Aspirin with or without an antiemetic for acute migraine headaches in adults

Varo Kirthi; Sheena Derry; R Andrew Moore; Henry J McQuay

doi:10.1002/14651858.CD008041.pub2

. Author manuscript; available in PMC: 2014 Sep 13.

Published in final edited form as: Cochrane Database Syst Rev. 2010 Apr 14;(4):CD008041. doi: 10.1002/14651858.CD008041.pub2

Aspirin with or without an antiemetic for acute migraine headaches in adults

Varo Kirthi ¹, Sheena Derry ¹, R Andrew Moore ¹, Henry J McQuay ¹

PMCID: PMC4163048 EMSID: EMS58706 PMID: 20393963

Abstract

Background

Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter analgesics. Co-therapy with an antiemetic should help to reduce nausea and vomiting commonly associated with migraine headaches.

Objectives

To determine the efficacy and tolerability of aspirin, alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine headaches in adults.

Search methods

We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies through 10 March 2010.

Selection criteria

We included randomised, double-blind, placebo- or active-controlled studies using aspirin to treat a discrete 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. Numbers of participants achieving each outcome were used to calculate relative risk and numbers needed to treat (NNT) or harm (NNH) compared to placebo or other active treatment.

Main results

Thirteen studies (4222 participants) compared aspirin 900 mg or 1000 mg, alone or in combination with metoclopramide 10 mg, with placebo or other active comparators, mainly sumatriptan 50 mg or 100 mg. For all efficacy outcomes, all active treatments were superior to placebo, with NNTs of 8.1, 4.9 and 6.6 for 2-hour pain-free, 2-hour headache relief, and 24-hour headache relief with aspirin alone versus placebo, and 8.8, 3.3 and 6.2 with aspirin plus metoclopramide versus placebo. Sumatriptan 50 mg did not differ from aspirin alone for 2-hour pain-free and headache relief, while sumatriptan 100 mg was better than the combination of aspirin plus metoclopramide for 2-hour pain-free, but not headache relief; there were no data for 24-hour headache relief.

Associated symptoms of nausea, vomiting, photophobia and phonophobia were reduced with aspirin compared with placebo, with additional metoclopramide significantly reducing nausea (P < 0.00006) and vomiting (P = 0.002) compared with aspirin alone.

Fewer participants needed rescue medication with aspirin than with placebo. Adverse events were mostly mild and transient, occurring slightly more often with aspirin than placebo.

Authors’ conclusions

Aspirin 1000 mg is an effective treatment for acute migraine headaches, similar to sumatriptan 50 mg or 100 mg. Addition of metoclopramide 10 mg improves relief of nausea and vomiting. Adverse events were mainly mild and transient, and were slightly more common with aspirin than placebo, but less common than with sumatriptan 100 mg.

Medical Subject Headings (MeSH): Anti-Inflammatory Agents, Non-Steroidal [*therapeutic use]; Antiemetics [*therapeutic use]; Aspirin [*therapeutic use]; Drug Therapy, Combination [methods]; Metoclopramide [therapeutic use]; Migraine Disorders [complications; *drug therapy]; Nausea [drug therapy; etiology]; Photophobia [drug therapy; etiology]; Randomized Controlled Trials as Topic; Sumatriptan [therapeutic use]; Vomiting [drug therapy; etiology]

MeSH check words: Adult, Humans

BACKGROUND

Description of the condition

Migraine is a common, disabling headache disorder, affecting about 12% of Western populations, and with considerable social and economic impact. It is more prevalent in women than men (on the order of 18% versus 6% 1-year prevalence), and in the age range 30 to 50 years (Hazard 2009; Lipton 2007; Moens 2007). The International Headache Society (IHS) classifies two major subtypes. Migraine without aura is the most common, and usually more disabling, 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 US$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

Medicines derived from willow bark, which is rich in salicylate, have been used for centuries for treating pain, fever and inflammation. In the mid-19th century, chemists first synthesised acetylsalicylic acid, and by the end of the century, Bayer had patented and were selling the drug, which they called aspirin, around the world.

Aspirin is used to treat mild to moderate pain, including migraine headache pain; inflammatory conditions such as rheumatoid arthritis; and, in low doses, as an antiplatelet agent in cardiovascular disease. It is a potent gastrointestinal irritant, and may cause discomfort, ulcers and bleeding. It may aIso cause tinnitus at high dose, and it is no longer used in children and adolescents, in whom it may cause Reye’s syndrome (swelling of the brain that may lead to coma and death). Its use as an analgesic and antipyretic agent has declined, largely due to these adverse events, as newer products have become available. However, in some countries it may be the only drug readily available, and for some conditions, such as migraine, some individuals report it to be an effective and reliable treatment.

In order to establish whether aspirin is an effective analgesic 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 analgesic 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

Aspirin irreversibly inhibits cyclo-oxygenase enzymes, which are needed for prostaglandin and thromboxane synthesis. Prostaglandins mediate a variety of physiological functions such as maintenance of the gastric mucosal barrier, regulation of renal blood flow, and regulation of endothelial tone. They also play an important role in mediating inflammatory and nociceptive processes. Suppression of prostaglandin synthesis is believed to underlie the analgesic effects of aspirin (Vane 1971).

The efficacy of oral medications is reduced in many migraineurs because of impaired gastrointestinal motility, which is associated with nausea, and because of non-absorption of the drug due to vomiting (Volans 1974). The addition of an antiemetic may improve outcomes by alleviating the often incapacitating symptoms of nausea and vomiting, and (at least potentially) by enhancing the bioavailability of the co-administered analgesic. In particular, prokinetic antiemetics such as metoclopramide, which stimulate gastric emptying, may improve outcomes by increasing absorption of the analgesic (in this case, aspirin; Ross-Lee 1983; Volans 1975). It has been claimed that treatment with metoclopramide alone can reduce pain in severe migraine attacks (Colman 2004; Salazar-Tortolero 2008), but this claim requires further investigation because it is based on studies involving few participants, and metoclopramide has not been shown to be an analgesic in classical pain studies. The present review will seek to determine whether treatment of acute migraine attacks with aspirin plus an antiemetic is in any way superior to treatment with aspirin alone.

Why it is important to do this review

Population surveys show that aspirin is frequently used to treat migraine headaches, but we could find no systematic review of the efficacy of this intervention in adults. It is important to know where this widely available and inexpensive drug fits in the range of therapeutic options for migraine therapy. For many migraineurs, non-prescription therapies offer convenience and may be the only therapies available or affordable.

OBJECTIVES

The objective of this review is to determine the efficacy and tolerability of aspirin, alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine headaches in adults.

METHODS

Criteria for considering studies for this review

Types of studies

Randomised, double-blind, placebo or active-controlled studies using aspirin to treat a discrete migraine headache episode were included. 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. Studies reporting treatment of consecutive headache episodes were accepted if outcomes for the first, or each, episode were reported separately. Cross-over studies were accepted if there was adequate washout between treatments.

Types of participants

Studies included adults (at least 18 years of age) with migraine. The diagnosis of migraine specified by the International Headache Society (IHS 1988; IHS 2004) was used, although other definitions were considered if they conformed in general to IHS diagnostic criteria. There were no restrictions on migraine frequency, duration or type (with or without aura). Participants taking stable prophylactic therapy to reduce the frequency of migraine attacks were accepted; details are provided in the Characteristics of included studies table.

Types of interventions

Included studies used either a single dose of aspirin to treat a discrete migraine headache episode when pain was of moderate to severe intensity, or investigated different dosing strategies and/or timing of the first dose in relation to headache intensity. There were no restrictions on dose or route of administration, provided the medication was self-administered.

Included studies could use either aspirin alone, or aspirin plus an antiemetic. The antiemetic had to be taken either combined with aspirin in a single formulation, or separately not more than 30 minutes before aspirin, and had to be self-administered.

A placebo comparator is essential to demonstrate that aspirin is effective in this condition. Active-controlled trials without a placebo were considered as secondary evidence. Studies to demonstrate prophylactic efficacy in reducing the number or frequency of migraine attacks were not included.

Types of outcome measures

Primary outcomes

The choice of main outcome measures for this review was made by taking into consideration 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), the main outcomes to be considered were:

Pain-free at 2 hours, without the use of rescue medication;
Reduction in headache pain (‘headache relief’) at 1 and 2 hours (pain reduced from moderate or severe to none or mild without the use of rescue medication);
Sustained pain-free over 24 hours (pain-free within 2 hours, with no use of rescue medication or recurrence within 24 hours);
Sustained pain reduction over 24 hours (headache relief at 2 hours, sustained for 24 hours, with no use of rescue medication or a second dose of study medication).

Pain intensity or pain relief was measured by the patient (not the investigator or carer). Pain measures accepted for the primary outcomes were:

Pain intensity (PI): 4-point categorical scale, with wording equivalent to none, mild, moderate and severe; or 100 mm VAS;
Pain relief (PR): 5-point categorical scale, with wording equivalent to none, a little, some, a lot, complete; or 100 mm VAS.

Only data obtained directly from the patient will be considered.

Secondary outcomes

Secondary outcomes considered included:

Participants with any adverse event over 24 hours post-dose;
Participants with particular adverse events over 24 hours post-dose;
Withdrawals due to adverse events over 24 hours post-dose;
Relief of headache-associated symptoms;
Functional disability.

Search methods for identification of studies

Electronic searches

The following databases were searched:

Cochrane CENTRAL, Issue 1, 2010;
MEDLINE (via OVID), 10 March 2010;
EMBASE (via OVID), 10 March 2010;
Oxford Pain Relief Database (Jadad 1996a).

See Appendix 1 for the search strategy for MEDLINE (via OVID), Appendix 2 for the search strategy for EMBASE, and Appendix 3 for the search strategy for CENTRAL. There were no language restrictions.

Searching other resources

Reference lists of retrieved studies and review articles were searched for additional studies. Grey literature and abstracts were not searched.

Data collection and analysis

Selection of studies

Two review authors independently carried out the searches and selected studies for inclusion. Titles and abstracts of all studies identified by electronic searches were viewed on screen, and any that clearly did not satisfy inclusion criteria were excluded. Full copies of the remaining studies were read 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. Data were entered into RevMan 5.0 by one author.

Assessment of risk of bias in included studies

Methodological quality was assessed 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.

A risk of bias table was also completed, using assessments of randomisation, allocation concealment and blinding.

Measures of treatment effect

Relative risk (or ‘risk ratio’, RR) was used to establish statistical difference. Numbers needed to treat (NNT) and pooled percentages were used as absolute measures of benefit or harm.

The following terms were used to describe adverse outcomes in terms of harm or prevention of harm:

When significantly fewer adverse outcomes occurred with aspirin 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 aspirin 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 to individual patient only.

Dealing with missing data

The most likely source of missing data is in cross-over studies. Where this was an issue, only first-period data were used.

Assessment of heterogeneity

Heterogeneity of studies was assessed visually (L’Abbe 1987).

Data synthesis

Studies using a single dose of aspirin in established pain of at least moderate intensity were analysed separately from studies in which medication was taken before pain was well established or in which a second dose of medication was permitted.

Effect sizes were calculated and data combined for analysis only for comparisons and outcomes where there were at least two studies and 200 participants (Moore 1998). In case only one study on relevant outcomes in at least 200 participants was available, prohibiting combining of data for analysis, a summary of data on relevant outcomes is provided. Relative risk of benefit or harm was calculated with 95% confidence intervals (CIs) using a fixed-effect model (Morris 1995). NNT, NNTp and NNH with 95% CIs were calculated using the pooled number of events by the method of Cook and Sackett (Cook 1995). A statistically significant difference from control was assumed when the 95% CI of the relative risk of benefit or harm did not include the number one.

Significant differences between NNT, NNTp or NNH for different groups in subgroup and sensitivity analyses were determined using the z test (Tramer 1997).

Subgroup analysis and investigation of heterogeneity

Issues for potential subgroup analysis were dose, monotherapy versus combination with an antiemetic, formulation and route of administration. For combined treatment with an antiemetic, we planned to compare different antiemetics if there were sufficient data.

Sensitivity analysis

Sensitivity analysis was anticipated 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 had to be available for any sensitivity analysis.

RESULTS

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Included studies

Thirteen studies fulfilled the inclusion criteria for this review (Boureau 1994; Chabriat 1994; Diener 2004a; Diener 2004b; Geraud 2002; Henry 1995; Lange 2000; Le Jeunne 1998; Lipton 2005; MacGregor 2002; Tfelt-Hansen 1995; Thomson 1992; Titus 2001), with a total of 5261 treated migraine attacks (4222 participants) providing data; Boureau 1994; Diener 2004b; MacGregor 2002 together provided information on treatment of 1039 more migraine attacks than participants. Details of the included studies are provided in the Characteristics of included studies table.

All included studies recruited participants between 18 and 65 years of age (mean ages ranging from 37 to 44 years), meeting IHS criteria for migraine with or without aura (IHS 1988; IHS 2004). All participants had a history of migraine symptoms for at least 12 months, with between one and six attacks per month of moderate to severe intensity, prior to the study period. One study (Thomson 1992) excluded participants needing prophylactic treatment. Four studies specified that any prophylactic treatment had to have been stable for at least 2 (Boureau 1994) or 3 (Chabriat 1994; Le Jeunne 1998; Lipton 2005) months before the study period, while the remainder did not mention prophylaxis.

Three studies excluded participants who vomited either at least 20% of the time during migraine attacks (Lange 2000; Lipton 2005) or during the majority of attacks (MacGregor 2002). Another study excluded participants whose migraine headaches were never accompanied by nausea or vomiting (Chabriat 1994). One study excluded data from migraine attacks with aura (Henry 1995), whilst another study used only data from migraine attacks without aura that also featured all three symptoms of nausea, photophobia and phonophobia (Diener 2004a). Five studies excluded participants who also experienced other types of headache (Boureau 1994; Diener 2004b; Geraud 2002; Henry 1995; Titus 2001).

Five studies had only a placebo comparator (Chabriat 1994; Henry 1995; Lange 2000; Lipton 2005; MacGregor 2002), four had only an active comparator (Geraud 2002; Le Jeunne 1998; Thomson 1992; Titus 2001), and four had both placebo and active comparators (Boureau 1994; Diener 2004a; Diener 2004b; Tfelt-Hansen 1995).

All treatments were administered orally, and when the headache was of moderate or severe intensity, except in Boureau 1994, where up to 15% of participants had “slight” headache at baseline. No studies specifically investigated early treatment of attacks while pain intensity was still mild. Aspirin 1000 mg was given either as a tablet or an effervescent solution to 940 participants in five studies (Boureau 1994; Diener 2004a; Diener 2004b; Lange 2000; Lipton 2005). In one study, aspirin was given to 73 participants as a 900 mg mouth-dispersible dose (MacGregor 2002). In seven studies, aspirin equivalent to 900 mg was given either as the lysine salt, calcium carbasalate (a soluble complex of aspirin) or effervescent solution, in combination with metoclopramide 10 mg, to 1186 participants (Chabriat 1994; Geraud 2002; Henry 1995; Le Jeunne 1998; Tfelt-Hansen 1995; Thomson 1992; Titus 2001). We did not identify any studies in which aspirin was combined with an antiemetic other than metoclopramide.

Sumatriptan 50 mg was given to 361 participants in two studies (Diener 2004a; Diener 2004b), and sumatriptan 100 mg to 294 participants in another two studies (Tfelt-Hansen 1995; Thomson 1992). Zolmitriptan 2.5 mg was given to 326 participants in one study (Geraud 2002). Four studies compared aspirin treatment with non-triptan medications: one gave acetaminophen 400 mg plus codeine 25 mg to 198 participants (Boureau 1994); one gave ibuprofen 400 mg to 212 participants (Diener 2004b); one gave ergotamine 1 mg plus 100 mg caffeine to 132 participants (Le Jeunne 1998); and the other gave ergotamine 2 mg plus caffeine 200 mg to 115 participants (Titus 2001). One thousand and four hundred and twenty-four (1424) participants received placebo.

Some studies were inconsistent in the denominators reported and, for instance, reported on one or two patients fewer than the intention-to-treat population for some outcomes, but not for others, without giving a reason. As the denominators were always within a few patients of the intention-to-treat population, we used the denominators given.

Most studies used a parallel-group design, in which participants received only one type of medication, but three (Boureau 1994; Diener 2004b; MacGregor 2002) used a cross-over design, in which participants treated consecutive headaches with different study medications. Most studies also asked participants to treat only one attack with a particular study medication, but in five studies more than one attack was treated with the same medication. In Chabriat 1994, Le Jeunne 1998 and Tfelt-Hansen 1995 two attacks were treated, while in Geraud 2002 and Thomson 1992 three attacks were treated; some outcomes were reported for each attack separately, while for other outcomes attacks were combined. We have used data for the first attack only, where these data were reported separately, for efficacy outcomes to avoid problems of double counting participants and repeated measures for the same individuals; for use of rescue medication and adverse event data, we have accepted data from multiple attacks in the absence of first-attack data in order to be inclusive and provide conservative estimates. In Geraud 2002, a second dose of study medication was permitted if there was an inadequate response to the first; data for the first dose in the first attack was available for one primary outcome. In Titus 2001 one attack was treated with up to three doses of the same medication if an adequate response was not obtained; data for our primary outcomes were not available for the first dose only.

Excluded studies

Six studies were excluded after reading the full report (Chabriat 1993; Diener 2005; Limmroth 1999; Nebe 1995; Tfelt-Hansen 1980; Tfelt-Hansen 1984). Reasons for exclusion are provided in the Characteristics of excluded studies table.

Risk of bias in included studies

All studies were randomised and double-blind, and all reported on withdrawals and dropouts, thus minimising bias. Four scored 5 of 5 (Diener 2004a; Diener 2004b; Geraud 2002; Titus 2001), six scored 4 of 5 (Boureau 1994; MacGregor 2002; Le Jeunne 1998; Lipton 2005; Tfelt-Hansen 1995; Thomson 1992) and three scored 3 of 5 (Chabriat 1993; Henry 1995; Lange 2000) on the Oxford Quality Score. Points were lost because of failure to adequately describe the methods of randomisation and blinding. Details are provided in the Characteristics of included studies table.

A risk of bias table was completed for randomisation, allocation concealment and blinding. No study described the method of allocation concealment, but none were at high risk of bias (Figure 1).

Methodological quality graph: review authors’ judgements about each methodological quality item presented as percentages across all included studies.

Effects of interventions

Aspirin doses of 900 mg and 1000 mg were considered sufficiently similar to combine for analysis. All included studies that provided data for analysis reported outcomes using the standard 4-point categorical pain intensity scale (none, mild, moderate, severe). Details of outcomes in individual studies are provided in Appendix 4 (efficacy), Appendix 5 (migraine-associated symptoms) and Appendix 6 (adverse events and withdrawals).

Pain-free at 2 hours

Aspirin 900 mg or 1000 mg versus placebo

Six studies (2027 participants) provided data on the proportion of patients pain-free at 2 hours. Three used a 1000 mg effervescent formulation of aspirin (Diener 2004a; Diener 2004b; Lange 2000), two used a 1000 mg oral tablet formulation (Boureau 1994; Lipton 2005) and one used a 900 mg mouth-dispersible dose (MacGregor 2002).

The proportion of participants pain-free at 2 hours with aspirin 1000 mg was 24% (240/1008; range 14% to 29%).
The proportion of participants pain-free at 2 hours with placebo was 11% (117/1019; range 5% to 17%).
The relative benefit of treatment compared with placebo was 2.1 (1.7 to 2.6; Figure 2) giving an NNT for pain-free at 2 hours of 8.1 (6.4 to 11; Summary of results A).

Forest plot of comparison: 1 Aspirin 900 mg or 1000 mg versus placebo, outcome: 1.2 Pain free at 2 hours.

Aspirin 900 mg plus metoclopramide 10 mg versus placebo

Two studies (519 participants) reported efficacy data for pain-free at 2 hours with 900 mg oral tablet formulation in combination with oral metoclopramide 10 mg versus placebo (Henry 1995; Tfelt-Hansen 1995).

The proportion of participants pain-free at 2 hours with aspirin 900 mg plus metoclopramide 10 mg was 18% (47/262; range 14% to 21%).
The proportion of participants pain-free at 2 hours with placebo was 7% (17/257; range 5% to 8%).
The relative benefit of treatment compared with placebo was 2.7 (1.6 to 4.6; Figure 3), giving an NNT for pain-free at 2 hours of 8.8 (5.9 to 17; Summary of results A).

Forest plot of comparison: 2 Aspirin 900 mg plus metoclopramide 10 mg versus placebo, outcome: 2.2 Pain free at 2 hours.

Subgroup analysis comparing studies using aspirin alone and studies using aspirin plus metoclopramide gave z = 0.3051, P = 0.76. There was no significant difference between treatments for this outcome.

A L’Abbé plot for this outcome shows a high degree of clinical homogeneity in these studies of aspirin ± metoclopramide versus placebo (Figure 4).

L’Abbé plot showing pain-free at 2 h response in individual studies. Each circle represents one study, with size on the inset scale.

Aspirin 1000 mg versus active comparator

Two studies (726 participants) compared effervescent aspirin 1000 mg with sumatriptan 50 mg (Diener 2004a; Diener 2004b).

The proportion of participants pain-free at 2 hours with aspirin 1000 mg was 26% (97/367).
The proportion of participants pain-free at 2 hours with sumatriptan 50 mg was 32% (116/359).
The relative benefit of aspirin compared with sumatriptan was 0.82 (0.65 to 1.03; Figure 5). There was no significant difference between treatments (Summary of results A).

Forest plot of comparison: 3 Aspirin 900 mg or 1000 mg versus active comparator, outcome: 3.2 Pain free at 2 hours.

One study (Boureau 1994) compared 1000 mg aspirin (tablet) with paracetamol 400 mg plus codeine 25 mg, while another (Diener 2004b) compared it with ibuprofen 400 mg. In both cases, there were insufficient data for analysis (Appendix 4).

Aspirin 900 mg plus metoclopramide 10 mg versus active comparator

Two studies (528 participants) compared aspirin 900 mg (tablet or lysine equivalent) plus metoclopramide 10 mg with sumatriptan 100 mg (Tfelt-Hansen 1995; Thomson 1992).

The proportion of participants pain-free at 2 hours with aspirin 900 mg or 1000 mg plus metoclopramide 10 mg was 18% (48/273).
The proportion of participants pain-free at 2 hours with sumatriptan 100 mg was 28% (71/255).
The relative benefit of aspirin plus metoclopramide compared with sumatriptan was 0.63 (0.45 to 0.87; Figure 6), giving an NNTp of 9.8 (5.8 to 32; Summary of results A). In other words, for every 10 participants treated with sumatriptan 100 mg, one would be pain-free within 2 hours who would not have been if treated with aspirin 900 mg plus metoclopramide 10 mg.

Forest plot of comparison: 4 Aspirin 900 mg plus metoclopramide 10 mg versus active comparator, outcome: 4.2 Pain free at 2 hours.

One study (Le Jeunne 1998) compared aspirin 900 mg (as calcium carbasalate) plus metoclopramide 10 mg with ergotamine 1 mg plus caffeine 100 mg (266 participants). There were insufficient data for analysis (Appendix 4).

Headache relief at 1 hour

Aspirin 900 or 1000 mg versus placebo

Four studies (1288 participants) comparing aspirin 900 mg or 1000 mg with placebo provided data. Two used an effervescent formulation (Diener 2004a; Diener 2004b), one a mouth dispersible formulation (MacGregor 2002) and one a tablet (Lipton 2005).

The proportion of participants experiencing headache relief at 1 hour with aspirin 900 mg or 1000 mg was 37% (236/641; range 34% to 42%).
The proportion of participants experiencing headache relief at 1 hour with placebo was 15% (99/647; range 11% to 21%).
The relative benefit of treatment compared with placebo was 2.4 (2.0 to 3.0; Analysis 1.3), giving an NNT of 4.7 (3.8 to 5.9; Summary of results A).

Aspirin 1000 mg versus active comparator

Two studies (726 participants) comparing aspirin 1000 mg with sumatriptan 50 mg provided data (Diener 2004a; Diener 2004b). Both used effervescent aspirin and oral sumatriptan.

The proportion of participants experiencing headache relief at 1 hour with aspirin 1000 mg was 38% (138/367; range 34% to 42%).
The proportion of participants experiencing headache relief at 1 hour with sumatriptan 50 mg was 24% (85/359; range 23% to 24%).
The relative benefit of treatment compared with sumatriptan 50 mg was 1.6 (1.3 to 2.0; Analysis 3.3), giving an NNT of 7.2 (4.9 to 14; Summary of results A).

One study (Diener 2004b) compared aspirin 1000 mg with ibuprofen 400 mg (432 participants). There were insufficient data for analysis.

Aspirin plus metoclopramide versus placebo or versus active comparator

No studies using aspirin plus metoclopramide reported on headache relief at 1 hour.

Headache relief at 2 hours

Aspirin 900 or 1000 mg versus placebo

Six studies (2027 participants) in which patients were treated with aspirin alone provided data for headache relief at 2 hours, defined as a pain reduction from moderate or severe intensity to mild or none. Three studies used an effervescent formulation (Diener 2004a; Diener 2004b; Lange 2000), whilst the other three studies used a mouth-dispersible (MacGregor 2002) or oral tablet formulation (Boureau 1994; Lipton 2005).

The proportion of participants experiencing headache relief at 2 hours with aspirin 900 mg or 1000 mg was 52% (525/1008; range 48% to 55%).
The proportion of participants experiencing headache relief at 2 hours with placebo was 32% (323/1019; range 19% to 37%).
The relative benefit of treatment compared with placebo was 1.6 (1.5 to 1.8; Analysis 1.1), giving an NNT of 4.9 (4.1 to 6.2; Summary of results A).

Aspirin 900 mg plus metoclopramide 10 mg versus placebo

Three studies (765 participants) provided data for headache relief at 2 hours with aspirin and metoclopramide combination treatment. Two studies used a lysine equivalent formulation of aspirin (Chabriat 1994; Tfelt-Hansen 1995), whilst the other study used an effervescent formulation (Henry 1995).

The proportion of participants experiencing headache relief at 2 hours with aspirin 900 mg plus metoclopramide 10 mg was 57% (219/386; range 54% to 59%).
The proportion of participants experiencing headache relief at 2 hours with placebo was 26% (100/379; range 24% to 29%).
The relative benefit of treatment compared with placebo was 2.2 (1.8 to 2.6; Analysis 2.1), giving an NNT of 3.3 (2.7 to 4.2; Summary of results A).

Subgroup analysis comparing studies using aspirin alone and studies using aspirin plus metoclopramide gave z = 2.48, P = 0.0131, showing that aspirin plus metoclopramide was significantly more effective than aspirin alone at achieving headache relief at 2 hours. A L’Abbé plot for this outcome shows a high degree of clinical homogeneity in these studies of aspirin ± metoclopramide versus placebo (Figure 7).

L’Abbé plot showing headache response at 2 h in individual studies. Each circle represents one study, with size on the inset scale.

Aspirin 1000 mg versus active comparator

Two studies (726 participants) compared effervescent aspirin 1000 mg with sumatriptan 50 mg (Diener 2004a; Diener 2004b).

The proportion of participants experiencing headache relief at 2 hours with aspirin 1000 mg was 51% (188/367).
The proportion of participants experiencing headache relief at 2 hours with sumatriptan 50 mg was 53% (191/359).
The relative benefit of aspirin compared with sumatriptan was 0.96 (0.84 to 1.1; Analysis 3.1). There was no significant difference between treatments (Summary of results A).

One study (Boureau 1994) compared 1000 mg aspirin (tablet) with paracetamol 400 mg plus codeine 25 mg, and another (Diener 2004b) compared it with ibuprofen 400 mg. In both cases, there were insufficient data for analysis (Appendix 4).

Aspirin 900 mg plus metoclopramide 10 mg versus active comparator

Two studies (523 participants) compared aspirin 900 mg plus metoclopramide 10 mg with sumatriptan 100 mg (Tfelt-Hansen 1995; Thomson 1992). One used the lysine equivalent and the other a standard oral tablet.

The proportion of participants experiencing headache relief at 2 hours with aspirin 900 mg plus metoclopramide 10 mg was 51% (138/271).
The proportion of participants experiencing headache relief at 2 hours with sumatriptan 100 mg was 54% (137/252).
The relative benefit of treatment compared with placebo was 0.93 (0.79 to 1.1; Analysis 4.1). There was no significant difference between treatments (Summary of results A).

One study each compared aspirin 900 mg plus metoclopramide 10 mg with zolmitriptan 25 mg (Geraud 2002) and ergotamine 1 mg plus caffeine 100 mg (Le Jeunne 1998). There were insufficient data for analysis for either comparator (Appendix 4). Titus 2001 compared aspirin 900 mg plus metoclopramide 10 mg with ergotamine 2 mg + caffeine 200 mg, but reported no usable data.

Participants with 24-hour sustained headache relief

This was defined as the proportion of treated patients that experienced headache relief at 2 hours (pain reduction from moderate or severe to mild or none) and sustained this relief throughout the remaining 24-hour assessment period, without use of additional medication.

Aspirin 1000 mg versus placebo

Three studies (1142 participants) provided data for this outcome. Two used an effervescent formulation (Diener 2004a; Diener 2004b) and one a tablet (Lipton 2005).

The proportion of participants with 24-hour sustained relief with aspirin 1000 mg was 39% (223/568; range 33% to 42%).
The proportion of participants with 24-hour sustained relief with placebo was 24% (138/574; range 22% to 25%).
The relative benefit of treatment compared with placebo was 1.6 (1.4 to 2.0; Analysis 1.4), giving an NNT for 24-hour sustained relief of 6.6 (4.9 to 10; Summary of results A).

Aspirin 900 mg plus metoclopramide 10 mg versus placebo

One study (257 participants) reported this outcome (Tfelt-Hansen 1995). Because there were more than 200 participants, for information and comparison the results are given in Summary of results A, plus a calculation of NNT where there was a significant benefit over placebo. Subgroup analysis comparing studies using aspirin alone and studies using aspirin plus metoclopramide gave z = 0.7789, P = 0.43. There was no significant difference between treatments for this outcome.

Participants with 24-hour sustained pain-free

None of the studies provided data on the proportion of participants who were pain-free at 2 hours and remained pain-free for 24 hours. Hence no analysis of this outcome was possible.

Summary of results A.

Pain-free and headache relief

	Studies	Attacks treated	Treatment (%)	Placebo or comparator (%)	NNT/NNTp (95% CI)	P for difference
Pain-free at 2 hours
Aspirin 900 or 1000 mg versus placebo	6	2027	24	11	8.1 (6.4 to 11)	z = 0.3051 P = 0.76
Aspirin 900 mg plus metoclopramide 10 mg versus placebo	2	519	18	7	8.8 (5.9 to 17)	z = 0.3051 P = 0.76
Aspirin 1000 mg versus sumatriptan 50 mg	2	726	26	32	Not calculated
Aspirin 900mg + metoclopramide 10 mg versus sumatriptan 100 mg	2	528	18	28	9.8 (5.8 to 32)
Headache relief at 1 hour
Aspirin 900 or 1000 mg versus placebo	4	1288	37	15	4.7 (3.8 to 5.9)
Aspirin 1000 mg versus sumatriptan 50 mg	2	726	38	24	7.2 (4.9 to 14)
Headache relief at 2 hours
Aspirin 900 or 1000 mg versus placebo	6	2027	52	32	4.9 (4.1 to 6.2)	z = 2.4847 P = 0.013
Aspirin 900 mg plus metoclopramide 10 mg versus placebo	3	765	57	26	3.3 (2.7 to 4.2)	z = 2.4847 P = 0.013
Aspirin 1000 mg versus sumatriptan 50 mg	2	522	51	53	Not calculated
Aspirin 900mg + metoclopramide 10 mg versus sumatriptan 100 mg	2	523	51	54	Not calculated
Sustained headache relief at 24 hours
Aspirin 1000 mg versus placebo	3	1142	39	24	6.6 (4.9 to 10)	z = 0.7789 P = 0.43
Aspirin 900 mg plus metoclopramide 10 mg versus placebo	1	257	37	17	6.2 (4.8 to 8.9)	z = 0.7789 P = 0.43

Placebo comparators	Studies	Attacks treated	Treatment (%)	Comparator (%)	Relative risk (95% CI)	NNTp (95% CI)
Aspirin (m± metoclopramide) versus placebo	8	2922	44	65	0.68 (0.63 to 0.73) 4	8 (4.1 to 5.7)
Aspirin 1000 mg versus placebo	5	1881	42	63	0.67 (0.61 to 0.73)	4.8 (3.9 to 6.0)
Aspirin 900 mg plus metoclopramide 10 mg versus placebo	3	1041	48	69	0.69 (0.62 to 0.77)	4.7 (3.7 to 6.5)
Active comparators	Studies	Attacks treated	Treatment (%)	Comparator (%)	Relative risk (95% CI)	NNH (95% CI)
Aspirin (± metoclopramide) versus sumatriptan 50 mg or 100 mg	4	1340	49	43	1.1 (1.01 to 1.3)	17 (8.8 to 140)
Aspirin 1000 mg versus sumatriptan 50 mg	2	726	44	40	1.1 (0.92 to 1.3)	Not calculated
Aspirin 900 mg plus metoclopramide 10 mg versus sumatriptan 100 mg	2	614	55	46	1.2 (1.01 to 1.4)	11 (6.0 to 120)

Intervention	Studies	Attacks with symptom present	Treatment (%)	Placebo (%)	Relative risk (95% CI)	NNT
Nausea
Aspirin 1000 mg versus placebo	4	878	56	44	1.3 (1.1 to 1.4)	9.0 (5.6 to 22)
Aspirin 900 mg plus metoclopramide 10 mg versus placebo	2	417	45	6	7.5 (4.2 to 14)	2.6 (2.1 to 3.1)
Aspirin 900 mg plus metoclopramide 10 mg versus sumatriptan 100 mg	2	410	35	31	1.1 (0.83 to 1.5)	Not calculated
Vomiting
Aspirin 1000 mg versus placebo	3	139	73	66	1.1 (0.94 to 1.3)	Not calculated
Aspirin 900 mg plus metoclopramide 10 mg versus placebo	2	59	46	0	17 (2.3 to 120)	2.1 (1.5 to 3.7) [12 events]
Aspirin 900 mg plus metoclopramide 10 mg versus sumatriptan 100 mg	2	67	33	0	11 (1.4 to 78)	3.3 (2.1 to 7.4) [11 events]
Photophobia
Aspirin 1000 mg versus placebo	5	1236	47	33	1.4 (1.2 to 1.6)	7.7 (5.4 to 13)
Aspirin 1000 mg versus sumatriptan 50 mg	2	575	60	66	0.91 (0.80 to 1.03)	Not calculated
Phonophobia
Aspirin 1000 mg	5	1217	49	34	1.4 (1.3 to 1.7)	6.6 (4.9 to 10)
Aspirin 1000 mg versus sumatriptan 50 mg	2	540	63	65	0.98 (0.86 to 1.1)	Not calculated

More or no more adverse events with treatment than comparator	Studies	Participants	Aspirin (%)	Comparator (%)	Relative risk (95% CI)	NNH (95% CI)
Aspirin ± metoclopramide versus placebo	7	2458	14	11	1.3 (1.02 to 1.6)	34 (18 to 340)
Aspirin 1000 mg versus placebo	5	1892	12	9	1.3 (1.00 to 1.7)	Not calculated
Aspirin 900 mg with metoclopramide 10 mg versus placebo	2	566	19	17	1.2 (0.82 to 1.7)	Not calculated
Fewer adverse events with treatment than comparator	Studies	Participants	Aspirin (%)	Comparator (%)	Relative risk (95% CI)	NNTp (95% CI)
Aspirin 1000 mg versus sumatriptan 50 mg	2	730	15	18	0.85 (0.61 to 1.2)	Not calculated
Aspirin 900 mg plus metoclopramide 10 mg versus sumatriptan 100 mg	2	642	24	36	0.66 (0.52 to 0.84)	*8.4 (5.3 to 21)*

Methods	Multicentre, randomised, double-blind, placebo-controlled, double-dummy, three-period, cross-over. Single oral dose of each treatment for each of three migraine attacks Assessments at 0 and 2 hours. If pain not controlled, participants asked to wait 2 hours before taking rescue medication
Participants	Aged 18-65 years, meeting IHS criteria for migraine without aura. At least 12-month history of migraine, with age of onset before 50 years and two to six attacks permonth. Prophylaxis permitted if stable for ≥ 2 months Excluded participants with other types of headache. Included participants with ‘slight’ migraine at baseline, but reported primary outcomes for those with ≥ moderate pain separately N = 247 (198 treated three attacks and analysed for efficacy) M = 57, F = 190 Mean age = 40 years 36.8% of randomised participants were taking prophylactic therapy
Interventions	Aspirin 1000 mg, n = 198 Acetaminophen 400 mg plus codeine 25 mg, n = 198 Placebo, n = 198
Outcomes	Headache relief at 2 hours Pain-free at 2 hours PI: 100 mm VAS Mean PID at 2 hours (from baseline) Relief of nausea and vomiting Use of rescue medication Patient preference for medication Adverse events
Notes	Oxford Quality Score: R1, DB2, W1. Total = 4
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	Not described
Allocation concealment?	Unclear	Not described
Blinding? All outcomes	Yes	Double-dummy design

Methods	Multicentre, randomised, double-blind, three-arm, parallel-group, double-dummy. Single oral dose Medication taken when migraine headache pain of moderate or severe intensity Assessments at 0, 0.5, 1, 1.5, 2 and 24 hours. If pain not controlled, participants asked to wait 2 hours before taking rescue medication
Participants	Aged 18-65 years, meeting IHS criteria for migraine with and without aura. At least 12-month history of migraine, with one to six attacks per month N = 433 M = 66, F = 367 Mean age 42 years
Interventions	Effervescent acetylsalicylic acid 1000 mg, n = 146 Sumatriptan 50 mg, n = 135 Placebo, n = 152
Outcomes	Headache relief at 1 and 2 hours Pain-free at 2 hours 24-hour sustained relief Adverse events Remission of associated symptoms: nausea, photophobia, phonophobia Overall impression of study medication Need for rescue medication
Notes	Oxford Quality Score: R2, DB2, W1. Total = 5.
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	“Computer-generated randomisation list”
Allocation concealment?	Unclear	Not described
Blinding? All outcomes	Yes	“Matching effervescent or tablet placebo”

Methods	Multicentre, randomised, double-blind, double-dummy, parallel-group. Single oral dose Each participant to treat two attacks, as soon as intensity was moderate or severe Assessmnets at 0, 2 and 24 hours If pain not controlled, participants encouraged to wait 2 hours before taking rescue medication
Participants	Aged 18-65 years, meeting IHS criteria for migraine with and without aura. At least 12-month history of migraine, with one to six attacks moderate or severe attacks per month. Prophylaxis permitted if stable for ≥3 months N = 296 randomised (268 took study medication) M = 47, F = 249 Mean age 37 years
Interventions	Calcium carbasalate 1145 mg (equivalent to 900 mg aspirin) plus metoclopramide 10 mg, n = 136 Ergotamine 1 mg plus metoclopramide 10 mg, n = 132
Outcomes	Headache relief at 2 hours Pain-free after 2 hours Relief of nausea PGE: 4-point scale Headache recurrence within 24 hours Use of rescue medication Adverse events
Notes	Oxford Quality Score: R1, DB2, W1. Total = 4.
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Predetermined randomisation list
Allocation concealment?	Unclear	Not described
Blinding? All outcomes	Yes	Double-dummymethod, using tablet and sachet

Study	Reason for exclusion
Chabriat 1993	Abstract (full data in Chabriat 1994)
Diener 2005	Mixed migraine and tension-type headaches
Limmroth 1999	Intravenous administration - self-administration not possible
Nebe 1995	Mixed migraine and tension-type headaches
Tfelt-Hansen 1980	Not randomised or double-blind
Tfelt-Hansen 1984	Included patients with mild headaches, headaches not IHS classified

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Headache relief at 2 hours	6	2027	Risk Ratio (M-H, Fixed, 95% CI)	1.64 [1.48, 1.83]
2 Pain free at 2 hours	6	2027	Risk Ratio (M-H, Fixed, 95% CI)	2.08 [1.70, 2.55]
3 Headache relief at 1 hour	4	1288	Risk Ratio (M-H, Fixed, 95% CI)	2.41 [1.96, 2.96]
4 24-hour sustained headache relief	3	1142	Risk Ratio (M-H, Fixed, 95% CI)	1.63 [1.37, 1.95]
5 Pain free at 2 hours - effect of formulation	6		Risk Ratio (M-H, Fixed, 95% CI)	Subtotals only
5.1 Soluble	4	1230	Risk Ratio (M-H, Fixed, 95% CI)	1.92 [1.51, 2.44]
5.2 Tablet	2	797	Risk Ratio (M-H, Fixed, 95% CI)	2.47 [1.70, 3.58]
6 Headache relief at 2 hours - effect of formulation	6		Risk Ratio (M-H, Fixed, 95% CI)	Subtotals only
6.1 Soluble	4	1230	Risk Ratio (M-H, Fixed, 95% CI)	1.65 [1.43, 1.89]
6.2 Tablet	2	797	Risk Ratio (M-H, Fixed, 95% CI)	1.64 [1.38, 1.95]
7 Relief of associated symptoms at 2 hours	6		Risk Ratio (M-H, Fixed, 95% CI)	Subtotals only
7.1 Nausea	4	878	Risk Ratio (M-H, Fixed, 95% CI)	1.26 [1.10, 1.44]
7.2 Vomiting	3	139	Risk Ratio (M-H, Fixed, 95% CI)	1.12 [0.94, 1.34]
7.3 Photophobia	5	1236	Risk Ratio (M-H, Fixed, 95% CI)	1.37 [1.20, 1.56]
7.4 Phonophobia	5	1217	Risk Ratio (M-H, Fixed, 95% CI)	1.44 [1.27, 1.64]
8 Persistence of associated symptoms after 2 hours	6		Risk Ratio (M-H, Fixed, 95% CI)	Subtotals only
8.1 Nausea	4	1446	Risk Ratio (M-H, Fixed, 95% CI)	0.79 [0.68, 0.93]
8.2 Vomiting	3	1182	Risk Ratio (M-H, Fixed, 95% CI)	0.77 [0.43, 1.37]
8.3 Photophobia	5	1639	Risk Ratio (M-H, Fixed, 95% CI)	0.79 [0.72, 0.87]
8.4 Phonophobia	5	1639	Risk Ratio (M-H, Fixed, 95% CI)	0.75 [0.68, 0.84]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Headache relief at 2 hours	3	765	Risk Ratio (M-H, Fixed, 95% CI)	2.15 [1.78, 2.60]
2 Pain free at 2 hours	2	519	Risk Ratio (M-H, Fixed, 95% CI)	2.68 [1.59, 4.55]
3 24-hour sustained headache relief	1	257	Risk Ratio (M-H, Fixed, 95% CI)	2.18 [1.39, 3.41]
4 Relief of associated symptoms at 2 hours	2		Risk Ratio (M-H, Fixed, 95% CI)	Subtotals only
4.1 Nausea	2	417	Risk Ratio (M-H, Fixed, 95% CI)	7.53 [4.20, 13.50]
4.2 Vomiting	2	59	Risk Ratio (M-H, Fixed, 95% CI)	16.14 [2.30, 113.05]
5 Persistence of associated symptoms after 2 hours	2		Risk Ratio (M-H, Fixed, 95% CI)	Subtotals only
5.1 Nausea	2	735	Risk Ratio (M-H, Fixed, 95% CI)	0.69 [0.58, 0.82]
5.2 Vomiting	2	728	Risk Ratio (M-H, Fixed, 95% CI)	0.33 [0.18, 0.59]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Use of rescue medication	8	2922	Risk Ratio (M-H, Fixed, 95% CI)	0.68 [0.63, 0.72]
1.1 Aspirin 100 mg alone	5	1881	Risk Ratio (M-H, Fixed, 95% CI)	0.67 [0.61, 0.73]
1.2 Aspirin 900 mg + metoclopramide 10 mg	3	1041	Risk Ratio (M-H, Fixed, 95% CI)	0.69 [0.62, 0.77]
2 Any adverse event within 24 hours	7	2458	Risk Ratio (M-H, Fixed, 95% CI)	1.26 [1.02, 1.55]
2.1 Aspirin alone	5	1892	Risk Ratio (M-H, Fixed, 95% CI)	1.30 [1.00, 1.68]
2.2 Aspirin + metoclopramide	2	566	Risk Ratio (M-H, Fixed, 95% CI)	1.17 [0.82, 1.67]

Study ID	Treatment	HR 1 h	HR 2 h	PF 2 h	24 h SHR	24 h SPF	Use of rescue medication
Boureau 1994	(1) Aspirin 1000 mg, n = 198 (2) Paracetamol 400 mg + codeine 25 mg, n = 198 (3) Placebo, n = 198	No data	(1) 104/198 (2) 98/198 (3) 59/198	(1) 36/198 (2) 44/198 (3) 22/198	No data	No data	(1) 110/198 (2) 100/198 (3) 148/198
Chabriat 1994	(1) LAS 1650 mg (= 900 mg aspirin) + metoclopramide 10 mg, n = 126 (2) Placebo, n = 124	No data	1st attack (1) 74/126 (2) 36/124	No usable data - denominator unclear	No usable data - total attacks	No data	Total attacks (1) 111/237 (2) 162/238
Diener 2004a	(1) Effervescent aspirin 1000 mg, n = 147 (2) Sumatriptan 50 mg, n = 135 (3) Placebo, n = 153	(1) 62/146 (2) 31/135 (3) 23/152	(1) 72/146 (2) 66/135 (3) 50/152	(1) 37/146 (2) 33/135 (3) 22/152	(1) 48/146 (2) 47/135 (3) 33/152	No data	(1) 62/146 (2) 53/135 (3) 98/152
Diener 2004b	(1) Effervescent aspirin 1000 mg, n = 222 (2) Ibuprofen 400 mg, n = 212 (3) Sumatriptan 50 mg, n = 226 (4) Placebo, n = 222	(1) 76/221 (2) 65/211 (3) 54/224 (4) 25/222	(1) 116/221 (2) 127/211 (3) 125/224 (4) 68/222	(1) 60/221 (2) 70/221 (3) 83/224 (4) 28/222	(1) 93/221 (2) 103/211 (3) 96/224 (4) 56/222	No data	(1) 99/221 (2) 87/211 (3) 92/224 (4) 147/222
Geraud 2002	(1) Aspirin 900 mg + metoclopramide 10 mg, n = 340 (2) Zolmitriptan 2.5 mg, n = 326	No data	1st attack (1) 226/340 (2) 197/326	No usable data - average over 3 attacks	No usable data - denominator unclear	No data	Overall use: (1) 255/949 (2) 229/909
Henry 1995	(1) Effervescent aspirin 900 mg + metoclopramide 10 mg, n = 152 (2) Placebo, n = 151	No data	(1) 69/127* (2) 34/131*	(1) 18/127 (2) 7/131	No usable data - denominator unclear	No data	(1) 66/152 (2) 91/151
Lange 2000	(1) Effervescent acetylsalicylic acid 1000 mg, n = 169 (2) Placebo, n = 174	No data	(1) 93/169 (2) 64/174	(1) 49/169 (2) 29/174	No data	No data	(1) 65/169 (2) 100/174
Le Jeunne 1998	(1) calcium carbasalate (= 900 mg aspirin) plus metoclopramide 10 mg, n = 134 (2) ergotamine tartrate 1 mg plus caffeine 100 mg, n = 132	No data	1st attack (1) 73/134 (2) 48/132	1st attack (1) 27/134 (2) 11/132	1st attack (1) 61/73 (2) 44/48	No data	1st attack (1) 49/134 (2) 61/131
Lipton 2005	(1) Aspirin 1000 mg, n = 205 (2) Placebo, n = 204	(1) 68/201 (2) 36/200	(1) 105/201 (2) 68/200	(1) 40/201 (2) 12/200	(1) 82/201 (2) 49/200	No data	(1) 68/201 (2) 104/200
MacGregor 2002	(1) Mouth-dispersible aspirin 900 mg, n = 73 (2) Placebo, n = 73	(1) 30/73 (2) 15/73	(1) 35/73 (2) 14/73	(1) 10/73 (2) 4/73	No usable data - recurrence less with aspirin	No usable data	No usable data - less with aspirin
Tfelt-Hansen 1995	(1) LAS 1620 mg (= 900 mg aspirin) + metoclopramide 10 mg, n = 137 (2) Sumatriptan 100 mg, n = 122 (3) Placebo, n = 126	No data	1st attack (1) 76/133 (2) 63/119 (3) 30/124	1st attack (1) 29/135 (2) 36/122 (3) 10/126	1st attack (1) 49/133 (2) 39/119 (3) 21/124	No data	1st attack (1) 74/137 (2) 77/122 (3) 102/126
Thomson 1992	(1) Aspirin 900 mg + metoclopramide 10 mg, n = 183 (2) Sumatriptan 100 mg, n = 175	No data	1st attack, in pts with mod/sev pain (1) 62/138 (2) 74/133	1st attack (1) 19/138 (2) 35/133	No usable data - data for 48 h	No data	1st attack (1) 102/183 (2) 59/175
Titus 2001	(1) LAS 1620 mg (= 900 mg aspirin) + metoclopramide 10 mg, n = 125 (2) Ergotamine 2 mg + caffeine 200 mg, n = 121	No data	No usable data	No usable data	No usable data	No usable data	No usable data

Study ID	Treatment	Any AE	Specific AEs	Serious AEs	AE withdrawal	Other withdrawals/exclusions
Boureau 1994	(1) Aspirin 1000 mg, n = 198 (2) Paracetamol 400 mg + codeine 25 mg, n = 198 (3) Placebo, n = 198	(1) 29/198 (2) 36/198 (3) 27/198		None	None	12 pts excl from analyses because of serious protocol deviations
Chabriat 1994	(1) LAS 1650 mg (= 900 mg aspirin) + metoclopramide 10 mg, n = 126 (2) Placebo, n = 124	No usable data	“Minor and transient AE reported” (no numbers): - constipation - nausea - dizziness and/or vertigo	One patient reported epigastric pain one month after one dose of LAS-MCP and was found to have a gastric ulcer.	None	None
Diener 2004a	(1) Effervescent aspirin 1000 mg, n = 147 (2) Sumatriptan 50 mg, n = 135 (3) Placebo, n = 153	(1) 19/147 (2) 19/135 (3) 16/153	Gastrointestinal: (1) 5/147 (2) 7/135 (3) 7/153	None reported	None reported	2 pts excl from efficacy - did not return diary
Diener 2004b	(1) Effervescent aspirin 1000 mg, n = 222 (2) Ibuprofen 400 mg, n = 212 (3) Sumatriptan 50 mg, n = 226 (4) Placebo, n = 222	(1) 36/222 (2) 26/212 (3) 45/226 (4) 32/222	No data	(1) 1/222 (renal colic) (2) 1/212 (perforated duodenal ulcer) (3) 0/226 (4) 0/222	Possibly 2 serious AEs, but unconfirmed	1 treated pt excluded from analysis - did not return diary
Geraud 2002	(1) Aspirin 900 mg + metoclopramide 10 mg, n = 340 (2) Zolmitriptan 2.5 mg, n = 326	(1) 99/340 (2) 133/326	Most common: (1) Abdominal pain (5.0%), somnolence (5.0%), asthenia (4.9%) (2) vertigo (6.7%), somnolence (5.5%), paraesthesia (4.3%)	(1) 5/340 (2) 6/326	Over 3 attacks: (1) 5/340 (diarrhoea, palpitations + asthenia, anxiety + dry mouth, phlebitis) (2) 3/326 (dizziness, somnolence, dizziness + vasodilatation)	Details provided, but numbers are for entire study period and most due to failure to treat 3 attacks.
Henry 1995	(1) Effervescent aspirin 900 mg + metoclopramide 10 mg, n = 152 (2) Placebo, n = 151	(1) 31/152 (2) 28/151	Vomiting: (1) 8/152, (2) 15/151 Stomach ache: (1) 4/152, (2) 3/151 Somnolence: (1) 4/152, (2) 1/151	No data	None reported	None reported, but 45 pts were asleep and did not contribute to the 2 h efficacy evaluation
Lange 2000	(1) Effervescent acetylsalicylic acid 1000 mg, n = 169 (2) Placebo, n = 174	(1) 14/169 (2) 5/174	Most frequent body systems: (1) whole (5), digestive (3), nervous (3), respiratory (3) (2) whole (3)	None	None reported	None reported
Le Jeunne 1998	(1) calcium carbasalate (= 900 mg aspirin) plus metoclopramide 10 mg, n = 134 (2) ergotamine tartrate 1 mg plus caffeine 100 mg, n = 132	Over 2 attacks: (1) 30/136 (2) 42/132	Any GI AE: (1) 9/136, (2) 28/132 Somnolence: (1) 6/136, (2) 5/132 Abdominal pain: (1) 5/136, (2) 12/132 Nausea: (1) 5/136, (2) 11/132	(1) 1/136 (pulmonary embolism) (2) 0/132	(1) 1/136 (pulmonary embolism) (2) 1/132 (back pain)	2 pts did not return diary cards
Lipton 2005	(1) Aspirin 1000 mg, n = 205 (2) Placebo, n = 204	(1) 18/205 (2) 10/204	Nausea: (1) 7/205 (2) 2/204 All other AE ≤1%	(1) 0/205 (2) 1/204 (perforated appendix)	Possibly one serious AE, but not confirmed	4 pts in each group treated non-migraine headaches, so excluded from efficacy analysis
MacGregor 2002	(1) Mouth-dispersible aspirin 900 mg, n = 73 (2) Placebo, n = 73	No usable data	Gastrointestinal: (1) 8/73 (dyspepsia, nausea, vomiting) (2) 4/73 (abdominal pain, nausea, vomiting)	(1) 1/73 (headache) (2) 1/73 (endometriosis)	(1) 4/73 (nausea, tinnitus, coughing, taste perversion) (2) 0/73	28 pts originally randomised were not included in analyses: insufficient attacks (6), unable to complete diary (7), withdrew consent (4), lost to follow-up (4) other (5)
Tfelt-Hansen 1995	(1) LAS 1620 mg (= 900 mg aspirin) + metoclopramide 10 mg, n = 137 (2) Sumatriptan 100 mg, n = 122 (3) Placebo, n = 126	Over 3 attacks:(1) 25/137 (2) 37/122 (3) 18/126	Most common over 3 attacks: (1) somnolence, abdominal pain, nausea + vomiting (2) nausea + vomiting, fatigue, constriction of throat/chest pain, paraesthesia, somnolence, abdominal pain (3) nausea + vomiting, fatigue	1 sumatriptan pt had acute AF requiring hospital admission	Over 3 attacks: (1) 1/138 (2) 4/125 (3) 2/126	32 pts originally randomised did not have any attacks and 4 took treatment but did not complete diaries
Thomson 1992	(1) Aspirin 900 mg + metoclopramide 10 mg, n = 183 (2) Sumatriptan 100 mg, n = 175	Over 3 attacks: (1) 53/183 (2) 74/175	Most common over 3 attacks: Nausea and/or vomiting: (1) 14/183, (2) 18/175 Malaise/fatigue: (1) 6/183, (2) 11/175 Dizziness/vertigo: (1) 4/183, (2) 9/175	No data	(1) 0/183 (2) 5/175 (headache + faintness + vomiting, scalp tingling + heaviness in chest + globus + prolonged aura, stomach pain, dyspnoea + heaviness in extremities, worsened headache + nausea	3 pts excl from efficacy because did not return diary cards 87 pts excl from efficacy because had mild or no pain at baseline.
Titus 2001	(1) LAS 1620 mg (= 900 mg aspirin) + metoclopramide 10 mg, n = 125 (2) Ergotamine 2 mg + caffeine 200 mg, n = 121	Over multiple attacks and with possible multiple dosing: (1) 21/125 (2) 28/121	Most common over multiple attacks: (1) somnolence, diarrhoea, dyspepsia, nausea (2) abdominal pain, malaise, anxiety	None	(1) 1/125 (sinusitis) (2) 0/121	Lost to follow-up, noncooperation, other: (1) 8/125 (2) 6/121

PERMALINK

Aspirin with or without an antiemetic for acute migraine headaches in adults

Varo Kirthi

Sheena Derry

R Andrew Moore

Henry J McQuay

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors’ conclusions

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

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

RESULTS

Description of studies

Included studies

Excluded studies

Risk of bias in included studies

Figure 1.

Effects of interventions

Pain-free at 2 hours

Aspirin 900 mg or 1000 mg versus placebo

Figure 2.

Aspirin 900 mg plus metoclopramide 10 mg versus placebo

Figure 3.

Figure 4.

Aspirin 1000 mg versus active comparator

Figure 5.

Aspirin 900 mg plus metoclopramide 10 mg versus active comparator

Figure 6.

Headache relief at 1 hour

Aspirin 900 or 1000 mg versus placebo

Aspirin 1000 mg versus active comparator

Aspirin plus metoclopramide versus placebo or versus active comparator

Headache relief at 2 hours

Aspirin 900 or 1000 mg versus placebo

Aspirin 900 mg plus metoclopramide 10 mg versus placebo

Figure 7.

Aspirin 1000 mg versus active comparator

Aspirin 900 mg plus metoclopramide 10 mg versus active comparator

Participants with 24-hour sustained headache relief

Aspirin 1000 mg versus placebo

Aspirin 900 mg plus metoclopramide 10 mg versus placebo

Participants with 24-hour sustained pain-free

Summary of results A.

Subgroup analyses

Dose, route of administration and choice of antiemetic drug

Formulation: soluble versus tablet

Monotherapy versus combination with an antiemetic

Sensitivity analyses

Use of rescue medication