Version May 2024
INTRODUCTION — The trigeminal autonomic cephalalgias (TACs) are a group of primary headache disorders characterized by unilateral trigeminal distribution pain that occurs in association with ipsilateral cranial autonomic features [1,2]. The TACs include cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks, and hemicrania continua [3].
This topic will review the treatment and prognosis of paroxysmal hemicrania. Other clinical aspects of paroxysmal hemicrania are reviewed separately. (See "Paroxysmal hemicrania: Clinical features and diagnosis".)
Other trigeminal autonomic cephalalgias are discussed elsewhere.
●(See "Cluster headache: Epidemiology, clinical features, and diagnosis" and "Cluster headache: Treatment and prognosis".)
●(See "Short-lasting unilateral neuralgiform headache attacks: Clinical features and diagnosis" and "Short-lasting unilateral neuralgiform headache attacks: Treatment and prognosis".)
●(See "Hemicrania continua".)
PHARMACOLOGIC TREATMENTS — The treatment of paroxysmal hemicrania is entirely prophylactic, as attacks are too short and intense for any acute oral treatment to be effective. Indomethacin is the treatment of choice for adults and children with paroxysmal hemicrania. Because it is rare and because indomethacin is highly effective, there are no large prospective clinical trials evaluating therapy for paroxysmal hemicrania.
For patients who cannot tolerate indomethacin, one faces a difficult challenge. No other drug is consistently effective in paroxysmal hemicrania. Alternative drug therapies that may be useful are reviewed below.
Indomethacin — By definition, paroxysmal hemicrania responds completely to indomethacin. (See "Paroxysmal hemicrania: Clinical features and diagnosis", section on 'Diagnostic criteria'.)
Evidence supporting the effectiveness of indomethacin comes mainly from observational case series [4-7]. In the two largest series, the following observations were reported:
●In a prospective study of 31 patients with paroxysmal hemicrania, 30 patients could tolerate indomethacin, and all had a positive response [7].
●In a retrospective study with data for indomethacin response in 40 patients diagnosed with chronic paroxysmal hemicrania, a consistent response to indomethacin was noted in 30 (75 percent). Of the 30 consistent responders, 24 had complete response, while 6 patients had a partial response. An inconsistent response was observed in 10 (25 percent) [4]. While patients with an inconsistent response did not meet strict diagnostic criteria for paroxysmal hemicrania, the investigators noted that all had a headache phenotype that best fit with paroxysmal hemicrania rather than cluster headache.
The existence of indomethacin-insensitive paroxysmal hemicrania is controversial. However, there are reports of patients who have clinical symptoms consistent with paroxysmal hemicrania yet do not respond to indomethacin [4,8].
Dosage and side effects — The starting dose of indomethacin for adults and older adolescents (≥15 years of age) is 75 mg daily in three divided doses (ie, 25 mg three times a day). The indomethacin dose should be increased to 150 mg daily in three divided doses for 3 to 10 days if there is an incomplete response to the starting dose after 3 days. The dose should be further increased to 225 mg daily in three divided doses for 10 days for partial responders if the index of suspicion is high.
For children (≤14 years of age), the indomethacin dose is 1 to 2 mg/kg daily given in two divided doses [9].
The use of indomethacin to confirm the diagnosis of paroxysmal hemicrania is reviewed separately. (See "Paroxysmal hemicrania: Clinical features and diagnosis", section on 'Indomethacin trial'.)
Complete resolution of the headache is typically prompt, usually occurring within one to two days of initiating the effective indomethacin dose. In patients who do not respond to indomethacin, the diagnosis of paroxysmal hemicrania should be reconsidered.
The typical maintenance dose of indomethacin is 25 to 100 mg daily. However, the effective maintenance dose can vary between 12.5 and 300 mg daily, depending on individual response and the fluctuation in attack severity [10]. Hence, dosage adjustments may be necessary to address the clinical fluctuations seen in paroxysmal hemicrania.
Suspicion for a secondary cause of paroxysmal hemicrania should be raised in patients who need escalating doses or become refractory to indomethacin treatment. Similarly, underlying pathology may be present in patients who require continuous high doses of indomethacin [11]. In such cases, we recommend careful diagnostic evaluation (or re-evaluation) for secondary causes, including brain imaging. (See "Paroxysmal hemicrania: Clinical features and diagnosis", section on 'Neuroimaging' and "Paroxysmal hemicrania: Clinical features and diagnosis", section on 'Secondary paroxysmal hemicrania'.)
Most patients can expect sustained efficacy of indomethacin treatment without developing tachyphylaxis, though about one-quarter develop gastrointestinal side effects [12]. The most common serious side effect of indomethacin is the development of peptic ulcers. Measures to prevent gastrointestinal side effects include testing and treating for Helicobacter pylori and the use of gastroprotection with misoprostol or proton pump inhibitors. These issues are discussed separately. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)
Indomethacin suppositories are occasionally helpful if gastric intolerance is a major problem or when high doses, such as 300 mg daily, are required.
Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin also have potentially important renal and cardiovascular effects. Renal adverse effects include acute renal failure due to renal vasoconstriction, worsening of underlying hypertension, and electrolyte and fluid abnormalities. Additionally, the risk of renal cell cancer may be increased. Cardiovascular effects include interference by some agents with the antiplatelet activity of aspirin, an effect on coronary risk, and worsening of heart failure. (See "Nonselective NSAIDs: Overview of adverse effects".)
Indomethacin discontinuation — Upon discontinuation of indomethacin, symptoms of paroxysmal hemicrania usually reappear within 12 hours to 2 weeks. During active headache cycles, however, skipping or even delaying doses may result in the prompt reoccurrence of the headache [5].
Indomethacin withdrawal strategies differ for patients with episodic and chronic forms of paroxysmal hemicrania.
●In patients with episodic paroxysmal hemicrania, indomethacin should be given for slightly longer than the typical headache bout and then gradually tapered.
●In patients with chronic paroxysmal hemicrania, long-term treatment is usually necessary. However, long-lasting remissions have been reported in rare patients following cessation of indomethacin. Thus, we suggest an indomethacin drug withdrawal trial at least once every six months for patients with chronic paroxysmal hemicrania. This should be done by gradually tapering the dose of indomethacin.
Alternative drug therapies — Patients who cannot tolerate indomethacin face a difficult challenge, since no other drug is consistently effective in paroxysmal hemicrania. Alternative drug therapies that may have some benefit for paroxysmal hemicrania include NSAIDs other than indomethacin, calcium channel blockers, and several other agents.
Other nonsteroidal anti-inflammatory drugs — Numerous other NSAIDs have been tried in paroxysmal hemicrania, but none show the consistent and exquisite response provided by indomethacin. The NSAIDs that have been reported to be partially or completely effective, mainly in isolated cases, include aspirin [13-15], ibuprofen [15], naproxen [15-18], diclofenac [15,19], ketoprofen [13], and piroxicam beta-cyclodextrin [20].
Limited success in the treatment of paroxysmal hemicrania has been reported with the cyclooxygenase-2 (COX-2) inhibitors rofecoxib [21-23], celecoxib [21,24], and etoricoxib [25]. However, prolonged use of these agents is associated with an increased risk of myocardial infarction and stroke. (See "NSAIDs: Adverse cardiovascular effects".)
Calcium channel antagonists — There are several case reports of patients with paroxysmal hemicrania who had a partial or complete response to verapamil [15,26-29], and verapamil is generally considered the best alternative drug treatment to indomethacin for paroxysmal hemicrania [30]. A pooled analysis of 16 patients from two studies reported a responder rate of 44 percent for verapamil [31]. Other calcium channel antagonists that have been reported to be effective in paroxysmal hemicrania include flunarizine [15,32] and nicardipine [32].
Given these data, we suggest verapamil for patients with paroxysmal hemicrania who are unable to tolerate indomethacin. Similarly, we suggest verapamil for patients with a clinical phenotype of paroxysmal hemicrania who have an incomplete or poor response to an adequate trial of indomethacin. Verapamil is usually started at 160 to 240 mg daily in two divided doses. A lower starting dose of 80 mg daily in two divided doses is suggested for older adult patients and adults of small stature. The dose can be increased as needed and as tolerated up to 480 mg daily in three to four divided doses. Most responders require a dose of 240 to 320 mg daily.
Other medications — Other drugs reported to be partially or completely effective in paroxysmal hemicrania, mainly in isolated cases, include acetazolamide [33], prednisone [13,17], ergotamines [13], lithium [13], and topiramate [34].
Limited data suggest other agents such as sumatriptan and carbamazepine are rarely effective [15,31,35,36].
Treatment approach for children — As in adults, indomethacin is the treatment of choice for children and adolescents with paroxysmal hemicrania [9]. (See 'Indomethacin' above.)
For children who cannot tolerate indomethacin, a number of second-line treatments have been tried; the list includes COX-2 inhibitors, calcium channel antagonists (eg, verapamil, flunarizine), topiramate, and greater occipital nerve blocks [9]. Some of these agents can be given in combination [37]. However, none are as effective as indomethacin.
INTERVENTIONAL THERAPIES FOR REFRACTORY CASES — Alternative approaches for the treatment of paroxysmal hemicrania include local blockades, neurostimulation, and surgical procedures.
Local blockades — Local anesthetic blockades of pericranial nerves, including the greater occipital nerve, supraorbital nerve, and lesser occipital nerve, have been generally ineffective for paroxysmal hemicrania, as have stellate ganglion blocks, sphenopalatine ganglion blocks, and cervical sympathetic blocks [13,38]. A prospective, open-label study of 119 patients with trigeminal autonomic cephalalgias (TACs) found that multiple cranial nerve blockade was associated with improvement in only 25 percent of patients with paroxysmal hemicrania, whereas the treatment was associated with improvement in 56 to 83 percent in patients with other TACs [39].
However, there are two reports of complete response with local blockades. One was a patient with episodic paroxysmal hemicrania who consistently showed a complete response to greater occipital nerve blockade with a combination of lidocaine and methylprednisolone but not bupivacaine [40]. Another case report described complete response to repetitive sympathetic chain block with a combination of bupivacaine and methylprednisolone introduced onto the C7 transverse process but not with saline placebo [41]. This patient subsequently had a stellate ganglionectomy (sympathectomy) that rendered him pain-free, though follow-up was limited to 15 months.
Neurostimulation — Retrospective case reports and observational studies have reported improvement of paroxysmal hemicrania in small numbers of patients treated with various neurostimulation techniques, including occipital nerve stimulation [42], percutaneous vagus nerve stimulation [43,44], and deep brain stimulation [45]. However, the actual benefit of each of these treatments should be considered unknown until more definitive evidence is available.
Invasive surgery — Response to surgical decompression of the supraorbital, supratrochlear, trigeminal, or greater occipital nerves has been reported in a small case series [46]. Other invasive surgical procedures, including trigeminal sensory root section, infraorbital nerve section, superficial petrosal nerve section, and sphenopalatine ganglionectomy, have been ineffective [13,41].
NATURAL HISTORY AND PROGNOSIS — Paroxysmal hemicrania is a rare syndrome, and there is a paucity of literature on its natural history and long-term prognosis. The available evidence suggests that it is a lifelong condition. Patients generally obtain sustained relief with indomethacin treatment. (See 'Indomethacin' above.)
Indomethacin does not seem to alter the condition in the long term, though a significant portion of patients can decrease the dose of indomethacin required to maintain a pain-free state.
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
●Indomethacin for initial preventive therapy – For adults and children with a paroxysmal hemicrania, we recommend treatment with indomethacin (Grade 1A). By definition, paroxysmal hemicrania responds completely to indomethacin. (See 'Indomethacin' above.)
•Dosing – The starting dose of indomethacin for adults is 75 mg daily in three divided doses. For those with a partial response to indomethacin, the dose may be increased to 150 mg daily in divided doses after three days and further increased to 225 mg daily in divided doses.
For children (≤14 years of age), the indomethacin dose is 1 to 2 mg/kg daily given in two divided doses.
•Duration of therapy – For patients with episodic paroxysmal hemicrania, indomethacin should be given for slightly longer than the typical headache bout and then gradually tapered. For patients with chronic paroxysmal hemicrania, we suggest an indomethacin drug withdrawal trial by gradual dose tapering at least once every six months.
•Adverse effects – The most common serious side effect of indomethacin is the development of peptic ulcers. Other adverse effects include acute renal failure due to renal vasoconstriction, worsening of underlying hypertension, worsening of heart failure, and electrolyte and fluid abnormalities.
●Alternative medications – For patients with paroxysmal hemicrania who are unable to tolerate indomethacin and for patients with a clinical phenotype of paroxysmal hemicrania who have an incomplete or poor response to an adequate trial of indomethacin, we suggest treatment with verapamil (Grade 2C). (See 'Calcium channel antagonists' above.)
Reasonable alternatives include aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen and diclofenac. (See 'Other nonsteroidal anti-inflammatory drugs' above.)
●Invasive procedures – With the exception of isolated case reports, local anesthetic blockades of pericranial nerves and invasive surgical procedures have been generally ineffective for the treatment of paroxysmal hemicrania. (See 'Interventional therapies for refractory cases' above.)
●Prognosis – The available evidence suggests that paroxysmal hemicrania is a lifelong condition. Patients generally obtain sustained relief with indomethacin treatment. (See 'Natural history and prognosis' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
