Expert Perspective

Medication overuse headache: Preventive treatment with or without detoxification?

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I recently came across an excellent review article covering medication overuse headache, by Sun-Edelstein and colleagues. I found the section covering treatment particularly interesting and of practical relevance. The article led me to a number of relevant studies that can help shape treatment decisions.

The goal of treating medication overuse headache is obvious: ceasing overuse of the medication in question in an effort to return to a headache pattern that is episodic and better managed. Although guidelines suggest withdrawal of the overused medication and initiating preventive treatment, there is debate about this approach versus withdrawal alone or preventive treatment without ceasing the overused medication. A recently published randomized trial from Carlsen and colleagues evaluated 3 treatment methods: 1) withdrawal plus preventive treatment; 2) preventive treatment only; and 3) withdrawal followed by optional preventive treatment 2 months after withdrawal. Investigators found all 3 approaches effective, but participants who underwent withdrawal plus preventive care saw their headache days reduced by 12.3 days, versus 9.9 days in the preventive-only group and 8.5 days in the withdrawal/optional preventive follow-up treatment contingent. No statistically significant differences were seen between the groups in terms of migraine days, days with short-term medication use, and headache pain intensity.

Particularly noteworthy was the finding that individuals treated with withdrawal plus preventive treatment were significantly more likely to achieve remission. Specifically, nearly 75% returned to experiencing episodic headache, compared with 60% in the preventive group and 42% in the withdrawal contingent. Nearly all (97%) of those on the withdrawal plus preventive regimen were cured of medication overuse headache, versus 90% (withdrawal) and 74% (preventive).

The bottom line: Individuals undergoing withdrawal plus preventive treatment were 30% more likely to be cured of medication overuse headache. Thus, it appears that detoxification is key.

Or is it?

On the one hand…

In studies, withdrawal from the offending medication is linked with substantial improvement in headache days. Additionally, individuals who previously responded poorly to preventive treatment fared better with such treatment after detoxification.

When treating medication overuse headache using the detoxification and preventive care approach, Sun-Edelstein and colleagues outline these important steps:

  • Educate your patients and their family/caregivers about the detoxification process
  • Wean patient off the offending medication with a goal of complete detoxification
  • Initiate preventive medical therapy or behavioral/non-drug strategies
  • Establish clear limits on acute medication intake
  • Arrange for regular follow-up to minimize or prevent relapse

While on the other hand…

Even though guidelines recommend detoxification, there is data supporting the concept of initiating preventive treatment without detoxification. A randomized, double-blind, placebo-controlled trial by Mei and colleagues found that 100 mg per day of topiramate led to a significant reduction in headache days and average amount of acute medication intake, versus placebo. However, treatment completion rates were low, leading Sun-Edelstein and colleagues to surmise that topiramate without detoxification would probably not have had a high success rate in practice.

Meanwhile, onabotulinumtoxin A was found in the PREEMPT trials conducted by Dodick and colleagues to reduce the number of headache days, migraine days, and moderate/severe headache days, compared with placebo, at week 24. Disappointingly, researchers found that acute medication frequency was not reduced in the overall treatment group, but they did note a significant reduction in the subgroup that was taking triptans. Moreover, a follow-up analysis by Aurora and colleagues involving 32 weeks of open-label treatment with onabotulinumtoxin A following the 24-week randomized study revealed significant reductions in acute headache days at 56 weeks.

Using anti-CGRPs without acute medication withdrawal

More recently, strong evidence is emerging about the value of using anti- calcitonin gene-related peptide (CGRP) monoclonal antibodies without acute medication withdrawal. The findings involve 4 anti-CGRP medications.

Erenumab: A subgroup analysis of a randomized, double-blind, placebo-controlled parallel-group trial by Tepper and colleagues showed that erenumab reduced frequency of migraine at 3 months in participants with chronic migraine and medication overuse. Patients receiving either 70 or 140 mg of erenumab saw their migraine frequency reduced by an average of 6.6 days, versus 3.5 days in the placebo group.

Additionally, a significantly greater number of patients in the treatment groups stopped overusing medication, and did so early, which led to improved patient-reported outcomes. Acute migraine-specific medication treatment days were reduced by an average of 5.4 days in the 70 mg group, 4.9 days in the 140 mg contingent, and 2.9 days in those who received placebo.

Overall, consistent improvement in measures of impact, disability and health-related quality of life were seen in individuals’ treatment with erenumab.

Galcanezumab: A post-hoc analysis of pooled data from the phase 3 EVOLVE-1 and EVOLVE-2 studies, as well as the phase 3 REGAIN trial found that in participants with medication overuse, 120 mg and 240 mg doses of galcanezumab cut the number of average migraine days and decreased medication overuse. Average migraine days were lowered in EVOLVE participants by 6.26 days in the 120 mg group, 5.77 days in the 240 mg contingent, and 2.71 in those who received placebo. In REGAIN, these numbers were 4.78, 4.51, and 2.25, respectively. Average monthly medication use rates in EVOLVE were 6.2%, 7.9%, and 15.9%, respectively; in REGAIN they were 24.3%, 23.1%, and 40.6%, respectively.

Notably, though the study demonstrated galcanezumab’s efficacy in those with and without medication overuse, improvement was more pronounced in patients with medication overuse.

Fremanezumab: In an analysis by Silberstein and colleagues, significantly more patients who received quarterly or monthly injections of fremanezumab reported no medication overuse during the 3-month study, versus placebo. Specifically, 61% of participants who received monthly injections of fremanezumab and 55% of those who took quarterly injections reported no medication overuse. Among those receiving placebo, only 46% reverted to no overuse. The effect was seen as early as week 4. Additionally, among patients with medication overuse at baseline, the number of days with acute medication use was significantly lower in the treatment groups versus placebo—1.8 days lower in the quarterly group and 2.8 days in the monthly contingent.

A subsequent post-hoc analysis presented at the 2019 American Headache Society (AHS) Annual Scientific Meeting showed that the benefits were sustained over time and the medication was effective in difficult cases. Continued treatment with either quarterly or monthly dosing resulted in a reduced number of headache days, acute medication overuse headache, and headache-related disability, compared with baseline measures. Notably, about 6 in every 10 individuals with medication overuse at baseline who received fremanezumab reverted to no acute medication overuse at 6 months. This effect was maintained through 1 year of treatment.

Eptinezumab: In PROMISE-2, a post-hoc analysis of the phase 3 trials evaluating quarterly IV infusions of eptinezumab 100 mg and 300 mg, Lipton and colleagues reported that participants with chronic migraine and medication overuse experienced greater reductions in monthly migraine days during weeks 1 through 12, versus placebo (100 mg, 7.7 days; 300 mg, 8.2 days; placebo, 5.6 days). Benefits, seen as early as the day after dosing, were generally maintained or improved over 24 weeks.

Acute care medication use was reduced by about 50% in the treatment group versus roughly 25% in the placebo contingent. Most encouraging was the finding that about one-third of individuals in the treatment cohort experienced 6 months without medication overuse and below the chronic migraine diagnostic threshold; only 10% of patients who received placebo resolved in this way. Consistent improvement across patient-reported outcomes was also observed in the treatment group versus placebo.

While the studies involving topiramate, onabotulinumtoxin A, and the anti-CGRP monoclonal antibodies suggest that preventive treatment alone may effectively treat acute medical overuse and medication overuse headache, it is the data behind the anti-CGRP treatments that seem to be most compelling and causing conventional thinking to be challenged. These medications appear to be able to convert individuals with chronic migraine and medication overuse, out of overuse and back to episodic migraine. Moreover, results show they may be able to reduce acute medication use in episodic migraine, which reduces the risk of the headache sufferer transforming to chronic migraine. It is worth considering this approach in patients’ overuse acute care medication, as well as those in whom discontinuation may otherwise prove difficult without concurrent preventive treatment.

The emerging role of gepants

Availability of the so-called “gepants”—small molecule CGRP receptor agonists—is shedding additional light on management of medication overuse headache and pointing to the future. Gepants—which include ubrogepant, rimegepant, and atogepant—have been shown in early data to have a preventive effect when used regularly. Thus, it is much less likely that their use will lead to excess use and medication overuse headache.

Preclinical data demonstrated that continued use of ubrogepant does not appear to produce early or latent trigeminal sensory sensitization. Meanwhile, rimegepant, when used every other day, and as needed for acute treatment of migraine in individuals suffering from moderate-to-high frequency episodic migraine, resulted in reductions in monthly migraine days. The preventive effects appear to be rapid and sustained. And in a phase 3 trial, atogepant demonstrated efficacy at doses of 10 mg, 30 mg, and 60 mg twice a day, compared with placebo over 12 weeks.

It is important to note that the link between the gepants and medication overuse and medication overuse headache have not yet been studied. Still, it is encouraging to see that migraine frequency improves and medication use days are reduced when gepants are taken preventively. Thus, gepants could emerge as a preferred approach for acute or preventive treatment in individuals who have or are at risk of developing medication overuse headache.

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