The introduction of CGRP mAbs has transformed migraine prevention1 but, despite the long half-lives and sustained efficacy of these agents in clinical trials, concerns have emerged in real world practice regarding the perceived “wearing-off” phenomenon, defined as a recurrence or worsening of migraine headaches towards the end of the dosing interval. Dr Reem Suliman and Dr Taoufik Alsaadi, from the American Center for Psychiatry and Neurology, Abu Dhabi, UAE, discuss their recent research aimed at addressing these “wearing-off” periods.
While recent observational data suggest that true pharmacological wearing off may be uncommon, a subset of patients, particularly those with a high baseline disease burden, continue to report breakthrough headaches before their next scheduled injection or infusion. Current strategies to mitigate this include dose escalation, in the case of erenumab or eptinezumab, shortening dosing intervals, or combining CGRP mAbs with gepants as a bridging therapy.
With these background observations, we conducted a retrospective, real-world observational study to evaluate the efficacy, safety and tolerability of gepants when added as short-term bridging therapy in patients exhibiting wearing-off symptoms while receiving CGRP mAbs. The study was carried out at a single secondary outpatient clinic in Abu Dhabi and included adult patients with a confirmed diagnosis of either episodic migraine (EM) or chronic migraine (CM) who had been treated with CGRP mAbs and met predefined criteria for wearing-off,2 ie. a consistent increase of two or more migraine days during the last week of the dosing interval in comparison to the second week of the cycle, sustained over two visits (approximately eight weeks apart), verified by the patient’s diaries.
Patients used daily gepant therapy during the final week of their CGRP mAb dosing cycle and were followed prospectively for a minimum of 12 months.
A total of 65 patients met the inclusion criteria and were included in the final analysis, and the majority were female (86%) with a mean age of 40 years. EM predominated (68%) while the remaining patients were diagnosed with CM. Most patients who met the criteria of wearing-off were treated with eptinezumab (55%) followed by erenumab (26%) and galcanezumab (19%). Rimegepant was the commonly used bridging gepant. Weekly headache days (WHD), rather than monthly migraine days, were selected as the primary outcome to capture short-term fluctuations associated with the end of the dosing cycle.
The addition of gepants as a bridging strategy was associated with a rapid, sustained, and statistically significant reduction in headache frequency. Mean WHD decreased from approximately four days at baseline to near zero by the final follow-up visit, with improvements maintained across up to 16 visits spanning two years of observation. Importantly, variability in headache burden diminished over time, suggesting not only efficacy but also consistency of response. Statistical analysis confirmed significant reductions in WHD at six, 12, and 16 visit timepoints. From a safety perspective, no adverse events were reported during the bridging period, supporting the favourable tolerability profile of short-term combined CGRP inhibition.3
Implications for clinical practice
These findings have several practical implications for clinicians managing migraine in routine practice. First, they reinforce the importance of individualising treatment strategies rather than relying on a one-size-fits-all approach. Patients with high baseline migraine frequency, predictable end-of-cycle breakthrough headaches, or faster drug metabolism may be particularly susceptible to wearing-off symptoms and, therefore, ideal candidates for bridging therapy. While both patients with EM and CM benefited, those with EM constituted the majority of responders, consistent with prior evidence suggesting greater treatment responsiveness in this group.
Age also appeared to influence outcomes, with patients aged 40-59 years demonstrating more robust and stable responses compared with younger adults. This may reflect greater adherence, more stable migraine patterns, and reduced hormonal variability. Comorbidities, including metabolic, psychiatric and neurological conditions, were common and highlight the need for a holistic multidisciplinary approach when selecting preventive strategies. Gepants may be especially attractive in such populations due to their favourable pharmacokinetic profile and flexibility of use.
From a broader perspective, this study supports the evolving paradigm of layered migraine prevention, where combining CGRP-targeted therapies is not only safe but clinically meaningful for selected patients. For physicians, recognising and validating patient-reported wearing-off symptoms and proactively addressing them may improve adherence, satisfaction and long-term outcomes.
Summary
Our real world data suggest that gepants are an effective and well-tolerated bridging option for patients experiencing wearing-off phenomena while on CGRP mAbs. The sustained reduction in WHD, lack of any safety signals, and their benefits across diverse patient subgroups underscore the value of personalised CGRP-targeted strategies. Prospective, multicentre controlled studies are, undoubtedly, needed to validate our findings, identify predictors of response and refine optimal dosing and timing strategies. As migraine care continues to advance, bridging therapies such as gepants could offer clinicians a practical tool to optimise outcomes and maintain continuity of preventive benefit.
References
- Sacco S, Amin FM, Ashina M et al. European Headache Federation guideline on the use of monoclonal antibodies targeting the calcitonin gene related peptide pathway for migraine prevention - 2022 update. J Headache Pain. 2022 Jun 11;23(1):67.
- Florescu AM, Lannov LV, Younis S et al . No wearing-off effect of erenumab or fremanezumab for chronic migraine prevention: a single-center, real-world, observational study. Cephalalgia. 2024 Jan;44(1):3331024231222915.
- Alsaadi TM, Adel F, Alsaffarini KWB et al.Bridging CGRP mAbs with Gepants: An innovative approach to address the wearing-off phenomenon. Clinical Neurology and Neurosurgery 2025; 258, 109183.
