Guest: Dr. Olivia Begasse de Dhaem

View the recording from our Migraine Clinician Masterclass, developed in partnership with IVPN Neuropsychiatry. In this webinar, we hear from Dr. Olivia Begasse de Dhaem, who discusses selecting an appropriate preventive medication for migraine management. Please note that this video is intended for healthcare providers.

TRANSCRIPT

Dr. Olivia Begasse de Dhaem: Hi, everyone. As-salamu alaykum. Thank you so much for having me. I’m very excited to be talking about how to select preventive treatment for migraine. So we’ll talk about the rationale for migraine preventions, the different options available, and what consideration do we think of when choosing migraine preventive treatment. 

So the rationale. So according to the American Headache Society consensus guidelines, the indication for starting migraine preventive therapy is a main indication is a combination of the migraine attack disability and the frequency of the attack. Other indications to start migraine preventive treatment, if people have contraindications, lack of response, side effects to acute treatment, overuse of acute treatment, patient preference. Having migraine attack can lead to a lot of anticipatory anxiety, so it can help for some people to be on migraine prevention. And then people with types of migraine that limits the acute treatment options, such as hemiplegic migraine, migraine with brain stem aura, migraine with prolonged aura, and prior migrainous infarction. So that’s what I was alluding to.

So there’s a good table from that paper combining the frequency of headache days and the degree of disability. So prevention should be offered for people who have at least 6 headache-days per month if they have no disability associated with these attacks, but then if there is disability, the threshold of frequency of headache-days decreases. 

So what are the goals of migraine preventive therapy? So the main goals are to decrease the frequency, severity, duration, disability, increase responsiveness to acute treatment, help people regain function, decrease disability, try to limit acute treatment use, help with anticipatory anxiety, help with quality of life.

So what are the success measures? The most common one nowadays is a reduction in monthly migraine-days or reduction in monthly headache-days, but the success measures have to be discussed with patients, especially for people with daily chronic headaches. Preventive treatment may not be able to reduce the frequency too much, but some people can have significant regain of function and be able to go back to work with preventive treatment that does not always necessarily decrease the frequency but decreases the severity of the attacks and the associated symptoms. So also other success measures increase responsiveness to acute treatment, decrease acute treatment use, and decrease anticipatory anxiety.

So picking a preventive migraine treatment plan is highly personalized, a different consideration that we think of. And then based on what you think is a good option for patients, I think it’s important to leave the option to the patient and have a joint decision as to what to start. But we obviously take into account efficacy, trying to start with established efficacy treatment first, the side effect profile, any other medical conditions, comorbidities, contraindication, drug-drug interaction with medications that are currently on, ease of use, different formulation, frequency, patient preference, family planning. We have to be mindful of safety of medication and pregnancy and breastfeeding. We start low and uptitrate slowly until the target dose or target response, or if there is a side effect, we go back to the lower previously tolerated dose. Then sometimes we can get away trying to treat different condition with one medication, but one medication is not recommended for multiple condition if that puts a risk of undertreating, for example, if the patient has migraine and depression.

So patient education, including the patient and that discussion on choice is very important. So it’s important to talk with the patients about the indication for preventive therapy, what are the goals, what are the types of preventive treatment, what are the options based on the possible side effects, benefit, what are the expectation and the success measures for them. It has to be realistic expectation. We don’t have a cure for migraine. It’s not like they’ll take this preventive medication for one month and everything will be gone. They can stop it and it’s not like they’re not going to have migraine breakthrough attack while on preventive treatment. And unfortunately, we cannot predict who responds to what. So it’s a trial and error process. We want to be about 6 weeks of trial for daily pills and then at least 3 months of trial for monoclonal antibodies.

So we have many options for migraine preventive treatment. I know this talk is about pharmacological options. I’ll briefly mention the other ones just to give you some perspective on a full picture because we can also combine things when discussing options with our patients. So in nutraceuticals is riboflavin, which is vitamin B2 recommended at 400 mg daily. It makes the urine fluorescent yellow. It contains breast milk too. So it’s good to tell people about that before starting it. Magnesium, which can be used oxide, gluconate, glycinate, aspartate or chelated, less than 250 mg tend to not work. Above 400 mg, people can have diarrhea. So people have to find the dose that work for them. And that’s mostly evidence for migraine with visual aura. And then there’s also coenzyme Q10 that is well tolerated, a little bit less quality of evidence. And then whatever is not recommended due to the concern for hepatotoxicity. 

Lifestyle modification. So Dr. Robblee and Dr. Starling came up with a mnemonic that I like, SEEDS for Success. So sleep, ensuring people have good sleep hygiene. If they have insomnia, considering cognitive behavioral therapy for insomnia. Regular exercise. Eating healthy and regularly, trying to not skip breakfast, even if it’s a yogurt or a few almonds in the morning. Making sure they stay hydrated. Ways of dealing with stress. 

So pharmacological prevention. So this is a table adapted from the AHS consensus statement. So established efficacy and probable efficacy according to the 2012 ANAHS guidelines with established efficacy with two high-quality studies, at least supporting it on probable efficacy with at least one high-quality and one lower-quality study or two lower-quality studies. So pharmacological prevention with established efficacies, blood pressure medications, propranolol, timolol, metoprolol, candesartan, antiepileptics, topiramate, divalproex sodium, CGRP monoclonal antibodies, onabotulinumtoxinA. For the prevention of chronic migraine,

options with probable efficacy, amitriptyline, venlafaxine, memantine, cyproheptadine, lisinopril, atenolol, nadolol, atogepant, rimegepant. Then I put other ideas there that were not in the table in case you run out of ideas or have tried all of the things in the prior columns. I personally don’t have experience with flunarizine and pizotifen because it’s not approved in the US, but to try to have different ideas.

Okay, so beta-blockers are also good to consider if people have anxiety, postural orthostatic tachycardia syndrome, hypertension, essential tremor, sexually induced headache. The side effects to look for, bradycardia, presyncope, erectile dysfunction, nausea, vomiting. Propranolol if the blood pressure is okay on the higher side. I usually start at 60-mg extended release, but if people have POTS or other issues or slightly low blood pressure, I usually start lower at 10 mg short-acting twice a day. Just so you know, it increases the plasma concentration of rizatriptan. And then it has been found that co-administration of propranolol with lasmiditan further reduces the heart rate, but it seems like it has been well tolerated. Then other option, atenolol, which we often use for people with asthma because it’s more beta-1 receptor selective, and metoprolol. 

So it’s also good for people with migraine or hypertension. Side effects to look for, cough, angioedema. Lisinopril. I usually start very low actually because I’ve seen people do well on 5 of lisinopril. So why go higher if it’s not necessary? And then candesartan usually started at 4 mg, and titrating up. Verapamil, maybe helpful for prolonged aura, frequent aura, brainstem aura, hemiplegic migraine. I think a lot of us like to do electrocardiogram before starting it with increased doses to look for heart block, bradycardia. Other side effects include edema, GI discomfort, constipation, dull headache, gingival hyperplasia.

Topiramate can also help for people with migraine who are looking for options for weight loss, if they have obesity. It has good efficacy, but tends to have more side effects, such as cognitive slowing, usually worse at higher doses, decreased appetite, paresthesia, tingling, which tend to get better with time and with enough hydration, kidney stone, acute angle closure, glaucoma, so trying to avoid in people with glaucoma or at risk of glaucoma, metabolic acidosis, and mood changes. And then sometimes people respond to regular topiramate, but don’t have too many side effects, and sometimes they do better on the longer-acting options available. Usually start at 25 mg, increase by 25 mg every week up to 100 mg, and it starts to interact with birth control at higher doses. 

So, valproic acid. Side effects to look for, weakening, somnolence, hair loss, tremor, thrombocytopenia, hepatotoxicity. So, those side effects tend to be discouraging and have actually good result with very low dose valproic acid extended release in people who have not that much response to other preventive treatments. I think it’s always a good option to keep in mind. And some people actually already do good at 125 or 250 extended release once per day at night. So, it’s a consideration to try low doses. 

Amitriptyline can also help with insomnia, fibromyalgia, neuropathic pain. Also more side effects with increased dosing. So, weight gain, constipation, dry eyes, dry mouth. I usually start people at 10 mg. A lot of people actually do well at 10 mg, but then sometimes we have to go up. And some people go also higher to 50 mg. You have to look for tachycardia, especially at higher doses. And be careful if people have asthma because albuterol can increase the QTc interval and high risk of ventricular arrhythmias with amitriptyline and albuterol. 

So, other options, SNRIs such as venlafaxine and duloxetine. Venlafaxine can be helpful for underlying depression, anxiety, other hot flashes of premenopausal transition. So, both several side effects, hypertension, constipation, diarrhea, withdrawal symptoms if stopped abruptly. So, it has to be a titrated stop. Usually start at 37.5 mg. Increase is an extended release option available. Sometimes duloxetine is used instead of venlafaxine because it has less withdrawal symptoms. It has better evidence in the pain world for people who also have other pains. 

Another option is memantine, tend to be well tolerated. Some people can have constipation or somnolence, and then you can start at 5 or 10 mg. So, cyproheptadine, which can cause sedation and weight gain. So, it’s not often used. 

So, I put the CGRP monoclonal antibodies in a table. So, I think it’s easier to compare them a little bit. So, erenumab is the one that binds to the CGRP receptors. The other ones bind to the ligand. They’re all subcutaneous except for eptinezumab, which is an IV infusion. And then eptinezumab is made from yeast compared to the other one from Chinese hamster ovary cell. They tend to have very similar half-lives, but the Tmax for eptinezumab is much shorter. So, some people can benefit as early as the next day. So, most of them are monthly injection. Fremanezumab can be quarterly, and eptinezumab is also quarterly. 

So, looking at the trial, and this is not head-to-head. This is from the different respective trials for the episodic migraine trial. So, the percent of patients with at least 50% reduction in the mean monthly migraine-days was, in general for them, between 19% and 24% reduction compared to the placebo. And then for the chronic migraine trial, so they were between 12% and 20%, less of the proportion of patients with proportion of patients with at least 50% reduction in mean monthly migraine-days for those with the CGRP monoclonal antibodies. So, they’re very effective. 

They tend to be well tolerated, too. One of the main side effects is injection site reaction from the studies. Erenumab tends to have less injection site reaction compared to fremanezumab and galcanezumab. There has been hypersensitivity reactions reported with fremanezumab, galcanezumab, and eptinezumab. My clinical practice, things have not been severe with the self-injectable, so I don’t retreat just to make sure when I send people for eptinezumab, I just ask all of them to be pre-treated with some IV Benadryl, just to be on the safe side. Then constipation is one of the side effects of the self-injectable CGRP monoclonal antibodies, seemingly a little bit more so for erenumab. There has also been some data of increased blood pressure for people on erenumab. And the good thing is that they don’t have drug-drug interactions.

So looking at the consensus-based recommendation on the use of CGRP-based therapies for migraine prevention in the UAE, so CGRP monoclonal antibodies should be considered as a first-line option, and rimegepant may be considered as a first-line option for episodic migraine. The CGRP mAbs should be initiated by a neurologist. There should be a consideration for a pause in treatment after a minimum of 12 months. The meaningful improvement suggested is at least 50% decrease in the pain burden at 3 months for episodic migraine, and at least 30% of decreased pain burden at 6 months for chronic migraines. They also said that if there is inadequate or loss of response, there can be a switch in the CGRP monoclonal antibody agent, and to avoid in pregnancy and breastfeeding, and to be cautious for people with cardiovascular risk factors. 

So gepants, also putting them in a table so it’s easier to visualize. Atogepant is a regular pill. Rimegepant is a dissolvable tablet. So the dose is either 10, 30, or 60 mg of atogepant for episodic migraine, 60 mg for chronic migraine, and atogepant is 75 mg every other day. They tend to have very similar half-life, Tmax. So side effects of atogepant include nausea, constipation, fatigue. And with rimegepant, nausea and sedation.

So also because they’re newer medication, result from the randomized control trial. So for rimegepant, they were including episodic migraine and chronic migraine baseline about 10 monthly migraine-days, and about 0.8-point difference in the change in monthly migraine days between placebo and rimegepant, about also 8% difference in the proportion of patients with at least 50% of decreased monthly migraine-days. 

For atogepant, there’s a trial for episodic migraine and one for chronic migraine. So baseline monthly migraine-days for episodic migraine was 7.4, with about a 1.7 difference in change in monthly migraine-days between placebo and 60 mg, and about a 30% difference in proportion of patient with at least 50% decrease in monthly migraine-days. And then for chronic migraine, the baseline was about 19 monthly migraine-days with about a 1.8 difference in the change in monthly migraine-days, and about 15% difference in the proportion of patients with at least 50% reduction in monthly migraine-days. 

So just to be mindful of drug interaction with the gepants. So try to avoid with potent CYP3A4 inhibitors because they’re metabolized by CYP3A4, so ketoconazole, itraconazole, like antifungus, some antibiotics. And then you can use a lower gepant dose when it’s possible, like for example, a lower dose of atogepant with moderate CYP3A4 inhibitors, and then avoid with potent CYP3A4 inducers. 

OnabotulinumtoxinA, so usually doing between 155 and 195 units every 3 months for the prevention of chronic migraine. Good thing, there’s no drug-drug interaction, no systemic side effects. So in the PREEMPT trials, mean monthly migraine-days was 19 days at 6 months away, 1.5 difference in transient monthly migraine-days between placebo and Botox injection. So side effects to look for, neck pain, eyelid ptosis, musculoskeletal stiffness, injection site pain. And then the effects of onabotulinumtoxinA injection actually tend to increase over time. So people tend to have even more benefits with repeated injections. 

So it’s not a head-to-head comparison, just like to put things in a table to visualize things, but these are just separate trials for the different medications, just to give some idea about this in a way, head-to-head trials. There has been some trial comparing onabotulinumtoxinA and topiramate and comparing onabotulinumtoxinA and amitriptyline, showing similar efficacy. OnabotulinumtoxinA was better tolerated, but in general, basically putting the results that we have discussed all in a table on all of this have been shown to have good efficacy.

So there is some rationale for combining onabotulinumtoxinA and CGRP blockade. So there are some preclinical data that suggest that onabotulinumtoxinA inhibits the CGRP release from the C-fibers, but then that’s the CGRP monoclonal antibodies, and atogepant mainly prevents a delta-fiber activation. So it may be they act on different areas so there may be a synergistic effect. And there’s a case series on the retrospective study of patients who have been on CGRP monoclonal antibodies and onabotulinumtoxinA as a combination with increased effect of using the combination. So we definitely need more data, but that’s something that seems to have some rationale.

So just considerations in pregnancy, so cyproheptadine, memantine, propranolol, verapamil, flunarizine at low doses. Other option, nerve block with lidocaine, riboflavin, CoQ10, optimizing the behavioral therapy or acupuncture. There is some evidence for devices in pregnancy, like the external trigeminal nerve stimulation and the remote electrical neurostimulation. Regular exercise. And for most people, migraine tends to get better during pregnancy. So sometimes it’s actually more of an issue during conception planning than as pregnancy progress, but unfortunately, some people can also continue to have severe migraine during pregnancy. 

So then based on your comfort and discussion with patients, you can consider things like low dose amitriptyline or onabotulinumtoxinA injection. In the Allergan safety database, there were comparable prevalence of fetal defects in people exposed to Botox injections in pregnancy compared to the general population.

So medications that we try to avoid in pregnancy. Venlafaxine, ACE, ARBs, divalproex sodium, topiramate, CGRP monoclonal antibodies, gepants. And then consideration for breastfeeding. And I also like to ask because for a lot of women, breastfeeding is protective. So when they’re fully breastfeeding, for a lot of people, they tend to not have migraine, but then when they’re weaning their kid of breastfeeding and they breastfeed just a tiny bit at night, once per day, sometimes that’s when the migraine attack come back. So that’s actually important. If they’re barely breastfeeding, that can give more options.

First line, verapamil, propranolol. Other consideration, tricyclics, gabapentin, Lyrica, memantine, riboflavin. There is no data that I know of Botox or CGRP mAbs or gepants. And then being careful with beta-blockers and tricyclics. If the baby is sleepy, low birth weight, not gaining enough weight.

So for the prevention of pure menstrual migraine, when women only have migraine, but migraine attacks around menses, they may not want to be on a daily preventive or on a monthly injectable prevention. So then we consider mini prevention. There’s some data for naratriptan or frovatriptan used that way. Some people use naproxen or nabumetone, longer-acting NSAID during those 5 days that is needed as standing mini prevention. And then there’s been some evidence of ubrogepant working as well for menstrually related attacks compared to non-menstrually related attacks. So also consideration of a standing gepant during that time.

So it’s easier for women who don’t have aura. So we don’t start continuous birth control for pure menstrual migraine, but if they have other indications or are willing to use birth controls and consideration of continuous birth control. So we have different options that don’t really either completely skip the inactive or they don’t really have an inactive period. During that period, they still receive estrogen, but at a lower dose. And these three options in the table actually have some evidence of addressing menstrually related migraine. If women have a contraindication to estrogen or have migraine with aura, it tends to be more tricky. We can try a continuous progesterone or monophasic progesterone, but as far as I know, there’s no good evidence that it actually impacts the menstrual migraine part of things. 

So this is a table modified from Dr. Burch’s article in Continuum in 2021 to try to summarize how we approach migraine preventive therapy. So there’s a characteristic of the patient and then which preventive medication would make sense to try and then which one to avoid.

So for hypertension, trying hypertensive medication, avoiding erenumab, venlafaxine, duloxetine, things that can increase blood pressure. For POTS, considering propranolol, avoiding lisinopril, candesartan, tricyclic. Migraine with fibromyalgia, neuropathic pain, trying tricyclic, SNRIs. Same thing for depression, trying to avoid the beta-blockers for severe depression. Migraine and anxiety, again, tricyclic, SNRIs, good try propranolol. Hydroxyzine, avoiding topiramate, as it can make it worse. Insomnia, trying tricyclics, obesity, trying topiramate since it can decrease appetite and also avoiding preventive medications such as tricyclics, valproate, cyproheptadine that can increase weight. If people have fatigue, exercise intolerance, trying topiramate, venlafaxine, CGRP mAbs, onabotulinumtoxinA, and trying to avoid tricyclics, beta-blockers, verapamil, atogepant. 

Then with cognitive symptoms, can try lisinopril, candesartan, venlafaxine, memantine, avoiding topiramate. With glaucoma, avoid topiramate, amitriptyline. Frequent migraine aura, you can try magnesium, topiramate, valproate, verapamil, avoid topiramate and zonisamide in people who have a history of calcium kidney stones. And then pregnancy, breastfeeding, we went over it. And hot flashes too. I put it back just for making this table comprehensive. 

And if people have a lot of different issues, I like CGRP monoclonal antibodies or Botox injections because they don’t interact with other medications. And sometimes people are already on so many medications, for those that don’t want to take yet another pill every day, and then you are stuck in all these drug-drug interactions. And also if they have issues with medication absorption, in which case do a trial of rimegepant ODT is a good idea. And then chronic migraine, CGRP monoclonal antibodies, Botox injections, topiramate.

So this was a summary for basically the pharmacological options, which is the main topic of this talk, but just to give you a brief overview, just for sake of completion of mind, body, physical, and behavioral intervention. So there’s great evidence for biofeedback, cognitive behavioral therapy, mindfulness, and relaxation training. And then there’s also emerging evidence for yoga and acceptance commitment therapy. And there’s also evidence for acupuncture. 

So the good thing of these interventions is that with regular practice, the process tends to benefit, they tend to be free of side effects. They can be combined with other preventive options. Some people prefer to not jump to pharmacological intervention. Then also to be considered in people with very high migraine-related disability and a lot of comorbidities. 

So biofeedback basically is an easy way to visualize people’s physiologic function. People get training to gain voluntary control to self-regulate those functions, and then continued self-practice maintains the benefits over time. Cognitive behavioral therapy is another possible preventive option. It tends to be a lot of homework for the patients, so expectations have to be set. It’s time-limited and it has been shown to increase self-efficacy, decrease pain catastrophizing, decrease the frequency of medication use, but we need more data on more migraine-specific outcomes. 

And there’s different ways of doing relaxation training. It can be taught by a healthcare professional or support material. And again, you need independent practice for sustained benefit. Mindfulness and acceptance commitment therapies were a good paper by Dr. Wells on the mindfulness-based stress reduction intervention for people with migraine that was shown to decrease disability, increase quality of life, increase self-efficacy, and decrease pain catastrophizing.

Acupuncture, so from the Cochrane database review, it seems that acupuncture is at least similarly effective as prophylactic medication, but this was done before the newer CGRP blockade medication. And then, as I mentioned earlier, it’s always very important to educate patients and their loved ones as much as possible and make them part of the treatment plan to help empower them, and then they can be their own self-advocate. 

Neurostimulation, so it can be used as an adjunct if people have insufficient benefit from pharmacological prevention, or it may be the patient’s preference, or if people have too much side effects from pharmacological prevention. So, I put in one slide the ones that have been approved, at least in the US, for the prevention of migraine, just for the sake of completion of this talk about the different preventive options.  So, the external trigeminal nerve simulations and noninvasive vagus nerve simulation, single-pulse transcutaneous magnetic simulation, and the remote electrical neurostimulation. 

So, hopefully this gives you an overview of the different migraine preventive treatment, and we can combine things, too, including patient education, lifestyle, nutraceutical, all the pharmaceutical options, neuromodulation, biobehavioral options. And that’s it.

*The contents of this video are intended for general informational purposes only and does not constitute professional medical advice, diagnosis, or treatment. Always seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition. AMD and the speaker do not recommend or endorse any specific course of treatment, products, procedures, opinions, or other information that may be mentioned. Reliance on any information provided by this content is solely at your own risk.