Headache

Etiology and PathogenesisTop

Headache is a symptom that may be caused by various diseases. It may develop through a wide range of pathogenetic mechanisms that depend on the underlying condition. The International Headache Society (IHS) classifies headache using a hierarchical organization and specific diagnostic criteria based on symptoms, signs, and associated medical conditions. Classification is an important step in accurately identifying the probable headache etiology, natural history, and treatment.

The IHS divides headache into 2 groups: primary (not caused by an underlying disease process) or secondary (caused by an underlying disease process). The pathogenesis of primary headache, such as migraine, is not completely understood, although proposed mechanisms include various neuronal, vascular, receptor, and electrophysiologic changes. The pathogenesis of secondary headache usually involves irritation, ischemia, or stretching of pain-sensitive structures around the brain (meninges, vessels) or pain-sensitive structures around the head (muscle, bone, peripheral nerve, joint, and sinus).

1. Primary headache: The most common primary headache types are migraine (with or without aura), tension-type headache, and cluster headache (trigeminal autonomic cephalalgias).

1) Migraine: Features: Table 1. The headache cannot be better explained by another diagnosis. A particularly disabling form of migraine is chronic migraine, which is diagnosed in patients with a headache present ≥15 days in a month for ≥3 subsequent months, provided that on ≥8 days of each month the headache fulfills the criteria for migraine and the patient has a history of ≥5 migraine attacks (with or without aura).

2) Tension-type headache: Features: Table 2. The headache cannot be better explained by another diagnosis.

3) Trigeminal autonomic cephalalgias: These headaches include cluster headache (episodic or chronic), paroxysmal hemicrania (episodic or chronic), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). The classification of trigeminal autonomic cephalalgias is mainly based on the frequency and duration of individual attacks.

a) Characteristics of cluster headache: Table 3. The headache cannot be better explained by another diagnosis.

b) Paroxysmal hemicrania refers to attacks of severe strictly unilateral pain, which is orbital, supraorbital, temporal, or any combination of these sites, lasts 2 to 30 minutes, and occurs several or many times a day.

c) SUNCT: The attacks are even more frequent (up to 100 times a day) and most often last <1 minute.

4) Other (rare) types of primary headache: Primary stabbing headache, primary cough headache, primary exertional headache, primary headache associated with sexual activity, hypnic headache, primary thunderclap headache, new-onset daily persistent headache, nummular headache, and hemicrania continua.

2. Secondary headache: Causes of secondary headache are multiple and include (as listed by the IHS) head or neck trauma (immediate or delayed); cranial or cervical vascular disorders (aneurysm, arterial dissection, cerebral vein and sinus thrombosis [CVST]); nonvascular intracranial disorders (tumor, after seizures); substance abuse or withdrawal (medication overuse headache); infections (meningitis, encephalitis); disorders of cerebrospinal fluid (CSF) flow (intracranial hypertension or hypotension); disorders of the neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial structures (cervical radiculopathy or myofascial pain, sinusitis); psychiatric disorders (depression, anxiety, posttraumatic stress disorder).

3. Additional considerations:

1) Medication overuse headache is a common cause of chronic headache that occurs on ≥15 days per month in a patient with a preexisting headache disorder and with regular overuse for >3 months of ≥1 drug that can be taken for acute or symptomatic treatment of headache. The headache cannot be explained by another diagnosis. Discontinuation of the involved drug (offending agent) can often improve the headache and also increases responsiveness to treatments for other headache etiologies.

2) Severe sudden-onset headache: Sudden-onset headache is a common presentation in the emergency room or primary care setting. Only a small percentage is a result of a life-threatening illness; more than half of the life-threatening diseases are due to vascular causes (subarachnoid hemorrhage, intracranial hemorrhage, CVST, arteriovenous malformation, giant cell arteritis, arterial dissection); the other causes include tumors and meningitis. The label of thunderclap headaches (TCH) is sometimes used to describe severe headache with a rapid onset that tends to peak within one minute. Traditionally associated with subarachnoid aneurysm, this clinical syndrome may occur in other conditions, including reversible cerebral vasoconstriction syndrome (RCVS), posterior reversible encephalopathy syndrome (PRES), and intracerebral hemorrhage.

Patients with a severe sudden-onset headache require urgent evaluation, as the headache may be a symptom of subarachnoid hemorrhage or another life-threatening condition.

DiagnosisTop

1. History and physical examination: Start from excluding secondary headache that may be life-threatening. Pay special attention to alarming symptoms (red flags), which may suggest a serious etiology of the headache and require urgent diagnostics (Table 4). “SNOOP4” is a useful bedside mnemonic for secondary causes: systemic symptoms/signs/disease, neurologic symptoms/signs, onset sudden, onset after the age of 50 years, pattern change. This may include clinical situations with presumed migraine but with unusual, prolonged, or persistent aura; clearly increasing frequency, severity, or change in clinical features; first or worst migraine; migraine with brainstem aura; migraine with confusion; migraine with motor manifestations such as hemiplegia. The other clinical scenarios may present as very severe headaches, especially of thunderclap variety, and physical activity–induced headache. After excluding the most common and most serious causes of secondary headache, reevaluate the patient, paying particular attention to atypical features of the headache or comorbidities.

2. Diagnostic studies: Available tests include neuroimaging (computed tomography [CT], magnetic resonance imaging [MRI], in some cases angiography [CTA, MRA]), lumbar puncture, and blood tests, each depending on the suspected secondary headache (its presence and potential causes).

Neuroimaging is indicated in the following situations:

1) Severe sudden-onset headache that is new or associated with red flag symptoms.

2) Nonacute headache with abnormal neurologic signs.

Neuroimaging is suggested in:

1) Nonacute headache with red flag symptoms.

2) Patients with possible migraine that do not meet all the criteria for migraine or have some atypical symptoms.

Neuroimaging is generally not necessary if the patient’s history of headaches is consistent with typical and common headache disorders (migraine, tension-type headache) and no abnormal findings have been identified on physical (including neurologic) examination.

TreatmentTop

Treatment of Migraine

The approach to treating migraine is dependent on the severity and frequency of attacks and, most importantly, on the impact on the quality of life of the patient. Acute treatment is used at the start of migraine attacks; prophylactic treatment is used when the frequency, severity, or impact on the patient is such that prevention of attacks is warranted; and rescue therapy is used when acute treatment has not aborted the migraine attack and symptomatic treatment for pain and nausea or vomiting is required.

1. Acute attacks of migraine: Mild to moderate acute attacks of migraine may respond to oral analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs): acetylsalicylic acid (ASA) 1000 mg, acetaminophen (INN paracetamol) 1000 mg, ibuprofen 200 to 600 mg, diclofenac 50 to 100 mg, or a combination of these drugs taken as soon as possible with the onset of headache.

In patients with moderate to severe acute attacks of migraine or in those not responsive to analgesics or NSAIDs, triptan therapy is more effective. Various triptan drugs are available with different speed of onset, duration, and tolerability. Subcutaneous sumatriptan 6 mg has the most rapid mode of onset and highest probability of decreasing pain. Patient preference, individual response, and adverse effects guide the choice of a particular triptan drug and whether the dose should be increased, the formulation changed, or another triptan tested. Triptans are contraindicated in patients with coronary artery, cerebrovascular, and peripheral vascular disease.

Newer agents such as gepants (small-molecule antagonists of calcitonin gene-related peptide [CGRP] receptor) and ditans (highly selective 5-HT1F receptor agonists without vasoconstrictive properties) may have fewer adverse effects and carry lower cardiovascular risk than triptans, but they lack evidence of efficacy compared with other migraine treatments, including triptans.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and imprecision. Ducros A, de Gaalon S, Roos C, et al. Revised guidelines of the French headache society for the diagnosis and management of migraine in adults. Part 2: Pharmacological treatment. Rev Neurol (Paris). 2021 Sep;177(7):734-752. doi: 10.1016/j.neurol.2021.07.006. Epub 2021 Jul 30. PMID: 34340810.

As migraine attacks are very often accompanied by nausea or vomiting, administer an antiemetic as soon as possible: metoclopramide 10 to 20 mg orally or 10 mg IM or IV or domperidone 10 mg orally.

Emergency room treatment of migraine, including status migrainosus (a migraine attack with a prolonged headache phase that lasts >72 hours; the headache may temporarily resolve but not for >4 hours), is often necessary when oral treatment has failed at home. Treatment in this situation can include IV rehydration in the context of nausea and vomiting, IV metoclopramide 10 to 40 mg, subcutaneous sumatriptan 6 mg, IV lysine acetylsalicylate 1000 mg, and IV dexamethasone 4 to 8 mg.

2. Prophylactic treatment of migraine: Migraine-preventive treatment should last ≥3 months, optimally ~6 months.

1) First-line agents: Metoprolol 50 to 200 mg/d, propranolol 40 to 240 mg/d, bisoprolol 5 to 10 mg/d, flunarizine 5 to 10 mg/d, valproic acid 500 to 1500 mg/d, topiramate 25 to 100 mg/d, amitriptyline 50 to 75 mg/d may all be effective.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Diener HC, Holle-Lee D, Nägel S, et al. Treatment of migraine attacks and prevention of migraine: Guidelines by the German Migraine and Headache Society and the German Society of Neurology. Clin Transl Neurosci. 2019 Jan 30;3(1). doi: 10.1177/2514183X18823377.

Monoclonal antibodies targeting the CGRP pathway have been shown to be effective in preventing episodic and chronic migraine. These treatments are given as monthly or quarterly injections. Long-term safety and cost effectiveness data are still needed.Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Ducros A, de Gaalon S, Roos C, et al. Revised guidelines of the French headache society for the diagnosis and management of migraine in adults. Part 2: Pharmacological treatment. Rev Neurol (Paris). 2021 Sep;177(7):734-752. doi: 10.1016/j.neurol.2021.07.006. Epub 2021 Jul 30. PMID: 34340810.

2) Second-line agents (drugs that are less effective or cause more adverse effects than first-line agents): Opipramol 50 to 150 mg/d, ASA 300 mg/d, magnesium 600 mg/d, magnesium + vitamin B2 400 mg/d + coenzyme Q10 150 mg/d, lisinopril 10 mg/d, candesartan 16 mg/d, or telmisartan 80 mg/d.Evidence 4Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias, imprecision, and inconsistency. Diener HC, Holle-Lee D, Nägel S, et al. Treatment of migraine attacks and prevention of migraine: Guidelines by the German Migraine and Headache Society and the German Society of Neurology. Clin Transl Neurosci. 2019 Jan 30;3(1). doi: 10.1177/2514183X18823377.

Nonpharmacologic treatments that may be considered, either used alone or in combination with other options, include biofeedback, relaxation therapy, and cognitive behavioral therapy.

3. Chronic migraine: Options include topiramate 100 to 200 mg/d, valproic acid 500 to 1500 mg/d, botulinum toxin type A 155 to 195 IU (a total dose per 1 series) administered to muscles around the head according to an appropriate regimen.

Treatment of Cluster Headache

Treatment of individual attacks is difficult because they are relatively short-lived and resolve spontaneously, which means that almost no traditional analgesics become effective before the spontaneous cessation of pain.

1. Acute attacks of cluster headache:

1) First-line agents: Sumatriptan 6 mg subcutaneously, zolmitriptan 5 to 10 mg as nasal spray, oxygen 6 to 12 L/min.

2) Second-line agents: Sumatriptan 20 mg as nasal spray, zolmitriptan 5 to 10 mg orally.

2. Prophylactic treatment of cluster headache:

1) First-line agents: Suboccipital steroid injection, civamide 0.025% nasally daily.

2) Second-line agents (limited data): Lithium 900 mg/d, verapamil 360 mg/d, warfarin with a target international normalized ratio (INR) of 1.5 to 1.9, melatonin 10 mg/d.

Treatment of Paroxysmal Hemicrania

The drug of choice is indomethacin 150 to 225 mg/d. A very good response to indomethacin additionally supports the diagnosis of paroxysmal hemicrania.

Treatment of Medication Overuse Headache

Agents used for abortive treatment of headache are strictly contraindicated because their overuse may be the underlying cause of the headache. Explain to the patient what has caused the pain and why they need to discontinue the overused drugs. An abrupt discontinuation is recommended in the case of overuse of simple analgesics, ergotamine, or triptans, while tapering the dose down to discontinuation is recommended in the case of overuse of opioids, benzodiazepines, and barbiturates. In some patients discontinuation of analgesic agents may be facilitated by using a preventive medication, such as topiramate 100 mg/d (maximum, 200 mg/d), a short course of glucocorticoids (prednisone or prednisolone ≥60 mg/d), or amitriptyline (maximum, 50 mg/d).

TablesTop