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Headache

A headache is pain in any region of the head, which may occur on one or both sides, be isolated to a certain location, or radiate across the head from one point; it can manifest as a sharp or throbbing pain or a dull ache and may develop gradually or suddenly, lasting from less than an hour to several days.^[1] Headaches represent a symptom rather than a disease itself and are among the most common neurological disorders globally, affecting about 35% of the world's population, or 2.9 billion people as of 2023, with higher prevalence among females across all age groups from 5 to 80 years.^[2] They impose a significant burden, causing personal suffering, reduced quality of life, economic costs from lost productivity, and associations with conditions like anxiety and depression.^[3] Headaches are broadly classified into primary and secondary types. Primary headaches arise independently due to overactivity or dysfunction in pain-sensitive structures such as blood vessels, muscles, or nerves in the head and neck, without an underlying medical condition; common examples include tension-type headaches, migraines, and cluster headaches, which account for nearly 98% of all cases.^[4]^[5] Secondary headaches, in contrast, are symptoms of another underlying issue, such as infection, trauma, vascular disorders, or medication overuse, and though less common, require prompt evaluation to identify and treat the root cause.^[6]^[7] Among primary headaches, tension-type headaches are the most prevalent, affecting over one-third of men and more than half of women in developed countries, often described as a tight band around the head with mild to moderate, non-throbbing pain.^[8] Migraines, which involve moderate to severe throbbing pain typically on one side, nausea, and sensitivity to light or sound, affect about 14-15% of the global population and rank as one of the leading causes of disability worldwide, measured by disability-adjusted life years (DALYs).^[3]^[9] Cluster headaches, rare but intensely painful, occur in cycles and primarily affect one side around the eye, impacting a small fraction of sufferers but causing severe autonomic symptoms like tearing or nasal congestion.^[10] Overall, while most headaches are benign and manageable through lifestyle changes, rest, or over-the-counter remedies, persistent or severe cases warrant medical attention to rule out serious secondary causes.^[11]

Classification and Types

Primary Headaches

Primary headaches are defined as headache disorders that are not caused by or attributed to another underlying disorder, distinguishing them from secondary headaches that arise as symptoms of other conditions. These conditions are generally benign and involve dysfunction in the brain's nociceptive pathways, leading to pain without identifiable structural or systemic causes. The International Classification of Headache Disorders, 3rd edition (ICHD-3), categorizes primary headaches into four main groups: migraine, tension-type headache, trigeminal autonomic cephalalgias, and other primary headache disorders. Among these, migraine is a common subtype characterized by recurrent attacks of moderate to severe headache, often unilateral and throbbing in quality, accompanied by nausea, vomiting, photophobia, and phonophobia. Migraine is subdivided into those without aura and those with aura. For migraine without aura, the ICHD-3 diagnostic criteria require at least five attacks fulfilling the following: headache lasting 4-72 hours (untreated or unsuccessfully treated); headache having at least two of the following characteristics—unilateral location, pulsating quality, moderate or severe pain intensity, or aggravation by routine physical activity; during the headache, at least one of nausea/vomiting or photophobia/phonophobia; and not better accounted for by another ICHD-3 diagnosis.^[12] For migraine with aura, at least two attacks are required, each with one or more aura symptoms (visual, sensory, speech/language, motor, brainstem, or retinal) that develop gradually over ≥5 minutes, last 5-60 minutes, are accompanied or followed by headache lasting 4-72 hours, and are not better accounted for by another diagnosis.^[13] Tension-type headache (TTH) is another major subtype, featuring bilateral pressing or tightening pain that is mild to moderate in intensity, without nausea or significant aggravation by physical activity. It is divided into episodic and chronic forms. Episodic TTH includes infrequent (occurring <12 days/year) and frequent (1-14 days/month for >3 months) variants. The ICHD-3 criteria for infrequent episodic TTH are at least 10 episodes of headache occurring on <1 day/month on average (<12 days/year) for >3 months, lasting from 30 minutes to 7 days, with at least two of bilateral location, pressing/tightening quality, mild/moderate intensity, and no nausea or more than one of photophobia, phonophobia, or mild nausea, not better accounted for by another diagnosis.^[14] For frequent episodic TTH, the criteria are similar but with at least 10 episodes occurring on 1-14 days/month on average for >3 months (≥12 and ≤179 days/year).^[15] Chronic TTH involves headache on ≥15 days/month on average for >3 months (≥180 days/year), with the same pain characteristics as episodic forms.^[16] Cluster headache, a trigeminal autonomic cephalalgia, presents as severe unilateral orbital, supraorbital, or temporal pain lasting 15-180 minutes, occurring from every other day to eight times per day, often with ipsilateral autonomic symptoms such as conjunctival injection, lacrimation, nasal congestion, rhinorrhea, eyelid edema, forehead/facial sweating, or miosis/ptosis. The ICHD-3 criteria require at least five attacks fulfilling severe or very severe unilateral pain (lasting 15-180 minutes if untreated), accompanied by either at least one ipsilateral autonomic symptom or a sense of restlessness or agitation, with attacks occurring in bouts or episodically, and not better accounted for by another diagnosis.^[17] It can be episodic (with remission periods) or chronic (without remission ≥3 months). New daily persistent headache (NDPH) is a distinctive primary headache disorder marked by a sudden onset of continuous daily headache that the patient can clearly recall, persisting for more than 3 months. The ICHD-3 diagnostic criteria include persistent headache fulfilling the requirements for either tension-type headache or migraine but with a distinct and clearly remembered onset, becoming continuous and unremitting within 24 hours, lasting >3 months, and not better accounted for by another diagnosis.^[18] Within primary headaches, tension-type headache is the most prevalent, with a 1-year prevalence of approximately 26.8% globally and lifetime prevalence ranging from 30% to 78% in the general population, accounting for the majority of cases compared to migraine (15.2% 1-year prevalence) or rarer forms like cluster headache.^[19]^[20]

Secondary Headaches

Secondary headaches are those that arise as a symptom of an identifiable underlying medical condition or external trigger, distinguishing them from primary headaches which lack a clear structural or etiological cause.^[21] According to the International Classification of Headache Disorders, third edition (ICHD-3), secondary headaches are attributed directly to the causative disorder and are classified into several major categories based on the underlying pathology.^[22] The primary categories in ICHD-3 include headache attributed to trauma or injury to the head and/or neck (e.g., post-traumatic headache following concussion), cranial or cervical vascular disorders (such as subarachnoid hemorrhage or giant cell arteritis), non-vascular intracranial disorders (like tumors or idiopathic intracranial hypertension), substances or their withdrawal (including medication-overuse headache and caffeine-withdrawal headache), infection (e.g., bacterial meningitis or viral encephalitis), disorders of homeostasis (such as hypoxia), disorders of cranial, neck, ocular, otic, nasal, sinus, dental, or other facial/cervical structures (e.g., acute rhinosinusitis causing facial pain or acute angle-closure glaucoma), and psychiatric disorders.^[22]^[23] Other notable examples include carbon monoxide-induced headache from toxic exposure, which resolves within 72 hours after elimination of the toxin.^[24] Diagnostically, secondary headaches require prompt evaluation to exclude life-threatening etiologies, such as intracranial tumors, strokes, or subarachnoid hemorrhage, which may present with sudden onset or progressive worsening and necessitate urgent neuroimaging or intervention.^[25] Although life-threatening secondary headaches are uncommon, accounting for significant abnormalities in only about 1% of cases requiring neuroimaging, their identification is critical to prevent morbidity.^[26] Recent updates in headache classification and research have incorporated post-COVID-19 headaches as a secondary type under infectious etiologies (ICHD-3 code 9.1.2, headache attributed to viral infection), particularly in long COVID cases where symptoms persist beyond 90 days in up to 35.8% of affected individuals, often manifesting as new daily persistent headache or chronic migraine phenotypes.^[27]

Trigeminal Autonomic Cephalalgias

Trigeminal autonomic cephalalgias (TACs) are a group of primary headache disorders characterized by unilateral trigeminal distribution pain accompanied by ipsilateral cranial autonomic symptoms, reflecting activation of the trigeminovascular system and parasympathetic outflow. According to the International Classification of Headache Disorders, third edition (ICHD-3), TACs include cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA).^[28] This section focuses on SUNCT/SUNA and paroxysmal hemicrania, which are distinguished by their ultrashort attack durations and high frequencies. For SUNCT, ICHD-3 criteria require at least 20 attacks of moderate-to-severe unilateral pain in the orbital, supraorbital, temporal, or V1/V2 facial distribution, lasting 1–600 seconds, occurring 1–200 times per day, and accompanied by both ipsilateral conjunctival injection and lacrimation (or tearing).^[29] SUNA shares identical criteria except that it requires only one or more cranial autonomic symptoms, such as lacrimation, nasal congestion, or rhinorrhea, without mandatory conjunctival injection.^[29] Paroxysmal hemicrania involves at least 20 attacks of severe unilateral orbital, supraorbital, or temporal pain lasting 2–30 minutes, with a frequency of more than five per day for more than half the time, accompanied by at least one ipsilateral autonomic symptom, and showing absolute responsiveness to indomethacin.^[30] Pathognomonic features of SUNCT/SUNA and paroxysmal hemicrania include severe, stabbing or neuralgiform pain centered around the eye or temple, often triggered by touching the face, chewing, or washing, with prominent ipsilateral autonomic manifestations such as lacrimation, conjunctival injection, nasal congestion, rhinorrhea, or eyelid edema.^[31] These autonomic signs arise from parasympathetic activation via the trigeminal-parasympathetic reflex, distinguishing TACs from other unilateral headaches.^[32] In paroxysmal hemicrania, attacks may cluster in bouts lasting weeks to months, separated by remission periods of months to years in the episodic form, while the chronic form lacks remission longer than three months.^[33] SUNCT/SUNA attacks, by contrast, are often unremitting in frequency without clear periodicity, emphasizing their relentless nature.^[34] SUNCT/SUNA differ from cluster headache, another TAC, primarily by their much shorter attack duration (seconds to minutes versus 15–180 minutes) and higher daily frequency (up to 200 attacks versus 1–8), despite sharing unilateral pain and autonomic features; this ultrashort profile aids differentiation and rules out cluster in cases with sub-minute episodes.^[34] There is some overlap with cluster headache in pathophysiology, involving hypothalamic activation, but SUNCT/SUNA lack the circadian rhythmicity often seen in cluster.^[35] These disorders are rare, with SUNCT/SUNA estimated to affect 6.6 per 100,000 individuals and an annual incidence of 1.2 per 100,000, typically onset in middle age (40–50 years).^[36] Paroxysmal hemicrania has a lower prevalence of 1.4 per 100,000 (95% CI: 1.0–1.8), with a female predominance.^[37] Unlike cluster headache's male bias, paroxysmal hemicrania shows a roughly 2:1 female-to-male ratio across reported cases.^[38] Recent advances highlight the efficacy of neuromodulation for refractory TACs, particularly non-invasive vagus nerve stimulation (nVNS), which has shown preventive benefits in reducing attack frequency for SUNCT/SUNA and paroxysmal hemicrania unresponsive to standard therapies like indomethacin.^[39] A 2024 review underscores nVNS as a safe, tolerable option for these hard-to-treat cases, complementing pharmacological approaches.^[34]

Pathophysiology

Mechanisms in Primary Headaches

Primary headaches, including migraine, tension-type headache, and cluster headache, arise from intrinsic brain and neural dysfunctions without identifiable underlying pathology. These disorders involve complex interactions between peripheral and central nervous system components, leading to recurrent episodes of pain. The predominant mechanisms revolve around neurogenic inflammation, sensitization of pain pathways, and genetic predispositions that lower the threshold for headache initiation.^[40] The neurovascular theory posits that primary headaches, particularly migraine, stem from activation of the trigeminovascular system, where trigeminal nerve endings innervating cerebral and dural blood vessels release neuropeptides such as calcitonin gene-related peptide (CGRP). This release promotes neurogenic inflammation, vasodilation, and sensitization of nociceptive afferents, transmitting pain signals to the brainstem and thalamus. In migraine specifically, cortical spreading depression (CSD)—a wave of neuronal depolarization followed by suppression of activity—originates in the cortex and propagates at 2-5 mm/min, activating the trigeminovascular pathway and contributing to aura and subsequent headache. CSD triggers CGRP release from trigeminal ganglia, amplifying pain signaling via CGRP receptors on vascular smooth muscle and sensory neurons.^[41]^[40]^[42]^[43] Central sensitization plays a key role in tension-type headache and the chronification of primary headaches, characterized by heightened responsiveness of central neurons to peripheral inputs. In chronic tension-type headache, repeated nociceptive input from pericranial muscles leads to sensitization in the trigeminocervical complex and higher brainstem centers, including the periaqueductal gray (PAG), which modulates descending pain inhibition but becomes dysfunctional in chronic states. The PAG's altered connectivity reduces endogenous opioid-mediated analgesia, perpetuating allodynia and hypersensitivity to normal stimuli. This process transforms episodic pain into persistent forms, with evidence from functional imaging showing PAG hyperactivity during attacks.^[44]^[45]^[46]^[47] Genetic factors contribute to primary headache susceptibility, most notably in familial hemiplegic migraine (FHM), a subtype of migraine with aura. Mutations in the CACNA1A gene, encoding the α1A subunit of P/Q-type voltage-gated calcium channels, disrupt calcium influx in neurons, leading to hyperexcitability and impaired neurotransmitter release. These mutations, found in approximately 50% of FHM families, lower the threshold for CSD and enhance trigeminovascular activation, resulting in hemiplegic episodes with motor weakness. Over 30 distinct CACNA1A mutations have been identified, often linked to cerebellar ataxia in affected families.^[48]^[49]^[50] Recent research from 2024-2025 highlights epigenomic changes as modulators of migraine susceptibility, particularly through histone modifications influencing CGRP pathways. Epigenetic alterations, such as histone acetylation and methylation, regulate gene expression in trigeminal neurons, enhancing CGRP receptor sensitivity and promoting neuroinflammation. For instance, environmental triggers like stress can induce histone deacetylase (HDAC) activity changes, altering chromatin structure around CGRP-related genes and increasing attack frequency. Studies also link microRNA-mediated epigenetics to CGRP system dysregulation, suggesting therapeutic potential in HDAC inhibitors for personalized migraine management. These findings underscore how epigenomic plasticity bridges genetic predisposition and environmental factors in primary headaches.^[51]^[52] Mechanisms differ across primary headache types, reflecting distinct pathophysiological emphases. In migraine, the throbbing quality arises from pulsatile vasodilation of dural vessels, synchronized with heartbeat due to CGRP-induced relaxation of vascular smooth muscle, amplifying mechanosensitive nociceptor firing. In cluster headache, intense pain is driven by activation of the trigeminal-autonomic reflex, with involvement of the hypothalamus, leading to ipsilateral autonomic symptoms like lacrimation and nasal congestion through parasympathetic outflow. Conversely, tension-type headache involves sustained myofascial contraction, where trigger points in pericranial muscles—hyperirritable nodules in taut bands—generate constant pressure-like pain through local ischemia and referred sensitization, without prominent vascular pulsation.^[53]^[54]^[55]^[56]^[57]

Mechanisms in Secondary Headaches

Secondary headaches arise from underlying pathological conditions that disrupt normal physiological processes, leading to activation of pain-sensitive structures in the brain and meninges. Unlike primary headaches, which stem from intrinsic neural dysfunctions, secondary headaches are provoked by external insults such as structural, vascular, infectious, or metabolic disturbances. These mechanisms often involve direct irritation, inflammation, or ischemia of nociceptive pathways, including the dura mater, cranial nerves, and vascular endothelium, resulting in referred pain to the head.^[58] One key mechanism in secondary headaches is traction and inflammation caused by mass lesions, such as tumors, which exert mechanical stress on pain-sensitive intracranial structures. For instance, the expansion of a pituitary tumor within the sella turcica can stretch the dura mater and stimulate afferent nerve fibers innervating these tissues, triggering localized headache pain independent of elevated intracranial pressure. Similarly, in cases of pituitary apoplexy associated with neuroendocrine tumors, rapid hemorrhage or infarction leads to traction on the dura mater, cranial nerves, and blood vessels, amplifying nociceptive signaling and causing severe, acute headaches. This traction-induced activation of meningeal nociceptors is a primary pathway for headache in intracranial masses, often presenting as progressive or positional pain.^[59] Vascular disruptions, including ischemia and hemorrhage, represent another critical pathway for secondary headaches through meningeal irritation and secondary inflammation. In ischemic stroke, such as middle cerebral artery occlusion, cerebral edema and tissue infarction can distend the dura and activate the trigeminovascular system, leading to headache in up to 25-44% of cases, often with tension-type features that may persist chronically. Hemorrhagic events, like subarachnoid hemorrhage, directly irritate the leptomeninges via blood breakdown products, provoking a sterile inflammatory response that sensitizes nociceptors and causes thunderclap headaches. These vascular mechanisms highlight how acute changes in cerebral blood flow or vessel integrity propagate pain signals via perivascular nerves.^[60]^[61]^[62] Infectious processes induce secondary headaches primarily through cytokine-mediated inflammation of the meninges. In meningitis, whether bacterial or viral, pathogens trigger the release of pro-inflammatory cytokines like interleukin-1β (IL-1β), which promote aseptic inflammation and vasodilation of meningeal vessels, directly activating trigeminal nociceptors. This leads to the characteristic severe, diffuse headache accompanied by photophobia and neck stiffness, as the inflamed meninges sensitize surrounding pain pathways. Viral infections, in particular, can cause persistent cytokine elevation in the cerebrospinal fluid, exacerbating neurogenic inflammation even after pathogen clearance.^[63]^[64]^[65] Toxic and metabolic derangements, such as those in carbon monoxide (CO) poisoning, provoke headaches via systemic hypoxia that impairs neuronal function and activates peripheral nociceptors. CO binds hemoglobin with high affinity, reducing oxygen delivery and causing cerebral hypoxia, which in turn stimulates trigeminal nerve endings in the dura and vessels, resulting in throbbing headaches reported in 70-90% of mild to moderate cases. This hypoxic activation disrupts mitochondrial function in nociceptive neurons, lowering their threshold for firing and contributing to the flu-like headache profile. Beyond acute effects, prolonged exposure can lead to delayed neurological sequelae with persistent headache due to ongoing oxidative stress.^[66]^[67]^[68] Recent insights into post-viral secondary headaches, particularly in long COVID, emphasize persistent neuroinflammation as a driving mechanism. Following SARS-CoV-2 infection, headaches can endure for months due to sustained microglial activation and cytokine release in the central nervous system, leading to low-grade meningeal inflammation and blood-brain barrier dysfunction. A 2025 review highlights how this immune dysregulation, involving elevated levels of IL-6 and TNF-α, sensitizes trigeminovascular pathways, resulting in migraine-like or tension-type headaches in up to 20% of long COVID patients. These findings underscore the role of viral-induced autoimmunity in prolonging secondary headache syndromes beyond acute infection.^[69]^[70]

Diagnosis

Clinical Assessment and Red Flags

Clinical assessment of headache begins with a detailed history to characterize the pain and identify potential underlying causes. Key elements include the onset, which may be sudden (suggesting vascular events like subarachnoid hemorrhage) or gradual (more typical of primary headaches such as migraine), location (unilateral versus bilateral, focal versus diffuse), quality (throbbing, pressure-like, or sharp), and severity (often rated on a 0-10 scale). Associated symptoms are crucial, such as nausea or photophobia in migraine versus fever, neck stiffness, or altered mental status indicating infection or meningitis.^[71]^[72]^[73] Distinguishing "old" from "new" headaches is essential for risk stratification; longstanding patterns with stable features are generally reassuring for primary disorders, while a new-onset headache or sudden change in a chronic pattern (e.g., increased frequency or severity) warrants further evaluation for secondary causes.^[74]^[75] The physical examination focuses on a targeted neurological screening to detect focal deficits, such as weakness, sensory loss, or ataxia, alongside fundoscopy to assess for papilledema indicating raised intracranial pressure, and evaluation for neck stiffness suggestive of meningeal irritation. Vital signs, general appearance, and cranial nerve testing complete the initial exam to rule out systemic involvement.^[76]^[73]^[77] Red flags, as described in clinical guidelines such as the SNNOOP10 list and supported by guidelines from the National Institutes of Health (NIH), signal the need for urgent investigation to exclude serious secondary headaches. These include thunderclap onset (reaching maximum intensity within 1 minute, often due to subarachnoid hemorrhage), focal neurological deficits (e.g., hemiparesis or visual field loss), papilledema, and signs of systemic illness such as fever, weight loss, or jaw claudication in giant cell arteritis.^[78]^[79]^[58] Additional red flags encompass a history of neoplasm or immunosuppression, progressive worsening, or headaches triggered by exertion, valsalva maneuvers, or positional changes, which may indicate structural lesions or vascular issues. Post-exertional headaches are considered potential red flags, warranting prompt evaluation to differentiate benign primary exercise headache from secondary causes like subarachnoid hemorrhage or Chiari malformation, as noted in clinical guidelines.^[80]^[81]^[82]

Imaging and Laboratory Investigations

Imaging and laboratory investigations play a crucial role in evaluating headaches when clinical assessment suggests a secondary cause, such as sudden onset or associated neurological symptoms, to rule out serious underlying conditions. These tests are typically reserved for cases with red flags identified during history and examination, as routine use in uncomplicated primary headaches yields low diagnostic value. Guidelines from the American Headache Society recommend neuroimaging only for new, atypical, or worsening headaches, emphasizing that imaging is not indicated for stable migraine without worrisome features.^[83]^[84] Non-contrast computed tomography (CT) is the initial imaging modality of choice for acute headaches suspicious for hemorrhage, particularly subarachnoid hemorrhage (SAH), due to its high sensitivity of approximately 95% when performed within 6 hours of symptom onset.^[85] For chronic headaches or those involving the posterior fossa, magnetic resonance imaging (MRI) is preferred for its superior soft tissue resolution and ability to detect ischemic changes, tumors, or vascular malformations without radiation exposure.^[86] The diagnostic yield of neuroimaging in uncomplicated, low-risk headache patients—such as those with longstanding primary headaches and normal neurological exams—is less than 1%, with abnormalities rarely altering management.^[87] In contrast, imaging for "new" headaches with atypical features shows higher yield, up to 5-10% for significant findings, justifying selective use based on evidence-based criteria.^[88] Lumbar puncture (LP) is indicated for headaches with suspected infectious or pressure-related etiologies, such as meningitis, where cerebrospinal fluid (CSF) analysis reveals pleocytosis (elevated white blood cell count) confirming inflammation.^[89] In cases of suspected idiopathic intracranial hypertension (IIH), LP measures elevated opening pressure (typically >25 cm H₂O) while excluding other causes through CSF composition analysis, aiding diagnosis in patients with papilledema and chronic daily headaches.^[90] Contraindications include signs of increased intracranial pressure on imaging, and LP is performed after neuroimaging to mitigate risks like herniation. Laboratory investigations complement imaging in targeted scenarios. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are essential for evaluating giant cell arteritis (GCA) in older patients with new-onset headaches, where elevated levels (CRP often more sensitive than ESR) support temporal artery biopsy; normal values do not fully exclude the diagnosis but prompt further testing if clinical suspicion persists.^[91] Toxicology screening via urine or serum assays is recommended for headaches potentially linked to substance use or withdrawal, identifying toxins like carbon monoxide or illicit drugs that may precipitate secondary headaches.^[92] Advances in neuroimaging, including functional MRI (fMRI), have emerged by 2025 to map cortical spreading depression associated with migraine aura, providing insights into brain activation patterns during attacks through consensus reporting standards for enhanced reproducibility in research settings.^[93] These techniques, while not routine for diagnosis, support pathophysiological studies and may guide future personalized therapies. As of 2025, ongoing research continues to explore AI and advanced imaging for improved diagnostic precision in headache disorders.

Diagnostic Classification Systems

The International Classification of Headache Disorders, third edition (ICHD-3), published in 2018 by the International Headache Society, establishes a standardized hierarchical framework for diagnosing headache disorders, comprising 14 main categories divided into primary headaches (categories 1-4), secondary headaches (categories 5-12), painful cranial neuropathies and other facial pain (category 13), and other headache disorders (category 14).^[78] This structure emphasizes operational diagnostic criteria that require specific combinations of headache characteristics, such as frequency, duration, location, quality, and associated symptoms, to ensure precise categorization of primary headaches like migraine and tension-type headache, secondary headaches attributed to underlying causes, and painful cranial neuropathies including trigeminal neuralgia.^[94] A 2024 study proposed refinements to the ICHD-3 criteria for migraine-associated symptoms based on evidence from a multicenter headache registry in youth, to better capture atypical presentations while maintaining the core hierarchical approach.^[95] ICHD-3 represents an evolution from its predecessor, the second edition (ICHD-2) released in 2004, which featured a similar but less refined structure with 11 main categories and broader criteria that often led to diagnostic overlap. Key advancements in ICHD-3 include the formal recognition of short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) as a distinct trigeminal autonomic cephalalgia, previously grouped under SUNCT in ICHD-2, and refinements to medication-overuse headache criteria that lower the threshold for acute medication intake (e.g., 10-15 days per month for triptans or simple analgesics) to reflect better the continuum from episodic to chronic forms without requiring exclusion of primary headache types.^[78] These changes enhance diagnostic specificity and address gaps in ICHD-2, such as inconsistent handling of comorbid conditions. In parallel, the National Institutes of Health (NIH) has promoted symptom-based classifications for research purposes, particularly focusing on chronic daily headaches defined as occurring on 15 or more days per month for at least three months.^[96] The Silberstein-Lipton criteria, developed through NIH-supported field trials, provide a practical, phenotype-driven approach that subdivides chronic daily headaches into transformed migraine, chronic tension-type headache, hemicrania continua, and new daily persistent headache based on pain features, duration (>4 hours per day for long-duration types), and absence of structural causes, facilitating epidemiological studies and trial enrollment where full ICHD application may be cumbersome.^[97] These classification systems offer substantial utility by promoting reproducibility across clinical trials, enabling consistent patient selection and outcome measurement—for instance, ICHD-3 criteria have standardized endpoints in over 90% of migraine drug trials since 2018, reducing inter-rater variability to below 10% in structured assessments.^[98] However, limitations persist, including reduced applicability in diverse cultural contexts where symptom expression, such as somatic versus psychological descriptors of pain, may not align with the operational criteria, leading to underdiagnosis in non-Western populations.^[99] A 2025 systematic review highlighted the potential of AI-assisted tools, such as machine learning models, to augment traditional classification criteria by predicting headache subtypes with accuracies ranging from 70% to 98% in validated models.^[100]

Management

Acute and Preventive Strategies

Acute treatment strategies for headaches focus on providing rapid relief from pain and associated symptoms while minimizing the risk of medication overuse. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or aspirin, and acetaminophen are recommended as first-line options for mild to moderate acute headaches due to their efficacy in reducing pain intensity and improving function.^[101] For headaches accompanied by nausea or vomiting, antiemetics like metoclopramide can be added to enhance tolerability and absorption of analgesics.^[102] To prevent rebound headaches, acute medication use should be limited to no more than 15 days per month for simple analgesics like NSAIDs or acetaminophen.^[103] Preventive pharmacological approaches aim to reduce headache frequency, severity, and disability in patients experiencing recurrent episodes. Beta-blockers, particularly propranolol at doses starting from 40 mg daily, are established as effective first-line agents, with evidence from multiple randomized trials showing a 50% reduction in attack frequency in responsive patients.^[104] Tricyclic antidepressants like amitriptyline (starting at 10-25 mg nightly) and anticonvulsants such as topiramate (titrated to 100 mg daily) are also recommended, supported by meta-analyses demonstrating significant prophylactic benefits over placebo.^[102] Preventive therapy is typically initiated when headaches occur more than four days per month or cause substantial impairment, as per guidelines from major headache societies.^[105] Recent endorsements by the American Headache Society in 2024 position calcitonin gene-related peptide (CGRP) monoclonal antibodies, such as erenumab (70-140 mg monthly subcutaneously), as first-line preventive options alongside traditional agents, based on phase 3 trials showing sustained reductions in monthly headache days.^[106] Lifestyle modifications serve as foundational preventive measures, addressing common triggers to decrease headache occurrence without pharmacological risks. Strategies include maintaining consistent sleep hygiene (7-9 hours nightly), ensuring adequate hydration (at least 2 liters daily), and employing stress management techniques like relaxation training or mindfulness. A 2024 systematic review found that behavioral interventions, including sleep optimization and stress reduction, can reduce headache frequency by approximately 1 day per month in adults with episodic headaches (low strength of evidence).^[107] Monitoring treatment efficacy relies on patient-maintained headache diaries, which track attack frequency, severity, triggers, and medication use to guide adjustments and assess progress toward a 50% reduction in headache days.^[108] The American Headache Society endorses this tool in its 2024 guidelines, recommending its use alongside objective measures for evaluating preventive therapies like CGRP inhibitors.^[106] Medication overuse headache (MOH) arises from excessive acute treatment and exacerbates underlying headaches, meeting International Classification of Headache Disorders (ICHD-3) criteria when headaches occur on 15 or more days per month in individuals with a pre-existing headache disorder who have overused acute medications for more than three months—specifically, simple analgesics on 15 or more days or triptans/opioids on 10 or more days.^[109] Withdrawal protocols emphasize abrupt cessation of the overused medication, often supported by short-term bridging with non-overused analgesics or preventive initiation, with randomized trials showing resolution in 60-70% of cases within two months.^[110] Patient education on adherence limits is crucial to prevent recurrence.^[111]

Treatments for Specific Headache Types

Treatments for migraine, a primary headache disorder, focus on both acute relief and preventive strategies tailored to attack frequency and severity. For acute management, triptans such as sumatriptan are first-line options, providing pain relief in approximately 70% of attacks within 2 hours post-administration.^[112] Gepants, including ubrogepant, offer an alternative for patients intolerant to triptans; approved by the FDA for acute treatment, ubrogepant demonstrated significant pain freedom in clinical trials.^[113] Ditans like lasmiditan provide efficacy comparable to triptans in triptan-nonresponders, achieving headache relief in a substantial proportion of patients without vasoconstrictive effects.^[114] Preventive therapies, such as the monoclonal antibody fremanezumab, reduce monthly migraine days by 4-5 on average in phase 3 studies, particularly benefiting those with episodic or chronic migraine.^[115] Recent 2025 data from the PREVAIL study on eptinezumab, an intravenous CGRP antagonist, showed sustained reductions in monthly headache days for chronic migraine, with about half of patients achieving at least 50% improvement over long-term treatment.^[116] Tension-type headaches, the most common primary headache, are primarily managed with nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen or aspirin for episodic cases, which effectively alleviate mild to moderate pain in most patients.^[117] For chronic tension-type headache, occurring 15 or more days per month, botulinum toxin type A (Botox) injections represent an option; a 2023 meta-analysis indicated a 79% greater response rate compared to controls in reducing headache frequency and severity.^[118] Cluster headaches, part of the trigeminal autonomic cephalalgias, require rapid acute interventions due to their intense, short-duration attacks. Inhalation of 100% oxygen at 12 L/min via a non-rebreather mask for 15-20 minutes aborts attacks in up to 80% of cases, as recommended by the European Academy of Neurology.^[119] Prophylactic treatment with verapamil, starting at 240 mg daily and titrating up to 960 mg, is the cornerstone for preventing bouts in both episodic and chronic forms, significantly reducing attack frequency.^[120] Secondary headaches necessitate addressing the underlying etiology to resolve symptoms. For instance, bacterial sinusitis-induced headaches are treated with antibiotics such as amoxicillin, alongside decongestants if needed, to clear the infection and alleviate pressure.^[121] In giant cell arteritis, a vascular cause of secondary headache, high-dose corticosteroids like prednisone (typically 40-60 mg daily) are initiated promptly to prevent complications such as vision loss.^[122]

Non-Pharmacological and Neuromodulation Approaches

Non-pharmacological approaches to headache management encompass behavioral therapies that target psychological and physiological factors contributing to headache onset and persistence. Cognitive behavioral therapy (CBT) has demonstrated efficacy in reducing migraine frequency, with meta-analyses showing significant decreases in monthly headache days and disability scores, such as the Migraine Disability Assessment Scale (MIDAS), in adults.^[123] For instance, trials indicate that CBT can lead to a 50% or greater reduction in migraine attacks for many participants, particularly when combined with standard care.^[124] Biofeedback, another behavioral intervention, is particularly effective for tension-type headaches, where electromyographic feedback helps patients gain control over muscle tension, resulting in substantial improvements in headache frequency and intensity compared to placebo or monitoring alone.^[125] Neuromodulation therapies offer device-based options for modulating neural pathways involved in headache generation, providing alternatives for patients with inadequate response to other treatments. Non-invasive vagus nerve stimulation (nVNS), such as with the gammaCore device, has shown acute efficacy in migraine relief, with randomized trials reporting higher pain-free rates (up to 30-40%) at 2 hours post-treatment compared to sham devices.^[126] Similarly, transcutaneous electrical nerve stimulation (TENS) via the Cefaly device, applied to the supraorbital area, serves as a preventive measure for episodic migraine, with studies confirming reduced monthly headache days and improved tolerability as an at-home option.^[127] A 2025 review of neuromodulation in chronic migraine highlighted an average 30% reduction in headache days across non-invasive techniques, underscoring their role in long-term management for refractory cases.^[128] Alternative therapies like acupuncture and yoga provide adjunctive relief for migraine, supported by recent systematic evidence. Acupuncture has been associated with superior outcomes in reducing migraine frequency and severity when used prophylactically, with 2024 meta-analyses recommending 7-16 sessions over 1.5-2 months for optimal effects.^[129] Yoga, incorporating breathing and relaxation elements, similarly decreases headache frequency and disability, with 2024 reviews identifying it as one of the most effective exercise interventions based on low-quality but consistent evidence from randomized trials.^[130] Surgical neuromodulation remains a rare intervention reserved for highly refractory cases, such as chronic cluster headache unresponsive to other therapies. Occipital nerve stimulation (ONS), involving implanted electrodes to target the greater occipital nerve, has demonstrated sustained pain relief and attack reduction in up to 60-70% of patients with refractory cluster headache over long-term follow-up.^[131] Emerging updates in neuromodulation incorporate machine learning to optimize protocols, aligning with 2024 priorities from the American Headache Society (AHS) and related research initiatives. These AI-driven approaches, including predictive models for attack forecasting based on symptoms, aim to personalize stimulation timing and parameters, enhancing efficacy in diverse headache populations.^[132]

Epidemiology

Global Prevalence and Incidence

Headache disorders represent one of the most common neurological conditions globally, affecting approximately 40% of the world's population, or about 3.1 billion people as of 2021. Updated estimates from the Global Burden of Disease Study indicate that headache disorders affected nearly 3 billion people worldwide in 2023, with an age-standardized prevalence of 34.6%.^[3]^[133] Among specific types, tension-type headache is the most prevalent, impacting around 26% of the global population and an estimated 2 billion individuals, while migraine affects 14-15% or roughly 1.2 billion people.^[134]^[135] These figures underscore the widespread occurrence of headaches, with one-year prevalence estimates for any headache reaching 65% among adults aged 18-65.^[134] Incidence rates for headache disorders have shown a gradual rise, reflecting an age-standardized incidence rate increase from 1990 levels.^[136] For migraine specifically, new-onset cases typically peak during the 20s and 30s, though incidence is highest in the 10-14 age group before stabilizing.^[137] Cluster headache remains exceptionally rare, with a global prevalence of about 0.1%, or 1 in 1,000 people.^[138] The global burden of headache disorders is substantial, particularly for migraine, which the World Health Organization's 2025 fact sheet identifies as the leading cause of disability among those under 50 years old, contributing to over 1 billion cases and significant years lived with disability.^[3] Gender variations are pronounced, with migraine prevalence being three times higher in women than in men.^[139] Recent data from 2024 highlight a post-pandemic uptick in chronic daily headaches, driven by persistent symptoms in 7-26% of individuals recovering from COVID-19.^[140]

Risk Factors and Demographics

Headaches, particularly migraine, exhibit notable demographic patterns, with a pronounced predominance in females attributed to hormonal influences such as fluctuations in estrogen levels during menstrual cycles, pregnancy, and menopause.^[141] Global prevalence data indicate that migraine affects approximately 20.7% of women compared to 9.7% of men, reflecting this sex-based disparity.^[142] Age-related peaks for migraine typically occur between 15 and 55 years, aligning with reproductive years when hormonal variations are most influential, though incidence may begin earlier in adolescence.^[143] Modifiable risk factors play a significant role in headache susceptibility, including obesity, which increases the risk of progression to chronic migraine up to five times in affected individuals.^[144] Smoking, particularly current tobacco use, is associated with an elevated risk of migraine, potentially exacerbating vascular and inflammatory pathways, while showing no such link or even a protective effect for tension-type headache.^[145] Poor sleep quality and deprivation further contribute as triggers, with studies demonstrating that inadequate sleep predicts subsequent headache onset and heightened pain sensitivity the following day.^[146] Genetic factors underlie a substantial portion of headache risk, with migraine heritability estimated at 40-60% based on twin and family studies, indicating a strong polygenic component.^[147] Environmental triggers, such as chronic stress, interact with this genetic predisposition to precipitate attacks, amplifying susceptibility in vulnerable populations.^[148] Socioeconomic status influences headache prevalence, with higher rates observed in low-income groups due to barriers in healthcare access and management resources.^[149] Studies have shown that urban pollution, linking exposure to particulate matter and other air pollutants, is associated with increased tension-type headache incidence in densely populated areas.^[150]

Special Populations

Headaches in Children and Adolescents

Headaches are a common complaint among children and adolescents, with prevalence rates varying by age and type. The overall prevalence of primary headaches in this population is estimated at 62% over periods ranging from one month to lifetime, based on a 2023 meta-analysis of global studies.^[151] For recurrent headaches, rates are lower, affecting approximately 10-20% of children aged 5-15 years, rising to about 28-30% in adolescents due to hormonal and environmental factors. Migraine, a subtype, has a prevalence of approximately 11% globally in children and adolescents, and it often exhibits a strong familial pattern, with up to 50-60% of affected youth having a first-degree relative with the condition, highlighting genetic influences such as mutations in ion channel genes.^[151] Tension-type headaches are the most prevalent primary headache disorder in children and adolescents, accounting for the majority of cases and typically presenting as mild to moderate bilateral pain without nausea or photophobia. These headaches are often triggered by stress, poor sleep, or screen time and can occur episodically or chronically. In contrast, migraines in this age group may manifest differently from adults, with shorter duration (2-72 hours) and more bilateral involvement. A unique pediatric variant is abdominal migraine, which affects 1-4% of school-aged children, primarily those aged 4-15 years, and involves recurrent episodes of intense midline abdominal pain lasting 1-72 hours, often accompanied by nausea, vomiting, pallor, and anorexia, without headache in up to 70% of cases. This condition is considered a migraine equivalent and tends to resolve by adolescence, evolving into typical migraines in about 70% of cases. Diagnosing headaches in children presents unique challenges due to developmental limitations in verbal expression, particularly in those under 7 years, who may struggle to describe pain location, quality, or severity, leading to reliance on behavioral cues like irritability or withdrawal. Adolescents may underreport symptoms due to stigma or fear of missing school activities. School absenteeism serves as a key proxy for headache impact, with children experiencing frequent or severe headaches more than twice as likely to miss school days compared to peers, and this absence correlating with lower academic performance and functional disability. Comprehensive evaluation often involves parent and teacher input, headache diaries, and screening for comorbidities like anxiety or sleep disorders to differentiate primary from secondary causes. Management of headaches in children and adolescents emphasizes age-appropriate strategies to minimize risks, starting with non-pharmacological measures such as lifestyle modifications including regular sleep, hydration, and stress reduction. Pharmacological treatments require weight-based pediatric dosing to avoid adult equivalents, which can lead to overdose or inefficacy; for acute relief, ibuprofen at 7.5-10 mg/kg per dose (maximum 400-600 mg) is recommended as first-line therapy for both tension-type and migraine headaches due to its efficacy and safety profile in clinical trials. Acetaminophen at 15 mg/kg serves as an alternative, while triptans like sumatriptan nasal spray are reserved for migraines in children over 12 years after NSAIDs fail. Preventive options for frequent migraines include topiramate or propranolol at adjusted doses, but recent studies highlight non-drug approaches; for instance, mindfulness-based interventions have been shown to reduce headache frequency in adolescents through techniques like guided breathing and body awareness, improving overall quality of life without side effects. Red flags warranting urgent evaluation mirror those in adults—such as sudden severe onset, progressive worsening, or associated neurological deficits—but in children, additional considerations include a history of head trauma, which raises concern for intracranial injury or post-traumatic headache, and early morning vomiting suggesting increased intracranial pressure. Other pediatric-specific red flags include systemic symptoms like fever or rash indicating infection, or behavioral changes such as lethargy, prompting neuroimaging or specialist referral to rule out sinister etiologies.

Headaches in Pregnancy and Elderly

Headaches during pregnancy often exhibit distinct patterns influenced by hormonal changes, with approximately 60-70% of women experiencing remission of migraines, particularly in the second and third trimesters.^[152] This improvement is attributed to elevated estrogen levels stabilizing neuronal excitability, though a subset of women may see worsening or new-onset headaches. Secondary headaches pose significant risks, including thunderclap headaches associated with preeclampsia, a hypertensive disorder affecting up to 8% of pregnancies and characterized by sudden, severe head pain often accompanied by visual disturbances or hypertension.^[153] Safe acute treatments prioritize acetaminophen at doses up to 1,000 mg, which is recommended as first-line therapy without evidence of fetal harm, while magnesium supplementation (up to 400 mg daily) serves as a preventive option for migraines due to its role in vascular relaxation and low risk profile.^[154]^[155] Diagnostic approaches in pregnancy emphasize non-invasive methods to minimize fetal exposure; magnetic resonance imaging (MRI) without gadolinium contrast is preferred for evaluating concerning headaches, as contrast agents like gadolinium cross the placenta and carry potential developmental risks.^[156] Migraines with aura during pregnancy elevate stroke risk, with a 2025 study indicating approximately a 10-fold increase in ischemic events compared to non-migraineurs, underscoring the need for vigilant monitoring of vascular symptoms.^[157] As of 2025, emerging data from pharmacovigilance analyses and case series suggest CGRP monoclonal antibodies may not confer substantial adverse risks when used periconceptionally, though ongoing trials continue to assess long-term gestational safety, and discontinuation 4-6 months preconception remains standard guidance.^[158]^[159] In the elderly, new-onset headaches after age 65 warrant heightened suspicion for secondary causes, occurring in about 15% of cases and including giant cell arteritis (temporal arteritis), which accounts for a notable proportion—up to 20% in some cohorts—of urgent presentations due to its potential for vision loss if untreated.^[160]^[161] This vasculitis typically manifests as unilateral temporal pain with scalp tenderness, necessitating prompt erythrocyte sedimentation rate testing and temporal artery biopsy. Elderly patients exhibit reduced tolerance to standard headache medications owing to comorbidities, polypharmacy, and altered pharmacokinetics, increasing risks of side effects like gastrointestinal bleeding from NSAIDs or cognitive impairment from triptans.^[161] Treatment adaptations favor low-dose acetaminophen or short-term corticosteroids for arteritis, with preventive strategies like beta-blockers used cautiously to avoid bradycardia. Diagnostic imaging in the elderly employs a low threshold, favoring MRI or CT to exclude structural lesions like subdural hematomas or tumors, given the higher prevalence of secondary etiologies compared to younger adults.^[160]

History

Early Concepts and Descriptions

One of the earliest recorded descriptions of headache appears in ancient Egyptian medical texts, such as the Ebers Papyrus dating to approximately 1500 BCE, which details a condition termed "half-head" pain, akin to hemicrania or unilateral headache, and prescribes remedies including incantations and topical applications of substances like honey and electric catfish to alleviate symptoms.^[162] This reflects an early recognition of localized head pain, though treatments were rooted in magical and empirical practices rather than systematic anatomy. Similarly, prehistoric evidence suggests that trepanation—surgically drilling holes into the skull—was performed as far back as the Neolithic period (circa 7000–3000 BCE) potentially to relieve intracranial pressure or chronic headaches, with healed bone edges on some skulls indicating survival and possible therapeutic intent, though direct causation remains speculative. In ancient Greece, Hippocrates of Kos (circa 460–370 BCE) provided more detailed clinical observations in works like the Corpus Hippocraticum, describing severe unilateral headaches accompanied by prodromal visual phenomena, such as "flashes of light" or scintillations, which modern interpretations identify as migraine auras; he also noted vomiting and unilateral pain spreading from the temples.^[163] These accounts shifted focus toward natural causes over supernatural ones, emphasizing environmental triggers like strong winds or dietary factors, and recommended lifestyle adjustments alongside bloodletting or purgatives based on humoral theory. During the medieval period, Islamic scholar Avicenna (Ibn Sina, 980–1037 CE) advanced headache classification in his Canon of Medicine (completed 1025 CE), delineating multiple types—including throbbing, pressing, and piercing pains—attributed to imbalances in the four humors (blood, phlegm, yellow bile, black bile), with migraines specifically linked to excessive hot or dry humors affecting the meninges; treatments involved dietary moderation, herbal poultices, and humoral rebalancing.^[164] By the 17th century, English physician Thomas Willis (1621–1675) marked a transition toward neuroanatomical explanations in his Cerebri Anatome (1664) and subsequent works like De Anima Brutorum (1672), where he described "megrim"—an archaic term for migraine—as arising from nervous system dysfunction rather than solely vascular or humoral causes, detailing symptoms like unilateral pain, visual disturbances, and gastrointestinal upset, and advocating nerve-targeted therapies such as blistering or narcotics.^[165] The term "megrim" persisted into the 19th century, notably in medical literature around 1817, underscoring episodic, severe headaches distinct from routine ailments. Early understandings, however, lacked differentiation between primary headaches (idiopathic, like migraine) and secondary ones (due to underlying pathology), a distinction not formalized until the 20th century, leaving pre-modern concepts broadly encompassing all head pains under humoral or mystical frameworks.^[163]

Modern Developments and Classifications

The modern classification of headache disorders is primarily guided by the International Classification of Headache Disorders (ICHD), developed by the International Headache Society (IHS) to provide a standardized, evidence-based framework for diagnosis and research. The first edition (ICHD-1) was published in 1988, establishing a hierarchical structure that distinguished primary headaches (those not attributable to another disorder) from secondary headaches (those caused by an underlying condition). Subsequent revisions incorporated accumulating clinical and scientific evidence; the second edition (ICHD-2) appeared in 2004, refining criteria and adding new entities like medication-overuse headache as a distinct secondary type.^[166]^[167] The third edition (ICHD-3), published in 2018, represents the current standard and builds on prior versions by integrating advances in neuroimaging, genetics, and epidemiology to enhance diagnostic precision without shifting to a purely mechanistic model. It maintains a three-part hierarchical structure: Part 1 covers primary headaches, subdivided into migraine (e.g., with or without aura, chronic migraine), tension-type headache, trigeminal autonomic cephalalgias (e.g., cluster headache, paroxysmal hemicrania), and other primary headaches (e.g., new daily persistent headache, primary exercise headache); Part 2 addresses secondary headaches across eight categories, including those from head/neck trauma, vascular disorders, infections, and substance withdrawal; Part 3 encompasses cranial neuralgias, facial pain, and other headaches. Key updates from ICHD-2 include shortened attack duration for pediatric migraine (2–72 hours versus 4–72 hours), explicit criteria for probable diagnoses to account for incomplete information, and relocation of entities like nummular headache from the appendix to the main classification based on validated evidence. This edition aligns with the World Health Organization's ICD-11 for coding compatibility, facilitating global epidemiological studies.^[168]^[169] Since ICHD-3, developments have focused on validation, refinement, and expansion through ongoing research, with the IHS Classification Committee initiating work on ICHD-4 as early as 2023 via international meetings to address emerging phenotypes. Studies from 2020–2025 have emphasized methodological improvements, such as case-series descriptions for potential new entities (e.g., refinements in short-lasting unilateral neuralgiform headache attacks) and validation of criteria using large cohorts, revealing high inter-rater reliability for core types like migraine and cluster headache (kappa >0.8 in tertiary settings). Advances include incorporating genetic markers (e.g., for familial hemiplegic migraine) and biomarkers into diagnostic comments, though the core remains phenotype-driven to ensure clinical applicability. Research priorities identified in 2024 highlight needs for better outcome measures and studies on headache comorbidities to inform future revisions. In October 2025, the International Headache Society announced a topical collection in Cephalalgia titled "Toward International Classification of Headache Disorders – 4 (ICHD-4)" open to submissions to support the development of the next edition.^[170]^[171]^[172]^[173]

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