Breakthrough Medicines – Migraine Headache

Migraine headaches are a neurological condition characterized by intense, throbbing pain, typically on one side of the head. They are often accompanied by other symptoms such as nausea, vomiting, and sensitivity to light and sound. Migraines can last for hours or even days, and they can significantly affect a person’s quality of life.

Common Symptoms of Migraines:

1. Intense headache (usually one-sided but can occur on both sides)
2. Nausea and vomiting
3. Sensitivity to light (photophobia)
4. Sensitivity to sound (phonophobia)
5. Aura: About 25% of migraine sufferers experience an “aura” before or during the migraine, which can include visual disturbances like flashes of light, blind spots, or zigzag patterns.
6. Fatigue and irritability before or after the headache.

Migraine Phases:

1. Prodrome: Occurs hours or even days before a migraine. Symptoms include mood changes, food cravings, and fatigue.
2. Aura: Some individuals experience visual or sensory disturbances before the headache.
3. Headache: The main phase, with severe pain, nausea, and sensitivity to light and sound.
4. Postdrome: The “migraine hangover” where people feel exhausted, confused, or unwell even after the pain subsides.

Types of Migraines:

• Migraine with Aura: Visual or sensory disturbances precede the headache.
• Migraine without Aura: The most common type, where no aura occurs.
• Chronic Migraine: Occurs more than 15 days per month.Causes and Triggers:

 

While the exact cause of migraines is not fully understood, they are believed to be related to abnormal brain activity affecting blood flow, neurotransmitter levels, and nerve signaling.

Common triggers include:

• Stress
• Hormonal changes (e.g., during menstruation)
• Certain foods (like chocolate, aged cheeses, and processed meats)
• Alcohol (especially red wine)
• Changes in sleep patterns
• Environmental factors (bright lights, loud sounds, strong smells)
• Weather changes

Treatment:

Migraines can be managed with medications, lifestyle adjustments, and preventive strategies:

1. Pain relievers: Over-the-counter (OTC) medications like ibuprofen or prescription drugs.
2. Triptans: These medications specifically target migraine-related brain activity.
3. Preventive medications: For frequent migraines, doctors may prescribe drugs such as beta-blockers, antidepressants, or anti-seizure medications.
4. Non-medication treatments: Biofeedback, relaxation therapy, acupuncture, and lifestyle changes (like maintaining regular sleep, eating, and exercise routines).

Medication Advancements

There have been several notable advancements in the treatment of migraines in recent years, particularly with the development of medications that target specific pathways involved in migraine pathophysiology. Here’s an overview of some of the most important developments:

1. Calcitonin Gene-Related Peptide (CGRP) Inhibitors

Calcitonin Gene-Related Peptide (CGRP) inhibitors are a class of medications primarily used to prevent migraines. They work by targeting and blocking the action of CGRP, a neuropeptide involved in the transmission of pain and the dilation of blood vessels in the brain, which are key processes in migraine attacks.

Mechanism of Action:

• CGRP is released during a migraine attack and is thought to contribute to the headache by promoting inflammation and dilation of blood vessels in the brain.
• CGRP inhibitors are designed to block CGRP or its receptor. By doing this, they reduce the peptide’s ability to cause inflammation and vasodilation, which helps to prevent or reduce the severity of migraines.

Types of CGRP Inhibitors:

• Monoclonal Antibodies are designed to bind to CGRP itself or its receptor and are administered via injection. Examples include erenumab (Aimovig), fremanezumab (Ajovy), and galcanezumab (Emgality).
• Small Molecules are oral medications that block the CGRP receptor, such as rimegepant and ubrogepant.

• IV Infusion, such as Eptinezumab (Vyepti), is administered via IV infusion every three months, this CGRP inhibitor is designed for rapid onset of action in preventing migraines.

Overall, CGRP inhibitors offer a targeted approach to migraine prevention by addressing a key component of the migraine pathophysiology.

 

2. Gepants

Gepants are a class of oral medications used for the acute treatment of migraines. They work by targeting and blocking the CGRP receptor, which is crucial in the migraine process.

Mechanism of Action:

1. Gepants are selective antagonists of the CGRP receptor. They bind to this receptor and prevent CGRP from attaching to it.
2. By blocking the CGRP receptor, gepants inhibit the effects of CGRP, which include the dilation of blood vessels and the promotion of inflammatory responses in the brain that are associated with migraine attacks.
3. By interfering with the CGRP signaling pathway, gepants help alleviate the symptoms of migraines, such as headache pain, by counteracting the peptide’s role in migraine pathophysiology.

Examples of gepants:

• Ubrogepant (Ubrelvy): Approved for the acute treatment of migraines, this medication works by blocking the CGRP receptor, providing relief from migraine attacks.
• Rimegepant (Nurtec ODT): Initially approved as an acute treatment, it has also been approved for preventive treatment, offering a flexible option for migraine management.

Gepants offer an alternative to traditional triptans, especially for patients who cannot tolerate triptans or for whom triptans are contraindicated (e.g., those with cardiovascular disease.

This type of treatment is distinct from other migraine treatments, such as triptans, which work by agonizing serotonin receptors to constrict blood vessels. Instead, gepants provide a different approach by focusing on the CGRP pathway.

 

3. Ditans

Ditans are a class of medications used for the acute treatment of migraines, and they work through a different mechanism compared to other migraine treatments like triptans or gepants.

Mechanism of Action:

1. Ditans act as selective agonists for the 5-HT_1F serotonin receptor. Unlike triptans, which agonize the 5-HT_1B and 5-HT_1D receptors to cause vasoconstriction, by specifically targeting the 5-HT_1F receptor.
2. The activation of the 5-HT_1F receptor by ditans helps to modulate the release of neurotransmitters involved in the migraine process. This receptor agonism can help reduce the release of pro-inflammatory neuropeptides, including CGRP.
3. By focusing on the 5-HT_1F receptor, they help to inhibit the activation of trigeminal neurons and reduce the associated neurogenic inflammation, which contributes to migraine pain.
4. Unlike triptans, ditans do not cause significant vasoconstriction, making them a potentially safer option for individuals with cardiovascular concerns.

As an example, Lasmiditan (Reyvow) is an oral ditan approved for the acute treatment of migraines, particularly for patients who may not tolerate triptans due to cardiovascular concerns. It provides effective pain relief without causing vasoconstriction.

Overall, ditans provide an alternative mechanism for migraine relief, particularly for those who may not tolerate triptans or need a different approach to managing their symptoms.

 

4. Combination Therapies

Overview: Research is ongoing into combining newer migraine medications with traditional treatments (e.g., triptans, NSAIDs) to improve efficacy and patient outcomes. The goal is to create more personalized treatment plans that address the specific needs of migraine patients.

Studies combining CGRP inhibitors with gepants, or gepants with triptans, have shown potential for enhanced efficacy with reduced side effects.

 

These advancements represent significant progress in the management of migraines, offering new options for both acute treatment and prevention. They also provide hope for patients who have not found relief with older medications, as well as those who are at risk for medication overuse headaches or have contraindications to existing therapies