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11 Articles in Volume 15, Issue #2
Chronic Headache Management: Outpatient Strategies
Magnesium Sulfate Helpful in Treatment of Acute Migraines
New Guide to Migraine Rx Garners Mixed Reviews
Pain Education Across VA Clinics
12 Classes Offered at VA Pain School
Practical Guide to the Safe Use of Methadone
Chronic Pain Patients Who Fail Standard Treatment
Balancing State Opioid Policies With Need for Access to Pain Therapies
New Mexico’s Approach to Improving Pain and Addiction Management
Editor's Memo: Prescription Opioid Abuse is Declining
Ask the Expert: Lupus and Suicidal Ideation

New Guide to Migraine Rx Garners Mixed Reviews

The American Headache Society has released a comprehensive review of migraine therapies, but some experts in the field have found the results somewhat perplexing, even misleading.

It has been 15 years since the American Academy of Neurology (AAN) published its guidelines for treating acute migraines,1 an affliction that affects some 36 million Americans.2 Now, a new assessment of migraine therapies has been published, although its findings have attracted some mixed feelings from practitioners in the field.

A team of experts from the American Headache Society (AHS) performed a comprehensive review of migraine literature spanning from 1998 to 2013 and outlined a new system of judging migraine therapies based on the drugs’ efficacies compared to placebo, triaging numerous therapies into specific levels: A (effective/ineffective), B (probably effective/ineffective), C (possibly effective/ineffective), or U (conflicting or inadequate evidence).

Various triptans, nonsteroidal anti-inflammatory drugs (NSAID, prescription and over-the-counter), opioids, and combination of therapies were deemed level A, or effective, therapies. Other drugs, such as ketoprofen, intravenous (IV) and intramuscular (IM) ketorolac, flurbiprofen, and IV magnesium, were classified as level B, or probably effective, therapies. Some drugs, including phenazone, IV tramadol, methadone, butorphanol or meperidine injections, intranasal lidocaine, and corticosteroids, were classified as being level C, or possibly effective, therapies (Table 1).

“Some of the results fit our common experience, and that of numerous studies,” said Lawrence Robbins, MD, a neurologist at Robbins Headache Clinic in Northbrook, Illinois, and an editorial board member of Practical Pain Management. Dr. Robbins found some of the assessment’s results agreeable, like how triptans were deemed level A, or effective. And intravenous valproate was rated level C, or possibly effective, which “has been only mildly effective” in studies, he said.

“Other results clearly do not fit our common experience [such as ibuprofen (200 mg) receiving a better rating than IV/IM ketorolac], which most ER’s and headache physicians find much more useful,” he said. Some of the results even perplexed Dr. Robbins—oral acetaminophen, ibuprofen, along with butorphanol nasal spray all were listed higher than IV dihydroergotamine (DHE) and IV ketorolac.

“This goes against all of our experience,” he said. “The problem lies with the studies. They are done at different times, eras, with different endpoints, patients, amounts of medication,    among many other variables.”

Michael J. Marmura, MD, lead author of the assessment and an assistant professor at Thomas Jefferson University in Philadelphia, Pennsylvania, said that such a criticism was valid, but also pointed out the heterogeneity of the outcome variables used amongst the studies limited how the drugs were triaged.

“The studies themselves could be assessed but it would be a mistake to suggest that just because a drug has good evidence means it is the best drug,” Dr. Marmura said. “The IV infusion or emergency treatments we commonly use are almost all Class B or lower due to the fact that ER studies are harder to fund and smaller. A separate review of outpatient and infusion treatments may be valuable.”

How the Studies Were Picked

Many data and studies were excluded from the analysis, including those that compared 2 or more drugs against each other rather than a placebo, studied children or elderly patients, assessed preventative treatments (like menstrual migraine), or used patient satisfactory, disability, or some other nonstandard primary outcome measure. Conference abstracts, editorials, medical procedure or devices studies, and animal studies were also excluded from the assessment.

Of the 132 articles selected, the studies were labeled by 4 classes. “Class I studies, well-designed, double blind, randomized, placebo-controlled trials, were considered best, while Class IV studies were often retrospective studies or case reports with unclear outcomes data,” noted the authors. According to Dr. Robbins, this system’s focus on double-blind research may have been detrimental to the representation of useful therapies.

“Some drugs that would probably be listed higher, such as butalbital compounds, were developed prior to the common use of double blind studies. Once butalbital became generic [many years ago], few companies would fund an adequate trial,” Dr. Robbins said, further adding that “many of the double blind controlled trials in the US are multi-centered, sponsored by a company. The patients often are ‘cherry picked,’ leading to less than ideal results.”

Study Limitations

The AHS’s assessment also excludes studies not published originally in the English language, as well as drugs unavailable or pending in the United States. Some drugs not common to the ER setting seem to have been ignored altogether, like IV ketamine. John Claude Krusz, MD, PhD, director at Anodyne Headache and PainCare in Dallas, Texas, and another editorial board member of Practical Pain Management, said he found the assessment’s results to be “conservative” and its methods “somewhat arbitrary” because smaller studies were excluded. He found there to be less focus on therapies that he has found useful, particularly in treating patients who do not respond well to the common, first-line approaches.

“IV tramadol happens to work well in my hands, but they downplayed it since it isn’t available in the US. IV lidocaine is also downplayed as it is also not a ‘mainstream’ medicine,” Dr. Krusz said. “They had to rate usual and commonly used medications [typical ER meds] because very few physicians anywhere are familiar with lidocaine, ketamine, and propofol, let alone IV baclofen and tramadol.”

A limitation of the assessment is that it does not take into account the drugs’ side effects or possible harms, an aspect of guidelines that is now officially recommended by the US Institute of Medicine. Because of this, some drugs, like butorphanol nasal spray, received a high rating of efficacy over placebo, although doctors should consider the dangers of dependence, addiction, or medication-overuse headache, the authors noted.

“It’s extremely tough to compare side effects/adverse events from different studies due to [the] heterogeneous nature of their reporting. Some studies looked at the treatment of a single attack, others crossover studies or multiple attacks. Some report all adverse events and others just treatment-related AEs,” Dr. Marmura said.

Utility of Guidelines

With the results of the assessment being disputed by doctors and the lack of other important data, such as side effects and clinical guidelines, Practical Pain Management experts agree the utility of the guidelines is limited.

“Discretion is always, always very advisable. This may be why most people who aren’t comfortable with certain treatment approaches send patients to others who might be,” said Dr. Krusz. “Yes, (the AHS assessment) is a partial sort of indicator of efficacy, but not necessarily the real world in the trenches of headache treatment.”

Dr. Robbins similarly found that the assessment was of questionable use to health care providers. “There was a prodigious amount of work that went into this paper. I commend the authors for that. However, the utility of these ‘levels’ is minimal, if anything,” Dr. Robbins said. “Practically, I am not sure I know of anyone that would actually use these levels, and how they might use them. The incongruity of the results negates, in my mind, the practical application of the findings.”

Indeed, even Dr. Marmura said that the assessment is not meant as a straight-ahead guideline for practitioners to rely on. “These assessments compare only the quality of the evidence, so basing treatment on the levels alone would be unwise,” he said, mentioning how acetaminophen (Tylenol) received a high rating in the assessment, although he wouldn’t recommend it as a first-line treatment because “most patients seeing a doctor for severe migraines have tried over-the-counter medications.”

Dr. Marmura said a companion piece to the assessment is being developed, which “will help to address these realities and provide more ‘real world’ advice for applying these guidelines.”

The study was funded by the American Headache Society. Dr. Marmura has received royalty income from Demos Medical, Cambridge University Press, and MedLink Neurology. Todd J. Schwedt, MD, MSCI, has received consulting fees and/or honoraria from Allergan, Inc., Supernus, and Zogenix. Dr. Schwedt has received royalty income from UpToDate. Stephen D. Silberstein, MD, FACP, has received consulting fees and/or honoraria from Allergan, Inc., Amgen, Avanir Pharmaceuticals, Inc., eNeura Inc, ElectroCore Medical LLC, Medscape, LLC, Medtronic, Inc, Mitsubishi Tanabe Pharma America, Inc., Neuralieve, NINDS, Pfizer, Inc, Supernus Pharmaceuticals, Inc., and Teva Pharmaceuticals. Dr. Silberstein’s employer, Jefferson University Hospitals, receives research support from Allergan, Inc., Amgen, Cumberland Pharmaceuticals, Inc., ElectroCore Medical, LLC, Labrys Biologics, Eli Lilly and Company, Merz Pharmaceuticals, and Troy Healthcare.

—Reported by Thomas Ciccone

Last updated on: June 23, 2017

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