BOSTON—Certain classes of analgesics may cause headache pain when used excessively, and such use of these medications should be considered a risk factor for transformed or chronic migraine, according to Marcelo E. Bigal, MD, PhD, who addressed the 50th Annual Scientific Meeting of the American Headache Society.
An Evolving Understanding of Migraine
The perception of migraine has evolved in recent years from that of an episodic recurrent disorder stemming from neurovascular mechanisms to a chronic, sometimes progressive disorder involving integrated brain mechanisms. A controversial aspect of this evolution in understanding has been the role of acute medications for migraine (analgesics and medications used specifically to treat migraine) and whether medication overuse is a cause or consequence of the process leading to what researchers now call “transformed” migraine.
In a longitudinal population-based study, Dr. Bigal and colleagues assessed individuals who reported experiencing episodic migraine and found that use of medications containing barbiturates or opioids was associated with a twofold increased risk for progression to transformed migraine. Use of triptans was generally not associated with an increased risk, unless individuals had very frequent headaches to begin with (>10 days per month). NSAIDs appeared to have a protective effect in patients whose frequency of headache was less than 10 days per month and were associated with an increased risk for transition to chronic migraine in those who reported 10 or more headache days per month.
One view that emerged from the findings is that the association between use of certain types of analgesics and migraine progression is complex. Within a given class of acute migraine medications, the influence of drug is clearly modified by the frequency of headaches and, to a lesser extent, gender, as well as by the frequency of drug use. In the study, the influence of drug remained after investigators adjusted for baseline headache characteristics, and frequency of headaches and uses of specific classes of acute medication were both independently associated with the development of transformed migraine.
Dr. Bigal’s group also found that among individuals who experienced episodic migraine, the average annual incidence of transformed migraine was 2.5%, a rate similar to that of previous reports in the literature, including an earlier longitudinal population-based study conducted by Castillo et al. The rate more than doubled in individuals using opiates and barbituates. The rate further increased in those with frequent use of these substances. Dr. Bigal’s study was based on an initial survey of 120,000 representative households in the United States, accounting for more than 300,000 people 13 or older. Excluding individuals whose self-report indicated that they were already experiencing chronic migraine, the study followed 24,000 patients with episodic headache, which included an annual interview beginning in 2005.
Clinical Implications
The findings yield several important clinical implications for the current practice of neurology, asserted Dr. Bigal, who until recently was Assistant Clinical Professor at the Albert Einstein College of Medicine in New York City and is now Global Director of Scientific Affairs in Neuroscience at Merck Research Laboratories in Whitehouse Station, New Jersey.
“We think we demonstrated that not all medications—but specific classes of medications—are associated with chronic migraine,” he said in an interview with Neurology Reviews. “Use of opioids and barbiturates should be limited and well monitored in migraine. It’s not wrong, and in infrequent situations, these classes may even be the most appropriate. Nonetheless, doctors should be aware of this potential risk and limit their use into very specific situations…. We are not talking about abuse or addiction; we are talking about risk of developing chronic migraine.
“Caution is also advised in individuals with high frequency of headaches [ie, 10 or more days per month] using any medication,” he added. “It is not that these individuals should not receive treatment [for] their headaches; it is that they need something else, such as using preventive medications or receiving nonpharmacologic therapies.”
The results indicated that the use of barbiturates in excess of five days per month was especially problematic. “I’m not suggesting that doctors who [prescribe] more than five days of barbiturates per month are wrong,” Dr. Bigal emphasized. “This is a risk factor in some but not in everyone. In the population, five is a magic number for barbiturates. Therefore, doctors should be aware of this number, monitor the patient closely, and eventually consider preventive medication or not using this medication at first.”
By contrast, the “magic” number for opioids was eight to nine days—a finding that surprised Dr. Bigal. “My a priori assumption was that opioids were the bad guy. They are bad, but seem not to be the worst.”
Balance Sought Between Overuse and Undertreatment
In Dr. Bigal’s view, the findings of the substudy go a long way toward answering the chicken-or-the-egg question, “Do patients use a lot of pain medication because they have too much pain, or do they have too much pain because they use a lot of pain medication?,” by clearly establishing excessive use of certain analgesics as a risk factor for transformed migraine. However, neurologists and other clinicians should not interpret the results as a rationale for not treating patients who have migraine, asserted Dr. Bigal.
“[The results] don’t mean that if you have 12 days of headache per month you should not treat,” he said. “If you have 12 or more days of headache per month … you should receive your medication, such as a triptan or an NSAID. But the doctor needs to do something else, such as giving a preventive medication, biofeedback, [or] nonpharmacologic therapies.”
He recounted how one of his coauthors expressed concern that the findings could encourage some clinicians to undertreat migraine. “[The coauthor’s] fear was if we say that by using a medication more than 10 days per month, you increase your chance of chronic migraine, [that] you’ll leave several attacks untreated and suffer now because of your fear of future problems,” Dr. Bigal recounted. “That’s definitely not what we are advocating. What we are advocating is that pain needs to be treated, headache needs to be treated, and if you have too many headaches, certain classes of medication should be avoided. But if you have too many headaches, you need to treat … and your doctor [should] use something else to bring the frequency lower.”
A number of other questions remain unanswered by the substudy, and research is ongoing via the larger American Migraine Prevalence and Prevention study, which is under the direction of Richard B. Lipton, MD, of the Albert Einstein College of Medicine. “What we have not established in the paper [includes] the true potential for inducing [transformed migraine] of medications containing caffeine, and for the NSAIDs, we don’t know if they are all the same,” Dr. Bigal said. “We just [studied] NSAIDs as a single class, and now what we have to do, as we increase our power, is look for specific [medications].”
As for the more distant future, Dr. Bigal envisions a time when patients with migraine are classified and treated by the stage of their disease, much as patients with myocardial infarction are managed today. “A 50-year-old man comes to the office and is overweight,” he postulated. “What do we do? Is the cholesterol high or not? Does the man have diabetes or not? How does the man exercise, etc? And based on that, we calculate the risk for cardiovascular events. We stage patients according to their future risk, and based on this staging, what do we do? ‘This patient needs a statin,’ or ‘This patient needs exercise only,’ or ‘I want you to follow this patient more closely.’
“What I envision in the future is something similar for migraine pain, where migraineurs will come in and, based on their pain and disability now, they receive a treatment that includes a preventive medication, [for example], or a triptan … but also we stage them for risk of poor prognosis. So let’s say, ‘This guy is obese; I know this is a risk factor for migraine.’ … We develop validated scales for progression, and based on that, doctors would get a message, such as ‘Stay away from opioids in this guy’ or ‘Follow up more closely.’ This is what we call refining our phenotypic characterization of migraineurs, based on prognosis,” concluded Dr. Bigal.

—Fred Balzac

Excessive Use of Some Analgesics May Lead to Transformed or Chronic Migraine