Clinical manifestations

Presentation and course

All cases of chronic unilateral daily headaches should have a trial of indomethacin (25). Indomethacin-responsive headaches are diverse in character and can be traditionally divided based on their response to indomethacin. Absolute responsiveness to indomethacin, defined as complete resolution of symptoms, is observed with paroxysmal hemicrania and hemicrania continua, whereas relative responsiveness is apparent in primary cough (Valsalva maneuver) headache, primary exercise headache, primary headache associated with sexual activity, and primary stabbing headache (13; 16).

Absolute responsiveness to indomethacin

Paroxysmal hemicrania. Paroxysmal hemicrania is a rare primary headache disorder belonging to the group of trigeminal autonomic cephalalgias (11). It is characterized by sudden bursts of severe, strictly unilateral head pain lasting 2 to 30 minutes, several times a day, in association with at least one ipsilateral cranial autonomic feature, such as conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial sweating, miosis, ptosis, eyelid edema, or a sense of restlessness or agitation (13). The attacks demonstrate an absolute response to indomethacin (13). Paroxysmal hemicrania can be classified as episodic or chronic, with the latter comprising 65% of patients (35). Episodic paroxysmal hemicrania is defined as attacks of paroxysmal hemicrania occurring in periods lasting from 7 days to 1 year, separated by pain-free periods lasting at least 3 months, whereas chronic paroxysmal hemicrania is characterized by attacks occurring for more than 1 year without remission or with remission periods lasting less than 3 months (13).

Paroxysmal hemicrania usually occurs in adulthood, with numerous case series reporting years of onset in the late third decade (05; 26; 13). There is no clear evidence of female preponderance (M:F ratio approximately 1:1) or racial preference (15; 05). Attacks are typically spontaneous with an absence of circadian periodicity; however, mechanical triggers, such as bending or rotating the head, account for 10% of paroxysmal hemicrania attacks, and attacks can be triggered by NO donor glyceryl trinitrate (08). Approximately 20% of patients believe alcohol is a trigger for paroxysmal hemicrania attacks, a distinguishing difference from cluster headaches in which alcohol is a well-known potent trigger in the majority of cases (11; 35). Notably, cutaneous triggers, such as touching the face, are not associated with paroxysmal hemicrania (35). Similarly, menstruation does not appear to worsen attacks, and pregnancy does not appear to terminate attacks (11).

Attacks of paroxysmal hemicrania are recurrent throughout the day, with one case series reporting a mean of 11 daily attacks lasting 17 minutes on average (05). The pain traditionally involves the ophthalmic division of the trigeminal nerve, with a typical pain distribution of V1>C2>V2>V3 (11). In one case series (n = 31), patients reported maximal tenderness at orbital and temporal locations (77%), followed by retro-orbital (61%), frontal (55%), and occipital (42%), amongst other locations, with 65% of patients rating their attacks as 10 out of 10 on a verbal rating scale (05). Of the cranial autonomic features reported, lacrimation was the most common (87%), followed by conjunctival injection (68%), rhinorrhea (58%), nasal congestion (55%), ptosis (55%), eyelid edema (42%), and forehead and facial sweating (32%); the least common was miosis (10%). Agitation is common throughout attacks and can be observed in 80% of patients (35). Migrainous features lateralized to side of the head pain are frequently reported in patients with paroxysmal hemicrania, with the highest associations to motion sensitivity (52%), nausea (43%), photophobia (30%), phonophobia (17%), and vomiting (17%) (05; 26). Outside of the acute attacks, interictal pain has been reported in 47% of patients; this is often described as intermittent and milder, unlike hemicrania continua (26; 32).

Hemicrania continua. Hemicrania continua was reclassified as a trigeminal autonomic cephalalgia in ICHD-3 beta as a result of its shared clinical and pathophysiological features with other trigeminal autonomic cephalalgia syndromes, such as unilateral head pain, cranial autonomic symptoms, and indomethacin responsiveness (14). It is characterized by a persistent, strictly unilateral headache that varies in severity and is associated with ipsilateral conjunctival injection; lacrimation; nasal congestion; rhinorrhea; forehead and facial sweating; miosis; ptosis or eyelid edema; or restlessness or agitation (13). The headache displays an absolute response to indomethacin (13). Hemicrania continua can be classified as remitting or unremitting. Patients with the remitting subtype may experience relief of symptoms for at least 24 hours as opposed to patients with the unremitting subtype who suffer from continuous pain for at least 1 year, without remission periods of at least 24 hours (13).

Hemicrania continua has been reported in a range of ages (31 to 79 years) with a mean age of 51 years reported in a large case-series study (n = 39) (04). It is somewhat more likely to occur in females (M:F ratio approximately 1:2) and is likely underdiagnosed as a result of its rarity and difficulties distinguishing interparoxysmal pain from other trigeminal autonomic cephalalgias, paroxysmal hemicrania, and the interparoxysmal allodynia observed in cluster headache (11; 35). Some patients report alcohol as a mild trigger of hemicrania continua, but it cannot be triggered by cutaneous touch or nitroglycerin (35).

Patients typically describe a persistent, baseline pain that is often dull in quality and of moderate severity (mean score of 5.8, measured by a verbal rating scale), with superimposed exacerbations of more intense, sharp, or throbbing pain that recur throughout the day (mean score of 9, measured by a verbal rating scale) (04). The pain is often described as “excruciating” (71%) and most commonly affects the frontal and temporal regions of the head (04; 32). Exacerbations are daily in 50% of patients, with an average attack duration ranging from 30 minutes to 3 days (35). Cranial autonomic features may be present unilaterally or bilaterally in exacerbations, with lacrimation being the most common (73%), followed by nasal congestion (51%), conjunctival injection (46%), ptosis (40%), and flushing (40%), amongst others (04). Moreover, agitation and restlessness are frequently observed during exacerbations in 69% and 28% of patients, respectively. Underlying migrainous biology additionally occurs, with 70.6% of patients meeting the diagnosis of migraine in the exacerbation period. Individuals often experience nausea (43% to 53%), photophobia (30% to 79%), and motion sensitivity (69%) (25; 04; 27).

Atypical cases of hemicrania continua have been reported and challenge the diagnostic criteria set by the International Headache Society, eg, cases of hemicrania continua with no cranial autonomic features or bilateral hemicrania continua. Indomethacin-nonresponsive hemicrania continua has been reported and suggests a different disorder (32).

Relative responsiveness to indomethacin

Primary cough (Valsalva maneuver) headache. Primary cough headache manifests as a sudden-onset bilateral headache dominating the posterior region of the head and is brought on by coughing, straining, or other Valsalva maneuvers (excluding prolonged physical exercise) in the absence of any other intracranial disorder (13). The headache arises moments after the cough or other Valsalva-associated stimulus and reaches peak intensity almost immediately; it then subsides over several seconds to a few minutes (although some patients report symptoms up to 2 hours) (13). Pain is generally described as moderate to severe with a stabbing, sharp, or splitting quality, and a significant correlation is observed between the frequency of cough and the severity of headache (13; 22). Associated symptoms can be seen in 60% of patients and include vertigo, nausea, and sleep abnormalities (13). It predominantly affects patients over the age of 40 with a mean age of onset of 70 years (range 44–81) and has a clear male predominance (12). The diagnosis of primary cough headache is confirmed by normal neuroimaging studies. In approximately 50% of patients seeking help for primary cough headache, a structural lesion is found. This is usually (approximately 90%) a Chiari type I deformity and, in a few cases, space-occupying lesions in the posterior fossa/foramen magnum area, which cause at least intermittent local blocking of CSF circulation, constituting a diagnosis of secondary cough headache (12; 22). Response to indomethacin cannot be used to differentiate primary and secondary cough headache, and neuroimaging is required to differentiate between the subtypes (03).

Primary exercise headache. Primary exercise headache is precipitated during or after physical exercise in the absence of any other intracranial disorder; patients must have at least two episodes to fulfil the diagnostic criteria set by the International Headache Society (13). On first presentation, it is important to exclude subarachnoid hemorrhage, arterial dissection, and reversible cerebral vasoconstriction syndrome (13). Primary exercise headache can occur in both trained and untrained athletes and may be triggered by any form of strenuous activity, which is often described as enough to double the resting pulse for over 10 seconds (12). Patients typically describe multiple episodes of pulsating, aching, and throbbing head pain that occur at the peak of exercise and extend up to 48 hours in some cases (13). The typical age of onset is below 50 years, and it is four times more common in men (12). Approximately 50% of patients with primary exercise headache also have a personal history of migraine. Secondary exercise headache should be suspected for (1) a single episode; (2) females; (3) other neurologic symptoms, such as loss of consciousness; (4) people older than 40 to 50 years old; and (5) a duration over 24 hours.

Primary headache associated with sexual activity. Primary headache associated with sexual activity is characterized by at least two episodes of headache that increase in intensity with increasing sexual excitation or mount to explosive intensity just before or with orgasm in the absence of any other intracranial disorder (13). Head pain has a median duration of 30 minutes; however, it may last up to 72 hours, with the first 24 hours potentially being severe (13; 12). On first presentation, it is important to exclude subarachnoid hemorrhage, intra- and extracranial arterial dissection, and reversible cerebral vasoconstriction syndrome (18). Patients typically describe a bilateral, occipital, or holocephalic head pain that starts as a dull ache and worsens with increasing sexual excitement, reaching peak intensity at orgasm (12). It has a clear male predominance (around 4:1) and usually begins between 20 to 45 years of age. Some patients may have comorbidities of hypertension, migraine, or tension-type headache (17).

Primary stabbing headache. Primary stabbing headache is defined as head pain occurring spontaneously as a single stab or series of stabs that recur with irregular frequency and last for a few seconds in the absence of cranial autonomic symptoms and underlying organic disease of the cranial nerves (13). Stabs are sudden onset, with 80% of stabs lasting for 3 seconds or less, and they are most frequently reported in extratrigeminal locations in 70% to 80% of patients (13; 16). Stabs can be multifocal and migrate between areas; this has been observed in up to 64% of patients (16). Relative indomethacin responsiveness has been described, with a success rate of complete remission of between 30% to 50%.

Clinical vignette

Case 1. Hemicrania continua. A 47-year-old female presented with a 7-year history of daily right-sided headache. She described a constant, generalized headache of mild intensity that waxed and waned in severity, but never completely resolved. Her husband said that her right eye watered and her eyelid looked droopy when the pain was bad. She had no other medical conditions. She had a normal neurologic examination. Routine laboratory studies and neuroimaging (MRI head) were normal.

Case 2. Episodic paroxysmal hemicrania. A 33-year-old female presented with a 5-year history of an acutely painful, stabbing headache dominating her left frontal and retro-orbital head regions. She described that the pain would last 10 to 15 minutes and occur five times daily. At the time of the headache, she noticed watering of her left eye and nasal stuffiness. She became restless and could not sit down. She had not noticed whether her attacks happened at a certain time of day or followed a certain pattern. She described having daily attacks for 6 months, with an intervening break of 10 to 12 months in which she would be headache-free.

Case 3. Primary cough headache. A 67-year-old male with no significant past medical history presented with a 4-month history of headache. He indicated that he developed a bitemporal headache with some dizziness when he coughed or during defecation. He did not have headache with sexual activity, exercise, or in relation to postural changes. There were no positive findings on the neurologic exam. Neuroimaging was normal.

Biological basis

Etiology and pathogenesis

The pathophysiology surrounding indomethacin-sensitive headaches remains unclear (35; 12; 16).

Paroxysmal hemicrania and hemicrania continua show an absolute responsiveness to indomethacin and belong to a larger subgroup of headaches termed “trigeminal autonomic cephalalgias” (10). Trigeminal autonomic cephalalgias are marked by brief episodes of head pain alongside heightened cranial parasympathetic autonomic reflex activation to nociceptive input in the ophthalmic division of the trigeminal nerve, although the other trigeminal autonomic cephalalgias are not indomethacin responsive (10; 35). The trigeminal-autonomic reflex has been implicated in the coactivation of the trigeminocervical-mediated pain pathway and the accompanying autonomic phenomena (02). Treatment with indomethacin has been shown to inhibit both the trigeminocervical pain pathway and autonomic activation, demonstrating further evidence for the proposed mechanism (02). Functional neuroimaging studies reveal contralateral hypothalamus activation in both paroxysmal hemicrania and hemicrania continua; however, the role of the hypothalamus as the generator or potentiator still remains unclear (20; 19).

An increase in central venous pressure is proposed as the central mechanism of pain in primary cough headache, mediated through the jugular venous system and epidural venous plexus secondary to rises in intrathoracic and intra-abdominal pressure (22). The presence of venous stenosis was found to be statistically significant between patients with primary cough headache and controls, further supporting the hypothesis of raised central venous pressure (06). Other hypotheses for the mechanism of primary cough headache include increased receptor hypersensitivity within the venous system and crowding of the posterior cranial fossa, although none have been fully confirmed (22). Primary exercise headache has been suggested to be of vascular origin, with various theories postulating the role of vasodilation secondary to impaired myogenic cerebrovascular autoregulation as well as the incompetence of the internal jugular valve or stenosis of the intracranial venous sinuses, leading to transient retrograde venous flow and increased intracranial pressure (12). Moreover, the pathophysiology of headache associated with sexual activity remains uncertain, with hypotheses proposing impaired metabolic cerebrovascular autoregulation, aberrant central sympathetic response, and venous stenosis central to its underlying mechanism (12).

Proposed explanations of the pathophysiology underlying primary stabbing headache are based on its clinical features and remain largely unknown, with many suggesting a nonpathological process without axonal damage (16). The intermittent nature of abrupt, irregularly frequent attacks is thought to be secondary to the spontaneous, temporary firing of nociceptive nerve endings, primarily A-delta and C fibers, originating from sensory afferents of the trigeminal and occipital nerves as a result of hyperexcitable free nerve endings and partial loss or dysfunction of nociceptive Schwann cells, leading to transient failure of the pain-gating mechanism (16).

Pharmacology of indomethacin. Indomethacin is classified as a nonsteroidal anti-inflammatory drug (NSAID) and serves as a potent reversible inhibitor of cyclooxygenase (COX) 1 and 2, with greater COX1 over COX2 activity, blocking prostaglandin synthesis (21). It is available in various formulations, such as oral, rectal, intramuscular, and intravenous. Notably, indomethacin exhibits the highest penetration into the central nervous system when compared to the other NSAIDs. On average, it takes approximately 30 minutes to take effect and provides relief for 4 to 6 hours. The average plasma half-life is 3 hours, with a range extending from 3 to 10 hours (32).

The specific impact of indomethacin on headache disorders remains uncertain and may vary between differing headache disorders, with proposed mechanisms of action, including the inhibition of prostaglandin synthesis via the COX pathway, suppression of nitric oxide, reduced cerebral blood flow, and the attenuation of oxidative stress (34). Vasodilation as well as increased prostaglandin levels alongside other transmitters, including nitrates, calcitonin gene-related peptide (CGRP), and vasoactive intestinal peptide (VIP) have been found to be elevated in spontaneous migraine attacks. Treatment with indomethacin is able to inhibit prostaglandin production, and one case report describes the normalization of both CGRP and VIP levels following administration of indomethacin (09). However, the administration of prostaglandin antagonists does not prevent vasodilation of the middle cerebral and superficial temporal artery and did not change headache intensity in the attacks (34). Likewise, in preclinical models of trigeminovascular nociception, indomethacin was unable to inhibit CGRP-induced dural vasodilation.

Indomethacin's therapeutic response to primary cough headache may be attributed to decreases in intracranial pressure. The precise mechanisms by which indomethacin achieves this effect are not well-understood but are likely influenced by the modulation of prostaglandin production on cerebral vasodilation and direct vasoconstriction of cerebral blood vessels (34). Nilsson and colleagues investigated the effects of indomethacin on a porcine model of intracranial hypertension and found that indomethacin can decrease intracranial pressure and, at higher doses, decrease cerebral blood flow, venous pH, and electrocortical activity while simultaneously increasing the arteriovenous oxygen difference (23). Human studies further support that indomethacin can reduce CSF pressure in intracranial hypertension. Following the intravenous administration of 50 mg indomethacin, a mean reduction of 139 mm H2O was seen in the CSF opening pressure (07).

Epidemiology

Paroxysmal hemicrania has an estimated prevalence of 0.5 per 1000 individuals in the general population (34). The incidence and prevalence of hemicrania continua remain unknown; however, it is thought to be likely underdiagnosed, with an underestimated prevalence as a result of its similar characteristics with chronic migraine (04; 34).

Primary cough headache was estimated to have a lifetime prevalence of around 1% (95% CI: 0%–2%, n = 1000), with 0.6% of new patient consultations in a specialized headache clinic (n = 3498) meeting the diagnostic criterion (28; 12). Approximately 20% of patients with primary cough headache were previously seen by respiratory physicians (13). Similarly, the prevalence of both primary exercise headache and headache associated with sexual activity was found to be 1% to 2% (95% CI: 0% to 2%, n = 1000) (28). However, more recent epidemiological studies have reported a higher prevalence of primary exercise headache in the general population, up to 12.3% in Norway (n = 1838) and up to 30.4% in Taiwan (n = 1963), which may suggest that headache sufferers are less likely to seek medical attention than patients with other headache disorders (12). Interestingly, an epidemiological study by Chen and colleagues found that primary exercise headache in adolescents was common (03). In 1963 students aged 13 to 15 years, the prevalence of exercise headache was 30.4% (n = 596), and it was more common in those with coexistent migraine (47.5% vs. 21.1%, P < 0.001).

Several population-based studies have attempted to estimate the lifetime prevalence of primary stabbing headache in the general population, with reports ranging from 2% (n = 740) to 35.2% (n = 1779) (16). The differences in values most likely represent differences in case definition, such as the location and duration of stabs (16).

Differential diagnosis

Confusing conditions

The major differential diagnoses of indomethacin-responsive headaches are migraine, trigeminal neuralgia, occipital neuralgia, nummular headache, headache secondary to raised intracranial pressure, headache secondary to structural abnormalities, and other forms of trigeminal autonomic cephalalgias, including cluster headache; short-lasting, unilateral, neuralgiform headache attacks with conjunctival injection and tearing (SUNCT); and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) (35; 12; 16).

For both paroxysmal hemicrania and hemicrania continua, the absolute response to indomethacin is a distinctive feature that can be used to aid diagnosis (13). Despite each headache disorder being clinically heterogenous, patients may have overlapping features that can be diagnostically challenging; for example, attack duration in both paroxysmal hemicrania and cluster headache may overlap, and shorter, more frequent attacks of cluster headache may be misdiagnosed as paroxysmal hemicrania (35). This reiterates the importance of indomethacin testing and understanding triggering patterns, such as the response to alcohol that is more often seen in patients with cluster headache and the response to oxygen treatment (likely to abort cluster headache attacks, with no efficacy in paroxysmal hemicrania). Similarly, hemicrania continua may be confused with other forms of headache, commonly chronic migraine, as a result of their similar clinical features of persistent, lateralized interparoxysmal head pain with associated exacerbations. This diagnostic dilemma can be overcome by assessing the patient’s response to indomethacin.

Exertional headaches, such as primary exercise headache and headache associated with sexual activity, may be mistakenly misdiagnosed as primary cough headaches and seen as a precipitant factor for “cough” headache (12). Primary exercise headache as well as headache associated with sexual activity are more frequently seen in a younger population and are associated with underlying migrainous biology. Other headaches that may be aggravated by cough or other Valsalva maneuvers include migraine and headache associated with raised intracranial pressure.

Primary stabbing headache can often be confused with both occipital and trigeminal neuralgia (16). Trigeminal neuralgia is characterized by pain, with brief episodes of severe pain precipitated by innocuous stimuli followed by a distinct refractory period within the affected trigeminal distribution. The precipitation of pain by innocuous stimuli, such as touching the face, chewing, speaking, or brushing teeth, can be a differentiating factor favoring trigeminal neuralgia over primary stabbing headache. Similarly, occipital neuralgia produces pain within the dermatome of the occipital nerve branch and is associated with dysesthesia, allodynia, and tenderness in the affected area. Pain in primary stabbing headache typically tends to be more focal and often has little to no symptoms interictally, helping to differentiate between the two conditions.

Diagnostic workup

It is important to first assess the headache phenotype when considering the diagnosis of indomethacin-sensitive headaches. The ability to distinguish several key features is key to assessing the diagnosis at hand, such as the presence of cranial autonomic symptoms, attack duration, and precipitant factors to an attack (35; 12; 16). Trigeminal autonomic cephalalgias should be at the forefront of a clinician’s mind when presented with a patient experiencing unilateral head pain in the presence of cranial autonomic symptoms, with some clinicians advocating indomethacin trial early, if not first, in treatment to elicit the diagnoses of paroxysmal hemicrania and hemicrania continua (25; 35). Antonaci and colleagues proposed the standardized 50 mg intramuscular “indotest” in 1998 to identify the diagnoses of paroxysmal hemicrania and hemicrania continua, which demonstrate an absolute response to indomethacin (01). A placebo-controlled single-blinded indomethacin test is preferred (35). Importantly, patients with new presentations of trigeminal autonomic cephalalgias should be thoroughly investigated with an MRI head with gadolinium and pituitary function tests to exclude pituitary and peripituitary gland disease (35). In patients with a diagnosis of a pituitary tumor (n = 84), 10% report a trigeminal autonomic cephalalgia–like headache, an approximate 100-fold increase compared to the normal population (35). Moreover, urgent neuroimaging should be considered if the patient has abnormal examination findings to look for secondary causes of headache (32). Similarly, patients presenting with primary exercise headache or headache associated with sexual activity for the first time should have urgent neuroimaging and angiographic studies to exclude underlying vascular pathology, such as subarachnoid hemorrhage, arterial dissection, and reversible cerebral vasoconstriction syndrome (13; 12). Younger patients presenting with primary cough headache should signal to physicians to perform neuroimaging to look for underlying structural lesions, most commonly (approximately 90%) Chiari type 1 malformations in cough headache (22). A suggested algorithm for the diagnostic flow of indomethacin-sensitive headaches has been proposed.

Management

Absolute responsiveness to indomethacin

Both hemicrania continua and paroxysmal hemicrania show absolute responsiveness to indomethacin, with a median response time of 4 and 7 hours from drug administration, respectively (32). Treatment is usually initiated at a dose of 25 mg thrice daily with meals. Patients should be prescribed a concurrent protein pump inhibitor to prevent gastrointestinal irritation (10). If relief is not obtained within 48 hours of therapeutic intervention, the dose can be increased to 50 mg thrice daily and, if necessary, to 75 mg three times daily 1 week later (10). Dosing of indomethacin should remain as low as possible. A mean dose of 92.5 ± 42.6 mg was found to be effective in maintaining complete and sustained relief of symptoms for 10 patients with chronic paroxysmal hemicrania for approximately 1 month (24). For patients with hemicrania continua, one study (n = 34) found that the reported effective dose ranged from 50 to 300 mg daily, with the most common dose reported as 150 mg daily (range 25 to 225 mg) (25). Complete pain relief was achieved in 2 hours (25). Once an effective dose is achieved, it should be maintained for several weeks and then slowly reduced by 25 mg every 3 days. The dose should continue to be slowly reduced until either headache recurrence in which the dose is maintained or indomethacin is discontinued (32). There is disagreement amongst headache specialists on the maximal dose trialed before labelling a patient as nonresponsive to indomethacin, with some suggesting doses as high as 300 mg daily (32).

Although the response to indomethacin is absolute, patients who develop gastrointestinal problems pose an important clinical challenge. A comprehensive review by Goadsby outlines other alternative treatments for patients who are intolerant to indomethacin (11). The review highlights that in cases of paroxysmal hemicrania, topiramate, cyclooxygenase 2 (COX2) selective inhibitors, and greater occipital nerve blocks with lidocaine and methylprednisolone appear to be useful in managing attacks. Patients who experience attacks with a longer duration may find subcutaneous sumatriptan beneficial; however, 80% of patients find that their attacks are too brief to be aborted by triptans. Similarly, for patients living with hemicrania continua who are unable to take indomethacin, topiramate and greater occipital nerve blocks are also recommended, but not COX2 inhibitors. Goadsby highlights the promising future therapeutic benefit of neuromodulation in paroxysmal hemicrania and hemicrania continua.

In a study examining the effect of noninvasive vagal nerve stimulation (nVNS) on patients with paroxysmal hemicrania (n =6) and hemicrania continua (n =9), 78% of patients with hemicrania continua reported experiencing a reduced severity of continuous pain, with two patients reporting a reduced frequency of exacerbations, decreased severity, and a shorter duration of exacerbations with acute treatment (31). A third of patients with hemicrania continua reported experiencing a reduced duration of exacerbations. Amongst patients with paroxysmal hemicrania, four (67%) reported therapeutic benefit from nVNS, with one patient becoming attack-free and a further three patients reporting reduced attack frequency, reduced severity, and a shorter duration.

Relative responsiveness to indomethacin

Primary cough headache. Treatment of primary cough headache is multifactorial. Prophylactic indomethacin doses of 25 to 150 mg daily may be used alongside optimization of respiratory health and withdrawal of medications that can cause cough as a side effect, such as angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (12). Secondary cough headache does not respond to indomethacin, and patients typically require neurosurgical intervention for symptomatic relief (22).

Primary exercise headache. The management of primary exercise headache includes both pharmacological and nonpharmacological interventions. For patients with predictable attacks who do not exercise regularly, preemptive treatment, such as ergotamine, triptans, gepants, or indomethacin, can be administered prior to exercise. For patients with frequent attacks who regularly exercise, prophylactic therapy with beta-blockers (metoprolol 1–2 mg/kg/daily) or indomethacin (25–150 mg/daily) has proven efficacious for managing pain. Nonpharmacological therapeutic interventions recommend adequate hydration, regular sports training, and the importance of warm-up routines prior to exercise (12).

Primary headache associated with sexual activity. Treatment of headache associated with sexual activity is similar to that of primary exercise headache. For predictable attacks, 25 to 100 mg of indomethacin 1 to 2 hours before intercourse is a preemptive treatment that may help control pain. Ergotamine, triptans, gepants, and erenumab have also shown positive preemptive results. Preventive treatments, such as daily beta-blockers, may also be used. Some patients find relief in transiently stopping or taking a passive role in sexual activities (12).

Primary stabbing headache. Primary stabbing headache is typically self-limiting and does not require medical treatment. Treatment may be initiated if there is a significant detriment to quality of life. Primary stabbing headache is often markedly improved by indomethacin; however, several other agents have shown similar efficacy for the treatment of primary stabbing headache. These include nonsteroidal anti-inflammatory drugs (NSAIDs) (naproxen and ibuprofen), selective COX2 inhibitors (rofecoxib, celecoxib, and etoricoxib), prednisolone, gabapentin, tricyclic antidepressants (amitriptyline or nortriptyline), carbamazepine, and melatonin (16).

Outcomes

Long-term treatment with indomethacin is safe and generally well tolerated, with no major adverse events (34). Side effects, specifically of a gastrointestinal nature, are present in more than 30% of patients (34). These include dyspepsia, nausea, vomiting, abdominal pain, and diarrhea (34). The effect can be mitigated by the concomitant commencement of protein pump inhibitors (35). Central nervous system adverse events are rare, with reports of dizziness, nausea, and psychosis in line with a possible direct central action of indomethacin (35; 34).

Special considerations

Pregnancy

The British National Formulary advises avoiding indomethacin use in the first and second trimesters unless essential. Additional antenatal monitoring may be required if treatment with indomethacin is considered necessary by a doctor from week 20 of pregnancy onwards.