Acute Migraine Treatment in Emergency Settings Prepared for

Acute Migraine Treatment in Emergency Settings Prepared for: Agency for Healthcare Research and Quality (AHRQ) www. ahrq. gov

Outline of Material Agency for Healthcare Research and Quality Comparative Effectiveness Review (CER) Process Background Clinical Questions Addressed in the CER Summary of CER Results Conclusions Gaps in Knowledge Resources for Shared Decisionmaking Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, the public, and others. A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment. The results of these reviews are summarized into a Clinician Research Summary and a Consumer Research Summary for use in decisionmaking and in discussions with patients. The Research Summaries and the full report are available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm. Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Strength-of-Evidence Ratings The strength-of-evidence ratings are classified into four broad ratings: High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect. Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate. Low confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of effect and is likely to change the estimate. Insufficient Evidence either is unavailable or does not permit a conclusion. AHRQ Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Available at www. effectivehealthcare. ahrq. gov/methodsguide. cfm. Owens DK, Lohr KN, Atkins D, et al. J Clin Epidemiol. 2010 May; 63(5): 513 -23. PMID: 19595577. Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Background: Migraine Headaches Migraine is a primary headache disorder, which may be associated with abnormalities of the central and peripheral nervous systems and the intracranial vasculature. In 2010, migraine was the third most prevalent disorder and seventh highest specific cause of disability worldwide. Migraine affects 12 percent of the population in the United States. Headache Classification Committee of the International Headache Society. Cephalalgia. 2013; 33(9): 629 -808. PMID: 23771276. Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Background: Classification of Migraine Headaches Migraines are classified using criteria established by the International Headache Society within the International Classification of Headache Disorders (ICHD). Migraine with aura: a migraine headache preceded or accompanied by an “aura” (e. g. , a set of self-limited sensory [visual, tactile, and/or olfactory] symptoms) Migraine without aura: the most common type of migraine and often more disabling than migraines with aura Chronic migraine: a migraine headache that occurs on > 15 days per month for at least 3 months Headache Classification Committee of the International Headache Society. Cephalalgia. 2013; 33(9): 629 -808.

Background: Migraine With Aura n Diagnostic Criteria A. B. C. At least two attacks fulfilling criteria B and C One or more of the following fully reversible aura symptoms: 1. Visual 2. Sensory 3. Speech and/or language 4. Motor 5. Brainstem 6. Retinal At least two of the following four characteristics: 1. At least one aura symptom spreads gradually over 5 minutes, and/or two 2. 3. 4. D. or more symptoms occur in succession Each individual aura symptom lasts 5– 60 minutes At least one aura symptom is unilateral The aura is accompanied, or followed within 60 minutes, by headache Have a headache not better accounted for by another ICHD-3 diagnosis and a transient ischemic attack has been excluded Headache Classification Committee of the International Headache Society. Cephalalgia. 2013; 33(9): 629 -808. PMID: 23771276.

Background: Migraine Without Aura n Diagnostic Criteria A. At least five attacks fulfilling criteria B, C, and D B. Attacks lasting 4– 72 hours (untreated or unsuccessfully treated) C. At least two of these characteristics: 1. Unilateral location 2. Pulsating quality 3. Moderate or severe intensity 4. Aggravation by or causing avoidance of routine physical activity D. At least one of the following during headache: 1. Nausea and/or vomiting 2. Photophobia and phonophobia E. Not better accounted for by another ICHD-3 diagnosis Headache Classification Committee of the International Headache Society. Cephalalgia. 2013; 33(9): 629 -808. PMID: 23771276.

Background: Chronic Migraine Diagnostic Criteria A. Headache occurring on 15 or more days per month for more than 3 months, which has the features of migraine headache on at least 8 days per month B. A tension-like and/or migraine-like headache on 15 days per month for >3 months and fulfill criteria 1 and 2 1. Occurring in a patient who has had at least five attacks fulfilling criteria B, C, and D for migraine without aura and/or criteria B and C for migraine with aura 2. On 8 days per month for >3 months, fulfilling any of the following: a. Criteria C and D for migraine without aura b. Criteria B and C for migraine with aura c. Believed by the patient to be migraine at onset and is relieved by a triptan or an ergot derivative C. Not better accounted for by another ICHD-3 diagnosis Headache Classification Committee of the International Headache Society. Cephalalgia. 2013; 33(9): 629 -808. PMID: 23771276.

Background: Incidence of Migraine Headaches Leading to Emergency Department Visits in the United States A severe headache associated with disabling pain may result in a visit to an emergency department (ED). Headaches account for 2. 1 million ED visits, or 2. 2 percent of all ED visits, annually in the United States. About 7 percent of Americans with migraine have used an ED or urgent care center for treatment of severe headache within the previous 12 months. Of patients who use an ED for treatment of migraine, 19 percent make multiple visits over the course of 1 year. Hu XH, Markson LD, Lipton RB, et al. Arch Intern Med. 1999; 159(8): 813 -8. PMID: 10219926. Lambert J, Carides GW, Meloche JP, et al. Can J Clin Pharmacol. 2002; 9(3): 158 -64. PMID: 12422253.

Background: Economic Burden of Migraine Headaches Migraine has a negative impact on overall quality of life and is associated with: Decreased productivity Missed time from work, school, and other activities Medical comorbidities In the United States, migraine and related medical issues result in costs of more than $13 billion per year due to lost productivity. In Canada, this annual cost has been estimated at $3, 025 per patient due to medical and indirect costs. Bamford CC, Tepper SJ. Tech Reg Anesth Pain Manag. 2009; 13(1): 20 -7. DOI: 10. 1016/j. bbr. 2011. 031. Bigal ME, Ferrari M, Silberstein SD, et al. Headache. 2009; 49 Suppl 1: S 21 -S 33. PMID: 19161562. Cutrer FM. Semin Neurol. 2010; 30(2): 120 -30. PMID: 20352582. Diamond S, Bigal ME, Silberstein S, et al. Headache. 2007; 47(3): 355 -63. PMID: 17371352. Headache Classification Committee of the International Headache Society. Cephalalgia. 2004; 24(Suppl 1): 629 -808. PMID: 23771276.

Background: Treatment of Migraine in the Emergency Setting Substantial practice variability exists among emergency departments (EDs) and emergency clinicians. Approximately 20 different parenteral agents are used to treat acute migraine in EDs. Some physicians use agents in sequence; others use combination treatments. Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Background: Summary of Pharmacological Interventions Used To Treat Acute Migraine Drug Class Pharmacological Interventions in Each Drug Class Antiemetics/ neuroleptics chlorpromazine*, droperidol*, haloperidol*, metoclopramide*, prochlorperazine*, and trimethobenzamide* Corticosteroids betamethasone, budesonide, cortisone, dexamethasone*, hydrocortisone, methylprednisolone, and prednisone* Ergots Dihydroergotamine (DHE)* Nonsteroidal antiinflammatory drugs diclofenac*, ibuprofen, ketorolac*, and lysine clonixinate* Opioids butorphanol*, buprenorphine, fentanyl, hydromorphone, meperidine (pethidine)*, morphine*, nalbuphine*, and tramadol* Triptans sumatriptan* Other agents dimenhydrinate *, hydroxyzine*, lidocaine*, olanzapine*, ondansetron*, and promethazine* *These interventions were studied in the trials included in the systematic review. Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Objectives of the Systematic Review To assess the effectiveness and adverse effects of parenteral medications for adult patients with moderate to severe acute migraine who present to an emergency department (ED) for treatment To examine the benefits and adverse effects of using corticosteroids to prevent recurrence of acute migraine that results in a return visit to a physician or an ED Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Key Questions Regarding Treatment of Acute Migraine Headaches in the Emergency Setting The comparative effectiveness of parenteral pharmacological interventions versus standard care, placebo, or an active treatment The comparative effectiveness of adding parenteral or oral corticosteroids versus adding placebo to prevent recurrence of acute migraine The associated and comparative short-term adverse effects of these interventions The effectiveness and safety of these interventions in different subgroups Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Outcomes of Interest Benefits Pain relief (complete or partial)/change in pain score Elimination of pain before emergency department (ED) discharge Time in the ED (in minutes of total time and post-ED physician time) Adverse Effects (up to 3 months after intervention) Sedation/somnolence Dizziness Restless legs/akathisia Anxiety Vomiting Recurrence of headache (headache relieved in the ED and recurring within the followup period) Chest symptoms (e. g. , palpitations) Health services utilization Local reactions Patient satisfaction with experience Other side effects Skin flushing Quality of life/return to activities Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Overview of Studies Included in the Systematic Review Unique eligible studies = 71 Several drugs or classes of drugs were included: head trials. Where head-to-head trials were lacking, indirect comparisons across trials were made using Antiemetics/neuroleptics statistical analysis to draw Dihydroergotamine (DHE) conclusions. Nonsteroidal anti-inflammatory A meta-analysis of adverse drugs effects was not conducted; only Opioids summaries were provided. Corticosteroids Triptans “Orphan agents” (refers to drugs not easily classified or infrequently studied) Evidence is included from placebo-controlled and head-to. Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Overview of Studies: Assessing Pain Across Trials That Use Different Pain Scales The majority of studies used the visual analog scale (VAS) to assess pain. When pain scores were reported in any format other than VAS (in mm), they were converted to a VAS scale (in mm) using a conversion factor. All pain scales were subjective and anchored by “severe” and “zero” extremes. Conversion to a 100 -point scale was used for comparative purposes across trials. Changes in pain intensity are reported as the mean difference when compared with placebo or another intervention on a 100 -point VAS (in mm). Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Clinical Bottom Line: Efficacy of Interventions for Achieving “Pain-Free” Status Versus Placebo Neuroleptics, nonsteroidal anti-inflammatory drugs, and sumatriptan improve the likelihood of achieving pain-free status at various time points after administration versus placebo. Medication Time Points Taken in ED Relative Risk (95% CI) Strength of Evidence Sumatriptan 30 to 120 min 4. 73 (3. 77 to 5. 94) Moderate Neuroleptics* 60 min 3. 38 (1. 16 to 9. 83) Moderate NSAIDs 60 to 120 min 2. 74 (1. 26 to 5. 98) Moderate *Neuroleptics here include chlorpromazine, droperidol, and prochlorperazine. 95% CI = 95 -percent confidence interval; NSAIDs = nonsteroidal anti-inflammatory drugs; ED = emergency department Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Clinical Bottom Line: Comparative Effectiveness of Interventions for Achieving a “Pain-Free” Status More patients report full relief from headaches with droperidol when compared with prochlorperazine (relative risk = 0. 81; 95 -percent confidence interval 0. 68 to 0. 98). Strength of Evidence = Moderate The evidence is insufficient to permit conclusions about the comparative effectiveness of other interventions. Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Clinical Bottom Line: Efficacy of Interventions for Providing Headache Relief (Complete or Partial) Versus Placebo Neuroleptics and sumatriptan provide significant headache relief at various time points versus placebo. Medication Time Points Taken in ED Relative Risk (95% CI) Strength of Evidence Neuroleptics* 60 min 2. 69 (1. 66 to 4. 34) Moderate Sumatriptan 60 min 3. 03 (2. 59 to 3. 54) Moderate Sumatriptan 120 min 2. 61 (2. 09 to 3. 26) Moderate *Neuroleptics here include haloperidol, chlorpromazine, prochlorperazine, and droperidol. 95% CI = 95 -percent confidence interval; ED = emergency department Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Clinical Bottom Line: Efficacy of Interventions for Reducing Pain Intensity (VAS in mm) Neuroleptics, metoclopramide, opioids, and sumatriptan significantly improve pain intensity (as measured on a visual analog scale [VAS] in mm) at various time points versus placebo. Mean Difference in Visual Analog Scale in Millimeters (95% CI) Medication Time Points in ED Strength of Evidence Neuroleptics* 30 min to 4 hrs -46. 59 (-54. 87 to -38. 32) Moderate Metoclopramide 30 to 60 min -21. 88 (-27. 38 to -16. 38) Moderate Opioids** 45 to 60 min -16. 73 (-24. 12 to -9. 33) Moderate Sumatriptan 30 min -15. 45 (-19. 49 to -11. 41) Moderate *Neuroleptics here include prochlorperazine, chlorpromazine, and haloperidol. **Opioids here include pethidine, nalbuphine, tramadol, and hydroxyzine + nalbuphine. 95% CI = 95 -percent confidence interval; ED = emergency department Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Clinical Bottom Line: Comparative Effectiveness of Interventions for Reducing Pain Intensity (VAS in mm*) Neuroleptics (chlorpromazine and prochlorperazine) as a group reduce pain intensity more than metoclopramide (mean difference = 16. 45 mm; 95 -percent confidence interval 2. 08 to 30. 83). Strength of Evidence = Low There are no differences in the reduction of pain intensity when metoclopramide and prochlorperazine are compared alone. Strength of Evidence = Low There are no significant differences in the reduction in pain between prochlorperazine and droperidol. Strength of Evidence = Low *Pain was measured on a visual analog scale (VAS) in millimeters. Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Clinical Bottom Line: Preventing Recurrence occurs when a patient’s headache is successfully relieved in the emergency department and then comes back within the followup period. Dexamethasone plus standard abortive therapy is less likely to result in recurrence of pain or headache up to 72 hours after discharge when compared with placebo plus standard abortive therapy (relative risk [RR] = 0. 68, 95 -percent confidence interval [95% CI] 0. 49 to 0. 96). Strength of Evidence = Moderate Sumatriptan may have a lower rate of headache recurrence within 24 hours versus placebo (RR = 0. 72, 95% CI 0. 57 to 0. 90). Strength of Evidence = Low Evidence on recurrence rates for other interventions is insufficient to permit conclusions. Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Clinical Bottom Line: Indirect Comparisons Across Trials for Reducing Pain Intensity (1 of 2) Improvement in pain intensity is greatest with combination therapy (dihydroergotamine added to either prochlorperazine or metoclopramide) and neuroleptic monotherapy, with a reduction of about 40 mm on a visual analog scale (VAS; 95 -percent confidence intervals [95% CIs] ranging from 60. 9 to 22. 1). Strength of Evidence = Low Metoclopramide, opioids, and nonsteroidal antiinflammatory drugs are the next most effective treatments, with a pain reduction of about 24 mm on the VAS (95% CIs ranging from 38. 8 to 12. 0). Strength of Evidence = Low Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Clinical Bottom Line: Indirect Comparisons Across Trials for Reducing Pain Intensity (2 of 2) Dihydroergotamine monotherapy, sumatriptan, and orphan agents are less effective, with a pain reduction of approximately 12 to 16 mm on the visual analog scale (95 -percent confidence intervals ranging from 32. 6 to 0. 5). Strength of Evidence = Low No statistically significant difference in effect on pain intensity is noted for other antinauseants. Strength of Evidence = Low Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Clinical Bottom Line: Adverse Effects—Akathisia is a state of restlessness or agitation. It can be described as a feeling of muscle quivering. It can occur at any time and more often when a sufferer is sitting. Akathisia is usually self-limited but creates patient discomfort and distress. The risk of akathisia after taking a neuroleptic agent or metoclopramide was about 10 times greater than with placebo. No strength-of-evidence rating is associated with any of these results. Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Clinical Bottom Line: Adverse Effects—General (1 of 2) Evidence is insufficient to determine which treatment(s) result in more or less adverse effects. Rates of adverse effects are reported without strength-of -evidence ratings. The risk of sedation was common after receiving metoclopramide or prochlorperazine (17% for both). The most common adverse effects from dihydroergotamine included pain or swelling at the injection site, IV site irritation, sedation, digestive issues, nausea or vomiting, and chest symptoms (palpitations, arrhythmia, or irregular heartbeat). Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Clinical Bottom Line: Adverse Effects—General (2 of 2) The most common adverse effects of injectable triptans are local reactions including pain or swelling at the injection site. According to the U. S. Food and Drug Administration, there is a risk of coronary vasospasm if sumatriptan is given to patients with known or unknown coronary or vascular risk factors. Few short-term effects were reported for nonsteroidal anti-inflammatory drugs. The risk with opioids is associated with continuing or frequent use, which can lead to dependency. Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Overview of Conclusions Several common parenteral treatments for migraine pain (e. g. , sumatriptan, metoclopramide, neuroleptics, and nonsteroidal anti-inflammatory drugs) in emergency departments are effective at reducing pain intensity and/or achieving pain-free status. Direct head-to-head comparisons are very limited; however, moderate-strength evidence suggests that droperidol may provide full headache relief better than prochlorperazine. Low-strength evidence from indirect comparisons made across trials using statistical techniques to assess pain reduction suggests that dihydroergotamine, in combination with either prochlorperazine or metoclopramide, and neuroleptic monotherapy are the most effective (approximately a 40 -mm reduction on a 100 -point visual analog scale). Patients who receive dexamethasone plus abortive therapy are less likely to have a recurrence of a migraine. Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Overview of Adverse Effects Most adverse effects are minor and self-limiting. Data on pain relief must be weighed carefully with the data on side effects, especially akathisia, which is associated more with the neuroleptics and metoclopramide. Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Gaps in Knowledge The systematic review identified several areas where future research will help to address the gaps in clinical knowledge. Additional studies are needed in these areas: Head-to-head comparisons to determine which treatments are most effective in quickly reducing migraine pain, achieving pain-free status, and reducing the likelihood of relapse The effects of sex, race, and duration of headache on the response to treatment The differences in effectiveness among different parenteral delivery routes (intravenous, intramuscular, and subcutaneous) Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Shared Decisionmaking: What To Discuss With Your Patients Effectiveness of chosen treatments Evidence of adverse effects Reasons for using combination therapy Use of dexamethasone to prevent relapse The availability of treatments for chronic migraine to prevent recurrent emergency treatment Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.

Resource for Patients Treating Severe Migraine Headaches in the Emergency Room, A Review of the Research for Adults is a free resource that can help patients talk with their health care professionals about treatment options. It provides information about: Migraine headaches Benefits and possible side effects of migraine headache treatments Questions to discuss with their doctor Sumamo Schellenberg E, Dryden DM, Pasichnyk D, et al. AHRQ Comparative Effectiveness Review No. 84. Available at www. effectivehealthcare. ahrq. gov/migraine-emergency. cfm.