluded studies
No studies required the authors to read the full publication in order to be excluded.
Risk of bias in included studies
Included studies were all randomised and double‐blind. Half of the studies did not provided adequate information about withdrawals and dropouts. We determined the methodological quality of the trials using the Oxford Quality Scale. One study scored 5 of 5 on the scale, one scored 4 of 5, six scored 3 of 5, and four scored 2 of 5. Points were lost due to inadequate description of the methods of randomisation or double‐blinding, and also lack of information about withdrawals and dropouts. Details are provided in the Characteristics of included studies table.
In addition, we created a 'Risk of bias' table which considered random sequence generation, allocation concealment, blinding, and study size (Figure 1). We considered no studies to be at high risk of bias from sequence generation, allocation concealment, or blinding, although we considered only five studies to be at low risk of bias from blinding, and only one from sequence generation. Five studies (Djupesland 2010; Salonen 1991; Salonen 1994 One Nostril Study and Two Nostril Study; Wang 2007) did not include 50 or more participants in each treatment arm and we therefore considered them to be at high risk of bias from their size.
1.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Effects of interventions
Details of results for efficacy in individual studies are provided in Appendix 5.
Pain‐free at two hours
Sumatriptan 10 mg versus placebo
Five studies (1115 participants) provided data (Djupesland 2010; Peikert 1999; Ryan 1997 Study 1 and Study 2; S2BT50).
The proportion of participants pain‐free at two hours with sumatriptan 10 mg was 24% (157/655; range 21% to 54%).
The proportion of participants pain‐free at two hours with placebo was 10% (47/460; range 4% to 25%).
The relative benefit of treatment compared with placebo was 2.5 (1.8 to 3.4; Analysis 2.1); the NNT was 7.3 (5.5 to 11).
2.1. Analysis.
Comparison 2 Sumatriptan nasal spray 10 mg versus placebo, Outcome 1 Pain‐free at 2 h.
Sumatriptan 20 mg versus placebo
Six studies (1379 participants) provided data (Djupesland 2010; Peikert 1999; Ryan 1997 Study 1 and Study 2; S2BT50; Wang 2007).
The proportion of participants pain‐free at two hours with sumatriptan 20 mg was 32% (283/891; range 25% to 57%).
The proportion of participants pain‐free at two hours with placebo was 11% (52/488; range 4% to 25%).
The relative benefit of treatment compared with placebo was 3.1 (2.4 to 4.1; Analysis 3.1; Figure 2); the NNT was 4.7 (4.0 to 5.9).
3.1. Analysis.
Comparison 3 Sumatriptan nasal spray 20 mg versus placebo, Outcome 1 Pain‐free at 2 h.
2.
Forest plot of comparison: 3 Sumatriptan nasal spray 20 mg versus placebo, outcome: 3.1 Pain‐free at 2 h.
Sumatriptan 20 mg was significantly more effective than sumatriptan 10 mg (z = 2.43; P = 0.015; see Summary of Results B).
Other doses of sumatriptan versus placebo
Two studies (Peikert 1999; Salonen 1991) provided data on other doses of sumatriptan, including 2.5 mg, 5 mg, and 40 mg doses. The proportion of participants who were pain‐free at two hours was 13% (16/122), 21% (26/122), and 53% (19/36), respectively, for the 2.5 mg, 5 mg, and 40 mg doses of sumatriptan, compared to 11% (11/101) with placebo.
Sumatriptan versus active comparators
One study (SUM40031) provided data comparing sumatriptan 20 mg with rizatriptan wafer 10 mg. The proportion of participants who were pain‐free at two hours was 37% (76/208) with sumatriptan 20 mg and 40% (79/200) with rizatriptan.
Pain‐free at one hour
Sumatriptan 20 mg versus placebo
Two studies (499 participants) provided data (S2BT50; Wang 2007).
The proportion of participants pain‐free at one hour with sumatriptan 20 mg was 12% (39/320; range 11% to 25%).
The proportion of participants pain‐free at one hour with placebo was 2% (4/179; range 1% to 7%).
The relative benefit of treatment compared with placebo was 6.2 (2.2 to 18; Analysis 3.2); the NNT was 10 (7.1 to 17).
3.2. Analysis.
Comparison 3 Sumatriptan nasal spray 20 mg versus placebo, Outcome 2 Pain‐free at 1 h.
Other doses of sumatriptan versus placebo
Two studies (S2BT50; Salonen 1991) provided data on other doses of sumatriptan, including 10 mg and 40 mg. The proportion of participants pain‐free at one hour was 10% (29/288) and 33% (12/36) for the 10 mg and 40 mg doses, respectively, compared with 1% (2/151) and 11% (4/37) of the placebo‐treated participants.
Sumatriptan versus active comparators
One study (SUM40031) provided data comparing sumatriptan 20 mg with rizatriptan wafer 10 mg. The proportion of participants who were pain‐free at one hour was 16% (34/208) with sumatriptan 20 mg and 15% (30/200) with rizatriptan.
Headache relief at one hour
Sumatriptan 5 mg versus placebo
Four studies (830 participants) provided data (Diamond 1998; Peikert 1999; Salonen 1994 One Nostril Study and Two Nostril Study).
The proportion of participants with headache relief at one hour with sumatriptan 5 mg was 39% (193/496; range 31% to 48%).
The proportion of participants with headache relief at one hour with placebo was 28% (95/334; range 25% to 34%).
The relative benefit of treatment compared with placebo was 1.4 (1.1 to 1.7; Analysis 1.1); the NNT was 9.6 (5.9 to 25).
1.1. Analysis.
Comparison 1 Sumatriptan nasal spray 5 mg versus placebo, Outcome 1 Headache relief at 1 h.
Sumatriptan 10 mg versus placebo
Eight studies (1755 participants) provided data (Djupesland 2010; Diamond 1998; Peikert 1999; Ryan 1997 Study 1 and Study 2; S2BT50; Salonen 1994 One Nostril Study and Two Nostril Study).
The proportion of participants with headache relief at one hour with sumatriptan 10 mg was 38% (392/1025; range 31% to 73%).
The proportion of participants with headache relief at one hour with placebo was 25% (180/730; range 14% to 38%).
The relative benefit of treatment compared with placebo was 1.6 (1.4 to 1.9; Analysis 2.2); the NNT was 7.4 (5.6 to 11).
2.2. Analysis.
Comparison 2 Sumatriptan nasal spray 10 mg versus placebo, Outcome 2 Headache relief at 1 h.
Sumatriptan 20 mg versus placebo
Nine studies (2020 participants) provided data (Djupesland 2010; Diamond 1998; Peikert 1999; Ryan 1997 Study 1 and Study 2; S2BT50; Salonen 1994 One Nostril Study and Two Nostril Study; Wang 2007).
The proportion of participants with headache relief at one hour with sumatriptan 20 mg was 46% (579/1262; range 34% to 74%).
The proportion of participants with headache relief at one hours with placebo was 25% (192/758; range 14% to 43%).
The relative benefit of treatment compared with placebo was 1.9 (1.6 to 2.2; Analysis 3.3); the NNT was 4.9 (4.1 to 6.1).
3.3. Analysis.
Comparison 3 Sumatriptan nasal spray 20 mg versus placebo, Outcome 3 Headache relief at 1 h.
Sumatriptan 20 mg was significantly more effective than sumatriptan 10 mg (z = 2.28; P = 0.023; see Summary of Results B).
Sumatriptan 40 mg versus placebo
Three studies (220 participants) provided data (Salonen 1991; Salonen 1994 One Nostril Study and Two Nostril Study).
The proportion of participants with headache relief at one hour with sumatriptan 40 mg was 59% (66/112; range 58% to 64%).
The proportion of participants with headache relief at one hour with placebo was 32% (35/108; range 30% to 34%).
The relative benefit of treatment compared with placebo was 1.8 (1.3 to 2.5); Analysis 4.1); the NNT was 3.8 (2.6 to 7.2).
4.1. Analysis.
Comparison 4 Sumatriptan nasal spray 40 mg versus placebo, Outcome 1 Headache relief at 1 h.
Other doses of sumatriptan versus placebo
Two studies (Salonen 1994 One Nostril Study and Two Nostril Study ‐ with fewer than 200 participants) provided data on sumatriptan 1 mg versus placebo. The proportion of participants with headache relief at one hour was 27% (20/73) with sumatriptan 1 mg and 34% (24/71) with placebo. One study (Peikert 1999) provided data on sumatriptan 2.5 mg versus placebo. The proportion of participants with headache relief at one hour with sumatriptan 2.5 mg was 28% (34/122) compared with 25% (16/64) treated with placebo.
Sumatriptan versus active comparators
One study (SUM40031) provided data comparing sumatriptan 20 mg with rizatriptan wafer 10 mg. The proportion of participants with headache relief at one hour was 50% (103/208) with sumatriptan 20 mg and 48% (95/200) with rizatriptan.
Headache relief at two hours
Sumatriptan 5 mg versus placebo
Four studies (830 participants) provided data (Diamond 1998; Peikert 1999; Salonen 1994 One Nostril Study and Two Nostril Study).
The proportion of participants with headache relief at two hours with sumatriptan 5 mg was 48% (236/496; range 45% to 57%).
The proportion of participants with headache relief at two hours with placebo was 34% (114/334; range 25% to 38%).
The relative benefit of treatment compared with placebo was 1.4 (1.2 to 1.7; Analysis 1.2); the NNT was 7.4 (5.0 to 15).
1.2. Analysis.
Comparison 1 Sumatriptan nasal spray 5 mg versus placebo, Outcome 2 Headache relief at 2 h.
Sumatriptan 10 mg versus placebo
Eight studies (1755 participants) provided data (Djupesland 2010; Diamond 1998; Peikert 1999; Ryan 1997 Study 1 and Study 2; S2BT50; Salonen 1994 One Nostril Study and Two Nostril Study).
The proportion of participants with headache relief at two hours with sumatriptan 10 mg was 50% (510/1025; range 42% to 84%).
The proportion of participants with headache relief at two hours with placebo was 32% (230/730; range 23% to 44%).
The relative benefit of treatment compared with placebo was 1.6 (1.4 to 1.8; Analysis 2.3); the NNT was 5.5 (4.4 to 7.3).
2.3. Analysis.
Comparison 2 Sumatriptan nasal spray 10 mg versus placebo, Outcome 3 Headache relief at 2 h.
Sumatriptan 20 mg versus placebo
Nine studies (2020 participants) provided data (Djupesland 2010; Diamond 1998; Peikert 1999; Ryan 1997 Study 1 and Study 2; S2BT50; Salonen 1994 One Nostril Study and Two Nostril Study; Wang 2007).
The proportion of participants with headache relief at two hours with sumatriptan 20 mg was 61% (767/1262; range 52% to 80%).
The proportion of participants with headache relief at two hours with placebo was 32% (245/758; range 23% to 54%).
The relative benefit of treatment compared with placebo was 1.9 (1.7 to 2.2; Analysis 3.4; Figure 3); the NNT was 3.5 (3.1 to 4.1).
3.4. Analysis.
Comparison 3 Sumatriptan nasal spray 20 mg versus placebo, Outcome 4 Headache relief at 2 h.
3.
Forest plot of comparison: 3 Sumatriptan nasal spray 20 mg versus placebo, outcome: 3.4 Headache relief at 2 h.
Sumatriptan 20 mg was significantly more effective than sumatriptan 10 mg (z = 3.20; P = 0.002; see Summary of Results B).
Sumatriptan 40 mg versus placebo
Three studies (220 participants) provided data (Salonen 1991; Salonen 1994 One Nostril Study and Two Nostril Study).
The proportion of participants with headache relief at two hours with sumatriptan 40 mg was 69% (77/112; range 66% to 75%).
The proportion of participants with headache relief at two hours with placebo was 36% (39/108; range 32% to 38%).
The relative benefit of treatment compared with placebo was 1.9 (1.4 to 2.5; Analysis 4.2); the NNT was 3.1 (2.2 to 5.0).
4.2. Analysis.
Comparison 4 Sumatriptan nasal spray 40 mg versus placebo, Outcome 2 Headache relief at 2 h.
Other doses of sumatriptan versus placebo
Two studies (Salonen 1994 One Nostril Study and Two Nostril Study ‐ with fewer than 200 participants) provided data on sumatriptan 1 mg versus placebo. The proportion of participants with headache relief at two hours was 38% (28/73) with sumatriptan 1 mg and 38% (27/71) with placebo. One study (Peikert 1999) provided data on sumatriptan 2.5 mg versus placebo. The proportion of participants with headache relief at two hours with sumatriptan 2.5 mg was 37% (45/122) compared with 25% (16/64) treated with placebo.
Sumatriptan versus active comparators
One study (SUM40031) provided data comparing sumatriptan 20 mg with rizatriptan wafer 10 mg. The proportion of participants with headache relief at two hours was 65% (136/208) with sumatriptan 20 mg and 71% (141/200) with rizatriptan.
Sustained pain‐free during the 24 hours postdose
None of the included studies reported on the IHS‐preferred outcome of sustained pain‐free during the 24 hours postdose. One study (Djupesland 2010) reported instead, the proportion of participants with a 48‐hour sustained pain‐free response (defined as pain‐free at two hours with no use of rescue medication or relapse within 48 hours). The proportion of participants achieving a 48‐hour sustained pain‐free response after sumatriptan 10 mg and 20 mg was 47% (17/37) and 49% (17/35), respectively, while 22% (7/32) of placebo‐treated participants achieved the same response.
Sustained headache relief during the 24 hours postdose
Only one study (S2BT50) reported on the proportion of participants with sustained headache relief during the 24 hours postdose (defined as headache relief at two hours with no use of rescue medication or relapse within 24 hours). The proportion of participants with 24‐hour sustained headache relief after sumatriptan 10 mg and 20 mg was 19% (56/288) and 27% (78/292), respectively, while 10% (15/151) of placebo‐treated participants achieved the same response.
| Summary of results A: Pain‐free and headache relief in placebo controlled studies | ||||||
| Studies |
Attacks treated |
Treatment (%) | Placebo (%) |
Relative risk (95% CI) |
NNT (95% CI) |
|
| Pain‐free at 2 hours | ||||||
| Sumatriptan 10 mg | 5 | 1115 | 24 | 10 | 2.5 (1.8 to 3.4) | 7.3 (5.5 to 11) |
| Sumatriptan 20 mg | 6 | 1379 | 32 | 11 | 3.1 (2.4 to 4.1) | 4.7 (4.0 to 5.9) |
| Pain‐free at 1 hour | ||||||
| Sumatriptan 20 mg | 2 | 499 | 12 | 2 | 6.2 (2.2 to 18) | 10 (7.1 to 17) |
| Headache relief at 1 hour | ||||||
| Sumatriptan 5 mg | 4 | 830 | 39 | 28 | 1.4 (1.1 to 1.7) | 9.6 (5.9 to 25) |
| Sumatriptan 10 mg | 8 | 1755 | 38 | 25 | 1.6 (1.4 to 1.8) | 7.4 (5.6 to 11) |
| Sumatriptan 20 mg | 9 | 2020 | 46 | 25 | 1.9 (1.6 to 2.2) | 4.9 (4.1 to 6.1) |
| Sumatriptan 40 mg | 3 | 220 | 59 | 32 | 1.8 (1.3 to 2.5) | 3.8 (2.6 to 7.2) |
| Headache relief at 2 hours | ||||||
| Sumatriptan 5 mg | 4 | 830 | 48 | 34 | 1.4 (1.2 to 1.7) | 7.4 (5.0 to 15) |
| Sumatriptan 10 mg | 8 | 1755 | 50 | 32 | 1.6 (1.4 to 1.8) | 5.5 (4.4 to 7.3) |
| Sumatriptan 20 mg | 9 | 2020 | 61 | 32 | 1.9 (1.7 to 2.2) | 3.5 (3.1 to 4.1) |
| Sumatriptan 40 mg | 3 | 220 | 69 | 36 | 1.9 (1.4 to 2.5) | 3.1 (2.2 to 5.0) |
| Summary of results B: Statistical tests for the effect of dose | ||
| z | P | |
| Pain‐free at 2 hours | ||
| Sumatriptan 10 mg versus sumatriptan 20 mg | 2.43 | 0.015 |
| Headache relief at 1 hour | ||
| Sumatriptan 10 mg versus sumatriptan 20 mg | 2.28 | 0.023 |
| Headache relief at 2 hours | ||
| Sumatriptan 10 mg versus sumatriptan 20 mg | 3.20 | 0.002 |
Subgroup analyses
Single dose in single nostril versus split dose between two nostrils
Most of the included studies treated participants with a single insufflation of study medication to one nostril, while two studies (Salonen 1991; Salonen 1994 Two Nostril Study) treated participants with a split dose as two insufflations of study medication, one to each nostril. There were insufficient data to assess the effect of splitting the dose between two nostrils on the efficacy of sumatriptan.
Sensitivity analyses
We carried out sensitivity analyses to take into consideration and assess the effect of variation in methodological quality of the included studies. We considered studies with an Oxford Quality Score of 2 of 5 to be at greater risk of bias and we therefore analysed them separately for each outcome. Where there were insufficient data to provide a meaningful comparison of these lower‐quality trials with the higher‐quality trials (scoring 3 or more out of 5) for a particular outcome, we performed sensitivity analyses simply to remove the lower‐quality trials from the original all‐trials analyses.
There were insufficient data to carry out any sensitivity analyses for participants with and without aura.
Pain‐free at two hours
Sumatriptan 10 mg versus placebo
Of the five studies originally analysed comparing sumatriptan 10 mg with placebo, two had a quality score of 2/5 (Ryan 1997 Study 1 and Study 2). Removing these studies from the analysis made no significant difference to the calculated relative benefit of treatment versus placebo (analysis not shown).
Sumatriptan 20 mg versus placebo
Of the six studies originally analysed comparing sumatriptan 20 mg with placebo, two had a quality score of 2/5 (Ryan 1997 Study 1 and Study 2). Removing these studies from the analysis made no significant difference to the calculated relative benefit of treatment versus placebo (analysis not shown).
Pain‐free at one hour
Neither of the two studies originally analysed for pain‐free at one hour had a quality score of less than 3/5.
Headache relief at one hour
Sumatriptan 5 mg versus placebo
Of the four studies originally analysed comparing sumatriptan 5 mg with placebo, two had a quality score of 2/5 (Salonen 1994 One Nostril Study and Two Nostril Study). Removing these studies from the analysis made no significant difference to the calculated relative benefit of treatment versus placebo (analysis not shown).
Sumatriptan 10 mg versus placebo
Of the seven studies originally analysed comparing sumatriptan 10 mg with placebo, four had a quality score of 2/5 (Ryan 1997 Study 1 and Study 2; Salonen 1994 One Nostril Study and Two Nostril Study). Removing these studies from the analysis made no significant difference to the calculated relative benefit of treatment versus placebo (analysis not shown).
Sumatriptan 20 mg versus placebo
Of the eight studies originally analysed comparing sumatriptan 20 mg with placebo, four had a quality score of 2/5 (Ryan 1997 Study 1 and Study 2; Salonen 1994 One Nostril Study and Two Nostril Study). Removing these studies from the analysis made no significant difference to the calculated relative benefit of treatment versus placebo (analysis not shown).
Headache relief at two hours
Sumatriptan 5 mg versus placebo
Of the four studies originally analysed comparing sumatriptan 5 mg with placebo, two had a quality score of 2/5 (Salonen 1994 One Nostril Study and Two Nostril Study). Removing these studies from the analysis made no significant difference to the calculated relative benefit of treatment versus placebo (analysis not shown).
Sumatriptan 10 mg versus placebo
Of the seven studies originally analysed comparing sumatriptan 10 mg with placebo, four had a quality score of 2/5 (Ryan 1997 Study 1 and Study 2; Salonen 1994 One Nostril Study and Two Nostril Study). Removing these studies from the analysis made no significant difference to the calculated relative benefit of treatment versus placebo (analysis not shown).
Sumatriptan 20 mg versus placebo
Of the eight studies originally analysed comparing sumatriptan 20 mg with placebo, four had a quality score of 2/5 (Ryan 1997 Study 1 and Study 2; Salonen 1994 One Nostril Study and Two Nostril Study). Removing these studies from the analysis made no significant difference to the calculated relative benefit of treatment versus placebo (analysis not shown).
Use of rescue medication
All studies allowed participants whose symptoms were not adequately controlled to take additional rescue or 'escape' medication (usually a different analgesic). Participants were asked to wait, usually for two hours, before taking any additional medication in order to give the test medication enough time to have an effect. The number of participants using rescue medication at or after a defined time point was reported in some studies and is a measure of treatment failure (lack of efficacy). The time over which use of rescue medication was measured varied between studies; some reported use at two hours (Djupesland 2010; Salonen 1991), while others reported use at three hours (Salonen 1994), and others reported use up to 24 hours (Peikert 1999; S2BT50; SUM40031).
This inconsistency in reporting limited any pooled analysis of the use of rescue medication.
Sumatriptan 10 mg versus placebo
Two studies (640 participants) provided data for the use of rescue medication up to 24 hours after initial dosing (Peikert 1999; S2BT50).
The proportion of participants requiring rescue medication with sumatriptan 10 mg was 41% (171/420; range 29% to 71%).
The proportion of participants requiring rescue medication with placebo was 49% (108/220; range 37% to 78%).
The relative benefit of treatment compared with placebo was 0.84 (0.72 to 0.99; Analysis 2.4); the NNTp was 12 (6.1 to 370).
2.4. Analysis.
Comparison 2 Sumatriptan nasal spray 10 mg versus placebo, Outcome 4 Use of rescue medication within 24 h.
Sumatriptan 20 mg versus placebo
Two studies (642 participants) provided data for the use of rescue medication up to 24 hours after initial dosing (Peikert 1999; S2BT50).
The proportion of participants requiring rescue medication with sumatriptan 20 mg was 32% (136/422; range 22% to 59%).
The proportion of participants requiring rescue medication with placebo was 49% (108/220; range 37% to 78%).
The relative benefit of treatment compared with placebo was 0.66 (0.55 to 0.79; Analysis 3.5); the NNTp was 5.9 (4.0 to 11).
3.5. Analysis.
Comparison 3 Sumatriptan nasal spray 20 mg versus placebo, Outcome 5 Use of rescue medication within 24 h.
There was no significant difference between sumatriptan 10 mg and 20 mg for the use of rescue medication within 24 hours of initial dosing.
Other doses of sumatriptan versus placebo or active comparators
Djupesland 2010 compared sumatriptan 10 mg and 20 mg with placebo for the use of rescue medication at two hours after dosing. The proportion of participants using rescue medication ranged from 11% (4/37) to 26% (9/35) for those treating with sumatriptan, compared with 38% (12/32) for those treating with placebo.
Salonen 1991 compared sumatriptan 40 mg with placebo for use of rescue medication at two hours after dosing. Thirty‐two percent (12/37) of participants treating with sumatriptan required rescue medication, compared with 84% (31/37) of placebo‐treated participants.
Salonen 1994 provided data comparing sumatriptan 20 mg and 40 mg with placebo for the use of rescue medication up to three hours after dosing. The proportion of participants using rescue medication ranged from 15% (6/41) to 31% (11/35) for those treating with sumatriptan compared with 35% (14/40) to 56% (18/32) for those treating with placebo.
Peikert 1999 compared sumatriptan 2.5, 5, 10, and 20 mg with placebo for the use of rescue medication up to 24 hours after dosing. The proportion of participants using rescue medication ranged from 59% (71/120) to 77% (94/122) in those treating with sumatriptan, compared with 78% (50/64) of those treating with placebo.
SUM40031 compared sumatriptan 20 mg with rizatriptan wafer 10 mg for use of rescue medication within 24 hours of dosing. Twenty‐eight percent (59/208) of sumatriptan‐treated participants required rescue medication compared with 22% (44/200) of rizatriptan‐treated participants.
Relief of headache‐associated symptoms
In general, relief of headache‐associated symptoms (defined as a symptom reduction from any intensity at baseline to none at two hours) was inconsistently reported. Of the four studies that reported any data for symptom relief, only two reported on relief of all four major symptoms of interest. Some studies did not report baseline incidence of associated symptoms from which relief could be calculated, but did report presence of symptoms two hours after treatment. The incidence of vomiting was very low in all studies and where reported did not permit analysis.
Two studies providing data on relief of associated symptoms (Peikert 1999; S2BT50) included a small number (< 10%) of participants with mild baseline pain intensity. It is possible that these participants had fewer or less severe associated symptoms, but the number was considered small enough that even if this were so, there would not be a major effect on the overall result; these studies were therefore included in pooled analyses.
Effects of treatment on relieving associated symptoms are presented in Summary of results C.
Sumatriptan at doses of 10 mg and 20 mg showed efficacy in relief of the associated symptoms of nausea, photophobia, and phonophobia compared to placebo. In addition, sumatriptan 5 mg was more effective than placebo for the relief of nausea alone. Sumatriptan was equally effective at relieving each of the three associated symptoms. About 50% to 60% of nausea present at baseline was relieved within two hours of sumatriptan treatment, while only about 30% was relieved with placebo (Analysis 1.3; Analysis 2.5; Analysis 3.6), giving NNTs of 6.4, 6.4, and 4.1 for the 5 mg, 10 mg, and 20 mg doses, respectively. About 35% to 50% of photophobia and 40% to 50% of phonophobia present at baseline was relieved within two hours of sumatriptan treatment, compared with about 25% after placebo treatment (Analysis 2.5; Analysis 3.6), giving NNTs for the 10 mg and 20 mg doses of 7.9 and 4.0 for relief of photophobia, and 6.8 and 4.1 for relief of phonophobia. The 20 mg dose gave significantly better (lower) NNTs for relief of all three associated symptoms than the 10 mg dose (Summary of results D).
1.3. Analysis.
Comparison 1 Sumatriptan nasal spray 5 mg versus placebo, Outcome 3 Relief of associated symptoms.
2.5. Analysis.
Comparison 2 Sumatriptan nasal spray 10 mg versus placebo, Outcome 5 Relief of associated symptoms.
3.6. Analysis.
Comparison 3 Sumatriptan nasal spray 20 mg versus placebo, Outcome 6 Relief of associated symptoms.
One study (SUM40031) provided data comparing sumatriptan 20 mg with rizatriptan 10 mg for the relief of headache‐associated symptoms. The proportion of participants with relief of nausea, photophobia, and phonophobia at two hours was 54% (70/129), 56% (75/135), and 55% (87/158), respectively, for sumatriptan‐treated participants, versus 73% (92/126), 64% (87/135), and 60% (86/143) for rizatriptan‐treated participants.
| Summary of results C: relief of associated symptoms at 2 hours in placebo controlled studies | ||||||
| Intervention | Studies |
Attacks with symptom present |
Treatment (%) | Placebo (%) |
Relative risk (95% CI) |
NNT (95% CI) |
| Nausea | ||||||
| Sumatriptan 5 mg | 2 | 476 | 48 | 32 | 1.5 (1.2 to 1.9) | 6.4 (4.1 to 15) |
| Sumatriptan 10 mg | 5 | 1098 | 50 | 34 | 1.5 (1.3 to 1.7) | 6.4 (4.7 to 10) |
| Sumatriptan 20 mg | 5 | 1272 | 59 | 34 | 1.7 (1.5 to 2.0) | 4.1 (3.3 to 5.3) |
| Photophobia | ||||||
| Sumatriptan 10 mg | 3 | 841 | 36 | 24 | 1.5 (1.2 to 1.9) | 7.9 (5.3 to 15) |
| Sumatriptan 20 mg | 3 | 1021 | 49 | 24 | 2.1 (1.7 to 2.5) | 4.0 (3.2 to 5.1) |
| Phonophobia | ||||||
| Sumatriptan 10 mg | 3 | 767 | 42 | 27 | 1.5 (1.2 to 1.9) | 6.8 (4.7 to 13) |
| Sumatriptan 20 mg | 3 | 933 | 52 | 27 | 1.9 (1.6 to 2.3) | 4.1 (3.3 to 5.4) |
| Summary of results D: Statistical tests for the effect of dose | ||
| z | P | |
| Nausea | ||
| Sumatriptan 10 mg versus sumatriptan 20 mg | 2.17 | 0.030 |
| Photophobia | ||
| Sumatriptan 10 mg versus sumatriptan 20 mg | 2.93 | 0.003 |
| Phonophobia | ||
| Sumatriptan 10 mg versus sumatriptan 20 mg | 2.14 | 0.032 |
We also analysed studies according to the presence of associated symptoms two hours after treatment, irrespective of whether they were present at baseline, and calculated NNTps (Appendix 6). Significantly fewer participants reported nausea, photophobia, and phonophobia with sumatriptan 10 mg and 20 mg than with placebo. Sumatriptan was found to be most effective against photophobia at two hours, with NNTps ranging from 4.2 to 8.1, and slightly less effective against nausea and phonophobia, with NNTps ranging from 5.1 to 9.5. There was no substantial difference between sumatriptan of either dose and placebo for incidence of vomiting at two hours (while the higher dose produced a statistically significant benefit over placebo, the NNTp of 27 is unlikely to be of any clinical significance). In general, the 20 mg dose of sumatriptan resulted in better (lower) NNTps for presence of associated symptoms after two hours; however, this reached statistical significance only for photophobia (P = 0.008).
Relief of functional disability
Only two studies (Djupesland 2010; Peikert 1999) reported on relief of functional disability (defined as improvement from moderate or severe disability at baseline to mild or none at two hours on a four‐point scale).
One study providing data on relief of functional disability (Peikert 1999) included a small number (˜1%) of participants with mild baseline pain intensity. It is possible that these participants had fewer or less severe symptoms, but the number was considered small enough that even if this were so, there would not be a major effect on the overall result; this study was therefore included in pooled analyses.
Sumatriptan 10 mg versus placebo
Two studies (214 participants) provided data (Djupesland 2010; Peikert 1999).
The proportion of participants with relief of functional disability at two hours with sumatriptan 10 mg was 48% (64/133; range 46% to 57%).
The proportion of participants with relief of functional disability at two hours with placebo was 16% (13/81; range 15% to 16%).
The relative benefit of treatment compared with placebo was 3.0 (1.8 to 5.1; Analysis 2.6); the NNT was 3.1 (2.3 to 4.9).
2.6. Analysis.
Comparison 2 Sumatriptan nasal spray 10 mg versus placebo, Outcome 6 Relief of functional disability at 2 h.
Sumatriptan 20 mg versus placebo
Two studies (225 participants) provided data (Djupesland 2010; Peikert 1999).
The proportion of participants with relief of functional disability at two hours with sumatriptan 20 mg was 62% (89/144; range 59% to 63%).
The proportion of participants with relief of functional disability at two hours with placebo was 16% (13/81, range 15% to 16%).
The relative benefit of treatment compared with placebo was 3.8 (2.3 to 6.4; Analysis 3.7); the NNT was 2.2 (1.8 to 2.9).
3.7. Analysis.
Comparison 3 Sumatriptan nasal spray 20 mg versus placebo, Outcome 7 Relief of functional disability at 2 h.
There was no significant difference between the 10 mg and 20 mg doses for relief of functional disability at two hours.
Some studies (Diamond 1998; Ryan 1997 Study 1 and Study 2) did not report baseline incidence of functional disability from which relief could be calculated, but did report presence of disability two hours after treatment. We therefore also analysed studies according to the presence of functional disability (of moderate or severe intensity on a four‐point scale) two hours after treatment, and calculated NNTps (Appendix 6). Sumatriptan 5 mg, 10 mg, and 20 mg resulted in fewer participants with functional disability compared with placebo, with the 20 mg appearing to be more effective (NNTp 4.4, P = 0.024) than the two smaller doses (NNTps of 9.7 and 7.2 respectively).
Adverse events
Details of results for adverse events and withdrawals in individual studies are provided in Appendix 7.
Nine studies (Boureau 2000; Djupesland 2010; Peikert 1999; S2BT50; Salonen 1991; Salonen 1994 One Nostril Study and Two Nostril Study; SUM40031; Wang 2007) reported on the total number of participants experiencing any adverse events after treatment, but there was significant variability in many details of adverse event reporting. Most studies appeared to collect data using spontaneous reports in diary cards and at follow‐up review after the end of treatment. In addition, all nine studies reported adverse events regardless of their causal relationship to the study drug. However, the duration over which data were collected was not always specified, and where it was, there were differences between studies. Four studies (Boureau 2000; S2BT50; Salonen 1991; Wang 2007) collected data during the 24 hours postdose, while one study (Djupesland 2010) collected data over 48 hours, one (SUM40031) over one to four days, and the remaining three studies (Peikert 1999; Salonen 1994 One Nostril Study and Two Nostril Study) collected data for five days after treatment. One study (Salonen 1994) also failed to report incidence of adverse events separately for each treatment arm, instead reporting a pooled incidence for all sumatriptan‐treated participants (1 mg to 40 mg) versus placebo‐treated participants.
In half of the studies a second dose of study medication could be taken, and in all but one study, rescue medication was allowed if there was an inadequate response after a given period of time. Only two studies (Boureau 2000; S2BT50) stopped collecting adverse event data when a second dose of study medication was administered, and it is likely that the other studies continued to collect data regardless of any additional medication taken.
Despite accepting these inconsistencies, there were sufficient comparable data for pooled analysis of adverse events only for the 20 mg dose of sumatriptan.
Treatments were generally described as well tolerated, with most adverse events being of mild or moderate severity and self limiting.
Participants experiencing any adverse event during the 24 hours postdose
Sumatriptan 20 mg versus placebo
Two studies (516 participants) provided data (S2BT50; Wang 2007).
The proportion of participants experiencing adverse events within 24 hours with sumatriptan 20 mg was 38% (125/331; range 35% to 66%).
The proportion of participants experiencing adverse events within 24 hours with placebo was 15% (27/185; range 10% to 41%).
The relative harm of treatment compared with placebo was 2.9 (2.0 to 4.2; Analysis 3.8; Figure 4); the NNH was 4.3 (3.3 to 6.3).
3.8. Analysis.
Comparison 3 Sumatriptan nasal spray 20 mg versus placebo, Outcome 8 Any adverse event within 24 h.
4.
Forest plot of comparison: 3 Sumatriptan nasal spray 20 mg versus placebo, outcome: 3.8 Any adverse event within 24 h.
Other doses of sumatriptan versus placebo
One study (Salonen 1991) provided data comparing sumatriptan 40 mg with placebo. The proportion of participants treated with sumatriptan experiencing any adverse event was 46% (17/37), compared with 14% (5/37) of placebo‐treated participants.
One study (Djupesland 2010) provided data comparing sumatriptan 10 mg and 20 mg with placebo. The proportion of participants treated with sumatriptan experiencing any adverse event was 18% (7/39) and 23% (9/39) for the 10 mg and 20 mg doses respectively, compared with 5% (2/39) of placebo‐treated participants.
Sumatriptan versus active comparators
Only one study (Boureau 2000) provided data comparing sumatriptan with an active comparator for the incidence of adverse events within 24 hours of treatment. The proportion of participants treated with sumatriptan 20 mg who experienced any adverse event was 10% (39/388), compared with 10% (39/385) of those treated with DHE 1 mg.
Participants experiencing specific adverse events
Two studies did not report on the incidence of individual adverse events (Boureau 2000; Salonen 1991). The remaining eight studies reported the incidence of at least one specific adverse event, although there was significant variability in the manner of reporting that further limited the number of studies that provided data for pooled analyses. As discussed previously, the duration over which adverse event data were collected varied between studies and, as with the total incidence of adverse events, four studies (Peikert 1999; Salonen 1994 One Nostril Study and Two Nostril Study; SUM40031) could not be included in any pooled analyses due to non‐comparable collection periods.
Individual adverse events were reported inconsistently between studies. The majority of studies reported only the most commonly occurring adverse events, for example those occurring in more than 3% of participants in any of the treatment arms, while others used different terms to describe the same or similar events. In order to be as inclusive as possible we have pooled related adverse events into groups (described in detail in Appendix 8). Where one study provided data on more than one event in a particular group, for example reporting both nasal discomfort and nasal stuffiness, we have used the higher incidence in order not to double‐count participants. This will lead to an underestimation of incidence if all those with the less frequent event did not also have the more frequent one.
Where two or more studies reported data for at least 200 participants investigating the incidence of specific adverse events within 24 hours of study treatment, we carried out pooled analysis to calculate the relative risk, and where appropriate the NNH (Summary of results E; Analysis 2.7; Analysis 3.9).
2.7. Analysis.
Comparison 2 Sumatriptan nasal spray 10 mg versus placebo, Outcome 7 Individual adverse events.
3.9. Analysis.
Comparison 3 Sumatriptan nasal spray 20 mg versus placebo, Outcome 9 Individual adverse events.
| Summary of results E: Number of participants experiencing specific adverse events within 24 hours of study treatment in placebo‐controlled studies | ||||||
| Studies |
Participants treated |
Treatment (%) | Placebo (%) |
Relative risk (95% CI) |
NNH (95% CI) |
|
| Malaise/fatigue/asthenia | ||||||
| Sumatriptan 20 mg | 2 | 516 | 1 | 1 | 1.0 (0.17 to 6.2) | Not calculated |
| Dizziness/vertigo | ||||||
| Sumatriptan 10 mg | 3 | 885 | 2 | 1 | 2.2 (0.65 to 7.5) | Not calculated |
| Sumatriptan 20 mg | 4 | 1146 | 2 | 1 | 1.4 (0.48 to 4.2) | Not calculated |
| Nausea/vomiting | ||||||
| Sumatriptan 10 mg | 4 | 1380 | 17 | 18 | 0.99 (0.79 to 1.2) | Not calculated |
| Sumatriptan 20 mg | 5 | 1637 | 19 | 18 | 1.1 (0.90 to 1.4) | Not calculated |
| Disturbance of taste | ||||||
| Sumatriptan 10 mg | 4 | 1380 | 22 | 1 | 15 (7.6 to 31) | 4.9 (4.3 to 5.7) |
| Sumatriptan 20 mg | 5 | 1637 | 27 | 1 | 20 (9.9 to 39) | 3.9 (3.5 to 4.4) |
| Chest pain/symptoms | ||||||
| Sumatriptan 20 mg | 2 | 516 | 1 | 1 | 2.0 (0.32 to 12) | Not calculated |
| Temperature sensations | ||||||
| Sumatriptan 10 mg | 3 | 885 | 1 | 0 | 2.1 (0.23 to 18) | Not calculated |
| Sumatriptan 20 mg | 4 | 1146 | 2 | 1 | 3.2 (0.78 to 13) | Not calculated |
| Palpitations/tachycardia | ||||||
| Sumatriptan 20 mg | 2 | 516 | 1 | 1 | 0.73 (0.11 to 4.9) | Not calculated |
| Paraesthesia/numbness | ||||||
| Sumatriptan 10 mg | 3 | 885 | 1 | 1 | 1.6 (0.40 to 6.7) | Not calculated |
| Sumatriptan 20 mg | 3 | 1088 | 1 | 1 | 1.2 (0.31 to 4.6) | Not calculated |
| Drowsiness/somnolence | ||||||
| Sumatriptan 10 mg | 3 | 885 | 1 | 1 | 1.7 (0.37 to 8.2) | Not calculated |
| Sumatriptan 20 mg | 3 | 1088 | 1 | 1 | 1.5 (0.31 to 7.6) | Not calculated |
| Disturbance of nasal cavity/sinuses | ||||||
| Sumatriptan 10 mg | 3 | 885 | 3 | 2 | 1.3 (0.53 to 3.1) | Not calculated |
| Sumatriptan 20 mg | 4 | 1146 | 4 | 2 | 2.1 (0.99 to 4.3) | Not calculated |
| Throat symptoms | ||||||
| Sumatriptan 10 mg | 4 | 1380 | 2 | 1 | 2.2 (0.92 to 5.5) | Not calculated |
| Sumatriptan 20 mg | 5 | 1637 | 3 | 1 | 2.8 (1.2 to 6.4) | 53 (31 to 180) |
Participants experiencing serious adverse events
Six studies did not specifically comment on serious adverse events (Boureau 2000; Diamond 1998; Peikert 1999; Salonen 1991; Salonen 1994 One Nostril Study and Two Nostril Study), four studies reported that there were none during the study (Djupesland 2010; Ryan 1997 Study 1 and Study 2; Wang 2007), and two (S2BT50; SUM40031) reported at least one serious adverse event.
In studies reporting occurrence of serious adverse events separately for sumatriptan and comparator treatment arms (S2BT50; SUM40031), or the absence of such events (Djupesland 2010; Ryan 1997 Study 1 and Study 2; Wang 2007), the incidence was less than 1% in any treatment arm.
Sumatriptan versus placebo
Five studies (1783 participants) provided data on sumatriptan versus placebo (Djupesland 2010; Ryan 1997 Study 1 and Study 2; S2BT50; Wang 2007).
The overall incidence of serious adverse events was 0.22% (3/1346) for all doses of sumatriptan (including second doses and rescue medication), and 0% (0/437) for placebo. There were too few events to calculate relative risk or NNH. Further details of individual studies are in Appendix 7.
Sumatriptan versus active comparators
One study (408 participants) comparing sumatriptan with rizatriptan for the incidence of serious adverse events provided data (SUM40031). The overall incidence was 0.48% (1/208) for sumatriptan 20 mg, compared with 0% (0/200) for rizatriptan 10 mg. There were too few events to calculate relative risk or NNH.
Withdrawals due to adverse events
Six studies did not specifically report on adverse event withdrawals or did not report data for each treatment arm separately. The remaining six studies reported the number of withdrawals due to adverse events per treatment group (Boureau 2000; Diamond 1998; Djupesland 2010; S2BT50; Salonen 1991; SUM40031). One study (Diamond 1998) did not report how multiple attacks were combined but was included anyway in order to be more inclusive and conservative.
In studies reporting the occurrence of adverse event withdrawals, four reported none (Djupesland 2010; S2BT50; Salonen 1991; SUM40031), and two reported an incidence in any treatment arm of less than 1% (Boureau 2000; Diamond 1998).
Sumatriptan versus placebo
Four studies (2040 participants) provided data on sumatriptan versus placebo (Diamond 1998; Djupesland 2010; S2BT50; Salonen 1991).
The overall incidence of adverse event withdrawal was 0.19% (3/1609) for all doses of sumatriptan (including second doses and rescue medication), and 0.23% (1/431) for placebo. There were too few events to calculate relative risk or NNH.
Sumatriptan versus active comparators
One study (773 participants) comparing sumatriptan 20 mg with DHE (either 1 or 2 mg depending on use of second dose) provided data for adverse event withdrawal (Boureau 2000). The overall incidence of adverse event withdrawal was 0% (0/388) for sumatriptan and 0.52% (2/385) with DHE.
One study (408 participants) comparing sumatriptan 20 mg with rizatriptan 10 mg provided data for adverse event withdrawal (SUM40031). Neither treatment resulted in any withdrawals due to adverse events.
Discussion
Summary of main results
This review included 12 randomised, double‐blind, controlled studies with 4755 participants. Ten studies had only a placebo control and the remaining two studies used only active comparators (dihydroergotamine (DHE) and rizatriptan). Sumatriptan was studied in doses of 1, 2.5, 5, 10, 20, and 40 mg as an intranasal spray (given either as a single insufflation in one nostril or two insufflations, one in each nostril). Most of the data were for the 10 mg and 20 mg doses. In every study the majority of participants treated established attacks of moderate to severe intensity so no separate analyses were carried out for mild baseline pain.
For all efficacy outcomes, sumatriptan was superior to placebo, although lower doses did not always give clinically useful numbers needed to treat (NNTs). The remarkably consistent response between studies for the primary outcomes, as illustrated by L'Abbé plots (Appendix 9), was not unexpected given the inclusion criteria for the studies and the well‐defined outcomes. There was a trend for lower (better) NNTs at higher doses, with significant differences between 10 mg and 20 mg sumatriptan for pain‐free at two hours, headache relief at one hour, and headache relief at two hours, as well as for the relief of headache‐associated symptoms.
For the International Headache Society (IHS)‐preferred outcome of pain‐free at two hours, sumatriptan 10 mg and 20 mg versus placebo gave NNTs of 7.3 and 4.7, respectively. Response rates ranged from 24% to 32% with sumatriptan, compared to 10% to 11% for placebo. For pain‐free at one hour, sumatriptan 20 mg versus placebo gave a NNT of 10 (12% responders with sumatriptan, 2% with placebo). For headache relief at one hour, sumatriptan 5 mg, 10 mg, 20 mg, and 40 mg compared with placebo gave NNTs of 9.6, 7.4, 4.9, and 3.8, respectively (38% to 59% responders with sumatriptan, 25% to 32% with placebo), and for headache relief at two hours sumatriptan 5 mg, 10 mg, 20 mg, and 40 mg gave NNTs of 7.4, 5.5, 3.5, and 3.1, respectively, when compared with placebo (48% to 69% responders with sumatriptan, 32% to 36% with placebo).
Data were available for the use of rescue medication, and for the relief of headache‐associated symptoms and functional disability. Sumatriptan 10 mg and 20 mg compared with placebo gave NNTps of 12 and 5.9, respectively, for use of rescue medication. The number of participants requiring rescue medication after treating with sumatriptan was 41% and 32% for the 10 mg and 20 mg doses, respectively, compared with 49% of those treated with placebo. Reported headache‐associated symptoms included nausea, photophobia, and phonophobia; vomiting occurred too infrequently for reliable analysis. Sumatriptan 5, 10, and 20 mg compared with placebo gave NNTs ranging from 4.1 to 6.4 for relief of nausea at two hours, and the 10 mg and 20 mg doses gave NNTs ranging from 4 to 8 for relief of photophobia and phonophobia. Approximately half of participants treated with sumatriptan achieved relief of these symptoms, compared with approximately one‐third of those treated with placebo. Functional disability was relieved (i.e. reduced from moderate or severe at baseline to mild or none at two hours) in 48% and 62% of participants treated with sumatriptan 10 mg and 20 mg, respectively, compared with 16% of participants treated with placebo. This gave NNTs for relief of functional disability of 3.1 and 2.2 for sumatriptan 10 mg and 20 mg, respectively, when compared with placebo.
Analysis of adverse events was compromised by the variability in the time period over which the data were collected. Furthermore, studies allowed use of rescue medication for inadequate response (usually after two hours), and many allowed a second dose of study medication for headache recurrence (or sometimes lack of efficacy), without specifying whether adverse event data continued to be collected from participants who had taken additional medication. With these caveats, we chose to pool as much data as possible; however, there were sufficient comparable data for pooled analysis of adverse events for only one dose of sumatriptan. Sumatriptan 20 mg compared with placebo gave a number needed to harm (NNH) of 4.3, with 38% of sumatriptan‐treated participants experiencing an adverse event within 24 hours of treatment, compared with 15% of placebo‐treated participants. For the most part adverse events were described as mild to moderate in intensity, self limiting, and were reported more frequently in individual studies after sumatriptan treatment than placebo treatment. Serious adverse events were uncommon, and the three reported were not considered to be related to the study drug (vomiting and worsening of migraine after sumatriptan 20 mg). Withdrawals due to adverse events were also uncommon. In placebo‐controlled studies the rate of adverse event withdrawal after treating with sumatriptan was equivalent to that after placebo. For the most part individual adverse events were no more common with sumatriptan than with placebo. The only exception to this was disturbance of taste, which occurred significantly more often after treatment with either sumatriptan 10 mg or 20 mg than placebo (incidence of 22% to 30% after sumatriptan compared to 1% after placebo), giving NNHs of 3.5 and 4.8, respectively.
Two active comparators were used in the included studies: DHE and rizatriptan. Only one study with no usable efficacy data compared sumatriptan 20 mg with DHE 1 mg, and one study compared sumatriptan 20 mg with rizatriptan 10 mg. Treatment with rizatriptan 10 mg resulted in a higher proportion of participants with headache relief at two hours and relief of the headache‐associated symptoms, nausea, photophobia, and phonophobia, by two hours than treatment with sumatriptan 20 mg. Other than that, the proportions of participants achieving outcomes, including safety outcomes, were equivalent for sumatriptan and rizatriptan.
Overall completeness and applicability of evidence
Included participants suffered from migraine in accordance with IHS criteria, with the majority suffering one to six attacks per month, and a history of attacks for at least one year. In general, treated attacks had to be established, with moderate or severe pain intensity, before medication could be taken. The use of prophylactic medication during the study period was variable, with some studies requiring participants to discontinue any prophylactic medication at least two weeks before receiving study medication, while others allowed stable prophylactic medications, and others failed to comment at all. One study excluded participants if they had previously taken 5HT1 agonists for the treatment of acute migraine, and one study excluded participants specifically if they had previously used either intranasal or the dispersible tablet formulation of sumatriptan. Overall there did not appear to be a particular bias towards a certain type of migraine patient, but some studies recruited participants through headache clinics, which may have selected for those with more severe or hard to treat pain. Individuals were carefully screened before study entry, and those with certain conditions, particularly cardio‐ or cerebrovascular disease, were excluded from the studies. Other exclusions included pregnant or lactating women, individuals with hepatic disease or who regularly experience vomiting, and individuals who suffer from frequent non‐migraine headaches or basilar, hemiplegic, or ophthalmic migraine. This may mean that the study population is not a reflection of a less carefully screened general population who may use sumatriptan.
While the majority studies reported IHS‐preferred outcomes, they did not all report all the outcomes of interest for this review so that numbers of participants in any comparison were usually smaller than numbers treated.
This review has several important limitations. There was insufficient evidence to address a number of important primary and secondary outcomes. Twenty‐four hour sustained efficacy data were reported by only a single trial (with another reporting 48‐hour sustained efficacy data), preventing any pooled analyses; while inconsistent or incomplete reporting limited the amount of data that could be pooled in analyses of important secondary outcomes. The lack of 24‐hour sustained efficacy data is particularly important due to the increased emphasis currently placed on longer‐term outcomes. There is a similar lack of stringent information about the efficacy of intranasal sumatriptan at early time points, i.e. within one hour of administration; only four of the included studies addressed the outcome of pain‐free at one hour. Another important limitation of this review is the relatively small numbers of participants in a number of the studies and treatment arms. This resulted in wide confidence intervals for some of the point estimates of efficacy, and, consequently, uncertainty over the true size of the treatment effect (Moore 1998). Finally, none of the studies included in this review address the efficacy of intranasal sumatriptan to treat migraine headache during the mild pain phase. In clinical practice many people treat their headache during this mild phase, and there is also some evidence that treating attacks in the early stages is beneficial (Gendolla 2008; Pascual 2002), particularly for more common routes of administration such as oral sumatriptan (Derry 2012a).
Quality of the evidence
The majority of included studies were of acceptable methodological quality, but 4 of the 12 were deemed to be of low quality (scoring 2 of 5 using the Oxford Quality Scale). In addition, 11 studies did not adequately describe random sequence generation, 12 studies did not provide information about allocation concealment, and seven studies did not provide details on the method of blinding. While some uncertainty therefore remains about their methodological quality, sensitivity analysis did not suggest that these studies gave significantly different results from those that provided more information. In a number of studies withdrawals and dropouts were not reported adequately by treatment group, and for some outcomes reported denominators differed from the intention‐to‐treat (ITT) population, presumably because some participants failed to record data at that point. Wherever an adequate explanation was not given we have used the ITT denominator if it gave a more conservative estimate; in general the numbers of missing participants was not sufficient to significantly alter the results. One study had at least 200 participants in each treatment arm, a further six had between 50 and 200 in one or more treatment arms (the placebo arm was often smallest with other treatment arms having over 200 participants), and five had fewer than 50 participants in all treatment arms. Overall methodological quality of the included studies was acceptable and treatment group sizes were sufficiently big to avoid major bias in the results for efficacy.
While most studies used patient diaries and reported some information about adverse events, the outcomes were not always our preferred ones, and the time over which data were collected was frequently not explicit. It is likely that data continued to be collected after intake of rescue medication or a second dose of study medication, so that total dose over the period assessed is uncertain.
Potential biases in the review process
We identified a moderate amount of data in comparisons with placebo, the majority being for the 10 mg and 20 mg doses. Over 1400 participants would need to have been involved in unpublished trials with zero treatment effects for the NNT for headache relief at two hours to increase above 6 (which we considered the limit of clinical utility in this situation) for the 20 mg dose (Moore 2008). Similarly, over 900 participants would be needed for the NNT for pain‐free at two hours to increase above 8 (considered to be the limit of clinical utility in this situation) for the 20 mg dose. It is unlikely, but not impossible, that such unidentified data exist, so publication bias is not a major concern.
The methods of review were such as to minimise bias due to the review process itself, but use of data from both phases of cross‐over studies may introduce unknown biases. For cross‐over studies a 48‐hour period between qualifying attacks should limit potential for carryover effects, but such a washout period is not always explicitly stated in reports.
We specified that a minimum of 200 participants in at least two studies were required before carrying out any pooled analysis, but ideally we would need at least 200 participants in each treatment arm where there is an event rate of 50% to be reasonably confident in the size of an effect (Moore 2010). The magnitude of effect for outcomes with fewer participants and/or lower event rates should be interpreted with caution.
Agreements and disagreements with other studies or reviews
An earlier review of sumatriptan nasal spray in the acute treatment of migraine (Dahlöf 1999) included data from eight randomised, double‐blind trials, of which all but one are included in this review. One of the unpublished studies (Glaxo Study No. S2B‐T60) has subsequently been published as Boureau 2000, which is included in this review, and the data from another study (Becker 1997) has subsequently been published again in a peer‐reviewed journal as Peikert 1999, which is also included in this review. The one study included in the Dahlöf 1999 review but not included in this review is an unpublished study comparing sumatriptan tablets with sumatriptan nasal spray (S2CM12). This study was excluded due to the absence of a placebo or active comparator arm (other than a different dose/formulation of sumatriptan; see Characteristics of excluded studies). The results of this review are consistent with those presented in Dahlöf 1999, although here we also provide pooled analyses for outcomes, including relative risks and NNTs.
Another systematic review (Oldman 2002) included six trials of intranasal sumatriptan (all included here) and reported NNTs for many of the same efficacy outcomes used in this review. For the 20 mg intranasal dose of sumatriptan, that review calculated NNTs of 3.4, 5.6, and 4.6 for headache relief at one and two hours and pain‐free at two hours, respectively. These results are consistent with the NNTs calculated in our review.
Authors' conclusions
Implications for practice.
Intranasal sumatriptan is an effective treatment for the relief of headache pain, other symptoms associated with migraine, and functional disability, with single doses of 10 mg or more providing clinically useful levels of relief. Higher doses are effective in more individuals, but at the expense of greater numbers of adverse events. Most adverse events were described as mild and of short duration.
These data suggest that a 10 mg dose may be a sensible starting dose, with increase to 20 mg if there is an inadequate response.
Implications for research.
Intranasal sumatriptan is considered most appropriate for patients who have difficulty taking oral medication. While intranasal administration may be easier than swallowing a solid tablet in the presence of nausea and vomiting, the drug itself is not well absorbed through the nasal mucosa, and must be ingested in order to be bioavailable. It is unclear whether gastric stasis and vomiting (where present) negate any advantage from the route of administration. Future studies should recruit from this subgroup of migraineurs to assess efficacy and tolerability.
There is a reasonable amount of data on the efficacy of sumatriptan in terms of pain relief, but in general reporting of long‐term (sustained to 24 hours) and secondary outcomes such as relief of headache‐associated symptoms, functional disability, and adverse events is poor. Future studies should address sustained outcomes and consistently report relief of associated symptoms, functional disability, and adverse events using standard definitions and terminology.
Additional studies are needed to establish whether treating pain early, while still mild, gives better short‐term (two‐hour) and long‐term (sustained to 24 hours) outcomes, and better patient satisfaction. Furthermore, studies directly comparing intranasal sumatriptan with other non‐oral active treatments would improve understanding of treatment options for the subgroup of patients who do not tolerate oral medications.
What's new
| Date | Event | Description |
|---|---|---|
| 29 May 2019 | Amended | Contact details updated. |
| 11 October 2017 | Review declared as stable | No new studies likely to change the conclusions are expected. |
History
Review first published: Issue 2, 2012
| Date | Event | Description |
|---|---|---|
| 1 November 2016 | Review declared as stable | See Published notes. |
Notes
This review is one of a series of reviews on sumatriptan for acute migraine attacks in adults which replaces an earlier Cochrane review of oral sumatriptan (McCrory 2003).
At November 2016, this review has been stabilised. A restricted search did not identify any potentially relevant studies likely to change the conclusions. Therefore, this review has now been stabilised following discussion with the authors and editors. If appropriate, we will update the review if new evidence likely to change the conclusions is published, or if standards change substantially which necessitate major revisions.
Acknowledgements
We would like to acknowledge the helpful comments and editorial expertise of Timothy Steiner, Douglas McCory, and Rebecca Gray, and those who contributed to the various stages of peer review.
Appendices
Appendix 1. Definitions
All terms relating to primary efficacy outcomes are defined according to the effect of the treatment on headache pain, measured using a four‐point pain intensity scale (ranging from 0 to 3 or none, mild, moderate, and severe).
Baseline pain intensity ‐ level of pain participant must be experiencing in order to receive study medication, either 1 (mild pain) or 2/3 (moderate or severe pain).
Pain‐free at two hours ‐ number of participants with a pain intensity of 0 (none) at two hours after administration of study medication, expressed as a fraction of the treated participants with the appropriate baseline pain.
Headache relief at two hours ‐ number of participants with a reduction in pain intensity from 2/3 (moderate/severe) to 0/1 (none/mild) at two hours after administration of study medication, expressed as a fraction of the treated participants with grade 2/3 baseline pain.
24‐hour sustained headache relief ‐ number of participants with a reduction in pain intensity from 2/3 (moderate/severe) to 0/1 (none/mild) at two hours after administration of study medication which is then sustained between 2 and 24 hours without recurrence of headache or use of rescue medication, expressed as a fraction of the treated participants with grade 2/3 baseline pain.
24‐hour sustained pain‐free ‐ number of participants with a pain intensity of 0 (none) at two hours after administration of study medication which is then sustained between 2 and 24 hours without recurrence of headache or use of rescue medication expressed as a fraction of the treated participants with the appropriate baseline pain.
Use of rescue medication ‐ number of participants requiring the use of additional medication to treat either recurrence of headache or an inadequate response to study medication, provided that the additional medication is not, or does not include, the study drug.
Relief of associated symptoms ‐ number of participants with an absence of a headache‐associated symptom (nausea, vomiting, photophobia, or phonophobia) at two hours after administration of study medication, expressed as a fraction of the treated participants for whom the symptom was present at baseline.
Presence of associated symptoms ‐ presence of a headache‐associated symptom (nausea, vomiting, photophobia, or phonophobia) at two hours after administration of study medication, expressed as a fraction of all treated participants.
Relief of functional disability ‐ reduction in the level of functional disability, measured using a four‐point scale, from moderate or severe disability (grade 2/3) at baseline to mild or none (grade 1/0) at two hours after administration of study medication, expressed as a fraction of the treated participants with moderate or severe functional disability at baseline.
Presence of functional disability ‐ presence of functional disability (of moderate or severe intensity) at two hours after administration of study medication, expressed as a fraction of all treated participants.
Appendix 2. Search strategy for MEDLINE (via OVID)
Serotonin Agonists/ OR Tryptamines/
(sumatriptan OR Imitrex OR Imigran).mp.
1 OR 2
Headache/ OR exp Headache Disorders/ OR exp Migraine Disorders/
(headach* OR migrain* OR cephalgi* OR cephalalgi*).mp.
4 OR 5
randomized controlled trial.pt.
controlled clinical trial.pt.
randomized.ab.
placebo.ab.
drug therapy.fs.
randomly.ab.
trial.ab.
groups.ab.
OR/7‐14
3 AND 6 AND 15
Appendix 3. Search strategy for EMBASE (via OVID)
Serotonin Agonists/ OR Tryptamines/
(sumatriptan OR Imitrex OR Imigran).mp.
1 OR 2
exp Headache and facial pain
exp Migraine
(headach* OR migrain* OR cephalgi* OR cephalalgi*).mp.
4 OR 5 OR 6
clinical trials.sh.
controlled clinical trials.sh.
randomized controlled trial.sh.
double‐blind procedure.sh.
(clin* adj25 trial*).ab.
((doubl* or trebl* or tripl*) adj25 (blind* or mask*)).ab.
placebo*.ab.
random*.ab.
OR/8‐15
3 AND 7 AND 16
Appendix 4. Search strategy for CENTRAL
MeSH descriptor Serotonin Agonists OR MeSH descriptor Tryptamines
(sumatriptan OR Imitrex OR Imigran):ti,ab,kw
1 OR 2
MeSH descriptor Headache/ OR MeSH descriptor Headache Disorders explode all trees
MeSH descriptor Migraine Disorders explode all trees
(headach* OR migrain* OR cephalgi* OR cephalalgi*):ti,ab,kw
4 OR 5 OR 6
3 AND 7
Limit 8 to Clinical Trials (CENTRAL)
Appendix 5. Summary of outcomes: efficacy
| Study ID | Treatment | Headache relief 1 h | Headache relief 2 h | Pain‐free 1 h | Pain‐free 2 h | Sustained headache relief 24 h | Sustained pain‐free 24 h | Use of rescue medication |
| Boureau 2000 | (1) Sumatriptan 20 mg (+ optional placebo at 30 mins), n = 207 (2) DHE 1 mg (+ optional 1 mg DHE at 30 mins), n = 198 |
No data | No data | No data | No data | No data | No data | No data |
| Diamond 1998 | (1) Sumatriptan 5 mg, n = 299 (2) Sumatriptan 10 mg, n = 296 (3) Sumatriptan 20 mg, n = 292 (4) Placebo, n = 199 |
1st attack (1) 119/299 (2) 129/296 (3) 130/292 (4) 55/199 |
1st attack (1) 134/299 (2) 156/296 (3) 173/292 (4) 71/199 |
No data | No data | No data | No data | No data |
| Djupesland 2010 | (1) Sumatriptan 10 mg, n = 39 (37 for efficacy) (2) Sumatriptan 20 mg, n = 39 (35 for efficacy) (3) Placebo, n = 39 (32 for efficacy) |
(1) 27/37 (2) 26/35 (3) 12/32 |
(1) 31/37 (2) 28/35 (3) 14/32 |
No data | (1) 20/37 (2) 20/35 (3) 8/32 |
No data | No data for 24 h SPF 48 h SPF: (1) 17/37 (2) 17/35 (3) 7/32 |
At 2 h: (1) 4/37 (2) 9/35 (3) 12/32 |
| Peikert 1999 | (1) Sumatriptan 2.5 mg, n = 123 (122 with moderate or severe baseline pain intensity) (2) Sumatriptan 5 mg, n = 122 (3) Sumatriptan 10 mg, n = 115 (4) Sumatriptan 20 mg, n = 120 (119 with moderate or severe baseline pain intensity) (5) Placebo, n = 64 |
(1) 34/122 (2) 38/122 (3) 41/115 (4) 61/119 (5) 16/64 |
(1) 45/122 (2) 59/122 (3) 51/115 (4) 76/119 (5) 16/64 |
No data | (1) 16/122 (2) 26/122 (3) 28/115 (4) 50/119 (5) 7/64 |
No data | No data | At 24 h: (1) 89/123 (2) 94/122 (3) 82/115 (4) 71/120 (5) 50/64 |
| Ryan 1997 | Study 1 (1) Sumatriptan 10 mg, n = 106 (2) Sumatriptan 20 mg, n = 202 (3) Placebo, n = 101 Study 2 (1) Sumatriptan 10 mg, n = 109 (2) Sumatriptan 20 mg, n = 215 (3) Placebo, n = 112 |
Study 1 (1) 32/106 (2) 93/202 (3) 31/101 Study 2 (1) 37/109 (2) 103/215 (3) 21/112 |
Study 1 (1) 56/106 (2) 127/202 (3) 35/101 Study 2 (1) 47/109 (2) 133/215 (3) 33/112 |
No data | Study 1 (1) 21/106 (2) 63/202 (3) 4/101 Study 2 (1) 25/109 (2) 69/215 (3) 22/112 |
No data | No data | No data |
| S2BT50 | (1) Sumatriptan 10 mg, n = 305 (288 with moderate or severe baseline pain intensity) (2) Sumatriptan 20 mg, n = 302 (292 with moderate or severe baseline pain intensity) (3) Placebo, n = 156 (151 with moderate or severe baseline pain intensity) |
(1) 89/288 (2) 100/292 (3) 21/151 |
(1) 120/288 (2) 153/292 (3) 34/151 |
(1) 29/288 (2) 32/292 (3) 2/151 |
(1) 63/288 (2) 72/292 (3) 6/151 |
(1) 56/288 (2) 78/292 (3) 15/151 |
No data | At 24 h: (1) 89/305 (2) 65/302 (3) 58/156 |
| Salonen 1991 | (1) Sumatriptan 40 mg (delivered as 2 insufflations separated by 15 minutes), n = 37 (36 for efficacy) (2) Placebo, n = 37 |
(1) 23/36 (2) 11/37 |
(1) 27/36 (2) 12/37 |
(1) 12/36 (2) 4/37 |
(1) 19/36 (2) 4/37 |
No data | No data | At 2 h: (1) 12/37 (2) 31/37 |
| Salonen 1994 | One Nostril Study (dose administered as single insufflation via 1 nostril) (1) Sumatriptan 1 mg, n = 40 (39 for efficacy) (2) Sumatriptan 5 mg, n = 42 (3) Sumatriptan 10 mg, n = 40 (39 for efficacy) (4) Sumatriptan 20 mg, n = 41 (41 for efficacy) (5) Sumatriptan 40 mg, n = 42 (6) Placebo, n = 40 Two Nostril Study (dose administered as 2 insufflations, 1 in each nostril) (1) Sumatriptan 1 mg, n = 34 (2) Sumatriptan 5 mg, n = 33 (3) Sumatriptan 10 mg, n = 36 (35 for efficacy) (4) Sumatriptan 20 mg, n = 40 (39 for efficacy) (5) Sumatriptan 40 mg, n = 35 (34 for efficacy) (6) Placebo, n = 32 (31 for efficacy) |
One Nostril Study (1) 10/39 (2) 21/42 (3) 20/39 (4) 25/40 (5) 22/42 (6) 11/40 Two Nostril Study (1) 10/34 (2) 15/33 (3) 17/35 (4) 24/39 (5) 22/34 (6) 13/31 |
One Nostril Study (1) 15/39 (2) 28/42 (3) 26/39 (4) 31/40 (5) 25/42 (6) 14/40 Two Nostril Study (1) 13/34 (2) 15/33 (3) 23/35 (4) 29/39 (5) 25/34 (6) 13/31 |
No data | No data | No data | No data | At 3 h: One Nostril Study (1) no data (2) no data (3) no data (4) 6/41 (5) no data (6) 14/40 Two Nostril Study (1) no data (2) no data (3) no data (4) 12/40 (5) 11/35 (6) 18/32 |
| SUM40031 | (1) Sumatriptan 20 mg, n = 208 (2) Rizatriptan 10 mg, n = 200 |
(1) 103/208 (2) 95/200 |
(1) 136/208 (2) 141/200 |
(1) 34/208 (2) 30/200 |
(1) 76/208 (2) 79/200 |
No data | No data | At 24 h: (1) 59/208 (2) 44/200 |
| Wang 2007 | (1) Sumatriptan 20 mg, n = 29 (28 for efficacy) (2) Placebo, n = 29 (28 for efficacy) |
(1) 17/28 (2) 12/28 |
(1) 17/28 (2) 15/28 |
(1) 7/28 (2) 2/28 |
(1) 9/28 (2) 5/28 |
No data | No data | No data |
Appendix 6. Associated symptoms: presence two hours after treatment
| Associated symptoms: symptom present 2 hours after taking study medication | |||||||
| Intervention | Studies | Attacks treated | Treatment (%) | Placebo (%) | Relative risk (95% CI) | NNTp (95% CI) | P for difference |
| Nausea | |||||||
| Sumatriptan 5 mg versus placebo | 2 | 684 | 37 | 47 | 0.77 (0.64 to 0.92) | 9.5 (5.5 to 34) | |
| Sumatriptan 10 mg versus placebo | 5 | 1563 | 35 | 47 | 0.77 (0.68 to 0.87) | 8.8 (6.1 to 16) | N/S |
| Sumatriptan 20 mg versus placebo | 5 | 1763 | 30 | 47 | 0.65 (0.58 to 0.73) | 6.1 (4.7 to 8.6) | |
| Vomiting | |||||||
| Sumatriptan 10 mg versus placebo | 4 | 1384 | 5 | 7 | 0.74 (0.48 to 1.2) | Not calculated | |
| Sumatriptan 20 mg versus placebo | 4 | 1579 | 3 | 7 | 0.44 (0.28 to 0.70) | 27 (17 to 71) | |
| Photophobia | |||||||
| Sumatriptan 10 mg versus placebo | 3 | 923 | 58 | 70 | 0.83 (0.75 to 0.91) | 8.1 (5.4 to 16) | z = 2.64, P = 0.008 |
| Sumatriptan 20 mg versus placebo | 3 | 1121 | 46 | 70 | 0.66 (0.60 to 0.73) | 4.2 (3.4 to 5.6) | |
| Phonophobia | |||||||
| Sumatriptan 10 mg versus placebo | 3 | 923 | 49 | 60 | 0.82 (0.73 to 0.92) | 9.0 (5.7 to 21) | N/S |
| Sumatriptan 20 mg versus placebo | 3 | 1121 | 40 | 60 | 0.67 (0.59 to 0.76) | 5.1 (3.9 to 7.4) | |
| Functional disability | |||||||
| Sumatriptan 5 mg versus placebo | 2 | 684 | 44 | 55 | 0.80 (0.69 to 0.93) | 9.7 (5.6 to 37) | |
| Sumatriptan 10 mg versus placebo | 5 | 1171 | 39 | 53 | 0.72 (0.63 to 0.82) | 7.2 (5.1 to 12) | z = 2.26, P = 0.024 |
| Sumatriptan 20 mg versus placebo | 5 | 1372 | 30 | 53 | 0.57 (0.50 to 0.65) | 4.4 (3.5 to 5.7) | |
| N/S = not significant | |||||||
Appendix 7. Summary of outcomes: adverse events and withdrawals
| Study ID | Treatment | > 1 dose of study medication available | Any AE | Specific AEs | Serious AEs | AE withdrawal | Other withdrawals/exclusions |
| Boureau 2000 | (1) Sumatriptan 20 mg (+ optional placebo at 30 mins), n = 207 (2) DHE 1 mg (+ optional 1 mg DHE at 30 mins), n = 198 |
Yes | Probably within 24 h: (1) 39/388 (2) 39/385 |
No data | No data | (1) 0/388 (2) 2/385 |
No data |
| Diamond 1998 | (1) Sumatriptan 5 mg, n = 299 (2) Sumatriptan 10 mg, n = 296 (3) Sumatriptan 20 mg, n = 292 (4) Placebo, n = 199 |
Yes | No data | Within 24 h after a single dose only and occurring in more than 2% of participants in any treatment group: Taste disturbance: (1) 55/299; (2) 67/296; (3) 87/292; (4) 4/199 Nausea/vomiting: (1) 74/299; (2) 79/296; (3) 91/292; (4) 64/199 Migraine: (1) 14/299; (2) 18/296; (3) 21/292; (4) 17/199 Photophobia: (1) 8/299; (2) 13/296; (3) 7/292; (4) 11/199 Phonophobia: (1) 18/299; (2) 13/296; (3) 8/292; (4) 10/199 Throat symptoms: (1) 1/299; (2) 6/296; (3) 9/292; (4) 4/199 |
No data | (1) 0/299 (2) 0/296 (3) 3/292 (4) 1/199 |
No data |
| Djupesland 2010 | (1) Sumatriptan 10 mg, n = 39 (2) Sumatriptan 20 mg, n = 39 (3) Placebo, n = 39 |
No | Probably within 48 h: (1) 7/39 (2) 9/39 (3) 2/39 |
Bad taste: (1) 4/39; (2) 5/39; (3) no data |
(1) 0/39 (2) 0/39 (3) 0/39 |
(1) 0/39 (2) 0/39 (3) 0/39 |
14 participants excluded from efficacy analyses: 1 lost to follow‐up from placebo group 12 treated mild headache (1 from sumatriptan 10 mg, 4 from sumatriptan 20 mg, and 7 from placebo group) 1 used rescue medication within 2 hours from sumatriptan 10 mg group |
| Peikert 1999 | (1) Sumatriptan 2.5 mg, n = 123 (2) Sumatriptan 5 mg, n = 122 (3) Sumatriptan 10 mg, n = 115 (4) Sumatriptan 20 mg, n = 120 (5) Placebo, n = 64 |
No | Within 5 days: (1) 24/123 (2) 32/122 (3) 30/115 (4) 32/120 (5) 15/64 |
Occurring in more than 2 participants in any group: Nausea/vomiting: (1) 2/123; (2) 6/122; (3) 2/115; (4) 2/120; (5) 4/64 Bad/bitter taste: (1) 10/123; (2) 11/122; (3) 12/115; (4) 17/120; (5) 3/64 Agitation: (1) 3/123; (2) 0/122; (3) 0/115; (4) 0/120; (5) 0/64 Tremor: (1) 3/123; (2) 0/122; (3) 0/115; (4) 0/120; (5) 1/64 Nasal symptoms: (1) 0/123; (2) 3/122; (3) 1/115; (4) 1/120; (5) 2/64 Tingling: (1) 0/123; (2) 0/122; (3) 1/115; (4) 3/120; (5) 0/64 |
No data | No data | No data |
| Ryan 1997 | Study 1 (1) Sumatriptan 10 mg, n = 106 (2) Sumatriptan 20 mg, n = 202 (3) Placebo, n = 101 Study 2 (1) Sumatriptan 10 mg, n = 109 (2) Sumatriptan 20 mg, n = 215 (3) Placebo, n = 112 |
Yes | No data | Within 24 h: Taste disturbance: Study 1 (1) 20/106; (2) 51/202; (3) 2/101 Study 2 (1) 26/105; (2) 77/215; (3) 0/112 Nausea/vomiting: Study 1 (1) 19/106; (2) 34/202; (3) 15/101 Study 2 (1) 17/105; (2) 39/215; (3) 18/112 Disturbance of nasal cavity/sinuses: Study 1 (1) 4/106; (2) 11/202; (3) 3/101 Study 2 (1) 3/105; (2) 9/215; (3) 3/112 Phonophobia: Study 1 (1) 1/106; (2) 5/202; (3) 6/101 Study 2 (1) 3/105; (2) 3/215; (3) 1/112 Throat symptoms: Study 1 (1) 4/106; (2) 4/202; (3) 0/101 Study 2 (1) 3/105; (2) 7/215; (3) 1/112 Photophobia: Study 1 (1) 3/106; (2) 4/202; (3) 1/101 Study 2 (1) 1/105; (2) 2/215; (3) 1/112 Dizziness/vertigo: Study 1 (1) 4/106; (2) 2/202; (3) 1/101 Study 2 (1) 2/105; (2) 4/215; (3) 0/112 Tingling: Study 1 (1) 0/106; (2) 2/202; (3) 0/101 Study 2 (1) 2/105; (2) 3/215; (3) 2/112 Drowsiness/sedation: Study 1 (1) 1/106; (2) 0/202; (3) 0/101 Study 2 (1) 3/105; (2) 4/215; (3) 1/112 Burning sensation: Study 1 (1) 0/106; (2) 4/202; (3) 0/101 Study 2 (1) 0/105; (2) 4/215; (3) 0/112 |
Study 1 (1) 0/106 (2) 0/202 (3) 0/101 Study 2 (1) 0/109 (2) 0/215 (3) 0/112 |
No data | 1 participant withdrew from study (reason not reported) and failed to return diary card |
| S2BT50 | (1) Sumatriptan 10 mg, n = 305 (2) Sumatriptan 20 mg, n = 302 (3) Placebo, n = 156 |
Yes | Within 24 h, after single dose only: (1) 100/305 (2) 106/302 (3) 15/156 |
Disturbance of taste: (1) 65/305; (2) 62/302; (3) 2/156 Nausea and/or vomiting: (1) 27/305; (2) 26/302; (3) 7/156 Throat symptoms: (1) 6/305; (2) 11/302; (3) 1/156 Disease of nasal cavity/sinuses: (1) 6/305; (2) 7/302; (3) 2/156 Dizziness/vertigo: (1) 3/305; (2) 5/302; (3) 2/156 Burning sensation: (1) 4/305; (2) 4/302; (3) 1/156 Migraine: (1) 0/305; (2) 4/302; (3) 0/156 Flushing: (1) 1/305; (2) 3/302; (3) 0/156 Tremors: (1) 1/305; (2) 3/302; (3) 0/156 Headache: (1) 2/305; (2) 3/302; (3) 2/156 Chest pressure/heaviness: (1) 1/305; (2) 3/302; (3) 1/156 Drowsiness/sedation: (1) 0/305; (2) 2/302; (3) 1/156 Malaise/fatigue: (1) 3/305; (2) 2/302; (3) 1/156 Feeling of tightness: (1) 2/305; (2) 2/302; (3) 1/156 Paraesthesia: (1) 2/305; (2) 2/302; (3) 0/156 Numbness: (1) 2/305; (2) 1/302; (3) 0/156 Palpitations: (1) 1/305; (2) 1/302; (3) 1/156 Pressure sensation: (1) 1/305; (2) 0/302; (3) 1/156 Tingling: (1) 5/305; (2) 0/302; (3) 1/156 |
(1) 0/305 (2) 3/302 (3) 0/156 |
(1) 0/305 (2) 0/302 (3) 0/156 |
No withdrawals for any reason from study |
| Salonen 1991 | (1) Sumatriptan 40 mg (delivered as 2 insufflations separated by 15 minutes), n = 37 (2) Placebo, n = 37 |
No | Within 24 h: (1) 17/37 (2) 5/37 |
No data | No data | (1) 0/37 (2) 0/37 |
1 participant received only 1 insufflation of trial medication and was therefore excluded from the efficacy population |
| Salonen 1994 | One Nostril Study (dose administered as single insufflation via 1 nostril) (1) Sumatriptan 1 mg, n = 40 (2) Sumatriptan 5 mg, n = 42 (3) Sumatriptan 10 mg, n = 40 (4) Sumatriptan 20 mg, n = 41 (5) Sumatriptan 40 mg, n = 42 (6) Placebo, n = 40 Two Nostril Study (dose administered as 2 insufflations, 1 in each nostril) (1) Sumatriptan 1 mg, n = 34 (2) Sumatriptan 5 mg, n = 33 (3) Sumatriptan 10 mg, n = 36 (4) Sumatriptan 20 mg, n = 40 (5) Sumatriptan 40 mg, n = 35 (6) Placebo, n = 32 |
No | Within 5 days: No useable data (not reported separately by treatment arm) |
No useable data (not reported separately by treatment arm) | No data | No data | 7 participants (3 in One Nostril Study and 4 in Two Nostril Study) were excluded from efficacy analysis due to treating mild headache |
| SUM40031 | (1) Sumatriptan 20 mg, n = 208 (2) Rizatriptan 10 mg, n = 200 |
Yes | Within 1 to 4 days: (1) 67/208 (2) 58/200 |
Disturbance of taste: (1) 35/208; (2) 3/200 Nausea: (1) 16/208; (2) 12/200 Vomiting: (1) 10/208; (2) 0/200 Malaise and fatigue: (1) 7/208; (2) 8/200 Dizziness: (1) 5/208; (2) 5/200 Paraesthesia: (1) 5/208; (2) 5/200 Temperature sensation: (1) 5/208; (2) 5/200 Other pressure/tightness: (1) 4/208; (2) 6/200 Throat and tonsil discomfort/pain: (1) 4/208; (2) 2/200 Feeling strange: (1) 3/208; (2) 3/200 Chest symptoms: (1) 1/208; (2) 6/200 Somnolence: (1) 1/208; (2) 5/200 Headache: (1) 0/208; (2) 6/200 Hyposalivation (1) 0/208; (2) 4/200 |
(1) 1/208 (2) 0/200 |
(1) 0/208 (2) 0/200 |
Withdrawn for other reasons after randomisation (possibly before taking study medication): (1) 58/266 (2) 66/266 |
| Wang 2007 | (1) Sumatriptan 20 mg, n = 29 (2) Placebo, n = 29 |
Yes | Within 24 h: (1) 19/29 (2) 12/29 |
Bitter taste: (1) 6/29; (2) 0/29 Vomiting: (1) 4/29; (2) 1/29 Nasal discomfort: (1) 4/29; (2) 0/29 Muscle soreness: (1) 2/29; (2) 0/29 Dizziness: (1) 1/29; (2) 2/29 Weakness: (1) 1/29; (2) 1/29 Palpitations: (1) 1/29; (2) 1/29 Throat discomfort: (1) 1/29; (2) 1/29 Anxiety: (1) 0/29; (2) 2/29 Photosensitivity: (1) 1/29; (2) 0/29 Chest tightness: (1) 1/29; (2) 0/29 Diarrhoea: (1) 1/29; (2) 0/29 Wet nostrils: (1) 1/29; (2) 0/29 Nasal stuffiness: (1) 1/29; (2) 0/29 Fatigue: (1) 1/29; (2) 0/29 Chills: (1) 1/29; (2) 0/29 Sweating: (1) 1/29; (2) 0/29 Nausea: (1) 0/29; (2) 1/29 Flushing: (1) 0/29; (2) 1/29 Heat sensation in throat: (1) 0/29; (2) 1/29 |
(1) 0/29 (2) 0/29 |
No data | 2 participants excluded from efficacy analysis: 1 for wrong diagnosis and 1 for loss of diary card |
Appendix 8. Breakdown of individual adverse event groups
We used the following groupings of individual adverse events in all four reviews of sumatriptan whenever it was possible to combine studies for analysis (all routes of administration except rectal).
Malaise/fatigue/asthenia:
Malaise/fatigue
Fatigue
Malaise and fatigue
Asthenia/fatigue
Fatigue/weakness
Asthenia
Weakness
Dizziness/vertigo:
Dizziness/vertigo
Dizziness
Dizziness (excl. vertigo)
Dizziness (not vertigo)
Nausea/vomiting:
Nausea/vomiting
Nausea
Vomiting
Nausea and vomiting
Disorder of mouth/disturbance of taste:
Disorder of mouth/tongue
Mouth disorder
Dry mouth
Disturbance of taste
Bad taste
Drug taste
Chest pain/symptoms:
Chest pressure/heaviness
Chest tightness
Chest discomfort
Chest pain
Chest symptoms
Constriction of throat/chest pain
Tightness of throat
Heat sensations/flushing:
Warm/hot sensation
Flushing
Vasodilation
Heat flashes
Warm sensation
Temperature sensations
Hot flush
Burning sensation
Palpitations/tachycardia:
Palpitations
Tachycardia
Diarrhoea:
Diarrhoea
Feeling of tightness/heaviness:
Feeling of heaviness
Heaviness other than chest or neck
Feeling of heaviness in head
Heaviness/pressure sensation
Heaviness in lower limbs
Heaviness, regional
Head pressure
Tightness
Other pressure/tightness
Sweating:
Sweating
Abdominal pain/discomfort/dyspepsia:
Abdominal discomfort
Abdominal pain
Abdominal pain or cramps
Dyspepsia
Gastric symptoms
Gastroesophageal reflux
Paraesthesia/numbness:
Paraesthesia
Tingling
Numbness/paraesthesia/tingling
Numbness
Headache:
Headache
Drowsiness/somnolence:
Drowsiness/sedation
Somnolence
Sleepiness
Drowsiness
Anxiety:
Anxiety
Neck/back pain:
Neck pain/stiffness
Neck pain
Back or neck pain
Back pain
Disorder of nasal cavity/sinuses:
Disorder of nasal cavity/sinuses
Nasal discomfort
Nasal stuffiness
Wet nostrils
Throat symptoms
Throat symptoms
Throat discomfort
Injection‐site reaction:
Injection‐site reaction
Application‐site reaction
Appendix 9. L'Abbé plots for sumatriptan 20 mg versus placebo
L'Abbé plots for sumatriptan 50 mg versus placebo for the outcomes pain‐free at two hours (Figure 27), headache relief at one hour (Figure 28), and headache relief at two hours (Figure 29) show consistency in response across studies for these outcomes.
5.
L'Abbé plot showing results for sumatriptan 20 mg versus placebo for pain‐free at two hours. Each circle represents a different study; size of circle is proportional to size of study; diagonal is line of equivalence
6.
L'Abbé plot showing results for sumatriptan 20 mg versus placebo for headache relief at one hour. Each circle represents a different study; size of circle is proportional to size of study; diagonal is line of equivalence
7.
L'Abbé plot showing results for sumatriptan 20 mg versus placebo for headache relief at two hours. Each circle represents a different study; size of circle is proportional to size of study; diagonal is line of equivalence
Data and analyses
Comparison 1. Sumatriptan nasal spray 5 mg versus placebo.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Headache relief at 1 h | 3 | 830 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.40 [1.14, 1.71] |
| 2 Headache relief at 2 h | 3 | 830 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.41 [1.19, 1.69] |
| 3 Relief of associated symptoms | 2 | 476 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.49 [1.16, 1.91] |
| 3.1 Relief of nausea at 2 h | 2 | 476 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.49 [1.16, 1.91] |
| 4 Individual adverse events | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.1 Nausea/vomiting | 2 | 684 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.58, 1.02] |
| 4.2 Taste disturbance | 2 | 684 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.90 [2.77, 12.54] |
1.4. Analysis.
Comparison 1 Sumatriptan nasal spray 5 mg versus placebo, Outcome 4 Individual adverse events.
Comparison 2. Sumatriptan nasal spray 10 mg versus placebo.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Pain‐free at 2 h | 4 | 1115 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.48 [1.81, 3.38] |
| 2 Headache relief at 1 h | 6 | 1755 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.59 [1.37, 1.85] |
| 3 Headache relief at 2 h | 6 | 1755 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.62 [1.44, 1.84] |
| 4 Use of rescue medication within 24 h | 2 | 640 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.72, 0.99] |
| 5 Relief of associated symptoms | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.1 Relief of nausea at 2 h | 4 | 1098 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.46 [1.26, 1.70] |
| 5.2 Relief of photophobia at 2 h | 2 | 841 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.52 [1.22, 1.90] |
| 5.3 Relief of phonophobia at 2 h | 2 | 767 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.52 [1.23, 1.87] |
| 6 Relief of functional disability at 2 h | 2 | 214 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.03 [1.79, 5.13] |
| 7 Individual adverse events | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 7.1 Dizziness/vertigo | 2 | 885 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.21 [0.65, 7.49] |
| 7.2 Nausea/vomiting | 3 | 1380 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.79, 1.24] |
| 7.3 Disturbance of taste | 3 | 1380 | Risk Ratio (M‐H, Fixed, 95% CI) | 15.29 [7.61, 30.73] |
| 7.4 Temperature sensations | 2 | 885 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.05 [0.23, 18.15] |
| 7.5 Paraesthesia/numbness | 2 | 885 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.63 [0.40, 6.69] |
| 7.6 Disturbance of nasal cavity/sinuses | 2 | 885 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.29 [0.53, 3.13] |
| 7.7 Throat symptoms | 3 | 1380 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.24 [0.92, 5.48] |
Comparison 3. Sumatriptan nasal spray 20 mg versus placebo.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Pain‐free at 2 h | 5 | 1379 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.11 [2.36, 4.10] |
| 2 Pain‐free at 1 h | 2 | 499 | Risk Ratio (M‐H, Fixed, 95% CI) | 6.21 [2.19, 17.67] |
| 3 Headache relief at 1 h | 7 | 2020 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.88 [1.64, 2.15] |
| 4 Headache relief at 2 h | 7 | 2020 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.93 [1.72, 2.16] |
| 5 Use of rescue medication within 24 h | 2 | 642 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.66 [0.55, 0.79] |
| 6 Relief of associated symptoms | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 6.1 Relief of nausea at 2 h | 4 | 1272 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.71 [1.49, 1.97] |
| 6.2 Relief of photophobia at 2 h | 2 | 1021 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.07 [1.70, 2.53] |
| 6.3 Relief of phonophobia at 2 h | 2 | 933 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.89 [1.56, 2.29] |
| 7 Relief of functional disability at 2 h | 2 | 225 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.83 [2.29, 6.42] |
| 8 Any adverse event within 24 h | 2 | 516 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.87 [1.96, 4.20] |
| 9 Individual adverse events | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 9.1 Malaise/fatigue/asthenia | 2 | 516 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.17, 6.15] |
| 9.2 Dizziness/vertigo | 3 | 1146 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.42 [0.48, 4.18] |
| 9.3 Nausea/vomiting | 4 | 1637 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.11 [0.90, 1.37] |
| 9.4 Disturbance of taste | 4 | 1637 | Risk Ratio (M‐H, Fixed, 95% CI) | 19.52 [9.87, 38.62] |
| 9.5 Chest pain/symptoms | 2 | 516 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.95 [0.32, 11.95] |
| 9.6 Temperature sensations | 3 | 1146 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.18 [0.78, 12.91] |
| 9.7 Palpitations/tachycardia | 2 | 516 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.73 [0.11, 4.92] |
| 9.8 Paraesthesia/numbness | 2 | 1088 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.20 [0.31, 4.60] |
| 9.9 Disturbance of nasal cavity/sinuses | 3 | 1146 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.06 [0.99, 4.28] |
| 9.10 Throat symptoms | 4 | 1637 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.77 [1.20, 6.38] |
Comparison 4. Sumatriptan nasal spray 40 mg versus placebo.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Headache relief at 1 h | 2 | 220 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.82 [1.33, 2.48] |
| 2 Headache relief at 2 h | 2 | 220 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.90 [1.44, 2.52] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Boureau 2000.
| Methods | Multicentre, randomised, double‐blind, double‐dummy, cross‐over. Participants treated 2 consecutive attacks. Assessments at 15, 30, 45, 60, 90, and 129 minutes after dosing Participants treating with DHE had the option of taking a second dose of study medication after 30 minutes if insufficient relief was obtained, while participants treating with sumatriptan were offered a placebo Rescue medication (not ergotamine‐containing compounds, DHE or sumatriptan) was available after 2 h if migraine symptoms not relieved |
|
| Participants | Aged 18 to 65 years, meeting IHS criteria for migraine (1988) with or without aura. At least 1‐year history of migraine (untreated severity ≥ moderate) with an average of 1 to 6 attacks per month. Normal prophylactic medication for migraine was permitted provided it did not contain ergotamine or DHE and the dosage remained unchanged throughout the study No analgesics or antiemetics within 6 h, or ergotamine, DHE, or commercially available sumatriptan within 24 h before administration of study medication N = 405 (368 completed study) M 59, F 309 (84%) Mean age 41 years Without aura 76% |
|
| Interventions | Sumatriptan 20 mg (+ optional placebo at 30 mins), n = 207 Intranasal DHE 1 mg (+ optional 1 mg DHE at 30 mins), n = 198 |
|
| Outcomes | No useable data reported | |
| Notes | Oxford Quality Score: R1, DB2, W0. Total = 3. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not reported |
| Allocation concealment (selection bias) | Unclear risk | Not reported |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Double‐dummy |
| Study size | Unclear risk | One treatment groups > 200 participants, other treatment group 50 to 200 participants |
Diamond 1998.
| Methods | Multicentre, randomised, double‐blind, placebo‐controlled, parallel‐group. Single dose to treat each of 3 consecutive attacks. Medication administered when migraine headache pain was of moderate or severe intensity Assessments at 15, 30, 45, 60, 90, and 120 minutes after dosing Second dose of study medication available to treat recurrence, provided no use of rescue medication had occurred Rescue medication available after 2 h for inadequate symptom relief |
|
| Participants | Aged 18 to 65 years, meeting IHS criteria for migraine (1988) with or without aura. At least 1‐year history of migraine (untreated severity ≥ moderate) with an average of 2 to 8 attacks per month. Participants excluded if they experienced more than 15 days per month with headache during the 2 months prior to screening No ergotamine‐containing medications or oral/injectable sumatriptan within 24 h of taking study medication. No monoamine oxidase inhibitors at any time during the study. N = 1086 M 130, F 956 (88%) Mean age 41 years Without aura 70% |
|
| Interventions | Sumatriptan 5 mg, n = 299 Sumatriptan 10 mg, n = 296 Sumatriptan 20 mg, n = 292 Placebo, n = 199 |
|
| Outcomes | Headache relief (at 1 and 2 h) Improvement in nausea, vomiting, photophobia, and phonophobia at 2 h Presence of functional disability at 2 h Adverse events Withdrawals |
|
| Notes | Oxford Quality Score: R1, DB1, W1. Total = 3. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not reported |
| Allocation concealment (selection bias) | Unclear risk | Not reported |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | Not reported |
| Study size | Unclear risk | Active treatment groups > 200 participants, placebo treatment group 50 to 200 participants |
Djupesland 2010.
| Methods | Multicentre, randomised, double‐blind, placebo‐controlled, parallel‐group. Single dose to treat a single attack. Medication administered when migraine headache pain was of moderate or severe intensity Assessments at 15, 30, 60, 90, and 120 minutes after dosing Rescue medication available after 2 h if participants were not pain‐free |
|
| Participants | Aged 18 to 65 years, meeting IHS criteria for migraine with or without aura. At least 1‐year history of migraine (untreated severity ≥ moderate) with a 3‐month well‐documented retrospective history and an average of ≤ 1 and ≥ 6 attacks per month. Participants excluded if they experienced more than 6 days per month with any other headache or used medication for acute headache for more than 10 days each month. No current use of drugs for migraine prophylaxis No ergotamine, ergot‐type medications or any 5‐HT1 agonist or narcotic analgesics within previous 24 hours before treatment. No use of any analgesic within 12 hours before treatment. No treatment with monoamine oxidase A inhibitors within 2 weeks of study treatment, or use of selective serotonin‐reuptake inhibitors during the study. No use of a decongestant within 6 hours of attendance at the clinic on the treatment day. Participants excluded for known nasal obstruction due to nasal deviations, polyposis, or mucosal swelling, or for current uncontrolled nasopharyngeal illness N = 117 M 17, F 100 (85%) Mean age 42 years Without aura 91% |
|
| Interventions | Sumatriptan 10 mg, n = 39 (37 for efficacy) Sumatriptan 20 mg, n = 39 (35 for efficacy) Placebo, n = 39 (32 for efficacy) |
|
| Outcomes | Headache relief (at 1 and 2 h) Pain‐free (at 2 h) 48‐h sustained pain‐free Improvement in functional disability at 2 h Use of rescue medication Adverse events Withdrawals |
|
| Notes | Oxford Quality Score: R1, DB2, W1. Total = 4. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not reported |
| Allocation concealment (selection bias) | Unclear risk | Not reported |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Administrative devices were identical in appearance |
| Study size | High risk | Treatment groups < 50 participants |
Peikert 1999.
| Methods | Multicentre, randomised, double‐blind, placebo‐controlled, parallel‐group. Single dose to treat single attack. Assessments at 15, 30, 60, 90, and 120 minutes after dosing Rescue medication (not ergotamine or sumatriptan) available after 2 h for inadequate relief |
|
| Participants | Aged 18 to 65 years, meeting IHS criteria for migraine (1988) with or without aura. At least 1‐year history of migraine (untreated severity ≥ moderate) with an average of 1 to 6 attacks per month. Participants required to stop prophylactic migraine medication at initial study enrolment N = 544 (542 with moderate or severe baseline pain intensity) M 83, F 461 (85%) Mean age 41 years Without aura 89% |
|
| Interventions | Sumatriptan 2.5 mg, n = 123 (122 with moderate or severe baseline pain intensity) Sumatriptan 5 mg, n = 122 Sumatriptan 10 mg, n = 115 Sumatriptan 20 mg, n = 120 (119 with moderate or severe baseline pain intensity) Placebo, n = 64 |
|
| Outcomes | Headache relief (at 1 and 2 h) Pain‐free (at 2 h) Improvement in nausea at 2 h Improvement in functional disability at 2 h Use of rescue medication Adverse events |
|
| Notes | Oxford Quality Score: R1, DB2, W0. Total = 3. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not reported |
| Allocation concealment (selection bias) | Unclear risk | Not reported |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Placebo supplies were matched in appearance to the sumatriptan‐containing supplies |
| Study size | Unclear risk | Treatment groups 50 to 200 participants |
Ryan 1997.
| Methods | Multicentre, randomised, double‐blind, placebo‐controlled, parallel‐group. Single dose to treat single attack. Medication administered when migraine headache pain was of moderate or severe intensity Assessments at 15, 30, 60, 90, and 120 minutes after dosing Second dose of study medication available after 2 h for participants experiencing recurrence of headache but did not use rescue medication Rescue medication available after 2 h for inadequate relief 2 replicate studies: Study 1 and 2 |
|
| Participants | Aged 18 to 65 years, meeting IHS criteria for migraine (1988) with or without aura. At least 1‐year history of migraine with an average of 1 to 6 attacks per month. No ergotamine‐containing medications or subcutaneous sumatriptan was permitted during the 24 h period before or after study treatment. No monoamine oxidase inhibitors, serotonin reuptake inhibitors, or lithium during the study. Study 1 N = 409 M 58, F 351 (86%) Mean age 40 years Proportion with/without aura not reported Study 2 N = 436 M 63, F 373 (86%) Mean age 41 years Proportion with/without aura not reported |
|
| Interventions | Study 1 Sumatriptan 10 mg, n = 106 Sumatriptan 20 mg, n = 202 Placebo, n = 101 Study 2 Sumatriptan 10 mg, n = 109 Sumatriptan 20 mg, n = 215 Placebo, n = 112 |
|
| Outcomes | Headache relief (at 1 and 2 h) Pain‐free (at 2 h) Improvement in nausea, vomiting, photophobia, and phonophobia at 2 h Presence of functional disability at 2 h Adverse events |
|
| Notes | Oxford Quality Score: R1, DB1, W0. Total = 2. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not reported |
| Allocation concealment (selection bias) | Unclear risk | Not reported |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | Not reported |
| Study size | Unclear risk | Some active treatment groups > 200 participants, others and placebo treatment groups 50 to 200 participants |
S2BT50.
| Methods | Multicentre, randomised, double‐blind, placebo‐controlled, parallel‐group. Single dose to treat single attack. Assessments at 15, 30, 60, 90, and 120 minutes after dosing Second dose of study medication available after 2 h for participants experiencing recurrence of headache but did not use rescue medication Rescue medication (excluding sumatriptan and ergotamine) available after 2 h if symptom relief was inadequate |
|
| Participants | Aged 18 to 65 years, meeting IHS criteria for migraine (1988) with or without aura. At least 1‐year history of migraine (untreated severity ≥ moderate) with an average of 1 to 6 attacks per month. Participants excluded if had previously used sumatriptan nasal spray or dispersible tablet formulation of sumatriptan N = 763 M 119, F 644 (84%) Mean age 40 years Proportion with/without aura not reported |
|
| Interventions | Sumatriptan 10 mg, n = 305 (288 with moderate or severe baseline pain intensity) Sumatriptan 20 mg, n = 302 (292 with moderate or severe baseline pain intensity) Placebo, n = 156 (151 with moderate or severe baseline pain intensity) |
|
| Outcomes | Headache relief (at 1 and 2 h) Pain‐free (at 1 and 2 h) 24‐h sustained headache relief Improvement in nausea, vomiting, and photophobia/phonophobia at 2 h Use of rescue medication Adverse events Withdrawals |
|
| Notes | Oxford Quality Score: R1, DB1, W1. Total = 3. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not reported |
| Allocation concealment (selection bias) | Unclear risk | Not reported |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | Not reported |
| Study size | Unclear risk | Active treatment groups > 200 participants, placebo treatment group 50 to 200 participants |
Salonen 1991.
| Methods | Multicentre, randomised, double‐blind, placebo‐controlled, parallel‐group. Single dose to treat single attack. Medication administered when migraine headache pain was of moderate or severe intensity Assessments at 30, 60, and 120 minutes after dosing Rescue medication (not ergotamine) available 2 h after initial dosing for inadequate relief of symptoms |
|
| Participants | Aged 18 to 60 years, meeting IHS criteria for migraine (1988) with or without aura No narcotic analgesics or ergotamine within the previous 24 h, or any other analgesics within the 6 h before administration of study medication N = 74 M 11, F 63 (85%) Mean age 39 years Without aura 74% |
|
| Interventions | Sumatriptan 40 mg (delivered as 2 insufflations separated by 15 minutes), n = 37 (36 for efficacy) Placebo, n = 37 |
|
| Outcomes | Headache relief (at 1 and 2 h) Pain‐free (at 1 and 2 h) Improvement in nausea, vomiting, and photophobia at 2 h Use of rescue medication Adverse events Withdrawals |
|
| Notes | Oxford Quality Score: R1, DB1, W1. Total = 3. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not reported |
| Allocation concealment (selection bias) | Unclear risk | Not reported |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | Not reported |
| Study size | High risk | Treatment groups < 50 participants |
Salonen 1994.
| Methods | Multicentre, randomised, double‐blind, placebo‐controlled, parallel‐group. Single dose to treat single attack. Medication administered when migraine headache pain was of moderate or severe intensity Assessments at 30, 60, 90, 120, 150, and 180 minutes after dosing Rescue medication (excluding ergotamine or ergotamine‐containing medications) available after 180 minutes for inadequate response to treatment 2 studies: One Nostril Study and Two Nostril Study |
|
| Participants | Aged 18 to 65 years, meeting IHS criteria for migraine (1988) with or without aura. At least 1‐year history of migraine (untreated severity ≥ moderate) with an average of up to 6 attacks per month. All prophylactic medication for migraine was stopped at the pre‐study visit One Nostril Study N = 245 M 53, F 192 (78%) Mean age 41 years Without aura 89% Two Nostril Study N = 210 M = 37, F = 173 (82%) Mean age 43 years Without aura 88% |
|
| Interventions | One Nostril Study (dose administered as single insufflation via one nostril) Sumatriptan 1 mg, n = 40 (39 for efficacy) Sumatriptan 5 mg, n = 42 Sumatriptan 10 mg, n = 40 (39 for efficacy) Sumatriptan 20 mg, n = 41 (41 for efficacy) Sumatriptan 40 mg, n = 42 Placebo, n = 40 Two Nostril Study (dose administered as 2 insufflations, one in each nostril) Sumatriptan 1 mg, n = 34 Sumatriptan 5 mg, n = 33 Sumatriptan 10 mg, n = 36 (35 for efficacy) Sumatriptan 20 mg, n = 40 (39 for efficacy) Sumatriptan 40 mg, n = 35 (34 for efficacy) Placebo, n = 32 (31 for efficacy) |
|
| Outcomes | Headache relief (at 1 and 2 h) Use of rescue medication Adverse events |
|
| Notes | Oxford Quality Score: R1, DB1, W0. Total = 2. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not reported |
| Allocation concealment (selection bias) | Unclear risk | Not reported |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | Not reported |
| Study size | High risk | Treatment groups < 50 participants |
SUM40031.
| Methods | Multicentre, randomised, double‐blind, double‐dummy, parallel‐group. Single dose to treat single attack. Medication administered when migraine headache pain was of moderate or severe intensity Assessments at 10, 20, 30, 60, 90, and 120 minutes after dosing Second dose of study medication available to treat recurrence between 2 and 24 hours Rescue medication available after 2 hours for inadequate relief |
|
| Participants | Aged 18 to 65 years, meeting IHS criteria for migraine (1988) with or without aura. Suffered 1 to 6 moderate or severe migraine attacks per month for at least 2 months preceding screening. No migraine prophylactic medication containing ergotamine, ergotamine‐derivatives, methysergide, or propanolol (propanolol must have been discontinued at least 1 week before screening). No monoamine oxidase inhibitors or selective serotonin receptor inhibitors within 2 weeks before screening. Participants were excluded if they had previously used 5HT1 agonists in the treatment of acute migraine N = 408 M 69, F 339 (83%) Mean age 38 years Proportion with/without aura not reported |
|
| Interventions | Sumatriptan 20 mg, n = 208 Rizatriptan wafer 10 mg, n = 200 |
|
| Outcomes | Headache relief (at 1 and 2 h) Pain‐free (at 1 and 2 h) Improvement in nausea, vomiting, photophobia, and phonophobia at 2 h Use of rescue medication Adverse events Withdrawals |
|
| Notes | Oxford Quality Score: R1, DB1, W1. Total = 3. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not reported |
| Allocation concealment (selection bias) | Unclear risk | Not reported |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Double‐dummy |
| Study size | Low risk | Treatment groups > 200 participants |
Wang 2007.
| Methods | Single‐centre, randomised, double‐blind, placebo‐controlled, parallel‐group. Single dose to treat single attack. Medication administered when migraine headache pain was of moderate or severe intensity Assessments at 15, 30, 45, 60, 90, and 120 minutes after dosing Second dose of study medication available to treat recurrence between 2 and 24 h Rescue medication (not sumatriptan) available after 2 h for insufficient pain relief |
|
| Participants | Aged 18 to 65 years, meeting IHS criteria for migraine (1988) with or without aura. At least 1‐year history of migraine (untreated severity ≥ moderate) with an average of 2 to 8 attacks per month. Participants excluded if they experienced more than 15 days per month with tension‐type headache during the 12 months prior to screening Participants excluded if taking ergotamine or dihydroergotamine‐containing prophylactic migraine medication, monoamine oxidase inhibitors, or lithium. Normal prophylaxis was allowed provided it did not contain ergotamine or dihydroergotamine. N = 58 (56 for efficacy) M 8, F 48 (83%) Mean age 37 years Without aura 88% |
|
| Interventions | Sumatriptan 20 mg, n = 29 (28 for efficacy) Placebo, n = 29 (28 for efficacy) |
|
| Outcomes | Headache relief (at 1 and 2 h) Pain‐free (at 1 and 2 h) Adverse events Withdrawals |
|
| Notes | Oxford Quality Score: R2, DB2, W1. Total = 5. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated |
| Allocation concealment (selection bias) | Unclear risk | Not reported |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Placebo spray with identical appearance |
| Study size | High risk | Treatment groups < 50 participants |
DB: double‐blinding; DHE: dihydroergotamine; h: hour; IHS: International Headache Society; R: randomisation; W: withdrawals
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| S2CM12 | No placebo or active comparator arm (other than a different dose/formulation of sumatriptan) |
Differences between protocol and review
We have considered data for two outcomes not specified in the protocol.
Use of rescue medication was reported by the majority of studies, and provides a measure of efficacy from the point of view of the patient. In taking rescue medication the patient is saying that the efficacy of the medication is not adequate and that they need alternative analgesia. They are effectively withdrawing due to lack of efficacy, where efficacy is defined by their preparedness to carry on without additional analgesia, rather than a predefined outcome such as headache relief at two hours. We believe this is useful additional information relevant to clinical practice.
Pain‐free at one hour provides, along with headache relief at one hour, a measure of the speed of onset of the medication. This is an important feature of some anti‐migraine treatments and can vary significantly between different routes of administration of the same drug. We chose to analyse pain‐free at one hour to provide a stringent measure of the early efficacy of intranasal sumatriptan, which we believe to be important information for clinical practice.
We have included data for withdrawals due to adverse events over reporting periods longer than the 24 hours stated in the protocol. Many studies collected adverse event data for longer than 24 hours after treatment, and it is likely that in these cases data on withdrawals due to adverse events were also collected over longer time periods. Adverse event withdrawals were infrequent in all of the trials reporting, regardless of the time period over which they were collected, but are an important measure of drug safety and tolerability. We therefore decided to be as inclusive as possible with data on adverse event withdrawals, in the hope of providing the most comprehensive picture possible of sumatriptan tolerability.
For calculations of susceptibility to publication bias we have used a NNT of ≥ 8 as the limit of clinical utility for pain‐free at two hours and ≥ 6 for headache relief at two hours. In the protocol we said we would use a NNT of ≥ 8 for headache relief at two hours, but made the change following a discussion with the field editor.
Contributions of authors
SD and RAM wrote the protocol. CD and SD carried out searches, data extraction, and analyses. RAM acted as arbitrator. All authors were involved with writing the final review.
Sources of support
Internal sources
Oxford Pain Relief Trust, UK.
NIHR Biomedical Research Centre Programme, UK.
External sources
Cochrane Review Incentive Scheme 2010, UK.
-
Lifting The Burden: the Global Campaign against Headache, UK.
Funding for administrative costs associated with editorial and peer review
Declarations of interest
RAM and SD have received research support from charities, government, and industry sources at various times. RAM has consulted for various pharmaceutical companies, including GlaxoSmithKline, the manufacturers of sumatriptan. RAM has received lecture fees from pharmaceutical companies related to analgesics and other healthcare interventions. GlaxoSmithKline were not in any way involved in this review.
Stable (no update expected for reasons given in 'What's new')
References
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