Headache a Common Side Effect of Interferon-beta Treatment, Study Finds

New or worsening headaches are a more common side effect of interferon-beta (IFN-beta) treatment in people with multiple sclerosis (MS) than previously appreciated, a new study suggests.

The study, “Interferon-Beta-Induced Headache in Patients with Multiple Sclerosis: Frequency and Characterization,” was published in the Journal of Pain Research.

IFN-beta is a signaling protein that helps modulate the activity of the immune system. IFN-beta therapies, such as Avonex, Rebif, and Betaseron, are mainstays of MS treatment; they are used to reduce the inflammation that damages the nervous system.

The most commonly recognized side effects of IFN-beta treatment include flu-like symptoms, injection site reactions, fatigue, and temporary abnormalities in laboratory tests. Some studies have suggested that IFN-beta could cause headaches or make them worse, but it is unclear how common this side effect is, or how it tends to manifest.

To shed light on this matter, researchers at Cairo University, Egypt, assessed the frequency and characteristics of headaches in people with MS treated with IFN-beta.

The team analyzed data from 796 patients with relapsing-remitting MS (RRMS) — 283 male, 513 female, average age 30.84 years — who were treated with IFN-beta at one of several centers in Egypt.

Participants were followed-up monthly for one year, starting before they began IFN-beta treatment, and were asked routinely if they were experiencing headaches. Individuals who did experience headaches provided further details by means of questionnaires and “headache diaries.”

Of the study participants, 276 (34.67%) experienced headaches prior to being diagnosed with MS or starting IFN-beta treatment. Of these, 153 (55.43%) reported that their headaches became worse — more intense, more frequent, and/or longer in duration — within one month of starting on IFN-beta.

There were 122 (34.27%) participants who reported no history of headaches prior to their MS diagnosis, but started experiencing headaches around the time they were diagnosed. Among these, 55 (45.08%) reported that the headaches worsened after starting on IFN-beta.

Additionally, 234 (29.39%) participants had no history of headaches prior to starting on IFN-beta, but developed headaches shortly after beginning treatment.

Collectively, 442 (55.53%) participants reported new or worsening headaches after starting treatment with IFN-beta. There were no significant differences between these individuals and those who didn’t have new or worsening headaches in terms of age, sex, disease duration, type of MS, or family history of headaches.

“[T]reatment with IFN-β [beta] significantly worsened pre-existing headaches and headaches that occurred concurrently with onset of MS in more than half of patients with histories of headaches that preceded commencement of IFN-β treatment,” the researchers wrote.

“Treatment with IFN-β also triggered de novo headaches in about one-third of those who did not report having headaches prior to treatment,” they added, noting that “these three categories of patients accounted for more than half of our cohort.”

The team noted that headaches could be divided into two broad groups. In the first, which included 113 people, headaches developed after starting IFN-beta, but went away within three months (headaches with remission). Among these, most patients (82) were specifically classified as having migraine headaches.

In the second group, which included 329 people, headaches lasted for a longer time (i.e., more than three months). Most of these persistent headaches were classified as episodic — that is, the person would experience headaches less than half of the days in a month. In this group, 216 (65.65%) people required additional medications to help control or prevent their headaches (such as topiramate and amitriptyline).

Researchers also compared the relative risk of headache among individual IFN-beta therapies.

Compared to low-dose (22 mcg) Rebif, the risk of headache for patients treated with Avonex was more than sixfold higher, and about fivefold higher for those treated with high-dose (44 mcg) Rebif.

Betaseron was not linked with a significantly different headache risk, compared to low-dose Rebif.

Overall, the team concluded that IFN-beta “therapy aggravated pre-existing headaches and caused primary headaches in patients with MS.”

“Interferon-beta pivotal trials and post-market evidence underestimated the prevalence of headaches as an adverse effect,” the researchers noted. “In these studies, headaches were either not included among adverse events, or may have been considered flu-like symptoms. However, headache is one of the most common adverse events associated with IFN-β treatment.”