Headaches are usually an inconvenience but a migraine can be so disabling it stops a person from getting on with their life. Steve Titmarsh explains...
The International Headache Society classifies headaches as primary or secondary. Primary headache, such as tension-type headache and migraine, is the most common. Secondary headache, as its name suggests, is caused by another condition.1
The British Association for the Study of Headache (BASH) recognises four categories of primary headache: migraine; medication overuse headache; tension-type headache, and trigeminal autonomic cephalagias – cluster headache, for example.1
Tension-type headache is the most common primary headache, with an average 42 per cent of the world’s population experiencing symptoms during their lifetime. Symptoms affect both sides of the head, described as pressing or tightening, but are usually mild or moderate, rarely disabling, and are not made worse by routine physical activity.
Attacks can last from a few hours to a few days. People who have symptoms on 15 or more days a month for three months are said to have chronic tension-type headache.1
The cause of tension-type headache is not fully understood. However, there are a number things that can trigger it, including:2
• poor posture
• dehydration and missing meals
• lack of physical activity
• bright sunlight
• noise and certain smells
Broadly, migraine can be classified as migraine without aura, migraine with aura or chronic migraine,1 although many subtypes exist.3 It affects around one third of women and about 13 per cent of men during their lifetime. Symptoms commonly occur in adults aged 25 to 55 years, and it is often underdiagnosed.4
Chronic migraine is headache that happens 15 days or more each month for more than 3 months and which on at least 8 days each month has the characteristics of migraine and is not better explained by another condition.3 This type of migraine affects about 8 per cent of people with migraine,4 who can experience anxiety, depression, and chronic pain resulting in reduced quality of life.1
Migraine pain is often described as pulsating (or throbbing), which up to 1 in 5 people experience on one side of the head only. Symptoms may be moderate or severe and include nausea, vomiting, and sensitivity to light and sound. About 33 per cent of people with migraine experience aura. An aura may involve visual, sensory or speech symptoms.1
People with migraine often have one or two attacks a month that typically last from four to 72 hours.1
Symptoms may disappear without intervention. Severe or sudden symptoms may signal a more serious problem that needs medical investigation (see When to refer).
Simple analgesics such as paracetamol, aspirin (for people over 16 years old) or ibuprofen, taken as soon as possible after symptoms start, are usually sufficient to control symptoms. Opioids should not be used to treat occasional tension-type headache symptoms. Other causes such as stress, poor sleep, some mood disorders and chronic pain may be associated with tension-type headache and should be treated.5
Headache do’s and don’ts6
• Keep well hydrated by drinking sufficient water
• Relax – stress can aggravate headache symptoms
• Take plenty of exercise
• Take plenty of rest, especially if a headache is accompanied by a cold or flu
• Drink alcohol
• Stop eating even if there is loss of appetite
• Sleep longer than usual
• Strain eyes by, for example, staring at a screen for long periods of time.
When to refer6
Refer patients with headache symptoms to their GP if:
• Their headache appears suddenly or symptoms are severe
• Their headaches, despite treatment, frequently recur or become worse
• They feel sick, vomit and find light or noise painful
• They have associated symptoms such as numbness or weakness in their arms or legs
• They are dizzy or have blurred or double vision.
Preventive treatment for chronic migraine helps reduce the risk of medication overuse that can happen if acute treatment, such as triptans, is used too frequently. Around two-thirds of people with chronic migraine overuse medication, which is itself a cause of a chronic disorder known as medication overuse headache.
People who take triptans, opioids or combination analgesics on 10 days or more each month are likely to develop medication overuse headache more quickly than those who take simple analgesics, such as paracetamol, 15 days or more each month. Symptoms tend to resolve once medication is stopped.1
The BASH Headache Management System for Adults 2019 says that migraine on four or more days each month is associated with significant disability and recommends that patients with that frequency of attacks should be offered preventive treatment.1 Choice of medication is guided by drug side-effect profiles, patient preferences and co-morbidities.7
BASH recommends that the dosage is slowly increased until effective, or to the maximum tolerated, and continued for at least 6–8 weeks to properly assess whether a drug is effective. Patients may be asked to keep a headache diary to help assess drug effectiveness. Gradual treatment withdrawal can be considered after 6–12 months of successful treatment.1
Drugs recommended as preventive treatment for chronic migraine include propranolol, amitriptyline, candesartan and topiramate.1 Contraindications limit the use of these drugs - for example, asthma with propranolol, and heart disease and epilepsy with amitriptyline. Sodium valproate has also been used off-licence to prevent migraine but should not be given to women of childbearing age or used during pregnancy.7
More recently calcitonin gene-related peptide (CGRP) antagonists, which act by blocking CGRP receptors, have been developed and specifically licensed for migraine, including erenumab, fremanezumab and galcanezumab.1 These drugs bind to CGRP or its receptor to block the effects of excessive CGRP released in trigeminal sensory nerves during migraine attacks.8
Another class of drugs, known as gepants (ubrogepant, rimegepant and atogepant),9 which block CGRP receptors centrally and peripherally,8 can be given orally for migraine symptoms.10 In trials ubrogepant and rimegepant resulted in freedom from pain at two hours in around 1 in 5 patients.
They may prove beneficial for people with migraine for whom triptans do not work or cannot be tolerated, or those with significant cardiac or cerebral vascular risk factors because gepants do not cause cardiac or cranial artery constriction. At the time of writing the gepants were not approved for prevention.9
Botulinum toxin type A is also licensed for prophylaxis of headaches in adults with chronic migraine. Although its use is recommended only after three other treatments have failed, and it should be stopped if patients experience less than a 30 per cent reduction in headache days each month after two treatment cycles, or their migraine becomes episodic for more than three consecutive months.11
In the pipeline
In March 2020 NICE issued a draft recommendation for fremanuzemab for the prevention of chronic migraine in adults where three other preventive drugs have failed.12,13 The drug must be stopped if migraine frequency is not reduced by at least 30 per cent after 12 weeks. No date for publication of the final document was available on the NICE website at the time of writing (it has been delayed by the COVID-19 pandemic).12
Similar draft guidance for erenumab said the drug was not recommended for preventing migraine in adults who have at least four migraine days a month.14 Guidance for galcanezumab for preventing migraine is in development.15
Fremanuzemab was studied in a double-blind, placebo-controlled trial lasting 12 weeks, involving 1,130 patients with chronic migraine who had a mean of 21 headache days each month of which 13 were of moderate severity. Participants were allowed to use acute migraine treatment as well as fremanuzemab.
Patients taking fremanuzemab saw a significant mean change in the number of days they had a headache of moderate severity or worse of -4.3 to -4.6 days compared with -2.5 for patients taking placebo (p<0.0001).16
The exact mechanism by which CGRP antagonists such as fremanuzemab prevent headache is still not known, but during migraine attacks CGRP levels have been seen to rise significantly then return to normal once the migraine subsides.16
CGRP is thought to have a role in pain modulation, perception and sensitisation.8 The compound is thought to have central and peripheral effects linked to migraine, for example, vasodilatation of vascular smooth muscle.17
The Migraine Trust says that for some patients fremanuzemab can be life changing, which underlines the significant impact migraine can have on people’s lives.18
Another CGRP antagonist – epitinezumab – was recently approved by the Food and Drug Administration in the USA for migraine prevention.19 Two randomised trials compared a 100mg or 300mg dose given every three months with placebo
In a phase 2 trial – Prevention of Migraine via Intravenous ALD403 Safety and Efficacy (PROMISE-1) – in months one to three there was a significant reduction in the mean number of migraine days of -3.9 days (p=0.018) and -4.3 days (p<0.001) for the 100mg and 300mg doses, respectively, compared with -3.2 days for placebo. Baseline migraine frequency was 8.6 days per month.20
In a phase 3 trial – PROMISE-2 – the mean change in monthly migraine days from baseline (16.1) during months one to three was -7.7 days in the 100mg (p<0.001) and -8.2 days in the 300mg (p<0.001) groups compared with -5.6 days for placebo.21
A new class of migraine drugs – serotonin (5-HT) 1F receptor agonists (also known as ditans) – includes compounds such as lasmiditan, which was approved in the USA for acute migraine treatment in adults in October 2019.22 Unlike triptans that cause vasoconstriction via their effects at the 5HT1B receptor subtype, the targeted nature of the ditans may make them more suitable for patients with cardiovascular disease.
In clinical trials significantly more participants taking lasmiditan were pain free at two hours compared with placebo – around 28–38 per cent versus about 15–21 per cent among those given placebo.23
1. British Association for the Study of Headache (BASH). National headache management system for adults 2019. Hull: BASH, 2019.
2. www.nhs.uk/conditions/tension-headaches/stress and anxiety; accessed 20.5.20.
3. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalagia 2018;38:1–211.
4. Clinical Knowledge Summaries. Migraine (https://cks.nice.org.uk/migraine#!scenario; accessed 15 May 2020).
5. Clinical Knowledge Summaries. Headache – tension-type (https://cks.nice.org.uk/headache-tension-type#!topicSummary; accessed 20 May 2020).
6. www.nhs.uk/conditions/headaches; accessed 19 May 2020.
7. British National Formulary. Preventative migraine treatment (https://bnf.nice.org.uk/treatment-summary/migraine.html; accessed 25 May 2020).
8. Agostini EC, Barbanti P, Calabresi P, et al. Current and emerging evidence-based treatment options in chronic migraine: a narrative review. J Headache Pain 2019;20:92.
9. www.practicalpainmanagement.com/treatments/pharmacological/new-migraine-medications-oral-gepants-ditan-tablet-more; accessed 25 May 2020.
10. www.aamc.org/news-insights/new-era-migraine-relief; accessed 25 May 2020.
11. National Institute for Health and Care Excellence (NICE). Botulinum toxin type A for the prevention of headaches in adults with chronic migraine. Technology appraisal guidance (TA260). London: NICE, 2012.
12. www.nice.org.uk/guidance/gid-ta10339/documents/final-appraisal-determination-document; accessed 18 May 2020.
13. www.medicines.org.uk/emc/product/10386; accessed 25 May 2020.
14. www.nice.org.uk/guidance/gid-ta10302/documents/final-appraisal-determination-document; accessed 25 May 2020.
15. www.nice.org.uk/guidance/indevelopment/gid-ta10454; accessed 25 May 2020.
16. Teva UK Limited. Ajovy (fremanuzemab) 225mg pre-filled syringe for injection Summary of Product Characteristics. www.medicines.org.uk/emc/product/10386/smpc; accessed 18 May 2020.
17. Benemei S, De Cesaris F, Fusi C, et al. TRPA1 and other TRP channels in migraine. J Headache Pain 2013;14(1):71.
18. www.migrainetrust.org/nice-gives-chronic-migraine-patients-access-to-life-changing-new-drug; accessed 18 May 2020.
19. www.neurologytimes.com/headache-and-migraine/eptinezumab-approved-migraine-prevention; accessed 26 May 2020.
20. Ashina M, Saper J, Cady R, et al. Eptinezumab in episodic migraine: A randomized, double-blind, placebo-controlled study (PROMISE-1) Cephalagia 2020;40:241–54.
21. Lipton RB, Goadsby PJ, Smith J, et al. Efficacy and safety of eptinezumab in patients with chronic migraine. PROMISE-2. Neurology 2020;94:e1365–77.
22. www.neurologylive.com/clinical-focus/lasmiditan-approved-for-migraine-treatment-in-adults; accessed 28 May 2020.
23. Do TP, Guo S, Ashina M. Therapeutic novelties in migraine: new drugs, new hope? J Headache Pain 2019;20:37.
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