Parenteral Dihydroergotamine for Acute Migraine Headache: A Systematic Review of the Literature

Transcription

1 NEUROLOGY/ORIGINAL RESEARCH Parenteral Dihydroergotamine for Acute Migraine Headache: A Systematic Review of the Literature Ian Colman, MSc Michael D. Brown, MD, MSc Grant D. Innes, MD Eric Grafstein, MD Ted E. Roberts, MD Brian H. Rowe, MD, MSc From the Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom (Colman); Program in Emergency Medicine, Michigan State University, Grand Rapids, MI (Brown); the Department of Emergency Medicine, Providence Health Care and St. Paul s Hospital, Vancouver, British Columbia, Canada (Innes, Grafstein); and the Department of Medicine (Roberts) and the Division of Emergency Medicine (Rowe), University of Alberta, Edmonton, Alberta, Canada. Study objective: Many therapies are used in the treatment of acute migraine headache, with little agreement on effectiveness. This systematic review is designed to determine the effectiveness of parenteral dihydroergotamine in reducing pain, nausea, and relapse for episodes of acute migraine in adults. Methods: Randomized controlled trials were identified using MEDLINE, EMBASE, other computerized databases, hand searching, bibliographies, and contacts with industry and authors. Studies in which dihydroergotamine (alone or in combination with an antiemetic) was compared with placebo or any other common migraine therapy were considered. Relevance, inclusion, and study quality were assessed independently by 2 reviewers. Results: From 281 potentially relevant abstracts, 11 studies met the inclusion criteria. Solitary dihydroergotamine use was compared to sumatriptan and phenothiazines in 3 studies; results failed to demonstrate a significant benefit of dihydroergotamine over these therapies. In 8 combination treatment studies, heterogeneity in study methodology prevented statistical pooling. However, dihydroergotamine administered with an antiemetic was as effective as or more effective than meperidine, valproate, or ketorolac across all pain, nausea, and relapse outcomes reported in all studies. Conclusion: This evidence suggests that dihydroergotamine is not as effective as sumatriptan or phenothiazines as a single agent for treatment of acute migraine headache; however, when administered with an antiemetic, dihydroergotamine appears to be as effective as opiates, ketorolac, or valproate. Given its nonnarcotic properties, parenteral dihydroergotamine combined with an antiemetic should be considered as effective initial therapy in clinical practice. [Ann Emerg Med. 2005;45: ] /$-see front matter Copyright ª 2005 by the American College of Emergency Physicians. doi: /j.annemergmed INTRODUCTION Migraine headache is a common health problem around the world. Surveys suggest that 6% of men and 15% to 17% of women experience migraine headaches. 1 The typical person with migraine experiences an average of 36 attacks per year. 2 These attacks can be particularly disabling, requiring an average of 4.5 hours of bed rest for men and 6.0 hours of bed rest for women, 2 which has a significant effect on the lives of individuals with migraine, impairing relationships and limiting regular daily activities. 3 In addition, migraine-related disability has significant economic implications through increased use of health care 2,4 and lost productivity in the workplace. 2,4,5 Ergot extracts have long been used in the treatment of migraine headache. The first pure ergot alkaloid, ergotamine tartrate, was used to treat acute migraine as early as Although ergotamine tartrate remained a common and effective treatment for decades, it aggravated the nausea and vomiting commonly associated with migraine, and it often provoked adverse effects related to vasoconstriction. The desire to reduce adverse effects led to the development of dihydroergotamine in Dihydroergotamine s antimigraine effects were originally believed to be due to its ability to cause vasoconstriction and venoconstriction. However, as debate grows over whether Volume 45, no. 4 : April 2005 Annals of Emergency Medicine 393

2 Treatment of Migraine With Dihydroergotamine Colman et al Editor s Capsule Summary What is already known on this topic Dihydroergotamine is listed as a second-line agent for migraine. Data on its efficacy and tolerability are often conflicting. What question this study addressed This systematic review examines the safety and tolerability of dihydroergotamine alone and with antiemetics, with evidence from controlled clinical trials. What this study adds to our knowledge The combination of dihydroergotamine with an antiemetic is as effective as ketorolac, meperidine, or valproate. Dihydroergotamine alone is probably not an effective first-line agent for migraine compared with sumatriptan or phenothiazines. How this might change clinical practice In appropriate patients, dihydroergotamine with an antiemetic should be considered as an effective agent for migraine in the emergency department. migraine is indeed a vascular phenomenon, dihydroergotamine has also been shown to block the development of neurovascular inflammation in the trigeminal nerve terminal. 8 Regardless of its mechanism of action, dihydroergotamine remains a common second-line treatment for acute migraine. Although recommended in many guidelines as an evidencebased, nonnarcotic analgesic, these assertions are based on conflicting and limited evidence. The objective of this systematic review was to describe and assess the evidence from controlled trials about the efficacy and tolerability of parenteral dihydroergotamine for acute migraine headache in adult patients. MATERIAL AND METHODS Before the review was begun, a study protocol was developed to outline the search strategy, to establish explicit trial selection criteria, to clarify the data abstraction process, and to define the analysis. 9 Several methods were used to identify potentially relevant studies. The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, and CINAHL databases were searched using the terms headache or migraine and dihydroergotamine or DHE up until June The search results were further refined to identify randomized controlled trials using the methodology described by Dickersin et al. 10 In addition to searching electronic databases, we hand searched conference proceedings from major neurology, headache, and emergency medicine meetings from the past 6 years; reviewed clinical practice guidelines for the management of acute migraine; searched Web sites housing clinical trial details, theses, or dissertations; and contacted headache experts, pharmaceutical companies (Novartis Pharmaceuticals Corp.), and authors of previously identified studies. Finally, we searched the reference lists of all potentially relevant studies to identify additional important studies. Language of publication and nonpublication were not reasons for exclusion. Studies were considered eligible for review if they were randomized controlled trials of parenteral dihydroergotamine given for acute migraine attacks in adults (R18 years) and if reasonable criteria were used to distinguish migraine from other headache types. Finally, trials were included only if they were conducted in a setting that indicated that the headache was an acute migraine (ie, emergency department [ED] or headache clinic). Three outcomes describing headache relief were considered, and these were assessed at the point closest to 2 hours posttreatment. Outcomes included self-reported complete relief from migraine pain, pain reduction from moderate or severe to mild or none, and improvement measured on a 10-cm visual analog scale. Secondary outcomes included improvement in functional status, migraine relapse within 48 hours of treatment, reduction in nausea, number of cointervention ( rescue ) medications required after dihydroergotamine treatment, and adverse events associated with the therapy. Titles and abstracts of studies identified by the literature search were screened for eligibility by 2 independent reviewers (IC, GDI). Articles deemed potentially relevant were obtained, and the full manuscripts were reviewed for possible inclusion, again by 2 independent reviewers (IC, MDB). Disagreements were resolved through consensus. Information on patients, methods, interventions, outcomes, and adverse events were abstracted from the original reports onto specially designed, pretested paper forms by 2 independent reviewers (IC, MDB). Disagreements were resolved through discussion. The internal validity of individual trials was assessed using the scale devised by Jadad et al, 11 which evaluates quality of randomization, blinding, and withdrawals in a trial and assigns a score from 0 to 5, with higher scores indicating higher quality in the conduct or reporting of the trial. All data were entered into Review Manager software (version 4.1, Update Software, Oxford, United Kingdom). Results of studies were pooled using fixed-effects models, if appropriate, after consideration of heterogeneity between the trials. For dichotomous variables, individual and pooled statistics were calculated as odds ratios (ORs) with 95% confidence intervals (CIs). For continuous outcomes, individual trials reported mean differences, and pooled statistics were calculated as weighted mean differences when data were on a uniform scale or standardized mean differences when data were on different scales, along with associated 95% CIs. Heterogeneity was tested using a c 2 test that considered a P value of less than.10 to indicate significant heterogeneity between the trials. When heterogeneity could be explained by clinical dissimilarities, trials were not pooled statistically. 394 Annals of Emergency Medicine Volume 45, no. 4 : April 2005

3 Colman et al Treatment of Migraine With Dihydroergotamine Figure 1. Inclusion of potentially relevant studies in the review. A priori planned sensitivity analyses were completed, comparing studies with high quality of conduct or reporting versus studies of low quality, using the Jadad scale (assigning studies with a score of R3 as high quality and those with a score of %2 as low quality ). 11 These sensitivity analyses of quality were performed only on outcomes for which there was a minimum of 3 studies reporting. In addition, sensitivity analyses were performed to examine the use of random-effects versus fixed-effects comparisons. RESULTS The comprehensive search identified 440 abstracts for review. Two independent reviewers identified 53 abstracts as potentially relevant to this review. Independent review of the full manuscripts of the 53 potentially relevant studies resulted in 11 studies being included in this review (Figure 1). There were no disagreements between 2 independent reviewers about inclusion of studies in the review. Study methodology varied significantly among the included trials, particularly with regard to comparison agents, outcomes reported, and study quality. The Table summarizes the key features of the included trials. The trials described 2 patterns of dihydroergotamine administration; consequently, results were grouped into 2 treatment comparisons: (1) dihydroergotamine alone versus other agents, and (2) dihydroergotamine with an antiemetic versus other treatments. Three studies involving 423 patients compared dihydroergotamine administered alone to other agents. Two studies compared dihydroergotamine to sumatriptan, 13,14 whereas the third compared dihydroergotamine to 2 treatment arms; one arm received chlorpromazine and the other received lidocaine. 12 The first 2 treatment agents have been recommended as safe, effective, evidence-based treatments in acute migraine The results of the sumatriptan studies were pooled, whereas the third study, because of heterogeneous comparison and results, was not pooled; results are described below. Although the 2 sumatriptan studies shared only 1 common outcome (pain reduction), 5 outcomes were reported. Dihydroergotamine was found to be less effective than sumatriptan for outcomes describing relief of headache pain. Dihydroergotamine was less effective than sumatriptan in completely resolving migraine (OR 0.05; 95% CI 0.01 to 0.42), 13 in reducing headache pain (OR 0.44; 95% CI 0.25 to 0.77), 13,14 and in improving functional ability (OR 0.39; 95% CI 0.22 to 0.69). 14 Dihydroergotamine was also less effective than sumatriptan in reducing nausea associated with migraine (OR 0.25; 95% CI 0.13 to 0.49). 14 However, patients treated with Volume 45, no. 4 : April 2005 Annals of Emergency Medicine 395

4 Treatment of Migraine With Dihydroergotamine Colman et al Table. Descriptive characteristics of studies included in the review. Primary Study Author Year Sample Setting Treatment Comparison Quality on Jadad Scale Belgrade et al ED Metoclopramide 10 mg IV plus DHE 1 mg IV Bell et al EDs of 2 hospitals DHE 1 mg IV Callaham and Raskin ED Prochlorperazine 5 mg IV plus DHE 0.75 mg IV Carletonet al EDs at 11 sites Hydroxyzine hydrochloride 0.75 mg/kg IM plus DHE 1 mg IM Edwards et al Headache clinic Metoclopramide 10 mg IM plus DHE 1 mg IM Hydroxyzine 50 mg IM plus meperidine 75 mg IM or butorphanol 2 mg IM Chlorpromazine 12.5 mg IV or lidocaine 50 mg IV Prochlorperazine 5 mg IV plus placebo Hydroxyzine hydrochloride 0.75 mg/kg IM plus meperidine 1.5 mg/kg IM Valproate 500 mg IV 1 Gonzalez-Espinosa et al Hospital clinic DHE 1 mg IM Sumatriptan 6 mg SC 3 Klapper and Stanton Private headache clinic Klapper and Stanton Private headache clinic Klapper and Stanton Private headache clinic Scherl and Wilson General medicine clinic Metoclopramide 5 mg IV plus DHE 1 mg IV Metoclopramide 5 10 mg and DHE mg IV Metoclopramide 10 mg IV plus DHE 1 mg IV Metoclopramide 10 mg IV plus DHE 0.5 mg IV Ketorolac 60 mg IM 1 Metoclopramide 5 10 mg and dexamethasone 6 mg IV Hydroxyzine 75 mg IM plus meperidine 75 mg IM Promethazine 25 mg IM plus meperidine 75 mg IM Winner et al clinic sites DHE 1 mg SC Sumatriptan 6 mg SC 3 DHE, Dihydroergotamine; IM, intramuscular; IV, intravenous; SC, subcutaneous dihydroergotamine were significantly less likely to have a migraine relapse (OR 0.26; 95% CI 0.15 to 0.46). 14 Numerous adverse events were studied. Nausea was more common in the dihydroergotamine groups (OR 3.70; 95% CI 1.91 to 7.16), 14 whereas chest pain was less common (OR 0.24; 95% CI 0.08 to 0.74). 13,14 No differences were noted for drowsiness (OR 0.20; 95% CI 0.01 to 4.38), 13 flushing (OR 0.24; 95% CI 0.02 to 2.31), 13 neck stiffness (OR 0.50; 95% CI 0.08 to 3.00), 13 vertigo (OR 1.70; 95% CI 0.26 to 11.16), 13 cramping (OR 3.55; 95% CI 0.34 to 36.56), 13 or weakness (OR 1.44; 95% CI 0.34 to 6.10). 13 There were conflicting results for pain at injection site because one study found a significant difference against dihydroergotamine, whereas the other found a nonsignificant trend against sumatriptan (pooled OR 6.10; 95% CI 3.76 to 9.88). 13,14 The remaining study 12 produced mixed results with few statistically significant differences. No differences were found between dihydroergotamine and chlorpromazine (OR 0.60; 95% CI 0.17 to 2.09) and lidocaine (OR 3.60; 95% CI 0.65 to 19.84) for complete resolution of migraine. Visual analog scale pain intensity differences were smaller with dihydroergotamine (2.75) than with chlorpromazine (6.75) or lidocaine (4.00), but SDs were not reported, and statistical significance was unclear. Patients treated with dihydroergotamine were more likely to require rescue medication (OR 3.80; 95% CI 1.09 to 13.26) and to have a migraine relapse (OR 7.20; 95% CI 1.28, 40.37) than patients treated with chlorpromazine; however, there were no significant differences between dihydroergotamine and lidocaine in terms of escape medications and headache relapse. Specific adverse events were not reported consistently; however, rates of any adverse event were higher in the dihydroergotamine group than either the chlorpromazine group (OR 3.67; 95% CI 0.97 to 13.81) or the lidocaine group (OR 3.08; 95% CI 0.88 to 10.72). The paucity of studies using dihydroergotamine alone precluded formal sensitivity analyses of study quality. A random-effects model was tested on the single pooled outcome for dihydroergotamine versus sumatriptan (patients with reduction in headache pain), and the results and interpretation were unchanged from the fixed-effects model. Eight studies involving 384 patients compared dihydroergotamine administered with an antiemetic (most commonly metoclopramide) with various other agents across several outcomes Because of significant heterogeneity in study methodology (Table), particularly with regard to the comparison treatments, studies were not pooled statistically. The results, however, are summarized below and presented in Figures 2 to 9. Only 1 study reported complete resolution of migraine; dihydroergotamine with an antiemetic was more effective in 396 Annals of Emergency Medicine Volume 45, no. 4 : April 2005

5 Colman et al Treatment of Migraine With Dihydroergotamine Figure 2. Dihydroergotamine with an antiemetic versus other agents in terms of patients with complete relief of headache pain. Figure 3. Dihydroergotamine with an antiemetic versus other agents in terms of patients with a reduction in headache pain. Figure 4. Dihydroergotamine with an antiemetic versus other agents in terms of patients with a reduction on a visual analog scale. completely resolving migraine (Figure 2). 15 Results from 3 trials showed that dihydroergotamine with an antiemetic was equally or more effective in reducing headache pain than other treatments (Figure 3) 18,19,21 and as effective as other treatments in 3 studies that reported reduction in headache pain on a visual analog scale (Figure 4) Three studies indicated that dihydroergotamine with an antiemetic was equally or more effective in improving functional ability (Figure 5), 17,19,20 whereas the 1 study that reported the number of patients needing rescue medication did not find a significant difference between groups (Figure 6). 17 Dihydroergotamine with an antiemetic was as effective as other treatments with regard to reduction in nausea in 2 studies (Figure 7), 17,18 and patients treated with dihydroergotamine with an antiemetic were as likely or less likely to have a migraine relapse in 4 studies (Figure 8) Most studies reported a variety of adverse events (Figure 9). Most notably, nausea was equally common in patients treated with dihydroergotamine and an antiemetic and comparison treatments, 15-18,22 whereas drowsiness 15-17,22 and dizziness 15,17,22 were as common or less common in patients treated with dihydroergotamine and an antiemetic (Figure 9). Among adverse events that were reported in only 1 or 2 studies (results not shown), restlessness, 15,16 dysphoria, 15 and flushing 15,16 were as common or more common in patients treated with dihydroergotamine and an antiemetic. Pain at injection site 16,17 was equally common in 2 studies, and an orthostatic blood pressure response 22 was less common in patients treated with dihydroergotamine and an antiemetic in 1 study. Because studies in the section of the review were not statistically combined, planned sensitivity analyses were impossible. LIMITATIONS Some limitations of this review should be acknowledged. First, it is possible that individuals with nonmigraine headache could have been included in some of the studies in this review. Although most studies identified inclusion and exclusion criteria and these criteria were relatively similar across trials, some studies reported no such information. Similarly, some studies reported no information about demographic characteristics of the patient population, and most studies reported no information about the initial severity and duration of the migraine before presentation. Consequently, it is difficult to determine how generalizable these results may be. Second, most studies had relatively small sample sizes; consequently, their ability to detect meaningful differences in the rates of adverse events was low, which is of particular concern for any serious adverse events that are relatively rare. This review may not have had the power to make definitive Volume 45, no. 4 : April 2005 Annals of Emergency Medicine 397

6 Treatment of Migraine With Dihydroergotamine Colman et al Figure 5. Dihydroergotamine with an antiemetic versus other agents in terms of patients with an improvement in functional ability. Figure 6. Dihydroergotamine with an antiemetic versus other agents in terms of patients requiring rescue medication. Figure 7. Dihydroergotamine with an antiemetic versus other agents in terms of patients with a reduction in nausea. conclusions about the safety profile of dihydroergotamine versus comparison treatments. Third, there is a possibility of publication bias in this review. Negative trials that do not show a significant treatment effect may be less likely to be published, and if so, their exclusion could affect the results of this review. However, a comprehensive search strategy was used to identify any unpublished trials that could be relevant to this review, including hand searching of recent conferences to detect recently completed work that may be unpublished. Several additional studies were identified through these searches of the gray literature. We do not believe that it is likely that there is a publication bias in this review. Finally, there is a possibility of selection bias in this review. However, all abstracts and full manuscripts were reviewed by 2 independent reviewers, and standardized criteria for inclusion of studies was used to attempt to eliminate this bias. DISCUSSION This systematic review identified and evaluated the best available evidence about the use of dihydroergotamine in the treatment of acute migraine headache. A comprehensive search of the literature identified 11 studies relevant to this topic. Overall, it appears that dihydroergotamine as a single therapy may not be as effective as sumatriptan or phenothiazines; however, when administered as an adjunct with an antiemetic agent, the combination with dihydroergotamine appears to be as effective as or more effective than meperidine, valproate, or ketorolac. Definitive conclusions about treatment with dihydroergotamine with an antiemetic cannot be made due to important differences among studies with respect to the antiemetic used. The results of this review provide consistent evidence about the use of dihydroergotamine as a single-agent therapy. One study comparing dihydroergotamine to either chlorpromazine or lidocaine (a weak analgesic) found no differences between dihydroergotamine and lidocaine, whereas some outcomes indicated that chlorpromazine may be a superior treatment to dihydroergotamine. Two studies compared dihydroergotamine to sumatriptan, and these studies found that sumatriptan was more effective than dihydroergotamine in relieving pain and nausea associated with migraine. However, rates of migraine relapse were significantly higher for patients treated with sumatriptan, which is particularly notable, given that patients consider migraine relapse as 1 of the top 2 most important outcomes in the successful treatment of migraine headache. 26,27 In addition, although nausea was more common in patients treated with dihydroergotamine, the far more serious adverse event of chest pain was significantly more likely in patients treated with sumatriptan. Clinicians and patients must 398 Annals of Emergency Medicine Volume 45, no. 4 : April 2005

7 Colman et al Treatment of Migraine With Dihydroergotamine Figure 8. Dihydroergotamine with an antiemetic versus other agents in terms of patients with a relapse of migraine within 48 hours of original treatment. Figure 9. Dihydroergotamine with an antiemetic versus other agents in terms of adverse events. determine the relative importance of immediate relief from migraine versus increased rates of migraine relapse and adverse effects when considering treatment with sumatriptan versus dihydroergotamine. A cost-effectiveness analysis based on one of these studies concluded that the more cost-effective treatment depends on the relative importance of outcomes to patients and physicians. 28 Overall, these results suggest that dihydroergotamine may not be the most effective or appropriate single agent for acute migraine treatment in the ED. The evidence summarized here indicates that when dihydroergotamine is combined with an antiemetic (most commonly metoclopramide), it appears to be as effective as or more effective than meperidine, valproate, or ketorolac in relieving pain associated with migraine headache. Dihydroergotamine combined with an antiemetic also appears to be as effective as these treatments in preventing migraine relapses. Most adverse events reported were relatively benign; nevertheless, some of these adverse events were more common for those treated with dihydroergotamine. Methodologic heterogeneity in the studies precluded combining them statistically and prevents a firm conclusion with regard to the effectiveness of dihydroergotamine with an antiemetic. Results of the studies, however, demonstrate that dihydroergotamine combined with an antiemetic had an equivalent or better effect across all outcomes in all trials, suggesting that, at worst, dihydroergotamine with an antiemetic has a treatment effect similar to that of the comparison treatments used in these studies. Although dihydroergotamine with an antiemetic appears to be an effective treatment, the additional contribution of the dihydroergotamine to the antiemetic alone is unclear. Metoclopramide, which was the most common antiemetic used, is known to relieve migraine headache when administered alone. 29 It is therefore possible that the antiemetic is responsible for the beneficial effects of dihydroergotamine treatment with an antiemetic; however, the comparison treatments in many of these trials included the same antiemetic, reducing the chance of Volume 45, no. 4 : April 2005 Annals of Emergency Medicine 399

8 Treatment of Migraine With Dihydroergotamine Colman et al a confounding effect. An ideal methodology to study this would be to compare dihydroergotamine with an antiemetic versus the same antiemetic alone. One study in this review used such a comparison. 16 The only outcome available for analysis was pain relief at 30 minutes after treatment because of a treatment crossover at this point. This study did not show a significant difference between dihydroergotamine with prochlorperazine and prochlorperazine alone. However, in addition to this study, other studies used comparison treatments that included an antiemetic in addition to another agent (most commonly meperidine). These studies reported many outcomes that showed that dihydroergotamine with an antiemetic was superior to other agents with an antiemetic, indicating that the inclusion of dihydroergotamine had an additional beneficial effect. The different comparison agents present an alternative interpretation of the results of this review. It is possible that dihydroergotamine as a single agent was less effective because it was compared with sumatriptan and phenothiazines, whereas dihydroergotamine with an antiemetic was more effective because it was compared with agents such as opiates, valproate, and ketorolac. However, given that antiemetics are known to relieve nausea and pain of migraine headache, 29 we believe that the combination treatment of dihydroergotamine with an antiemetic should be superior to dihydroergotamine alone. The ideal study to judge such a comparison would be dihydroergotamine alone versus dihydroergotamine with an antiemetic; however, we are unaware of any studies that provide such evidence. The degree of methodologic variation was considerable in this review. Several agents were used as comparison treatments, and numerous outcomes were reported, which makes quantitative pooling difficult and precludes the use of many study outcomes that might shed light on the efficacy of different treatments. It would be highly desirable for future randomized controlled trials of treatments for acute migraine to follow standardized guidelines such as those prescribed in the International Headache Society s Guidelines for Controlled Trials of Drugs in Migraine. 30 In addition, the varying quality of studies in this review undermines the conclusions that can be drawn from it. It is recommended that future acute migraine trials include the highest possible quality of methods, including blinding of all study personnel until the study is complete, double dummy treatment whenever required, well-described and valid randomization methods, concealment of treatment allocation, and follow-up to determine relapse events. In addition, studies should follow the Consolidated Standards of Reporting Trials guidelines 31 when reporting the methods used to ensure that the reader can make an adequate assessment of study quality. In conclusion, there is little evidence to support dihydroergotamine as a first-line monotherapy for treatment of acute migraine headache. However, when administered in combination with an antiemetic, dihydroergotamine appears to be as effective as meperidine, valproate, or ketorolac across several outcomes. Given its nonnarcotic properties, parenteral dihydroergotamine should be considered as effective adjuvant therapy in clinical practice. We thank the Cochrane Library Pain, Palliative and Supportive Care Review Group for their guidance in the development of this review. We also thank the Division of Emergency Medicine at the University of Alberta, Edmonton, Alberta, Canada, and the Canadian Association of Emergency Physicians Research Consortium for supporting this study. We also thank Novartis Pharmaceuticals Corp. for responding to our requests about any unpublished data for this review. We also thank the corresponding study authors: Drs. M. J. Belgrade, R. Bell, M. Callaham, K. R. Edwards, J. A. Klapper, J. F. Wilson, and P. Winner. Author contributions: IC and BHR conceived the project. IC conducted searches, and IC and BHR coordinated reviewers. BHR secured study funding. IC and MDB conducted data collection and extraction. MDB, GDI, EG, TER, and BHR contributed to the study protocol. GDI, EG, and TER selected articles. IC and BHR coordinated manuscript preparation, and MDB, GDI, EG, and TER reviewed the manuscript. BHR takes responsibility for the paper as a whole. Funding and support: The authors report this study did not receive any outside funding or support. Publication dates: Received for publication March 11, Revisions received June 8, 2004, and July 14, Accepted for publication July 15, Available online January 11, Data from this study have been reported at the Canadian Association of Emergency Physicians annual meeting, Winnipeg, Manitoba, Canada, June Reprints not available from the authors. Address for correspondence: Brian H. Rowe, MD, MSc, Division of Emergency Medicine, University of Alberta, 1G1.43 Walter Mackenzie Health Sciences Center, Street, Edmonton, Alberta, Canada T6G 2B7; , fax ; Brian.Rowe@ualberta.ca. REFERENCES 1. Stewart WF, Shechter A, Rasmussen BK. Migraine prevalence: a review of population-based studies. Neurology. 1994;44 (6 Suppl 4):S17-S Hu XH, Markson LE, Lipton RB, et al. Burden of migraine in the United States: disability and economic costs. Arch Intern Med. 1999;159: Edmeads J, Findlay H, Tugwell P, et al. Impact of migraine and tension-type headache on life-style, consulting behaviour, and medication use: a Canadian population survey. Can J Neurol Sci. 1993;20: Ferrari MD. The economic burden of migraine to society. Pharmacoeconomics. 1998;13: Solomon GD, Price KL. Burden of migraine: a review of its socioeconomic impact. Pharmacoeconomics. 1997;11(Suppl 1): Rothlin E. Historical development of the ergot therapy of migraine. Int Arch Allergy. 1955;7: The Dihydroergotamine Nasal Spray Multicenter Investigators. Efficacy, safety, and tolerability of dihydroergotamine nasal spray 400 Annals of Emergency Medicine Volume 45, no. 4 : April 2005

9 Colman et al Treatment of Migraine With Dihydroergotamine as monotherapy in the treatment of acute migraine. Headache. 1995;35: Moskowitz MA. Basic mechanisms in vascular headache. Neurol Clin. 1990;8: Colman I, Innes G, Brown MD, et al. Parenteral dihydroergotamine (DHE) for acute migraine (protocol for a Cochrane Review). In: The Cochrane Library. Issue 1. Oxford, United Kingdom: Update Software; Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. BMJ. 1994;309: Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clin Trials. 1996;17: Bell R, Montoya D, Shuaib A, et al. A comparative trial of three agents in the treatment of acute migraine headache. Ann Emerg Med. 1990;19: Gonzalez-Espinosa LE, Gomez-Viera N, Olivera-Leal I, et al. [Treatment of acute attack of migraine with sumatriptan] [Spanish]. Revista de Neurologia. 1997;25: Winner P, Ricalde O, Le Force B, et al. A double-blind study of subcutaneous dihydroergotamine vs subcutaneous sumatriptan in the treatment of acute migraine. Arch Neurol. 1996;53: Belgrade MJ, Ling LJ, Schleevogt MB, et al. Comparison of single-dose meperidine, butorphanol, and dihydroergotamine in the treatment of vascular headache. Neurology. 1989;39: Callaham M, Raskin N. A controlled study of dihydroergotamine in the treatment of acute migraine headache. Headache. 1986;26: Carleton SC, Shesser RF, Pietrzak MP, et al. Double-blind, multicenter trial to compare the efficacy of intramuscular dihydroergotamine plus hydroxyzine versus intramuscular meperidine plus hydroxyzine for the emergency department treatment of acute migraine headache. Ann Emerg Med. 1998;32: Edwards KR, Norton J, Behnke M. Comparison of intravenous valproate versus intramuscular dihydroergotamine and metoclopramide for acute treatment of migraine headache. Headache. 2001;41: Klapper JA, Stanton JS. Ketorolac versus DHE and metoclopramide in the treatment of migraine headaches. Headache. 1991; 31: Klapper JA, Stanton JS. The emergency treatment of acute migraine headache: a comparison of intravenous dihydroergotamine, dexamethasone, and placebo. Cephalalgia. 1991;11: Klapper JA, Stanton JS. Current emergency treatment of severe migraine headaches. Headache. 1993;33: Scherl ER, Wilson JF. Comparison of dihydroergotamine with metoclopramide versus meperidine with promethazine in the treatment of acute migraine. Headache. 1995;35: Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55: Pryse-Phillips WEM, Dodick DW, Edmeads JG, et al. Guidelines for the diagnosis and management of migraine in clinical practice. CMAJ. 1997;156: Moore KL, Noble SL. Drug treatment of migraine, part I: acute therapy and drug-rebound headache. Am Fam Physician. 1997; 56: , Lipton RB, Stewart WF. Acute migraine therapy: do doctors understand what patients with migraine want from therapy? Headache. 1999;39(Suppl 2):S20-S Lenert LA. Use of willingness to pay to study values for pharmacotherapies for migraine headache. Med Care. 2003;41: Payne K, Kozma CM. Comparing dihydroergotamine mesylate and sumatriptan in the management of acute migraine: a retrospective cost-efficacy analysis. Pharmacoeconomics. 1996;10: Colman I, Brown MD, Innes GD, et al. Parenteral metoclopramide for acute migraine: meta-analysis of randomised, controlled trials. BMJ. 2004;329: Tfelt-Hansen P, Block G, Dahlof C, et al. International Headache Society Clinical Trials Subcommittee. Guidelines for controlled trials of drugs in migraine: second edition. Cephalalgia. 2000; 20: Begg CB, Cho M, Eastwood S, et al. Improving the quality of reporting of randomized controlled trials: the CONSORT statement. JAMA. 1996;276: Volume 45, no. 4 : April 2005 Annals of Emergency Medicine 401