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Managing migraine over time

Are anti-CGRP treatments robust in the long run?
Read time: 15 mins
Last updated:3rd Feb 2022
Published:3rd Feb 2022

Clinical trial data support the effectiveness and safety of CGRP monoclonal antibodies (mAbs) for prevention of migraine, along with emerging real-world evidence.

  • Does evidence indicate these treatments remain safe and effective over the longer term?
  • Considering their monthly and/or quarterly dosing regimens, do CGRP mAbs show signs of ‘wearing-off’ towards the end of their dosing interval?

In this second article in the 3-part series on managing migraine, join Professor Egilius Spierings, Medical Director at the Boston Headache Institute at Boston PainCare in Massachusetts, United States, in exploring the evidence and what this may mean for prescribers who are managing patients with migraine.

Are CGRP mAbs safe and effective for long-term migraine prevention?

Professor Egilius Spierings describes key findings from the longer-term follow-up data on the safety and effectiveness of CGRP mAbs, and their implications for clinical practice.

Since the original clinical trials which led to regulatory approvals of CGRP mAbs for prevention of migraine, longer-term follow-up data has become available from open-label extensions, real-world studies, post-hoc and retrospective analyses (Table 1).

Overall, across patients with episodic migraine (EM) or chronic migraine (CM), long-term evidence indicates that CGRP mAbs have sustained efficacy and maintain a similar safety profile for up to 1 year with galcanezumab1,2, 1.25 years with fremanezumab3–9, 2 years with eptinezumab10–13, and up to 5 years with erenumab14–17

Table 1. Long-term efficacy/effectiveness and safety data for CGRP mAbs in managing migraine1–3,5–23. AEs, adverse events; CGRP, calcitonin gene-related peptide; CM, chronic migraine; CVAE, cardiovascular adverse event; EM, episodic migraine; EQ-5D, EuroQol 5-Dimension 5-Level questionnaire; HFEM, high frequency episodic migraine; HIT-6, headache impact test; mAb, monoclonal antibody; MBS, patient-identified most bothersome symptom associated with migraine; MHD, mean headache days; MIDAS, migraine disability assessment questionnaire; MMD, mean migraine days; MSQoL, Migraine-Specific Quality of Life; PGIC, Patient global impression of change; PHQ-9, 9-Item Patient Health Questionnaire; PROs, patient-reported outcomes; SAE, serious adverse event; TEAE, treatment-emergent adverse event; TF, migraine preventative treatment failure; TR, treatment refractory; WPAI, Work Productivity and Activity Impairment.


Key findings from long-term studies

Higher dose of erenumab (140 mg monthly) may be favoured for longer-term migraine efficacy

A dose increase from 70 mg to 140 mg was reported for the majority of patients taking erenumab in over 1 to 5 years of treatment15–17, either due to lack of response or loss of prior effectiveness17, or as required by protocol amendment14,15. A post-hoc analysis of long-term trials favoured the 140 mg dose for efficacy at 1 year 15, and a comparison of raw efficacy data across trials suggested 140 mg monthly may be preferred over 70 mg in patients with prior preventative treatment24. Indeed, the authors of one study concluded 140 mg monthly should be considered as the starting dose, particularly in treatment-refractory patients17.

Higher-than expected rates of constipation with erenumab in real-world migraine patients

Although the incidence of constipation and/or hypertension reported across long-term clinical trial data from CGRP mAbs was generally low (<2%) at 1 to 5 years of follow-up3,11,14,18,19, constipation was reported in 10.3% of real-world patients treated with erenumab for up to 11 months17. This higher-than-expected rate of constipation with erenumab in real-world versus clinical trial patients has been reported across multiple studies25–29, and may be associated with factors such as use of concomitant medications29–31.

CGRP mAbs remain well-tolerated

Across the CGRP mAbs, the incidence of hypersensitivity treatment-emergent adverse events (TEAEs) (including rash, pruritus11,19) was considered low; most were not serious, and a low proportion led to dose interruption or discontinuation for eptinezumab (i.e. 0.8% and 0.7%, respectively)11,13,18–20,22. Injection or infusion-site reactions were reported for all CGRP mAbs, generally including erythema and pain, plus induration, bruising and/or haematoma in some studies3,11,15,17,19. Although some studies reported injection or infusion-site reactions in >10% of patients (i.e. induration, pain and erythema for fremanezumab3; pain and general injection site reactions for galcanezumab19), such information was not clearly reported across all studies10–13,22, and rates of reporting may have been influenced by active monitoring for injection site reactions in others3. Overall, injection site reactions were generally transient, not serious, and few resulted in dose interruption or discontinuation3,11,13,15,17,19.

However, further long-term data is needed to characterise the long-term safety of CGRP mAbs, particularly in patients with comorbid cardiovascular disease or a history of those conditions32,33.

Is wearing-off an issue for CGRP mAbs in patients with migraine?

Wearing-off has been reported previously with migraine preventive medications such as onabotulinumtoxinA for prevention of CM, and as early as 4 weeks prior to next treatment7.

Is there evidence to suggest wearing-off with CGRP mAbs? Professor Spierings discusses the evidence and outlines some possible contributing factors.

In patients with migraine, wearing-off has been consistently reported for erenumab across multiple studies28,34, and inconsistent results have been reported across studies for wearing-off with fremanezumab and galcanezumab in patients with CM and EM7,34–36 (Figure 1)

Across the CGRP mAbs, published evidence indicates wearing-off can occur with erenumab, but not with fremanezumab or galcanezumab.

  • Wearing-off was self-reported in 34.7% of real-world patients with CM or EM treated with erenumab (70 mg or 140 mg), in most cases occurring at 1 week prior to the next monthly injection28
  • In two post-hoc analyses of clinical trial data, no wearing off effect was reported towards the end of the dosing interval for monthly galcanezumab36 for up to 6 months, or fremanezumab (monthly or quarterly7) for up to 15 months

However, when unpublished preliminary data is considered, wearing-off has been reported for all three of these CGRP mAbs.

  • In a single-centre retrospective analysis, 20% of real-world patients with CM or EM who were prescribed a CGRP mAb had wearing-off documented in their electronic medical record34. Of these patients, 50% were prescribed galcanezumab, 16% were prescribed fremanezumab, and 24% were prescribed erenumab34. On average, wearing-off was 8 days prior to their next injection34
  • A further preliminary post-hoc analysis reported wearing-off with galcanezumab in HFEM or CM patients in clinical trials, and the reported incidence of wearing-off in CM patients was higher with galcanezumab compared to placebo (9% versus 3%, respectively)35

However, limited details for these preliminary findings were available, and they remain to be confirmed in peer-reviewed publications.

For eptinezumab, no published or preliminary data were located on the presence/absence of wearing-off.


Figure 1. Do CGRP mAbs show signs of ‘wearing-off’ in patients with migraine?7,28,34–36 CGRP, calcitonin gene-related peptide; CM, chronic migraine; EM, episodic migraine; HFEM, high-frequency episodic migraine; mAb, monoclonal antibody.*For erenumab, 34.7% of real-world patients self-reported wearing-off, and in 80% of these cases this was at 1 week prior to next injection28; preliminary data reported wearing-off was reported on average at 8 days prior to next injection for erenumab, galcanezumab or fremanezumab34. †For eptinezumab, no publications or preliminary data reporting on presence/absence of wearing-off were found.

CGRP mAbs and wearing-off: what does this mean for managing patients with migraine?

Professor Spierings discusses the implications of long-term efficacy and safety data, and wearing off on the use of CGRP mAbs in clinical practice.

Considering the inconsistent findings between studies, more research will be required to determine implications for prescribing, including factors which may impact the likelihood and timing of wearing-off. At this stage, it is unclear whether frequency of dosing and/or patient characteristics such as treatment history, migraine severity or concomitant medications play a role in likelihood of wearing-off 7,34.

There is currently a lack of practical guidance to help prescribers to manage wearing-off. Although a shorter dosing interval or use of a higher dose have been suggested to reduce the risk of wearing-off, the safety implications of these approaches are not yet clear7,28. In the meantime, prescribers are encouraged to document use of any bridging therapies during the wearing-off period28,34.


Overall, results from longer-term follow up indicate CGRP mAbs have sustained efficacy and a similar safety profile for 1 to 5 years of treatment. Evidence favours use of the 140 mg dose of erenumab for efficacy in the longer term, and real-world evidence suggests a higher rate of constipation with erenumab compared to clinical trials. Wearing-off has been reported towards the end of the dosing interval for erenumab, and mixed evidence has been reported for wearing-off with fremanezumab and galcanezumab.

Which anti-CGRP treatment is the best option for your patient? Keep an eye out for the third and final article in this 3-part article series on managing migraine, where we will explore some key factors to consider when choosing between the available anti-CGRP treatments

Learn more about the real-world evidence on CGRP mAbs for managing migraine

About Professor Egilius Spierings

Professor Egilius Spierings is the medical director of The Boston Headache Institute at Boston PainCare in Waltham, Massachusetts, United States. He is a former clinical professor of neurology and craniofacial pain at Tufts University Schools of Medicine and Dental Medicine in Boston, Massachusetts, and a former associate clinical professor of neurology at Harvard Medical School.


Professor Spierings is a member of the speaker bureaus of Abbvie, Amgen, Biohaven Pharmaceuticals, Lundbeck, Teva Pharmaceuticals, and Eli Lilly.


  1. Gklinos P, Mitsikostas DD. The role of galcanezumab in migraine prevention: Existing data and future directions. Pharmaceuticals. 2021;14(3):245.
  2. Schiano di Cola F, Caratozzolo S, Bolchini M, di Cesare M, Liberini P, Rao R. Galcanezumab in real life: safety and efficacy over 12 months of treatment. 2021. Presented at 7th Congress of European Academy of Neurology (EAN) 2021, June 19–22 2021. Virtual. EP0-417.
  3. Goadsby P, Silberstein S, Yeung P, Cohen JM, Ning X, Yang R, et al. Long-term safety, tolerability, and efficacy of fremanezumab in migraine: A randomized study. Neurology. 2020;95(18):e2487–e2499.
  4. Nahas S, Cohen J, Ramirez Campos V, Ning X, Janka L, Dodick D. Clinically meaningful responses to fremanezumab treatment in episodic and chronic migraine over up to 15 months. 2021. Presented at the 63rd Annual Scientific Meeting American Headache Society 2021, June 3-6 2021. Virtual. P-163.
  5. Dougherty C, Cohen J, Ramirez Campos V, Ning X, Barash S, Spierings E. Sustained, clinically meaningful responses to fremanezumab treatment in migraine patients with inadequate response to 2–4 prior classes of migraine preventive medications. 2021. Presented at the 63rd Annual Scientific Meeting American Headache Society 2021, June 3-6 2021. Virtual. P-159.
  6. Spierings ELH, Ning X, Ramirez Campos V, Cohen JM, Barash S, Buse DC. Improvements in quality of life and work productivity with up to 6 months of fremanezumab treatment in patients with episodic and chronic migraine and documented inadequate response to 2 to 4 classes of migraine-preventive medications in the phase 3b FOCUS study. Headache. 2021;61(9):1376–1386.
  7. Blumenfeld AM, Stevanovic DM, Ortega M, Cohen JM, Seminerio MJ, Yang R, et al. No “Wearing-Off Effect” Seen in Quarterly or Monthly Dosing of Fremanezumab: Subanalysis of a Randomized Long-Term Study. Headache. 2020;60(10):2431–2443.
  8. Nagel S, Cohen J, Ramirez Campos V, Barash S, Ning X, Kudrow D. Long-term Efficacy of Fremanezumab in Patients With Chronic or Episodic Migraine and Documented Prior Inadequate Response to 2–4 Classes of Migraine Preventive Medications. 2021. Presented at International Headache Congress IHC and EHF Joint Congress 2021, September 8–12 2021. Virtual. P0315.
  9. Buse D, Cohen J, Ramirez Campos V, Ning X, Janka L, Mechtler L. Long-term Tolerability and Improvements in Disability and Quality of Life With Fremanezumab in Patients With Chronic or Episodic Migraine and Documented Inadequate Response to 2–4 Prior Classes of Migraine Preventive Medications. 2021. Presented at International Headache Congress IHC and EHF Joint Congress 2021, September 8–12 2021. Virtual. P0327.
  10. Smith TR, Janelidze M, Chakhava G, Cady R, Hirman J, Allan B, et al. Eptinezumab for the Prevention of Episodic Migraine: Sustained Effect Through 1 Year of Treatment in the PROMISE-1 Study. Clinical Therapeutics. 2020;42(12):2254-2265.e3.
  11. Kudrow D, Cady RK, Allan B, Pederson SM, Hirman J, Mehta LR, et al. Long-term safety and tolerability of eptinezumab in patients with chronic migraine: a 2-year, open-label, phase 3 trial. BMC Neurology. 2021;21(1):126.
  12. Silberstein S, Diamond M, Hindiyeh NA, Biondi DM, Cady R, Hirman J, et al. Eptinezumab for the prevention of chronic migraine: Efficacy and safety through 24 weeks of treatment in the phase 3 PROMISE-2 (Prevention of migraine via intravenous ALD403 safety and efficacy-2) study. Journal of Headache and Pain. 2020;21(1). doi:10.1186/s10194-020-01186-3.
  13. Smith TR, Spierings ELH, Cady R, Hirman J, Schaeffler B, Shen V, et al. Safety and tolerability of eptinezumab in patients with migraine: a pooled analysis of 5 clinical trials. Journal of Headache and Pain. 2021;22(1). doi:10.1186/s10194-021-01227-5.
  14. Ashina M, Goadsby PJ, Reuter U, Silberstein S, Dodick DW, Xue F, et al. Long-term efficacy and safety of erenumab in migraine prevention: Results from a 5-year, open-label treatment phase of a randomized clinical trial. European Journal of Neurology. 2021;28(5):1716–1725.
  15. Tepper SJ, Ashina M, Reuter U, Brandes JL, Doležil D, Silberstein SD, et al. Long-term safety and efficacy of erenumab in patients with chronic migraine: Results from a 52-week, open-label extension study. Cephalalgia. 2020;40(6):543–553.
  16. Barbanti P, Aurilia C, Egeo G, Fofi L, Cevoli S, Colombo B, et al. Erenumab in the prevention of high-frequency episodic and chronic migraine: Erenumab in Real Life in Italy (EARLY), the first Italian multicenter, prospective real-life study. Headache. 2021;61(2):1–10.
  17. Barbanti P, Aurilia C, Cevoli S, Egeo G, Fofi L, Messina R, et al. Long-term (48 weeks) effectiveness, safety, and tolerability of erenumab in the prevention of high-frequency episodic and chronic migraine in a real world: Results of the EARLY 2 study. Headache. 2021;61(9):1–13.
  18. Ashina M, Kudrow D, Reuter U, Dolezil D, Silberstein S, Tepper SJ, et al. Long-term tolerability and nonvascular safety of erenumab, a novel calcitonin gene-related peptide receptor antagonist for prevention of migraine: A pooled analysis of four placebo-controlled trials with long-term extensions. Cephalalgia. 2019;39(14):1798–1808.
  19. Camporeale A, Kudrow D, Sides R, Wang S, van Dycke A, Selzler KJ, et al. A phase 3, long-term, open-label safety study of Galcanezumab in patients with migraine. BMC Neurology. 2018;18(1). doi:10.1186/s12883-018-1193-2.
  20. Ashina M, Saper J, Cady R, Schaeffler BA, Biondi DM, Hirman J, et al. Eptinezumab in episodic migraine: A randomized, double-blind, placebo-controlled study (PROMISE-1). Cephalalgia. 2020;40(3):241–254.
  21. Buse DC, Gandhi SK, Cohen JM, Ramirez-Campos V, Cloud B, Yang R, et al. Improvements across a range of patient-reported domains with fremanezumab treatment: Results from a patient survey study. Journal of Headache and Pain. 2020;21(1). doi:10.1186/s10194-020-01177-4.
  22. Lipton RB, Goadsby PJ, Smith J, Schaeffler BA, Biondi DM, Hirman J, et al. Efficacy and safety of eptinezumab in patients with chronic migraine: PROMISE-2. Neurology. 2020;94(13):E1365–E1377.
  23. Pederson S, Biondi DM, Allan B, Cady R, Schaeffler B, Baker B, et al. Clinical Immunogenicity Evaluation of Eptinezumab, a Therapeutic Humanized Monoclonal Antibody Targeting Calcitonin Gene-Related Peptide (CGRP) for the Preventive Treatment of Migraine. Frontiers in Immunology. 2021;12. doi:10.3389/fimmu.2021.765822.
  24. Ornello R, Tiseo C, Frattale I, Perrotta G, Marini C, Pistoia F, et al. The appropriate dosing of erenumab for migraine prevention after multiple preventive treatment failures: a critical appraisal. The Journal of Headache and Pain. 2019;20(1):99.
  25. Ornello R, Casalena A, Frattale I, Gabriele A, Affaitati G, Giamberardino MA, et al. Real-life data on the efficacy and safety of erenumab in the Abruzzo region, central Italy. Journal of Headache and Pain. 2020;21(1). doi:10.1186/s10194-020-01102-9.
  26. Lambru G, Hill B, Murphy M, Tylova I, Andreou AP. A prospective real-world analysis of erenumab in refractory chronic migraine. Journal of Headache and Pain. 2020;21(1):61.
  27. Scheffler A, Messel O, Wurthmann S, Nsaka M, Kleinschnitz C, Glas M, et al. Erenumab in highly therapy-refractory migraine patients: First German real-world evidence. Journal of Headache and Pain. 2020;21(1). doi:10.1186/s10194-020-01151-0.
  28. Robblee J, Devick KL, Mendez N, Potter J, Slonaker J, Starling AJ. Real-World Patient Experience With Erenumab for the Preventive Treatment of Migraine. Headache. 2020;60(9):2014–2025.
  29. Raffaelli B, Kalantzis R, Mecklenburg J, Overeem LH, Neeb L, Gendolla A, et al. Erenumab in Chronic Migraine Patients Who Previously Failed Five First-Line Oral Prophylactics and OnabotulinumtoxinA: A Dual-Center Retrospective Observational Study. Frontiers in Neurology. 2020;11. doi:10.3389/fneur.2020.00417.
  30. Haanes KA, Edvinsson L, Sams A. Understanding side-effects of anti-CGRP and anti-CGRP receptor antibodies. Journal of Headache and Pain. 2020;21(1). doi:10.1186/s10194-020-01097-3.
  31. US Food and Drug Administration. Full Prescribing Information - Erenumab. 2021 Accessed 26 October 2021.
  32. Datta A, Maryala S, John R. A Review of Eptinezumab Use in Migraine. Cureus. 2021;13(9):e18032.
  33. Sacco S, Bendtsen L, Ashina M, Reuter U, Terwindt G, Mitsikostas DD, et al. European headache federation guideline on the use of monoclonal antibodies acting on the calcitonin gene related peptide or its receptor for migraine prevention. Journal of Headache and Pain. 2019;20(1). doi:10.1186/s10194-018-0955-y.
  34. Garcia-Ayala M, Veronesi M, Verhaak A, Grosberg B. Calcitonin gene-related peptide (CGRP) monoclonal antibody (MAB) wear-off phenomenon in the treatment of migraine. 2021. Presented at the 63rd Annual Scientific Meeting American Headache Society 2021, June 3-6 2021. Virtual. P-107.
  35. Ailani J, Kuruppu D, Rettiganti M, Oakes T, Wietecha L, Port M, et al. Does wearing off of efficacy occur in galcanezumab-treated patients at the end of the monthly treatment cycle: A post hoc analysis of four phase 3 randomized trials. 2021. Presented at the 63rd Annual Scientific Meeting American Headache Society 2021. 3–6 June 2021. Virtual. P-65 Accessed 3 November 2021.
  36. Pozo-Rosich P, Samaan KH, Schwedt TJ, Nicholson RA, Rettiganti M, Pearlman EM. Galcanezumab Provides Consistent Efficacy Throughout the Dosing Interval Among Patients with Episodic and Chronic Migraine: A Post Hoc Analysis. Advances in Therapy. 2021;38(6):3154–3165.

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