2012 AAN 成人阵发性偏头痛预防药物治疗循证指南

DOI 10.1212/WNL.0b013e3182535d20 2012;78;1337Neurology S.D. Silberstein, S. Holland, F. Freitag, et al. and the American Headache Society Standards Subcommittee of the American Academy of Neurology episodic migraine prevention in adults : Report of the Quality Evidence-based guideline update: Pharmacologic treatment for May 7, 2012This information is current as of http://www.neurology.org/content/78/17/1337.full.html located on the World Wide Web at: The online version of this article, along with updated information and services, is rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X. Allsince 1951, it is now a weekly with 48 issues per year. Copyright © 2012 by AAN Enterprises, Inc. ® is the official journal of the American Academy of Neurology. Published continuouslyNeurology ? ? ? w w w . m edl i v e. cn Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society S.D. Silberstein, MD, FACP S. Holland, PhD F. Freitag, DO D.W. Dodick, MD C. Argoff, MD E. Ashman, MD ABSTRACT Objective: To provide updated evidence-based recommendations for the preventive treatment of migraine headache. The clinical question addressed was: What pharmacologic therapies are proven effective for migraine prevention? Methods: The authors analyzed published studies from June 1999 to May 2009 using a struc- tured review process to classify the evidence relative to the efficacy of various medications avail- able in the United States for migraine prevention. Results and Recommendations: The author panel reviewed 284 abstracts, which ultimately yielded 29 Class I or Class II articles that are reviewed herein. Divalproex sodium, sodium val- proate, topiramate, metoprolol, propranolol, and timolol are effective for migraine prevention and should be offered to patients with migraine to reduce migraine attack frequency and severity (Level A). Frovatriptan is effective for prevention of menstrual migraine (Level A). Lamotrigine is ineffective for migraine prevention (Level A). Neurology® 2012;78:1337–1345 GLOSSARY AAN � American Academy of Neurology; AE � adverse event; CI � confidence interval; ER � extended-release; MAM � menstrually associated migraine; PMP� perimenstrual period; RCT� randomized controlled trial. Epidemiologic studies suggest approximately 38% of migraineurs need preventive therapy, but only 3%–13% currently use it.1 In 2000, the American Academy of Neurology (AAN) published guide- lines for migraine prevention.2,3 Since then, new clinical studies have been published on the efficacy and safety of migraine preventive therapies. This guideline seeks to assess this new evidence to an- swer the following clinical question: For patients with migraine, which pharmacologic therapies are proven effective for prevention, as measured by reduced migraine attack frequency, reduced num- ber of migraine days, or reduced attack severity? This article addresses the safety and efficacy of pharmacologic therapies for migraine prevention. Separate guidelines are available for botulinum toxin.4 The 2008 guideline included a Level B re- commendation that botulinum toxin was probably ineffective for treatment of episodic migraine. A new guideline is in development. An updated guideline on nonsteroidal anti-inflammatory drugs5 and com- plementary alternative treatments has been approved for publication as a companion to this guideline.5 DESCRIPTION OF THE ANALYTIC PROCESS The AAN and the American Headache Society partic- ipated in the development process. An author panel of headache and methodologic experts was assembled to review the evidence. Computerized searches of the MEDLINE, PsycINFO, and CINAHL databases iden- tified new studies (published in English). The search strategy used the MeSH term “headache” (exploded) and a published search strategy for identifying ran- domized controlled trials (RCTs) published between June 1999 and May 2007. Additional MEDLINE searches revealed studies published through May Seepage1346 Supplemental data at www.neurology.org Supplemental Data Podcast CME From Thomas Jefferson University (S.D.S.), Jefferson Headache Center, Philadelphia, PA; the Armstrong Atlantic State University (S.H.), Savannah, GA; Comprehensive Headache Center (F.F.), Baylor University Headache Medicine Center, Dallas, TX; Mayo Clinic (D.D.), Scottsdale, AZ; New York University School of Medicine (C.A.), Albany; and Elmendorf Air Force Base (E.A.), AK. Appendices e-1–e-5, reference e1, and tables e-1 and e-2 are available on the Neurology�Web site at www.neurology.org. Approved by the Quality Standards Subcommittee on February 19, 2011; by the Practice Committee on June 19, 2011; by the AHS Board of Directors on March 29, 2012; and by the AAN Board of Directors on January 27, 2012. Study funding: This guideline was developed with financial support from the American Academy of Neurology and the American Headache Society. None of the authors received reimbursement, honoraria, or stipends for their participation in development of this guideline. Go to Neurology.org for full disclosures. Disclosures deemed relevant by the authors, if any, are provided at the end of this article. Correspondence & reprint requests to American Academy of Neurology: guidelines@aan.com SPECIAL ARTICLE Copyright © 2012 by AAN Enterprises, Inc. 1337 ? ? ? w w w . m edl i v e. cn 2009, which were reviewed and included as supple- mental articles. Studies of pharmacologic agents available in the United States were included in the analysis if they randomized adult patients with migraine to the agent under study or a comparator drug (including placebo) and utilized masked outcome assessment. At least 2 panelists independently reviewed each study and rated it according to the AAN therapeutic classification of ev- idence scheme (appendix e-3 on the Neurology® Web site at www.neurology.org). Differences in ratings were resolved by author panel discussion. ANALYSIS OF EVIDENCE The original search identified 179 articles. A supplemental search (2007–2009) yielded 105 additional articles. Of the total 284 articles, 29 were classified as Class I or Class II and are reviewed herein. Studies were excluded if they: • Assessed the efficacy of therapeutic agents for headache other than episodic migraine in adults • Assessed acute migraine treatment, migraine aura treatment/prevention, or nonpharmaco- logic treatments (e.g., behavioral approaches) • Used quality of life measures, disability assess- ment, or nonstandardized outcomes as primary efficacy endpoints • Tested the efficacy of drugs not available in the United States Since the 2000 guideline publication, the AAN revised its evidence classification criteria to in- clude study completion rates. Studies with com- pletion rates below 80% were downgraded; several studies in the original guideline have thus been downgraded. We found no new Class I or II studies published for acebutolol, atenolol, bisoprolol, carbamazepine, Table 1 Classification of migraine preventive therapies (available in the United States) Level A: Medications with established efficacy (>2 Class I trials) Level B: Medications are probably effective (1 Class I or 2 Class II studies) Level C: Medications are possibly effective (1 Class II study) Level U: Inadequate or conflicting data to support or refute medication use Other: Medications that are established as possibly or probably ineffective Antiepileptic drugs Antidepressants/ SSRI/SSNRI/TCA ACE inhibitors Lisinopril Carbonic anhydrase inhibitor Established as not effective Divalproex sodium Amitriptyline Angiotensin receptor blockers Acetazolamide Antiepileptic drugs Sodium valproate Venlafaxine Candesartan Antithrombotics Lamotrigine Topiramate �-Blockers �-Agonists Acenocoumarol Probably not effective �-Blockers Atenolola Clonidinea Coumadin Clomipraminea Metoprolol Nadolola Guanfacinea Picotamide Possibly not effective Propranolol Triptans (MRMb) Antiepileptic drugs Antidepressants SSRI/SSNRI Acebutolola Timolola Naratriptanb Carbamazepinea Fluvoxaminea Clonazepama Triptans (MRMb) Zolmitriptanb �-Blockers Fluoxetine Nabumetonea Frovatriptanb Nebivolol Antiepileptic drugs Oxcarbazepine Pindolola Gabapentin Telmisartan Antihistamines TCAs Cyproheptadine Protriptylinea �-Blockers Bisoprolola Ca�� blockers Nicardipinea Nifedipinea Nimodipine Verapamil Direct vascular smooth muscle relaxants Cyclandelate Abbreviations: ACE� angiotensin-converting-enzyme; MRM�menstrually relatedmigraine; SSNRI� selective serotonin– norepinephrine reuptake inhibitor; SSRI� selective serotonin reuptake inhibitor; TCA� tricyclic antidepressant. a Classification based on original guideline and new evidence not found for this report. b For short-term prophylaxis of MRM. 1338 Neurology 78 April 24, 2012 ? ? ? w w w . m edl i v e. cn clonazepam, clonidine, clomipramine, fluvoxamine, guanfacine, nabumetone, nadolol, nicardipine, ni- fedipine, or protriptyline. Recommendations for these agents are based on the evidence reviewed in the original guideline (see table 1). Currently, no Class I or Class II studies exist for anticoagulants (limited Class III and IV studies were identified; ta- ble 1 includes anticoagulants). Angiotensin receptor blockers and angiotensin- converting-enzyme inhibitors. In the 2000 guide- line, there were no studies testing the efficacy of angiotensin receptor blockers or angiotensin- converting-enzyme (ACE) inhibitors for migraine prevention. Since that publication, 3 reports have been published. Candesartan. In a Class II crossover study (12-week treatment separated by 4-week washout), the mean number of headache days was 18.5 with placebo (26.3% reduction from baseline) vs 13.6 with cande- sartan (45.6% reduction from baseline; p � 0.001).6 Selected secondary endpoints also favored candesar- tan: headache hours (139 vs 95; p � 0.001), mi- graine days (12.6 vs 9.0; p � 0.001), migraine hours (92.2 vs 59.4; p � 0.001), and headache severity in- dex (293 vs 191; p � 0.001). No serious adverse events (AEs) occurred. The most common AEs were dizziness (31%), “symptoms of the musculoskeletal system” (21%), and fatigue (14%); none occurred significantly more often than with placebo. Lisinopril. One Class II study reported significant reduction in all 3 primary endpoints with lisinopril vs placebo (headache hours: 129 vs 162 [mean change in hours 20, confidence interval (CI) 5–36]; headache days: 19.7 vs 23.7 [20, CI 5–30]; migraine days: 14.5 vs 18.5 [21, CI 9–34]).7 AEs included cough (26%; 10% discontinued treatment due to cough), dizziness (23%), and “tendency to faint” (10%). No serious AEs were reported. Telmisartan. In a single Class II placebo- controlled trial, telmisartan 80 mg did not show a significant difference from placebo for reduction in migraine days (�1.65 vs �1.14).8 Conclusions. Lisinopril and candesartan are possibly effective for migraine prevention (1 Class II study each). Telmisartan is possibly ineffective for reducing the number of migraine days (1 negative Class II study). Antiepileptic drugs. Divalproex. The original guideline found strong, consistent support (5 studies) for the effi- cacy of divalproex sodium and its corresponding com- pound, sodium valproate, for migraine prevention. Since the 2000 publication, 1 double-blind, ran- domized, Class I placebo-controlled 12-week trial showed extended-release (ER) divalproex sodium 500–1,000 mg/day had a mean reduction in 4-week migraine headache rate from 4.4/week (baseline) to 3.2/week (�1.2 attacks/week) in the ER divalproex so- dium group and from 4.2/week to 3.6/week (�0.6 attacks/week) in the placebo group (CI 0.2–1.2; p � 0.006).9 No significant differences were de- tected between groups in the number of treatment-emergent AEs. Clinical context. In most headache trials, patients taking divalproex sodium or sodium valproate re- ported no more AEs than those on placebo. How- ever, weight gain has been clinically observed with divalproex sodium long-term use.9,10 Treatment with these agents requires careful follow-up and testing because of pancreatitis, liver failure, and teratogenic- ity risks.11 Gabapentin. Since the 2000 publication, a Class III study12 reported that a stable gabapentin dose (4- week titration phase to 2,400 mg/day; 8-week main- tenance phase) significantly reduced the median monthly migraine rate vs placebo on the basis of a modified intention-to-treat analysis. Lamotrigine. The original guideline reported a sin- gle Class I lamotrigine study13 that failed to show a significant effect for migraine prevention. A second, new Class I study comparing lamotrigine 50 mg/day with placebo or topiramate 50 mg/day reported lam- otrigine was not more effective than placebo (for both primary endpoints) and was less effective than topiramate in reducing migraine frequency and in- tensity.14 The primary outcome measure (responder rate: �50% monthly migraine frequency reduction) was 46% for lamotrigine vs 34% for placebo (p � 0.093, CI 0.02–0.26) and 63% for topiramate vs 46% for lamotrigine (p � 0.019, CI 0.03–0.31). Treatment-related AEs (rash, giddiness, sleepiness, and gastrointestinal intolerance) occurred in 10% of patients on lamotrigine. Oxcarbazepine.One Class II trial evaluated the effi- cacy of oxcarbazepine (1,200 mg/day) vs placebo.15 There was no difference between oxcarbazepine (�1.30 [SE 0.282]) and placebo for mean change in number of migraine attacks from baseline during the last 28 days of the double-blind 15-week treatment phase (�1.74 [SE 0.283]; p � 0.2274). Topiramate. Four Class I studies14,16–18 and 7 Class II studies19–25 report topiramate (50–200 mg/day) is effective in migraine prevention. In a Class I placebo-controlled study (mean topi- ramate dose 125 mg/day [range 25–200 mg/day]), patients given topiramate experienced a significantly lower 28-day migraine frequency vs with placebo (3.31� 1.7 vs 3.83� 2.1; p� 0.002).18 In a second placebo-controlled Class I double-crossover study (reviewed above), topiramate was more effective than Neurology 78 April 24, 2012 1339 ? ? ? w w w . m edl i v e. cn placebo and lamotrigine for primary efficacy mea- sures.14 In the topiramate groups, 15% of patients experienced AEs, most commonly paresthesias, sleepiness, and gastrointestinal intolerance. The pla- cebo group reported gastrointestinal intolerance (3%) and anorexia (3%). Two additional Class I studies report topiramate is as effective as propranolol16 or sodium valproate,17 drugs previously established as effective for migraine prevention. In the first study, subjects given topiramate 50 mg/day had reduced mean migraine frequency (epi- sodes/month) from baseline (6.07 � 1.89 to 1.83 � 1.39; p� 0.001) at 8 weeks, decreased headache inten- sity VAS score from 7.1 � 1.45 to 3.67 � 2.1 (p � 0.001), and decreased headache duration from 16.37� 7.26 hours to 6.23 � 5.22 hours (p � 0.001).16 Sub- jects given topiramate reported paresthesias (23%), weight loss (16%), and somnolence (13%). In pa- tients treated with propranolol 80 mg/day, mean headache frequency (episodes/month) decreased from 5.83 � 1.98 to 2.2 � 1.67 (p � 0.001) at 8 weeks, headache intensity VAS score decreased from 6.43 � 1.6 to 4.13 � 1.94 (p � 0.001), and head- ache duration decreased from 15.10� 6.84 hours to 7.27 � 6.46 hours (p � 0.001). Although monthly headache frequency, intensity, and duration de- creased in both groups, the topiramate group re- ported significantly greater mean reduction (topiramate frequency decrease 4.23 � 1.2 vs pro- pranolol 3.63 � 0.96 [p � 0.036; CI 0.39–1.16]; topiramate intensity decrease 3.43 � 1.38 vs pro- pranolol 2.3 � 1.2 [p � 0.001; CI 0.46–1.8]; topi- ramate duration decrease 10.1 � 4.3 vs propranolol 7.83 � 4.5 [p � 0.048; CI 0.17–4.6]). In a crossover Class I trial (2-month washout be- tween therapies) comparing topiramate 50 mg/day with sodium valproate 400 mg/day, both groups showed improvement from baseline in headache fre- quency, intensity, and duration.17 Average monthly migraine frequency decreased by 1.8 times with so- dium valproate (baseline 5.4 � 2.5; posttreatment 3.6 � 2.1; CI 1.0–2.6; p � 0.001), as compared with a 3-time reduction with topiramate (baseline 5.4� 2.0; posttreatment 2.4� 2.4; CI 2.1–3.9; p� 0.001). Headache intensity decreased by 3.7 with so- dium valproate (baseline 7.7� 1.2; treatment 4.0� 2.1; CI 2.9–4.6; p � 0.001), as compared with a reduction of 3.6 with topiramate (baseline 6.9� 1.2, treatment phase 3.3� 1.5; CI 2.9–4.3; p� 0.001). The average headache episode duration decreased by 13.4 hours from baseline with sodium valproate (baseline 21.3� 14.6; treatment 7.9� 7.7; CI 7.5– 19.3; p � 0.001) as compared with an 11.9-hour reduction with topiramate (baseline 17.3 � 8.4; treatment 5.4 � 6.4; CI 8.2–15.6; p � 0.001). The overall analysis of repeated-measures analysis of vari- ance demonstrated no differences in monthly head- ache frequency, intensity, or duration after the first or second treatment rounds. Topiramate AEs were weight loss (18.8%), paresthesias (9.4%), or both (25%). Sodium valproate AEs were weight gain (34.5%), hair loss (3.1%), and somnolence (3.1%). Results of 5 Class II studies support those of the Class I studies showing topiramate as effective for migraine prevention.19–25 Four studies demonstrated significant improvement over placebo19,20,23,24; one included an active comparator arm, suggesting equivalence of topiramate (100, 200 mg/day) and propranolol (160 mg/day).20 Two studies comparing topiramate and amitriptyline (25–150 mg/day) re- ported no difference in efficacy for primary end- points; however, amitriptyline was associated with a significant AE increase, and the amitriptyline- topiramate combination suggested improvement in depression scores vs monotherapy.21,22 In one of these studies,21 the most common AEs were similar to those previously reported. One Class II placebo-controlled 24-week pilot study failed to show a difference in effi- cacy between topiramate 200 mg and placebo.26 Conclusions. Divalproex sodium and sodium val- proate are established as effective in migraine preven- tion (multiple Class I studies). Data are insufficient to determine the effectiveness of gabapentin (1 Class III study). Lamotrigine is established as ineffective for migraine prevention (2 Class I studies). Oxcarba- zepine is possibly ineffective for migraine prevention (1 Class II study). Topiramate is established as effec- tive for migraine prevention (4 Class I studies, multi- ple Class II studies; 1 negative Class II study). Topiramate is probably as effective for migraine pre- vention as propranolol (1 Class I study), sodium val- proate (1 Class I study), and amitriptyline (2 Class II studies). Antidepressants. Fluoxetine. In the original guideline, 1 Class II study27 showed fluoxetine (racemic) was significantly better than placebo for migraine preven- tion, but the results were not duplicated in a second study.28 Since the original guideline, a Class II study has shown fluoxetine 20 mg/day was more effective than placebo in reducing total pain index scores (calcu- lated as [Dl � 1]� [D2 � 2]� [D3 � 3], where D1, D2, and D3 represent headache hours calculated in a month, with pain intensity shown by 1, 2, 3) at 6 months.29 After the 6 months, pain index scores for the fluoxetine group decreased from 135 (baseline) to 41.3 (SD� 63.8; p� 0.001). The placebo group pain index was 98 at baseline and 61.1 at 6 months (SD � 57.7; p � 0.07); however, differences were noted between treatment groups for baseline measures. 1340 Neurology 78 April 24, 2012 ? ? ? w w w . m edl i v e. cn Venlafax