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Pharmacological treatments for acute migraine: quantitative systematic review |
Oldman A D, Smith L A, McQuay H J, Moore R A |
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Authors' objectives To compare the analgesic efficacy and adverse effects of different pharmacological treatments for acute migraine.
Searching Pfizer provided the data on all relevant randomised controlled trials (RCTs) for eletriptan. For all other drugs, the following databases were searched for studies reported in any language: MEDLINE (from 1966 to July 2000), EMBASE (from 1980 to June 200), the Cochrane Library (Issue 3, 2000) and the Oxford Pain Relief Database (from 1950 to 1994). The search strategy included a series of free text terms for generic and trade names of each medication indicated for migraine and any widely available analgesics. The search was restricted to published reports.
Study selection Study designs of evaluations included in the reviewOnly double-blind randomised placebo-controlled trials were considered for inclusion.
Specific interventions included in the reviewAny pharmacological treatment for acute migraine was considered for inclusion, but only studies that examined the use of single-dose treatment at a standard dose were included. The drugs evaluated by the included studies were rizatriptan (5 and 10 mg), naratriptan (2.5 mg), sumatriptan (6, 20, 50 and 100 mg), aspirin (900 mg) plus metoclopramide (10 mg), zolmitriptan (2.5 and 5 mg), dihydroergotamine mesilate (2 mg), Excedrin (paracetamol 500 mg plus aspirin 500 mg plus caffeine 130 mg), tolfenamic acid rapid release (200 to 400 mg), eletriptan (40 and 80 mg), Cafergot (ergotamine tartrate 2 mg plus caffeine 200 mg) and placebo. Sumatriptan (6 mg) was administered subcutaneously, sumatriptan (20 mg) and dihydroergotamine mesilate (2 mg) were intranasal drugs, and the remainder were oral drugs.
Participants included in the reviewAdult patients suffering from a single migraine attack of moderate or severe intensity were eligible for inclusion. Only studies that used the International Headache Society's diagnostic criteria for migraine with or without aura (see Other Publications of Related Interest) were included.
Outcomes assessed in the reviewOnly studies reporting dichotomous or percentage data for at least one of the following outcomes were eligible for inclusion: headache relief (headache pain reduced from moderate or severe to mild or none) at 2 hours; headache relief at 1 hour; pain-free response (headache pain reduced from moderate or severe to none) at 2 hours; sustained relief over 24 hours (headache relief at 2 hours sustained for 24 hours after treatment, i.e. pain did not return to moderate or severe, and without use of rescue or second-dose medication); and pain-free over 24 hours (pain-free at 2 hours, sustained for 24 hours after treatment, i.e. pain did not return to moderate or severe, and without use of rescue or second-dose medication).
The review also considered the evaluation of adverse effects that occurred within 24 hours of treatment in terms of the following: the incidence of major harm resulting in withdrawal from the study; any undesirable side-effects considered to be related to the study drug; and the incidence of particular adverse effects.
How were decisions on the relevance of primary studies made?The authors do not state how the papers were selected for the review, or how many of the reviewers performed the selection.
Assessment of study quality The studies were scored for quality according to the Jadad criteria. Two reviewers independently assessed each study. It was not stated how any disagreements were resolved.
Data extraction The authors do not state how the data were extracted for the review, but do mention that two reviewers independently read each report. The following data were extracted for each trial: the number of patients treated per group, dosing regimens, study design (parallel or crossover), the number of attacks studied, and the timing and type of rescue medication used. Data that were contaminated by rescue medication or a second dose were not extracted. For each RCT, the proportion of patients who had the outcome of interest in the treatment group (for each drug evaluated) and the placebo group were used to calculate the risk benefit (RB) and the number-needed-to-treat (NNT) for each specified outcome measure. Data on adverse effects were extracted from reports along with the method of data collection, time period over which the data were collected, and whether it had been affected by rescue medication or a second dose of the study medication.
Methods of synthesis How were the studies combined?The RB estimates for the individual studies were pooled using a fixed-effect model and the NNT was calculated when the results were found to be statistically significant. The NNT for tolfenamic acid (200 to 400 mg) was not estimated, as the data for a single dose (200 mg) could not be calculated. To assess the effect of dose on efficacy, the differences between NNTs were tested for significance using the z-statistic.
How were differences between studies investigated?No formal statistical test for heterogeneity was performed. However, differences between the studies were discussed in the text of the review.
Results of the review Forty-eight publications reporting on 54 trials were included (21,022 patients).
The quality scores of included trials ranged from 2 to 5 (median 4).
Headache relief at 2 hours: there were 73 placebo comparisons for 16 different interventions. All of the drugs, except Cafergot, were found to be statistically significantly superior to placebo. The NNTs ranged from 2.0 (95% confidence interval, CI: 1.8, 2.2) for sumatriptan 6 mg to 5.4 (95% CI: 3.8, 9.2) for naratriptan 2.5 mg. There was a statistically-significant dose-response for rizatriptan (10 mg versus 5 mg, p<0.001) and for sumatriptan (100 mg versus 50 mg, p=0.017).
Headache relief at 1 hour: there were 63 placebo comparisons for 14 different interventions. All of the drugs, except Cafergot, were found to be statistically significantly superior to placebo; the two drugs not included for this outcome measure were aspirin (900 mg) plus metoclopramide (10 mg) and tolfenamic acid (200 to 400 mg). The NNT ranged from 2.1 (95% CI: 1.9, 2.2) for sumatriptan 6 mg to 10.0 (95% CI: 7.3, 17.0) for Excedrin. There was a statistically-significant dose-response for rizatriptan (10 mg versus 5 mg, p=0.014).
Patients pain free at 2 hours: there were 59 placebo comparisons for 15 different interventions. All of the drugs, except Cafergot, were found to be statistically significantly superior to placebo; dihydroergotamine (2 mg was not included for this outcome measure. The NNT ranged from 2.1 (95% CI: 1.9, 2.4) for subcutaneous sumatriptan 6 mg to 8.6 (95% CI: 6.2, 14.0) for aspirin 900 mg plus metoclopramide 10 mg. There was a statistically-significant dose-response for eletriptan (40 mg versus 80 mg, p=0.024), rizatriptan (5 mg versus 10 mg, p<0.0001), zolmitriptan (2.5 mg versus 5 mg, p<0.0059) and sumatriptan (50 mg versus 100 mg, p<0.0002).
Sustained pain relief over 24 hours: there were 26 placebo comparisons for 9 different interventions. All of the drugs, except zolmitriptan (5 mg), were found to be statistically significantly superior to placebo; the drugs not included for this outcome measure were naratriptan (2.5 mg), sumatriptan (20 mg), aspirin (900 mg) plus metoclopramide (10 mg), zolmitriptan (2.5 mg), sumatriptan (6 mg), dihydroergotamine mesilate (2 mg), Excedrin (paracetamol 500 mg plus aspirin 500 mg plus caffeine 130 mg) and tolfenamic acid rapid release (200 to 400 mg). The NNT ranged from 2.8 (95% CI: 2.5, 3.2) for eletriptan 80 mg to 8.3 (95% CI: 6.0, 14.0) for rizatriptan 5 mg. There was a statistically-significant dose-response for eletriptan (40 mg versus 80 mg, p=0.004) and rizatriptan (5 mg versus 10 mg, p=0.035).
Patients pain free over 24 hours: none of the included studies reported information to allow the calculation of this outcome.
Adverse effects: it was not possible to carry out a meaningful analysis of the adverse effects because of the data collection methods used by the included studies and the poor quality of reporting.
Authors' conclusions The authors concluded that, considering all outcomes, at the dose used subcutaneous sumatriptan and newer oral triptans (except natriptan) provided the best efficacy.
CRD commentary The review is based on a clear question with predefined inclusion and exclusion criteria. However, the pre-specified inclusion criterion relating to the intervention was that only studies that used a single-dose treatment would be considered. One study that examined the use of tolfenamic acid (200 to 400 mg) was included, despite the fact that the data for the single dose (200 mg) could not be calculated (consequently, the NNT for this study was not estimated). The table of included studies showed 32 referenced studies as having used two or more doses, and it was not stated how the data relating to a single dose were extracted from these studies.
Three relevant electronic databases were searched with no language restrictions, but specific details of the search strategy were not provided. There was no attempt to look for unpublished data for any of the interventions, other than eletriptan. Relevant studies relating to this drug were obtained directly from Pfizer. It was not stated how the retrieved studies were assessed for relevancy. The data extraction and quality assessment appear to have been performed in duplicate, but it was not stated how any disagreements were resolved.
A summary table of the included studies was available on the Internet, but very few study details were provided. In the text of the review the authors noted that there were 79 placebo comparisons for the primary outcome measure headache relief at 2 hours, yet only 73 were reported in summary table 1. The authors did not examine statistical heterogeneity, but did report that they considered the studies to be clinically homogeneous and, therefore, a fixed-effect model was used to pool the data. They also noted that for the intervention Excedrin, three of the included studies may not be comparable with other included studies, as patients with severely debilitating migraine attacks were excluded. For the outcome measure of sustained pain relief over 24 hours, the authors note that it was not possible to extract the data for a number of interventions because of the wide variation in the design of migraine trials. However, no further information about this variation was reported.
The authors' conclusions follow from the results presented.
Implications of the review for practice and research Practice: The authors did not state any implications for practice.
Research: The authors state that efficiency measures should be rigorous and include what is important to the sufferers, as well as include well-defined long-term outcomes such as the proportion who are pain free at 2 hours and remain pain free for the next 24 hours. The authors also state that current trials often fail to collect useful adverse effects data.
Funding Pain Relief Funds; Pfizer UK Ltd.
Bibliographic details Oldman A D, Smith L A, McQuay H J, Moore R A. Pharmacological treatments for acute migraine: quantitative systematic review. Pain 2002; 97(3): 247-257 Other publications of related interest Headache Classification Committee of the International Headache Society. Classification and diagnosis criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1998;8:19-28.
These additional published commentaries may also be of interest. Loder E. Review: several drugs, especially triptans, are effective for pain relief in acute migraine. ACP J Club 2002;137:103. Loder E. Review: several drugs, especially triptans, are effective for pain relief in acute migraine. Evid Based Med 2002;7:180.
Indexing Status Subject indexing assigned by NLM MeSH Acute Disease; Analgesics /administration & Clinical Trials as Topic; Humans; Migraine Disorders /drug therapy; Serotonin Receptor Agonists /administration & dosage /adverse effects; dosage /adverse effects AccessionNumber 12002001654 Date bibliographic record published 31/10/2003 Date abstract record published 31/10/2003 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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