Migraine prophylaxis in adults

See also the separate Migraine and Migraine management articles.

Migraines are a major cause of morbidity, and can have substantial impacts on quality of life and employment. Migraine prophylaxis can reduce the frequency and severity of migraine, but is under-used by people who might benefit from it.¹

Most migraine prophylaxis options can be initiated and monitored in primary care, although some are available only in specialist settings.

Aim of migraine management and prophylaxis

Migraine cannot be cured and the aim, shared with the patient, is to minimise the impact of the illness on the patient's life and lifestyle. The aim of preventative treatment is to reduce the frequency, severity, and duration of migraine attacks, and avoid medication-induced headache.²

Indications for prophylaxis

British Association for the Study of Headache (BASH) guidelines state that prophylaxis should be used when symptoms are inadequately controlled with acute prescriptions, or the frequency of attacks is leading to overuse of acute medicines.³

The National Institute for Health and Care Excellence (NICE) Clinical Knowledge Summary (CKS), synthesising information from different guidelines, suggests prophylaxis where:²

• Migraine attacks are having a significant impact on quality of life and daily function - eg, they occur frequently (more than once a week on average) or are prolonged and severe despite optimal acute treatment.

• Acute treatments are either contra-indicated or ineffective.

• There is risk of medication-induced headache due to frequent use of acute drugs.

Uncommon types of migraine, such as hemiplegic migraine, or migraine with prolonged aura, should be seen by a specialist for appropriate management.

Non-pharmacological therapies for migraine prophylaxis ²⁴

Consider non-pharmacological therapies as an adjunct or alternative to pharmacological therapy - for example:

Biofeedback, relaxation technique, and cognitive behavioural therapies have shown efficacy in the prevention of episodic migraine but data regarding efficacy in chronic migraine are limited. Cognitive behavioural therapy can be helpful as part of a combined treatment programme, and should be integrated with pharmacological interventions.

Acupuncture (up to 10 sessions over 5-8 weeks) if both topiramate and propranolol are unsuitable or ineffective. The available evidence suggests that adding acupuncture to symptomatic treatment of attacks reduces the frequency of headaches.⁵

Riboflavin 400 mg once a day - may be effective in reducing migraine frequency and intensity for some people (avoid if planning a pregnancy or pregnant).

Choice of drug for migraine prophylaxis^{1 26}

The choice of treatment depends on factors such as patient preference, drug interactions, and other comorbidities. Treatment should be started at a low dose and gradually increased to the maximum effective and tolerated dose.

Preventative treatment should be tried for at least three months at the maximum tolerated dose, before deciding whether or not it is effective. A good response to treatment is defined as a 50% reduction in the severity and frequency of migraine attacks.

A review of ongoing prophylaxis should be considered after 6-12 months; treatment can be gradually withdrawn in many patients. Patients should be referred to a neurology or specialist headache clinic if trials with three or more drugs have been unsuccessful.

Propranolol
Propranolol hydrochloride (80-160 mg daily, in divided doses) is recommended as first-line preventative treatment in patients with episodic or chronic migraine. If propranolol is unsuitable, other beta-blockers that can be considered are metoprolol tartrate, atenolol (unlicensed indication), nadolol, and timolol maleate. Bisoprolol fumarate (unlicensed indication) may also be considered, especially in patients already taking it for cardiac reasons under the advice of their cardiologist.

Topiramate
Topiramate (50-100 mg daily, in divided doses (contra-indicated in pregnancy). Topiramate can be given if a beta-blocker is unsuitable. In women of childbearing potential, advice should be given on the associated risks during pregnancy, the need to use highly effective contraception and to seek further information if pregnant or planning a pregnancy.

Amitriptyline
Amitriptyline hydrochloride is effective (25-75 mg at night) for migraine prophylaxis and should be considered for patients with episodic or chronic migraine. A less sedative tricyclic antidepressant, such as nortriptyline, can be used if amitriptyline hydrochloride is not tolerated.

Candesartan cilexetil
This can be considered in patients with episodic or chronic migraine, although there is limited evidence to support its use, and it is unlicensed for this indication.

Sodium valproate
This can also be considered in patients with episodic or chronic migraine. However, valproate has an increasingly limited role due to its side-effect profile. Valproate is teratogenic, and may impair male fertility whilst being taken. It is also unlicensed for migraine prophylaxis.

Therefore, MHRA has advised that sodium valproate should not be started in any new patients (male or female) under the age of 55, unless two specialists independently consider and document that there is no other effective or tolerated treatment, or there are compelling reasons that the reproductive risks do not apply.

If valproate is still going to be used, it should only be used in women of childbearing potential if the Pregnancy Prevention Programme is in place. They should be reviewed annually by a specialist using the valproate Annual Risk Acknowledgement Form.⁷

Most people will be able to find a safer alternative for migraine prophylaxis. It must not be used during pregnancy for migraine prophylaxis.

Atogepant and rimegepant (gepants)

These are oral calcitonin gene-related peptide (CGRP) receptor antagonists, and are recently-developed medicines specifically for migraine treatment. Some can also be used as acute treatment for migraine, and do not carry the risk of medication overuse headache.

Two gepant drugs are currently available in the UK:

• Atogepant (for prophylaxis only).

• Rimegepant (for acute treatment and prophylaxis).

Ubrogepant and zavegepant (the latter administered as a nasal spray) are licensed in the USA, but, at the time of writing, had not been approved by the MHRA in the UK, or been appraised by NICE.

NICE has approved the use of atogepant and rimegepant:⁹¹⁰

• In episodic or chronic migraine (for atogepant), or episodic migraine only (for rimegepant).

• When at least 3 preventative agents have already been tried and failed.

• For people with at least 4 migraine attacks or headache days per month (and, for rimegepant, fewer than 15 attacks per month).

Treatment should be reviewed at 12 weeks, and stopped if the frequency of episodic migraines has not reduced by at least 50%, or, for atogepant in chronic migraine, at least 30%.

Local prescribing policies vary, but in some areas, gepants can be initiated in primary care, following specialist advice.¹¹

Galcanezumab, erenumab, fremanezumab, and eptinezumab (CGRP monoclonal antibodies)^12131415

These are monoclonal antibodies with activity against either CGRP itself, or the CGRP receptor. Galcanezumab, erenumab, and fremanezumab are given as subcutaneous injections monthly or three-monthly, and eptinezumab as a three-monthly intravenous infusion.

NICE recommends them as an option for episodic or chronic migraine according to the same criteria as gepants, ie:

• For people with at least four migraine attacks or migraine days per month.

• Where at least three other preventative agents have been tried and failed.

Treatment should be reviewed at 12 weeks, and stopped if:

• In episodic migraine (fewer than 15 headache days a month) the frequency does not reduce by at least 50%.

• In chronic migraine (15 headache days a month or more with at least eight of those having features of migraine) the frequency does not reduce by at least 30%.

Local prescribing policies may vary, but these medicines are usually specialist-prescription-only.

Flunarizine (unlicensed)
This can also be considered in patients with episodic or chronic migraine (specialist use only). Pizotifen is used but evidence to recommend its use is limited.

Gabapentin
This should not be used for migraine prophylaxis. A Cochrane review found that there was evidence that gabapentin was not effective for the prophylaxis of episodic migraine in adults.¹⁶

Botulinum toxin type A

Botulinum toxin type A (specialist use only) is recommended for prophylaxis of chronic migraine where medication overuse has been addressed and where three or more oral prophylactic treatments have failed.

Botulinum toxin type A is recommended by NICE as an option for the prophylaxis of headaches in adults with chronic migraine:¹⁷

• That has not responded to at least three prior pharmacological prophylaxis therapies; and

• Whose condition is appropriately managed for medication overuse.

Treatment with botulinum toxin type A that is initially recommended should be stopped in people whose condition:¹⁷

• Is not adequately responding to treatment (defined as less than a 30% reduction in headache days per month after two treatment cycles); or

• Has changed to episodic migraine (defined as fewer than 15 headache days per month) for three consecutive months.

Menstrual migraine ^{26 18}

Menstrual migraine is under-recognised. It encompasses pure menstrual migraine - migraines that only occur between days -2 and +3 of the menstrual cycle, on at least two out of three menstrual cycles, with no migraines at other times - and menstrually-related migraines - migraine patterns similar to pure menstrual migraine but with migraine attacks at other points in the cycle.

The pathophysiology of menstrual migraines is thought to involve oestrogen withdrawal and prostaglandin release in the perimenstrual period.

Preventative options for menstrual migraine include:

• Standard prophylaxis options as discussed above, taken continuously.

• Treatment taken only in the perimenstrual period, such as:

  • Non-steroidal anti-inflammatory drugs, including mefanemic acid, started two days before the expected onset of menstrual migraine, and continued until menstrual bleeding stops.

  • Triptans (fromatriptan 2.5mg BD and zolmitriptan 2.5mg TDS are most effective), started two days before menstruation starts, and continued for three days afterwards. These are unlicensed for this indication.

  • These treatment options require a predictable and regular menstrual cycle.

• Hormonal contraceptives, such as:

  • Combined hormonal contraception (although contra-indicated in migraine with aura, and combined hormonal contraception causes new-onset or worsening migraines). Oestrogen withdrawal during the hormone-free interval is a potential trigger for menstrual migraine; therefore, extended or continuous regimes with a shortened hormone-free interval (eg, 4 days rather than 7) should be used.

  • Progestogen-only methods. There is some data supporting the use of desogestrel (eg, Cerazette®). Depot injections, the contraceptive implant, and intrauterine systems may also be helpful, although data are lacking. Contraceptive methods that produce amenorrhoea may reduce the frequency of menstrual migraines.¹⁹

• Mefenamic acid 500 mg qds as first-line if menorrhagia and/or dysmenorrhoea co-exist, taken at the onset of menstruation and continued prophylactically until the last day of bleeding.

• Progestogen-only methods (that inhibit the ovarian cycle) may also be used if contraception is also required. Cerazette®, Nexplanon® or depot medroxyprogesterone acetate are all suggested.

Migraine in pregnancy and lactation

Often migraine improves during pregnancy and prophylaxis is not required. Propranolol and amitriptyline have the best evidence for safety and efficacy but drugs should be avoided if possible.

Follow-up²

Arrange follow-up to monitor effectiveness, titrate dose and assess for adverse effects.
Review regularly during titration (for example every 2-3 weeks). Advise the person:

• To keep a headache diary.

• To seek review sooner if adverse effects/new features develop.

• That improvement may take 4-8 weeks from initiation of treatment to become apparent.

Consider the need for referral to neurology if prophylactic treatment in primary care fails, is not appropriate or any red flags or atypical clinical features develop.

Treatment is considered to have failed if there is a lack of response to the highest tolerated dose after three months of treatment.

After 6-12 months of successful therapy:

• Review the need for continuing migraine prophylaxis.

• Consider gradual drug withdrawal.

Referral ²

Consider admission or urgent referral if:

• A serious cause of headache is suspected.

• There is severe, uncontrolled status migrainosus (migraine lasting for more than 72 hours).

Seek advice/refer to neurology (with urgency depending on the clinical situation) if:

• A complication of migraine has developed.

• Atypical symptoms (such as motor weakness or poor balance) are present.

• The diagnosis is uncertain.

• Optimal treatment in primary care does not adequately control the symptoms (consider medication overuse headache).