Hypnic headache

INTRODUCTION — Hypnic headache is an uncommon headache syndrome characterized by recurrent episodes of dull or throbbing head pain that develops only during sleep. It was previously termed "alarm clock headache" due to the characteristic early morning onset that awakens patients from sleep.

This topic will discuss hypnic headache. Other uncommon headache syndromes characterized by recurrent episodes of brief head pain are reviewed separately.

●(See "Exercise (exertional) headache".)

●(See "Primary headache associated with sexual activity".)

●(See "Primary cough headache".)

●(See "Primary stabbing headache".)

EPIDEMIOLOGY — Hypnic headache is one of the few headache disorders to occur almost exclusively in later life. The onset of hypnic headache typically occurs after age 50 years, although some cases in patients younger than age 40 years have been reported [1-4]. In addition, a few cases of hypnic headache in children have also been reported, including those as young as three years old [5-7].

Hypnic headache appears to be a rare condition, but the actual incidence and prevalence are unknown. In data from tertiary headache centers and clinics, the overall proportion of patients with hypnic headache ranged from 0.07 to 0.35 percent, while the proportion among older patients (age ≥65 years old) with headache ranged from 1.4 to 1.7 percent [2].

Hypnic headache is more common among female adults and female children, with an overall predominance of approximately 2:1 [2-4,7].

PATHOPHYSIOLOGY — The cause of primary hypnic headache is not understood. The circadian pattern and association with sleep suggest a pathophysiologic connection with hypothalamic dysfunction [3,8]. In a voxel-based morphometric MRI study, gray matter volume in the posterior hypothalamus was lower in patients with hypnic headache than in matched controls [9]. An earlier report using similar methods found increased gray matter volume in a similar location among patients with cluster headache [10]. Nevertheless, both studies implicate the posterior hypothalamus in headache disorders with a tendency toward cyclical and nocturnal occurrence.

Hormonal changes have also been implicated in the etiology of hypnic headache. Hypnic headache has been reported to occur following weaning from lithium therapy [11] which can alter melatonin and serotonin levels and influence circadian rhythmicity [12].

Although early reports suggested that hypnic headache might be a rapid eye movement (REM) sleep disorder, later studies showed that the majority of hypnic headache attacks arise from non-REM sleep stages, mainly sleep stage N2 [3,8].

CLINICAL FEATURES

Temporal features — Hypnic headache has also been called "alarm clock" headache because it develops during sleep and awakens patients from sleep [13]. The most common time of headache onset is between midnight and four o’clock in the morning [2,4].

For most patients with hypnic headache, symptoms typically persist for 15 minutes up to two hours after awakening, although longer durations may occur. In one large review of 343 patients with hypnic headache, the mean headache duration was 94 minutes [4].

Hypnic headache attacks occur frequently (≥10 days per month) and may occur daily for many patients [1,2].

Headache features — The pain in hypnic headache is typically dull or throbbing in character and moderate or severe in intensity [2,4]. However, some patients report pulsatile or stabbing/burning pain. Up to two-thirds of patients have bilateral head pain, often frontotemporal in location, but others have unilateral or even holocephalic pain [4].

Most patients report engaging in some type of motor activity (eg, getting out of bed and eating, drinking, showering, or reading) when awakened by headache, but they typically do not exhibit the restless pacing that is associated with cluster headache [3].

Migrainous features such as nausea and phonophobia/photophobia occur in a minority of patients. Cranial autonomic features such as rhinorrhea/nasal congestion, lacrimation, and ptosis are uncommon, occurring in less than 10 percent of cases [2].

Comorbid conditions — Many patients with hypnic headache have other primary headache disorders such as migraine or tension-type headaches [14]. Migraine history appears to be the most common headache syndrome, reported to occur in as many as 40 to 50 percent [15,16].

Other comorbid conditions frequently reported in patients with hypnic headache include hypertension, seizures, and obstructive sleep apnea (OSA) [3]. The relationship between these conditions and hypnic headache is uncertain. They may occur as independent conditions, as both hypertension and OSA are common conditions, especially in older patients. However, cases of hypnic headache attributed to nocturnal hypertension have also been reported [17,18]. Symptoms improved with treatment of hypertension in these cases.

Morning headaches may occur as a presenting feature of OSA and may mimic hypnic headaches. (See 'Differential diagnosis' below.)

DIAGNOSIS — Hypnic headache should be considered in patients with recurring headaches that cause awakening from sleep. The diagnosis of hypnic headache is made in patients with symptoms that fulfill diagnostic criteria after diagnostic evaluation to exclude other causes to the symptoms [2,3].

Diagnostic criteria — Diagnostic criteria for hypnic headache, according to the International Classification of Headache Disorders third edition (ICHD-3), are as follows [1]:

●A) Recurrent headache attacks fulfilling criteria B through E

●B) Developing only during sleep and causing wakening

●C) Occurring on ≥10 days per month for more than three months

●D) Lasting ≥15 minutes and for up to four hours after waking

●E) No cranial autonomic symptoms or restlessness

●F) Not better accounted for by another ICHD-3 diagnosis

One area of debate is that the ICHD-3 criteria exclude the diagnosis of hypnic headache if there are associated cranial autonomic symptoms (tearing, runny nose, ptosis, or miosis) or restlessness, features that can be prominent in cluster headache and other trigeminal autonomic cephalalgias [1]. However, cranial autonomic features can accompany hypnic headache in a small proportion of cases [2]. (See 'Headache features' above.)

Evaluation

●Neuroimaging – For all patients with new nocturnal headache, we suggest neuroimaging of the brain to evaluate for structural causes. We prefer brain magnetic resonance imaging (MRI) with gadolinium contrast. Head computed tomography (CT) with contrast may be performed as an alternative imaging test for patients with a contraindication to MRI but has a lower sensitivity and exposes patients to radiation.

●Other testing for selected patients – Additional testing is generally performed for patients with features atypical for hypnic headache and those with additional symptoms suggestive of an alternative diagnosis.

•We obtain erythrocyte sedimentation rate and C-reactive protein for patients with features suggestive of giant cell arteritis, such as those with atypical headaches (eg, scalp tenderness, associated visual changes) and those with additional constitutional symptoms (eg, fever, weight loss, jaw claudication). (See "Diagnosis of giant cell arteritis".)

•We assess for obstructive sleep apnea (OSA) for at-risk patients with excessive daytime sleepiness and those with both clinical features consistent with OSA (eg, obesity, snoring) and conditions associated with OSA (eg, atrial fibrillation, congestive heart failure) (table 1). (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)

•Ambulatory blood pressure monitoring may be helpful to detect nocturnal hypertension for selected patients with symptoms of hypnic headache associated with a new diagnosis or suboptimal control of hypertension [18]. (See "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring".)

•Electroencephalography (EEG) should be performed when seizures are suspected, such as for patients with morning headaches and confusion or transient neurologic deficits. Ambulatory EEG may increase diagnostic yield when routine EEG is nondiagnostic. (See "Electroencephalography (EEG) in the diagnosis of seizures and epilepsy".)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of hypnic headache includes other conditions that present with recurrent headaches that occur during sleep or at awakening. These conditions include both primary and secondary headaches, as well as structural intracranial and some systemic conditions. These alternative causes may be discriminated from hypnic headache by specific clinical features or results of diagnostic testing.

●Headache disorders – Other headache conditions that may mimic hypnic headache include:

•Migraine (see "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults")

•Cluster headache (see "Cluster headache: Epidemiology, clinical features, and diagnosis")

•Chronic and episodic paroxysmal hemicrania (see "Paroxysmal hemicrania: Clinical features and diagnosis")

•Medication overuse headache (see "Medication overuse headache: Etiology, clinical features, and diagnosis")

•Cervicogenic headache (see "Cervicogenic headache")

The absence of daytime attacks is the main feature that distinguishes hypnic headache from most other headache types. Other discriminating features vary by form of headache. Migraine may be the most common alternative headache disorder as it can both mimic and be comorbid with hypnic headache. Features suggestive of the diagnosis of migraine include presence of aura and prominent migrainous symptoms (eg, nausea, photophobia, or phonophobia) [3]. Features suggestive of cluster headache or paroxysmal hemicrania include severe pain, prominent cranial autonomic symptoms, and multiple daily attacks. Medication overuse headache may be identified by eliciting a history of medication use, such as opioids, barbiturates, simple and combination analgesics, triptans, and polypharmacy. Patients with cervicogenic headache typically report unilateral head pain that is aggravated by head or neck movement/positioning.

●Intracranial structural causes – The differential diagnosis of hypnic headache also includes headaches caused by structural intracranial conditions that result in elevated intracranial pressure or traction on nociceptor-containing dural membranes. These conditions may be identified with brain imaging and include:

•Primary or metastatic tumor [19,20] (see "Brain tumor headache")

•Vestibular schwannoma [21] (see "Vestibular schwannoma (acoustic neuroma)")

•Subdural hematoma [22] (see "Subdural hematoma in adults: Etiology, clinical features, and diagnosis")

•Obstructive hydrocephalus [23] (see "Evaluation and management of elevated intracranial pressure in adults")

●Systemic conditions – Some systemic conditions may present with headache symptoms that may mimic hypnic headache. However, the headache in many of these conditions does not typically occur exclusively at awakening from sleep, in contradistinction to hypnic headache. In addition, these conditions may also feature additional symptoms not found in patients with hypnic headache. These conditions include:

•Obstructive sleep apnea – Headache may be a presenting feature of obstructive sleep apnea (OSA). Headache may occur daily. However, daytime sleepiness and other features associated with this condition are not found in patients with hypnic headache. Headaches attributed to OSA typically resolve with positive airway pressure or another treatment for the condition. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)

•Nocturnal hypertension – Patients with new or suboptimal control of hypertension with nocturnal blood pressure spikes may develop symptoms suggestive of hypnic headache [17,18,24]. In these cases, headache symptoms resolve with effective treatment of hypertension.

Pheochromocytoma can also cause fluctuating blood pressure, including nocturnal hypertension. In addition to headache, patients with pheochromocytoma typically present with episodic sweating and tachycardia. Patients may also have episodic or sustained hypertension. Testing to identify catecholamine hypersecretion is used to diagnose pheochromocytoma. (See "Clinical presentation and diagnosis of pheochromocytoma".)

•Giant cell arteritis – The headache of giant cell arteritis is often nonspecific and can mimic other headache disorders including hypnic headache. However, some patients report scalp tenderness, and the condition may also be identified by the presence of constitutional symptoms (eg, fatigue, fever, weight loss) as well as vision loss. (See "Clinical manifestations of giant cell arteritis".)

Diagnostic testing including erythrocyte sedimentation rate and C-reactive protein levels should be performed for patients with suspected giant cell arteritis. (See "Diagnosis of giant cell arteritis".)

•Seizures – Patients with nocturnal seizures may awaken with postictal headache. Other features suggestive of seizure over primary hypnic headache include headache associated with confusion or incontinence or a history of seizures. Electroencephalography (EEG) is warranted for patients with suspected postictal headache. (See "Seizures and epilepsy in older adults: Etiology, clinical presentation, and diagnosis".)

OSA and seizures can also be comorbid with hypnic headache. (See 'Comorbid conditions' above.)

MANAGEMENT — Pharmacologic treatment is the mainstay of the management of hypnic headache. We typically use with preventive therapy because most patients with hypnic headache have frequent or daily recurring headaches. Acute treatment is used for symptomatic patients with breakthrough pain.

Acute treatment — We suggest caffeine for symptomatic treatment of hypnic headache. We typically start with caffeinated beverages such as coffee or a single dose of a caffeine oral tablet (eg, 65 to 200 mg). Alternative options include caffeine-containing combination oral analgesics such as a tablet of combined acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg. The effectiveness of caffeine for acute treatment of hypnic headache ranges from 60 to nearly 85 percent in case series [2,15,25].

Other options that have been used for acute treatment of hypnic headache include simple analgesics (eg, acetaminophen, aspirin, nonsteroidal antiinflammatory drugs), ergotamines, and triptans [15,25,26].

Preventive treatment

Initial therapy — For most patients with hypnic headache, we suggest initial preventive therapy with either caffeine at bedtime or indomethacin. The selection of agent varies by patient preference and adverse effect profile. Caffeine is available without prescription, including as coffee or another beverage, but may impair sleep when taken at bedtime. Indomethacin may be preferred for patients with other indications for nonsteroidal antiinflammatory medications such as rheumatoid or osteoarthritis.

Options and typical dosing for initial preventive treatment of hypnic headache include either of the following:

●Caffeine – Given as a tablet (65 to 200 mg) or beverage at bedtime [25,27]

●Indomethacin – Administered at 50 mg three times daily [28]

We typically continue preventive therapy for three to six months before attempting to wean [2]. For patients with recurrent symptoms, we resume treatment. The evidence of efficacy of these medications is limited to small case series. The response rate to caffeine or indomethacin in various studies ranges from approximately 50 to 60 percent [2,15,25,27,29].

Alternative options — For patients with a contraindication or inadequate response to initial therapy, we switch to or add an alternative medication such as lithium, melatonin, or amitriptyline.

●Lithium – The starting dose of lithium carbonate is 300 mg once daily and may be increased after one week to 600 mg once daily as needed and tolerated [13,27,30]. Laboratory monitoring prior to starting lithium and for ongoing surveillance includes urinalysis, kidney function studies, thyroid function, and electrolytes. In addition, an electrocardiogram should be performed to assess for conduction abnormalities.

Nonsteroidal antiinflammatory drugs should be avoided when taking lithium, if possible, as these agents can increase lithium levels in the blood and increase the risk for serious adverse effects.

The most common acute side effects associated with lithium are nausea, tremor, polyuria and thirst, weight gain, loose stools, and cognitive impairment. Severe or a sudden worsening of side effects may be a sign of lithium toxicity. Important long-term adverse effects of lithium involve kidney and thyroid dysfunction as well as cardiac rhythm disturbances. (See "Bipolar disorder in adults and lithium: Pharmacology, administration, and management of adverse effects", section on 'Laboratory tests and monitoring' and "Lithium and the thyroid" and "Renal toxicity of lithium".)

Case series have reported response rates of 70 to 80 percent with lithium [31-33]. However, lithium is a second-line agent for hypnic headache due to its narrow therapeutic index, particularly in older adult patients, and is contraindicated in those with significant cardiovascular disease or kidney impairment.

●Melatonin – Small case series have reported up to 50 percent response rates with melatonin [4,27,34]. Melatonin is typically given at doses of 3 to 5 mg at bedtime.

Adverse effects of melatonin include vivid dreams, dizziness, and sedation. Melatonin is a dietary supplement available in the United States by several formulations including tablets, patches, and liquids. However, melatonin is available only by prescription in several other countries. (See "Pharmacotherapy for insomnia in adults", section on 'Melatonin'.)

●Amitriptyline – Low doses of amitriptyline, typically 10 to 50 mg once each night, may be effective for some patients with hypnic headache [15]. In several case studies and reports, the response rate with amitriptyline or other tricyclic antidepressants is approximately 20 percent [4].

Baseline testing prior to starting amitriptyline includes electrolytes to assess for hypokalemia and an electrocardiogram to assess for conduction abnormalities. Common adverse effects with amitriptyline include sedation, confusion, and cardiac conduction disturbances. It should be used with caution in patients with a history of cardiovascular disease. (See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects".)

Several other medications have also been reported to be effective in case reports of hypnic headache including:

●Topiramate 25 to 100 mg daily [35,36]

●Flunarizine 5 mg at bedtime [37]

●Aspirin 325 mg plus caffeine 40 mg at bedtime [25]

●Atenolol 25 mg at bedtime [25]

●Lamotrigine 25 to 75 mg daily [38]

●Botulinum toxin [39,40]

●Prednisone 25 mg daily for 15 days, then 12.5 mg daily for 15 days [41]

●Sodium ferulate 75 to 300 mg daily in three divided doses [42]

PROGNOSIS — Hypnic headache is a chronic disorder that can last for years, though a substantial proportion of patients may respond to treatment. However, the natural history of hypnic headache is not well studied. In one review, the average time from onset to the correct diagnosis of hypnic headache was five years [3]. A systematic review of hypnic headache reported outcomes in 72 patients with follow-up ranging from six months to five years [2]. Symptoms persisted in 47 percent, resolved after treatment in 43 percent, recurred following an attempt to wean in 7 percent, and spontaneously resolved in 3 percent.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Migraine and other primary headache disorders".)

SUMMARY AND RECOMMENDATIONS

●Definition and epidemiology – Hypnic headache, also known as "alarm clock headache," occurs most commonly after the age of 50 years and is characterized by episodes of dull or throbbing head pain, often bilateral, that awaken the patient from sleep. (See 'Introduction' above and 'Epidemiology' above.)

●Clinical features – Hypnic headache typically occurs between midnight and four o’clock in the morning. The headache is often bilateral, dull or throbbing in character, and moderate or severe in intensity. It typically persists for 15 minutes up to two hours after awakening. (See 'Epidemiology' above and 'Clinical features' above.)

●Diagnosis and evaluation – The diagnosis of hypnic headache is made in patients with symptoms that fulfill diagnostic criteria after diagnostic evaluation to exclude other causes to the symptoms. (See 'Diagnosis' above.)

For all patients with new nocturnal headache, we suggest brain MRI with gadolinium to evaluate for structural causes. Additional testing is generally performed for patients with features atypical for hypnic headache and those with additional symptoms suggestive of an alternative diagnosis. Testing may include laboratory testing (eg, erythrocyte sedimentation rate and C-reactive protein), ambulatory blood pressure monitoring, polysomnography, and electroencephalography (EEG). (See 'Evaluation' above.)

●Management

•Acute treatment – We suggest caffeine for symptomatic treatment of hypnic headache (Grade 2C). We typically start with caffeinated beverages such as coffee or a single dose of a caffeine oral tablet (eg, 65 to 200 mg). Alternative options include caffeine-containing combination oral analgesics such as a tablet of combined acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg.

•Preventive treatment – For most patients with hypnic headache, we suggest initial preventive therapy with either caffeine at bedtime or indomethacin (Grade 2C). The selection of agent varies by patient preference and adverse effect profile. Caffeine may be given as a tablet (65 to 200 mg) or as a beverage at bedtime. Indomethacin is typically given at 50 mg three times daily. In case series, approximately half of patients respond to either of these medications. (See 'Initial therapy' above.)

We use an alternative agent for patients who do not respond to initial preventive therapy. Options include lithium carbonate (300 to 600 mg daily), melatonin (3 to 5 mg at bedtime), or amitriptyline (10 to 50 mg at bedtime). Response rates may be highest with lithium, but the agent may be poorly tolerated or contraindicated for many older adult patients. Melatonin and amitriptyline may cause sedation, and amitriptyline should be used with caution in patients with cardiovascular disease. (See 'Alternative options' above.)

●Prognosis – Hypnic headache is a chronic disorder that can last for years, though a substantial proportion of patients may respond to treatment. (See 'Prognosis' above.)