A review of 357 global reports on headache prevalence published in previous years found that among headache sufferers worldwide, about 14% have migraine, 26% have tension-type headache, and 4.6% experience headaches on more than 15 days per month [1]. Globally, approximately 15% of adults have been troubled by chronic headache, with 13.9% of headaches becoming chronic. In China, about 8 million people rely on long-term medication for headaches, leading to drug dependence.
Headaches are generally classified into three categories: primary headaches, secondary headaches, and painful cranial neuropathies. Primary headaches refer to common types like migraine, tension-type headache, and cluster headache. Secondary headaches are often caused by head or neck trauma, craniocervical vascular factors, intracranial disorders, psychiatric conditions, or infections. Painful cranial neuropathies primarily involve intracranial neuralgia [2].
The factors causing headaches are extensive and their pathogenesis is complex. According to an article published by Wenzhou Medical University, about 25% of migraine patients experience attacks on average at least twice a month, each lasting 4–72 hours. It is the leading cause of disability among women aged 15–49 and the second leading cause among men, ranking as the second most common disabling neurological disorder globally. In China, approximately 130 million people are affected by migraine, and the rate of comorbid anxiety with migraine is as high as 47%.
A migraine attack can make it difficult to concentrate on daily life and work, and is often accompanied by symptoms such as nausea, vomiting, photophobia, and phonophobia. In severe cases, symptoms like blurred vision, dizziness, and even auditory or visual hallucinations may occur. Migraine is highly associated with an increased risk of mortality from cardiovascular diseases [3] and can even pose a direct threat to life and health. Long-term suffering from headaches can reduce the body's resistance, increase the risk of other illnesses, and impact the patient's mental health, raising the likelihood of developing anxiety, depression, and cognitive dysfunction. Even benign headaches, if frequent or severe, can disrupt daily life. Chronic headaches may also lead to emotional problems such as anxiety and depression, further affecting mental well-being.
Regarding headache treatment, medical consultation is necessary upon the first occurrence of a headache or when the pain reaches a moderate severity level or higher to determine the specific cause. Headaches should neither be endured nor managed through long-term, excessive reliance on medication. Clinical data analysis shows that many patients develop medication-overuse headache (MOH) due to prolonged dependent use of non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, aspirin, and paracetamol for relief. Conversely, approximately 38% of migraine patients can experience significant symptom reduction through preventive treatment. Preventive medications typically include antiepileptics, beta-blockers, antidepressants, and calcium channel blockers. However, the efficacy of these drugs and issues related to dependence still require improvement.
With in-depth research into the pathogenesis of migraine, scientists have discovered that calcitonin gene-related peptide (CGRP) plays a crucial role. Intravenous infusion of CGRP into migraine patients during the interictal period can induce migraine-like headaches [4]. Furthermore, after drug treatment in migraine patients, the decrease in CGRP levels corresponds to the reduction in headache severity [5].
Activation of CGRP and its receptor triggers the activation of adenylyl cyclase (AC), thereby increasing intracellular cyclic adenosine monophosphate (cAMP) levels. This leads to vascular smooth muscle relaxation and vasodilation, ultimately inducing migraine. Simultaneously, CGRP release from the trigeminal system further triggers neurogenic inflammation and increases vascular permeability, allowing inflammatory substances to penetrate neural tissue more easily, thereby significantly exacerbating pain perception and inflammatory responses. When chronic migraine patients are exposed to high CGRP levels for extended periods, the central nervous system increases pain sensitivity, making patients more susceptible to pain and lowering their pain tolerance [6].
Studies have found that novel drugs targeting CGRP and its receptor can block the CGRP signaling pathway within the trigeminal ganglion during migraine attacks, thereby preventing and aborting migraine episodes [7, 8]. These drugs have demonstrated good tolerability and safety in clinical practice. Currently, there are four antibody drugs focusing on CGRP: Erenumab targets the CGRP receptor, while Fremanezumab, Galcanezumab, and Eptinezumab directly target CGRP ligand.
Erenumab, co-developed by Novartis and Amgen, was the first FDA-approved humanized monoclonal antibody (IgG2-λ type) targeting the CGRP receptor for preventive treatment. A clinical study involving 274 patients with chronic migraine (CM) and medication-overuse headache (MOH) compared continuous use of 70 mg, 140 mg Erenumab, or placebo for three months. The results showed that the proportions of patients achieving at least a 50% reduction in mean monthly headache days were 36%, 35%, and 18%, respectively [9]. CGRP monoclonal antibodies like Fremanezumab and Eptinezumab have also demonstrated significant therapeutic effects in numerous clinical trials, effectively alleviating symptoms such as nausea, vomiting, photophobia, and phonophobia. Patients with medication-overuse headache resulting from excessive drug dependence can also be treated with CGRP antibody drugs [10]. Other small molecule CGRP receptor antagonists also show considerable therapeutic efficacy. Common adverse reactions for CGRP small molecule drugs include constipation and nasopharyngitis, with fewer than 3% of patients discontinuing treatment due to serious adverse events. CGRP monoclonal antibodies are administered via injection, with primary adverse reactions being injection site pain, induration, and rash; no serious adverse events have been observed in long-term clinical trials.
At present, CGRP-based drugs show relatively ideal preventive effects for migraine patients without major adverse events. However, due to their short time on the market and the lack of research on their application in populations such as children, adolescents, and patients with underlying diseases, their safety and drug risks still need to be evaluated. Furthermore, most patients do not show effective sensitivity to these drugs, with a treatment response rate of 26%–42%. Therefore, we should further improve the rate of precise medication use and adjust drug development strategies or drug carriers to gradually enhance treatment effectiveness.
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