Monthly Injection for Migraines: How CGRP Drugs Compare

Monthly migraine injections refer to a class of self-administered antibody drugs that block a protein called CGRP, one of the key chemical drivers of migraine attacks. Three of these antibodies are approved for monthly subcutaneous injection: erenumab (Aimovig), fremanezumab (Ajovy), and galcanezumab (Emgality). In pivotal trials, they reduced migraine days per month by roughly one and a half to two more days than placebo, and real-world studies in harder-to-treat patients often show even larger drops. The drugs were first approved starting in 2018, and they represented the first migraine preventives designed from the ground up to target migraine biology rather than borrowed from another field like cardiology or psychiatry.

How CGRP Drives Migraine Pain

CGRP stands for calcitonin gene-related peptide. It is a signaling molecule found in high concentrations in the trigeminal nerve system, the network of sensory nerves that covers the face, scalp, and the membranes surrounding the brain. During a migraine attack, trigeminal nerve fibers release CGRP at both ends: at the peripheral terminals near blood vessels in the meninges and at the central terminals deeper in the brainstem. At the peripheral end, CGRP triggers blood vessel dilation and sets off a cascade that sensitizes the surrounding nerve fibers, making them fire more easily. Inside the trigeminal ganglion itself, secreted CGRP interacts with neighboring neurons and support cells, perpetuating that sensitization. At the central end, it acts on second-order neurons to relay pain signals up through the brainstem and thalamus to the cortex, where you actually perceive the headache.

Multiple lines of evidence built the case that CGRP was central to migraine before any antibody drug was developed. Researchers found elevated CGRP in the cranial circulation during attacks, and those levels normalized when patients got relief from triptans. Intravenous infusions of CGRP could trigger migraine-like headaches in people with migraine but not in healthy volunteers. And small-molecule drugs that blocked the CGRP receptor proved effective in clinical trials, providing what researchers considered definitive pharmacological proof.

The Three Monthly Injections and How They Differ

Although all three monthly injections target the same CGRP pathway, they do so in slightly different ways. Erenumab is the only one that blocks the CGRP receptor itself. Fremanezumab and galcanezumab both neutralize the CGRP molecule (the “ligand”) before it can bind to any receptor. This receptor-versus-ligand distinction sounds academic, but it has practical consequences when one drug fails and the question becomes whether switching to the other type might help.

Lab studies have shown that erenumab does more than just block the classic CGRP receptor. It also binds and internalizes at a related receptor called AMY1, which is part of the amylin receptor family. Fremanezumab does not interact with the AMY1 receptor at all. Erenumab also blocks signaling from other peptides in the same family, such as adrenomedullin, while fremanezumab’s effects are limited to CGRP itself.

These mechanistic differences between receptor and ligand antibodies may explain why some patients respond well to one class but not the other, and they form the rationale for trying a switch before abandoning the CGRP antibody approach altogether.

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A fourth antibody, eptinezumab (Vyepti), targets the CGRP ligand like fremanezumab and galcanezumab but is given as an intravenous infusion every three months in a clinic rather than as a monthly self-injection at home. Fremanezumab also has an approved quarterly dosing option, where a larger dose is injected once every three months instead of monthly.

How Many Migraine Days They Prevent

In the landmark trial for erenumab in episodic migraine, participants started with an average of about eight migraine days per month. Over a six-month treatment period, the 70-mg dose reduced monthly migraine days by about three compared to baseline, and the 140-mg dose reduced them by close to four. The placebo group saw a drop of fewer than two days, meaning the drug’s net benefit over placebo was roughly one and a half to two fewer migraine days per month.

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Fremanezumab trials showed similar results. In the episodic migraine study, patients on monthly dosing went from about eight and a half migraine days per month down to about five, a reduction of close to four days from baseline. The placebo group dropped by about two days, giving a net benefit of roughly one and a half fewer migraine days with the drug.

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These numbers might sound modest in isolation, but two things put them in context. First, they are averages across entire study populations, including partial responders and non-responders who pull the mean down. Second, real-world studies in patients with chronic migraine who had already failed multiple prior preventives show bigger absolute reductions. One prospective analysis of erenumab in refractory chronic migraine found a mean reduction of six migraine days at three months and seven and a half days at six months. By the six-month mark, about 60% of patients had achieved at least a 30% reduction in migraine days, and roughly one in five had achieved a 75% reduction.

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The drugs also work in older adults, a group sometimes underrepresented in migraine trials. A pooled analysis of fremanezumab trials in patients aged 60 and older found reductions in monthly migraine days of about four days with monthly dosing, significantly greater than the roughly two-day reduction seen with placebo.

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Side Effects and Safety

One of the biggest selling points of these injections compared to older migraine preventives like topiramate or amitriptyline is their side-effect profile. The most common complaint is injection-site reactions: pain, redness, itching, or a localized skin reaction at the spot where the needle goes in. In studies of galcanezumab, about one in five patients on the drug reported at least one injection-site reaction, compared to about one in eight on placebo. Injection-site pain itself was roughly as common with the drug as with placebo and tended to occur within the first hour.

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Beyond injection-site effects, constipation is the side effect that gets the most attention. An analysis of FDA adverse-event reports found that constipation ranked as the second most commonly reported event for erenumab but barely registered for fremanezumab or galcanezumab.

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Integrated safety data from galcanezumab trials listed constipation, vertigo, and pruritus (itching) among the events that occurred more frequently on the drug than on placebo, though none at high rates.

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One area where researchers urge caution is blood pressure. CGRP is a potent vasodilator throughout the body, so blocking it raises a theoretical concern about cardiovascular effects. A systematic review found that while the antibodies offer substantial migraine prevention benefits, the potential risk of increased blood pressure warrants monitoring. The same review noted that the evidence is still limited but encouraged clinicians to check blood pressure regularly in patients on these treatments.

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Cardiovascular events like heart attack or stroke did not rank in the top ten reported adverse events for any of the three subcutaneous antibodies in the first six months after market launch.

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When the First Drug Does Not Work

Not everyone responds to the first CGRP antibody they try. There is growing evidence that switching between the receptor antibody (erenumab) and a ligand antibody (fremanezumab or galcanezumab) can rescue some of these patients. In a prospective analysis of patients with treatment-refractory chronic migraine who had failed erenumab and were switched to fremanezumab, about a quarter were considered responders after three months, and that figure rose to roughly a third by six months.

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Another retrospective study examined switching in both directions, from receptor to ligand antibody and vice versa. By the third month after the switch, about a third of patients achieved at least a 30% reduction in headache days.

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These are not blockbuster response rates, but in a population that has already failed multiple preventives, converting one in three patients from non-responder to responder is clinically meaningful. The rationale circles back to those mechanistic differences: because erenumab interacts with additional receptors that fremanezumab does not touch, and vice versa, the two classes are not simply interchangeable.

Combining Monthly Injections With Botox

For people with chronic migraine who get a partial response from onabotulinumtoxinA (Botox) injections alone, adding a CGRP antibody is increasingly common. A review of the available evidence found that partial responders to Botox could gain additional headache relief by adding an anti-CGRP antibody, and that the combination appeared safe. The most common side effects of dual therapy were constipation (more with erenumab) and injection-site reactions, which are already familiar from each drug used alone.

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A prospective real-world study combining Botox with the oral CGRP blocker atogepant (a related but pill-form drug) over 24 weeks found no novel safety concerns beyond what would be expected from either drug separately.

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Clinical trials are now underway to evaluate more rigorously whether combining Botox with CGRP antibodies like eptinezumab or erenumab provides a true synergistic benefit in refractory chronic migraine.

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What Happens When You Stop

Many insurance plans and national guidelines require patients to take a treatment break after 12 months of continuous use to reassess whether the drug is still needed. The evidence on what happens after stopping is sobering. In one cohort study, monthly migraine days, acute medication intake, and disability scores all climbed progressively after discontinuation but remained somewhat lower than they had been before treatment started. Among patients who had reverted from chronic to episodic migraine during treatment, about a third relapsed back to chronic migraine within the first month of stopping, and nearly half had relapsed by three months out.

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A separate real-life cohort study found a similar pattern. Monthly migraine days averaged six in the first month off treatment, jumped to nine in the second month, and reached 11 by the third month. Nearly nine out of ten patients ended up restarting treatment. The study’s authors concluded that very little of the therapeutic effect outlasts the drug’s pharmacological presence in the body, and that the data do not support mandating a fixed treatment pause after 12 months.

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Who Responds Best

Predicting which patients will benefit from a CGRP antibody before they try it remains a challenge, but some patterns have emerged. A large multicenter prospective study of 864 migraine patients found that certain clinical features predicted a better response at 24 weeks. Patients with one-sided headache pain combined with cranial autonomic symptoms on the same side (things like a teary or red eye, nasal congestion, or eyelid drooping during attacks) were significantly more likely to achieve at least a 50% reduction in migraine days. Obesity was negatively associated with response in chronic migraine patients.

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A Japanese retrospective study identified age as a positive predictor (older patients responded somewhat better) and a higher number of prior treatment failures as a negative predictor.

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Machine-learning models trained on clinical data like headache days, migraine days, and disability scores have shown promising accuracy in predicting who will respond, though these tools are not yet routinely used in clinics.

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Long-Term Effectiveness Beyond Six Months

Most pivotal trials lasted three to six months, but real-world follow-up data offer a longer view. A study tracking patients on all three subcutaneous antibodies for up to 12 months found that disability scores (measured by the MIDAS questionnaire, which captures how many days migraine interfered with work, household chores, and social activities) dropped dramatically, with 84% to 100% of patients who reached the 12-month mark achieving at least a 50% reduction in that score. The percentage achieving at least a 50% reduction in raw monthly migraine days was lower, ranging from about 36% to 67% depending on the drug and time point. Dropout over the year was about 17%.

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The gap between migraine-day reductions and disability-score reductions is a recurring finding. It suggests that even when the number of migraine days does not drop by half, the attacks that remain may be less severe, shorter, or easier to treat with acute medication. In other words, the injections may be improving quality of life in ways that a simple migraine-day count does not fully capture.

Medication Overuse and These Injections

People with chronic migraine often develop medication-overuse headache, a cycle where frequent use of painkillers or triptans paradoxically makes headaches worse. Traditional preventives require patients to first detox from the overused medication, which can mean weeks of worsening symptoms. CGRP antibodies appear to work even in patients who are actively overusing acute medications. A review of randomized trials, post-hoc analyses, and real-world studies found that the antibodies are effective in chronic migraine patients with concurrent medication overuse, without requiring a separate withdrawal period.

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The Practical Side of Self-Injecting

All three monthly injections come in autoinjector or prefilled syringe formats designed for home use. In a usability study, more than 90% of participants agreed that the autoinjector was easy to use, that they felt confident self-injecting, and that they could manage the process on their own.

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A multi-country discrete choice experiment explored which device features matter most to patients. Given a choice, people overwhelmingly preferred autoinjectors over oral non-CGRP preventives, choosing the injector in about 86% of paired comparisons. Among device features, patients cared most about shorter injection duration (preferring 10 or 5 seconds over 30), a needle that retracts automatically after injection, and flexible storage that allows the device to stay outside the refrigerator for more than a day. Interestingly, dosing frequency (monthly vs. quarterly) did not significantly influence preferences once other features were controlled for, suggesting that the experience of each injection matters more to patients than how often they have to do it.

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Cost and the Bigger Access Picture

The most persistent barrier to these injections is price. In the United States, list prices for the monthly antibodies typically run into several hundred dollars per injection without insurance coverage. A 2025 review in The BMJ noted that the higher cost of new CGRP-targeted treatments and unclear evidence for cost-effectiveness in most situations remains a limitation.

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Most insurers require step therapy, meaning you have to try and fail at least two cheaper oral preventives (often a beta-blocker or anticonvulsant) before they will cover a CGRP antibody. Manufacturer copay assistance programs exist but vary in eligibility and coverage. For patients in countries with single-payer systems, access often depends on how many prior preventive failures are documented. The clinical argument for wider access is straightforward: these drugs work in populations where older preventives have already failed, and their side-effect profile is cleaner. The economic argument is harder, partly because the trials were not designed to demonstrate cost savings and partly because migraine, despite its enormous societal burden, has historically been underfunded relative to other neurological conditions.