Modern Migraine Treatment: Gepants, CGRP, Triptans and Botulinum Toxin Therapy

Modern migraine treatment includes both acute treatment for individual attacks and preventive therapy. In addition to NSAIDs and triptans, current options include gepants, monoclonal antibodies targeting CGRP or its receptor, and botulinum toxin therapy. Treatment is selected according to attack frequency and severity, comorbidities, previous treatment response, and patient preference.

For infrequent attacks, the main goal is rapid and complete relief of pain and associated symptoms. Preventive treatment is considered when attacks are frequent, prolonged, disabling, or insufficiently controlled. For chronic migraine, botulinum toxin therapy according to the PREEMPT protocol has a specific established role.

What Happens During Migraine and the Role of CGRP

Migraine is a primary neurological disorder associated with increased excitability of sensory brain networks and activation of the trigeminovascular system. One of the key mediators involved in migraine is CGRP (calcitonin gene-related peptide).

CGRP participates in pain transmission, sensitization of trigeminal pathways, and regulation of vascular tone. Understanding this mechanism led to the development of therapies that directly block CGRP or its receptor: monoclonal antibodies and gepants.

Acute Treatment of a Migraine Attack

The aim of acute treatment is to achieve, whenever possible, freedom from pain and the most bothersome associated symptoms within the first few hours and to reduce the risk of recurrence. Treatment is generally most effective when taken early in the attack, before pain reaches maximum intensity.

NSAIDs and Analgesics

Common options for mild to moderate attacks include:

• ibuprofen;
• naproxen;
• paracetamol (acetaminophen);
• acetylsalicylic acid (aspirin);
• combination analgesics containing caffeine.

Frequent use of acute medication may lead to medication-overuse headache. As a general threshold, simple analgesics used on 15 or more days per month and triptans or combination analgesics used on 10 or more days per month for more than three months are associated with increased risk.

Triptans

Triptans remain among the most effective specific therapies for moderate to severe migraine attacks. Available agents include sumatriptan, rizatriptan, zolmitriptan, eletriptan, and others.

They act mainly through 5-HT1B/1D receptors and suppress activity within the trigeminovascular system. If one triptan is ineffective, another triptan may still work, and in selected cases a triptan may be combined with an NSAID.

Because triptans have vasoconstrictive effects, they are unsuitable for some patients with ischemic heart disease, previous stroke, peripheral arterial disease, or uncontrolled hypertension. In such situations, non-vasoconstrictive options may be considered.

Gepants for Migraine: What They Are and How They Work

Gepants are modern antagonists of the CGRP receptor. They are used for acute migraine treatment, and some agents in this class are also approved for prevention. Unlike triptans, gepants do not cause vasoconstriction.

Depending on country and availability, acute-treatment options include ubrogepant, rimegepant, and intranasal zavegepant. Rimegepant is available as an orally disintegrating formulation and can be used both for acute treatment and for prevention of episodic migraine.

Gepants may be particularly useful when triptans are ineffective, poorly tolerated, or undesirable because of vascular contraindications. However, the absence of vasoconstriction does not mean that these drugs are free of precautions: drug interactions, hepatic and renal function, and current warnings regarding possible hypertension or Raynaud phenomenon should be taken into account.

Lasmiditan

Lasmiditan is a selective 5-HT1F receptor agonist without clinically significant vasoconstrictive activity. It may be used for acute treatment in patients for whom triptans are unsuitable. Its main limitations are dizziness and somnolence; restrictions on driving after a dose should be followed according to prescribing information.

Nausea and Non-Oral Treatment Options

For severe nausea or vomiting, antiemetic therapy and non-oral migraine treatments such as nasal or injectable formulations may be useful. This is especially relevant when gastrointestinal absorption is impaired during an attack.

When Preventive Migraine Treatment Is Needed

Preventive therapy is not determined by attack count alone. It may be considered when there are:

• frequent migraine days;
• significant impairment of work, daily activity, or quality of life;
• prolonged or difficult-to-treat attacks;
• poor efficacy or tolerability of acute treatment;
• frequent use of acute medication and risk of medication-overuse headache;
• a patient preference to reduce attack frequency.

Traditional Preventive Medications

Several pharmacological classes are used for migraine prevention, including:

• beta-blockers such as propranolol and metoprolol;
• topiramate;
• amitriptyline and selected other antidepressants;
• other agents depending on comorbidities and the individual clinical situation.

These drugs remain effective preventive options, but their use may be limited by adverse effects and the need for gradual dose titration.

CGRP-Targeted Prevention

Preventive therapies targeting the CGRP pathway include monoclonal antibodies and selected gepants. According to the 2024 American Headache Society position statement, CGRP-targeted therapy can be considered a first-line option for migraine prevention without requiring prior failure of two older preventive drug classes. Access and reimbursement rules still vary by country and insurance system.

Monoclonal Antibodies Targeting CGRP

Four major agents are currently used:

• erenumab — targets the CGRP receptor;
• galcanezumab, fremanezumab, and eptinezumab — bind the CGRP ligand.

Most are administered subcutaneously once monthly or once every three months; eptinezumab is given intravenously. These therapies are used for episodic and chronic migraine according to the indication of the individual drug.

Advantages include infrequent dosing and generally favorable tolerability. Possible adverse effects include injection-site reactions, constipation with some agents, and other less common events, so treatment selection remains individualized.

Gepants for Migraine Prevention

Atogepant and rimegepant are used for preventive treatment.

• Atogepant is taken daily and is used for prevention of episodic and chronic migraine in adults.
• Rimegepant is taken every other day for prevention of episodic migraine and is also approved for acute treatment.

These drugs provide an oral alternative to injectable CGRP-targeted therapies. Choice of a specific gepant should take into account drug interactions, hepatic and renal function, comorbidities, and concomitant medications.

Botulinum Toxin Therapy for Chronic Migraine

OnabotulinumtoxinA is used for the preventive treatment of chronic migraine. According to international diagnostic criteria, chronic migraine is defined by headache on at least 15 days per month for more than three months, with migraine features on at least 8 days per month.

The standard treatment is based on the PREEMPT protocol. The core protocol includes 155 units injected at 31 sites across the head and neck, repeated approximately every 12 weeks. The PREEMPT paradigm also allows additional sites, increasing the total dose to up to 195 units and the number of injection sites to 39.

Effectiveness should be assessed over several treatment cycles rather than after a single procedure. In some patients, the most substantial reduction in headache frequency becomes apparent after the second or third treatment cycle.

When a single preventive approach is insufficient, botulinum toxin therapy may in selected cases be combined with CGRP-targeted treatment. Combination therapy is individualized.

How Treatment Is Selected

There is no single treatment strategy that is optimal for every patient with migraine. One person may respond well to a triptan and need no prevention, while another may require a gepant, a CGRP monoclonal antibody, or botulinum toxin therapy. In clinical practice, treatment is tailored to the number of migraine days, symptom burden, comorbidities, previous treatment response, and the patient's lifestyle and preferences.

Key References

1. Charles AC, Digre KB, Goadsby PJ, et al. Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: An American Headache Society position statement update. Headache. 2024;64(4):333–341. PubMed.
2. Qaseem A, et al. Pharmacologic Treatments of Acute Episodic Migraine Headache in Outpatient Settings: A Clinical Guideline From the American College of Physicians. Ann Intern Med. 2025. PubMed.
3. International Headache Society. International Classification of Headache Disorders, 3rd edition (ICHD-3): chronic migraine and medication-overuse headache. ICHD-3.
4. FDA. NURTEC ODT (rimegepant) Prescribing Information, revised 2025. FDA label.
5. FDA. UBRELVY (ubrogepant) Prescribing Information, 2025. FDA label.
6. FDA. QULIPTA (atogepant) Prescribing Information, 2025. FDA label.
7. FDA. ZAVZPRET (zavegepant) Prescribing Information, 2025. FDA label.
8. Bendtsen L, Sacco S, Ashina M, et al. Guideline on the use of onabotulinumtoxinA in chronic migraine: a consensus statement from the European Headache Federation. J Headache Pain. 2018;19:91. PubMed.
9. FDA. BOTOX (onabotulinumtoxinA) Prescribing Information: chronic migraine dosing and PREEMPT trial data. FDA label.