Migraine has a profound impact on the lives of female patients, especially menstrual migraine, which is related to the menstrual cycle. These headaches, due to their close association with hormonal fluctuations, pose unique challenges in both diagnosis and treatment. This article aims to provide a comprehensive overview of the epidemiological status of migraine in Chinese women, existing treatment options and their limitations, the pathogenesis of menstrual migraine, major drug development targets, and the progress of therapies targeting calcitonin gene-related peptide (CGRP). Additionally, I will introduce currently ongoing Phase 2 and Phase 3 clinical trials for menstrual migraine treatments, providing the latest information for patients and colleagues.
Epidemiological Status of Migraine in Chinese Women
Migraine is a chronic neurovascular disorder characterized by recurrent episodes of moderate to severe headache, often unilateral and pulsating, accompanied by nausea, vomiting, and photophobia/phonophobia. In China, approximately 9.3% of adults aged 18–65 suffer from migraine, with a higher prevalence in women due to hormonal influences. Among women of childbearing age, the prevalence of migraine can be as high as 20%, with 7–10% of these women experiencing menstrual migraine, defined as headaches occurring from 2 days before the onset of menstruation to 3 days after its cessation.
China has over 130 million migraine sufferers, ranking first globally. Menstrual migraine, due to its more severe attacks, longer duration, and poorer response to treatment, significantly impacts patients' quality of life. However, the diagnosis rate is low, with only 52.9% of patients seeking medical help and only 13.8% receiving a correct diagnosis. This reflects the urgent need to improve public and medical personnel's awareness of migraine.
Current Treatment Strategies and Their Limitations
In China, the treatment of menstrual migraine typically includes acute and preventive therapies, individually adjusted based on the frequency and severity of attacks. Acute treatment aims to relieve symptoms during an attack, while preventive treatment focuses on reducing the frequency and intensity of attacks.
Acute Treatment
For acute attacks, nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen are often the first-line treatment due to their anti-inflammatory and analgesic effects. Triptans (5-hydroxytryptamine receptor agonists) are widely used for acute treatment by constricting dilated cerebral blood vessels and inhibiting pain pathways. However, menstrual migraine, due to its specific mechanisms, often responds poorly to these drugs, leading to incomplete relief. Overuse of acute medications can also trigger medication-overuse headache, further exacerbating the condition.
Preventive Treatment
Preventive treatment is recommended for patients with a higher number of headache days per month (e.g., more than 4–6 days). Commonly used drugs include beta-blockers (such as propranolol), antiepileptic drugs (such as topiramate), and tricyclic antidepressants (such as amitriptyline). For menstrual migraine, hormonal therapies (such as oral contraceptives or estrogen supplementation) are sometimes used to stabilize hormonal fluctuations. However, these therapies are not effective for all patients, and hormone treatment may increase the risk of thrombosis, especially in women with cardiovascular risk factors.
Non-pharmacological treatments, such as lifestyle adjustments (including stress management, regular sleep patterns, and dietary optimization) and complementary therapies like acupuncture, are also often recommended. While these methods may benefit some patients, their efficacy varies, and sufficient scientific evidence to support them is lacking.
Overall Efficacy and Unmet Clinical Needs
While existing treatment options can provide symptom relief for some patients, the overall efficacy is unsatisfactory. The severity and treatment resistance of menstrual migraine limit the effectiveness of acute medications, and preventive treatments often fail to significantly reduce the frequency or severity of attacks. Furthermore, drug side effects (such as fatigue from beta-blockers and cognitive impairment from antiepileptic drugs) often affect patient compliance.
Low diagnosis rates and underutilization of preventive treatment further exacerbate the burden of menstrual migraine. Many women rely on over-the-counter medications or silently endure the pain, leading to a significant decline in their quality of life. Additionally, cultural factors may make Chinese women hesitant to discuss menstruation-related health issues, hindering them from seeking professional help. Therefore, we urgently need more effective, better-tolerated treatment options that target the unique mechanisms of menstrual migraine, while also strengthening patient education and public awareness.
The Mechanism of Menstrual Migraine: A Simple Explanation
To understand why menstrual migraine is difficult to treat, we need to understand the underlying mechanisms. Imagine the brain as a busy command center that coordinates various signals in the body. During menstruation, the sharp drop in estrogen levels is like a sudden "short circuit," disrupting the normal functioning of the brain. Estrogen affects the brain's pain pathways and blood vessel regulation, and its rapid decline triggers a series of events leading to migraine.
Calcitonin gene-related peptide (CGRP) plays a crucial role in this process. CGRP is like an overactive "messenger"; when its levels rise, it's like someone turning the stereo volume up to maximum, causing excessive dilation of cerebral blood vessels, activating pain-sensitive nerves, and triggering pulsating headaches, nausea, and sensory hypersensitivity. In menstrual migraine, the decrease in estrogen further amplifies CGRP activity, making attacks more severe.
In addition, inflammatory responses and the activation of the trigeminal nerve (the main pain pathway) also play important roles, but CGRP's central position makes it a primary therapeutic target. In essence, CGRP is the spark that ignites the "flame" of migraine, and blocking it may prevent the "fire" from spreading.
CGRP-Targeted Therapies: A New Milestone in Migraine Treatment
The discovery of CGRP's role has brought a revolutionary breakthrough in migraine treatment, offering new hope for patients with menstrual migraine. CGRP-targeted drugs are mainly divided into two categories: monoclonal antibodies (mAbs) and small molecule CGRP receptor antagonists.
Monoclonal Antibodies (mAbs)
Monoclonal antibodies are large molecule drugs administered by injection, usually once a month or every three months. They act by targeting CGRP or its receptor, effectively "intercepting the messenger" and preventing the amplification of pain signals. Four monoclonal antibodies have been approved globally for migraine prevention, and clinical trials have shown that they can significantly reduce the number of monthly migraine days (typically by 2–4 days), suitable for patients with episodic or chronic migraine.
For patients with menstrual migraine, monoclonal antibodies are significantly effective in prevention, especially for women with frequent attacks. They are generally well-tolerated, with the most common side effect being mild injection site reactions. However, their high cost and injectable administration may limit their adoption in China, especially in areas with limited medical resources. Furthermore, monoclonal antibodies have a slower onset of action and are not suitable for acute treatment.
Small Molecule CGRP Receptor Antagonists
Small molecule CGRP receptor antagonists are oral medications that rapidly "shut down" the transmission channel of migraine signals by blocking the CGRP receptor. Four small molecule CGRP receptor antagonists have been approved globally, mainly for acute treatment, with some showing preventive potential. Small molecule CGRP receptor antagonists have a fast onset of action, usually relieving symptoms within 1–2 hours, making them an ideal choice for acute menstrual migraine. In terms of prevention, daily use can reduce monthly migraine days by 4–7 days, especially effective for chronic migraine patients.
The oral administration of small molecule CGRP receptor antagonists improves patient compliance and convenience, especially for menstrual migraine patients. However, their specific efficacy in menstrual migraine is still under investigation, and some patients may experience side effects such as nausea or fatigue. Additionally, small molecule CGRP receptor antagonists are expensive, limiting their widespread use.
Limitations of CGRP-Targeted Therapies
Although CGRP-targeted therapies represent a significant advancement in migraine treatment, they are not a panacea. Some patients experience only partial relief, and menstrual migraine, due to its hormone-driven nature, may require a combination of other strategies to address estrogen fluctuations. Long-term safety data are still being accumulated, especially for small molecule CGRP receptor antagonists, and cost and accessibility are also pressing issues.
Emerging Therapies in Clinical Trials
The development of therapeutic drugs for menstrual migraine is booming, with several candidate drugs in Phase 2 and Phase 3 clinical trials offering hope for meeting unmet needs. These trials not only focus on CGRP-targeted therapies but also explore new treatment pathways.
Phase 2 Clinical Trials
- Novel CGRP Receptor Antagonists: A new oral small molecule CGRP receptor antagonist is being studied for acute and preventive treatment. Early Phase 2 data show that it can reduce monthly headache days by 3–5 in women with menstrual migraine, with good safety. Its oral administration and rapid onset of action make it a promising option for acute treatment.
- Dual-Target Therapies: A Phase 2 trial is exploring a drug that simultaneously targets CGRP and another pain-related pathway (such as pituitary adenylate cyclase-activating polypeptide, PACAP). This is like using two "fire extinguishers" to put out different "sources of fire" in migraine, potentially providing stronger efficacy for severe patients.
Phase 3 Clinical Trials
- Preventive Oral CGRP Antagonists: A Phase 3 trial is evaluating an oral small molecule CGRP receptor antagonist for the preventive treatment of menstrual migraine. Preliminary results show a reduction of 5–7 monthly headache days, with flexible dosing suitable for use around menstruation. This could be a significant breakthrough for patients who prefer non-injectable medications.
- Long-Acting CGRP Monoclonal Antibodies: A Phase 3 trial is testing a new monoclonal antibody administered every three months, aiming to improve compliance. Early data indicate a reduction of 4–6 monthly headache days with mild side effects, suitable for patients with hormone-driven migraine.
- Hormone Modulation Therapies: A Phase 3 study is exploring a novel hormonal drug that indirectly reduces CGRP activity by stabilizing estrogen levels during the menstrual cycle, preventing the "short circuit" effect of hormonal fluctuations. This therapy provides a complementary option to CGRP-targeted drugs.
These trials reflect the growing emphasis on personalized treatment for menstrual migraine. The development of oral formulations, long-acting injectables, and combination therapies suggests that future treatments will be more flexible and accessible.
Conclusion
Menstrual migraine poses a significant health challenge for Chinese women, and low diagnosis rates and poor treatment outcomes further exacerbate the disease burden. While the emergence of CGRP-targeted therapies (monoclonal antibodies and small molecule CGRP receptor antagonists) has brought new hope for migraine management, issues such as cost, accessibility, and incomplete efficacy still need to be addressed. Ongoing Phase 2 and Phase 3 clinical trials offer a bright prospect for developing more effective and better-tolerated treatment options, with novel CGRP antagonists, dual-target therapies, and hormone modulation drugs potentially significantly improving patients' quality of life.
Female migraine patients should actively seek professional medical care, find a comprehensive treatment plan that combines suitable medications and non-pharmacological therapies, and pay attention to the progress of emerging therapies. At the same time, we need to strengthen public education, eliminate the taboo surrounding menstruation-related health topics, and encourage more women to seek help and break free from the torment of migraine. In the future, with in-depth scientific research and innovative treatment methods, I believe we will bring a brighter tomorrow for patients with menstrual migraine.