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FEATURE STORY Out With the Old, In With (Mostly) the Old

Recent changes to the acute migraine guidelines were more subtle than sweeping. BY ZAC HAUGHN, SENIOR ASSOCIATE EDITOR

f guidelines serve as a clinician’s GPS to treatment, the treatments, along with the combination of sumatriptan and American Headache Society’s effort to find best practices .1 These medications join naratriptan, rizatriptan, in acute migraine therapy involve a good deal of looking sumatriptan, and zolmitriptan, which the 2000 guidelines in the rearview mirror found effective. I “I think it reinforced the old guidelines, but just as The dihydroergotamine inhaler joined the dihydroer- importantly it showed that there’s good evidence that gotamine nasal spray from the previous guidelines on the these drugs work,” said Stephen Silberstein, MD, FACP of strength of two Class I studies. Jefferson University Hospitals, and one of the authors of the A Class I study of patients with non-incapacitating update to the 2000 guidelines by the American Academy of migraine raised oral acetaminophen to Level A from Level B. Neurology. “Some of the newer drugs in combination work. The study revealed acetaminophen produced higher two- We have evidence, for example, for the new DHE inhaled hour headache-free rates than placebo. product, for the sumatriptan patch, and for new formula- Based on four Class I studies, researchers also lifted diclof- tions of non-steroidals,” he said. enac to Level A from Level B. The primary outcome of one But, he added, “I think it’s important to realize there’s noth- was two-hour headache intensity using a visual analog scale ing really new. There was no new major class of medication.” where 100 was maximal headache. Both 50mg While there are indeed new formulations of older drugs, and 100mg were superior to placebo (22 average with Dr. Silberstein said the disappointing news is that they found 100mg, 26 with 50mg, and 46 with placebo; P < .001). less research on new drugs in the last 10 years than the pre- No high quality studies have been conducted on the vious 10-year period. “The 10 years before was the age of all combination therapy acetaminophen//caffeine, and it the new triptans. Things are now being developed, but at retains its Level A rank. the time we did the literature search there was absolutely nothing really new.” LEVEL B (PROBABLY EFFECTIVE) Specifically, researchers found no new Class I or II studies There was no movement from the previous guidelines for published since the most recent guidelines for ergotamine/caffeine and intravenous, intramuscular, or sub- (intramuscular or nasal spray), combinations of butalbital/ cutaneous dihydroergotamine. aspirin/caffeine or butalbital/aspirin/caffeine/, acet- Droperidol was added to the level after a Class I 2003 study aminophen/codeine, dihydroergotamine (DHE) (nasal spray, showed the drug provided superior rates of two-hour head- intramuscular, or intravenous), , , ache relief compared with placebo. Subjects were randomized isometheptene, intranasal , and meperidine. When no to receive injections of 0.1mg, 2.75mg, 5.5mg, and 8.25mg or new review of previous studies was done, researchers assigned placebo for treatment of moderate to severe migraine. Two- levels of evidence for these agents based on the 2000 AAN hour headache relief rates were superior for subjects receiving guidelines. Medical devices were excluded from their search. 2.75 mg (87 percent), 5.5 mg (81 percent), and 8.25 mg (85 per- cent) compared with placebo (57 percent). Headache relief LEVEL A (EFFECTIVE) from droperidol was superior to placebo as early as one hour Triptans again show strong evidence for effective treat- for the 2.75mg dose, 90 minutes for the 5.5mg dose, and 30 ment of acute migraine. The three triptans approved since minutes for the 8.25mg dose. the release of the previous guidelines—almotriptan, eletrip- The other anti-emetics used to treat migraine—chlor- tan, frovatriptan—have been added to the list of effective promazine, metoclopramide, and prochlorperazine—also

MARCH 2015 PRACTICAL NEUROLOGY 11 FEATURE STORY

TABLE 1. LEVEL OF EVIDENCE Level Interpretation Evidence Level A Established as effective (or ineffective) for acute migraine ≥2 Class I studies Level B Probably effective (or ineffective) for acute migraine 1 Class I study or 2 Class II studies Level C Possibly effective (or ineffective) for acute migraine 1 Class II study or 2 Class III studies remain “probably effective” on the strength of the 2000 metheptene since the most recent guidelines. There were, guidelines.1 however, two Class II studies that demonstrated intrave- There is Level B evidence about the effectiveness of the nous magnesium sulfate provided significantly better relief NSAIDs , IV and IM (though not the than placebo. intranasal formulation), and flurbiprofen. There were no new Class I or II studies published on flurbiprofen or iso- THE PROCESS The researchers conducted a systematic review of clinical CLASSIFICATIONS trials on the efficacy of acute migraine treatments vs. pla- cebo, published in medical journals between 1998 and 2013. Level A (Effective) Two study authors reviewed each research abstract identi- The specific effective medications: triptans (almotriptan, eletrip- fied in a formal literature search and determined whether tan, frovatriptan, naratriptan, rizatriptan, sumatriptan [oral, the full manuscript qualified for review. nasal spray, injectable, transcutaneous patch], zolmitriptan Two independent reviewers then reviewed each of the [oral and nasal spray]) and dihydroergotamine (nasal spray, selected manuscripts to determine whether it met study inhaler). inclusion criteria. In the event of a disagreement between Effective nonspecific medications: acetaminophen, nonsteroidal the two reviewers, a third member reviewed the abstract anti-inflammatory drugs (aspirin, diclofenac, , and or manuscript and served as a “tie breaker.” Each selected naproxen), (butorphanol nasal spray), sumatriptan/ study was rated on a number of factors that reflected naproxen, and the combination of acetaminophen/aspirin/ study rigor and significance, as well as findings. The caffeine. authors’ original research identified 805 articles, of which 132 were selected for review. Level B (Probably Effective) Based on these ratings, each class of drugs was deemed Ergotamine and other forms of dihydroergotamine are prob- effective (Level A), probably effective (Level B), possibly ably effective. Also in the category: ketoprofen, intravenous and effective (Level C), or judged to have inadequate or con- intramuscular ketorolac, flurbiprofen, intravenous magnesium flicting evidence to support or refute the medications’ use (in migraine with aura), and the combination of isometheptene (Level U). The determination of each efficacy level was compounds, codeine/acetaminophen and /acetamino- also based on the rigor and quantity of published studies phen. The antiemetics prochlorperazine, droperidol, chlorproma- on the drug class: to be in Level A, for example, a class of zine, and metoclopramide are also probably effective. drugs must have been supported by at least two “Class I” studies—well-designed, double-blind, randomized, placebo- Level C (Possibly Effective, Insufficient Evidence) controlled clinical trials. There is inadequate evidence for butalbital and butalbital “Essentially what we did is show what the evidence is for combinations, phenazone, intravenous tramadol, , drugs used for acute treatment of migraine,” Dr. Silberstein butorphanol or meperidine injections, intranasal lidocaine, said. “We didn’t talk about side effects or risks in general. and , including . There is Basically we said ‘all these drugs are effective’ but we really inadequate evidence to refute the efficacy of ketorolac nasal didn’t say when to use them, how to use them, or which spray, intravenous acetaminophen, chlorpromazine injection, drug you should choose over the other.” and intravenous granisetron. To fill that gap is a forthcoming companion piece to

confront those issues. For example, opioids require special Level B (Probably Ineffective) consideration. “Not because they’re not effective, but the The authors found that octreotide is probably not effective. risk of using them frequently can lead to many problems,” Dr. Silberstein said. n —Marmura MJ, et al. Headache. 2015;55:5 1. Summary of the American Headache Society Evidence Assessment. Migraine.com

12 PRACTICAL NEUROLOGY MARCH 2015