Sumatriptan (subcutaneous route of administration) for acute migraine attacks in adults

Christopher J Derry; Sheena Derry; R Andrew Moore

doi:10.1002/14651858.CD009665

. 2012 Feb 15;2012(2):CD009665. doi: 10.1002/14651858.CD009665

Sumatriptan (subcutaneous route of administration) for acute migraine attacks in adults

Christopher J Derry ¹, Sheena Derry ^2,^✉, R Andrew Moore ³

Editor: Cochrane Pain, Palliative and Supportive Care Group

PMCID: PMC4164380 EMSID: EMS58494 PMID: 22336869

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. Subcutaneous administration may be preferable to oral for individuals experiencing nausea and/or vomiting

Objectives

To determine the efficacy and tolerability of subcutaneous 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 subcutaneous 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

Thirty‐five studies (9365 participants) compared subcutaneous sumatriptan with placebo or an active comparator. Most of the data were for the 6 mg dose. Sumatriptan surpassed placebo for all efficacy outcomes. For sumatriptan 6 mg versus placebo the NNTs were 2.9, 2.3, 2.2, and 2.1 for pain‐free at one and two hours, and headache relief at one and two hours, respectively, and 6.1 for sustained pain‐free at 24 hours. Results for the 4 mg and 8 mg doses were similar to the 6 mg dose, with 6 mg significantly better than 4 mg only for pain‐free at one hour, and 8 mg significantly better than 6 mg only for headache relief at one hour. There was no evidence of increased migraine relief if a second dose of sumatriptan 6 mg was given after an inadequate response to the first.

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.

Sumatriptan was compared directly with a number of active treatments, including other triptans, acetylsalicylic acid plus metoclopramide, and dihydroergotamine, but there were insufficient data for any pooled analyses.

Authors' conclusions

Subcutaneous sumatriptan is effective as an abortive treatment for acute migraine attacks, quickly relieving pain, nausea, photophobia, phonophobia, and functional disability, but is associated with increased adverse events.

Plain language summary

Sumatriptan (subcutaneous 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 subcutaneous injection, and this route of administration may be preferable for individuals experiencing nausea and/or vomiting, or needing fast relief. This review found that a single subcutaneous 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 almost 6 in 10 people (59%) taking sumatriptan 6 mg, compared with about 1 in 7 (15%) taking placebo, and reduced from moderate or severe to no worse than mild pain by two hours in almost 8 in 10 people (79%) taking sumatriptan compared with about 3 in 10 (31%) taking placebo. Subcutaneous sumatriptan was fast‐acting, and the majority of people experiencing pain relief had done so by one hour. About 3 in 10 (31%) people had freedom from pain at two hours which was sustained during the 24 hours postdose without the use of rescue medication, compared with about 1 in 7 (15%) with 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 taking placebo. Adverse events, most of which were of short duration and mild or moderate in severity, were more frequent with sumatriptan than with placebo.

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, nasal spray, rectal suppositories, and subcutaneous (sc) injection. The subcutaneous formulation is available only by prescription. Generic (non‐proprietary) formulations are becoming available. The subcutaneous formulation may be particularly useful for individuals who experience severe nausea or vomiting with their attacks, or who need fast relief. In England in 2010 there were over 910,000 prescriptions for sumatriptan in primary care, of which 54,900 were for the subcutaneous injection (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.

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. Oral sumatriptan suffers from poor bioavailability due to metabolism in the gastrointestinal tract before reaching the bloodstream and target arteries. An early suggestion was that injecting the drug subcutaneously would lead to greater efficacy and faster onset of effect.

Why it is important to do this review

Sumatriptan was the first marketed triptan, is by far 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.

The present review considers subcutaneous administration only, for which a significant body of evidence exists. This is the most costly formulation of sumatriptan, and is likely to benefit primarily those who experience severe nausea and vomiting, and those needing fast relief; its place in the overall spectrum of migraine therapies needs to be evaluated with these considerations in mind. In addition to the original branded subcutaneous sumatriptan, generic versions and needle‐free injection devices that deliver sumatriptan beneath the skin's surface using compressed gas have recently become available and need to be addressed.

Objectives

The objective of this review is to determine the efficacy and tolerability of subcutaneous 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 subcutaneous 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), although we accepted diagnostic criteria equivalent to those of IHS 1988, where a specific reference was not provided. 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 subcutaneous 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. Active‐controlled trials without a placebo were considered 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). We accepted the following pain measures for the primary outcomes:

pain intensity: four‐point categorical scale, with wording equivalent to none, mild, moderate, and 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 (CENTRAL) (2011, Issue 10);
MEDLINE (via OVID) (to 13 October 2011);
EMBASE (via OVID) (to 13 October 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 www.clinicaltrials.gov). We made a written request for information about both published and unpublished data from the manufacturer of sumatriptan (GlaxoSmithKline), 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) where there were substantial missing data we commented on this and performed sensitivity analyses to investigate their effect.

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 a NNT of ≥ 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 was 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). We assumed a statistically significant difference from control when the 95% CI of the relative risk of benefit or harm did 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 and treatment regimens separately. No further subgroup analysis was planned.

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

Thirty‐five studies (32 publications) fulfilled the inclusion criteria for this review; 30 were published in full peer‐reviewed journals (Akpunonu 1995; Bates 1994; Bousser 1993; Cady 1991 Study 1 and Study 2; Cady 1993; Cady 1998; Dahlof 1992; Dahlof 1998; Diener 1999; Diener 2001; Facchinetti 1995; Ferrari 1991; Gross 1994; Henry 1993; Jensen 1995; Mathew 1992; Mushet 1996 Study 1 and Study 2; Pfaffenrath 1991; Russell 1994; Sang 2004; Schulman 2000; Thomson 1993; Visser 1992; Wendt 2006; Winner 1996; Winner 2006 Study 1 and Study 2), and five were available as Results Summaries on the manufacturer's website (S2BL99; S2BM03; S2BS78; SUM40286; SUM40287). These studies provided data on 9365 participants.

All of the included studies recruited adult participants only, with the majority (23/35) recruiting participants between 18 and 65 years of age (mean ages ranged from 37 to 45 years), and the remainder ranging from a 50‐year maximum age to no upper limit on age. The majority of participants were female (55% to 100%) and had a diagnosis of migraine without aura (61% to 100%). Most studies required participants to have had at least a 6‐ or 12‐month history of migraine attacks meeting IHS (or equivalent) diagnostic criteria (IHS 1988; IHS 2004) before screening, although five studies (Henry 1993; Jensen 1995; Mathew 1992; Thomson 1993; Wendt 2006) made no specific requirement for length of migraine history, and one (Russell 1994) had 90% of participants with IHS criteria in a post‐treatment analysis. Five studies required participants to discontinue any prophylactic medication at least two weeks before receiving study medication, while 14 studies allowed stable prophylactic medications (often excluding monoamine oxidase inhibitors, methysergide and ergotamine or ergotamine‐containing medications), and the remaining 16 studies did not report on prophylaxis. Twenty 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. The remaining 14 studies did not report on restricted acute migraine medications.

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 opthalmoplegic, basilar or hemiplegic migraine. In addition 14 studies excluded participants if they had previously taken sumatriptan: some limited this exclusively to subcutaneous sumatriptan and others excluded participants who had any experience with sumatriptan. Two studies (SUM40286; SUM40287) required participants to have successfully treated an attack with a 5HT₁ agonist in the past, but never to have used a subcutaneous formulation. One study (S2BM03) actually required participants to have regularly used sumatriptan for at least six months before study entry and to experience recurrence of headache in 50% or more of their treated attacks.

The baseline headache intensity at which study medication was administered was largely consistent amongst the included studies, with the majority (25/35) administering the study drug when migraine headache pain was of moderate or severe intensity. Of the remaining studies, one (Bates 1994) required participants to administer medication at the onset of aura, one (S2BM03) at the onset of migraine, and one (S2BS78) at the first sign of headache pain. Seven studies did not report the baseline headache intensity at which study medication was administered. Despite this variability in instruction on when to medicate, all 10 of these studies were dominated by participants with moderate or severe migraine attacks at the time of dosing, and all except one (S2BS78) provided data based on this population specifically. S2BS78 reported on a mixed population of participants treating either mild intensity headaches or moderate and severe intensity headaches, and failed to provide specific data for either population. Given the clinical heterogeneity between these two populations of participants, this study did not provide any data toward efficacy analyses.

Most of the included studies used a parallel‐group design (28/35), treating a single migraine attack (25/35). Of those studies treating multiple attacks, most (7/10) treated two separate attacks. The response of headaches to study treatment was measured using a standard four‐point pain intensity scale in all 35 studies. The majority of the studies (27/35) reported at least one IHS‐preferred outcome (IHS 2000); seven studies (Akpunonu 1995; Cady 1998; Jensen 1995; Russell 1994; S2BS78; Thomson 1993; Visser 1992) provided data for secondary outcomes only. Just over half of the studies (19/35) 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), (13 studies), or to treat recurrence alone (six studies). All studies reported allowing rescue medication (often excluding ergotamine or ergotamine‐derivatives) if the response to study treatment was insufficient after a defined time period. This time period varied between studies, with some studies allowing the use of some form of rescue medication 0.5, 1, 1.5, 2, and 4 hours after initial dosing (1, 3, 2, 20 and 1 study, respectively), while others allowed rescue medication at either one or two hours after administration of a second dose of study medication (five and three studies, respectively). In some cases rescue medication was available to treat recurrence as well as inadequate response, but most studies did not address this question specifically.

Twenty‐eight studies used only a placebo comparator, three studies used only active comparators, and four used both active and placebo comparators. All of the included studies used a needle‐based delivery system; no studies reporting efficacy results from needle‐free injection systems were found. The 35 studies reported on 18 different treatment comparisons:

Sumatriptan 1 mg versus placebo (Mathew 1992; Visser 1992).
Sumatriptan 2 mg versus placebo (Mathew 1992; Visser 1992).
Sumatriptan 3 mg versus placebo (Mathew 1992; Visser 1992).
Sumatriptan 4 mg versus placebo (Mathew 1992; Thomson 1993; Wendt 2006).
Sumatriptan 6 mg versus placebo (Akpunonu 1995; Bates 1994; Bousser 1993; Cady 1991 Study 1 and Study 2; Cady 1993; Cady 1998; Dahlof 1998; Diener 1999; Diener 2001; Facchinetti 1995; Ferrari 1991; Gross 1994; Henry 1993; Jensen 1995; Mathew 1992; Mushet 1996 Study 1 and Study 2; Pfaffenrath 1991; Russell 1994; S2BM03; S2BS78; Sang 2004; Schulman 2000; SUM40286; SUM40287; Winner 2006 Study 1 and Study 2).
Sumatriptan 6 mg versus subcutaneous naratriptan 0.5 mg (Dahlof 1998).
Sumatriptan 6 mg versus subcutaneous naratriptan 1 mg (Dahlof 1998).
Sumatriptan 6 mg versus subcutaneous naratriptan 2.5 mg (Dahlof 1998).
Sumatriptan 6 mg versus subcutaneous naratriptan 5 mg (Dahlof 1998).
Sumatriptan 6 mg versus subcutaneous naratriptan 10 mg (Dahlof 1998).
Sumatriptan 6 mg versus intravenous acetylsalicylic acid lysinate 1.8 g (Diener 1999).
Sumatriptan 6 mg versus subcutaneous alniditan 1.4 mg (Diener 2001).
Sumatriptan 6 mg versus subcutaneous alniditan 1.8 mg (Diener 2001).
Sumatriptan 6 mg versus intravenous LY293558 1.2 mg/kg (Sang 2004).
Sumatriptan 6 mg versus oral effervescent acetylsalicylic acid (ASA) 1000 mg + metoclopramide (MCP) 10 mg (S2BL99).
Sumatriptan 6 mg versus dihydroergotamine (DHE) nasal spray 1 mg (Touchon 1996).
Sumatriptan 6 mg versus subcutaneous DHE 1 mg (Winner 1996).
Sumatriptan 8 mg with placebo (Dahlof 1992; Mathew 1992; Ferrari 1991).

In total, 200 participants were treated with sumatriptan 1 mg, 201 with sumatriptan 2 mg, 202 with sumatriptan 3 mg, 442 with sumatriptan 4 mg, 4334 with sumatriptan 6 mg, 167 with sumatriptan 8 mg, 3018 with placebo, 60 with naratriptan 0.5 mg, 55 with naratriptan 1 mg, 42 with naratriptan 2.5 mg, 34 with naratriptan 5 mg, 34 with naratriptan 10 mg, 119 with intravenous acetylsalicylic acid lysinate 1.8 g, 309 with alniditan 1.4 mg, 141 with alniditan 1.8 mg, 13 with intravenous LY293558 1.2 mg/kg, 130 with oral effervescent acetylsalicylic acid (ASA) 1000 mg + metoclopramide (MCP) 10 mg, 277 with dihydroergotamine (DHE) nasal spray 1 mg, and 152 with subcutaneous DHE 1 mg.

Some studies were inconsistent in the treatment group denominators reported, so that the population varied slightly in size for different outcomes or at different time points. Where this variability was not explained in the text, the denominators were changed to match the treated efficacy population if this gave a more conservative estimate of the efficacy of the drug.

Full details of included studies are provided in the Characteristics of included studies table.

Excluded studies

We excluded 12 studies after reading the full report (Burke‐Ramirez 2001; Cady 1991; Cull 2001; Ensink 1991; Friedman 2005; Friedman 2006; Gonzalez‐Espinosa 1997; Melchart 2003; Pradel 2006; Russell 1995; S2BM04; Solbach 1993). The reasons for these exclusions are provided in the Characteristics of excluded studies table.

Risk of bias in included studies

Included studies were all randomised and double‐blind. The majority of the studies provided information about withdrawals and dropouts, although five studies either made no statement about withdrawals or did not give an adequate explantation for differing treatment group denominators. The reliability of the trials was determined using the Oxford Quality Scale. Six studies scored 5 of 5 on the scale, 10 studies scored 4 of 5, 17 studies scored 3 of 5, and two studies 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 random sequence generation, allocation concealment, or blinding. Fifteen studies (Akpunonu 1995; Bates 1994; Bousser 1993; Cady 1993; Dahlof 1992; Dahlof 1998; Diener 1999; Gross 1994; Henry 1993; Mathew 1992; Mushet 1996 Study 1 and Study 2; Sang 2004; Schulman 2000; Thomson 1993) 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.

'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 4 mg versus placebo

Two studies (664 participants) provided data (Mathew 1992; Wendt 2006).

The proportion of participants pain‐free at two hours with sumatriptan 4 mg was 49% (201/411; range 33% to 50%).
The proportion of participants pain‐free at two hours with placebo was 9% (23/253; range 3% to 11%).
The relative benefit of treatment compared with placebo was 4.8 (3.2 to 7.2; Analysis 1.1); the NNT was 2.5 (2.2 to 3.0).

1.1 — Comparison 1 Subcutaneous sumatriptan 4 mg versus placebo, Outcome 1 Pain‐free at 2 h.

Sumatriptan 6 mg versus placebo

Thirteen studies (2522 participants) provided data (Dahlof 1998; Diener 1999; Diener 2001; Facchinetti 1995; Mathew 1992; Mushet 1996 Study 1 and Study 2; S2BM03; Sang 2004; SUM40286; SUM40287; Winner 2006 Study 1 and Study 2).

The proportion of participants pain‐free at two hours with sumatriptan 6 mg was 59% (799/1351; range 48% to 76%).
The proportion of participants pain‐free at two hours with placebo was 15% (174/1171; range 3% to 19%).
The relative benefit of treatment compared with placebo was 3.9 (3.3 to 4.5; Analysis 2.1; Figure 2); the NNT was 2.3 (2.1 to 2.4).

2.1 — Comparison 2 Subcutaneous sumatriptan 6 mg versus placebo, Outcome 1 Pain‐free at 2 h.

Forest plot of comparison: 2 Subcutaneous sumatriptan 6 mg versus placebo, outcome: 2.1 Pain‐free at 2 h.

Sumatriptan 6 mg plus optional 6 mg versus placebo

Three studies (388 participants) provided data comparing sumatriptan 6 mg (with an optional second dose of sumatriptan 6 mg if initial relief was inadequate after one hour) with placebo (with an optional second dose of placebo if initial relief was inadequate) for a pain‐free response at two hours (Bousser 1993; Henry 1993; Pfaffenrath 1991). Overall, 34% (range 22% to 53%) of sumatriptan‐treated participants providing data for this comparison received two doses of medication (i.e. 6 mg + 6 mg), while 77% (range 74% to 81%) of placebo‐treated participants providing data received two doses of placebo.

The proportion of participants pain‐free at two hours with sumatriptan 6 mg (+ 6 mg) was 50% (117/233; range 47% to 51%).
The proportion of participants pain‐free at two hours with placebo (+ placebo) was 11% (17/155; range 8% to 15%).
The relative benefit of treatment compared with placebo was 4.6 (2.9 to 7.4; Analysis 4.1); the NNT was 2.6 (2.1 to 3.2).

4.1 — Comparison 4 Subcutaneous sumatriptan 6 mg (+ optional 6 mg) versus placebo, Outcome 1 Pain‐free at 2 h.

There was no significant difference in efficacy between a single dose of sumatriptan 6 mg and an initial dose of sumatriptan 6 mg plus an optional second dose after one hour in the event of inadequate relief from the initial dose.

Other doses of sumatriptan versus placebo

Two studies (Dahlof 1992; Mathew 1992) provided data comparing sumatriptan 8 mg with placebo, although the number of participants involved in this comparison was not sufficiently large to allow pooled analysis. Between 53% and 63% of participants treated with sumatriptan 8 mg were pain‐free at two hours compared with 0% to 3% of participants treating with placebo.

One study (Mathew 1992) provided data comparing sumatriptan 1 mg, 2 mg, and 3 mg with placebo, but there were insufficient data to carry out pooled analysis of these doses. The proportion of participants pain‐free at two hours after treatment with sumatriptan 1, 2, and 3 mg was 20%, 10%, and 27%, respectively, while only 3% of placebo‐treated participants were pain‐free at two hours.

Sumatriptan versus active comparators

Six studies (Dahlof 1998; Diener 1999; Diener 2001; S2BL99; Sang 2004; Touchon 1996) provided data comparing sumatriptan with an active comparator for pain‐free at two hours. None of these studies used comparable active comparators so no pooled analysis could be carried out.

Dahlof 1998 provided data comparing sumatriptan 6 mg with naratriptan at doses of 0.5, 1, 2.5, 5, and 10 mg. The proportion of participants pain‐free at two hours after treating with sumatriptan was 55%, compared to 30%, 44%, 60%, 79%, and 88% of participants treating with subcutaneous naratriptan 0.5, 1, 2.5, 5, and 10 mg, respectively.
Diener 1999 provided data comparing sumatriptan 6 mg with intravenous acetylsalicylic acid lysinate 1.8 g. The proportion of participants pain‐free at two hours after treating with sumatriptan was 76%, compared to 44% of participants treating with acetylsalicylic acid lysinate.
Diener 2001 provided data comparing sumatriptan 6 mg with subcutaneous alniditan 1.4 mg and 1.6 mg. The proportion of participants pain‐free at two hours after treating with sumatriptan was 66%, compared to 56% and 62% of participants treating with alniditan 1.4 mg and 1.6 mg, respectively.
S2BL99 provided data comparing sumatriptan 6 mg with oral effervescent ASA 1000 mg + MCP 10 mg. The proportion of participants pain‐free at two hours after treating with sumatriptan was 61%, compared to 37% of participants treating with oral ASA + MCP.
Sang 2004 provided data comparing sumatriptan 6 mg with intravenous LY293558 1.2 mg/kg. The proportion of participants pain‐free at two hours after treating with sumatriptan was 60%, compared to 54% of participants treating with LY293558.
Touchon 1996 provided data comparing sumatriptan 6 mg with DHE nasal spray 1 mg. The proportion of participants pain‐free at two hours after treating with sumatriptan was 66%, compared to 31% of participants treating with DHE nasal spray.

Pain‐free at one hour

Sumatriptan 4 mg versus placebo

Two studies (664 participants) provided data (Mathew 1992; Wendt 2006).

The proportion of participants pain‐free at one hour with sumatriptan 4 mg was 33% (134/411; range 17% to 34%).
The proportion of participants pain‐free at one hour with placebo was 6% (16/253; range 3% to 7%).
The relative benefit of treatment compared with placebo was 4.7 (2.8 to 7.7; Analysis 1.2); the NNT was 3.8 (3.2 to 4.8).

1.2 — Comparison 1 Subcutaneous sumatriptan 4 mg versus placebo, Outcome 2 Pain‐free at 1 h.

Sumatriptan 6 mg versus placebo

Sixteen studies (3592 participants) provided data (Bousser 1993; Cady 1991 Study 1 and Study 2; Cady 1993; Facchinetti 1995; Ferrari 1991; Henry 1993; Jensen 1995; Mathew 1992; Mushet 1996 Study 1 and Study 2; Pfaffenrath 1991; S2BM03; Sang 2004; SUM40286; SUM40287).

The proportion of participants pain‐free at one hour with sumatriptan 6 mg was 41% (905/2198; range 27% to 49%).
The proportion of participants pain‐free at one hour with placebo was 7% (99/1394; range 1% to 11%).
The relative benefit of treatment compared with placebo was 5.6 (4.6 to 6.8; Analysis 2.2); the NNT was 2.9 (2.7 to 3.2).

2.2 — Comparison 2 Subcutaneous sumatriptan 6 mg versus placebo, Outcome 2 Pain‐free at 1 h.

Sumatriptan 6 mg was significantly more effective than sumatriptan 4 mg for complete relief of pain by one hour (z = 2.560; P = 0.011; see Summary of results B).

Sumatriptan 8 mg versus placebo

Two studies (308 participants) provided data (Ferrari 1991; Mathew 1992).

The proportion of participants pain‐free at one hour with sumatriptan 8 mg was 46% (65/140; range 33% to 50%).
The proportion of participants pain‐free at one hour with placebo was 6% (10/168; range 3% to 8%).
The relative benefit of treatment compared with placebo was 7.1 (3.8 to 13; Analysis 3.1); the NNT was 2.5 (2.0 to 3.2).

3.1 — Comparison 3 Subcutaneous sumatriptan 8 mg versus placebo, Outcome 1 Pain‐free at 1 h.

Other doses of sumatriptan versus placebo

One study (Mathew 1992) provided data comparing sumatriptan 1 mg, 2 mg, and 3 mg with placebo, but there were insufficient data to carry out pooled analysis of these doses. The proportion of participants pain‐free at one hour after treatment with sumatriptan 1, 2, and 3 mg was 13%, 3%, and 23%, respectively, while only 3% of placebo‐treated participants were pain‐free at one hour.

Sumatriptan versus active comparators

Three studies (S2BL99; Sang 2004; Touchon 1996) provided data comparing sumatriptan with an active comparator for pain‐free at one hour. The two studies used different active comparators so no pooled analysis could be carried out.

S2BL99 provided data comparing sumatriptan 6 mg with oral effervescent ASA 1000 mg + MCP 10 mg. The proportion of participants pain‐free at one hour after treating with sumatriptan was 45%, compared to 21% of participants treating with oral ASA + MCP.
Sang 2004 provided data comparing sumatriptan 6 mg with intravenous LY293558 1.2 mg/kg. The proportion of participants pain‐free at one hour after treating with sumatriptan was 27%, compared to 31% of participants treating with LY293558.
Touchon 1996 provided data comparing sumatriptan 6 mg with DHE nasal spray 1 mg. The proportion of participants pain‐free at one hour after treating with sumatriptan was 47%, compared to 13% of participants treating with DHE nasal spray.

Headache relief at one hour

Sumatriptan 4 mg versus placebo

Two studies (664 participants) provided data (Mathew 1992; Wendt 2006).

The proportion of participants with headache relief at one hour with sumatriptan 4 mg was 66% (271/411; range 50% to 67%).
The proportion of participants with headache relief at one hour with placebo was 25% (64/253; range 24% to 26%).
The relative benefit of treatment compared with placebo was 2.6 (2.0 to 3.2; Analysis 1.3); the NNT was 2.5 (2.1 to 3.0).

1.3 — Comparison 1 Subcutaneous sumatriptan 4 mg versus placebo, Outcome 3 Headache relief at 1 h.

Sumatriptan 6 mg versus placebo

Twenty‐four studies (5177 participants) provided data (Bates 1994; Bousser 1993; Cady 1991 Study 1 and Study 2; Cady 1993; Dahlof 1998; Diener 1999; Diener 2001; Facchinetti 1995; Ferrari 1991; Gross 1994; Henry 1993; Jensen 1995; Mathew 1992; Mushet 1996 Study 1 and Study 2; Pfaffenrath 1991; S2BM03; Sang 2004; Schulman 2000; SUM40286; SUM40287; Winner 2006 Study 1 and Study 2).

The proportion of participants with headache relief at one hour with sumatriptan 6 mg was 71% (2229/3139; range 51% to 88%).
The proportion of participants with headache relief at one hour with placebo was 26% (532/2038; range 6% to 41%).
The relative benefit of treatment compared with placebo was 2.7 (2.5 to 2.9; Analysis 2.3; Figure 3); the NNT was 2.2 (2.1 to 2.4).

2.3 — Comparison 2 Subcutaneous sumatriptan 6 mg versus placebo, Outcome 3 Headache relief at 1 h.

Forest plot of comparison: 2 Subcutaneous sumatriptan 6 mg versus placebo, outcome: 2.3 Headache relief at 1 h.

Sumatriptan 8 mg versus placebo

Three studies (361 participants) provided data (Dahlof 1992; Ferrari 1991; Mathew 1992).

The proportion of participants with headache relief at one hour with sumatriptan 8 mg was 80% (133/166; range 79% to 85%).
The proportion of participants with headache relief at one hour with placebo was 23% (44/195; range 11% to 25%).
The relative benefit of treatment compared with placebo was 3.6 (2.7 to 4.7; Analysis 3.2); the NNT was 1.7 (1.5 to 2.0).

3.2 — Comparison 3 Subcutaneous sumatriptan 8 mg versus placebo, Outcome 2 Headache relief at 1 h.

Sumatriptan 8 mg was significantly more effective than sumatriptan 6 mg for headache relief at one hour (z = 2.818; P = 0.005; see Summary of results B).

Other doses of sumatriptan versus placebo

One study (Mathew 1992) provided data comparing sumatriptan 1 mg, 2 mg, and 3 mg with placebo, but there were insufficient data to carry out pooled analysis of these doses. The proportion of participants with headache relief at one hour after treatment with sumatriptan 1, 2, and 3 mg was 43%, 57%, and 57%, respectively, while only 24% of placebo‐treated participants had relief at one hour.

Sumatriptan versus active comparators

Seven studies (Dahlof 1998; Diener 1999; Diener 2001; S2BL99; Sang 2004; Touchon 1996; Winner 1996) provided data comparing sumatriptan with an active comparator for headache relief at one hour. None of these studies used comparable active comparators so no pooled analysis could be carried out.

Dahlof 1998 provided data comparing sumatriptan 6 mg with subcutaneous naratriptan at doses of 0.5, 1, 2.5, 5, and 10 mg. The proportion of participants with headache relief at one hour after treating with sumatriptan was 87%, compared to 60%, 64%, 81%, 85%, and 76% of participants treating with naratriptan 0.5, 1, 2.5, 5, and 10 mg, respectively.
Diener 1999 provided data comparing sumatriptan 6 mg with intravenous acetylsalicylic acid lysinate 1.8 g. The proportion of participants with headache relief at one hour after treating with sumatriptan was 74%, compared to 60% of participants treating with acetylsalicylic acid lysinate.
Diener 2001 provided data comparing sumatriptan 6 mg with subcutaneous alniditan 1.4 mg and 1.6 mg. The proportion of participants with headache relief at one hour after treating with sumatriptan was 79%, compared to 75% and 81% of participants treating with alniditan 1.4 mg and 1.6 mg, respectively.
S2BL99 provided data comparing sumatriptan 6 mg with oral effervescent ASA 1000 mg + MCP 10 mg. The proportion of participants with headache relief at one hour after treating with sumatriptan was 71%, compared with 46% of participants treating with oral ASA + MCP.
Sang 2004 provided data comparing sumatriptan 6 mg with intravenous LY293558 1.2 mg/kg. The proportion of participants with headache relief at one hour after treating with sumatriptan was 73%, compared to 69% of participants treating with LY293558.
Touchon 1996 provided data comparing sumatriptan 6 mg with DHE nasal spray 1 mg. The proportion of participants with headache relief at one hour after treating with sumatriptan was 71%, compared to 34% of participants treating with DHE nasal spray.
Winner 1996 provided data comparing sumatriptan 6 mg with subcutaneous DHE 1 mg. The proportion of participants with headache relief at one hour after treating with sumatriptan was 78%, compared to 57% of participants treating with DHE.

Headache relief at two hours

Sumatriptan 4 mg versus placebo

Two studies (664 participants) provided data (Mathew 1992; Wendt 2006).

The proportion of participants with headache relief at two hours with sumatriptan 4 mg was 70% (286/411; range 60% to 70%).
The proportion of participants with headache relief at two hours with placebo was 22% (56/253; range 22% to 23%).
The relative benefit of treatment compared with placebo was 3.1 (2.4 to 4.0; Analysis 1.4); the NNT was 2.1 (1.8 to 2.5).

1.4 — Comparison 1 Subcutaneous sumatriptan 4 mg versus placebo, Outcome 4 Headache relief at 2 h.

Sumatriptan 6 mg versus placebo

Fourteen studies (2738 participants) provided data (Dahlof 1998; Diener 1999; Diener 2001; Facchinetti 1995; Jensen 1995; Mathew 1992; Mushet 1996 Study 1 and Study 2; S2BM03; Sang 2004; SUM40286; SUM40287; Winner 2006 Study 1 and Study 2).

The proportion of participants with headache relief at two hours with sumatriptan 6 mg was 79% (1152/1459; range 68% to 91%).
The proportion of participants with headache relief at two hours with placebo was 31% (395/1279; range 10% to 41%).
The relative benefit of treatment compared with placebo was 2.5 (2.3 to 2.7; Analysis 2.4; Figure 4); the NNT was 2.1 (2.0 to 2.2).

2.4 — Comparison 2 Subcutaneous sumatriptan 6 mg versus placebo, Outcome 4 Headache relief at 2 h.

Forest plot of comparison: 2 Subcutaneous sumatriptan 6 mg versus placebo, outcome: 2.4 Headache relief at 2 h.

Sumatriptan 6 mg plus optional 6 mg versus placebo

Six studies (1728 participants) provided data comparing sumatriptan 6 mg (with an optional second dose of sumatriptan 6 mg if initial relief was inadequate after one hour) with placebo (with an optional second dose of placebo if initial relief was inadequate) for headache relief at two hours (Bousser 1993; Cady 1991 Study 1 and Study 2; Ferrari 1991; Henry 1993; Pfaffenrath 1991). Overall, 30% (range 22% to 53%) of sumatriptan‐treated participants providing data for this comparison received two doses of medication (i.e. 6 mg + 6 mg), while 87% (range 74% to 91%) of placebo‐treated participants providing data received two doses of placebo.

The proportion of participants with headache relief at two hours with sumatriptan 6 mg (+ 6 mg) was 79% (871/1098; range 69% to 94%).
The proportion of participants with headache relief at two hours with placebo (+ placebo) was 32% (203/630; range 21% to 39%).
The relative benefit of treatment compared with placebo was 2.4 (2.1 to 2.7; Analysis 4.2); the NNT was (1.9 to 2.3).

4.2 — Comparison 4 Subcutaneous sumatriptan 6 mg (+ optional 6 mg) versus placebo, Outcome 2 Headache relief at 2 h.

There was no significant difference in efficacy between a single dose of sumatriptan 6 mg and an initial dose of sumatriptan 6 mg plus an optional second dose in the event of inadequate relief after one hour from the initial dose.

Other doses of sumatriptan versus placebo

Two studies (Dahlof 1992; Mathew 1992) provided data comparing sumatriptan 8 mg with placebo, although the number of participants involved in this comparison was not sufficiently large to allow pooled analysis. Between 85% and 87% of participants treated with sumatriptan 8 mg had headache relief at two hours compared with 23% of participants treating with placebo.

One study (Mathew 1992) provided data comparing sumatriptan 1 mg, 2 mg, and 3 mg with placebo, but there were insufficient data to carry out pooled analysis of these doses. The proportion of participants with headache relief at two hours after treatment with sumatriptan 1, 2, and 3 mg was 40%, 47%, and 57%, respectively, while only 23% of placebo‐treated participants had relief at two hours.

Sumatriptan versus active comparators

Seven studies (Dahlof 1998; Diener 1999; Diener 2001; S2BL99; Sang 2004; Touchon 1996; Winner 1996) provided data comparing sumatriptan with an active comparator for headache relief at two hours. None of these studies used comparable active comparators so no pooled analysis could be carried out.

Dahlof 1998 provided data comparing sumatriptan 6 mg with subcutaneous naratriptan at doses of 0.5, 1, 2.5, 5, and 10 mg. The proportion of participants with headache relief at two hours after treating with sumatriptan was 89%, compared to 65%, 75%, 83%, 94%, and 91% of participants treating with naratriptan 0.5, 1, 2.5, 5, and 10 mg, respectively.
Diener 1999 provided data comparing sumatriptan 6 mg with intravenous acetylsalicylic acid lysinate 1.8 g. The proportion of participants with headache relief at two hours after treating with sumatriptan was 91%, compared to 74% of participants treating with acetylsalicylic acid lysinate.
Diener 2001 provided data comparing sumatriptan 6 mg with subcutaneous alniditan 1.4 mg and 1.6 mg. The proportion of participants with headache relief at two hours after treating with sumatriptan was 87%, compared to 81% and 85% of participants treating with alniditan 1.4 mg and 1.6 mg, respectively.
S2BL99 provided data comparing sumatriptan 6 mg with oral effervescent ASA 1000 mg + MCP 10 mg. The proportion of participants with headache relief at two hours after treating with sumatriptan was 81%, compared to 63% of participants treated with oral ASA + MCP.
Sang 2004 provided data comparing sumatriptan 6 mg with intravenous LY293558 1.2 mg/kg. The proportion of participants with headache relief at two hours after treating with sumatriptan was 87%, compared to 69% of participants treating with LY293558.
Touchon 1996 provided data comparing sumatriptan 6 mg with DHE nasal spray 1 mg. The proportion of participants with headache relief at two hours after treating with sumatriptan was 81%, compared to 52% of participants treating with DHE nasal spray.
Winner 1996 provided data comparing sumatriptan 6 mg with subcutaneous DHE 1 mg. The proportion of participants with headache relief at one hour after treating with sumatriptan was 85%, compared to 73% of participants treating with DHE.

Sustained pain‐free during the 24 hours postdose

Sumatriptan 6 mg versus placebo

Five studies (1336 participants) provided data (Cady 1993; SUM40286; SUM40287; Winner 2006 Study 1 and Study 2).

The proportion of participants with a 24‐hour sustained pain‐free response with sumatriptan 6 mg was 31% (222/713; range 20% to 34%).
The proportion of participants with a 24‐hour sustained pain‐free response with placebo was 15% (91/623; range 12% to 15%).
The relative benefit of treatment compared with placebo was 2.2 (1.8 to 2.8; Analysis 2.5); the NNT was 6.1 (4.8 to 8.2).

2.5 — Comparison 2 Subcutaneous sumatriptan 6 mg versus placebo, Outcome 5 24 h sustained pain‐free.

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 4 mg	2	664	49	9	4.8 (3.2 to 7.2)	2.5 (2.2 to 3.0)
Sumatriptan 6 mg	13	2522	59	15	3.9 (3.3 to 4.5)	2.3 (2.1 to 2.4)
Sumatriptan 6 mg (+ 6 mg)	3	388	50	11	4.6 (2.9 to 7.4)	2.6 (2.1 to 3.2)
Pain‐free at 1 hour
Sumatriptan 4 mg	2	664	33	6	4.7 (2.8 to 7.7)	3.8 (3.2 to 4.8)
Sumatriptan 6 mg	16	3592	41	7	5.6 (4.6 to 6.8)	2.9 (2.7 to 3.2)
Sumatriptan 8 mg	2	308	46	6	7.1 (3.8 to 13)	2.5 (2.0 to 3.2)
Headache relief at 1 hour
Sumatriptan 4 mg	2	664	66	25	2.6 (2.0 to 3.2)	2.5 (2.1 to 3.0)
Sumatriptan 6 mg	24	5177	71	26	2.7 (2.5 to 2.9)	2.2 (2.1 to 2.4)
Sumatriptan 8 mg	3	361	80	23	3.6 (2.7 to 4.7)	1.7 (1.5 to 2.0)
Headache relief at 2 hours
Sumatriptan 4 mg	2	664	70	22	3.1 (2.4 to 4.0)	2.1 (1.8 to 2.5)
Sumatriptan 6 mg	14	2738	79	31	2.5 (2.3 to 2.7)	2.1 (2.0 to 2.2)
Sumatriptan 6 mg (+6 mg)	6	1728	79	32	2.4 (2.1 to 2.7)	2.1 (1.9 to 2.3)
Sustained pain‐free during the 24 hours postdose
Sumatriptan 6 mg	5	1336	31	15	2.2 (1.8 to 2.8)	6.1 (4.8 to 8.2)

Summary of results B: Statistical tests for the effect of dose
	z	P
Pain‐free at 1 hour
Sumatriptan 4 mg versus sumatriptan 6 mg	2.560	0.011
Headache relief at 1 hour
Sumatriptan 6 mg versus sumatriptan 8 mg	2.818	0.005

Summary of results C: Number of participants experiencing specific adverse events within 24 hours of study treatment in placebo‐controlled studies
	Studies	Participants treated	Treatment (%)	Placebo (%)
Malaise/fatigue/asthenia
Sumatriptan 4 mg	2	669	3	2
Sumatriptan 6 mg	5	593	4	4
Dizziness/vertigo
Sumatriptan 4 mg	2	669	10	6
Sumatriptan 6 mg	8	993	6	4
Nausea/vomiting
Sumatriptan 4 mg	2	669	8	10
Sumatriptan 6 mg	11	1667	7	5
Mouth disorder/disturbance of taste
Sumatriptan 4 mg	2	669	4	1
Sumatriptan 6 mg	3	250	6	2
Chest pain/symptoms
Sumatriptan 4 mg	2	669	5	1
Sumatriptan 6 mg	6	466	4	1
Heat sensations/flushing
Sumatriptan 4 mg	2	669	8	4
Sumatriptan 6 mg	10	1149	9	2
Feeling of heaviness/tightness
Sumatriptan 4 mg	2	669	6	1
Sumatriptan 6 mg	7	962	6	3
Sweating
Sumatriptan 4 mg	2	669	1	0
Sumatriptan 6 mg	2	318	6	0
Paraesthesia/numbness
Sumatriptan 4 mg	2	669	12	4
Sumatriptan 6 mg	10	1241	7	3
Headache
Sumatriptan 6 mg	7	727	2	0
Drowsiness/somnolence
Sumatriptan 4 mg	2	669	3	2
Sumatriptan 6 mg	4	415	3	3
Neck/back pain
Sumatriptan 4 mg	2	669	2	1
Sumatriptan 6 mg	5	603	5	1
Throat symptoms
Sumatriptan 4 mg	2	669	1	0
Sumatriptan 6 mg	3	394	7	0
Injection‐site reaction
Sumatriptan 4 mg	2	669	45	19
Sumatriptan 6 mg	12	1848	11	6

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.

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
Akpunonu 1995	(1) Sumatriptan 6 mg, n = 88 (2) Placebo, n = 48	No data	No data	No data	No data	No data	No data	No data
Bates 1994	(1) Sumatriptan 6 mg, n = 90 (88 for efficacy, 47 with moderate or severe baseline pain intensity) (2) Placebo, n = 87 (83 for efficacy, 35 with moderate or severe baseline pain intensity)	(1) 24/47 (2) 10/35	No data	No data	No data	No data	No data	No data
Bousser 1993	(1) Sumatriptan 6 mg, n = 49 (41 for 1st attack efficacy) (2) Placebo, n = 47 (40 for 1st attack efficacy)	(1) 29/41 (2) 8/40	No data	(1) 14/41 (2) 4/40	No data	No data	No data	No data
Cady 1991	Study 1 (1) Sumatriptan 6 mg, n = 384 (2) Placebo, n = 190 Study 2 (1) Sumatriptan 6 mg, n = 350 (2) Placebo, n = 180	Pooled results for Study 1 and Study 2 (1) 515/734 (2) 81/370	No data	Pooled results for Study 1 and Study 2 (1) 356/734 (2) 35/370	No data	No data	No data	No data
Cady 1993	(1) Sumatriptan 6 mg, n = 166 (128 treating first attack with moderate or severe baseline pain intensity) (2) Placebo, n = 144 (42 treating first attack with moderate or severe baseline pain intensity)	1st attack: (1) 100/128 (2) 16/42	No data	1st attack: (1) 41/128 (2) 3/42	No data	(1) 39/128 (2) 5/42	(1) 26/128 (2) 5/42	No data
Cady 1998	(1) Sumatriptan 6 mg, n = 67 (2) Placebo, n = 68 (65 for efficacy)	No data	No data	No data	No data	No data	No data	At 24 h: (1) 5/67 (2) 20/65
Dahlof 1992	(1) Sumatriptan 8 mg, n = 27 (2) Placebo, n = 27	(1) 23/27 (2) 3/27	(1) 23/27 (2) 9/27	No data	(1) 17/27 (2) 0/27	No data	No data	At 2 h: (1) 3/27 (2) 24/27
Dahlof 1998	(1) Sumatriptan 6 mg, n = 47 (2) Naratriptan 0.5 mg, n = 60 (3) Naratriptan 1 mg, n = 55 (4) Naratriptan 2.5 mg, n = 42 (5) Naratriptan 5 mg, n = 34 (6) Naratriptan 10 mg, n = 34 (7) Placebo, n = 63	(1) 41/47 (2) 36/60 (3) 35/55 (4) 34/42 (5) 29/34 (6) 26/34 (7) 26/63	(1) 42/47 (2) 39/60 (3) 41/55 (4) 35/42 (5) 32/34 (6) 31/34 (7) 26/63	No data	(1) 26/47 (2) 18/60 (3) 24/55 (4) 25/42 (5) 27/34 (6) 30/34 (7) 11/63	No data	No data	At 24 h: (1) 2/47 (2) 21/60 (3) 12/55 (4) 5/42 (5) 2/34 (6) 1/34 (7) 22/63
Diener 1999	(1) Sumatriptan 6 mg, n = 114 (2) Intravenous acetylsalicylic acid lysinate 1.8 g, n = 119 (3) Placebo, n = 42	(1) 84/114 (2) 71/119 (3) 8/42	(1) 104/114 (2) 88/119 (3) 10/42	No data	(1) 87/114 (2) 52/119 (3) 6/42	No data	No data	At 24 h: (1) 2/114 (2) 5/119 (3) 7/42
Diener 2001	(1) Sumatriptan 6 mg, n = 317 (2) Alniditan 1.4 mg, n = 309 (3) Alniditan 1.8 mg, n = 141 (4) Placebo, n = 157 (156 for efficacy)	(1) 250/317 (2) 231/309 (3) 114/141 (4) 50/156	(1) 276/317 (2) 250/309 (3) 120/141 (4) 59/156	No data	(1) 209/317 (2) 174/309 (3) 87/141 (4) 22/156	No data	No data	At 24 h: (1) 155/317 (2) 142/309 (3) 65/141 (4) 123/156
Facchinetti 1995	(1) Sumatriptan 6 mg, n = 115 (77 for first dose efficacy with moderate or severe baseline pain intensity) (2) Placebo, n = 111 (92 for first dose efficacy with moderate or severe baseline pain intensity)	(1) 54/77 (2) 20/92	(1) 56/77 (2) 27/92	(1) 25/77 (2) 9/92	(1) 40/77 (2) 12/92	No data	No data	At 2 h: (1) 18/77 (2) 52/92
Ferrari 1991	(1) Sumatriptan 6 mg, n = 423 (422 for efficacy) (2) Sumatriptan 8 mg, n = 110 (109 for efficacy) (3) Placebo, n = 106 (105 for efficacy)	(1) 308/422 (2) 86/109 (3) 26/106	No data	(1) 186/422 (2) 55/109 (3) 8/106	No data	No data	No data	No data
Gross 1994	(1) Sumatriptan 6 mg, n = 60 (48 with moderate or severe baseline pain intensity) (2) Placebo, n = 26 (18 with moderate or severe baseline pain intensity)	(1) 42/48 (2) 2/18	No data	No data	No data	No data	No data	No data
Henry 1993	(1) Sumatriptan 6 mg, n = 37 (2) Placebo, n = 39	(1) 22/37 (2) 8/39	No data	(1) 12/37 (2) 4/39	No data	No data	No data	No data
Jensen 1995	(1) Sumatriptan 6 mg, n = 117 attacks (108 for cross‐over efficacy analysis) (2) Placebo, n = 109 attacks (108 for cross‐over efficacy analysis)	(1) 66/108 (2) 6/108	(1) 73/108 (2) 11/108	(1) 33/108 (2) 1/108	No data	No data	No data	At 2 h: (1) 24/108 (2) 81/108
Mathew 1992	(1) Sumatriptan 1 mg, n = 30 (2) Sumatriptan 2 mg, n = 30 (3) Sumatriptan 3 mg, n = 30 (4) Sumatriptan 4 mg, n = 30 (5) Sumatriptan 6 mg, n = 30 (6) Sumatriptan 8 mg, n = 30 (7) Placebo, n = 62	(1) 13/30 (2) 17/30 (3) 17/30 (4) 15/30 (5) 22/30 (6) 24/30 (7) 15/62	(1) 12/30 (2) 14/30 (3) 17/30 (4) 18/30 (5) 21/30 (6) 26/30 (7) 14/62	(1) 4/30 (2) 1/30 (3) 7/30 (4) 5/30 (5) 12/30 (6) 10/30 (7) 2/62	(1) 6/30 (2) 3/30 (3) 8/30 (4) 10/30 (5) 18/30 (6) 16/30 (7) 2/62	No data	No data	At 4 h: (1) 19/30 (2) 15/30 (3) 14/30 (4) 13/30 (5) 10/30 (6) 10/30 (7) 48/62
Mushet 1996	Study 1 (1) Sumatriptan 6 mg, n = 40 (2) Placebo, n = 39 Study 2 (1) Sumatriptan 6 mg, n = 40 (2) Placebo, n = 39	Study 1 (1) 28/40 (2) 10/40 Study 2 (1) 30/39 (2) 12/39	Study 1 (1) 29/40 (2) 11/40 Study 2 (1) 31/39 (2) 14/39	Study 1 (1) 12/40 (2) 0/40 Study 2 (1) 16/39 (2) 2/39	Study 1 (1) 24/40 (2) 4/40 Study 2: (1) 22/39 (2) 5/39	No data	No data	No data
Pfaffenrath 1991	(1) Sumatriptan 6 mg, n = 155 (147 with moderate or severe baseline pain intensity) (2) Placebo, n = 80 (69 with moderate or severe baseline pain intensity)	(1) 99/147 (2) 17/69	No data	(1) 40/147 (2) 3/69	No data	No data	No data	No data
Russell 1994	(1) Sumatriptan 6 mg, n = 209 (2) Placebo, n = 209	No data	No data	No data	No data	No data	No data	No data
S2BL99	(1) Sumatriptan 6 mg, n = 125 (122 with moderate or severe baseline pain intensity for attack 1) (2) Oral ASA 1000 mg + MCP 10 mg, n = 130 (125 with moderate or severe baseline pain intensity for attack 1)	1st attack: (1) 87/122 (2) 57/125	1st attack: (1) 99/122 (2) 79/125	1st attack: (1) 55/122 (2) 26/125	1st attack: (1) 75/122 (2) 46/125	No data	No data	1st attack, up to 24 h: (1) 27/125 (2) 45/130
S2BM03	(1) Sumatriptan 6 mg (+ placebo at 4 h), n = 106 (90 for cross‐over efficacy analysis, of which 87 had moderate or severe baseline pain intensity) (2) Placebo (+ sumatriptan 6 mg at 4 h), n = 106 (90 for cross‐over efficacy analysis, of which 81 had moderate or severe baseline pain intensity)	(1) 64/87 (2) 7/81	(1) 72/87 (2) 8/81	(1) 41/87 (2) 1/81	(1) 56/87 (2) 3/81	No data	No data	No data
S2BS78	(1) Sumatriptan 6 mg, n = 236 (2) Placebo, n = 117	No data	No data	No data	No data	No data	No data	No data
Sang 2004	(1) Sumatriptan 6 mg, n = 15 (2) Intravenous LY293558 1.2 mg/kg, n = 13 (3) Placebo, n = 16 (15 with moderate or severe baseline pain intensity)	(1) 11/15 (2) 9/13 (3) 2/15	(1) 13/15 (2) 9/13 (3) 4/15	(1) 4/15 (2) 4/13 (3) 1/15	(1) 9/15 (2) 7/13 (3) 1/15	No data	No data	At 2 h: (1) 2/15 (2) 4/13 (3) 14/16
Schulman 2000	(1) Sumatriptan 6 mg, n = 79 (76 for efficacy) (2) Placebo, n = 40	(1) 48/76 (2) 13/40	No data	No data	No data	No data	No data	At 24 h: (1) 4/76 (2) 4/40
SUM40286	(1) Sumatriptan 6 mg, n = 146 (145 for efficacy) (2) Placebo, n = 153 (152 for efficacy)	(1) 95/145 (2) 53/152	(1) 104/145 (2) 62/152	(1) 49/145 (2) 17/152	(1) 70/145 (2) 28/152	No data	(1) 47/145 (2) 22/152	No data
SUM40287	(1) Sumatriptan 6 mg, n = 149 (148 for efficacy) (2) Placebo, n = 139	(1) 105/148 (2) 47/139	(1) 114/148 (2) 44/139	(1) 64/148 (2) 9/139	(1) 84/148 (2) 26/139	No data	(1) 51/148 (2) 21/139	No data
Thomson 1993	(1) Sumatriptan 4 mg, n = 28 (2) Placebo, n = 23 (22 for efficacy)	No data	No data	No data	No data	No data	No data	No data
Touchon 1996	(1) Sumatriptan 6 mg, n = 278 (145 treated first attack, 266 in cross‐over analysis) (2) DHE nasal spray 1 mg, n = 277 (144 treated first attack, 266 in cross‐over analysis)	(1) 189/266 (2) 90/266	(1) 215/266 (2) 138/266	(1) 125/266 (2) 35/266	(1) 176/266 (2) 82/266	(1) 144/266 (2) 104/266	No data	No data
Visser 1992	(1) Sumatriptan 1 mg, n = 170 (2) Sumatriptan 2 mg, n = 171 (3) Sumatriptan 3 mg, n = 172 (4) Placebo, n = 172	No data	No data	No data	No data	No data	No data	No data
Wendt 2006	(1) Sumatriptan 4 mg, n = 384 (381 with moderate or severe baseline pain intensity) (2) Placebo, n = 193 (191 with moderate or severe baseline pain intensity)	(1) 256/381 (2) 49/191	(1) 268/381 (2) 42/191	(1) 129/381 (2) 14/191	(1) 191/381 (2) 21/191	No data	No data	At 24 h: (1) 84/384 (2) 86/193
Winner 1996	(1) Sumatriptan 6 mg, n = 158 (150 for efficacy) (2) Subcutaneous dihydroergotamine (DHE) mesylate 1 mg, n = 152 (145 for efficacy)	(1) 117/150 (2) 82/145	(1) 128/150 (2) 106/145	No data	No data	No data	No data	No data
Winner 2006	Study 1 (1) Sumatriptan 6 mg, n = 146 (145 for efficacy, 144 with moderate or severe baseline pain intensity) (2) Placebo, n = 153 (152 for efficacy, 151 with moderate or severe baseline pain intensity) Study 2 (1) Sumatriptan 6 mg, n = 149 (148 for efficacy) (2) Placebo, n = 139	Pooled results for Study 1 and Study 2 (1) 192/292 (2) 95/290	Study 1 (1) 103/144 (2) 61/151 Study 2 (1) 114/148 (2) 44/139	No data	Study 1 (1) 70/144 (2) 28/151 Study 2 (1) 84/148 (2) 26/139	No data	Study 1 (1) 47/144 (2) 22/151 Study 2 (1) 51/148 (2) 21/139	No data

Associated symptoms: symptom present 2 hours after taking study medication in placebo controlled studies
Intervention	Studies	Attacks treated	Treatment (%)	Placebo (%)	Relative risk (95% CI)	NNTp (95% CI)
Nausea
Sumatriptan 6 mg	9	1879	17	43	0.39 (0.33 to 0.46)	3.8 (3.3 to 4.4)
Vomiting
Sumatriptan 6 mg	8	1710	5	8	0.43 (0.29 to 0.63)	40 (21 to 1000)
Photophobia
Sumatriptan 6 mg	5	1324	26	55	0.49 (0.42 to 0.56)	3.4 (2.9 to 4.1)
Phonophobia
Sumatriptan 6 mg	5	1324	22	49	0.46 (0.39 to 0.54)	3.7 (3.2 to 4.6)
Any functional disability
Sumatriptan 6 mg	6	1455	39	73	0.53 (0.48 to 0.59)	2.9 (2.6 to 3.4)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pain‐free at 2 h	2	664	Risk Ratio (M‐H, Fixed, 95% CI)	4.82 [3.24, 7.17]
2 Pain‐free at 1 h	2	664	Risk Ratio (M‐H, Fixed, 95% CI)	4.66 [2.83, 7.67]
3 Headache relief at 1 h	2	664	Risk Ratio (M‐H, Fixed, 95% CI)	2.55 [2.02, 3.21]
4 Headache relief at 2 h	2	664	Risk Ratio (M‐H, Fixed, 95% CI)	3.12 [2.43, 4.01]
5 Any adverse event within 24 h	3	720	Risk Ratio (M‐H, Fixed, 95% CI)	1.83 [1.56, 2.16]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pain‐free at 1 h	2	307	Risk Ratio (M‐H, Fixed, 95% CI)	7.19 [3.86, 13.41]
2 Headache relief at 1 h	3	361	Risk Ratio (M‐H, Fixed, 95% CI)	3.58 [2.71, 4.72]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pain‐free at 2 h	3	388	Risk Ratio (M‐H, Fixed, 95% CI)	4.59 [2.85, 7.39]
2 Headache relief at 2 h	5	1728	Risk Ratio (M‐H, Fixed, 95% CI)	2.39 [2.13, 2.69]

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 by stopwatch and at discharge from emergency department (time not reported and may vary between participants) Rescue medication (excluding ergot derivatives) available after 90 minutes if headache relief not achieved Each participant provided with an open‐label 100 mg sumatriptan tablet to treat recurrence over the 24 h period after discharge
Participants	Aged 18 years or older, meeting IHS criteria for migraine (1988) with aura. At least 1‐year history of migraine. Participants with a frequency of tension headache of at least 15 days per month were excluded No concurrent use of monoamine oxidase inhibitors, lithium, or selective 5‐HT reuptake inhibitors No use of ergotamine within 24 h of study drug administration N = 136 Breakdown of participants by gender not reported Mean age not reported 100% with aura
Interventions	Sumatriptan 6 mg, n = 88 Placebo, n = 48
Outcomes	Adverse events
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 group 50 to 200 participants, placebo group < 50 participants

Methods	Single‐centre, randomised, double‐blind, placebo‐controlled, within‐patient cross‐over. Each participant treated 2 successive attacks with a single dose of one or other study medication. Medication administered when migraine headache pain was of moderate or severe intensity Assessments at 0.5, 1, 1.5, and 2 h after dosing Rescue medication (not ergotamine) was available after 2 h for inadequate relief of symptoms
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. Use of migraine prophylactic therapy was stopped at least 2 weeks before receipt of study medication. No ergotamine‐containing preparations within 24 h, and no analgesics within 6 h of taking study medication. Minimum of 48 h between treated attacks N = 27 M 5, F 22 (81%) Mean age 45 years Proportion with/without aura not reported
Interventions	Sumatriptan 8 mg, n = 27 Placebo, n = 27
Outcomes	Headache relief (at 1 and 2 h) Pain‐free (at 2 h) Use of rescue medication Presence of functional disability (at 1 and 2 h)
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	Matching placebo
Study size	High risk	Treatment groups < 50 participants

Methods	Multicentre, randomised, double‐blind, double‐dummy, placebo‐controlled, parallel‐group. Single dose to treat single attack. Medication administered when migraine headache pain was of moderate or severe intensity Assessment at 0.5, 1, 1.5, and 2 h after dosing Rescue medication available after 2 h
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 6 attacks per month. No analgesics or migraine drugs within 24 h of study medication administration. No use of compound analgesics, sumatriptan, ergotamine tartrate, DHE, codeine, or barbiturates for more than 10 days per month prior to screening. N = 278 (275 for efficacy) M 55, F 220 (80%) Mean age 41 years Without aura 67%
Interventions	Sumatriptan 6 mg, n = 114 Intravenous acetylsalicylic acid lysinate 1.8 g, n = 119 Placebo, n = 42
Outcomes	Headache relief (at 1 and 2 h) Pain‐free (at 2 h) Improvement in nausea, vomiting, photophobia, and phonophobia 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	Double‐dummy
Study size	High risk	Treatment groups 50 to 200 participants, placebo group < 50 participants

Methods	2‐phase study Phase one: multicentre, randomised, double‐blind, placebo‐controlled, cross‐over design. Single dose to treat each of 2 successive migraine attacks. Medication administered when migraine headache pain was of moderate or severe intensity Assessments at 0.5, 1, 1.5, and 2 h after initial dosing Second dose of study medication (identical to first dose) available to treat recurrence between 2 and 24 h Rescue medication (except ergotamine) available if initial treatment not effective within 2 h Phase 2: open‐label phase
Participants	Aged 18 to 65 years, meeting IHS criteria for migraine (1988) with or without aura. History of 1 to 6 moderate or severe migraine attacks per month. Participants were excluded if they had previous experience with subcutaneous sumatriptan No ergotamine in the 24‐h period before taking study medication or within 6 h afterwards N = 118 treated ≥ 1 attack (108 treated both attacks) M 12, F 106 (90%) Mean age 43 years Proportion with/without aura not reported
Interventions	Sumatriptan 6 mg, n = 117 attacks Placebo, n = 109 attacks
Outcomes	Headache relief (at 1 and 2 h) Pain‐free (at 1 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	Number in each treatment arm for first attack not reported

Methods	Multicentre, randomised, triple‐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, and 90 mins and 2, 3, 4, and 24 h after dosing Rescue medication (excluding ergot derivatives) was available at the participant's request after 2 h
Participants	Aged 18 years or older, 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 15 attacks per month. N = 44 M 20, F 24 (55%) Mean age 40 years Without aura 89%
Interventions	Sumatriptan 6 mg, n = 15 Intravenous LY293558 1.2 mg/kg, n = 13 Placebo, n = 16 (15 with moderate or severe baseline pain intensity)
Outcomes	Headache relief (at 1 and 2 h) Pain‐free (at 1 and 2 h) Use of rescue medication Adverse events
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)	Low risk	Allocation balanced between treatments with a block size equal to 3; randomisation code kept under lock and only accessed by pharmacist or designee
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double‐dummy
Study size	High risk	Treatment groups < 50 participants

Study	Reason for exclusion
Burke‐Ramirez 2001	Number of participants in each treatment arm not reported and no indication of baseline pain intensity for any treated participants
Cady 1994	First dose of subcutaneous sumatriptan not randomised, only for subsequent doses of oral sumatriptan for recurrence (from 2 to 24 h after initial dosing) were patients randomised to either sumatriptan or placebo
Cull 2001	All participants initially treat with sumatriptan at the onset of migraine headache, and are only randomised to either sumatriptan or placebo to treat any subsequent recurrence that occurred between 1 and 24 h after the first dose was administered
Ensink 1991	2 studies: Study 1 ‐ Baseline pain intensity of treated participants not reported and at least 50% of participants in each treatment arm took a second dose of study medication at 30 minutes. No useable efficacy data at 1 or 2 h and no adverse event data reported. Study 2 ‐ Data reported in Mathew 1992
Friedman 2005	Only comparator (intravenous metoclopramide 20 mg) was not self administrable. No placebo group.
Friedman 2006	Only comparator (intramuscular combination of trimethobenzamide 200 mg + diphenhydramine 25 mg) was not self administrable. No placebo group.
Gonzalez‐Espinosa 1997	Only comparator (intramuscular dihydroergotamine 1 mg) was not self administrable. No placebo group. In addition, blinding of study medication is uncertain (study does not appear to use double‐dummy technique) and the baseline pain intensity of treated participants is not reported
Melchart 2003	Non‐standard pain scale (50‐point categorical scale) and use of an additional dose of sumatriptan by the majority of participants at unknown, variable time point (any time after initial dosing if participants developed a full migraine attack: ˜60% used 2nd dose) meaning no useable efficacy or safety data
Pradel 2006	Not subcutaneous route of administration
Russell 1995	Data reported in Russell 1994
S2BM04	All participants initially treated with oral sumatriptan 100 mg; only those failing to respond to this initial treatment were subsequently randomised to receive either subcutaneous sumatriptan 4 mg or placebo
Solbach 1993	Subgroup analysis of data reported in Cady 1991 for menstruation‐associated migraine. No additional data reported.

PERMALINK

Sumatriptan (subcutaneous route of administration) for acute migraine attacks in adults

Christopher J Derry

Sheena Derry

R Andrew Moore

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Included studies

Excluded studies

Risk of bias in included studies

1.

Effects of interventions

Pain‐free at two hours

Sumatriptan 4 mg versus placebo

1.1. Analysis.

Sumatriptan 6 mg versus placebo

2.1. Analysis.

2.

Sumatriptan 6 mg plus optional 6 mg versus placebo

4.1. Analysis.

Other doses of sumatriptan versus placebo

Sumatriptan versus active comparators

Pain‐free at one hour

Sumatriptan 4 mg versus placebo

1.2. Analysis.

Sumatriptan 6 mg versus placebo

2.2. Analysis.

Sumatriptan 8 mg versus placebo

3.1. Analysis.

Other doses of sumatriptan versus placebo

Sumatriptan versus active comparators

Headache relief at one hour

Sumatriptan 4 mg versus placebo

1.3. Analysis.

Sumatriptan 6 mg versus placebo

2.3. Analysis.

3.

Sumatriptan 8 mg versus placebo

3.2. Analysis.

Other doses of sumatriptan versus placebo

Sumatriptan versus active comparators

Headache relief at two hours