Drug prophylaxis

The aim of drug prophylaxis is to achieve complete freedom from attacks in as short a time as possible. Clinically effective prophylactics can be divided into two groups. One group includes substances with a rapid and reliable onset of action, but which are not or only partially suitable for long-term therapy. These include corticosteroids, oral triptans and ergotamine tartrate. If the active cluster periods in a patient with an episodic cluster headache were only relatively short in the past, ie they lasted a maximum of 4 weeks, prophylaxis with one of these substances alone would be justified.

Fast-acting substances for temporary use (if necessary in combination with a substance for long-term use)

Preventative treatment is the focus of cluster headache therapy. There are a variety of different strategies available. Careful preliminary examinations are required. Cluster headaches should under no circumstances be treated independently.

I. Choice

  • Prednisolone (starting dose 100 mg orally, reduction by 20 mg in steps of 3 days, alternatively initially 500-1000 mg iv for 3 days)

2nd choice

  • Ergotamine tartrate (2 mg in the evening for night attacks, otherwise 2 x 2 mg)
  • Naratriptan (2.5 mg in the evening for night attacks, otherwise 2 x 2.5 mg)

Preventive treatment over a longer period of time

However, if you have chronic cluster headaches or cluster periods that usually last more than 4 weeks, additional substances that are suitable for long-term or long-term therapy should be used. This group includes verapamil, lithium, valproic acid and, previously, methysergide. The typical delayed onset of action of approximately 2 weeks for all of these substances during the dosage increase phase is easily covered by the simultaneous administration of a short-term prophylactic. According to open case series, gabapentin and topiramate may also be effective. However, extensive practical experience now shows that these substances are generally not effective.

Preventative treatment is the focus of cluster headache therapy. There are a variety of different strategies available. Careful preliminary examinations are required.

Planning drug prophylaxis

– Due to the high frequency of attacks during an active cluster period, the rule is that prophylactic therapy is generally indicated.

– The aim is to quickly suppress the next cluster attacks and maintain the freedom from attacks.

– In cluster headaches, suppression of the coming attacks should be achieved within 24 hours if possible. This differs from the preventative treatment of migraines, which usually requires a period of four to eight weeks to evaluate the effectiveness.

The choice of prophylactic depends on whether it is episodic or

– chronic cluster headache

acts. Newly diagnosed cluster headache in the first year of the course is treated like episodic cluster headache.

Various substances are used to prevent cluster headaches. For many of these substances, and even more so for the dosages, the effectiveness is proven more by empirical traditions than by scientific studies. In addition to effectiveness, the selection of substances focuses on tolerability, duration of applicability, ease of use and ability to combine with acute medication. The established substances and those that have been added in recent years are listed with their advantages and disadvantages.

The substances can be divided into 1st, 2nd and 3rd choice drugs. If the attacks stop under the prophylactic therapy measure, the therapy should be continued for at least 6 weeks after the last attack. However, discontinuation depends individually on the course of the disease. If the cluster headache has become active again during previous attempts to stop taking the medication, continuing prevention over a longer period of time should be considered.

Table 1. Medications in the prevention of episodic or chronic cluster headaches

Short-term prevention
of episodic cluster headache
Long-term prevention
of chronic cluster headache
1st Choice Verapamil
Ergotamine (fixed schedule)
Triptans (fixed schedule)
2nd choice Methysergide Valproate
Methysergide Valproate

Medication for prophylaxis
Ergotamine tartrate

Ergotamine tartrate can still be considered a first-line prophylactic treatment for episodic cluster headaches. The effectiveness was first described by Ekbom in 1947. Success rates of over 70% can therefore be expected in terms of suspending the active cluster period. If the contraindications of this vasoactive substance are observed, the side effects are usually remarkably low.

– Ergotamine tartrate is dosed orally or as a suppository in an amount of 3-4 mg per day, divided into 2 doses.

– Some patients may initially react with nausea or vomiting. If this is the case, metoclopramide 3 × 20 drops can also be administered for the first three days

– If the cluster attacks only occur at night, administering a suppository with 2 mg ergotamine at night may be sufficient.

– In the case of nocturnal attacks, the intramuscular injection of 0.25 to 0.5 mg ergotamine while going to bed can prevent the onset of the nocturnal cluster attack under stationary conditions.

– When traveling by plane, taking ergotamine 2 mg can prevent cluster attacks from occurring during the flight.

– A combination with DHE, methysergide or triptan is contraindicated.

The treatment period should be set at a maximum of four weeks. A rebound effect is not to be expected. If an active cluster period occurs again after discontinuing ergotamine administration, treatment can be continued.

Since therapy for episodic cluster headaches is limited in time, there is no need to fear long-term effects of taking ergotamine, particularly ergotism. However, it is necessary that the duration and dosage of intake are strictly limited and the course is carefully monitored.

If ergotamine tartrate is used to prevent cluster headaches, sumatriptan must not be used at the same time to treat attacks.


A possible alternative to ergot alkaloids is the use of Naratriptan 2 × 2.5 mg per day or other triptans. This option should also be considered as an add-on therapy if high-dose administration of verapamil retard does not sufficiently stop the cluster period. Naratriptan can be used preferentially because of its tolerability and long half-life. Alternatively, another triptan can also be used. The effectiveness must be tested individually. There are no controlled studies on this form of treatment.

With regard to the lead substance regulation and fixed amount regulation within the framework of statutory health insurance, sumatriptan 50 - 100 mg can also be used. Due to the shorter half-life, administration may need to be given every 6-8 hours, e.g. sumatriptan 3 × 50 mg/day. The advantage of using sumatriptan for prevention is that sumatriptan sc can also be used to stop attacks.

If possible, the duration of taking 5-HT agonists according to a fixed schedule should be limited to one week. Since these develop their preventative effectiveness within just a few hours, they are particularly suitable for new adjustments with the aim of rapid effectiveness. The attacks usually stop within 24 hours when they stop.

With the initial administration of 5-HT agonists, the period until long-term prophylactics such as verapamil or lithium begin to take effect can be bridged


Dihydroergotamine IV according to a fixed schedule over three days under inpatient conditions can be effective for both episodic and chronic cluster headaches. Different schemes are used. An initial test dose of 0.33 mg DHE plus 5 mg metoclopramide IV can be given. A follow-up dose of 0.5 mg DHE plus 5 mg metoclopramide IV is given every six hours for 48 to 72 hours. This allows the cluster period to be interrupted and a long-term prophylactic to be used in parallel.


Verapamil belongs to the group of calcium antagonists and is particularly suitable for long-term therapy for chronic cluster headaches due to its good tolerability. The effectiveness of cluster headache was first described by Meyer and Hardenberg (1983). However, verapamil often does not completely stop the active cluster headache phase. In studies, an improvement of more than 75% in cluster headache parameters was observed in 69% of patients. Verapamil and lithium show similar effectiveness. However, verapamil is more tolerable and the onset of action occurs more quickly.

– To maintain constant serum levels, only sustained-release preparations with an action time of 12 hours should be used.

– These allow sufficient serum concentrations to be maintained, especially at night.

– The dosage starts with 2 × 120 mg per day (e.g. Isoptin KHK 2 × 1), a medium dose is 2 × 240 mg (e.g. Isoptin RR 2 × 1).

Depending on the success of the therapy, dosages can be increased up to 1,200 mg (!) per day under inpatient conditions in specialized centers. Due to its good tolerability and ability to be combined with acute therapy such as oxygen or sumatriptan, verapamil is considered the substance of first choice.

– Since verapamil is usually only effective after a week, a high-dose corticoid shock therapy (e.g. methylprednisolone 1000 mg iv) accompanied by gastric protection (e.g. pantoprazole 40 mg) can initially be carried out for three days in order to achieve a rapid cessation of the attacks.

– Additionally or alternatively, ergotamine tartrate (e.g. ergotamine 2 × 1–2 mg) or a triptan (e.g. Naratriptan 2 × 2.5 mg) can be administered according to a fixed time schedule for one week to bridge the waiting period until verapamil takes effect.

– The adjustment should be carried out by experienced centers, if necessary under inpatient conditions, especially in the case of initial adjustment to oxygen therapy, initial diagnosis of an atypical case, failure of two prophylactic substances and restrictions on use.

Procedure in high-dose therapy with verapamil retard for cluster headaches

The maximum approved daily dose of verapamil for the indications hypertension and coronary heart disease is 480 mg. In neurology, this dose must be exceeded in individual cases in the preventative treatment of cluster headaches. Dosages of 240 mg to 960 mg/day and in individual cases even more may be necessary. Unreleased verapamil leads to fluctuations and gaps in the plasma level; effectiveness is reduced by unretarded verapamil. In addition, the verapamil level drops at night when administered without retardation. The risk of attacks is particularly high in the first few hours of the day. Therefore, only sustained-release verapamil should be used as standard.

– As with cardiological indications, patients with cluster headache are started with 240 mg/day (verapamil retard 2 × 120 mg at 12-hour intervals). In the case of very severe and frequent attacks, Verapamil retard 2 × 240 mg can be started immediately.

– In the first week, ergotamine tartrate (e.g. ergotamine 2 × 1–2 mg) or a triptan (e.g. Naratriptan 2 × 2.5 mg) according to a fixed schedule or a corticosteroid regimen can be given as concomitant medication until it becomes effective.

– If attacks occur again after the concomitant medication has been discontinued, Verapamil retard 2 × 240 mg can be steadily increased up to 960 mg every 12 hours and, if necessary, every 3 to 7 days.

– Attention must be paid to side effects such as conduction disorders, constipation, edema and flushing.

– All patients receiving verapamil must have a baseline ECG obtained and assessed for PQ time.

– This is standard for patients with heart disease and hypertension. If patients with cluster headache do not provide a current ECG, it must be obtained before initiating therapy with verapamil.

– An AV block of 1° (PQ > 0.20 s) is not a contraindication, but it is a limitation of use. Verapamil should not be prescribed for PQ times of around 0.25, and certainly from 0.30 s.

– Any higher AV block from II° is a contraindication, as is suspicion of heart failure.

– If there is a strict indication for the use of verapamil for cluster headaches with AV block I°, a control ECG must be written for the first time after 1-2 weeks, and also 1-2 weeks after each dose increase.

– If AV block increases, verapamil must be discontinued. If the AV block remains unchanged, checks should be carried out every 6 months. An interdisciplinary collaboration with a cardiologist to monitor progress should take place. Beta blockers must not be given at the same time.

– Deaths with verapamil in the prevention of cluster headaches have not yet been reported. There are also no known embryotoxic effects.

The use of verapamil in the prevention of cluster headache may be limited by cardiac side effects. A French working group examined the cardiac safety of high-dose verapamil treatments for cluster headache. The dosages were over 720 mg per day. Among 200 patients, 29 (14.8%) used dosages of 877 ± 227 mg per day. ECG changes were found in 38% (11/29). Seven patients (24%) had bradycardia as a mild adverse event and 4 patients (14%) had arrhythmias that were classified as serious adverse events. Patients who had ECG changes required higher doses (1003 ± 295 mg per day vs. 800 ± 143 mg per day). Mild or severe adverse events were independent of dosage level. Approximately three quarters of the patients showed a long-delayed onset of cardiac side effects with the symptoms described appearing after more than 2 years. The results demonstrate the need for patients receiving high-dose verapamil therapies to undergo regular and careful cardiac monitoring and also require detailed follow-up and success monitoring over the long term.


The clinical effect has been demonstrated in a number of open, uncontrolled studies. The therapy was introduced by Ekbom in 1974. Rationally, the periodic cyclical course was similar to cyclical illnesses in psychiatry. Improvement rates can be expected in up to 78% of treated patients. It is believed that better efficacy can be achieved for chronic cluster headache than for episodic cluster headache. It is of interest that after lithium treatment, a chronic form can be returned to an episodic form with free intervals. The effect of lithium in the treatment of cluster headaches is not clear. Comparative studies between lithium and verapamil show that both substances have largely similar effectiveness rates.

However, verapamil is preferable to lithium in terms of side effects. In addition, there is a faster onset of action after administration of verapamil. Lithium can also achieve dramatic improvements within the first week of therapy. In long-term therapy, a chronic course can remit into an episodic course. Resistance to therapy in long-term treatment may occur. Lithium is considered a second-line therapeutic agent. A combination with verapamil is possible.

The use of lithium is particularly known for the prophylaxis of manic-depressive illnesses. Due to the narrow therapeutic window of lithium, when deciding on lithium therapy, initiation should be carried out by a neurologist experienced in this form of therapy. Lithium is the only drug approved for the prophylaxis of cluster headaches.

– Normally a dose of 2 × 400 mg lithium is required, which corresponds to an amount of 2 × 10.8 mmol lithium.

- Therapy is initiated from the first to the third day with one 400 mg tablet daily in the morning. From the 4th day you increase to two tablets of 400 mg daily.

– Serum level checks should be carried out during therapy. The serum level is determined in the morning on an empty stomach, before the morning dose has been taken.

– A 12-hour interval from the last dose should be observed. The therapeutic range is a serum level between 0.7 mmol/l and 1 mmol/l.

– The therapeutic window is narrow. Side effects include weakness, nausea, thirst, tremor, speech problems and vision problems. Overdoses manifest as nausea, vomiting, loss of appetite, diarrhea, confusion, ataxia, extrapyramidal motor disorders and epileptic seizures. Hypothyroidism, polyuria (diabetes insipidus) and leukocytosis may occur in long-term therapy.

– At the beginning and during the course of therapy, kidney and thyroid function must be examined.

– The additional administration of NSAIDs, diuretics and carbamazepine is contraindicated.


Methysergide is one of the effective prophylactic medications in the treatment of episodic cluster headaches. The effectiveness was first described by Sicuteri in 1959. The active ingredient is an ergot alkaloid with an antagonistic effect on the 5-HT2A, 5-HT2B and 5HT2C receptors and an agonistic effect on the 5-HT1B and 5-HT1D receptors. While methysergide is often used very cautiously in migraine because long-term use can be associated with the risk of possible retroperitoneal fibrosis, this problem is less important in episodic cluster headaches because of the time-limited use. Success can be expected in approximately 73% of patients at doses of 3-12 mg/day. Just like prophylactic therapy with ergotamine, the use of methysergide can also lose effectiveness with repeated active cluster periods. However, the study results are inconsistent. Retrospective analyzes showed an effect in only about 25%.

– The dosage can be increased slowly until sufficient clinical success is achieved. You start with 3 × 1 mg methysergide per day and increase to a maximum of 3 × 4 mg per day if tolerated.

– Common side effects include nausea, vomiting, dizziness, crampi, abdominal pain and edema. Vasoconstrictor effects must be monitored over time.

– Fibrotic reactions (retroperitoneal, pulmonary, pleural and cardiac) in long-term therapy are rare but can occur. The active ingredient is therefore suitable for episodic clusters with treatment durations of less than three months. For long-term administration, there should be a four-week break every six months. When the break begins, the dosage can be slowly reduced to avoid a sudden new onset of attacks.

– Regular follow-up checks to detect visceral fibrosis and vascular complications with cardiac auscultation, echocardiography, chest X-ray, abdominal MRI, as well as laboratory and kidney checks should be carried out once a year in long-term therapy.

– Contraindications include pregnancy, vascular disease, arterial hypertension, thrombophlebitis, cellulitis, gastric ulcer, liver and kidney disease.

Side effects that can occur in individual cases include nausea, muscle pain, abnormal sensations, pressure in the head and foot edema. With uncontrolled long-term use, fibrotic complications can occur in various regions of the body.

For this reason, prophylactic therapy with methysergide should be limited to a maximum of three months.

Only after a minimum break of one month can renewed therapy with methysergide be initiated, if necessary. The timing of methysergide therapy during the active cluster phase can be similar to the timing with ergotamine. The effect of methysergide on cluster headaches is not clear. Due to the range of side effects, methysergide is a second choice drug.


The use of corticosteroids to prevent cluster headache attacks is often done and with reliable success in around 70-90% of patients, although controlled studies on this form of therapy are lacking. The effectiveness of cluster headache was first described by Horton in 1952 and first examined by Jammes in a double-blind study in 1975.

With regard to the pathophysiological model with an inflammatory change in the area of ​​the cavernous sinus, there is a justified rationale for the use of corticosteroids. Corticosteroids are very effective and can end an active period within a few hours at appropriately high doses.

For severe and frequent attacks, high-dose therapy with prednisolone over a few days can be used initially (e.g. predniolone 1000 mg IV over three days). This can then be followed by an oral cortisone regimen (see below).

With regard to the dosage and timing of the administration of corticosteroids in the prophylaxis of cluster headache attacks, one can usually only rely on empirical values ​​and not on controlled studies. There are no reliable comparative studies with other prophylactic medications.

A common procedure in various centers is to initially administer 100 mg of prednisone or prednisolone in the morning. Further dosage is carried out according to the following scheme:

– 1st – 2nd day: 100 mg

– 3rd – 4th day: 80 mg

– 4th – 6th day: 60 mg

– 7th – 8th day: 40 mg

– 9th – 10th day: 20 mg

– 11th – 12th day: 10 mg

– then put it down

Pantoprazole 40 mg is also administered during this period to protect the stomach. A significant reduction or even a complete remission of the attacks can often be observed initially after the first to fifth day.

– Contraindications include infections, including tuberculosis and psychoses.

– Serious side effects in long-term use must be taken into account, especially osteonecrosis of the femoral head. The dose should therefore generally be tapered off.

The threshold at which cluster headache attacks can occur again is often between 40 and 20 mg prednisone in chronic cluster headaches. In such cases, a maintenance dose, preferably not exceeding 7.5 mg of prednisone per day, can be administered. This maintenance dose should be given in the morning to implement circadian therapy. An alternating maintenance dose may also be considered. The maintenance dose required for two days is administered every 48 hours in the morning. If attacks occur again at low doses, effectiveness can be achieved by additional administration of ergotamine, triptans, verapamil or lithium.

If long-term corticoid therapy that has been carried out for months is discontinued, strict circadian oral therapy should be initiated with a reduction of the last dose taken by 1 mg per month.

In principle, prednisone should be administered after meals, primarily after breakfast. In general, if a satisfactory treatment result is achieved, therapy should be continued with the lowest possible maintenance dose. Due to long-term side effects, corticosteroids must be used for chronic cluster headaches with restriction and with careful monitoring of the course and success. Corticosteroids are second-line substances.

Topical corticosteroids

Another option is to use topical corticosteroids in the form of nasal sprays. There are no controlled studies available yet. However, according to our own experience, when using beclometasone dipropionate (Beconase) 4 × 1 spray per nostril, a cessation of the attacks can be observed in approx. 60% of patients.


The effectiveness of pizotifen in cluster headaches has been proven by several open studies. This results in effectiveness rates of approximately 50%. Pizotifen can be used as a third-line drug if there are contraindications to more effective substances or if these substances are ineffective. The dosage is 3 × 0.5 mg to 3 × 1 mg per day. Here, too, the dose is increased slowly over about a week and the dose is kept constant while it is effective. Side effects may include fatigue, dizziness and weight gain due to increased appetite.

Valproic acid

Older studies provide evidence that valproic acid can also be used to prevent cluster headaches. Conflicting results have been published. However, there is no evidence of any particular advantage or superiority of this form of therapy compared to the substance groups mentioned above. In a placebo-controlled study, no significant effectiveness of valproic acid in the prophylaxis of cluster headaches could be determined; there was a response rate of 62% in the placebo group and 50% in the verum group (El Amrani et al. 2002). In our experience, valproic acid has no reliable effect and can only be used in exceptional situations.

– A gradual dosage with a gradual build-up to the optimally effective dose is recommended.

– The initial dose is usually 5-10 mg/kg body weight, which should be increased by around 5 mg/kg every four to seven days.

– The average daily dose for adults is generally 20 mg/kg body weight.

Effectiveness can sometimes only be observed after two to four weeks. For this reason, the dose should be adjusted slowly and the success of the therapy should be awaited in individual cases. In adults, daily doses of 1,000 to 2,000 mg are usually given in three separate doses. Valproic acid can be used as a third-line therapeutic agent.


Topiramate has been used in several open-label studies to prevent episodic or chronic cluster headaches. Dosages between 15 mg and 250 mg per day have been used. A moderate to pronounced improvement was achieved in approximately 49% of the treated patients. Improvement should occur within 1 to 4 weeks. 57% of patients reported mild side effects, 33% reported moderate side effects and 11% reported severe or intolerable side effects, mostly at doses above 100 mg/day.

Side effects include, in particular, cognitive deficits, mood swings, fatigue, dizziness, ataxia, depressive phases, paresthesias and kidney stones.


Gabapentin has been reported to be effective at a daily dose of 900 mg in open studies. 12 out of 12 patients experienced rapid and effective improvement. In other series, these effects could only be partially replicated.

In our own experience, valproinate, topiramate and gabapentin are not reliably effective. Although there are some positive case reports of these substances in the literature, the picture may be distorted due to unpublished negative reports. You should not make an unnecessary and frustrating investment of time with these therapy options.


Leuprorelin belongs to the group of gonadotropin-releasing hormone analogues. Physiologically, it causes a reduction in testosterone levels in the blood. Clinical applications of leuprorelin include the treatment of uterine fibroids, breast cancer, endometriosis, metastatic prostate cancer, prepuberty in boys and girls, and the treatment of sex offenders due to testosterone suppression.

As early as 1993, the Italian working group of Nicolodi and Sicuteri reported the results of a randomized, single-blind, placebo-controlled pilot study on 60 male patients with chronic cluster headache. Pretreatment with lithium did not lead to sufficient improvement. The dose was a single 3.75 mg leuprorelin depot intramuscularly. As a placebo control, 30 patients received intramuscular injections with NaCl solution. In the authors' opinion, a double-blind study was not possible due to the reduction in libido expected in the test subjects. Subjects treated with placebo reported no change in pain intensity or number of attacks. In contrast, patients treated with 3.75 mg Leuprorelin Depot intramuscularly showed a maximum effect in the period from 20 to 30 days after the injection, with a reduction in the number of attacks from the previous 2.1 attacks to 0.37 attacks per day, and a reduction in the intensity of pain on average by 63% and a reduction in attack duration from 94 minutes per day to 0.4 minutes per day. 12 of 30 patients who received the verum were completely pain-free after 17 days. Leuprorelin had no effect in only 4 of 30 patients. The onset of action of leuprorelin occurred after an average of 10.1 days. The effect lasted an average of 3.25 months. Patients who initially experienced an effect received a second injection with a comparable effect.

Side effects of the subjects treated with leuprorelin were expressed in a temporary reduction in libido in 66%. There was no consistent association between reduced libido and clinical efficacy in cluster headache. No other undesirable side effects were reported in the study.

The authors presented the results of another study in 2010. They examined 67 patients who had previously been treated with lithium, verapamil, corticosteroids, topiramate or gabapentin without effect. Two male and female patients were also unsuccessfully treated with deep brain stimulation in addition to the preventative medications mentioned. The patients were severely affected. During the baseline phase, the patients had an average of three to six cluster attacks per day; the subjects who previously received deep brain stimulation had seven to eleven attacks per day. The attack duration was 35 to 67 minutes; the patients who previously received deep brain stimulation had attack durations of 47 to 110 minutes. A monthly injection of 11.75 mg leuprorelin was administered as treatment. The patients who previously received deep brain stimulation received this dosage 5 times per month. The patients did not receive any other preventive medication. The observation period was two to three months. Two to three leuprorelin depot injections at a dosage of 11.75 mg were therefore administered at monthly intervals. There was an average 50% improvement within the first 14 days. In 49 of 67 patients there was complete freedom from pain. Four years after treatment, there were no further active periods. The remaining 18 patients also showed complete freedom from pain for a period of 10 to 15 months. The recurrence of an active period could be effectively stopped after this period with further treatment with leuprorelin. Leuprorelin also achieved significant improvement in severely affected patients who previously received deep brain stimulation. Six months after treatment, these patients had attack frequencies of zero to four attacks per day; during the baseline phase, these patients had attack frequencies of seven to eleven attacks per day. Due to the severity of the active periods, 5 leuprorelin injections of 11.75 mg per month were administered in these patients. Preventive treatment made it possible to end overuse of acute medications, particularly sumatriptan sc and tramadol. No serious undesirable side effects were reported and no study discontinuations occurred. A reduction in libido was prevented in the male test subjects by the accompanying use of 50 mg testosterone per day.

Adverse side effects of leuprorelin include hot flashes, spontaneous skin and mucosal bleeding, fatigue, and irritation at the injection site. Other less common side effects include nasopharyngitis, nausea, itching, night sweats, joint pain, irregular urination, breast tenderness, testicular regression, rigidity, and prolonged bleeding time.

The results of these studies are unusually promising. This therapeutic option should therefore be further investigated and replicated.


Capsaicin is a herbal analgesic derived from chili pepper. Capsaicin releases substance P, a neuropeptide that plays a particular role in neurogenic inflammation and sensitization of nociceptive fibers. The release depletes substance P. The first phase of overreactivity, which manifests itself in the form of burning, is followed by a phase of insensitivity. A decrease in the number of microvesicles in the sensory nerve endings can then be seen. The use of capsaicin in cluster headache patients resulted in a significant improvement in the course of the disease in 67% of patients in an open study. The capsaicin solution is given as a suspension into both nostrils. This initially creates a clear burning sensation in the nasal mucosa and rhinorrhea. The application is carried out over a period of ten days. There are no comparative studies on other prophylactic therapy strategies. In a placebo-controlled study with intranasal Civamide (zucapsaicin), efficacy was 55.5% in the verum group and 25.9% in the placebo group.


Serum levels of melatonin are reduced in patients with cluster headaches. Melatonin is involved in the regulation of circadian rhythms. Leone et al. (1996) conducted a double-blind pilot study on 20 patients and compared melatonin 10 mg with placebo for two weeks. Patients in the verum group showed a reduction in the strength and number of attacks.

Another study suggests that the addition of melatonin 9 mg/die may improve the effectiveness of verapamil, which was not sufficiently effective as monotherapy.

Ineffective or obsolete therapy procedures

Common analgesics, be they opioid or non-opioid analgesics, are ineffective in the treatment of acute cluster attacks. Since cluster attacks can resolve spontaneously after thirty to sixty minutes, patients mistakenly assume that this resolution is achieved by the administration of an analgesic. The result is that ineffective medications that are prone to side effects are taken unnecessarily for years or decades. Carbamazepine, phenytoin, beta blockers, antidepressants, histamine antagonists, biofeedback, acupuncture, neural therapy, local anesthetics, physical therapy and psychotherapy are also without effectiveness.