With all of these new treatments of acute medications for migraine headache such as the CGRP antagonists, as well as the standard triptans, how do you know which one to pick?
Ubrelvy vs. Nurtec, Ubrelvy vs. triptans, Nurtec vs. triptans, Ubrelvy vs. Reyvow, Nurtec vs. Reyvow, Reyvow vs. triptans, Rimegepant vs. Ubrogepant, Ubrogepepant vs. triptans, Rimegepant vs. triptans, Lasmiditan vs. Ubrelvy, Nurtec vs. Lasmiditan, Lasmiditan vs. triptans, Ubrogepant vs. Lasmiditan, Rimegepant vs. Lasmiditan?
Let’s discuss how to pick the best one for you.
What Are Migraine Abortives?
Migraine abortive (acute) treatments are made to stop migraine attacks as soon as they start. The goal of abortive medications is pain freedom, or significant pain relief, along with resolution of migraine-associated symptoms of nausea, sensitivity to light and sound at 2 hours or sooner. Ultimately, the goal is to fully restore your function rather than having to miss the whole day in bed.
This is in contrast to migraine preventive treatments which are a continuous daily treatment. Preventive treatments include a daily pill, a monthly/quarterly treatment such as CGRP monoclonal antibodies (Aimovig, Ajovy, Emgality, Vyepti), or neuromodulation devices. The goal of migraine preventive treatment is to lessen the frequency and/or severity of migraine attacks.
If you have migraine, you want to have both a good abortive and preventive treatment plan to lessen migraine’s nasty habit of interfering and disrupting life and function.
Since the development and availability of sumatriptan in 1992, the main migraine abortive option available has been the triptan medications. Triptans (Imitrex, Maxalt, etc.) work at the serotonin receptors, and work well for most people. However, about 30% of patients do not respond to triptans. Others cannot tolerate side effects, or they cannot use them because of medical contraindications and safety concerns such as heart disease, heart attack, peripheral artery disease, cerebrovascular disease, stroke, uncontrolled blood pressure, narrow blood vessels, etc. Triptans are also contraindicated in patients with visual snow, persistent migraine aura, and migrainous stroke (infarction). They have been historically contraindicated in hemiplegic migraine (now called migraine with motor aura) or basilar migraine (now called migraine with brainstem aura) due to theoretical concerns of vasoconstriction potentially causing stroke. When the triptan studies were done previously, they excluded patients with these forms of migraine due to the ongoing vascular theory of migraine at that time. The vascular theory of migraine assumed that vasoconstriction and lack of blood flow was the cause of aura and neurologic features with migraine. So the thinking was that if you cause further vasoconstriction with a triptan, you may cause stroke. However, we now know that these phenomenon are primarily of an electrical basis and not a vascular basis. Therefore many specialists have gotten more liberal with the use of triptans in patients with hemiplegic or basilar migraine, and there have been a number of case series and case reports of these patients using triptans without any problems.
The alternatives to triptans have historically been the ergots (ergotamine, DHE) which can be complicated to use, tend to have an excess of side effects for many, and have the same medical contraindications as triptans. NSAIDs and over the counter analgesics are also commonly used, although many do not respond to or cannot take them due to other medical conditions. Even worse are opiates/opioids and butalbital medications such as fioricet, both of which (as do excess triptans, NSAIDS, OTCs) have a high risk of leading to medication overuse headache (rebound headache). For close to 3 decades, these have remained the only limited options of acute/abortive migraine treatment, despite migraine being such a widespread common disorder! More recently, neuromodulation devices have also become available as abortive options.
Thankfully, these limited options have now expanded to 4 new migraine abortive options in adults between 2 new classes which became available commercially in 2020; the gepants and the ditans. These medications can be used SAFELY in all of the medical contraindications mentioned above, including cardiovascular disease! These new medications for migraine patients are compared with one another, as well as with the triptans in the table below.
GEPANTS
The gepants were the first new class of medications to emerge as a migraine abortive. Ubrogepant (Ubrelvy) became available in January 2020 and Rimegepant (Nurtec) followed in February 2020. Most recently in July 2023, a new nasal spray abortive gepant called Zavegepant (Zavspret), became available.
How do the gepants work?
These new treatment options precisely target an important step in the pathophysiology of migraine. During a migraine attack, the trigeminal nerves release a variety of inflammatory proteins, one of which is called CGRP (calcitonin gene related peptide). CGRP causes inflammation around the brain and cerebral arteries (“sterile inflammation”) in the dural membrane surrounding the brain, increased transmission of pain signals through the trigeminal nerves into the brainstem and into the brain, and dilation of the cerebral arteries through the dural membrane, which in turn leads to further increasing pain signals via the trigeminal nerve endings covering the cerebral arteries. The result is intense migraine pain. So, if we can block these steps of migraine pain, the attack should be aborted quickly, and not as severe. That’s where the CGRP inhibitors (gepants and CGRP monoclonal antibodies) come into play.
Gepants work as CGRP receptor antagonists, which means they directly target and block (antagonist) the CGRP receptor. This results in the medication “blocking” the CGRP inflammatory protein from sticking to the CGRP receptor to activate it, and thus prevents it from “turning on” these migraine pathways. So, you get reversal of cerebral vasodilation, which decreases the firing off of the trigeminal nerves. Notably, the gepants do this in a way that does not cause vasconstriction (artery narrowing), in contrast to the triptans which do. Thus, they are felt to be safe in those with cardiovascular or cerebrovascular disease (as opposed to the triptans). By blocking the CGRP receptor, you also get reversal of the neurogenic inflammation going on through the brain and around the arteries, and you block the electrical transmission of migraine pain from traveling from the trigeminal nerves into the brain.
What are the side effects of the gepants?
The side effects of the gepants are minimal and similar to placebo compared to the triptans and their alternatives. In addition, there is no interaction with using them and triptans, NSAIDs, or other acute meds together. These medications are not associated with addiction potential, and do not cause medication overuse headache (rebound)! Compared to the triptans and ergots, these medications are NOT contraindicated in patients with stable cardiovascular or peripheral vascular disease or risk factors because they do not cause narrowing of the arteries, which is a HUGE benefit. There are many patients who have been stuck in limbo unable to use standard therapies such as triptans due to other medical problems such as heart disease, so we finally have a safe alternative for them, which is great step forward for migraine care.
Can gepants be used in pregnancy or breastfeeding?
There is not enough data yet on the safety of the gepants in pregnancy or breastfeeding, and therefore are not recommended. There was a study published showing that the amount of Nurtec that enters the breast milk is a very small fraction of the normal dose and felt to likely be negligible. Regardless, further data is needed.
Are there drug interactions with the gepants?
The primary drug interactions to be aware of with these medications are when used with other medications that are metabolized by the liver enzyme system called CYP3A4. Many commonly used medications are metabolized by this system. Strong or moderate inhibitors of CYP3A4 (which slow down the metabolism activity) will cause an increase in gepant exposure. Strong or moderate inducers of CYP3A4 (which increase the metabolism activity) will cause a decrease in gepant exposure and possibly decreased effectiveness. These medications should be avoided in patients with severe liver disease or end stage kidney disease such as those on dialysis.
Ubrelvy (Ubrogepant)
Ubrelvy is a quick acting abortive pill medicine. It is also the only gepant in which you can repeat a 2nd dose if needed (similar to how triptans are dosed). Clinical studies showed that Ubrelvy was effective whether taken right away at migraine onset or up to 4 hours, which means you have more flexibility in catching the attack if you miss the early stage, as opposed to triptans. The half life of Ubrelvy is 5-7 hours, so duration of effect is extended compared to many options that we had up to this point. With a single dose at 2 hours, 21% of patients became pain free, 71% were pain free at 4 hours, and 83% at 8 hours. At 1 hour Ubrelvy becomes statistically superior to placebo for pain relief in 43%, and at 2 hours 62% have significant pain relief. At 2 hours, 64% had normal function restored, 81% at 4 hours, and 91% at 8 hours. Ubrelvy was also statistically superior to placebo for freedom from most bothersome migraine symptom (nausea, photophobia or phonophobia) at 2 hours. These improvements continue into 48 hours.
A more recent study showed that by taking Ubrelvy 100 mg during pre-headache prodrome symptoms, 46% were able to prevent the subsequent migraine from reaching a moderate to severe pain level (compared to 29% of placebo). So by taking it early, they were more than 2x as likely to avoid moderate to severe level pain.
Side effects of Ubrelvy were similar to placebo and the most common were nausea (placebo 2%, Ubrelvy 50 mg 2%, Ubrelvy 100 mg 4%), and somnolence (sleepiness) (placebo 1%, Ubrelvy 50 mg 2%, Ubrelvy 100 mg 3%).
They currently have a savings card program which should work with commercial insurances for $0 per month (16 pills per month).
Nurtec ODT (Rimegepant)
Nurtec ODT dissolves under or on the tongue in seconds, and starts working in minutes (15 minutes in some patients). It does not require water or other liquids to take with the dose, so it can be taken anytime and anywhere. It is taken as a simple single strength single dose. Pain relief and pain freedom lasts up to 48 hours for many patients, which makes sense because it has the longest half-life (11 hours). The clinical data highlights of Nurtec ODT are that at 15 minutes, you get separation from placebo of both pain relief and return to normal function (but not yet statistically superior). At 1 hour, pain relief and return to normal function become statistically superior to placebo. At 1.5 hours, you get additional statistical superiority over placebo of pain freedom and freedom from most bothersome migraine symptom (nausea, photophobia or phonophobia). For the vast majority of patients, the superiority of all of these trial endpoints over placebo remain sustained through 48 hours.
Side effects of Nurtec were similar to placebo and the most common side effect was nausea (placebo 0.4%, Nurtec 2%).
There is a savings card program which should work with most commercial insurances for $0 per month (8-16 pills per month).
In 5/2021, Nurtec received additional FDA approval to use preventively by taking every other day. So it is the first and only FDA approved medication for BOTH abortive and preventive migraine treatment simultaneously, and the only option with this flexibility. Nurtec as a preventive migraine treatment is discussed here. This move followed clinical trials showing that patients taking 75 mg of Rimegepant every other day experienced a 4.3 day reduction from baseline in monthly migraine days, a 30% drop of migraines within even the first week, and 49% of patients had a greater than 50% reduction in monthly migraine days.
Zavspret Nasal Spray (Zavegepant)
Zavspret is the first and only abortive nasal gepant, so it is very fast acting. Not only is it also a great first line option, but a great choice for those with waking migraine, nausea and vomiting (where a pill won’t stay down), fast onset migraine, and for those that can’t take a pill. It became available in July 2023.
In the study, up to 24% (almost a quarter!) had complete pain relief by 2 hours (15% in placebo). 42% had freedom from their most bothersome migraine symptom at 2 hours (nausea, sensitivity to light or sound) (31% in placebo). Pain relief was seen as quick as 15 minutes. At 2 hours, 59% had significant pain relief (50% placebo). 36% had restored normal function at 2 hours (26% placebo). 36% had sustained pain relief at 48 hours (30% placebo).
Most side effects are similar to other nasal spray medicines in terms of some possible temporary nasal stuffiness and some may not like the taste.
So, Which Gepant Is The Best?
Given that Ubrelvy, Nurtec ODT, and Zavspret are of the same gepant class, they each have minor differentiations, although the bottom line is that they are all excellent options. Although they are all very effective, it is not uncommon to see patients who may respond to one better than another. So if one of them does not help, it is worth trying the other ones as well.
Can I Use A CGRP MAb (Aimovig, Ajovy, Emgality, Vyepti) With The Gepants (Nurtec, Ubrelvy, Zavspret)?
Many patients use once monthly CGRP antagonist monoclonal antibody (mAbs) self-injections which are FDA approved for migraine prevention and include Aimovig (Erenumab), Ajovy (Fremanezumab), Emgality (Galcanezumab), and Vyepti (Eptinezumab), which is a once quarterly 30 minute IV infusion). The CGRP mAbs are discussed in much greater detail and compared with one another here. These have little to no drug interactions and do not affect the liver or kidneys.
Patients often ask if the gepants and CGRP mAbs medications can be used together. It is felt that these medicines can be used safely together, and they are metabolized by completely different mechanisms. The gepants are metabolized in the liver, while the CGRP mAbs are metabolized and cleared in the reticuloendothelial system. In addition, they may even provide a synergistic effect by working together.
An insurance battle sometimes ensues when trying to use the CGRP mAbs with the gepants (Nurtec, Ubrelvy, Zavspret). Insurance companies will sometimes deny their use together, despite no good scientific basis. Actually, there is some limited evidence showing that these medications can work synergistically together, which would make sense when taking their mechanisms of action into account. Specifically, there was a publication showing that the use of these acute and preventive CGRP migraine therapies together can be successful and safe.
The patients in this publication had been using rimegepant (Nurtec) in a long-term safety study and they had added erenumab (Aimovig) once monthly injection as a preventive treatment. After Aimovig was added, patient 1 had 100% relief for 7 of 7 acute migraine attacks treated with Nurtec. Patient 2 had 100% relief for 9 of 9 acute migraine attacks treated with Nurtec. So, the combination of using Nurtec abortively in addition to using Aimovig preventively appeared to provide an even more effective acute migraine response. Theoretically, it would make sense that benefit would be greater with both classes of medicines combined because they are entirely different types of medications targeting aspects of the same migraine pathway simultaneously (either targeting the CGRP receptor or the CGRP ligand protein). Larger studies to confirm the suspicion that they likely work together synergistically will be helpful.
There was a larger safety study publication which evaluated the acute treatment of migraine with Rimegepant while using a CGRP monoclonal antibody for the prevention of migraine. The CGRP mAbs used were Erenumab (Aimovig) (7 patients), Fremanezumab (Ajovy) (4 patients), and Galcanezumab (Emgality) (2 patients). The study determined that Rimegepant used as an acute migraine treatment in combination with CGRP mAbs for migraine prevention was well tolerated with no safety issues identified. The researchers concluded that the probability between these 2 classes (gepants and CGRP mAbs) was low, especially because they have entirely different pathways of drug metabolism. They also concluded that existing evidence supports the safety of combined use, although further larger research was warranted.
DITANS
Reyvow (Lasmiditan)
The ditans are another new class of migraine abortive, premiering with Lasmiditan (Reyvow) in January 2020. Reyvow acts as a 5-HT1F (serotonin 1F) receptor agonist. It helps to stop the release of inflammatory pain producing neurotransmitters and neuropeptides including CGRP from the trigeminal nerves during a migraine attack. These receptors are also involved in interfering with other migraine pain pathways. Notably, like the gepants, they also do not cause arterial vasoconstriction. Again, this is a tremendous benefit and another great option in patients who may not be able to use triptans due to medical contraindications such as coronary or peripheral vascular disease. Caution should be used with other serotonergic drugs given a potential for serotonin syndrome, which has been reported infrequently.
Similar to the gepants, the Reyvow clinical data showed superiority over placebo at trial endpoints of 2 hour pain freedom, freedom from most bothersome migraine symptom (nausea, photophobia or phonophobia), and pain relief.
In a driving study, 50 mg, 100 mg, or 200 mg doses of Reyvow significantly impaired subjects’ ability to drive, and more sleepiness was reported at 8 hours following a single dose compared to placebo. Therefore, patients should wait at least 8 hours between dosing and driving or operating machinery. This can certainly be a drawback in terms of being a treatment option for many patients as the goal of abortive therapy is partly to be able to maintain and restore function in order to not disrupt work, plans, etc. However, if you are in a position where this would not be an issue for you, it could certainly be a valid option to have in your migraine war chest. It should also be used with caution in combination with alcohol or other central nervous system depressants.
Reyvow is a Schedule V controlled substance compared to the other abortive options. Schedule V represents the lowest abuse potential category from the DEA. The reason is because in a human abuse potential study, doses of 100 mg, 200 mg, and a supratherapeutic dose of 400 mg were associated with statistically significantly higher “drug liking” scores than placebo, indicating possible abuse potential. However, it had statistically significantly lower “drug liking” scores compared to alprazolam 2 mg. Lasmiditan also produced adverse events of euphoria and hallucinations to a greater extent than placebo, although it was a low frequency (about 1% of patients). They currently have a savings card program which should work with commercial insurances for $0 per month (8 pills per month).
SUMMARY
Overall, the triptans, gepants, and ditans are all very effective medications for the treatment of acute migraine. It’s great to have new options to include in the migraine war chest. Ubrelvy, Nurtec, Zavspret, and Reyvow were all proven to be superior to placebo at 2 hours with a single dose (some sooner) in terms of pain freedom, pain relief, and freedom from most bothersome migraine symptom (nausea, sensitivity to light, sensitivity to sound), and restoration of normal function. So there is no “bad” option.
The chart below compares and contrasts the treatment outcomes data between Rimegepant, Ubrogepant, Lasmiditan, and Sumatriptan (as representative of the triptan class since it was the first developed). The source of the data comes from the trials of each medication. The trials for each medication did not all include the same trial endpoints, so there may be some variation in comparisons. Also, this data is not reflective of head to head trials between these medications. The data is derived from separate independent trials, of which there were variations in study design and endpoints. So, they should not be thought of as head to head comparisons. In addition, the older triptan studies did not include many of the treatment outcome data points that have become standard in newer abortive medication trials. Therefore, many of these data points within the columns of the different medications may be labeled by N/A (not available). Regardless, I have highlighted some of the key differences in bold print.
| Rimegepant | Ubrogepant | Lasmiditan | Sumatriptan (100 mg) | |
|---|---|---|---|---|
| Class | Gepant | Gepant | Ditan | Triptan |
| Mechanism of Action | CGRP receptor antagonist | CGRP receptor antagonist | 5HT1F agonist | 5HT1B and 5HT1Dagonist |
| Available dosing | 75 mg orally dissolvable tablet | 50 mg, 100 mg pill | 50 mg, 100 mg, 200 mg (100 mg x 2) pill | 25 mg, 50 mg, 100 mg pill; 3 mg, 4 mg, 6 mg injection; 5 mg, 10 mg, 20 mg nasal spray |
| Max dose per 24 hours | 75 mg | 200 mg | 200 mg | 200 mg |
| Pills per prescription (standard, may be more depending on insurance) | 8 | 10 | 8 | 9 |
| Dosing frequency | 1 dose/24 hours | Dose can repeated once in 2 hours; 2 doses/24 hours | 1 dose/24 hours | Dose can repeated once in 2 hours; 2 doses/24 hours |
| Suggested number of migraine attacks treated per 30 days | 15 (however, currently also being studied as a daily preventive) | 8 | 4 | 10 |
| Time to reach statistically significant pain relief | 60 minutes (however, there was a 15 minute measured clinical beneficial effect) | 60 minutes with 50 mg or higher doses | 30 minutes with 100 mg or higher doses; 60 minutes with 50 mg dose | 30 minutes with 50 mg or higher doses |
| 1 hour significant pain relief | 37% 31% (placebo) | 43% (50 mg) N/A (100 mg) 36.7% (placebo) | 37.3% (50 mg) »41% (100 mg) »46% (200 mg) 30.6% (placebo) | 20-35% (100 mg) 12-21% (placebo) |
| Differences in pain relief at 15 minutes | 8% 5% (placebo) | N/A | N/A | N/A |
| Differences in pain relief at 30 minutes | 19% 17% (placebo) | 19% (50 mg) N/A (100 mg) 20% (placebo) | »15% (50 mg) 17.5% (100 mg) 19.1% (200 mg) 13.4% (placebo) | 11% (100 mg) 12% (placebo) |
| 2 hour pain relief | 59% 43% (placebo) | 61.7% (50 mg) 61.4% (100 mg) 48.7% (placebo) | 59% (50 mg) 59.4-64.8% (100 mg) 59.5-65% (200 mg) 42.2-47.7% (placebo) | 46-67% (100 mg) 18-44% (placebo) |
| 2 hour pain freedom | 21% 11% (placebo) | 20.5% (50 mg) 21.2% (100 mg) 13% (placebo) | 28% (50 mg) 28-31% (100 mg) 32-39% (200 mg) 15-21% (placebo) | 22-33% (100 mg) 3-13% (placebo) |
| 8 hour pain freedom with 1 dose | 56% 33% (placebo) | 82.3% (50 mg) 82.7% (100 mg) 69.8% (placebo) | N/A | N/A |
| 8 hour pain relief with 1 dose | 74% 56% (placebo) | 92% (50 mg) N/A (100 mg) 82% (placebo) | N/A | N/A |
| % of patients with 1st dose pain relief who achieved pain freedom after 2nddose | N/A | 54.7% (50 mg/50 mg) 33.3% (50 mg/placebo) 51.6% (100 mg/100 mg) 33.3% (100 mg/placebo) | N/A | N/A |
| Sustained pain freedom 2-24 hours | 15.7% 5.6% (placebo) | 13.6% (50 mg) 15.4% (100 mg) 8.4% (placebo) | 17.2% (50 mg) 14.8-17.9% (100 mg) 18.6-22.7% (200 mg) 7.6-13.4% (placebo) | N/A |
| Sustained pain relief 2-48 hours | 47.8% 27.7% (placebo) | 31.5% (50 mg) 34% (100 mg) 17.5% (placebo) | N/A | N/A |
| 2 hour absence of most bothersome migraine symptom | 35% 27% (placebo) | 38.7% (50 mg) 37.7% (100 mg) 27.6% (placebo) | 41% (50 mg) 41-44% (100 mg) 41-49% (200 mg) 30-33% (placebo) | N/A |
| 8 hour absence of most bothersome migraine symptom | N/A | 90.9% (50 mg) 92.4% (100 mg) 77.7% (placebo) | N/A | N/A |
| Time to peak plasma concentration TMAX | 1.5 hours | 1.5 hours | 1.8 hours | 1.5-2.5 hours |
| ½ life | 11 hours | 5-7 hours | 5.7 hours | 2-2.5 hours |
| Time to reach pharmacologically active concentration | 15 minutes | Within 11 minutes | N/A | N/A |
| Time the pharmacologically active concentration is maintained | 48 hours | 12 hours | N/A | N/A |
| Notable side effects | Nausea 2% 0.4% (placebo) | Nausea 2% (50 mg) 4% (100 mg) 2% (placebo) Somnolence/Sedation 2% (50 mg) 3% (100 mg) 1% (placebo) | Nausea 3% (50 mg) 4% (100 mg) 4% (200 mg) 2% (placebo) Somnolence/Sedation 6% (50 mg) 6% (100 mg) 7% (200 mg) 2% (placebo) Dizziness 9% (50 mg) 15% (100 mg) 17% (200 mg) 3% (placebo) Paresthesias 3% (50 mg) 7% (100 mg) 9% (200 mg) 2% (placebo) | Widely variable, most common: Dizziness, fatigue, paresthesias, sedation, nausea, palpitations, anxiety, muscle tightness sensation in chest/neck/throat |
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