Hospital Doctor News 08/03/01
Correct management of cluster headaches

Identifying and then knowing which treatment to choose for patients suffering from cluster headaches can pose problems for doctors. Here neurologists Prof Peter Goadsby and Dr Manjit Matharu outline modern management techniques

Cluster headache (CH) is a strictly unilateral headache that occurs in association with cranial autonomic features and, in most patients, has a striking circannual and circadian periodicity. It is an excruciating syndrome and is probably one of the most painful conditions known to mankind, with one female patient describing each attack as being worse than childbirth.

Epidemiology
The prevalence of CH is estimated to be 0.1 per cent, about the same as that of multiple sclerosis in the UK. The male-female ratio is 3.5-7:1. It can occur at any age, although the most common age of onset is the third or fourth decade of life.

Clinical features
A cluster headache or attack is an individual episode of pain that can last from a few minutes to some hours. A cluster bout or period refers to the time over which recurrent cluster attacks occur; it usually lasts some weeks or months. CH has highly distinctive clinical features which are dealt with here under two major headings - the cluster attack and the cluster bout.

The Cluster attack
The attacks are strictly unilateral, although the headache may alternate sides. The pain is excruciatingly severe. It is located mainly around the orbital and temporal regions, although any part of the head can be affected. The headache usually lasts 45 to 90 minutes but can range from 15 minutes to three hours. It has an abrupt onset and cessation.

The significant feature of CH is its association with autonomic symptoms, and it is extremely unusual for these to be reported. The International Headache Society classification diagnostic criteria require the cluster attacks to be accompanied by at least one of the following, which have to be present on the pain side: conjunctival injection (bloodshot eye), lacrimation (teary eye), miosis (constricted pupil), ptosis (droopy eyelid), eyelid edema (swollen eyelid), rhinorrhoea (runny nose), nasal blockage, and forehead or facial sweating. The autonomic features are transient, lasting only for the duration of the attack.

Premonitory symptoms of tiredness and yawning, and associated features of nausea, vomiting, photophobia, phonophobia and aura symptoms have all been described in relationship to cluster attacks. However, in contrast to migraine, CH sufferers are usually restless and irritable, preferring to move about, looking for movement or posture that may relieve the pain.

Cluster attack frequency varies between one on alternate days to three a day, although some have up to eight a day.

Alcohol, nitroglycerine, exercise and elevated environmental temperature are recognised precipitants of acute cluster attacks.

The cluster bout
CH is classified according to the duration of the bout. About 80 to 90 per cent of patients have episodic cluster headache (ECH), which is diagnosed when they experience recurrent bouts, each with a duration of more than a week and separated by remissions lasting more than two weeks. The remaining ten to 20 per cent of patients have chronic cluster headache (CCH) in which either no remission occurs within a year or the remissions last less than 14 days.

Natural History
There is a paucity of literature on the long-term prognosis of CH, but the available evidence suggests it is a lifelong disorder in most patients. In one study, about one-tenth of patients with ECH evolved into CCH, whereas one-third of patients with CCH transformed into ECH. An encouraging piece of information for CH sufferers is that a substantial proportion of them can expect to develop longer remission periods as they age.

Differential Diagnosis
In spite of the rather characteristic clinical picture, the differential diagnosis may be difficult in some cases because each feature of CH can be mimicked by other headaches.

Unilaterality of pain and the presence of migrainous and autonomic symptoms are common to both migraine and CH, and differentiating between them can be difficult in some cases. Features that can be useful in distinguishing CH from migraine are listed in the box (left).

Before a diagnosis of CH can be made, secondary headache disorders that mimic CH must be excluded. Symptomatic CH has been described after infectious, vascular and neoplastic intracranial lesions. Any atypical features in the history or abnormalities on neurological examination warrant further investigations to search for organic causes.

Paroxysmal hemicrania is a syndrome similar to CH except that it prevails in females and attacks are briefer and more frequent. It is absolutely responsive to adequate doses of indomethacin, which underlines the importance of not misdiagnosing it as CH.

Treatment
The management of CH includes offering patients advice on general measures, treatment with abortive and preventative agents and rarely surgery.

General measures and patient education
Patients should be advised to abstain from alcohol during the cluster bout. Otherwise, dietary factors seem to have little importance in CH. Anecdotal evidence suggest that patients should be cautioned against prolonged exposure to volatile substances, such as solvents and oil-based paints. They should be instructed to avoid afternoon naps because sleeping can precipitate attacks in some patients.

Abortive Agents
The pain of CH builds up very rapidly to such an excruciating intensity that most oral agents are absorbed too slowly to cure the pain within a reasonable time. The most efficacious abortive agents are those involving parentral or pulmonary administration.

Triptans
Subcutaneous sumatriptan (6mg) is the drug of choice in abortive treatment of a cluster attack. It has a rapid effect and high response rate. In CH, unlike migraine, subcutaneous sumatriptan can be prescribed at a frequency of twice daily, on a long-term basis if necessary, without risk of tachyphylaxis or rebound.

However, in this era of a cost-conscious NHS, some practitioners are reluctant to prescribe this relatively expensive drug. We feel that, given the devastating morbidity associated with this excruciating pain syndrome, it is unethical to withhold treatment for cost reasons. Although nasal sumatriptan is often used, it is considerably less efficacious than the subcutaneous formulation and there are no controlled studies to support its use.

Similarly, there is no evidence to support the use of oral sumatriptan in CH. Sumatriptan 100mg three times daily taken before an anticipated attack or at regular times does not prevent the attack and therefore should not be used for CH prophylaxis.

Zolmitriptan provides meaningful pain relief after oral administration of 5mg in the majority of patients with episodic CH, but not in chronic CH. However, its efficacy is modest and does not approach the efficacy or speed of subcutaneous sumatriptan or oxygen.

Oxygen
Inhalation of 100 per cent oxygen at seven to 12 litres/min is rapidly effective in relieving pain in most sufferers. But the high-flow rate oxygen regulator is not available on the NHS, and low-flow oxygen is generally unhelpful. So this treatment is an option only if the patient can afford to buy the high-flow rate regulator.

Topical Lignocaine
Lignocaine solution 20-60mg given as nasal drops (four to six per cent Lidocaine solution) or a spray deep in the nostril on the painful side results in mild to moderate relief in most patients, although only a few obtain complete pain relief. Intranasal lignocaine therefore serves as a useful adjunct to other abortive treatments but is rarely adequate on its own.

Ergotamine
Oral or rectal ergotamine is generally too slow in onset to provide timely, meaningful relief.

Analgesics
Opiates, non-steroidal anti-inflammatory drugs and combination analgesics have no role in the acute management of CH.

Preventative treatments
The aim of preventative therapy is to produce a rapid suppression of attacks and to maintain that remission with minimal side-effects until the cluster bout is over, or for a longer period in patients with chronic cluster headache.

Preventative treatments can be divided into short-term preventatives, suitable for rapidly controlling the attack frequency but not for prolonged use; and long-term therapies that are required for prolonged medical management of cluster headache.

Short-term prevention
Patients with either short bouts, perhaps in weeks, or in whom fast control of the attack frequency is desired, can benefit from short-term prevention. These medicines are distinguished by the fact that they cannot be used long-term and so may require replacement by long-term agents.

Steroids
Corticosteroids are highly efficacious and the most rapid-acting of the preventative agents. But caution must be exercised in using them because of the potential for serious side-effects. Treatment should be limited to a short intensive course of two to three weeks of tapering doses.

We start patients on oral prednisolone 1mg/kg to a maximum of 60mg once daily for five days, then decrease the dose by 10mg every three days. Unfortunately, relapse almost invariably occurs because the dose is tapered. For this reason, steroids are used as an initial therapy in conjunction with preventatives, until the latter are effective.

Methysergide
Methysergide is a potent prophylactic agent for treating CH. It is an ideal choice in patients with short cluster bouts which last less than four to five months. Doses up to 12mg daily can be used if tolerated. Patients are started on 1mg once daily and the daily dose is then increased by 1mg every three days until the daily dose is 5mg. Thereafter, the dose is incremented by 1mg every five days.

Prolonged treatment has been associated with fibrotic reactions (retroperitoneal, pulmonary, pleural and cardiac), but these are rare. Although it is occasionally used in CCH, a drug holiday is necessary after every six months of treatment and neurological supervision entirely appropriate.

Ergotamine
Ergotamine is an effective preventative agent that is particularly useful in short-term management of ECH when attacks occur predictably during the day or night. Ergotamine 1-2mg orally or rectally can be taken at bed time or about an hour before the attack is due. It is rarely suitable for use in CCH. Concomitant use of sumatriptan is contraindicated.

Long-term prevention
Some patients with either long bouts of episodic cluster headaches or chronic cluster headache will require preventative treatment over many months, or even years. Verapamil and lithium are particularly useful here.

Verapamil
Verapamil is the preventative drug of choice in both episodic and chronic CH. Clinical experience has demonstrated that higher doses than those used in cardiological indications are needed, so outpatient assessment and follow-up is appropriate. The dose is increased until the cluster attacks are suppressed, side-effects intervene or the maximum dose of 960mg daily is achieved.

Lithium
Lithium is an effective agent in CH prophylaxis, although the response is less robust in ECH and CCH. Renal and thyroid function tests are performed before therapy begins. Patients are then started on 300mg bd and the dose titillated using the protocol outlined in the British National Formulary, aiming for a serum lithium level in the upper part of the therapeutic range. Most patients will benefit from dosages between 600mg and 1,200mg daily. The concomitant use of non-steroidal anti-inflammatory drugs, diuretics and carbamazepine is contraindicated.

other drugs
Although sodium valproate, pizotifen, topiramate, gabapentin and melatonin are often used, as yet they are of unproven efficacy.

surgery
This is the last-resort measure in treatment-resistant patients. A number of procedures that interrupt the trigeminal sensory or autonomic (parasympathetic) pathways can be performed, but few are associated with long-lasting results and the side-effects can be devastating.

Prof Goadsby is a clinical neurologist consultant and Dr Matharu is a research registrar at the Headache Group, Institute of Neurology, London

Signs of cluster headache
Features of CH that help to distinguish it from migraine
Relatively short duration of headache
Rapid onset and cessation
Circadian periodicity
Precipitation by alcohol within an hour, rather than several hours
Clustering of attacks with intervening remissions in ECH
In contrast to migraine

CH sufferers are usually restless and irritable, preferring to move about

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