Objectives

The systematic review and pairwise meta-analysis had the objective of synthesizing new randomized clinical trials and further characterizing the preventive treatment response of both old and new migraine preventive therapies in adults.

All available data of relevance to clinicians was summarized, and expert guidance on utilization of therapies for migraine prophylaxis was provided through a consensus process. This guidance is intended for Canadian neurologists and primary care providers to have an approach for managing migraine prevention guided by a systematic synthesis and interpretation of the literature available in 2023.

Methods

Outcomes

Efficacy outcomes included a reduction in monthly migraine days and a 50% reduction in mean migraine days per month. Where migraine days were not reported, a reduction in headache days was used as a surrogate outcome.

Safety outcomes included percentage of patients reporting adverse events (AEs), serious AEs and withdrawal due to AEs.

Information sources and strategy

A systematic search strategy was developed by an experienced information specialist in consultation with the review team. A second experienced research librarian peer-reviewed the MEDLINE search prior to execution using the PRESS checklist. ^{Reference McGowan, Sampson, Salzwedel, Cogo, Foerster and Lefebvre22} Using the multifile option and deduplication tool available on the Ovid platform, Ovid MEDLINE® ALL, Embase and Cochrane CENTRAL were searched. The search strategy employed a combination of controlled vocabulary (e.g., “migraine,” “calcitonin gene-related peptide”) and related key words (e.g., migraine, migraine prevention, anti-CGRP mAbs, erenumab). For additional information on the search and gray literature sources, please see Appendix 1. Articles found outside the main search were identified in the Preferred Peporting Items for Systematic Review and Meta-analyses (PRISMA) flow diagram. ^{Reference Moher, Liberati, Tetzlaff and Altman23}

Study records

Risk of bias in individual studies

Risk of bias (ROB) assessments were carried out on each study independently by two review team members (IM and SC) using the Cochrane ROB 2 tool. If conflicts could not be resolved by discussion, ML or CS were available to cast a final vote.

Data synthesis

Data synthesis was done by one author (IM), although the data used was extracted independently and verified by two team members (IM and SC). For more details on data synthesis, please consult Appendix 1. We analyzed the doses which showed the best treatment responses, and we reported all the outcomes based on those doses. Meta-analyses were performed using random effects models where possible. We did meta-analyses where there were multiple studies with the same treatments. For all analyses, data for episodic migraine and chronic migraine was analyzed separately. To assess for publication bias, funnel plots and comparison-adjusted funnel plots were planned if sufficient studies were available; however, these were not undertaken because we did not have any treatment with more than 10 studies. ^{Reference Guyatt, Oxman and Montori25} Findings from the review are reported based upon updated guidance from the PRISMA. ^{Reference Page, McKenzie and Bossuyt26}

Confidence in cumulative evidence

A modified form of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process was used to determine confidence in evidence for each outcome. In this process, the evidence was analyzed based on various parameters of ROB (multiple types), consistency, directness, precision and publication bias. ^{Reference Guyatt, Oxman and Akl27} This has been the standard for neurology guidelines. ^{Reference Gronseth, Cox, Gloss and Merilliat1,28}

Across each intervention analyzed, we summarized all outcomes available from those we have prespecified by building a GRADE summary of finding tables, ^{Reference Guyatt, Oxman and Akl27} created using the GRADE profiler (GRADEpro) software. ²⁹ Outcome importance was ranked a priori into the groupings of critical in all outcomes. ^{Reference Guyatt, Oxman and Kunz30} The quality of evidence for all critical outcomes is reported in Appendix 2, but in this document, we report the lowest quality of evidence for critical outcomes. We identified the quality of evidence as high when we were confident the true effect was close to the estimate given, moderate when we felt that it was somewhat likely we were close to the true effect, low when we were not sure our estimate was close to the true effect and very low when we had little confidence in the effect estimate as we highlight in Table 1. ^{Reference Pringsheim, Davenport and Mackie17,Reference Balshem, Helfand and Schünemann31}

Table 1. Level of evidence in GRADE

After arriving at the quality of evidence for the evidence base, a modified Delphi consensus process ^{Reference Hsu and Sandford32} with members of the Steering Committee and the Recommendation Committee consisting of a panel of experts within the CHS was undertaken to provide recommendations, using Welphi. Welphi is an online survey platform that implements the Delphi method. ³³ Multiple rounds were circulated to the group until a 70% consensus was achieved.

A strong recommendation was made when the Recommendation Committee members were confident that the intervention could be used for most patients and that the benefits of therapy outweigh the potential risks. A weak recommendation was made when the Recommendation Committee members were less confident that the desirable effects probably outweighed the undesirable effects. The treatment may be considered in some but may not be appropriate in others, and the consideration may depend on the patient and clinical situation. These categories are highlighted in Table 2.

Table 2. GRADE recommendation and certainty of evidence explained

Questions for consideration in migraine prevention

1. 1. Who should receive preventive treatment? ^{Reference Pringsheim, Davenport and Mackie17}

   1. a. Patients with 4 or more moderate or severe headache days a month not responding to acute medication.

   2. b. Patients with 8 or more headache days a month, even when acute medications are effective, as the risk of medication overuse headache (MOH) is increased in this group.

   3. c. Patients who have migraine attacks with a significant impact on their life, despite using acute medications and trigger management/lifestyle modification strategies. The number of migraine days may be 3 or less in these situations if the impact is severe.

2. 2. What should be considered when choosing a migraine preventive drug? ^{Reference Pringsheim, Davenport and Mackie17}

   1. a. Efficacy: What is the confidence in the evidence and expected size of the effect of the drug in reducing migraine frequency?

   2. b. Drug side effect profile: How safe and well tolerated is the drug?

   3. c. Comorbid disorders (depression, anxiety, insomnia, obesity, hypertension, history of renal calculi, constipation, vascular disorders).

   4. d. Patient disability and migraine severity.

   5. e. Pregnancy planning and appropriate contraception.

   6. f. Patient preference.

3. 3. What constitutes an adequate preventive trial?

   1. a. Drugs should be continued at a target dose for at least 2 months for an adequate trial unless side effects make drug discontinuation necessary. ^{Reference Pringsheim, Davenport and Mackie17}

   2. b. In the case of anti-CGRP mAbs, the majority of patients can be evaluated for response after 3 months. However, especially in patients with a history of treatment-resistant chronic migraine, the improvement might be subtle over the first 3 months but become more apparent and clinically significant over 6 months. ^{Reference Schim, Anderson and Brunner90,Reference Kuruppu, North, Kovacik, Dong, Pearlman and Hutchinson91}

   3. c. In the case of onabotulinumtoxinA, patients should have a minimum of two quarterly injections, and three quarterly injections could be reasonable. ^{Reference Silberstein, Dodick and Aurora92}

4. 4. When should preventive therapy be considered effective? ^{Reference Pringsheim, Davenport and Mackie17}

   1. a. Headache diaries are important in evaluating treatment effectiveness, and we recommend patients use one of the mobile applications available or a paper diary. ^{Reference Baos, Ester and Castellanos93,Reference Nappi, Jensen, Nappi, Sances, Torelli and Olesen94}

   2. b. Headache frequency or intensity is reduced by 50% or more, although less reductions of headache frequency may be worthwhile, particularly if the drug is well tolerated.

   3. c. Reduction in headache intensity and migraine-related disability also need to be considered. ^{Reference Pringsheim, Davenport and Mackie17,Reference Society95}

      For example:

      1. (i) Migraine Disability Assessment (MIDAS) Score

         • Reduction of ≥5 points for a baseline score between 11 and 20

         • Reduction of >30% for a baseline score >20

      2. (ii) Headache Impact Test with 6 items (HIT-6) Score

         • Reduction of ≥5 points

5. 5. How long should successful preventive therapy be continued? ^{Reference Pringsheim, Davenport and Mackie17}

This opinion is from expert consensus, as there are no randomized studies providing clear guidance on the optimal duration of migraine preventive treatments. This broadly generalized approach may not be appropriate, and this may have to be assessed on a case-by-case basis. Longer duration of treatment may be particularly important with patients with a long history of chronic migraine. ^{Reference Sacco, Amin and Ashina96}

While using conventional oral preventive drugs, it is reasonable to consider tapering off medications at 12 months, especially if patients are doing well with a meaningful response to therapy and have reverted to an infrequent episodic pattern of headache (ideally 4–6 headache days) with good control with acute therapies, no risk of medications overuse headache and minimal disability. If headaches or migraine symptoms recur as the dose is decreased or as the drug is discontinued, the dose should be increased again, or the drug be restarted.

For those on newer agents such as onabotulinumtoxinA or anti-CGRP mAbs, discontinuation can also be considered based on patient preference. We recommend this only if there is an episodic pattern of migraine with very minimal disability for a period of at least 12 months. For onabotulinumtoxinA, a proposed method of attempting this is to increase the interval between injections and see if there is no worsening, the treatment can be stopped. ^{Reference Tassorelli, Sances and Avenali97} There are no long-term safety concerns with onabotulinumtoxinA to warrant discontinuation in patients who want to continue. ^{Reference Blumenfeld, Stark, Freeman, Orejudos and Manack Adams98} For anti-CGRP mAbs, this can also be attempted in a similar way with increasing the interval and restarting therapy if there is a worsening of attacks. There is some evidence that stopping anti-CGRP therapies leads to increased attacks, so patients should be warned accordingly. ^{Reference Blumenfeld, Stark, Freeman, Orejudos and Manack Adams98,Reference Al-Hassany, Lyons and Boucherie99} There are presently no known safety concerns with use that require stopping these medications after a specific treatment interval, ^{Reference Al-Hassany, Lyons and Boucherie99} but patients should be monitored for the possibility of new onset hypertension or worsening of existing hypertension. ^{Reference Wang, Fenton and Dao100–Reference Guerzoni, Castro, Brovia, Baraldi and Pani103}

What advice should be given to the patient with medication overuse when prevention is being considered? ^{Reference Pringsheim, Davenport and Mackie17}

1. a. When preventive therapy is started, patients should be evaluated for the presence of medication overuse and instructed accordingly regarding the appropriate amount of medication to use monthly, and the frequency of acute medication use should also be followed.

2. b. Evidence suggests that in many cases, a withdrawal may not be necessary and starting preventive therapy alone may be adequate. Still, a withdrawal may be necessary for some patients. ^{Reference Hird and Sandoe104–Reference Carlsen, Munksgaard and Nielsen106}

3. c. As opioid and barbiturate-induced MOH is more likely to occur, ^{Reference Bigal and Lipton107} and in clinical experience may be less likely to respond to prevention, we recommend taper in these situations. ^{Reference Diener, Antonaci and Braschinsky108}

Chronic migraine and overlap with high-frequency episodic migraine (HFEM)

The previous CHS Guideline of 2012 did not address chronic migraine. In the current definition of ICHD3, chronic migraine is currently defined as 15 or more headache days per month, with at least 8 days having migrainous features or response to migraine-specific medications. ¹⁹ This definition is somewhat arbitrary, ^{Reference Medrea and Christi109} and in fact chronic migraine and HFEM have a lot of similarities as we discuss below.

The following have been shown to be efficacious in the treatment of chronic migraine: propranolol, topiramate, onabotulinumtoxinA, erenumab, galcanezumab, fremanezumab, eptinezumab and atogepant.

Recent papers have highlighted that the disability burden experienced by migraine patients is driven by the number of migraine days per month and patients with episodic migraine who have 8 or more migraine days per month experience a high degree of disability, similar to chronic migraine patients who have 8 or more migraine days per month. ^{Reference Chalmer, Hansen, Lebedeva, Dodick, Lipton and Olesen110,Reference Ishii, Schwedt and Dumkrieger111} The degree of disability does tend to increase with the number of migraine days overall, and severe disability can start even at HFEM. ^{Reference Ishii, Schwedt and Dumkrieger111,Reference Torres-Ferrús, Quintana, Fernandez-Morales, Alvarez-Sabin and Pozo-Rosich112} This has led to the suggestion that the requirement for 15 or more headache days be dropped from the future ICHD definition of chronic migraine. ^{Reference Chalmer, Hansen, Lebedeva, Dodick, Lipton and Olesen110,Reference Ishii, Schwedt and Dumkrieger111}

Special considerations for anti-CGRP therapies

The CGRP-blocking medications are widely used in migraine. However, their place in first-line migraine prevention may not be cost-effective in all instances. ^{Reference Burch21,Reference Schulman, Lake and Goadsby113–Reference Blumenfeld, Frishberg and Schim117} As guideline developers in constrained resource settings, we must consider this aspect. ^{Reference Mechtler, Saikali, McVige, Hughes, Traut and Adams118,Reference Pellesi, Do, Ashina, Ashina and Burstein119} Additionally, a network meta-analysis performed by the Institute for Clinical and Economic Review found these medications not to be superior in efficacy to older medications for episodic migraine prevention however using older trials that may not be comparable. ^{Reference Burch120} For chronic migraine, only comparison possible was with topiramate. ^{Reference Burch120} Now we have a head-to-head trial of topiramate versus erenumab, this showed the superiority of erenumab both in terms of efficacy and tolerability. ^{Reference Reuter, Ehrlich and Gendolla76} These medications are also likely better tolerated in clinical practice when compared to oral preventives. ^{121–Reference Smirnoff123}

In a Canadian context, Canadian Agency for Drugs and Technologies in Health (CADTH) found the use of these newer treatments first line to not be cost-effective when looking only at direct costs. ^{Reference Schulman, Lake and Goadsby113–Reference Blumenfeld, Frishberg and Schim117} For chronic migraine and likely HFEM, cost-effectiveness on direct costs is likely not the only consideration. The quite high indirect costs are important, ^{Reference Wong, Khalil and Ahmed124} along with the high burden of disability of these patients ^{Reference Blumenfeld, Varon and Wilcox10,Reference Ishii, Schwedt and Dumkrieger111,125} and the evidence of poor tolerability of older medications in the context of these patients likely needing long-term use. ^{121,Reference Brin, Kirby and Slavotinek122} The only study in patients where no prior preventive failure was required (the population we are proposing these medications be used in) looking at indirect costs shows that these medications are cost-effective in chronic migraine patients ^{Reference Noseda, Bedussi, Gobbi, Ceschi and Zecca126} at a threshold likely acceptable in a Canadian setting. ^{Reference Bussiere, Davies and Dean127} In this particular study, their use is not cost-effective in episodic migraine patients, but there was no separate HFEM group. ^{Reference Noseda, Bedussi, Gobbi, Ceschi and Zecca126}

In patients with moderate-frequency episodic migraine (MFEM) (4 or more migraine days up to 7), we would consider it reasonable to allow the use of these medications after failure or intolerance of two preventive therapies unless data shows this to be cost-effective as first-line use.

In a Canadian context, the indirect and direct costs of chronic migraine and HFEM are similar and significantly higher than low-frequency episodic migraine. ^{Reference Wong, Khalil and Ahmed124} We believe it is reasonable to recommend that all patients with HFEM (8 or more migraine days, but less than 15 headache days) with moderate disability and all patients with chronic migraine (8 or more migraine days and 15 or more headache days) get access for first-line use of these medications with other medications, given the high indirect costs incurred by these patients, and because likely the use of these medications leads to savings overall on indirect costs. ^{Reference Yadav, Yadav, Goel, Singh, Natu and Negi128} Should the ICHD incorporate HFEM into the definition of chronic migraine in the future, then we would recommend that the requirement to demonstrate moderate disability be removed.

Indication for treatment with CGRP targeting agents (atogepant, eptinezumab, galcanezumab, erenumab, fremanezumab)

1. A. MFEM (4–7 MMD)

   1. (i) Intolerance/contraindication or inadequate response to an 8-week trial of at least two non-CGRP targeting oral preventive therapies.

2. B. HFEM (8–14 MMD)

   1. (i) At least moderate disability as shown by one of:

      1. a. MIDAS score ≥11

      2. b. HIT-6 score >50

      3. c. Clinical impression

   2. (ii) If condition (i) met, no requirement for a trial of non-CGRP oral preventive therapies

3. C. Chronic migraine

   No requirement for MIDAS, HIT-6 or trial of non-CGRP targeting oral preventive therapies.

   Treatment options include:

   1. (i) Atogepant, eptinezumab, galcanezumab, erenumab, fremanezumab

   2. (ii) OnabotulinumtoxinA

   3. (iii) Propranolol

   4. (iv) Topiramate

The choice among the different treatment options for episodic and chronic migraine would depend on the healthcare practitioner’s assessment of the clinical situation as well as patient preference.

We would like to acknowledge that the possibility of unknown and perhaps serious side effects is present with many new medications up to 10 years after their introduction in up to a third of drugs, and we should remain vigilant with these newer therapies and may revise our recommendations. ^129,130

Further considerations in clinical use:

1. a. Before starting these therapies, we recommend individualized clinical assessment of vascular disease and risk factors. Generally, anti-CGRP therapies have had a good cardiovascular and cerebrovascular safety profile in patients with no active cardiovascular or cerebrovascular disease, ^131,132 but caution should be exercised especially in patients with recent cerebrovascular or cardiovascular events as this population was excluded from clinical studies.

2. b. There have been reports of worsening and new onset Raynaud’s phenomena ^{130,133–135} and alopecia, ¹³⁰ and individualized decision-making should be considered.

3. c. In patients with severe constipation, erenumab and atogepant should be used with caution. ^{Reference Ailani, Lipton and Goadsby34–Reference Pozo-Rosich, Ailani and Ashina36,Reference Wang, Roxas and Saravia46,136}

4. d. There are reports of worsening of hypertension or de novo hypertension in some patients on erenumab and possibly other anti-CGRP therapies. ^{Reference de Vries Lentsch, van der Arend, VanDenBrink and Terwindt102}

5. e. Switching in cases of treatment failure should also be considered, some observational studies indicate that after the failure of one anti-CGRP therapy, it is possible that an individual may respond to another anti-CGRP therapy, ^137–139 and there is also the option of class switching from a receptor antibody to a ligand antibody and vice versa. ^{Reference Haycox, Bagust and Walley140,Reference Hill, Olson and Falck-Ytter141}

6. f. We do recommend that switching between anti-CGRP therapies in cases of side effects or patient preference:

   • – switching from erenumab or atogepant to a CGRP ligand blocker in cases of constipation

   • – switching to eptinezumab in cases of injection site reactions

   • – switching from erenumab to fremanezumab in cases of hypertension ^{Reference de Vries Lentsch, van der Arend, VanDenBrink and Terwindt102}

   • – switching to an antibody with quarterly dosing for patients preferring this option instead of monthly dosing.

Clinical strategies for migraine prevention ^{Reference Pringsheim, Davenport and Mackie17}

1. 1. First-time strategy

   1. (a) Beta-blocker strategy: Propranolol, nadolol, metoprolol

   2. (b) Candesartan: With caution in patients of childbearing potential regarding safety issues in pregnancy

   3. (c) CGRP-blocking strategy: Erenumab *, galcanezumab*, fremanezumab *, eptinezumab *, atogepant * in HFEM (with moderate disability using MIDAS, HIT-6 or clinical impression) and chronic migraine. For the anti-CGRP mAbs, caution should be exercised in patients of childbearing age.

   4. (d) Toxin strategy: OnabotulinumtoxinA should be considered first line in chronic migraine (≥8 migraine days per month and ≥15 headache days).

   5. (e) Tricyclic strategy: Amitriptyline

2. 2. Low side effect strategy

   1. (a) Candesartan

   2. (b) Herbal/vitamin/mineral: Magnesium citrate, riboflavin, coenzyme Q10, melatonin

   3. (c) CGRP-blocking strategy: Erenumab *, galcanezumab*, fremanezumab *, eptinezumab *, atogepant *

   4. (d) Toxin strategy: OnabotulinumtoxinA in chronic migraine.

3. 3. Increased body mass index strategy

   Topiramate

   Atogepant *

4. 4. Hypertension strategy

   Propranolol, candesartan, nadolol, metoprolol

5. 5. Depression/anxiety strategy

   Amitriptyline, venlafaxine

6. 6. Medications that can be considered in certain patients – weak recommendation

   These treatments are also recommended for use as monotherapy, in addition to the strategies outlined above.

   Levetiracetam* memantine* and rimegepant*, **

   Topiramate, valproic acid, pizotifen, flunarizine and verapamil

   *New treatments added since 2012 CHS Guideline

   ** Not approved for use in Canada

7. 7. Refractory patient strategy ^{Reference Pringsheim, Davenport and Mackie17}

   Refractory migraine is defined as a condition in which symptoms cause significant interference with the ability to function or quality of life despite the use of acute and preventive treatment. ^{Reference Pringsheim, Davenport and Mackie17,Reference Schulman, Lake and Goadsby113–Reference Martelletti, Katsarava and Lampl115} Treatment-resistant migraine is defined as a patient with a failure of properly dosed trials of medications from at least two classes of prophylactic medications. ^{Reference Schulman, Lake and Goadsby113–Reference Martelletti, Katsarava and Lampl115} In refractory patients, there is ample evidence that anti-CGRP mAbs ^{Reference Ashina, Lanteri-Minet and Pozo-Rosich41,Reference Reuter, Goadsby and Lanteri-Minet47,Reference Ferrari, Diener and Ning53,Reference Mulleners, Kim and Lainez60} and atogepant ^{Reference Tassorelli, Nagy and Pozo-Rosich37} can be effective even after other treatments fail. In all episodic migraine patients having failed other preventive therapies, anti-CGRP mAbs and atogepant should be offered. ^{Reference Ashina, Lanteri-Minet and Pozo-Rosich41,Reference Reuter, Goadsby and Lanteri-Minet47,Reference Ferrari, Diener and Ning53,Reference Mulleners, Kim and Lainez60}

Layering of treatment can also be considered in refractory patients. There is a rationale behind the layering of drugs; it is likely that different prophylactic drugs work by different mechanisms, and therefore, the effects of two drugs may be synergistic in reducing migraine frequency. Here are some strategies to consider and rationale:

1. i. There are observational studies showing increased benefit from using onabotulinumtoxinA and anti-CGRP mAbs or gepants in combination. ^{Reference Cohen, Armand, Lipton and Vollbracht116–Reference Mechtler, Saikali, McVige, Hughes, Traut and Adams118} This is reasoned to be due to the combined blockade of Adelta and C fibers CGRP signaling, likely adding synergistic benefit not seen with either therapy alone. ^{Reference Pellesi, Do, Ashina, Ashina and Burstein119} Based on expert consensus, we recommend considering layering of anti-CGRP therapies with onabotulinumtoxinA in refractory patients.

2. ii. There are observational studies on layering of older therapies with anti-CGRP therapies (erenumab), and although these studies are not randomized, there have been encouraging results with improvement in migraine days and acute medication use. ^{Reference Burch21,Reference McGowan, Sampson, Salzwedel, Cogo, Foerster and Lefebvre22} This strategy is recommended in other recent guidelines. ^{Reference Moher, Liberati, Tetzlaff and Altman23} Based on expert consensus, we recommend considering layering of older medications with anti-CGRP therapies in refractory patients, especially in cases where onabotulinumtoxinA can’t be used.

3. iii. There are observational studies showing improvement looking at combinations of older therapies beta-blockers or flunarizine with topiramate ^{Reference Vos, Abajobir and Abate15,Reference Goldberg16} and also valproate and beta-blockers. ^{Reference Pringsheim, Davenport and Mackie17} There was a negative randomized study looking at combining amitriptyline and topiramate; however, patient impression in this study was in favor of the combination. ¹⁸ Combination therapy using older therapies for refractory patients has been commonly recommended by other expert groups as well. ^19,20 In cases where newer anti-CGRP or toxin strategies can’t be used, we recommend considering layering of older therapies, being cognizant of possible side effects and interactions.

4. iv. There is also evidence for the use of other strategies such as behavioral interventions and neuro-modulation, but we have not reviewed these strategies for the current guideline. ^{Reference Higgins and Green24}

For further guidance, a review should be consulted, ^{Reference Higgins and Green24} and when possible, these patients should be considered for referral to a headache specialist for management.

These strategies are proposals. If a patient fits better in one strategy versus another, then the best medication should be used.

1. 8. Migraine during pregnancy and lactation strategy ^{Reference Schim, Anderson and Brunner90}

   1. (a) Migraine drug prophylaxis is best avoided during pregnancy and lactation, if possible. Strategies involving trigger avoidance and lifestyle factors should be considered.

   2. (b) If migraine drug prophylaxis is necessary during pregnancy or lactation, the best choice is a beta-blocker (propranolol or metoprolol), and if these are contraindicated or ineffective, amitriptyline can be considered. ^{Reference Burch120,121}

   3. (c) There is some evidence on the safety of onabotulinumtoxinA in patients exposed to it during pregnancy ^{Reference Brin, Kirby and Slavotinek122–Reference Wong, Khalil and Ahmed124} and also lactation. ¹²⁵ In patients with disabling treatment-resistant chronic migraine, this may be considered, but we caution that this data includes a small number of patients and can’t ascertain rare AEs. We recommend clinicians consider the use of onabotulinumtoxinA during pregnancy on a case-by-case basis.

   4. (d) There is some limited post-marketing data on the safety of anti-CGRP mAbs and gepants in pregnancy, ^{Reference Noseda, Bedussi, Gobbi, Ceschi and Zecca126} but this data includes very small numbers of patients and can’t ascertain AEs. As CGRP crosses the placenta ^{Reference Bussiere, Davies and Dean127} and is involved in uteroplacental circulation, ^{Reference Burch21} patients should not actively try to become pregnant until the treatment has been stopped for 6 months for anti-CGRP mAbs. For gepants, it should be sufficient to discontinue for a week before attempting to get pregnant based on the half-life of these agents. Patients should be advised accordingly.

   5. (e) Anti-CGRP mAbs are large molecules and would likely be destroyed in the gastrointestinal tract. They are not likely to be absorbed and transferred into breast milk. They may be safe, but there is a paucity of data available, ^129–132 and their use in lactation is currently not recommended. For available gepants, there is no data available on transfer to breast milk and infants, and their use in lactation is currently not recommended. Rimegepant, which is not approved for prevention in Canada, shows very low secretion in breast milk. ^{133,Reference Baker, Croop and Kamen134}

2. 9. Drugs not recommended

   1. (a) OnabotulinumtoxinA is not recommended for prophylaxis of episodic migraine, but there is an ongoing study, and as such, this recommendation may need to be reconsidered when more is known about the result of this study. ⁶⁵

   2. (b) Gabapentin is not recommended for prophylaxis of episodic migraine.

   3. (c) Statins alone or add-on are not recommended for prophylaxis of episodic migraine.

   4. (d) Ginger is not recommended for prophylaxis of episodic migraine.