Cephalalgias have a lifetime prevalence of more than 90% and an estimated prevalence of 50% in the adult population worldwide [2,3]. Primary headaches are the fourth most common cause for patients to seek emergency care in the United States [4,5]. Secondary headaches, although less frequent, have well-defined etiologies, including infections (e.g., sinusitis, meningitis), cerebrovascular disorders (e.g., ischemia, thrombus, hemorrhage), or neoplasias, and are diagnosed based on history, examination, laboratory tests, and imaging studies (e.g., computed tomography [CT] scan, magnetic resonance imaging [MRI]) [6; 7].

According to the International Classification of Headache Disorders, published by the International Headache Society, there are four main types of primary headaches: tension-type headache, cluster headache/trigeminal autonomic cephalalgias (TACs), migraine, and a group that includes miscellaneous types of primary headaches not included in the previous three groups [6,8]. Tension-type headache is the most common, with a prevalence of 30% to 78% [2,6,8,9]. Typically, tension-type headache is bilateral with mild-to-moderate intensity and non-pulsating quality. It is neither associated with nausea nor aggravated by routine physical activity [6,8,9].

Cluster headache and TACs are severe and uncommon headaches with a prevalence of 0.07% to 0.4% and occur more commonly in men than in women [10]. These headaches are intermittent, short-lasting, and excruciatingly painful unilateral headaches. The quality of the pain is sharp or stabbing but not pulsating, which typically differentiates them from migraines. The pain peaks within 10 to 15 minutes and persists for an average of one hour. During cluster headache, patients do not seek rest (quite unlike during migraine headache), but are noticeably agitated and restless and present with parasympathetic autonomic dysfunction (e.g., conjunctival injection, lacrimation) [6,8,9].

The miscellaneous group of primary headaches is made up of a variety of conditions, including thunderclap headache and exertional headache. These conditions can mimic potentially serious secondary headaches and require thorough clinical evaluation supported by appropriate laboratory tests and imaging procedures. Thunderclap headache occurs suddenly, reaches maximum intensity within one minute, and lasts 1 to 24 hours or even several days. Typically, patients describe the pain of a thunderclap headache as an "explosion in the head" or "being hit with a bat" [11]. Thunderclap headache mimics the pain of a ruptured cerebral aneurysm. Considering that up to 25% of patients with thunderclap headache have subarachnoid hemorrhage (SAH) and that the mortality rate from SAH is approximately 50%, these patients require emergency evaluation, including detailed physical examination and CT scan. Imaging tests are used in the differential diagnosis with other potentially life-threatening conditions, such as intracerebral hemorrhage, cerebral venous thrombosis, hypertensive emergency, and ischemic stroke, in addition to SAH. Lumbar puncture is recommended in patients with thunderclap headache and non-diagnostic CT scan. The risk/benefit of CT or MRI angiography should be taken into account in patients with normal brain CT and cerebrospinal fluid (CSF) analysis, considering that the risk of SAH and death is extremely low in this group [12,13]. Clinically, it is recommended that the diagnosis of thunderclap headache should apply only when no specific etiology is identified despite comprehensive diagnostic evaluation [8,11,12].

Traditionally, migraine was classified as a typical neurovascular disorder with unilateral extracranial vasodilation of the frontal branch of the superficial temporal artery ipsilateral to the headache [28]. The vasogenic theory is consistent with the headache-inducing properties of vasodilating drugs (e.g., nitroglycerine) and the therapeutic properties of vasoconstrictors (e.g., ergotamine). This localized vasodilation was considered to be the rebound of an initial vasoconstriction and transient hypovascularization in discrete brain regions. However, a number of imaging studies have revealed a discrepancy between the temporal profile of vascular dysregulation and migraine pain. This discrepancy is further supported by the fact that vasodilating neuropeptides, such as vasoactive intestinal peptide, do not induce migraine pain [29,30].

Alternatively, the neurogenic theory views migraine as the combination of neuronal hyperactivity with a local process of neurogenic inflammation triggered by an increase in pro-inflammatory mediators such as CGRP, neurokinin, and substance P [29,31]. In addition, low levels of the endogenous opioid enkephalin found during migraine correlate to a decrease in pain threshold and are responsible for the reported regional allodynia of the head and upper trunk [32,33].

Cortical spreading depression is an intense wave of neuronal and glial excitation (i.e., depolarization) progressing in the cerebral cortex at a rate of 2–3 mm per minute. This wave of depolarization is followed by transient suppression of spontaneous neuronal activity (hyperpolarization) and changes in vascular diameter and blood flow caused partly by introduction of inflammatory molecules and CGRP to the dura [37,229]. Clinically, the net effect is an aura followed by migraine headache. Cortical spreading depression is the neurophysiologic event typically associated with migraine with aura and the activation of N-methyl-D-aspartate (NMDA) glutamate receptors. The direct intercellular transfer of ions via gap junctions and the release of inflammatory mediators are required for cortical spreading depression to occur [32,38,39]. However, the precise role of cortical spreading depression in migraine without aura remains elusive. Animal models have shown that induction of cortical spreading depression causes meningeal vasodilation, a mechanism that requires participation of the trigeminal nerve [40]. The clinical relevance of cortical spreading depression in migraine has also been supported by imaging techniques, namely positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) [41,42,43,44].

Voltage-gated calcium and sodium channels regulate neuronal excitability and intracellular signaling pathways [52]. Mutations in the genes encoding for these channels cause them to malfunction, leading to a variety of conditions known as channelopathies. Augmented channel function and neuronal hyperexcitability is associated with clinical conditions such as epilepsy and migraine, whereas decreased function is associated with hypoexcitability and paralysis [54,55,56]. Accordingly, channel blockers such as valproate and topiramate used in the management of epilepsy are also effective in migraine prevention [36,56,57].

Additional mechanisms, including an increase in synthesis and release of signaling molecules such as neurotransmitters (e.g., serotonin), neuropeptides (e.g., CGRP), vasodilators (e.g., nitric oxide), and pro-inflammatory mediators (e.g., histamine), play a key role in the pathogenesis of migraine. The association between serotonin (5-hydroxytryptamine or 5-HT) and vascular changes is well-established. Increases in synthesis and concentrations of 5-HT in the brain, as well as elevated urinary levels of the 5-HT metabolite 5-hydroxyindolacetic acid (5-HIAA), are observed during migraine attacks [36,58,59]. The multiple vascular effects of 5-HT observed in different organs depend on the subtype of the receptors involved. The effectiveness of ergotamine and its derivatives in the treatment of acute migraine results from their vasoconstrictive properties, which are mediated by their binding to the 5-HT₁ receptors abundant in meningeal blood vessels [60,61]. These drugs are agonists at the 5-HT₁ autoreceptors and inhibit presynaptic release of serotonin, causing vasoconstriction. Triptans are selective agonists at the 5-HT_1B/1D receptor subtypes. This action triggers vasoconstriction of the cranial circulation, making these medications highly effective in the treatment of acute migraine and further supporting the role of the serotonergic system, and the 5-HT_1B/1D receptor in particular, in migraine pathophysiology [36,58,59]. 5-HT_1B/1D receptors are also present in high levels in cardiac vessels, thus explaining the potential for adverse cardiac effects (e.g., vasoconstriction of the coronary arteries) with ergotamine derivatives and triptans [60,61]. Although the therapeutic properties of triptans will be discussed in detail later in this course, it is relevant to point out that they result from the combination of three different mechanisms of action: vasoconstriction of meningeal vessels by direct effect on vascular smooth cells; inhibition of the release of vasoactive and proinflammatory peptides by trigeminal neurons; and inhibition of nociceptive transmission in the brainstem [60,62].

High levels of the excitatory neurotransmitter glutamate are present in the CSF of patients with migraine, and genetic studies support a crucial role played by a hyperactive glutamatergic system in migraine [63]. Furthermore, antagonists of the glutamate NMDA receptor (e.g., memantine) are effective in the prevention of migraine [54,55].

Useful evidence-based clinical guidelines for the diagnosis of migraine have been developed and are summarized in the mnemonic POUND: pulsatile headache; one-day duration (4 to 72 hours); unilateral location; nausea or vomiting; and disabling intensity [87,88].

Potential complications of migraine include [8]:

Of particular clinical relevance is mounting evidence of an increased comorbidity of migraine and neurologic (e.g., transient ischemic attacks, ischemic stroke, epilepsy), psychiatric (e.g., anxiety, depression, bipolar disorder), cardiovascular (e.g., Raynaud phenomenon, angina, myocardial infarction), and metabolic (e.g., hypercholesterolemia, insulin resistance, obesity) disorders [64,90,101,102,103,104,105,106]. When compared with the rest of the population, patients with migraine with aura have a doubled risk of developing an ischemic stroke [107]. Migraine with aura in women using oral contraceptives has been identified as a risk factor for cardiovascular comorbidity [8]. Particularly relevant are the seven-fold higher odds of stroke in women with migraine with aura who smoke and take oral contraceptives compared with women with probable migraine with visual aura who do not smoke or use oral contraceptives [108].

Chronic migraine is defined as headaches that occur on 15 or more days per month for more than three months, which have the features of migraine headache on at least eight days per month [8]. The criterion that a patient must have at least 15 days of headache monthly is not intended to be restrictive, but rather a guideline that patients with a high number of monthly headaches should be included in this group and receive appropriate therapy [26,27].

Chronic migraine has a prevalence of 1% to 2%, and it represents approximately half of all cases of chronic primary headache. It is more frequently observed in women of European heritage, in patients who are obese, and during the fourth decade of life [22,24,109].

In chronic migraine, it is impossible to distinguish the individual episodes, and the characteristics of the headache often change frequently, even within the same day. It is also difficult to keep patients medication-free in order to observe the natural history of the headache. The most common cause of symptoms suggestive of chronic migraine is medication overuse, and in at least 50% of these patients, the condition is reversed after discontinuation of medications. Other patients, however, do not improve after drug discontinuation and their condition should not be diagnosed as medication-overuse headache [8,27]. Patient education regarding the judicious use of medications should begin before rather than after medication-overuse headache is established [15].

The pattern of migraine presented by a patient changes over the lifetime, and its assessment determines the combination of clinical management with patient education, pharmacologic treatment, and behavioral interventions [15]. This evaluation takes into account frequency, intensity, and impact of migraine on the patient's life [15]. Based on the findings, patients may be categorized in one of four stages and treated accordingly.

In stage one, patients have one or fewer migraine attacks per month or two or fewer headache days per month and normal function between episodes. Early administration of over-the-counter medication (e.g., ibuprofen, naproxen, or a combination of acetaminophen, aspirin, and caffeine) and sleep are usually adequate to manage the condition. The patient is fully functional within a few hours and rarely presents for consultation. If severe pain is experienced, patients may seek medical treatment, and in these cases, either triptans or nonsteroidal anti-inflammatory drugs (NSAIDs) are usually effective to stop a migraine attack [15].

Patients in stage two present with one to three attacks monthly, with less than five headache days per month. Each event is limited in time, but occasional absenteeism from work or family or social functions may occur. Treatment with triptans, either alone or in combination with NSAIDs (e.g., sumatriptan, naproxen), is usually effective to stop a migraine attack [15]. Patient education should be aimed at limiting the use of analgesics to prevent medication-overuse headache, emphasizing that the use of analgesics should be limited to the early management of individual acute migraines and the need to limit drug administration to no more than twice per week [15].

In stage three, patients present with frequent attacks (four to eight per month with less than 12 headache days per month). Assessment should include the use of acute medications (NSAIDs and triptans) and determination of possible medication overuse. It is important to set strict limits on medication use or opt for discontinuation, with preventive therapy initiated concurrently. The choice among preventive medications should take into account the existence of comorbidities, such as beta-blockers in patients with hypertension and tricyclic antidepressants in patients with depression. However, it is important to remember that the appropriate dosage for prevention of migraine might be below the therapeutic effective for the comorbid condition [15].

Patients in stage four have more than eight attacks per month and more than 15 days of headache per month. These patients should be treated by headache specialists on interdisciplinary teams focused on pain management. Medication overuse should be evaluated in each patient and appropriately managed. The medication should be discontinued, and if necessary, a bridging therapy—such as naratriptan (1 mg twice daily for five days) or naproxen (440 mg twice daily for five days)—can be initiated to prevent or manage rebound headaches from the medication withdrawal. Preventive pharmacotherapy should preferably be initiated after discontinuation of previous medication(s). Management of patients with complex migraine often requires referral and interprofessional collaboration [111].

Approximately 20% of the population experiences orofacial pain more than once every six months [123]. Odontogenic pathology is the most common cause of orofacial pain, followed by nonodontogenic pain (e.g. temporomandibular disorders, neuropathies) and burning mouth syndrome [124,125]. Primary headaches, such as migraine, cluster headache, and tension-type headache, can also present as pain with orofacial location. The most prevalent etiology of nonodontogenic orofacial pain is musculoskeletal pathology (e.g., temporomandibular disorders), followed by episodic or chronic neuropathies (e.g., post-traumatic, trigeminal, post-herpetic) and oral cancer [121,126]. Sinusitis may also cause orofacial pain and headache, and a careful assessment of the patient is required to establish a differential diagnosis [8,50,124,127].

Odontogenic pain is caused by odontogenic pathology, such as injury or inflammation/infection of the dental pulp or periodontal tissues, and accounts for more than 50% of all orofacial pain [128]. Clinical and radiographic examination should be corroborated by at least one other test aimed at differentiating between odontogenic and nonodontogenic pain, including percussion, palpation, biting, or thermal. If radiographic and clinical examination are both negative, then two of these other tests must be positive in order to correctly establish the diagnosis and location of the pain [128].

Dentin hypersensitivity presents as a transient sharp pain in response to thermal, chemical, or tactile stimulation. Dental caries present as painful response to any stimulation and can be easily confirmed by clinical and radiographic examination.

Pulpitis is an inflammation of the dental pulp caused either by caries or fracture. Reversible pulpitis is a mild inflammation and presents as localized, sharp, and intermittent pain elicited by thermal changes, particularly cold drinks. Irreversible pulpitis results from chronic inflammation and infection associated with pulpar necrosis, which can be either associated with throbbing pain with no response to thermal stimuli or with poorly localized, dull, and persistent pain [128,129]. A localized periapical abscess is a common complication of pulpitis, and symptoms include tenderness on tapping and lymphadenopathy. This condition requires dental referral for drainage and subsequent reconstruction or extraction; antibiotics are usually not recommended. If the infection has spread to adjacent teeth or surrounding tissues, causing cellulitis, or if the clinical situation does not allow for immediate dental surgical treatment, appropriate antimicrobial therapy with broad-spectrum antibiotics, specifically amoxicillin with clavulanate, should be initiated before referral. Clindamycin is a recommended alternative, particularly in patients with an allergy to penicillins [128,129,130]. It is important to remember that antibiotics are not substitutes to curative dental treatment. In fact, very seldom are antibiotics an appropriate substitute for removal of the source of the infection (i.e., extraction, endodontic treatment, incision and drainage, periodontal scaling and root planing) [130].

Nonodontogenic tooth pain is defined as pain that presents as tooth pain but without dental pathology. Although it often coexists with true tooth pathology, its true nature is revealed when the dental pain is treated. It can present as a deep, dull ache with occasional lancinating pain in the ear, temple, or face. The most prevalent etiology of nonodontogenic tooth pain is muscular. These presentations include myospasm, myalgia, and myofascial pain syndrome, with pain elicited by the stimulation of trigger points in the muscles involved. For example, stimulation of the anterior digastric muscle trigger points can cause referred pain in the lower incisors, whereas stimulation of the anterior or posterior temporal muscle trigger points causes pain in the maxillary anterior or posterior teeth, respectively [131]. Local injection of neuromuscular blocker botulinum toxin (e.g., Botox, Dysport, Xeomin) is effective treatment.

Atypical odontalgia, also known as neuropathic tooth pain, neurovascular odontalgia, oral neuropathic pain, or atypical facial pain, is a nonodontogenic pain of neuropathic origin. Classically, atypical odontalgia presents as throbbing, persistent pain in the teeth or alveolar process occurring over a prolonged period of time without any pathologic, clinical, or radiologic findings [132]. Onset can coincide with dental treatment, including denervation or dental extraction, a condition known as phantom tooth pain [133]. Most patients are women in their mid-40s, and they are often misdiagnosed and submitted to repeated endodontic therapy and dental extractions that fail to relieve their pain [134]. Diagnosis and management are challenging, but tricyclic antidepressants such as amitriptyline or imipramine are the treatment of choice. Gabapentin, baclofen, topical anesthetics, and opioids are possible alternatives [135].

Typically, temporomandibular pain is triggered or aggravated by clinical examination with palpation, passive movement, and active movement (e.g., yawning, chewing, talking) and intensified when muscle is contracted against fixed resistance [124,136,137]. The role of temporomandibular disorder as a cause of chronic headaches and facial pain is often overlooked, and patients may be misdiagnosed as suffering from daily migraines or chronic sinusitis or rhinitis [124,127].

Giant cell arteritis should be considered as part of the differential diagnosis of orofacial pain in patients 50 years of age and older [141]. Arteritis of the temporal artery presents as sudden, severe, and pulsating temporal pain that worsens with cold temperatures. Patients also often display tenderness to palpation, jaw claudication with limited range of motion, and allodynia of the scalp. It is commonly associated with signs of systemic inflammation (e.g., fever, fatigue, malaise, anorexia, sweating). The constellation of signs associated with the throbbing temporal pain in giant cell arteritis allows for a reliable differential diagnosis with migraine. Imaging tests may appear normal, but laboratory tests will show elevated erythrocyte sedimentation rate (ESR) and C-reactive protein. Giant cell arteritis is considered a medical emergency because partial or total obstruction of the blood vessel may result in transient ischemic attacks, stroke, or permanent loss of vision. Prompt treatment with prednisone (starting at 10–20 mg and increasing up to 60 mg/day), either alone or in conjunction with aspirin (81 mg/day), is very effective in most cases. ESR values can be used to monitor progression and response to therapy [142,143,144].

Antidopaminergic drugs may be categorized as either antiemetics (e.g., metoclopramide) or neuroleptics (e.g., chlorpromazine, haloperidol, droperidol). Several antiemetics, including metoclopramide, are effective in the management of nausea in acute migraine. Metoclopramide blocks D2 dopamine and 5-HT₃ serotonin receptors in the chemoreceptor trigger zone and accelerates gastric emptying. Its antidopaminergic properties also offer additional antimigraine effects [87]. Metoclopramide (Reglan) 10–20 mg IV is used in emergency settings, and its efficacy is supported by an exhaustive review of the literature published in 2015 [164,218]. Granisetron (Granisol), a selective 5-HT₃ antagonist, has also been used in the emergency settings, although studies are limited and show a greater risk of adverse effects [84,164]. One study showed that granisetron is more beneficial than metoclopramide, because it also controls migraine-related emesis [219]. However, more studies are required to determine if the benefits outweigh the risks of granisetron.

The butyrophenones haloperidol (Haldol, generic, 5 mg in 500 mL IV solution) and droperidol (Inapsine, generic, 0.1–2.5 mg IV) are effective in 80% and 54% of the patients, respectively [84]. Common side effects include sedation and akathisia, and these effects have resulted in almost 20% of patients being unwilling to be treated with haloperidol again [167]. The neurologic side effects of butyrophenones and their cardiovascular risks (e.g., QT prolongation, arrhythmias) outweigh their benefits, and their use in the treatment of acute migraine is generally not recommended [164,218].

The phenothiazine neuroleptics, prochlorperazine (10 mg IV) and chlorpromazine (12.5–25 mg IV), have been found to provide pain relief to up to 90% and 70% of patients, respectively [84,164]. Side effects are less common with prochlorperazine than with chlorpromazine, but both agents are recommended in the treatment of acute migraine in emergency settings [84,164].

Antihistamine drugs (e.g., diphenhydramine, hydroxyzine) have been evaluated in combination with other medications for the treatment of acute migraine attack, with variable outcomes [84]. One trial showed benefits with diphenhydramine 12.5 mg IV plus prochlorperazine 10 mg IV, when compared with sumatriptan 6 mg subcutaneous [169]. However, another trial found that there was no improvement to migraine when diphenhydramine 50 mg IV was added in conjunction with metoclopramide 10 mg IV [220]. More high-quality data are required to determine the efficacy of diphenhydramine administered in combination with other drugs for the treatment of migraine.

The anticonvulsant valproate (900–1,200 mg IV) has been evaluated for intractable migraine attack in emergency settings, with a reduction in pain within 50 to 60 minutes in 75% of patients [170]. However, its use as acute therapy is not recommended due to a lack of clear evidence of a favorable risk-benefit profile [164].

Moderate and severe acute migraines are more effectively treated with migraine-specific medications, particularly ergots and triptans. Interestingly, these medications do not have analgesic properties; rather their clinical effectiveness results from their targeting of the pathophysiologic mechanism underlying migraine. Migraine-specific medications are agonists at the serotonin 5-HT_1B/1D autoreceptor, preventing release of serotonin from the presynaptic terminals and causing vasoconstriction of the meningeal blood vessels. These drugs also target the serotonin autoreceptors on terminals of the trigeminal nerve, which results in the inhibition of the release of proinflammatory vasoactive peptides and inhibition of nociceptive transmission in the brainstem [60,62,98,175].

The ergot alkaloids ergotamine and dihydroergotamine are non-selective agonists at the 5-HT₁ serotonin receptor, with a lower affinity for alpha-adrenergic and dopaminergic receptors. On the other hand, triptans are considered to be highly selective agonists at the 5-HT_1B/1D serotonin receptor subtype, with lower affinity for binding to other serotonin receptors.

Ergotamine is available in oral formulation (Ergomar) or in combination with caffeine for either oral (Cafergot) or rectal (Migergot) administration. Dihydroergotamine is available for nasal administration (Migranal, generic) or for IV and subcutaneous injection (DHE, generic). The use of ergots has declined since the introduction of triptans, although clinical studies have demonstrated that both drug groups have a similar efficacy in the treatment of acute migraine [161]. Adverse effects of ergots include nausea and vomiting, tingling of the extremities, muscle cramps, and chest discomfort [161]. As discussed, 5-HT_1B/1D receptors are also expressed in high levels in the coronary arteries, resulting in the increased potential for adverse cardiac effects (i.e., coronary vasoconstriction) associated with ergotamine derivatives and triptans [161]. Ergots are contraindicated in patients with heart conditions or hypertension, and any chest or cardiac symptoms should be appropriately evaluated [60,61,161,176]. Dihydroergotamine is oxytocic and should not be used during pregnancy or breastfeeding [175,176]. Dihydroergotamine causes fewer adverse effects than ergotamine, but the use of any ergot alkaloids should be avoided within 24 hours of administration of triptans and serotonergic agonists, due to risk of severe vasoconstriction, and within two weeks of discontinuing monoamine oxidase (MAO) inhibitors. Ergots are contraindicated with potent inhibitors of CYP3A4, such as azole antifungals, macrolide antibiotics, and protease inhibitors [157,176].

Preventive pharmacotherapy is used in conjunction with effective nonpharmacologic approaches as part of a comprehensive plan including avoidance of migraine triggers, implementation of lifestyle changes, stress management techniques, and a reduction in the use of analgesics or acute migraine medications [181]. Patients with migraine should be considered for preventive treatment in any of the following situations [182,183,230]:

Preventive medications improve patients' quality of life and health outcomes and reduce disability and healthcare costs [184,185]. The decision to opt for preventive pharmacotherapy should be discussed with the patient and should take into consideration the variability in patient response and the possibility of significant side effects [185].

In 2018, the first medications in a novel class of drugs received FDA-approval for the prevention of migraine [176,214,225,226]. As previously noted, CGRP is a potent vasodilatory neuropeptide that increases blood flow in the meningeal arteries [66]. It has long been postulated that one cause of episodic migraine is a combination of neuronal hyperactivity and a local process of neurogenic inflammation triggered by an increase in pro-inflammatory mediators such as CGRP, neurokinin, and substance P [29,31]. Following the development of a monoclonal antibody that blocks the activity of the CGRP peptide, a significant reduction in days with migraine was shown in clinical trials with CGRP antagonists [214,221,222,223].

The first of three clinical trials prior to FDA-approval showed that six months of treatment with erenumab-aaoe resulted in one to two fewer monthly migraine days on average than those on placebo among 955 patients. A second study of 577 patients with episodic migraine showed one fewer migraine day over the course of three months. A third study of 677 patients with chronic migraine showed 2.5 fewer monthly migraine days after three months of treatment [214,221]. Erenumab-aaoe is recommended for those who do not respond to conventional treatment.

Erenumab-aaoe is initially administered at a dose of 70 mg once-monthly by subcutaneous self-injection, but this can be increased to a maximum of 140 mg once-monthly in divided doses [176]. There are no contraindications to erenumab-aaoe, and known side effects are limited to injection site reactions (less than 6%) and constipation (3%) [176]. Pregnancy and breastfeeding considerations are unknown; however, adverse events were not seen in animal reproduction studies [176].

The results of multiple phase II and phase III clinical trials resulted in additional CGRP antagonists receiving FDA approval in 2018, 2019, and 2020 [222,227]. Like erenumad, fremanezumab-vfrm, galcanezumab, ubregepant, and eptinezumab-jjmr are administered subcutaneously for prevention of migraine in adults [225,226]. Fremanezumab-vfrm is administered either as a 225-mg monthly dose or 675 mg every three months [225]. The initial dose of galcanezumab is 240 mg, followed by 120-mg monthly doses [226]. Ubregepant is taken orally at a dose of 50–100 mg (maximum in 24 hours: 200 mg) [227]. The initial dose of eptinezumab-jjmr is 100 mg every three months, but it may be titrated up to a maximum of 300 mg every three months.

The precise mechanism of action of drugs used for the conventional prophylactic treatment of migraine is unclear. It has been postulated that these medications prevent the underlying processes that set a migraine attack into motion and raise the threshold for migraine headache.

Initially, treatment should begin with the lowest possible dose, and a trial of at least two medications at the appropriate dosage is typically required before effectiveness can be assessed. If required, the dose should be slowly titrated up until benefits or unacceptable adverse reactions are observed. When possible, long-acting formulations should be used in order improve patient compliance. In addition, selecting medication that may also treat co-existing conditions, such as hypertension or depression, can improve adherence to the treatment plan [186]. One challenging scenario is presented by migraineurs who become less responsive (i.e., tolerant) to preventive migraine medications. This greatly impacts quality of life, and the establishment of an effective treatment plan for these patients requires an understanding of the mechanisms underlying tolerance to migraine therapy [181].

Although preventive treatments do not completely prevent the occurrence of migraines, they do reduce the frequency by at least 50% [185,187]. Evidence-based guidelines regarding drug effectiveness for the prevention of episodic migraine have haven prepared by the American Headache Society and the American Academy of Neurology (AHS/AAN) (Table 2) [74,186,230]. These guidelines categorize the available prophylactic medications according to the level of available evidence. The following oral treatments have established efficacy and should be offered for prevention of migraine: antiepileptic drugs (e.g., divalproex sodium, valproate sodium, topiramate), beta-blockers (e.g., metoprolol, propranolol, timolol), and frovatriptan (for short-term preventive treatment of menstrual migraine). An exception to the use of valproate sodium and topiramate is that, due to risk of birth defects, it should not be prescribed to women of childbearing potential who are not using a reliable method of contraception [230]. Evidence indicates the following treatment options are probably effective and should be considered for prevention: antidepressants (e.g., amitriptyline, venlafaxine), beta-blockers (e.g., atenolol, nadolol), and angiotensin receptor blockers (e.g., cardisartan) (230).

Caution is required when NSAIDs are used for preventive therapy, as their use is associated with induction of medication-overuse headache and chronification of migraine [185]. Although the Canadian Headache Society guideline for migraine prophylaxis recommends the use of the anticonvulsant gabapentin, this is not supported by a 2014 Cochrane review or a 2016 review of literature, which confirmed the effectiveness of topiramate, divalproex, and sodium valproate, but concluded that the evidence was insufficient to support the use of gabapentin [152,188,224]. Extended-release topiramate is contraindicated in patients with metabolic acidosis taking metformin, during pregnancy, in women of childbearing age not using contraception, and in patients with recent alcohol use (within six hours prior or six hours following administration). Divalproex and sodium valproate are contraindicated in patients with impaired liver function, urea cycle disorders, and pregnant women (for the prevention of migrane) [176].