Drug prophylaxis
The goal of drug prophylaxis is complete freedom from attacks in the shortest possible time. Clinically effective prophylactic agents can be divided into two groups. One group includes substances with a rapid and reliable onset of action, but which are not suitable, or only suitable to a limited extent, for long-term therapy. This group includes corticosteroids, oral triptans, and ergotamine tartrate. If a patient with episodic cluster headaches has had relatively short active cluster periods in the past, i.e., lasting a maximum of four weeks, prophylaxis with one of these substances alone would be justified.
Fast-acting substances for short-term use (possibly in combination with a substance for long-term use)
Preventive treatment is the main focus of cluster headache therapy. A variety of different strategies are available. Thorough preliminary examinations are necessary. Cluster headaches should never be treated independently.
First choice
- Prednisolone (starting dose 100 mg orally, reduction by 20 mg in 3-day increments, alternatively 500-1000 mg IV for 3 days initially)
Second choice
- Ergotamine tartrate (2 mg in the evening for nighttime attacks, otherwise 2 x 2 mg)
- Naratriptan (2.5 mg in the evening for nighttime attacks, otherwise 2 x 2.5 mg)
Preventive treatment over a longer period
However, if chronic cluster headaches or cluster periods typically last more than four weeks are present, additional medications suitable for long-term or even continuous therapy should be used. This group includes verapamil, lithium, valproic acid, and, previously, methysergide. The delayed onset of action of approximately two weeks during the dose-up phase, typical for all these substances, is easily managed by the concurrent administration of a short-acting prophylactic. According to open case series, gabapentin and topiramate may also be effective. However, extensive practical experience now indicates that these substances are less likely to be effective.
Preventive treatment is a key focus of cluster headache therapy. A variety of strategies are available. Thorough preliminary examinations are necessary.
Planning of drug prophylaxis
– Due to the high frequency of attacks during an active cluster period, the rule is that prophylactic therapy is generally indicated.
The goal is to quickly suppress the next cluster attacks and maintain the continued freedom from attacks.
– In cluster headache treatment, the goal is to suppress future attacks within 24 hours, if possible. This differs from preventive migraine treatment, where a period of four to eight weeks is usually observed to assess effectiveness.
The choice of prophylactic depends on whether it is episodic or
– chronic cluster headache
Newly diagnosed cluster headaches in the first year of treatment are treated like episodic cluster headaches.
Various substances are used for the prophylaxis of cluster headaches. For many of these substances, and even more so for their dosages, efficacy is based more on empirical evidence than on scientific studies. Besides efficacy, the selection of substances focuses on tolerability, duration of use, ease of administration, and compatibility with acute medication. The established substances and those introduced in recent years are listed, along with their advantages and disadvantages.
The substances can be classified as first-, second-, and third-line medications. If attacks cease under prophylactic therapy, the treatment should be continued for at least six weeks after the last attack. However, discontinuation depends on the individual course of the disease. If cluster headaches have recurred during previous attempts to discontinue medication, continuing prophylaxis for a longer period should be considered.
Table 1. Medications used in the prevention of episodic and chronic cluster headaches
| Short-term prevention of episodic cluster headache |
Long-term prevention of chronic cluster headache |
|
| 1st choice | Verapamil, Ergotamine (fixed time regimen), Triptans (fixed time regimen), Corticosteroids , Lithium |
Verapamil Lithium |
| 2nd choice | Methysergide Valproate Topiramate Melatonin |
Methysergide Valproate Pizotifen Capsaicin Topiramate Gabapentin Melatonin |
Medication for prophylaxis
: Ergotamine tartrate
Ergotamine tartrate remains a first-line prophylactic treatment for episodic cluster headaches. Its efficacy was first described by Ekbom in 1947. Success rates of over 70%, meaning the cessation of active cluster periods, can be expected. When the contraindications of this vasoactive substance are observed, side effects are generally remarkably mild.
– Ergotamine tartrate is administered orally or as a suppository in a quantity of 3–4 mg per day, divided into 2 doses.
– Some patients may initially experience nausea or vomiting. If this occurs, 20 drops of metoclopramide three times a day can be administered in addition during the first three days
– If the cluster attacks occur exclusively at night, administering a suppository containing 2 mg of ergotamine at night may be sufficient.
– In the case of nocturnal attacks, under inpatient conditions, an intramuscular injection of 0.25 to 0.5 mg of ergotamine at bedtime can prevent the outbreak of the nocturnal cluster attack.
– When traveling by air, taking 2 mg of ergotamine can prevent the occurrence of cluster attacks during the flight.
– Combination with DHE, methysergide or triptan is contraindicated.
The treatment period should be limited to a maximum of four weeks. A rebound effect is not expected. If another active cluster period occurs after discontinuation of ergotamine administration, treatment can be continued.
Since treatment for episodic cluster headache is time-limited, long-term effects of ergotamine use, particularly ergotism, are not a concern. However, it is essential that the duration and dosage of treatment are strictly limited and the course of the condition is carefully monitored.
If ergotamine tartrate is used for the prophylaxis of cluster headaches, sumatriptan must not be used simultaneously for the treatment of attacks.
Triptane
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 add-on therapy if high doses of extended-release verapamil do not sufficiently halt the cluster period. Naratriptan may be preferred due to its tolerability and long half-life. Alternatively, another triptan can be used. Efficacy must be tested individually. No controlled studies are available for this treatment approach.
With regard to the prescribed drug regimen and fixed reimbursement amount within the framework of statutory health insurance, sumatriptan 50–100 mg can also be used. Due to its shorter half-life, administration may need to be given at intervals of 6–8 hours, e.g., sumatriptan 3 × 50 mg/day. An advantage of using sumatriptan for prevention is that subcutaneous administration can also be used to treat attacks.
The duration of treatment with 5-HT agonists, following a fixed schedule, should ideally be limited to one week. Since these medications exert their preventative effect almost immediately, within a few hours, they are particularly suitable for initiating treatment with the goal of rapid effectiveness. Attacks usually cease within 24 hours of starting the medication.
The initial administration of 5-HT agonists can, in particular, bridge the time until the onset of effectiveness of long-term prophylactic drugs such as verapamil or lithium
Dihydroergotamine
Intravenous dihydroergotamine (DHE) administered according to a fixed schedule over three days under inpatient conditions can be effective for both episodic and chronic cluster headaches. Different regimens are used. An initial test dose of 0.33 mg DHE plus 5 mg metoclopramide IV can be given. A subsequent dose of 0.5 mg DHE plus 5 mg metoclopramide IV is administered every six hours for 48 to 72 hours. This can interrupt the cluster period and allow for the concurrent initiation of long-term prophylactic medication.
Verapamil
Verapamil belongs to the group of calcium channel blockers and, due to its good tolerability, is particularly suitable for long-term therapy in chronic cluster headaches. Its efficacy in cluster headaches was first described by Meyer and Hardenberg (1983). However, verapamil often does not completely cessate the active phase of cluster headaches. Studies have shown an improvement of more than 75% in cluster headache parameters in 69% of patients. Verapamil and lithium show similar efficacy. However, verapamil is better tolerated and has a faster onset of action.
– To maintain constant serum levels, only delayed-release preparations with a duration of action of 12 hours should be used.
– These also allow for the maintenance of sufficient serum concentration, 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, the dosage can be increased to as high as 1,200 mg (!) per day under inpatient conditions in specialized centers. Due to its good tolerability and compatibility with acute therapies such as oxygen or sumatriptan, verapamil is considered a first-line treatment.
Since verapamil is usually only effective after one week, an initial three-day course of high-dose corticosteroid pulse therapy (e.g., methylprednisolone 1000 mg IV) accompanied by gastric protection (e.g., pantoprazole 40 mg) can be administered to achieve a rapid cessation of the attacks.
– Additionally or alternatively, to bridge the waiting time until the effect of verapamil begins, 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 schedule for one week.
– The adjustment should be made by experienced centers, possibly 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 application restrictions.
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, treatment for patients with cluster headaches begins with 240 mg/day (verapamil retard 2 × 120 mg at 12-hour intervals). In cases of very severe and frequent attacks, treatment can also be started directly with verapamil retard 2 × 240 mg.
– During the first week, until the onset of effectiveness, 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 schedule, or a corticosteroid regimen can be given as concomitant medication.
– If attacks recur after discontinuation of the accompanying medication, Verapamil retard 2 × 240 mg can be administered at 12-hour intervals and, if necessary, gradually increased every 3 to 7 days up to 960 mg.
– Attention must be paid to side effects such as conduction disorders, constipation, edema and flushing.
– All patients receiving verapamil must have a baseline ECG performed and evaluated with regard to the PQ interval.
This is standard practice for patients with heart disease and hypertension. If patients with cluster headaches do not have a recent ECG, one must be performed before initiating verapamil therapy.
– A first-degree AV block (PQ > 0.20 s) is not a contraindication, but it does limit its use. Verapamil should not be prescribed with PQ times of approximately 0.25 s or higher, and certainly not with PQ times of 0.30 s or higher.
Any higher AV block from grade II onwards is a contraindication, as is any suspicion of heart failure.
– If there is a strict indication for the use of verapamil in cluster headache with AV block I°, a control ECG must be recorded for the first time after 1–2 weeks, and likewise 1–2 weeks after each dose increase.
– If the AV block worsens, verapamil must be discontinued. If the AV block remains unchanged, follow-up examinations should be performed every 6 months. Interdisciplinary collaboration with a cardiologist for monitoring the course of treatment is recommended. Beta-blockers must not be administered concurrently.
– No deaths have been reported with verapamil for the prevention of cluster headaches. No embryotoxic effects are known either.
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.
lithium
Clinical efficacy has been demonstrated in a number of open-label, uncontrolled studies. The therapy was introduced by Ekbom in 1974. The rationale was the periodic, cyclical course of the headache, similar to cyclical disorders in psychiatry. Improvement rates of up to 78% of treated patients can be expected. It is assumed that greater efficacy can be achieved in chronic cluster headache than in episodic cluster headache. Of particular interest is the fact that after lithium treatment, a chronic form can revert to an episodic form with symptom-free intervals. The mechanism of action of lithium in the treatment of cluster headache is not fully understood. Comparative studies between lithium and verapamil show that both substances exhibit largely similar efficacy rates.
Verapamil is preferable to lithium in terms of side effects. Furthermore, verapamil shows a faster onset of action. Lithium can also achieve dramatic improvements within the first week of therapy. In long-term therapy, a chronic course may remit to an episodic course. Treatment resistance can occur with long-term treatment. Lithium should be considered a second-line therapy. Combination therapy with verapamil is possible.
Lithium is particularly well-known for its use in the prophylaxis of bipolar disorder. Due to lithium's narrow therapeutic window, the initiation of treatment should be carried out by a neurologist experienced in this form of therapy. Lithium is the only medication 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 begins with one 400 mg tablet daily in the morning, starting on the first three days. From the fourth day onwards, the dosage is increased to two 400 mg tablets daily.
Serum levels should be monitored during therapy. The serum level should be determined in the morning on an empty stomach, before the morning dose is taken.
A 12-hour interval should be observed between the last dose and the next dose. 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 disorders, and visual disturbances. Overdoses manifest as nausea, vomiting, loss of appetite, diarrhea, confusion, ataxia, extrapyramidal motor disorders, and seizures. Hypothyroidism, polyuria (diabetes insipidus), and leukocytosis may occur with long-term therapy.
– Kidney and thyroid function must be examined at the beginning and during the course of therapy.
– The additional administration of NSAIDs, diuretics and carbamazepine is contraindicated.
Methysergide
Methysergide is among the effective prophylactic medications in the treatment of episodic cluster headache. Its efficacy was first described by Sicuteri in 1959. The active ingredient is an ergot alkaloid with antagonistic activity at the 5-HT2A, 5-HT2B, and 5-HT2C receptors, as well as agonistic activity at 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 potential retroperitoneal fibrosis, this issue is less significant in episodic cluster headache due to the limited duration of treatment. Success can be expected in approximately 73% of patients with dosages of 3–12 mg/day. As with prophylactic ergotamine therapy, the use of methysergide can also lose efficacy during repeated active cluster periods. However, study results are inconsistent. Retrospective analyses showed an effect in only about 25% of cases.
The dosage can be gradually increased until sufficient clinical success is achieved. Treatment begins with 3 × 1 mg of methysergide per day and is increased to a maximum of 3 × 4 mg per day if tolerated.
Common side effects include nausea, vomiting, dizziness, cramps, abdominal pain, and edema. Vasoconstrictive effects must be monitored.
Fibrotic reactions (retroperitoneal, pulmonary, pleural, and cardiac) are rare during long-term therapy but can occur. Therefore, this drug is suitable for episodic cluster headaches with treatment durations of less than three months. During long-term use, a four-week break should be taken every six months. At the start of the break, the dosage can be gradually reduced to avoid a sudden recurrence of attacks.
– Regular follow-up examinations to detect visceral fibrosis and vascular complications, including cardiac auscultation, echocardiography, chest X-ray, abdominal MRI, as well as laboratory and kidney checks, should be performed annually during long-term therapy.
Contraindications include pregnancy, vascular diseases, arterial hypertension, thrombophlebitis, cellulitis, gastric ulcers, liver and kidney diseases.
Side effects may include nausea, muscle pain, paresthesia, headache, and foot swelling in isolated cases. Uncontrolled long-term use can lead to fibrotic complications in various parts of the body.
For this reason, prophylactic therapy with methysergide should be limited to a maximum of three months.
Only after a minimum one-month break can treatment with methysergide be restarted, if necessary. The timing of methysergide therapy during the active cluster headache phase can be similar to that used with ergotamine. The mechanism of action of methysergide in cluster headaches is not fully understood. Due to its side effect profile, methysergide is a second-line treatment.
Corticosteroids
The use of corticosteroids for the prophylaxis of cluster headache attacks is common and reliably successful in approximately 70–90% of patients, although controlled studies on this form of therapy are lacking. Its efficacy in cluster headache was first described by Horton in 1952 and first investigated in a double-blind study by Jammes in 1975.
In light of the pathophysiological model involving inflammatory changes in the cavernous sinus, there is a sound rationale for the use of corticosteroids. Corticosteroids are very effective and, at a sufficiently high dose, can terminate an active period within a few hours.
In cases of severe and frequent attacks, initial treatment may involve high-dose prednisolone therapy for a few days (e.g., 1000 mg IV prednisolone for three days). This can then be followed by an oral corticosteroid regimen (see below).
Regarding the dosage and timing of corticosteroid administration for the prophylaxis of cluster headache attacks, one can generally only rely on anecdotal evidence, not on controlled studies. Reliable comparative studies with other prophylactic medications are not available.
A common approach in various centers involves an initial dose of 100 mg of prednisone or prednisolone in the morning. Subsequent dosing follows this schedule:
– Days 1 and 2: 100 mg
– Days 3 and 4: 80 mg
– Days 4–6: 60 mg
– Days 7 and 8: 40 mg
– Days 9 and 10: 20 mg
– Days 11-12: 10 mg
– then discontinue
Pantoprazole 40 mg is administered concurrently during this period to protect the stomach. Often, a significant reduction or even complete remission of attacks can be observed as early as the first five days.
Contraindications include infections, such as tuberculosis and psychoses.
– Serious side effects of long-term use must be considered, especially osteonecrosis of the femoral head. Therefore, a gradual dose reduction should generally be implemented.
The threshold at which cluster headache attacks can recur in chronic cluster headache is often between 40 and 20 mg of prednisone. In such cases, a maintenance dose, ideally 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. In this case, the maintenance dose required for two days is administered every 48 hours, each morning. Should attacks recur at a lower dose, efficacy can be achieved by additionally administering ergotamine, triptans, verapamil, or lithium.
When discontinuing long-term corticosteroid therapy that has been carried out for months, a strictly circadian oral therapy should be initiated, reducing the last dose taken by 1 mg per month.
Prednisone should generally be administered after meals, preferably after breakfast. If a satisfactory treatment outcome is achieved, therapy should generally be continued with the lowest possible maintenance dose. Due to long-term side effects, corticosteroids for chronic cluster headaches must be used with caution and under careful monitoring of treatment progress and success. Corticosteroids are second-line treatment options.
Topical corticosteroids
Another option is the use of topical corticosteroids in the form of nasal sprays. Controlled studies are not yet available for this. However, based on our own experience, using beclomethasone dipropionate (Beconase) four times a day (one spray per nostril) has been observed to bring about a cessation of attacks in approximately 60% of patients.
Pizotifen
The efficacy of pizotifen in treating cluster headaches has been demonstrated in several open-label studies, showing efficacy rates of approximately 50%. Pizotifen can be used as a third-line treatment when contraindications to more effective medications exist or when these medications are ineffective. The dosage is 3 × 0.5 mg to 3 × 1 mg per day. Here, too, the dose is increased slowly over approximately one week and maintained at a constant level once the medication is effective. Side effects may include fatigue, dizziness, and weight gain due to increased appetite.
Valproic acid
Older studies suggest that valproic acid can also be used for cluster headache prophylaxis. However, conflicting results have been published. There is no evidence of any particular advantage or superiority of this therapy compared to the aforementioned drug classes. In a placebo-controlled study, no significant efficacy of valproic acid in cluster headache prophylaxis was found; the placebo group showed a response rate of 62%, while the valproic acid group had a response rate of 50% (El Amrani et al. 2002). In our experience, valproic acid is also ineffective and should only be used in exceptional circumstances.
– A gradual increase in dosage with a step-by-step build-up to the optimal effective dose is recommended.
– The initial dose is usually 5–10 mg/kg body weight, which should be increased by about 5 mg/kg every four to seven days.
– The average daily dose for adults is generally 20 mg/kg body weight.
Effectiveness may not be observed for two to four weeks. Therefore, the dose should be adjusted slowly, and the therapeutic effect should be monitored in each individual case. Adults typically receive daily doses of 1,000 to 2,000 mg, divided into three doses. Valproic acid can be used as a third-line treatment.
Topiramate
Topiramate has been used in several open-label studies for the prevention of episodic or chronic cluster headaches. Dosages between 15 mg and 250 mg per day were used. Approximately 49% of treated patients experienced moderate to marked improvement. Improvement is expected to occur within 1 to 4 weeks. 57% of patients reported mild side effects, 33% moderate side effects, and 11% severe or intolerable side effects, mostly at dosages above 100 mg/day.
Side effects include, in particular, cognitive deficits, mood swings, fatigue, dizziness, ataxia, depressive phases, paresthesia, and kidney stones.
Gabapentin
Open-label studies have reported an effect of gabapentin at a daily dose of 900 mg. In these studies, 12 out of 12 patients experienced rapid and effective improvement. Other studies have only partially replicated these effects.
In our experience, valproic acid, topiramate, and gabapentin are not reliably effective. While some positive case reports for these substances can be found in the literature, the picture may be distorted by unpublished negative reports. One should not waste unnecessary and frustrating time on these treatment options.
Leuprorelin
Leuprorelin belongs to the group of gonadotropin-releasing hormone analogs. Physiologically, it reduces testosterone levels in the blood. Clinical applications of leuprorelin include the treatment of uterine fibroids, breast cancer, endometriosis, metastatic prostate cancer, precocious puberty in boys and girls, and the treatment of sex offenders due to testosterone suppression.
As early as 1993, the Italian research group of Nicolodi and Sicuteri reported the results of a randomized, single-blind, placebo-controlled pilot study involving 60 male patients with chronic cluster headache. Prior treatment with lithium had not resulted in sufficient improvement. The dose was a single intramuscular injection of 3.75 mg leuprorelin depot. For the placebo control, 30 patients received intramuscular injections of saline solution. Due to the anticipated reduction in libido among the subjects, the authors felt a double-blind study was not feasible. The subjects treated with placebo reported no change in pain intensity or the number of attacks. In contrast, patients treated with 3.75 mg leuprorelin depot intramuscularly showed maximum effect within 20 to 30 days after injection, with a reduction in the number of attacks from 2.1 to 0.37 per day, an average reduction in pain intensity of 63%, and a reduction in attack duration from 94 minutes per day to 0.4 minutes per day. Twelve of the 30 patients who received the active treatment were completely pain-free after 17 days. Leuprorelin showed no effect in only 4 of the 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 comparable results.
Side effects in the subjects treated with leuprorelin manifested as a temporary reduction in libido in 66%. No consistent correlation was found between reduced libido and clinical efficacy in cluster headache. No other adverse 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 without effect with lithium, verapamil, corticosteroids, topiramate, or gabapentin. Two female and two male patients were also unsuccessfully treated with deep brain stimulation in addition to the aforementioned preventive medications. The patients were severely affected. During the baseline phase, the patients experienced an average of three to six cluster attacks per day, while the subjects who had previously received deep brain stimulation showed seven to eleven attacks per day. The attack duration ranged from 35 to 67 minutes, while the patients who had previously received deep brain stimulation experienced attack durations of 47 to 110 minutes. Treatment consisted of a monthly injection of 11.75 mg leuprorelin. The patients who had previously received deep brain stimulation received this dose five times per month. The patients did not receive any other preventive medications. The observation period was two to three months. Therefore, two to three leuprorelin depot injections at a dose of 11.75 mg were administered at monthly intervals. Within the first 14 days, an average improvement of 50% was observed. Forty-nine of 67 patients experienced complete pain relief. Four years after treatment, no further active episodes were observed. The remaining 18 patients also experienced complete pain relief for a period of 10 to 15 months. Any recurrence of an active episode after this period could be effectively terminated with further leuprorelin treatment. Significant improvement was also achieved with leuprorelin in severely affected patients who had previously undergone deep brain stimulation. Six months after treatment, the attack frequency was zero to four attacks per day, whereas during the baseline phase, these patients had experienced attack frequencies of seven to eleven attacks per day. Due to the severity of the active episodes, these patients received five leuprorelin injections of 11.75 mg per month. Preventive treatment successfully eliminated the overuse of acute medications, particularly sumatriptan subcutaneously and tramadol. No serious adverse events were reported, and no study discontinuations occurred. A reduction in libido was prevented in the male participants by the concomitant administration of 50 mg of testosterone per day.
Undesirable side effects of leuprorelin include hot flashes, spontaneous bleeding of the skin and mucous membranes, fatigue, and injection site irritation. Other less common side effects include nasopharyngitis, nausea, itching, night sweats, joint pain, irregular urination, breast tenderness, testicular atrophy, rigidity, and prolonged bleeding time.
The results of these studies are unusually promising. This treatment option should therefore be further investigated and replicated.
Capsaicin
Capsaicin is a plant-based analgesic derived from chili peppers. Capsaicin releases substance P, a neuropeptide that plays a key role in neurogenic inflammation and the sensitization of nociceptive fibers. This release leads to the depletion of substance P. The initial phase of hyperreactivity, manifested as a burning sensation, is followed by a phase of insensitivity. A decrease in microvesicles in the sensory nerve endings can then be observed. In an open-label study, the use of capsaicin in cluster headache patients resulted in a significant improvement in the course of the disease in 67% of patients. The capsaicin solution is administered as a suspension into both nostrils. This initially causes a pronounced burning sensation in the nasal mucosa and rhinorrhea. The application is carried out over a period of ten days. Comparative studies with other prophylactic treatment strategies are not available. In a placebo-controlled study with intranasally administered civamide (zucapsaicin), efficacy was found in 55.5% in the verum group and in 25.9% in the placebo group.
Melatonin
In patients with cluster headaches, serum melatonin levels are reduced. Melatonin is involved in the regulation of circadian rhythms. Leone et al. (1996) conducted a double-blind pilot study with 20 patients, comparing melatonin 10 mg with placebo over two weeks. Patients in the treatment group showed a reduction in attack severity and frequency.
Another study suggests that the additional administration of melatonin 9 mg/day may improve the effectiveness of verapamil, which was not sufficiently effective as monotherapy.
Ineffective or obsolete treatment methods
Conventional analgesics, whether opioid or non-opioid, are ineffective in treating acute cluster attacks. Because cluster attacks can subside spontaneously after thirty to sixty minutes, patients mistakenly believe that this relief is achieved by administering an analgesic. As a result, ineffective medications with significant side effects are taken unnecessarily for years or even decades. Carbamazepine, phenytoin, beta-blockers, antidepressants, histamine antagonists, biofeedback, acupuncture, neural therapy, local anesthetics, physical therapy, and psychotherapy are also ineffective.