Cluster headache guidance

Cluster Headache is much less common than migraine with a prevalence of about 0.1%. The duration and frequency of the attacks and the presence of cranial autonomic symptoms and restlessness help to differentiate it from other primary headache disorders.

The main difference from other TACs and Trigeminal Neuralgia is the duration and daily frequency of the attacks. The response to preventive treatment is also different.

Adapted from BASH

Certain ophthalmological conditions may mimic Cluster Headache. These may include conditions such as trochleitis, scleritis, uveitis, orbital inflammatory disease, and intermittent angle closure glaucoma and may present with recurrent pain, lacrimation, conjunctival injection, periorbital oedema, ptosis, and pupillary abnormalities.

In inflammatory ophthalmological conditions, the changes would usually be continuous rather than short lasting. In intermittent angle closure glaucoma, vision is often reduced, a third of patients describe halos around bright light and the pupil tends to be dilated rather than constricted.

It is recommended to consider Magnetic Resonance Imaging (MRI) neuroimaging in patients presenting with new onset Trigeminal Autonomic Cephalalgia or in those with chronic symptoms. The risk of a secondary cause in an individual with long history of episodic Cluster Headache and normal neurological examination is extremely low, so investigations in these patients are not required.

A possible association between pituitary adenoma and Cluster Headache has been reported, but the association is not proven, and recent case series refute this association. Dedicated pituitary MRI is not necessary in patients with cluster headache unless the clinical presentation or standard MRI suggests a pituitary abnormality.

Subcutaneous Sumatriptan 6mg is the acute treatment of choice in a cluster attack.

Patients who have cluster headache rarely develop Medication Overuse Headache, however when migraine coexists, they may develop exacerbation of their migraine disorder whilst using a triptan effectively for their cluster attacks.

In patients who do not tolerate subcutaneous Sumatriptan, intranasal Zolmitriptan or Sumatriptan are alternative options.

Adverse effects: Patients should be warned that triptan sensations and/or sedation may occur. Symptoms may include tightness in the jaw, throat, or chest, and pins and needles in the face.

Cautions and contraindications: Triptans are contraindicated in coronary heart disease, peripheral vascular disease, or those with a history of stroke, and are cautioned in those with Raynaud’s phenomenon. They should not be used in patients with a history of moderate or severe hypertension. Do not prescribe if blood pressure measurements are consistently above 140/90mmHg. While triptans are not licensed for adults over 65 years, there is no reason they can’t be used. Vascular risk factors are more common and should be actively looked for in this age group.

High Flow Oxygen 100% at 10 to 15 litres/minute for 15 to 20 minutes, using a non-rebreathable mask, is effective in aborting acute attacks of Cluster Headache. An on demand valve is available for those not tolerating a non-rebreathable mask. Oxygen is prescribed from specialist secondary care prescribers following established pathways.

There is no limit to the use of High Flow Oxygen, however cautions around nearby smoking, flames and fire hazards need to be considered/addressed. Oxygen is often used together with triptans in patients with multiple attacks.

The demand-valve oxygen system is a valve that allows oxygen to flow when the patient inhales and closes after inhalation. There is no evidence that it is better than a standard non-rebreathable mask, but some patients will find it beneficial, and it can be requested when ordering oxygen.

Whilst long term oxygen therapy is contra-indicated in smokers, home oxygen therapy may be considered for abortive therapy of cluster headache in smokers, provided neither they nor anyone else smoke in the house and appropriate safety measures are in place.

When triptans are contraindicated or insufficient, non-invasive vagal nerve stimulation can also be used. It is prescribed from secondary care following established pathways.

Patients may use interim measures while waiting for a preventive treatment to have therapeutic effect. Such measures can also be used instead of preventative treatment in patients with episodic Cluster Headache with short bouts. Although oral Prednisolone is often used, this should be given with caution because of its many side effects and the cyclical pattern of Cluster Headache.

Oral steroids

Oral steroids (60mg Prednisolone for 5 days then reduced by 10mg every 2 days until stopped) may be given at the beginning of the bout at the same time as preventive medication is started. Repeated courses of oral steroids or prolonged use in chronic Cluster Headache is not recommended.

Peripheral Nerve Blocks

Peripheral Nerve Blocks may be used as bridge treatment in episodic Cluster Headache or as rescue treatment in chronic Cluster Headache. Greater Occipital Nerve (GON) is the main target but when the effect is insufficient with a GON block alone, multiple cranial nerves may be blocked with greater effect.

Peripheral nerve blocks are safe. The main reported side effects include dizziness, nausea, vasovagal prodromes or syncope, injection site tenderness, neck pain and transient worsening of headaches. All adverse events were transient and resolved fully without treatment. Repeated GON blocks with steroids may cause skin atrophy and alopecia of the injected area.

A mixture of Lidocaine and Methylprednisolone is often used for the GON block. A mixture of Lidocaine and Levobupivacaine is preferred for the lesser occipital nerve and trigeminal nerve branches.

Peripheral Nerve Blocks may be repeated as required but repeated steroid use has been associated with focal skin atrophy, alopecia and systemic steroid complications. We recommend restricting steroids to no more than 4 times a year.

Dihydroergotamine

Dihydroergotamine (DHE) is used in specialist centres for patients with refractory headache, including Cluster Headache. Its use is limited due to the potential cardiovascular, gastrointestinal, and pro-emetic effects of the treatment. Long term treatment can lead to fibrosis (pericardial, retroperitoneal and interstitial) and requires cardiac and Computed Tomography (CT) body monitoring. This limits its long-term use in chronic Cluster Headache.

DHE is given in a pulse regimen, usually as an intravenous (IV) infusion over 3 to 5 days as an inpatient. Initial doses are often given IV, pre-treating patients with metoclopramide or ondansetron, followed by 0.5mg DHE (in 100 mL of normal saline) infusion. If side effects are tolerable, an additional 0.5mg may be given, followed by 1mg doses in 250ml of normal saline) every 8 to 12 hours to a maximum total dose of 9mg. The effect can last from weeks to months, and the treatment can be repeated after a few months.

Verapamil is widely accepted as the first line preventive treatment for Cluster Headache. It is the most effective preventative treatment but often has to be used at high doses. The standard release formulation is more effective than the slow release formulation in most patients. The main concern with Verapamil is the development of heart block. Minor first degree atrioventricular block is acceptable as long as the PR interval does not continue to increase. If second or third degree heart block develops, Verapamil must be stopped and a cardiology referral may be considered if changes do not reverse. Regular ECG monitoring is required while on Verapamil to ensure heart block does not develop.

Other side effects include nausea, fatigue, constipation, and ankle oedemas. Rarely gynaecomastia and gum hypertrophy occur with long term use. Hypotension may be a limiting factor.

Different authors suggest different starting regimes.

A gradual increase of the dose with regular Electrocardiogram (ECG) monitoring to ensure no significant prolongation of PR.

An ECG should be performed before Verapamil is started and before every dose increase. If normal, the dose can be increased after 2 weeks until the optimal or maximum is reached.

Two regimens are recommended. Both regimens are equivalent. Regimen 1 has a slower titration schedule and may be more appropriate in patients where side effects are an issue or where the clinician would prefer a slower titration schedule.

Regime 1:

^{From Neurology. 2007;69:668-75}

Regime 2:

^{Courtesy of Prof. Matharu}

Several open-label trials have shown some efficacy for topiramate, gabapentin, valproic acid, and levetiracetam for cluster headache, and they represent an alternative or add on treatment options of treatment.

Topiramate, Gabapentin and Valproate are not recommended during conception, pregnancy or lactation. For management of cluster in pregnancy, please see the drop-down section 'Treatment in pregnancy'.

Topiramate

Start topiramate at 25mg daily, increasing by 25mg every 1-2 weeks, to a target dose of 100mg twice a day. If partially effective and well tolerated further up titration to a maximum of 200mg twice a day could be considered in selected patients.

For a full list of contraindications and cautions we recommend review of the Summary of Product Characteristics (SPC). We do not recommend topiramate for use in patients who have a history of glaucoma or renal stones or who have anorexia nervosa. Caution should also be exercised in patients with a history of depression. There may be interactions with digoxin, metformin, carbonic anhydrase inhibitors, and thiazide derivatives. There is a potential for serious interaction with sodium valproate.

Prenatal exposure to topiramate has an increased risk of major congenital malformations (OR 2.02, 95% CI 0.97 to 4.21) and it was dose dependent. Cardiac malformations are the most frequent abnormality followed by hypospadias and multiple major congenital malformations. Children exposed to topiramate in utero are at high risk of serious developmental disorders (HR 3.53, 95% CI 1.42 to 8.74 for risk of developing intellectual disability, and HR 2.73, 95% CI 1.34 to 5.57 for autism spectrum disorder).There is also a risk of lower birth weight. It should not be used by women who are breastfeeding as it can be present in breast milk. Topiramate must no longer be prescribed to women and girls unless they fulfil the requirements of a Pregnancy Prevention Programme. As such, women under 55 years of age must use effective birth control throughout treatment and take a pregnancy test prior to starting topiramate. Healthcare professionals should make patients aware of the risks of the use of this medication during pregnancy and complete a risk awareness form. Advice on contraception is available from the Royal College of the Obstetricians and Gynaecologists Faculty of Sexual and Reproductive Healthcare.

For women who may become pregnant, topiramate should only be considered as a prophylactic treatment when:

• other treatment options have been exhausted
• patients are using highly effective contraception

Before commencing treatment women should be informed of:

• the risks associated with taking topiramate during pregnancy
• the risk that potentially harmful exposure to topiramate may occur before a woman is aware she is pregnant
• the need to use effective contraception
• the need to seek urgent advice on migraine prophylaxis if pregnant or planning a pregnancy.

Side effects are common and include acute glaucoma, peripheral paraesthesias, fatigue, nausea, diarrhoea or weight loss, taste change, concentration difficulties, word finding difficulties, insomnia, anxiety, and depression.

Sodium Valproate

Sodium Valproate should not be initiated for the prophylaxis of cluster headache in patients under the age of 55.

For a full list of contraindications and cautions we recommend review of the Summary of Product Characteristics (SPC).

Children exposed to sodium valproate in utero are at high risk of serious developmental disorders and congenital malformations. It should therefore not be used during pregnancy. There is also a risk of transient impaired fertility in men. In addition, animal studies raise the possibility of testicular toxicity. There is potential risk to the offspring of men taking valproate around the time of conception. The Commission on Human Medicines recommends that no patients (male or female) under the age of 55 years should be initiated on valproate unless two specialists independently consider and document that there is no other effective or tolerated treatment. For patients under 55 years currently receiving valproate, two specialists should independently consider and document that there is no other effective or tolerated treatment or the risks do not apply. If prescribing sodium valproate to a woman of childbearing age under these circumstances, the MHRA annual risk form should be completed with the patient. This should be repeated annually whilst the patient remains on sodium valproate.

For current contraceptive advice on patients prescribed sodium valproate check the MHRA website, www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency.

The use of Melatonin in Cluster Headache is unlicenced. Evidence for the use of Melatonin in cluster is limited, but this may be due to the timing and doses used in the different trials. The relatively mild side effect profile makes it a good choice for patients with Cluster Headache who are unable to tolerate other options. Melatonin may be used as adjunctive therapy. Somnolence (sleepiness or drowsiness for long periods) is the main side effect.

Due to abnormalities in the release of endogenous melatonin in patients with Cluster Headache, timing of supplementation is essential and it should be given 2 hours before bedtime.

Proposed starting doses:
The dose should be increased every few days up until the optimal or maximum dose is reached:

• 3mg tablets should be increased by 3mg every 3 days.
• 5mg tablets should be increased by 5mg every 5 days.

^{Courtesy of Prof. Matharu}

Lithium is more commonly used in chronic Cluster Headache. Its narrow therapeutic range and undesirable side effect profile make it a less desirable choice.

Lithium therapy requires regular blood monitoring to maintain a serum concentration between 0.8 and 1.0 mEq/L. Toxicity is common and can present as gastrointestinal and neurological symptoms. The main side effects include somnolence, cognitive impairment, diabetes insipidus, and hypothyroidism.

Renal and thyroid function should be checked before starting Lithium and regularly thereafter. Lithium dosing starts at 300mg twice a day. Trough lithium levels should be obtained, and the dose adjusted every 2 weeks until a stable dose is achieved (trough level of 0.8-1.0).

• If the trough lithium level is below 0.8 the dose should be increased by 100mg twice daily
• If between 0.8 and 1.0 then the dose should not be changed
• If above 1.0, the dose should be reduced.

Trough serum concentrations need to be checked 12 hours after dosing. Regular level monitoring is required once the dose is stable.

Suggestions on starting doses and titration for some preventative treatment for cluster headache.

Other treatments with some anecdotal evidence include gabapentin and levetiracetam.

Gammacore

Gammacore is a handheld external device. The Scottish Health Technologies Group recommended its use for acute and preventive treatment of cluster headaches in NHS Scotland.

The preventive effect may be achieved by 3 doses of 2-minute stimulation twice a day. On top of this, extra doses may be given as acute treatment for additional cluster attacks. It is prescribed from secondary care following established pathways.

Ideally drugs are avoided in pregnancy. The advice of a headache specialist should be sought.

Acute treatment:

Pregnancy	Breastfeeding
		Sumatriptan (nasal spray / subcutaneous injection) Can be used up to twice a day without risk of medication overuse headache
		Oxygen therapy High flow oxygen therapy through a non rebreathe mask is the preferred treatment of acute cluster headache

Transitional treatment:

		Prednisolone Risk of cleft palate in first trimester. Usually used as a steroid taper. 60mg Prednisolone for 5 days then reduced by 10mg every 2 days until stopped
		GON Blocks (Depomedrone and Lidocaine/Lidocaine alone) Avoid corticosteroid use in the first trimester. Useful to break cycle of cluster headaches.
		Weak Opioids Can be considered where other options are ineffective.

Preventive treatment:

Pregnancy	Breastfeeding
		Verapamil – CONSULT SPECIALIST Where preventative therapies are needed (continued only on specialist advice), Verapamil in the lowest effective dose remains first choice.
		Lithium Known teratogenicity
		Topiramate/valproate Known teratogenicity

Verapamil use in pregnancy appears to be low risk with no evidence of foetal harm. Verapamil is excreted into breast milk and therefore may theoretically have effects in the infant but was rated as compatible by the American Academy of Paediatrics. Available information is for doses up to 360mg daily, with breastfeeding avoided at higher doses.

Ashkenazi A, Blumenfeld A, Napchan U, et al. Peripheral nerve blocks and trigger point injections in headache management - a systematic review and suggestions for future research. Headache 2010 Jun;50(6):943-52. DOI: 10.1111/j.1526-4610.2010.01675.x

Blumenfeld A, Ashkenazi A, Napchan U, et al. Expert consensus recommendations for the performance of peripheral nerve blocks for headaches - a narrative review. Headache 2013 Mar;53(3):437-46. DOI: 10.1111/head.12053

British Association for the Study of Headache (BASH) National Management System 2019

Grangeon L, O'Connor E, Danno D, Ngoc TMP, Cheema S, Tronvik E, Davagnanam I, Matharu M. Is pituitary MRI screening necessary in cluster headache? Cephalalgia 2021 Jun;41(7):779-788. DOI: 10.1177/0333102420983303

Headache Academy, https://www.headacheacademy.com/resources/treatments-regimes-and-protocols/cluster-headache/

No author listed. Fibrosis due to ergot derivatives: exposure to risk should be weighed up. Prescrire Int. 2002 Dec;11(62):186-9.

Healthcare Improvement Scotland SHTG. Gammacore for Cluster Headache. 2021

Litwin AS, Malhotra R. Don't forget ophthalmic differential diagnoses of cluster headache. BMJ 2012 May 1;344:e3070. DOI: 10.1136/bmj.e3070

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Miller S, Lagrata S, Matharu M. Multiple cranial nerve blocks for the transitional treatment of chronic headaches. Cephalalgia 2019 Oct;39(12):1488-1499. DOI: 10.1177/0333102419848121

Nagy AJ, Gandhi S, Bhola R, Goadsby PJ. Intravenous dihydroergotamine for inpatient management of refractory primary headaches. Neurology 2011 Nov 15;77(20):1827-32. DOI: 10.1212/WNL.0b013e3182377dbb

Rasmussen BK. Epidemiology of headache. Cephalalgia 1995 Feb;15(1):45-68. DOI: 10.1046/j.1468-2982.1995.1501045.x

Schürks M, Kurth T, de Jesus J, Jonjic M, Rosskopf D, Diener HC. Cluster headache: clinical presentation, lifestyle features, and medical treatment. Headache 2006 Sep;46(8):1246-54. DOI: 10.1111/j.1526-4610.2006.00534.x

Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018 Jan;38(1):1-211. DOI: 10.1177/0333102417738202

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