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Reffat, N.; Pusec, C.; Price, S.; Gupta, M.; Mavrocordatos, P.; Abd-Elsayed, A. Pharmacotherapy for Migraine and Chronic Cluster Headache. Encyclopedia. Available online: (accessed on 21 April 2024).
Reffat N, Pusec C, Price S, Gupta M, Mavrocordatos P, Abd-Elsayed A. Pharmacotherapy for Migraine and Chronic Cluster Headache. Encyclopedia. Available at: Accessed April 21, 2024.
Reffat, Noora, Carolina Pusec, Scott Price, Mayank Gupta, Philippe Mavrocordatos, Alaa Abd-Elsayed. "Pharmacotherapy for Migraine and Chronic Cluster Headache" Encyclopedia, (accessed April 21, 2024).
Reffat, N., Pusec, C., Price, S., Gupta, M., Mavrocordatos, P., & Abd-Elsayed, A. (2024, February 19). Pharmacotherapy for Migraine and Chronic Cluster Headache. In Encyclopedia.
Reffat, Noora, et al. "Pharmacotherapy for Migraine and Chronic Cluster Headache." Encyclopedia. Web. 19 February, 2024.
Pharmacotherapy for Migraine and Chronic Cluster Headache

Headaches are defined as pain in any area of the head and can be categorized into three groups as defined by the International Classification of Headache Disorders (ICHD-III): (1) Primary being a headache without an identifiable cause, including tension, migraine, and chronic cluster; (2) Secondary being a headache with an identifiable cause, including potentially life threatening causes such as vascular disorders or traumatic brain injuries; and (3) Cranial neuropathies.

headache migraine chronic cluster headache treatment drugs

1. Introduction

Headaches compose nearly 3% of all chief complaints in the emergency room, posing significant burden on both the healthcare system and those who suffer from them [1][2]. Unlike many other chronic diseases which tend to present in the later decades of life, sufferers of headaches span all ages with a large proportion being young, female, and otherwise healthy [1][3]. Headaches are defined as pain in any area of the head and can be categorized into three groups as defined by the International Classification of Headache Disorders (ICHD-III): (1) Primary being a headache without an identifiable cause, including tension, migraine, and chronic cluster; (2) Secondary being a headache with an identifiable cause, including potentially life threatening causes such as vascular disorders or traumatic brain injuries; and (3) Cranial neuropathies [2][4][5]. Cranial neuropathies are defined as pain due to lesions or diseases affecting the cranial nerves, particularly cranial nerves (CN) V, VII, IX, and X, and the upper cervical roots, which transmit pain signals and result in perception of pain in the head and neck. Despite differences in their pathophysiology and presentation, the focus of this research will be on primary type headaches, specifically migraine and chronic cluster headaches (CCH), to reflect the headache sub-types for which neuromodulation has been the most well studied.

2. Pharmacotherapy for Migraine

Migraines encompass a diverse clinical profile, characterized by symptoms that may include headaches, auras, prodromal manifestations, and sensory disturbances. Generally, episodes manifest as a unilateral pulsating headache that persists between 4 and 72 h, exhibiting variation in frequency and intensity [6]. Presently, there is no definitive cure for migraine episodes, rather, therapeutic interventions aim to enhance the patient’s quality of life. From a non-pharmacological perspective, the aim is to recognize and avoid triggers. This goal often necessitates lifestyle adjustments, with emphasis on establishing routines to ensure quality of sleep, consistent exercise, and the prevention of prolonged fasting [7]. Conversely, pharmacological approaches can be categorized into abortive, prophylactic, and specialized treatments overseen by neurologists. Abortive treatments primarily consist of non-steroidal anti-inflammatory drugs (NSAIDs). These have a strong evidence base and function by suppressing cyclooxygenase (COX) isoforms 1 and 2, leading to a reduction in the production of inflammatory agents such as prostaglandins [8]. For moderate to severe migraines, triptans are the primary therapeutic option. These are serotonin agonists targeting the 5-hydroxytryptamine [5-HT] B and D serotonin receptors, suppressing the secretion of vasoactive peptides (VP), substance P (SP), and calcitonin gene-related peptide (CGRP). These compounds have been identified as neuroinflammatory precipitators, stimulating nociceptors affiliated with the trigeminal nerve and transmitting pain signals via the thalamus to the cerebral cortex. Ergot alkaloids are second line and similarly interact with [5-HT] receptors but are non-selective regarding receptor subtypes [9].
However, these pharmacological agents are not devoid of limitations. NSAIDs are inadvisable for individuals on anticoagulant therapy, or those with peptic ulcer disease or renal disorders. Given their vasoconstrictive nature, triptans and ergot alkaloids pose risks to patients with coronary artery, peripheral vascular, and cerebrovascular diseases. Furthermore, a critical challenge both clinicians and patients face are ensuring abortive medications are not excessively employed, as this can culminate in medication overuse headaches [8]. The gepants, another emerging class of drugs, antagonize the CGRP receptor directly and have proven efficacy against migraines when compared to placebo; however, further research is needed to evaluate the long-term efficacy and safety profile, as well as comparing the gepants against other established migraine therapies [10][11]. Moreover, monoclonal antibodies targeting CGRP or its receptor have also been developed and shown to be efficacious and well-tolerated for the prevention of episodic and chronic migraine. Given that CGRP is a potent vasodilator, there were concerns about its safety in acute vascular stress such as in stroke or myocardial infarctions [12]. That said, a 2017 randomized, double-blind, placebo-controlled study found no significant adverse cardiovascular effects when using one of the CGRP monoclonal antibodies against the CGRP receptor, erenumab, for patients with stable angina [13] However, the effect in patients where the blood brain barrier is disrupted remains unclear [14]. Additionally, its long half-life and potential to cross the placental barrier remains as a concern for affecting uteroplacental blood flow [15].
Numerous medications have undergone rigorous research for their role in preventing episodic migraines. Importantly, approximately 38% of patients experiencing episodic migraines report positive outcomes from such preventive treatments [16]. One of the first-line treatments for migraine prophylaxis is the beta blocker, of which propranolol predominates given the substantial evidence from research trials highlighting its therapeutic efficacy. Limitations to its use include patients with obstructive lung diseases, atrioventricular conduction defects, and peripheral vascular disease, and it can cause various other behavioral effects as well. Anticonvulsants such as valproic acid and topiramate and tricyclic antidepressants (TCA) such as amitriptyline also play a prominent role in prophylactic migraine therapy [9]. However, their widespread use is limited by the notable risk of adverse reactions associated with this class of drugs. For the anticonvulsants topiramate and divalproex sodium, which are the only two FDA approved anti-epileptic drugs for migraine prevention, careful follow-up testing is required due to risk of pancreatitis, liver failure, teratogenicity, and thrombocytopenia, among various other adverse effects. Additionally, the only TCA that has been demonstrated to have significant evidence affirming its efficacy is amitriptyline, which can be highly sedating and possesses anti-muscarinic and anti-adrenergic properties, among other intolerable effects [17]. In addition, for chronic headaches, OnabotulinumtoxinA (Botox®) injections have also proven effective and a randomized double blind trial comparing Botox to topiramate demonstrated superior tolerability [18][19]. The main limitations to its use are cost since it must be administered by a specialist and requires repeat injections every 3 months.

3. Pharmacotherapy for Chronic Cluster Headache (CCH)

While CCH affects about 0.1% of the population, their clinical course is difficult to predict and troublesome to treat. Unlike other headache subtypes, cluster headaches tend to predominantly affect Caucasian males, and are thought to be mediated by irritation of the trigeminal nerve [20][21]. Cluster headache attacks are described by patients to be excruciating, earning their nickname “suicide headaches”, and tend to be unilateral orbital, retro-orbital, or temporal pain, with cranial autonomic activation causing lacrimation, eye discomfort, nasal congestion, flushing, throat swelling, amongst other symptoms [20][21]. These attacks can include physical agitation or irritation, and last from a few minutes to hours without treatment, though patients may experience several episodic attacks at a time, called bouts [20]. These bouts are cyclical, meaning that patients will experience one or two attacks in a week, followed by nearly daily attacks, before the headaches enter a period of remission [21]. The cyclical nature of these headaches makes them difficult to treat, as medications need to be adjusted to account for changing attack frequency [21]. Therapies include inhalation of 100% oxygen during acute attacks, or the subcutaneous administration of sumatriptan, which has been shown to be the most effective therapy in randomized control trials [21][22]. Sumatriptan is a drug in the triptan class previously described for migraines and remains the first-line treatment for chronic cluster headache [23]. Prophylactic therapies include the calcium-channel blocker verapamil, which is the first-line prophylactic therapy, or the mood-stabilizer lithium, which has a larger side effect profile including potential nephrotoxicity [21]. Some evidence supports the use of other drugs including gabapentin, steroids, and melatonin, though these medications are used less often for CCH [21].


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Subjects: Neurosciences
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Update Date: 19 Feb 2024