OnabotulinumtoxinA Wear-off Phenomenon in the Treatment of Chronic Migraine

Alina Masters-Israilov, MD; Matthew S. Robbins, MD


Headache. 2019;59(10):1753-1761. 

In This Article

Abstract and Introduction


Objective: To evaluate the frequency and features of onabotulinumtoxinA (onabotA) wear-off in chronic migraine (CM).

Background: Clinical experience suggests that patients with CM frequently perceive onabotA treatment duration <12 weeks, but this phenomenon has not been well explored.

Methods: This study was a retrospective chart review of patients (n = 143) with CM initiated on onabotA over a 2-year period. Wear-off was considered present with the phrase documented, a quantitative headache day increase, or increased use of abortive medications, bridging therapies or emergency department visits in the 6 weeks preceding the subsequent administration.

Results: Wear-off was present in 90/143 patients (62.9%). Age, sex, medication overuse, psychiatric comorbidity, injector training level, and mean days between injections did not differ between the wear-off and no wear-off groups. Mean units injected per session in the wear-off group until first documented wear-off were significantly less vs no wear-off group (166.0 ± 13.1 vs 173.4 ± 10.3, P = .0005). Wear-off most commonly occurred 2–4 weeks before the next injection (43.3%) and after the very first injection (40.0%). Intramuscular ketorolac injections (33.3%) and peripheral nerve blocks (25.6%) were the most common bridge therapies used in the wear-off period.

Conclusions: Most patients with CM receiving onabotA experience wear-off. Clinicians may consider increasing the units used from the treatment onset to reduce the frequent need for bridging therapies.


Chronic migraine is defined as a headache that occurs for 15 or more days of the month for more than 3 months, of which headache on at least 8 of those days has phenotypic features of migraine.[1] The disorder affects about 6.6–8.8% of those with migraine.[2] It is a major public health problem, affecting approximately 1% of the U.S. population and up to 2.2% of the global population.[3] Migraine is the top cause of years lived with disability worldwide in the age group of 15–49 years,[4,5] and chronic migraine features disproportionate rates of burden, cost, and comorbidity relative to simply an increase in headache frequency.[6]

The goal of preventive therapy is to decrease the frequency, duration, and severity of headache,[7] and preventive medication has also been shown to reduce resource consumption.[8] However, a retrospective analysis found that adherence to oral preventive medication in those with chronic migraine declined as the time from onset of the medication initiation was measured; adherence declined further when other oral migraine preventive medications were tried.[9] This perhaps may be in part due to unwanted side effects, which are numerous and, depending on the medication used, include cognitive effects, weight changes, and anticholinergic effects.[10]

OnabotulinumtoxinA (OnabotA) has been approved for prophylaxis of chronic migraine after the completion of large clinical trials, which showed a significant reduction in the frequency of headache days as compared to placebo.[11,12] Its mechanism of action may include blocking the release of inflammatory neuropeptides from stimulated sensory neurons including substance P and calcitonin gene-related peptide (CGRP)[13] and may decrease the promotion of central sensitization.[14] Its therapeutic benefit and tolerability has been reported to maintain over 2- and even 3-year periods.[15,16] Patients with chronic migraine who do not respond to the first treatment cycle of onabotA are recommended to try at least 2 or 3 treatments before the determination of efficacy.[17]

As per the Phase 3 Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) protocol, patients receive onabotA injections every 12 weeks, which is the approved frequency of administration.[18] Two recent single-center retrospective studies suggest that the efficacy of onabotA may exceed the currently approved 3-month dosing schedule for chronic migraine[19,20] and a recent multicenter study has shown that the administration of onabotA may be successfully delayed to a 4- or 5-month dosing schedule after the third treatment cycle.[21] However, in our clinical experience, many patients who receive benefit from onabotA experience worse headaches in the time leading up to their next scheduled 12 weeks onabotA administration, which clinicians and patients may frame as a wear-off phenomenon and could prompt clinicians to consider more frequent dosing or more units injected per session. The PREEMPT protocol consists of injections into 31 specified sites for a total of 155 units with a "follow the pain" protocol that uses up to 195 units.[11,12] The "follow the pain" protocol was sometimes implemented in patients with chronic migraine whose onabotA response time was shorter than 3 months,[21] and one prospective study has shown potential benefit in using 195 vs 155 units in patients with chronic migraine with medication overuse.[22]

Literature on other indications for onabotA also raises the possibility that treatments may be indicated more frequently than the current 12-week schedule or may require more units per session to treat, and perhaps even prevent, the wear-off phenomenon. For cosmetic purposes in preventing wrinkles, effects of onabotA have been shown to peak at 4 weeks and then begin to wear off starting at 10 weeks.[23] One study showed that for the treatment of blepharospasm and cervical dystonia, onabotA had a duration of effect of 62.2 and 64.3 days, respectively,[24] which is shorter than 84 days (12 weeks). In refractory muscle tension dysphonia, duration of the benefit of onabotA lasted between 3 weeks and 6 months.[25]

The phenomenon of onabotA wear-off in the treatment of chronic migraine remains underexplored and we aimed to evaluate its rate, associated factors, features, and treatment characteristics.