US Pharm. 2021;46(1):17-20.
ABSTRACT: Hypnic headache (HH) is a rare primary headache disorder that occurs most commonly in persons older than age 50 years and awakens the patient from sleep. The first case of HH was not identified until 1988, and the rarity of this disorder has resulted in limited data on diagnosis and management. The pain, duration, and frequency of HH can present in variable fashion, but the defining factor is waking from sleep at roughly the same time each night. Case reports and anecdotal evidence suggest that potential treatments are limited to pharmacologic options including caffeine, lithium, indomethacin, melatonin, amitriptyline, and some anticonvulsants. Nonpharmacologic management options for HH may be helpful, but they require further evaluation.
Hypnic headache (HH) is a rare primary headache disorder in which headache attacks occur exclusively during sleep and awaken the patient. The incidence of HH is unknown but has been estimated at 0.07% to 0.3%, with approximately 250 case reports and case series have been described in the literature.1-3 First identified in 1988, HH was included in the International Classification of Headache Disorders (ICHD) in 2004.2-4 HH primarily affects persons older than age 50 years, with a few cases reported in younger adults and children, and it occurs more often in women than in men.5-13 Studies indicate that 30% to 60% of HH patients have a history of other headache types, the majority reporting migraine.1,5,7-9 HH is differentiated from other primary headaches based on its exclusive presentation of waking the patient during sleep. Because HH is so uncommon, research is needed to better understand its pathophysiology and management.13-16
The unique clinical feature of HH is that the attack awakens the patient at roughly the same time of night, reflected in the term alarm clock headache.3 Some patients have also reported attacks during daytime naps. The attacks usually occur between 2 am and 4 am and last from 5 minutes to 12 hours, and the headache frequency ranges from 1 to 21 days per month. Multiple attacks may occur in a given night, with patients able to sleep between attacks. Approximately 60% of patients report bilateral pain with frontotemporal or holocranial locations, but unilateral cases have been reported. Although the pain is usually mild to moderate, patient descriptions include “dull,” “sharp,” “stabbing,” “explosive,” and “throbbing”; one-fifth of patients have described the pain as severe. Upon waking with an attack, patients do not remain supine; rather, they get up and initiate activity that may provide some relief, such as walking, showering, or eating. This differs from migraine attacks, during which patients prefer to rest and lie supine in a quiet, dark room. The degree of restlessness with HH is less than what is seen in patients with cluster headache (CH). Although HH is usually not associated with migraine-associated symptoms, some case reports have described nausea, photophobia, and phonophobia. Some patients may experience drowsiness, head pressure, malaise, hunger, and yawning. Autonomic symptoms (e.g., conjunctival injection) may occur, but they are less common than in migraine or CH.3,17-22 The natural course of the disease is unclear; most cases present with persistent, daily to near-daily attacks, but episodic subtypes have also been reported. HH may have a significant impact on a patient’s mental health, with the risks of both anxiety and depression increased.23
The underlying pathophysiology of HH is poorly understood, but the disorder may share some pathophysiological predisposition with, or be a variant of, migraine. Its association with sleep has led to the theory that HH is a chronobiological disorder and that hypothalamic changes could be involved in its pathophysiology; this is further supported by the associated circadian rhythmicity. The anterior and posterior hypothalamus comprise a system associated with circadian rhythm, pain processing, and melatonin release. Dysfunction or decline of this system with age, especially the suprachiasmatic nucleus, could potentially activate mechanisms that result in sudden waking and headache precipitated by events during sleep.14,24-26 Imaging studies have identified the hypothalamus as a link between primary headaches and sleep and have pinpointed its involvement in pain modulation. A small case-control study of HH patients found a decrease in gray matter in pain-related areas of the hypothalamus, which is consistent with the circadian periodicity associated with this disorder.27 HH may also involve the occurrence of hypercapnia and subsequent vasodilation during sleep, which results in the intracranial artery placing pressure on the meninges, leading to pain.28 Polysomnographic data from HH patients do not support a relationship with either rapid eye movement (REM) sleep or non-REM sleep, as both patterns are associated with attacks.29-33
The differential diagnostic process for HH involves ruling out secondary causes, including other headache types. This may be a challenge in primary care, with data suggesting that fewer than 5% of patients are diagnosed prior to evaluation at a headache center.1 Nocturnal headaches in the elderly, especially new-onset headache, require appropriate evaluation for secondary causes. Neuroimaging is recommended in all cases to rule out intracranial lesions (e.g., adenomas, pituitary tumors, meningiomas, pontine infarcts). In addition, it is important to rule out nocturnal headache-hypertension syndrome via 24-hour blood-pressure monitoring. Other secondary causes include temporal arteritis, obstructive sleep apnea (OSA), hypoglycemia, psychiatric disorders, and chronic pain disorders.34-40 A diagnosis of OSA does not eliminate the possibility of a concurrent HH diagnosis.41 Medication-induced headache, medication-withdrawal headache, and medication-overuse headache (MOH) should also be considered in the diagnostic process.3,42,43
Other kinds of headache, especially those involving sleep-related attacks, should be ruled out, including migraine, tension headache, cervicogenic headache, and uncommon types such as paroxysmal hemicrania (PH).3 The key features that differentiate HH from other primary headache disorders are its exclusive occurrence with sleep and its development primarily in persons older than age 50 years. In contrast, CH and PH patients describe excruciating pain and concurrent marked autonomic features; additionally, PH has a much shorter duration (2-3 minutes). Patient age exceeding 50 years may help differentiate HH from MOH because patients in this age range rarely experience new-onset MOH, and after menopause women seldom experience MOH. In addition, only about 40% of MOH patients experience attacks that wake them during sleep. Given the lack of research on and knowledge of HH and the diagnostic challenges it poses, the incidence of HH may actually be greater than has been estimated.1,3,25,44,45
The most recent ICHD (3rd edition; ICHD-3) has updated the diagnostic criteria for HH (TABLE 1) and has demonstrated improved sensitivity for diagnosing HH over the previous classification (ICHD-2).3 One concern raised in some published case reports is the inclusion of “no cranial autonomic symptoms or restlessness” as a criterion, as these authors had reported an association between these symptoms and HH.2,3,46-48
Management and treatment parameters for HH are based on anecdotal clinician experience, with the majority of data coming from case studies or case series. No randomized, placebo-controlled trials in HH have been conducted.14
The sections below discuss abortive (acute) treatment. Because of the low prevalence of HH, evidence validating the most appropriate abortive treatments is limited.
Caffeine: Caffeine is considered an effective and a first-line option, including caffeinated beverages (e.g., a cup of strong black coffee) and caffeine-containing analgesics. Patients have reported that drinking a cup of black coffee at pain onset was effective in treating acute HH attacks. A summary of case series and open-label data noted that 16 of 23 patients with HH reported a response from caffeine use. An expected concern for some patients was caffeine-induced wakefulness or insomnia. The proposed analgesic mechanism of action (MOA) of caffeine in HH is its vasoconstrictor properties and vascular alterations through its antagonist activity on adenosine receptors (especially A2A and A2B). Unfortunately, action at the adenosine A2A receptor is also associated with the stimulating effects of caffeine, resulting in insomnia and wakefulness. Other proposed MOAs include reduction in cortical hyperexcitability, inhibition of prostaglandins, and action at alpha-adrenergic and/or gamma-aminobutyric acid receptors. Readily accessible sources of caffeine include coffee (up to 200 mg/serving), some teas (120 mg/serving), and certain sodas (70 mg/serving).49-51
Analgesics: Caffeine-containing analgesics are reported to be effective in treating HH. Caffeine doses ranging from 10 mg/kg to 30 mg/kg may potentiate the effects of simple analgesics. A case series noted a treatment benefit in five of nine HH patients taking acetaminophen-caffeine combinations.49,52 Caution is recommended with aspirin-caffeine combinations because of the risk of gastrointestinal (GI) bleeding and other effects. Avoiding the overuse of caffeine-containing analgesics is important because of the risk of developing MOH.3 Some clinicians have reported that a dramatic response to caffeine may assist in the diagnosis of HH.14,49,52-56 Monotherapy with other analgesics, including nonsteroidal anti-inflammatory drugs, acetaminophen, opioids, and ergotamine, is associated with variable response in HH, based primarily on anecdotal evidence.15,25,27
Serotonin Receptor Agonists: Serotonin receptor agonists (triptans) have been used for HH, although available evidence is based on case reports, case series, and anecdotal reports with mixed results. The older age of most HH patients requires consideration of triptans’ contraindications, including heart disease, hypertension, peripheral vascular disease, and cerebrovascular disease. In patients without risk factors, triptans may be considered a secondary option for HH, with anecdotal evidence suggesting that the fast-acting formulations (e.g., nasal spray) may provide optimal delivery.9,16,57,58
The preventive (prophylactic) management of HH includes a few pharmacologic options. Because HH patients may have multiple age-related comorbidities, it is important to consider the individual patient’s disease states, medication tolerability, and polypharmacy.59-62
Caffeine: Caffeine has been reported to be an effective prophylactic therapy when administered as a cup of coffee prior to going to sleep. A case series involving 40 patients reported a complete or moderate response in 15 patients, with four of the patients unresponsive after 1 year. A follow-up survey indicated that some patients in the caffeine group benefited from an additional caffeinated drink upon waking. As expected, caffeine—although safe in most patients—can have a significant impact on sleep, causing insomnia, and may not be appropriate for many patients.1,7,9,14,16,19,49,59,63-65
Lithium: Lithium is the most commonly used preventive agent for HH, although reports indicate variable efficacy and tolerability concerns. In case reports and case series, lithium used to treat HH was effective in 35% to 90% of patients. Response to treatment occurred in 2 to 4 weeks, with some patients reporting complete suppression of headaches. Lithium dosages of 150 mg/day to 600 mg/day with dose adjustments for plasma levels of 0.5 mmol/L to 1 mmol/L have been used, with 90% of responders taking 300 mg at bedtime. Proposed MOAs for lithium in HH treatment include effects on melatonin levels, downregulation of serotonin receptors, and increases in serotonin release. Although lithium is considered effective, tolerability is problematic, with discontinuation rates exceeding 50%. Adverse effects include drowsiness, tremor, diarrhea, thirst/polyuria, and worsened headaches. Lithium must be used cautiously—or is contraindicated—in patients with cardiovascular disease, renal disease, psoriasis, electrolyte disturbance, or hypothyroidism. Lithium should be considered as a first-line option for HH prevention with a trial of 3 to 4 months followed by a taper.1,7,9,15,18,19,28,30,66-69
Indomethacin: Indomethacin at dosages of 25 mg/day to 150 mg/day resulted in moderate-to-good responses in case reports, with some patients reporting headache freedom, although GI tolerability is problematic. In case reports and case series, two of five patients had an excellent response at dosages ranging from 25 mg to 100 mg daily, including one patient reporting headache freedom after 1 week. One patient was able to taper the dose over 2 months and remained headache-free after discontinuation. Some reports have suggested a greater response to indomethacin in unilateral HH.70,71 The MOA for indomethacin in HH is not understood, although reduction in cerebrospinal-fluid (CSF) pressure has been proposed. Indomethacin should be considered a second-line agent in the treatment of HH.71-76
Melatonin: Case reports and case series using melatonin 3 mg to 5 mg daily reported a 40% response in HH patients. One responsive patient described a reduction in headache frequency and intensity. The MOA is not understood, although the nocturnal onset of HH suggests that melatonin metabolism may be involved. Melatonin production by the pineal gland, regulation by the hypothalamus, and circadian rhythmicity may further support this relationship.76-79
Amitriptyline: In case reports, this tricyclic antidepressant was found to be effective in some HH patients. One case series noted efficacy—defined as a moderate response and >50% reduction of headaches within 4 weeks—in three of five patients treated with amitriptyline 10 mg to 75 mg daily. Tolerability was a problem in most patients, with adverse effects including dry mouth, personality changes, and cardiac arrhythmias.21,62,80,81
Anticonvulsants: Case reports involving various anticonvulsants noted efficacy in some HH patients. Case reports on topiramate reported efficacy for dosages of 25 mg to 100 mg daily. Response was considered a reduction in headache frequency and intensity, and complete relief occurred in one case.14,60,82,83 The MOA of topiramate in HH may involve modulation of abnormal activation of the hypothalamic pacemaker. Tolerability may be problematic in patients who experience drowsiness, vertigo, and cognitive effects, and discontinuation may result.9,24,25,27 Patients taking higher dosages who experience paresthesias and taste disturbances may benefit from the use of supplemental potassium as prescribed by the provider.82 Case reports of two HH patients treated with lamotrigine noted a good response and positive outcomes at 1 year.84 In a case report of a 78-year-old woman with HH, pregabalin 150 mg taken at bedtime resulted in a good response and tolerability maintained over 14 months.65
Other Medications: Numerous other medications and drug classes have been used to treat HH, with case reports or anecdotal evidence suggesting effectiveness—or lack thereof—of beta-blockers, verapamil, glucocorticoids, acetazolamide, clonidine, and benzodiazepines.7,15,18,28,33,35,49,52,85,86 OnabotulinumtoxinA injected into a variety of neck and cranial sites led to an effective response in one case report.59
Nonpharmacologic interventions have been used for HH, with some success. Some case reports and case series found that patients who get out of bed and initiate some type of physical activity at the onset of an attack may achieve some benefit. This may be due to a reduction in CSF pressure when moving from a supine position.1 Other nonpharmacologic options that may offer benefits include implanted occipital-nerve stimulation (ONS), occipital-nerve block (injections), and oxygen therapy. In a case report on refractory HH treated with a 10-day course of ONS, the patient reported an excellent response that was maintained for 36 months.62 A different case report described the benefits of ONS treatment for HH. Responses from two nerve blocks included reductions in pain intensity and pain frequency, with a pain-reduction benefit maintained over the next 6 months.87 Although oxygen has demonstrated benefits for CH, minimal evidence supports its use in the abortive treatment of HH, with just one of four patients reporting benefits in a case series.7,19,62
HH is a benign, recurrent headache disorder that occurs exclusively during slumber, awakening the patient. It occurs primarily in persons older than age 50 years, although rarely younger patients are affected. The pathology, diagnostic criteria, and management of HH continue to evolve with available evidence from case reports and case series. An extensive workup for patients with a suspected diagnosis is important to rule out secondary causes or other headache disorders. Limited evidence supports the use of caffeine, lithium, indomethacin, melatonin, amitriptyline, and some anticonvulsants in the treatment of HH, although efficacy reported for each of these agents is variable, and tolerability may be a problem with some agents. Future research in the areas of neurophysiology and treatment options for HH are necessary in order to better understand, and improve outcomes for, this rare headache disorder.
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