Barbiturates and Opiates Increase Risk for Chronic Migraine

December 4, 2008 — Treating headaches with narcotics and barbituates increases the risk for the development of chronic migraine. A new study shows that transformed migraine develops at a rate of 2.5% per year and that any use of barbiturates and opiates increases this risk.

Dr. Richard Lipton

“These treatments probably should not be considered first choice to relieve pain,” senior author Richard B. Lipton, MD, from the Albert Einstein College of Medicine, in Bronx, New York, told Medscape Neurology & Neurosurgery. “They may offer some relief on a short-term basis, but there could be long-term negative consequences.”

Dr. Lipton said he expected to see an increased risk with narcotics in this study. “It was not completely surprising,” he noted. “But the clear-cut dose response that we saw did make me gasp a little.”

The findings appear in the September issue of the journal Headache. The initiative is part of the American Migraine Prevalence and Prevention study.

Asked to comment on the study, Stephen D. Silberstein, MD, from Thomas Jefferson University in Philadelphia, Pennsylvania, said the results make sense. “Too much of a good thing is bad,” he noted.

Dr. Silberstein said that 4% of the world’s population experiences frequent headaches, and medication overuse is an important risk factor. “About half of these cases are chronic migraine and overtreatment is a problem.”

Dr. Silberstein says that this can be an issue with all medications and that clinicians and patients should focus on headache prevention.

Narcotics Should Not Be Considered First Choice for Pain Relief

Investigators surveyed 120,000 individuals to identify a sample of patients with migraine to be followed up annually for 5 years. They studied more than 8200 patients with episodic migraine.

Using logistic and linear regression, researchers modeled the probability that patients would transition from episodic to transformed migraine in relationship to medication use. They made adjustments for sex, headache frequency, severity, and use of prevention medication.

Dr. Lipton and his team found that baseline headache frequency was a risk factor for transformed migraine. Using acetaminophen as the reference group, researchers found that patients who used medications containing barbiturates or opiates were at increased risk for transformed migraine.

However, use of triptans at baseline was not associated with the prospective risk for chronic migraine, the researchers suggest, and overall, nonsteroidal anti-inflammatory drugs (NSAIDs) were not associated with chronic migraine either.

“Indeed,” they write, “NSAIDs were protective against transition to transformed migraine at low to moderate monthly headache days, but were associated with increased risk of transition at high levels of monthly headache days.”

Table. Risk for the Development of Transformed Migraine by Medication Use

*NSAIDs indicate nonsteroidal anti-inflammatory drugs.

Investigators found that both frequency of headaches and use of specific classes of medication are independently associated with the development of transformed migraine.

They observed that within a class of treatments, the influence of drug is modified by use as well as headache frequency. Also, the influence of the drug remains after adjusting for baseline headache characteristics.

“It is possible that choice of medication is a marker, rather than a cause, of transformed migraine incidence,” the researchers write. “However, our data suggest that headache severity is not a strong driver of these results given that the relationship persisted after adjusting for baseline headache severity.”

The investigators point to a number of limitations to their work including the fact that the study was not randomized and the definition of migraine was based on a questionnaire and not on an in-person clinical assessment. Medication use was also self-reported.

“While we await randomized trials, this study sets the stage for due caution,” Dr. Lipton said during an interview. “The use of opiates and barbiturates should be limited and well monitored. And caution is also advised in individuals with high frequency of headaches using any medication.”

This study was sponsored by the National Headache Foundation through a grant from Ortho-McNeil Neurologics Inc. Lead investigator Marcelo E. Bigal, MD, PhD, is an employee of Merck Research Laboratories. Dr. Silberstein is an uncompensated member of the editorial advisory board for Medscape Neurology & Neurosurgery.

Headache. 2008;48:1157-1168.

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

1. Define the 2 groups of migraines.
2. Report the relationship between excessive symptomatic medication use and transformed migraine.

Clinical Context

Migraines are a common cause of headache in a primary care practice. It is a disabling disorder that is divided into 2 broad groups based on the number of headache days. If attacks occur less than 15 days per month, the term episodic migraine or simply migraine is applied; when headaches occur on 15 or more days per month, the term chronic migraine or transformed migraine is used. In a single population study, the rate of transformation from episodic migraine to transformed migraine was reportedly 3% per year. Identifying risk factors for migraine transition from an episodic into a chronic status is important towards developing preventive strategies. Currently, in the general population, the prevalence of transformed migraine with medication overuse is approximately 1.5%. Although symptomatic medication overuse is believed to play a major role in progression from episodic to chronic or transformed migraine, population-based longitudinal data on these agents are limited.

The aim of this study was to assess the role of specific classes of acute medications in the development of transformed migraine in patients with episodic migraine after adjusting for other risk factors for headache progression.

Study Highlights

• As part of the American Migraine Prevalence and Prevention study, a population sample of 120,000 individuals were surveyed to identify a sample of migraineurs to be followed up annually for 5 years.
• The survey had been previously shown to have a sensitivity of 100% and a specificity of 82.3% for the diagnosis of migraine and a sensitivity of 93% and a specificity of 85% for the diagnosis of transformed migraine.
• Using logistic and linear regression, the investigators studied the probability of transition from episodic migraine in 2005 to transformed migraine in 2006 in relationship to medication use status. Sample demographics were similar.
• Individuals were specifically asked about each marketed triptan in all formulations, ergotamine compounds, 7 NSAIDs, 9 over-the-counter medications, 8 opioids, 2 butalbital-containing combinations, and medications containing isometheptene.
• Adjustments were made for sex, baseline headache frequency and severity, and baseline prevention medication use.
• Of 8219 individuals with episodic migraine in 2005, transformed migraine had developed in 209 (2.5%) by 2006.
• Baseline frequency of headache was a risk factor for transformed migraine.
• With use of acetaminophen user as the reference group, individuals who used medications containing barbiturates (odds ratio [OR], 2.06; 95% CI, 1.3 – 3.1) or opiates (OR, 1.98; 95% CI, 1.4 – 2.2) were at increased risk for transformed migraine.
• A dose-response relationship was found for use of barbiturates.
• Sex appears to influence the transition to transformed migraine, especially in men treated with opiates (OR, 2.76).
• Use of triptans (OR, 1.25; 95% CI, 0.9 – 1.7) at baseline was not associated with the prospective risk for transformed migraine.
• NSAIDs (OR, 0.85; 95% CI, 0.63 – 1.17) were not associated with transformed migraine.
• NSAIDs were found to be protective against the transition to transformed migraine at low to moderate monthly headache days but were associated with an increased risk for transition to transformed migraine at high levels of monthly headache days.

Pearls for Practice

• Migraines are divided into 2 groups: episodic and chronic migraines or transformed migraines. Episodic migraines refer to attacks occurring less than 15 days per month, whereas chronic or transformed migraines refer to headaches occurring more than 15 days per month.
• Results demonstrated that any use of barbiturates and opiates was associated with an increased risk for transformed migraine after adjusting for covariates, whereas triptans were not associated with an increased risk for transformed migraine. NSAIDs had a protective effect against transformed migraine or they were inducers, depending on the frequency of the headache.

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