Headache prophylaxis

Click here for an alternative version of the pathway

The decision if or when to start oral prophylaxis should be tailored to the individual patient. As per SIGN 155, there is no specific number of migraine days or migraine attacks per month that indicates the need for prophylaxis. For example, patients with a few disabling migraine days per month may elect to start treatment, but patients with a larger number of mild headache days per month may not.

Traditional migraine prophylactics may take many weeks to work. Judgment of efficacy should be made once on the target dose or highest tolerated dose at 8 weeks. If the migraine prophylactic is ineffective at 8 weeks, it should be weaned over 2 weeks and an alternative considered. If it is effective (i.e. reduced monthly headache days by at least 30-50%) consider weaning the drug after 6 to 12 months (it should be weaned at the approximate rate it was increased). If side effects are experienced after a dosage increase, decrease to the previous dose and then attempt a dosage increase after 2 weeks. If patients are drowsy they should be warned to refrain from driving.

We recommend gepants (atogepant or rimegepant) are trialled for 3 or more months before determining efficacy.

Migraine prophylaxis is usually not required in pregnancy, and certain medications are contraindicated in pregnancy (detailed in the pregnancy section). We recommend consideration of withdrawal of migraine prophylactics prior to conception. In particular, candesartan and topiramate must be avoided in pregnancy. In addition, we do not recommend gepants in pregnancy. Many forms of contraception are not suitable in patients taking topiramate (see section on Topiramate).

*U&Es = urea and electrolyte blood testing 

Amitriptyline

Start at 10mg and increase by 10mg every 1-2 weeks. The typical first target dose is 50mg. If well tolerated many patients benefit from a higher dose with further titration up to 1mg/kg, typically a maximum of 100mg. If side effects occur, alternatives include nortriptyline, or dosulepin.

For a full list of contraindications and cautions we recommend review of the Summary of Product Characteristics (SPC). Contraindications include concomitant use of monoamine oxidase inhibitors, recent myocardial infarction, heart block, disorders of cardiac rhythm, and coronary artery insufficiency, and severe liver disease. We also recommend avoiding use in those patients at risk of glaucoma, and QT prolongation. Caution in those patients taking serotonergic drugs.

Patients should be warned about side effects which include constipation, difficulty with micturition, arrhythmias, syncope, confusion, nausea, dry mouth, drowsiness and weight gain. Patients should seek immediate medical attention if they are unable to micturate or experience visual blurring.

Candesartan

Start at 2-4mg per day, increasing by 2-4mg every 1-2 weeks to a maximum of 16mg.

For a full list of contraindications and cautions we recommend review of the Summary of Product Characteristics (SPC). Caution in patients with renal artery stenosis, hypotension and renal impairment. Candesartan is cautioned in those patients receiving lithium therapy, and in those who are taking medications which increase serum potassium such as spironolactone.

Candesartan should not be used in pregnancy and should be discontinued before planning a pregnancy. Women of childbearing age should ensure appropriate contraception is in place. Candesartan is not recommended during breast feeding.

Consideration of alternative agents should be considered in those with renal impairment and those patients taking regular NSAIDS, since in such populations close monitoring of kidney function and potassium would be required. If using candesartan in older patients, monitoring of kidney function and potassium should be considered. Candesartan should be withheld if patients become acutely dehydrated (e.g. during a diarrhoea and vomiting illness).

Side effects include hypotension, renal impairment and cough.

Propranolol

Start propranolol 10-20mg twice a day, gradually up-titrating by 10-20mg twice a day every 1-2 weeks, to a target dose of 80mg twice a day. Propranolol 80mg MR, increasing to 160mg MR is an alternative. Some patients benefit from lower doses if they experience side effects at higher doses

For a full list of contraindications and cautions we recommend review of the Summary of Product Characteristics (SPC). Propranolol is contraindicated in several conditions including asthma, severe peripheral vascular disease and should not be used in patients taking verapamil.

Side effects include bradycardia, hypotension, fatigue, sexual dysfunction, wheezing.

Pizotifen

Although the evidence base is limited, pizotifen is widely used for the prevention of migraine and is another option. A suggested starting dose in 0.5mg at night, with weekly increments of 0.5mg, to a target dose of 1.5mg at night.
For a full list of contraindications and cautions we recommend review of the Summary of Product Characteristics (SPC).

Where prophylactic treatment is not successful after three preventative medications from different classes, consider referral to relevant secondary care services as per local arrangements. At this point, a gepant could be considered (see gepant section below) prior to referral into secondary care.

The following diagram gives an overview of the secondary care pathway. Click here for an alternative version of the pathway

• Chronic migraine: 15 headache days per month, of which 8 must be migraine
• Episodic migraine: 14 or less headache days per month

Patients should be defined as having episodic or chronic migraine using headache diaries. As per the primary care pathway, initial prophylaxis should be with oral medications, but it is expected that many agents will already have been tried in primary care. It is important to confirm that agents have been tried for an appropriate duration and at an appropriate dose.

Advanced therapies comprise gepants (Atogepant, Rimegepant), monoclonal antibodies to calcitonin gene related peptide (CGRP) and Botulinum Toxin A.

The choice of advanced therapy following traditional preventive treatment failure will depend on patients' characteristics and preferences as well as availability in each NHS Board. The gepants can be considered prior to secondary care referral. In health boards where they require secondary care approval prior to prescription, this could be supported by an advice and guidance referral.

Botulinum Toxin A and Erenumab are only approved for chronic migraine. Rimegepant is only approved for episodic migraine.

If a first monoclonal antibody is deemed to be ineffective it is reasonable to consider a trial of a second monoclonal antibody to CGRP, ideally one with a different mechanism.

In selected patients with disabling episodic migraine, treatment with gepants or a monoclonal antibody to CGRP (eptinezumab, fremanezumab or galcanezumab) can be considered if traditional oral prophylactics are ineffective.

Calcitonin gene related peptide (CGRP) small molecule antagonists (gepants) are a class of medications for the treatment of migraine. At the time of writing there are 2 such medications available in Scotland. Atogepant 60 mg daily is approved for use in episodic and chronic migraine whereas rimegepant 75mg every second day is approved for episodic migraine only. Where patients using rimegepant have a migraine attack on a non-treatment day, if there are no contraindications, then an additional dose can be used for acute treatment (refer to acute treatment section for detail).
Gepants are thought to relieve migraine by blocking CGRP-induced neurogenic vasodilation, returning dilated intracranial arteries to normal by halting the cascade of CGRP-induced neurogenic inflammation which leads to peripheral and central sensitisation and / or by inhibiting the central relay of pain signals from the trigeminal nerve to the caudal trigeminal nucleus.

Place in the migraine pathway

In selected patients with disabling episodic migraine there is the option to treat with a gepant (atogepant and rimegepant are both licensed in this scenario) if oral prophylactics are ineffective. The CGRP monoclonal antibodies (as detailed below) are an alternative in patients preferring an injectable treatment.

Atogepant can be considered for patients with chronic migraine who have not responded to first line oral prophylactics. Botulinum toxin A and the CGRP monoclonal antibodies (as detailed below) are an alternative in patients preferring an injectable treatment. At the time of writing the Scottish Medicines Consortium have accepted the restricted use of atogepant for patients with episodic migraine and chronic migraine where at least three prophylactic treatments have failed.
Rimegepant is restricted to patients with episodic migraine where three prophylactic agents have failed.
In patients with a partial effect to an oral prophylactic agent, there is no requirement to stop that agent as long as the patient fulfils the criteria for starting treatment with a gepant. Medication overuse with analgesics should be addressed prior to initiating treatment.

Adverse Effects and Cautions

Gepants are generally well tolerated. Side effects noted with atogepant in the clinical trials were constipation (7%), nausea (7%) and somnolence (5%). Atogepant should be avoided in severe hepatic impairment and dose reduction to 10mg is required in severe renal impairment. Baseline U&Es and LFTs should be considered if clinical concern. Routine monitoring is not required for patients with normal renal and liver function. Nausea is the main adverse effect with rimegepant, in 1.2% of patients. Hypersensitivity reactions have been reported but are uncommon occurring in <1%.

It is important to note that CGRP mediates vascular effects such as potentially mediating vasodilatation and having other potential effects on the vascular endothelium and vascular smooth muscle. Patients with certain cardiovascular diseases were excluded from clinical trials and long-term effects of these agents in such patients is unknown. We do not recommend the use of such agents in patients with uncontrolled hypertension, and use in patients with cerebrovascular and cardiovascular disorders is cautioned until further safety data becomes available. Regular BP checks are recommended for patients on gepants to ensure hypertension does not develop.

Pregnancy and Lactation

Gepants should not be used in pregnancy. They have a short half-life, and these agents should be stopped at least one week prior to trying for a pregnancy. Due to insufficient safety data, routine use of these agents in lactating women is not recommended.

Assessment of Response

Headache diaries should be used to assess the response. Response to treatment should be assessed after three or more months using headache diaries.
If there is a good response to treatment, the agent may be continued for a pre-defined period as determined locally (e.g. 12-24 months), before consideration of a treatment holiday. If there is recurrence of headache during a treatment holiday, treatment may be re-initiated. Alternatively, if there is a sustained positive response after a treatment holiday, the agent should not be re-initiated.
In episodic migraine, if one agent is ineffective after three or more months a second agent can be trialled.
Criteria for continuing and stopping may consider a number of indices:

1. Episodic migraine: reduction of at least 50% in frequency or severity of headache.
2. Chronic migraine: reduction of at least 30% in frequency or severity of headache / migraine.

Dosing

Dosing should be performed as per product license, considering medication interactions, and renal and hepatic function.

Atogepant 60mg daily may be prescribed from primary care or secondary care depending on local arrangements. If atogepant is prescribed along with a strong CYP3A4 inhibitor (e.g., clarithromycin, itraconazole) or a strong OATP inhibitor (e.g., rifampicin, atazanavir, ritonavir, tipranavir, ciclosporin, telmisartan) then the dose should be reduced to 10mg. Candesartan is a moderate OATP inhibitor and does not require dose reduction. For those where the strong CYP3A4 inhibitor or OATP inhibitor is prescribed for a short course of treatment then it is acceptable to temporarily stop atogepant and re-start it when the treatment course has completed.

Rimegepant 75 mg alternate days may be prescribed from primary care or secondary care depending on local arrangements. Where patients have a migraine attack on a non-treatment day, if there are no contraindications, then an additional dose can be used for acute treatment, except where the patient is on a moderate CYP3A4 inhibitor.

Concurrent administration of Rimegepant along with a strong CYP3A4 inhibitor (e.g., clarithromycin, itraconazole) is not recommended. If it is prescribed with a moderate CYP3A4 inhibitor (erythromycin, fluconazole) or strong inhibitor of P-glycoprotein or breast cancer resistance protein (e.g cyclosporine, verapamil, quinidine), a second dose should be delayed for 48 hours i.e. patients should not be allowed to use concurrent acute treatment whilst on a such interacting medications. Rimegepant is not recommended in patients with severe hepatic impairment, in patients with end stage renal disease, and in patients with concomitant use of strong or moderate inducers of CYP3A4.

For chronic migraine, if patients are either ineligible for, or do not respond to the oral prophylactics, they should be considered for Botulinum toxin A. Botulinum toxin A therapy is licensed for chronic migraine only (defined as at least 15 headache days per month, at least 8 of which are migraine). Medication overuse should be addressed prior to initiation. Botulinum toxin A should be administered by appropriately trained clinicians using the PRE-EMPT protocol.

An adequate trial consists of two cycles of treatment of 155-195 units, three months apart. Headache diaries should be completed by patients before and during therapy. Patients should be evaluated 3 months after the second cycle, against pre-defined criteria (NICE Technology Appraisal Guidance TA260), to determine whether the treatment should be stopped or continued. Treatment should be continued where there is a good response to treatment, but the patient continues to suffer a significant headache burden (e.g. remains in a chronic migraine pattern). Treatment should be stopped if there is an insufficient response to treatment, or alternatively if there is an excellent response to treatment (e.g. patient has well controlled episodic migraine). If treatment is continued, headache diaries should be reviewed at each injection visit to confirm the ongoing indication for treatment. A treatment holiday should be considered at 2 years.

Criteria for continuing and stopping may consider a number of indices, for example

• Headache days (reduction of 30% or more is typically considered a good response)
• Migraine days or severe headache days (reduction of 30% or more is typically considered a good response)
• Disability (reduction of 50% or more is typically considered a good response)

There is limited evidence for the safety of Botulinum Toxin A in pregnant or lactating women. Whilst the risk is likely to be low, treatment using Botox is not recommended in pregnant and lactating women. Practice varies between headache centres and some centres do use Botulinum Toxin A in selected patients who are pregnant or lactating. Before considering Botox in pregnancy or lactation the clinician should fully discuss the uncertainty and the potential risks with the patient, written consent should be obtained and the patient should be entered on a pregnancy registry.

Background

Monoclonal antibodies to calcitonin gene related peptide (CGRP) are a class of medications for the treatment of migraine. At the time of writing there are four such medications available in Scotland. Erenumab, fremanezumab and galcanezumab are provided by monthly subcutaneous injections. Fremanezumab can also be given quarterly. Eptinezumab is only available as a quarterly intravenous infusion. All medications target CGRP, a key neuropeptide involved in the pathogenesis of migraine. Erenumab is a monoclonal antibody directed toward the canonical CGRP receptor. Fremanezumab, galcanezumab and eptinezumab are monoclonal antibodies directed toward the CGRP ligand.

Place in the migraine pathway

At the time of writing the Scottish Medicines Consortium have accepted the restricted use of erenumab for patients with chronic migraine where at least three prophylactic treatments have failed. The SMC have accepted fremanezumab, galcanezumab and eptinezumab for patients with chronic and episodic migraine where three prophylactic agents have failed. In patients with a partial effect to an oral prophylactic agent, there is no requirement to stop that agent as long as the patient fulfils the criteria for starting the monoclonal antibody treatment. However, medication overuse with analgesics should be addressed prior to initiating treatment.
The specific choice of agent should be decided locally. Centres may benefit from developing dedicated clinics to pre-assess patients, provide training regarding injection technique, and to assess response. Injections are typically delivered to patients by a homecare service, and are self-administered by patients at home. Patients will require a hospital admission (or a suitable alternative) to receive intravenous eptinezumab.
In selected patients with episodic migraine there is the option to treat with a monoclonal antibody to CGRP (fremanezumab, galcanezumab and eptinezumab are licensed in this scenario) if oral prophylactics are ineffective.

Adverse Effects and Cautions

The cap of the erenumab pre-filled syringe / pen contains latex and should not be given to patients with a latex allergy.

Although the monoclonal antibodies have a favourable side effect profile, a number of side effects should be noted. Patients should be warned about side effects including the risk of constipation (mainly with erenumab, but only occasionally severe enough to warrant treatment cessation), injection site reactions, itch, rash, and hair loss. There have been reports of anaphylaxis and angioedema.

It is important to note that CGRP mediates vascular effects such as potentially mediating vasodilatation and having other potential effects on the vascular endothelium and vascular smooth muscle. Patients with certain cardiovascular diseases were excluded from clinical trials and long-term effects of these agents in such patients is unknown. There have been early reports in the post-marketing setting of increases in blood pressure after initiation of erenumab. We do not recommend the use of such agents in patients with uncontrolled hypertension, and use in patients with cerebrovascular and cardiovascular disorders is cautioned until further safety data becomes available. Regular BP checks are recommended for patients on CGRP monoclonal antibodies to ensure hypertension does not develop.

There is a small risk of hypersensitivity reactions during the infusion with eptinezumab.

Pregnancy and Lactation

Monoclonal antibodies to CGRP should not be used in pregnancy. Due to the long half-life, these agents should be stopped at least six months prior to pregnancy. Due to insufficient safety data, routine use of these agents in lactating women is not recommended.

Assessment of Response

Headache diaries should be used to assess the response. Response to treatment should be assessed after three or more months using headache diaries.

If there is a good response to treatment, the agent may be continued for a pre-defined period as determined locally (e.g. 12-24 months), before consideration of a treatment holiday. If there is recurrence of headache during a treatment holiday, treatment may be re-initiated. Alternatively, if there is a sustained positive response after a treatment holiday, the agent should not be re-initiated.

If one agent is ineffective after three or more months a second agent can be trialled. It is preferable for the second agent to be of a different class than the first. For example, if erenumab is ineffective, consider a trial of either fremanezumab, galcanezumab or eptinezumab; if either fremanezumab, galcanezumab or eptinezumab are ineffective, consider a trial of erenumab. The Scottish Medicines Consortium permits the use of fremanezumab, galcanezumab and eptinezumab for patients with episodic migraine. Where one of these agents is ineffective, another may be tried.

As with Botulinum Toxin A therapy, criteria for continuing and stopping may take into account a number of indices, for example

• Headache days (reduction of 30% or more is typically considered a good response)
• Migraine days or severe headache days (reduction of 30% or more is typically considered a good response)
• Disability (reduction of 50% or more is typically considered a good response)

Dosing

Dosing should be performed as per the product license.

Erenumab is delivered as a subcutaneous injection using a pre-filled syringe or pen. The dose is either 70mg or 140mg monthly.

Galcanezumab is delivered as a subcutaneous injection using a pre-filled pen. The recommended regimen is a 240mg loading dose, followed by 120mg monthly.

Fremanezumab is delivered as a subcutaneous injection using a pre-filled syringe. The dose is either 225mg monthly or 675mg quarterly.

Eptinezumab is delivered by intravenous infusion. The dose is 100mg quarterly.

Occipital nerve blocks have traditionally been used as a transitional treatment in migraine, but with conflicting evidence of efficacy. However, there is growing evidence for efficacy in migraine. A recent systematic review and meta-analysis identified five randomised controlled trials (RCTs) with methodological heterogeneity, and demonstrated beneficial effects in terms of headache intensity and frequency.

GON blocks may be used in migraine as a transitional treatment (short term effect to “switch off” a headache bout or provide temporary headache relief) in certain situations when the severity and frequency of the headaches are significant and other acute or preventive options are not available (i.e. pregnancy) or not effective. It may also be used as a temporary relief in the context of medication overuse headache when withdrawal of acute medication results in unbearable rebound headache. In certain situations, it may also be used as the principal treatment for the prevention of chronic migraine.

Additional options in secondary care include topiramate and flunarizine, as discussed below. Clinical experience suggests that these may be helpful in those with vestibular migraine or frequent aura. Sodium valproate is only used in exceptional circumstances and where patients are 55 years of age or more.

Topiramate

Start topiramate at 25mg daily, increasing by 25mg every 1-2 weeks, to a target dose of 50mg twice a day. If partially effective and well tolerated further up titration to a maximum of 100mg 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 breast feeding 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, https://www.rcog.org.uk/guidance/browse-all-guidance/green-top-guidelines/

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.

Flunarizine

This medication will be started and issued from the hospital pharmacy. The starting dose is either 5mg or 10mg taken orally at night. The maintenance dose is 10mg at night.
This medication is not licensed in the UK for any indication but is recognised in SIGN 155 as a viable and effective migraine prophylactic agent. In selected patients ECG monitoring for the p.r. interval may be performed.

Depression is a potential side effect, and patients should be warned to stop the medication if depression occurs. Severe depression occurs in a minority of people. Other potential side effects include sedation, weight gain, tremor and Parkinsonism, nausea, dry mouth, gingival hyperplasia, muscle aches and abdominal pain.
Concomitant use with beta blockers can cause bradycardia and impairment of cardiac conduction. We do not recommend this drug for use in pregnancy.

Contraindications include:

• Sick sinus syndrome
• Second and third degree heart block
• Heart failure
• Hypotension
• Severe left ventricular dysfunction
• Cardiogenic shock
• Porphyria
• Parkinsonism

Cautions include:

• History of severe depression
• Current depression
• Those taking frequent dopamine antagonist anti-emetics (increased risk of extra-pyramidal
  side effects)

Sodium Valproate

Sodium Valproate should not be initiated for the prophylaxis of migraine 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.

SIGN 155 Pharmacological management of migraine – updated May 2026; Pharmacological management of migraine

SIGN 155 patient guidance SIGN Migraine patient booklet PAT155 (revised May 2026)

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

National Institute for Health and Care Excellence (NICE). Botulinum toxin type A for the prevention of headaches in adults with chronic migraine (TA260) London: NICE; 2012 Jun 27  https://www.nice.org.uk/guidance/ta260

Migraine Trust: www.migrainetrust.org

   gjnh.cfsdpmo@gjnh.scot.nhs.uk

  www.nhscfsd.co.uk

@NHSScotCfSD

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