According to a recent decision by the Federal Joint Committee (G-BA), under statutory health insurance for the indication of cluster headache, even beyond its current approved indication . The Federal Joint Committee has included the drug in its drug guidelines.

Not all manufacturers have issued a statement. Therefore, only products from the manufacturers 1A/Hexal/Sandoz, Abbott, Aliud/Stada, Basics, Heumann, and Wörwag are eligible for prescription. Products from other manufacturers may not be prescribed on a public health insurance prescription.

The decision is very welcome and long overdue. On the other hand, it leaves many questions unanswered and leads to new uncertainties in practical therapy. Despite international consensus that cluster headache medication must be individually dosed and that high-dose therapy is necessary, especially for severely affected patients, an initial standard daily dose of 120 milligrams is specified, which can be increased to a maximum of 360 milligrams. Based on our experience and a review of the literature, this dosage can only effectively treat a small proportion of patients. Cluster headache is nicknamed "suicide headache"; patients are driven to despair by the pain and, without adequate treatment, occasionally take their own lives. Therefore, the current dosage limit does not appear to be a measure in the interest of patient safety. The decision does not provide operational criteria for ECG monitoring, and there is no mention of the use of extended-release preparations.

Our experience with verapamil in the treatment of cluster headaches is described below. It should be noted that, due to a lack of sufficient controlled studies, its use in specialized centers is based on many years of experience and must be individually tailored.

From a practical, statutory health insurance perspective, providing cluster headache patients with verapamil was not a problem, even without marketing authorization. Based on my personal experience, as well as the experience of many colleagues, I am not aware of a single conflict arising from prescribing verapamil for cluster headache prophylaxis. Therefore, providing cluster headache patients with verapamil was neither hindered nor limited, even without marketing authorization.

With this decision, verapamil is now officially approved for the prophylaxis of episodic and chronic cluster headache in adults aged 18 and over. Section 1(b) states that the treatment goal is "a clinically relevant reduction (i.e., at least 50%) in the frequency of attacks" of cluster headache. This reduction, transferred from the prophylaxis of migraine attacks, is, in my view, not appropriate for cluster headache. Due to the severity of the attacks, the treatment goal for cluster headache must be attack-free status. From the perspective of a general practitioner who, without detailed knowledge of the relevant literature, now manages treatment based on the approval text, they will assume that a corresponding 50% reduction is acceptable. However, reducing 60 monthly attacks to 30 is not a clinically relevant or acceptable treatment goal for the patient.

Section 1(f) provides dosage instructions. It recommends oral monotherapy with an initial dose of 120 mg, which can be increased to 360 mg. An inconsistency in the product information arises from the very next sentence: "The dose of verapamil necessary for complete suppression of cluster headache attacks varies considerably between individuals and can also fluctuate within the same individual." While section 1(b) states a treatment goal of at least a 50% reduction in attack frequency, this section correctly refers to complete suppression of cluster headache attacks. This will lead to further confusion among physicians in routine care.

From a practical standpoint, I don't believe it's justified to specify an initial daily dose of 120 mg as standard. Based on my personal experience and the literature, this low dose is only effective for a very small percentage of patients. Many patients will unnecessarily suffer cluster attacks with this insufficient dose, and I don't consider a standardized dosage in this form appropriate. Furthermore, the guidelines don't specify how and over what period the dose can be increased to 360 mg. Here, too, the prescribing physician is left to their own devices. Finally, it doesn't specify whether immediate-release or extended-release verapamil should be used. From a cardiological perspective, the use of immediate-release verapamil has been outdated for many years. Regrettably, this knowledge has only been reflected in neurological guidelines and clinical practice in a few isolated cases.

Section 1(g) states that therapeutic efficacy can only be assessed after at least one week of treatment. This is incorrect. Generally, it takes up to one week for the effect to occur with an adequate dose. However, some patients experience an effect even before one week. Furthermore, the effect depends on the dosage, and the onset of action also depends on initial concomitant therapies, such as corticosteroids or 5-HT agonists. Simply starting with 120 mg of verapamil and then waiting a week is, in my opinion, inadequate. Since the duration of the gradual increase in verapamil is not specified, the prescribing physician is left without guidance. There is also no precise instruction or even a recommendation regarding the dose increments to be used.

In my view, the statement that the treatment of episodic cluster headaches should generally last approximately six weeks is also not objectively justifiable. This statement may be based on the fact that episodic cluster headache periods usually last six weeks. However, this overlooks the fact that many patients experience significantly longer active periods, even with episodic cluster headaches, while others have shorter periods. There is no operational guideline for how long verapamil should be continued after the last attacks have ceased, regardless of the unknown duration of the current treatment period in any given case.

Section 1.h) states that treatment should be discontinued if the therapeutic goal of a 50% reduction in attack frequency is not achieved. I see a crucial problem with this statement, as many severely affected cluster headache patients only respond to doses above 360 ​​mg. For many patients, an adequate treatment effect is only achieved with 2 x 240 mg and above. This standardization in the approval process now forces these patients back into off-label use, and this previously unproblematic dose escalation is being stigmatized. With this approval, we must summon patients, inform them of the new situation, and adjust their treatment if necessary. At the same time, the approval creates a legal threat for prescribing physicians. The risk of complications is naturally increased with high doses. Now, the prescribing physician must prescribe not only at their own risk but even against the official approval, and they must be prepared to defend themselves. The consequence will be that patients who require high-dose therapy will be less likely to receive it and will suffer as a result. This will lead to resignation and the consideration of switching to combination therapies with further side effects, invasive therapies including deep brain stimulation, and treatments for acute attacks. This will result in a greater burden for the individual patient and significant cost increases for the healthcare system. In my view, the dosage standardization and limitation outlined in the marketing authorization are incompatible with the scientific literature and, in their current form, complicate treatment. Arterial hypertension is much easier to treat with verapamil, where dosages up to 480 mg are approved.

Section 1.i) mentions the necessity of regular ECG monitoring. However, it does not specify operational limits or indicate which ECG changes are relevant for discontinuing therapy. Practitioners receive no relevant guidance and, in cases of doubt, will refrain from treatment rather than administer it correctly.

Against this background, it is therefore understandable that numerous pharmaceutical companies did not submit a statement regarding the approval of their verapamil-containing drugs and, on this basis, showed no interest in their drug being eligible for prescription.

In summary, the approval of verapamil is certainly welcome in principle. However, in its current form, it will, in my view, hinder rather than promote the treatment of cluster headache patients. We are already seeing the consequences of this approval: patients receiving high-dose therapies of other medications with serious side effects, starting at 360 mg per day of verapamil, are becoming ineffective, leading to despair and resignation. Of course, we can disregard the dose limit in specialized centers. However, we would then be back in the off-label area, both quantitatively and qualitatively. In routine clinical practice, however, physicians will hardly consider this. Therefore, efforts should be made to appropriately adjust the approval to avoid disadvantages for the affected patients.

Discussion on the topic on Doc-Check

Verapamil in the treatment of cluster headaches
(Source: H. Göbel, Die Köpfe, 3rd ed., 2012, Springer-Verlag, Heidelberg )

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 therapeutic success, achieving therapeutic efficacy under inpatient conditions in specialized centers may require increasing the dosage to as high as 1,200 mg (!) per day. Due to its good tolerability and compatibility with acute therapies such as oxygen or sumatriptan, verapamil is considered the 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 takes hold, 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 headache

The maximum approved daily dose of verapamil for the indications of hypertension and coronary artery disease is 480 mg. In neurology, this dose must be exceeded in individual cases for the preventive treatment of cluster headaches. Dosages of 240 mg to 960 mg/day, and in individual cases even higher, may be required. Immediate-release verapamil leads to fluctuations and gaps in plasma levels, reducing its effectiveness. Furthermore, verapamil levels drop at night with immediate-release administration. The risk of attacks is particularly high during the first hours of the day. Therefore, only extended-release verapamil should be used as standard practice.

  • As with cardiological indications, treatment for cluster headache patients 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 a dose of 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 for PQ times of approximately 0.25 s or higher, and certainly not for 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 first-degree AV block, 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 prophylaxis of cluster headache may be limited by cardiac side effects. A French research group investigated the cardiac safety of high-dose verapamil therapies for cluster headache. Dosages exceeded 720 mg per day. Among 200 patients, 29 (14.8%) used doses of 877 ± 227 mg per day. ECG changes were observed in 38% (11/29). Seven patients (24%) experienced bradycardia as a minor adverse event, and four patients (14%) had arrhythmias, which were classified as major adverse events. Patients with ECG changes required higher doses (1003 ± 295 mg per day vs. 800 ± 143 mg per day). The occurrence of minor or major adverse events was independent of the dosage level. Approximately three-quarters of the patients experienced a significantly delayed onset of cardiac side effects, with the described symptoms appearing after more than two years. These results underscore the need for regular and careful cardiac monitoring of patients undergoing high-dose verapamil therapy, as well as the need for thorough follow-up and treatment success monitoring over the long term.