Prevention and treatment of cluster headache

Transcription

1 Anna S Cohen PhD, MRCP, Peter J Goadsby MD, PhD, FRACP, FRCP Prevention and treatment of cluster headache Cluster headache is an excruciatingly painful primary headache syndrome with rapid onset attacks that are relatively short, typically up to three hours. Management strategies involve avoidance of possible triggers to attacks, such as alcohol and naps, and pharmacological treatments aimed at either quickly aborting acute attacks, or preventive therapies to suppress the attacks entirely, or reduce their frequency, severity or duration. Cluster headache (CH) is a stereotypical primary headache syndrome, characterised by attacks of unilateral excruciating pain usually in the eye, periorbital region and temple, with associated cranial autonomic symptoms such as conjunctival injection, lacrimation, nasal blockage, rhinorrhea, ptosis, and eyelid oedema. Restlessness and agitation also feature prominently. Attacks last for minutes, and have a frequency of one every other day up to eight a day. 1 They can be triggered by alcohol, 2 usually in under an hour, in contrast to migraine for which alcohol typically takes longer to trigger an attack. CH attacks often occur with so-called clock-like regularity, and may be precipitated by sleep. CH has a prevalence of 0.1 to 0.3 per cent in the general population, 3 and affects slightly more men than women, with a male: female ratio of 2.5:1 in a recent study. 2 Episodic cluster headache (ECH) is defined as bouts of attacks lasting from seven days up to one year, with breaks of one month or more between bouts. In chronic cluster headache (CCH) attacks occur for more than one year without remission, or with remissions lasting less than one month. In CCH there are micro-periods, and seasonal variation is sometimes seen. Unaware of this, clinicians and patients may feel prophylactics have stopped working although in fact the disorder has changed. Over years this can lead to a creeping upwards of medicine doses and eventual accrual of side-effects. If one is aware of the phenomenon of periodicity even in CCH, the physician can, after a period of increased dosing, revert to the previous dose, or preferably use other strategies for short-term care to avoid changing the baseline preventive dose. CH is probably the most severe pain known to humans, with female patients describing each attack as worse than childbirth. Health-related quality of life is significantly impaired in CH sufferers. 4,5 Even though it is under-recognised and often suboptimally managed in primary care, 6,7 an early diagnosis and prompt treatment are essential to alleviate the devastating morbidity of these attacks. 8 Diagnosis The diagnosis is usually clear on taking a thorough history. The presence of autonomic symptoms, restlessness, and the length of the attacks usually distinguishes this from migraine, although a proportion of migraine patients may exhibit cranial autonomic features, 9-11 and migraine can coexist with CH by chance. The differential diagnosis for CH includes the other trigeminal autonomic cephalalgias (TACs), which are paroxysmal hemicrania (PH) and SUNCT (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing), although these differ from CH in that the attack lengths are shorter. 1 There is considerable overlap in attack frequency, such that typical CH patients have one to two attacks a day, typical PH patients 10 and typical SUNCT/SUNA patients 50, there is a marked skew that favours lower attack frequencies. 12 Another useful clinical pointer is the lateralisation of photophobia and phonophobia, which is more common in TACs than in migraine. 13 Investigating TACS the pituitary gland A remarkable range of pathology has been identified as presenting with TAC-like headaches. In particular it is observed that pituitary and peri-pituitary pathology can present as a phenotypic TAC. In a cohort of 84 patients with pituitary tumours and headache problems, 10 per cent had a TAC-like headache. 14 We therefore recommend MRI brain with pituitary views and pituitary function tests as a part of the work-up of any suspected TAC. Progress in Neurology and Psychiatry 9

2 ECH short bouts (<6 weeks) ECH long bouts (>6 weeks) CCH Abortive therapy Sumatriptan 6mg subcutaneously, maximum twice daily or sumatriptan 20mg intranasally, maximum three times daily or zolmitriptan 5mg intranasally, maximum three times daily or intranasal lidocaine and oxygen 100%, 9-12L per min, for 15 minutes at the start of attack, as required Preventive therapy short term Prednisolone 60mg rapidly reducing over three weeks GON injection Naratriptan 2.5mg twice daily As short-term add-on therapy to verapamil or eletriptan 40mg twice daily Preventive therapy longer term Verapamil Lithium Verapamil/lithium combination Methysergide (*) Topiramate ( ) Gabapentin ( ) Melatonin ( ) Non-pharmacological Suboccipital stimulator Hypothalamic stimulator * Stop methysergide after six months and have a month drug-free holiday, during which one of the shorter-term preventives can be considered These medicines have no placebo-controlled evidence, but may be considered if other treatment options fail Table 1. Suggested treatment regimen for management of episodic cluster headache (ECH) and chronic cluster headache (CCH). A indicates that option should be considered Management of CH Possible management strategies are given in Table 1. Avoidance of triggers During a bout, patients are advised to avoid factors that trigger their attacks, such as alcohol and naps, as well as strong smells, such as paint solvents and perfumes. It is noted that during remission periods, ECH patients can behave as normal and do not need to avoid their attack triggers. Avoidance of medication overuse From a cohort of 430 patients with cluster headache, seventeen (4 per cent) were reported to have medication overuse problems, 15 and patients were advised to avoid the overuse of analgesics. Interestingly patients who are susceptible to this problem almost always have a personal or family history of migraine or at least of disabling headache. 16 Abortive therapy Treatment for CH relies on the dual principles of acute therapies to abort the individual attack, and prophylactic therapy aiming to prevent or suppress attacks during the cluster bout. Abortive therapy must be fastacting, easily bioavailable and provide effective relief. A low side-effect profile is also desirable. Triptans The most effective treatment for an acute CH attack is the 5-HT 1B/1D receptor agonist sumatriptan, in parenteral form. Sumatriptan as 6mg subcutaneous injections has been shown to terminate attacks within a few minutes Sumatriptan nasal spray is also 10 Progress in Neurology and Psychiatry

3 effective, 8 albeit with a slower onset, and is better tolerated than the subcutaneous route. 8 There are two randomised placebo-controlled studies demonstrating the effectiveness of zolmitriptan 5-10mg nasal spray in acute CH. 20,21 The drawbacks of the triptans include limitations of daily usage. Current practice is to limit sumatriptan to two injections or three nasal sprays a day, in order to prevent tachyphylaxis and rebound, and for general safety considerations. At this dosage, there was no tachyphylaxis even in long-term use. 22 Triptans are contraindicated in patients for whom there is a significant vascular risk, such as ischaemic heart disease or stroke. It is foreseeable that a smaller sumatriptan dose, such as 4mg, may be used more frequently. 23 It is possible that CH patients could tolerate more dosing in 24 hours if there are no cardiovascular risk factors, and no personal or family history of migraine (in order to avoid the triptan overuse syndrome). Oxygen The other first-choice abortive treatment for acute CH attacks is inhaled high-flow (12L per min, 100 per cent) oxygen, with the advantages that it has no established side-effects, can be combined with other treatments, and can be used several times daily. Recently this has been confirmed in 80 patients with ECH and 28 patients with CCH, in a randomised placebo-controlled study. For the primary endpoint of pain free at 15 minutes the difference between oxygen and air (placebo) was significant, with no important adverse events. 24 The data suggest that oxygen should be widely and easily available to patients with CH. Other abortive therapies include topical agents such as intranasal lidocaine, which has been reported as successful. 24 Preventive treatment The importance of an effective preventive treatment is paramount. When optimally managed, a patient s attacks can be suppressed entirely on prophylactic therapy for the duration of the bout in ECH, or longerterm in CCH, with minimal side-effects and without the need for abortive agents. Short-term prophylaxis Many preventive drugs require several weeks of dose escalation, thus making them unsuitable for patients with shorter bouts. Short-term preventives may be appropriate in these cases, or in patients whose headaches are uncontrolled and who require rapid control of their attack frequency. 12 Progress in Neurology and Psychiatry Corticosteroids are very effective and fast-acting, 25,26 but should be used with care so as to avoid potential side-effects of long-term steroid use. A typical regimen is oral prednisolone 1mg per kg, up to 60mg, for five days, then reducing rapidly by 10mg every three days to zero, giving a total treatment duration of three weeks. However, the CH attacks usually recur shortly after the steroids are stopped. Steroids may therefore be used in conjunction with other preventives during their phase of dose escalation, until they are effective. Triptans There is some suggestion in the literature that triptans may have a short-term prophylactic role in CH. This follows logically from the use of ergotamine for this purpose. 27 Consequently naratriptan 2.5mg twice daily and eletriptan 40mg twice daily 31 have been used for that purpose. It is a complex road to take with the possibility of triptan-overuse headache and the issue of how one might then dose breakthrough attacks. Greater occipital nerve injections Greater occipital nerve (GON) injection is effective in a range of primary headaches, 32 including CH. 33 This has been confirmed in a placebo-controlled study in CH. 34 GON injection is safe and useful to reduce CH burden in the short term, and can be used at the same time as preventive medications are being titrated up. Being a nonsystemic treatment, the side-effects are rare and limited to mild paraesthesiae and some hair loss at the site of injection. 35 Botulinum toxin injections As for the use of botulinum toxin in CH, there has been a positive result in an open-label study of 12 CH patients. 36 This issue needs a randomised controlled trial. Longer-term prophylaxis In ECH, the preventives should be started as soon as the bout starts, continued at the dose attained to suppress or control the attacks without intolerable side-effects until the end of the bout, and reduced to zero over two to three weeks at the end of the bout. If the headaches resurge on the reduction phase, the dose can be increased again to suppress the attacks, and then reduced later. Some patients with entirely suppressed attacks may have difficulty ascertaining whether their bout has ended; however, in our experience most patients experience interictal dull aches or shadows, which remain for the duration of the bout and disappear during the remission. Verapamil is the treatment of choice for the preventive management of cluster headache when bouts are long enough to allow the dose to be sta-

4 bilised. The doses required are higher than those used in cardiovascular indications. Side-effects include constipation, leg swelling and gingival hyperplasia, and more importantly cardiovascular effects, including first-degree heart block. In an audit of verapamil use, a 20 per cent incidence of ECG abnormalities was noted. 37 We recommend performing a baseline ECG, and starting verapamil 80mg three times daily. Thereafter the daily dose is increased in increments of 80mg every days. An ECG is performed prior to each increment. The dose is increased until the cluster attacks are suppressed, side-effects intervene, or up to a maximum dose of 960mg daily. 37 Lithium has been proven effective in both ECH and CCH Side-effects include tremor, polyuria and diarrhoea. Renal and thyroid functions should be checked before and during treatment. The target serum lithium level is µmol per litre. The concomitant use of non-steroidal anti-inflammatory drugs, diuretics and carbamazepine is contraindicated. Methysergide has been used in cluster headache since the 1960s. 41,42 It is particularly useful in patients with short bouts of up to six months. The dose starts at 1mg daily and increases by 1mg every three days to a maximum of 12mg daily, or until the headaches are suppressed. 43 Prolonged treatment has been associated with fibrotic reactions, but these are rare, 44 and can be avoided by using methysergide for less than six months at a time. CCH patients will require a onemonth drug holiday every six months. Combination therapies may also be considered. There is some merit in combining verapamil and lithium, but care must be taken to avoid increased toxicity, especially in older patients. 45 Using methysergide in combination with sumatriptan is usually discouraged due to the risk of ischaemic cardiac and vascular side-effects. However, the only cases reported of adverse vasoconstrictive effects on this combination of drugs were in patients who already had predisposing ischaemic conditions. Therefore in our clinical practice we use methysergide and sumatriptan in combination, in patients who have been screened for potential risk factors. Topiramate, which is used in migraine and other headache syndromes, is beneficial at doses of mg daily in ECH and CCH However, there is some conflicting evidence, 50 and care must be taken to avoid sideeffects, which include dyspepsia, peripheral paraesthesiae, ataxia, dizziness, weight loss, exacerbation of renal stones, and cognitive impairment. However, if side-effects are minimal or tolerable, topiramate remains a feasible option in cluster headache. The dose should start at 12.5 or 25mg daily and increase weekly by 12.5 or 25mg to a maximum daily dose of mg. Both the therapeutic and unwanted effects may not occur in a strictly dose-dependent fashion. Other antiepileptic therapies such as sodium valproate 51,52 and gabapentin 53 have been used in CH but without good controlled evidence; indeed the evidence for valproate is negative. Given the diurnal nature of many CH attacks, melatonin has been tried in order to combat the reduced nocturnal melatonin in CH patients. A double-blind study of melatonin treatment significantly reduced headache frequency in ECH but not CCH, 54,55 although an open-label trial of melatonin as add-on therapy in two CCH patients was successful. 56 Neuromodulatory procedures Hypothalamic deep brain stimulation Even with advances in medical therapies there remains a cohort of patients who are medically intractable. 57 The identification using functional imaging methods of an important role for the region of the posterior hypothalamic grey matter in cluster headache 58 lead to the use of deep brain stimulation in that region to treat medically intractable CCH. 59 While this has been an effective strategy, it is not without concerns and its application prior to occipital nerve stimulation is questionable. 60 Occipital nerve stimulation Occipital nerve stimulation (ONS) has been used in primary headache syndromes, based on the interaction between trigeminal and cervical nociceptive inputs in the trigeminocervical complex 61 and functional imaging findings in chronic migraine patients with ONS. 62 Studies in patients with previously medically intractable CH show that most improved after ONS, 63,64 although their response is not necessarily predicted by GON injection. 65 Surgery Surgery is a last-resort measure for patients with CH that is resistant to all other treatments, including neuromodulation approaches. Destructive surgery in order to block trigeminal pathways should be considered only in patients with strictly unilateral attacks, as those whose attacks alternate sides may find an upsurgence of attacks on the contralateral side. Occasionally complete trigeminal anaesthesia is achieved, with subsequent risk of corneal injury. 66 Currently, we feel it is inappropriate to perform destructive procedures at all until a patient has had a trial of a neuromodulatory treatment. Progress in Neurology and Psychiatry 13

5 Summary CH is an excruciating condition that is relatively easy to diagnose. The management strategy centres on a firm diagnosis, avoidance of possible triggers, abortive therapies to manage the acute attack, and preventive treatments to suppress the CH attacks, either in the long term or as a shorter term measure while the prophylactic therapy starts to take effect. The choice of preventive medication is influenced by, and tailored to, the specific needs of the patient, including length of bout and risk of side-effects. In the future, neuromodulatory procedures such as GON injection, GON stimulation and deep brain hypothalamic stimulation may play an increasing role in the control of cluster headaches. Professor Goadsby is in the Headache Group, Department of Neurology at University of California in San Francisco, California, USA and Dr Cohen is a Specialist Registrar at the Institute of Neurology, Queen Square London, UK References 1.Headache Classification Committee of The International Headache Society.The International Classification of Headache Disorders (second edition). Cephalalgia 2004;24(Suppl 1): Bahra A, May A, Goadsby PJ. Cluster headache: a prospective clinical study in 230 patients with diagnostic implications. Neurology 2002;58: Sjaastad O, Bakketeig LS. Cluster headache prevalence.vaga study of headache epidemiology. Cephalalgia 2003;23: D'Amico D, Rigamonti A, Solari A, et al. Health-related quality of life in patients with cluster headache during active periods. Cephalalgia 2002;22: Ertsey C, Manhalter N, Bozsik G, et al. Health-related and condition-specific quality of life in episodic cluster headache. Cephalalgia 2004;24: Geweke LO. Misdiagnosis of cluster headache. Current Pain and Headache Reports 2002;6: Bahra A,Goadsby PJ.Diagnostic delays and mis-management in cluster headache. Acta Neurologica Scandinavica 2004;109: van Vliet JA, Bahra A, Martin V, et al. Intranasal sumatriptan in cluster headacherandomized placebo-controlled double-blind study. Neurology 2003;60: Dora B. Migraine with cranial autonomic features and strict unilaterality. Cephalalgia 2003;23: Barbanti P, Fabbrini G, Pesare M, et al. Unilateral cranial autonomic symptoms in migraine. Cephalalgia 2002;22: Obermann M,Yoon M-S, Dommes P, et al. Prevalence of trigeminal autonomic symptoms in migraine: a population-based study. Cephalalgia 2007;27: Goadsby PJ, Cittadini E, Burns B, et al.trigeminal autonomic cephalalgias- diagnostic and therapeutic developments. Curr Opin Neurology 2008;21: Irimia P, Cittadini E, Paemeleire K, et al. Unilateral photophobia or phonophobia in migraine compared with trigeminal autonomic cephalalgias. Cephalalgia 2008;28: Levy M, Matharu MS, Meeran K, et al.the clinical characteristics of headache in patients with pituitary tumours. Brain 2005;128: Paemeleire K, Bahra A, Evers S, et al. Medication-overuse headache in cluster headache patients. Neurology 2006;67: Goadsby PJ. Is medication-overuse headache a distinct biological entity? Nature Clinical Practice Neurology 2006;2: Ekbom K,The Sumatriptan Cluster Headache Study Group.Treatment of acute cluster headache with sumatriptan. N Engl J Med 1991;325: Ekbom K, Monstad I, Prusinski A, et al. Subcutaneous sumatriptan in the acute treatment of cluster headache: a dose comparison study. Acta Neurologica Scandinavica 1993;88: Hardebo JE. Subcutaneous sumatriptan in cluster headache:a time study in 14 Progress in Neurology and Psychiatry

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