By remaining alert for potential secondary causes and offering effective analgesics and management advice, pharmacy teams can do much to help patients with headache and migraine

Learning objectives

After reading this feature you should be able to:

• Explain the causes and management options for headache and migraine
• Discuss the latest research into possible treatments
• Recognise red flag symptoms and know when to refer.

We’ve all suffered occasional headaches, after too long in front of a computer, too little sleep or too indulgent a celebration…but some headaches are frequent and debilitating. 

I suffer from migraines. They begin as an intense throbbing usually around my right temple, almost as if someone is going to work on my skull with a drill, a vampiric aversion to light and a rapid erosion of any ability to string thoughts together. Thankfully, such attacks are rare and short-lived. I cannot begin to imagine the suffering and disability of life with chronic migraine, defined, rather arbitrarily, as headaches on at least 15 days a month. Some headache disorders may be even worse. 

Cluster headache is often described as “the most painful disorder known to affect humans”.¹ The finding that 55 per cent of cluster headache patients report suicidal thoughts shows just how distressing the condition can be.²

To be able to help, it is important to understand the number of people affected. In 2016 in the UK, 17.3 million people suffered from tension-type headache and 11.3 million had migraine.

Causing a mild or moderate sensation of a tight band or pressing pain on both sides of the head that lasts from several hours up to a few days, tension-type headaches may be more common – but migraines cause more disability: 77,508 and 496,293 years lived with disability during 2016 in the UK respectively.^3,4 

Cluster headache is mercifully rare. The lifetime prevalence is about 0.4 per cent, although as the condition may be misdiagnosed as migraine it is probably under-recognised.^5,6

Headaches emerge from a plethora of causes.⁷ Primary headaches can arise from some 300 separate diagnoses, including migraine, tension-type headache and cluster headache.^7,8 Many people experience more than one primary headache – for example, over 80 per cent of migraineurs also report tension-type headaches.⁷ 

Secondary headaches can arise from, among other causes, trauma, vascular malformations and infections. People aged 65 years and older are more likely than younger people to have a serious secondary cause.⁷ To complicate diagnosis further, some people have a primary headache and a superimposed secondary headache.⁷ If there is any doubt about the diagnosis or treatment, patients should be rapidly referred.

Key facts

• Recognition of CGRP’s central role in migraine and chronic headache is leading to new drug treatments
• About 20-25 per cent of female migraineurs experience attacks around the time of menstruation
• Between 30 and 50 per cent of patients who develop chronic headaches overuse medication.

From blood vessel to brain

Many aspects of headache biology remain poorly understood. For many years, for example, researchers suggested that migraines began with abnormal blood flow in the cranial circulation^8,9 – a theory that led to some important and effective treatments. Neuroimaging, however, reveals that migraines seem to arise after activation of the hypothalamus, which starts up to 48 hours before the person feels the headache.^8,10 This activation seems to account for some early symptoms such as sleep disturbances, food craving and yawning.¹⁰ 

The abnormal brain activity spreads to connected areas, such as the thalamus and brain stem, and then to the trigeminal nerves that innervate cranial blood vessels.⁸ A wave of ‘depression’ (excitation followed by inhibition) spreads across the cortex, which seems to evoke the aura.¹⁰ The pons, in the brain stem, is associated with pain perception during headaches.¹⁰ Repeated migraines, even as few as four attacks a month, can sensitise the nervous system, making attacks more frequent, more severe and less responsive to treatment.^7,11

Activation of pain fibres, such as those releasing calcitonin gene-related peptide (CGRP), gives rise to the headache.⁸ Blood vessel walls throughout the body, including those in the head, face and meninges, receive CGRP innervation (more below).¹ 

CGRP could sensitise nerves by increasing their firing rate and triggering inflammation. CGRP also dilates blood vessels and these could push on adjacent pain receptors, triggering pain signals to release even more CGRP.⁹ This recognition of CGRP’s central role in migraine and cluster headache is leading to new drugs.²

Migraine is two to three times more common in women than men and is most frequent between 18 and 50 years of age,⁸ which offers another clue about the cause. About 20-25 per cent of female migraineurs experience attacks around the time of menstruation.¹² These can occur by chance but menstrual migraines show a more intimate relationship. 

Some women experience migraines only from two days before to three days after menstruation. Other women also experience attacks at other times of the month but the attacks around menstruation may be particularly disabling and long lasting. Changes in hormone levels may contribute to menstrual migraines.¹²

Think about triggers

The relationship between menstruation and migraine demonstrates the importance of asking about headache triggers. People with frequent headaches should be encouraged to keep a diary of the date, duration, symptoms, treatment and outcome.7 Recording treatment helps identify analgesic overuse headache, a topic we’ll return to.

There is a lot of advice pharmacists can offer, such as reminding people with tension-type headaches to watch their posture. Poor posture and head alignment can strain neck and shoulder muscles which, in turn, can activate the myofascial trigger points linked with tension-type headaches.⁴ Stress, skipping meals, sleeping too long or too little, inappropriate or insufficient exercise and consuming too much caffeine can trigger tension-type headaches.⁴ Numerous factors can trigger a migraine, so suggest patients check the relevant list on the NHS website.

Histamine, alcohol, nitroglycerine, weather changes and stress can all trigger cluster headache⁶ but sleep is particularly influential. In one study, 80 per cent of people with episodic or chronic cluster headache said that sleep at night triggered a headache. Only a third said that napping had a similar effect.⁶ 

Cluster headache tends to occur at specific times during the night, typically between 2-4am.¹ Unlike migraine, sleep does not relieve the pain.⁶ 

One theory associates cluster headache with rapid eye movement (REM) sleep, which may contribute to learning, memory consolidation, regulation of synapses and vivid dreams. Indeed, some cluster headache patients report vivid dreams about the time the acute headache begins. 

Cluster headache attacks tend to decrease toward the end of spring then increase from early autumn, so pronounced light-dark cycles may stress systems that respond to environmental changes. Further studies need to unravel the relationship between sleep, environmental cues and cluster headache.⁶ 

Focus on calcitonin gene-related peptide

Calcitonin gene-related peptide (CGRP), one of the most abundant peptides in the peripheral and central nervous systems, influences gastrointestinal, respiratory, cardiovascular, urogenital, endocrine and sensory function. It is present in the parts of the brain linked with cluster headache, such as the posterior hypothalamus, which is active during attacks.¹ 

Levels of several hormones change in people with cluster headache. Several of these, including melatonin and cortisol, are controlled by the hypothalamus.^1,2 

Administering CGRP can trigger an acute headache. During the active phase, CGRP levels in the blood in the jugular vein on the side of the head affected by the attack rise. These and several other lines of evidence link CGRP with cluster headache, making the neuropeptide a logical target for new treatments.²

Lockdown and migraine 

Trigger factors may help explain a seemingly curious finding. Researchers in the Netherlands discovered that 592 migraineurs reported experiencing a migraine or using acute medication on fewer days (both by, on average, 0.48 days) and improved general wellbeing during the first month of lockdown compared with the previous month. The results were consistent in 469 patients followed for two months before and two months after lockdown. In contrast, lockdown did not affect non-migraine headaches.¹³

The authors speculate that the improvement reflects the opportunity to work from home, fewer demands on social lives and freedom to schedule time. For example, migraineurs could rest during an attack, which may reduce the risk of recurrence.¹³ The lack of face-to-face consultations also encouraged some migraineurs to monitor their symptoms. This, in turn, could help patients recognise the behaviours, such as lifestyle habits and medication overuse, that exacerbate migraines.¹⁴

Pharmacy teams could suggest that people with frequent headaches try non-pharmacological therapies, such as relaxation, biofeedback, cognitive behavioural therapy, acupuncture and physical therapy.⁷  

The authors of the Dutch study comment that the improvement during lockdown shows the importance of “making full use of behavioural interventions to maximise the effect of pharmacological treatment and obtain the best possible results for patients”.¹⁴

Treating headaches

Most people with headaches need pharmacological treatment. Usually OTC analgesics, such as ibuprofen and paracetamol, alleviate tension-type headaches.⁴ Patients should be advised to take the full dose of analgesics as soon as they feel a headache developing to maximise pain relief.⁴ 

During moderate or severe migraines, ibuprofen or aspirin provided freedom from pain within two hours in 26 and 24 per cent of migraineurs respectively, compared with 12 and 11 per cent after placebo.¹⁵ 

In general, drugs used for the acute treatment of non-menstrual attacks are effective for perimenstrual migraine. There is, however, a “clinical impression that perimenstrual attacks in women diagnosed with menstrually-related migraine do not respond as well to acute treatment as do their attacks outside of this window”.¹²

If OTC drugs don’t offer sufficient relief, refer to a GP. 

Triptans (5HT₁B and 5HT₁D agonists), for example, provide pain relief lasting at least two hours in up to half of people with migraine.9,16 Triptans are most effective when taken, while the person experiences mild pain (i.e. early in the headache phase).¹⁵

Monoclonal antibodies and small chemical drugs that target CGRP are effective for the acute treatment and prevention of migraine and seem promising for cluster headache.^2,9 

When used to prevent migraine, drugs that target CGRP almost entirely stop attacks in about 25 per cent of people while another 50 per cent report fewer attacks.⁹ Indeed, monoclonal antibodies targeting CGRP reduce migraine frequency in patients with episodic and chronic migraine who didn’t respond to up to four classes of preventive drugs (e.g. topiramate, amitriptyline and propranolol).^15,16 

Cluster headache

Cluster headache treatment comprises three phases.² Vasoconstrictors, including sumatriptan, oxygen and devices, such as non-invasive vagus nerve stimulation (VNS), may alleviate acute headaches.¹ Subcutaneous sumatriptan alleviates pain in 75 per cent of patients within 15 minutes, for instance. A third are pain-free.² 

Verapamil, VNS, lithium, topiramate and prednisolone may prevent cluster headache.¹ Verapamil and lithium have delayed onsets of action and need slow titration¹⁷, so transitional treatment (e.g. with oral steroids or suboccipital steroid injections) bridges the gap between preventive drug use and the benefits emerging.^5,17

Despite these benefits, pharmacy teams need to be alert for people who overuse headache treatments. Between 30 and 50 per cent of patients who develop chronic headaches overuse medication and develop analgesic overuse headaches. In other words, a patient with a primary headache experiences headache on at least 15 days a month because they regularly overused acute or symptomatic headache treatments for more than three months.⁷ 

Each year, about 2.5 per cent of people with episodic migraine (fewer than 15 headache days a month) develop chronic migraine. Again, a plethora of factors contribute to the transition. For instance, overuse of opioids (odds ratio OR 4.4), triptans (OR 3.7), ergotamines (OR 2.9), non-opioid analgesics (OR 2.7) and missing the opportunity to treat an attack before the headache develops increased the risk of migraine escalation.⁷ As one review comments, “addressing medication overuse may be the most important intervention for increasingly frequent headaches”.⁷ 

Cluster headache explained

Cluster headache patients report sudden, severe pain on one side of the head or face, usually around the eyes, that peaks within seconds, and lasts between 15 minutes and three hours.^2,6 

The frequency of headaches during a cluster varies from one every other day to up to eight times a day.² Not surprisingly, cluster headache patients can feel restless or agitated.² 

Many cluster headache sufferers experience autonomic symptoms, such as ptosis (dropping eyelid), miosis (excessive pupil constriction), facial redness or flushing, nasal congestion, rhinorrhoea and swelling around the eye, on the same side as the headache.⁶ About 85 per cent of patients have episodic cluster headache: i.e. they experience clusters of attacks over weeks to months. The remissions last months to years.^1,2 

The remainder have chronic cluster headache with few, if any, remissions, which, if they occur, tend to be short-lived.¹

Secondary headaches

It is also important to be alert for red flags that may suggest underlying disease. For example, headache and fever accompanied by symptoms including neck stiffness, decreased consciousness and neurological deficits may suggest an infection, such as meningitis. Research shows that 49-81 per cent of people with a brain abscess report headaches, while 29-57 per cent experience fever.¹⁸ 

Headaches in a person with a malignancy, especially lung or breast cancer or malignant melanoma, could arise from an intracranial metastasis. People with brain cancer may also report emesis, onset in the last 10 weeks, an atypical pattern (e.g. pulsating quality and moderate to severe intensity) and unstable gait.¹⁸

About a quarter of people report headache during an acute, particularly haemorrhagic, stroke. Headache severity does not relate to the size of the stroke but a thunderclap headache (a sudden, very painful, headache) may be the only initial symptom of subarachnoid haemorrhage.

It should be noted that other types of stroke and neurological conditions (e.g. thrombi) can cause thunderclap headaches.¹⁸ 

Causes of menstrual migraine

Several mechanisms may contribute to menstrual migraine. Oestrogen, for example, excites the µ-opioid system so reducing pain, influences the serotonin system and regulates sensitisation of trigeminal neurons by modulating the release of neuropeptides, including CGRP.¹² The endometrium releases prostaglandins during the first 48 hours of menstruation, but their role in menstrual migraines needs further investigation.¹² 

A recent review concludes that, “menstrual migraine is a common condition associated with considerable disability, but with pathophysiological mechanisms not yet fully understood and few effective preventive options. It should be considered as a distinct disorder warranting greater recognition and research investment.”¹²

References

1. Brain Sciences 2020; 10:30
2. CNS Drugs 2020; 34:171-184
3. Lancet Neurology 2018; 17:954-976
4. International Journal of Clinical Practice. Supplement 2015; 17-20
5. Lancet Neurology 2021; 20:19-20
6. Pain and Therapy 2020; 9:359-371
7. American Family Physician 2020; 101:419-428
8. Trends in Pharmacological Sciences 2021; 42:217-225
9. Nature (Outlook: headaches) 2020; 586:S4-S6
10. Lancet 2021; 397:1496-1504
11. Nature (Outlook: headaches) 2020; 586:S12-S14
12. The Lancet Neurology 2021; 20:304-315
13. Cephalalgia 2021; DOI: 10.1177/0333102420981739
14. Nature Reviews Neurology 2021; 17:195-196
15. Lancet 2021; 397:1505-1518
16. Lancet Neurology 2021; 20:7-8
17. The Lancet Neurology 2021; 20:29-37
18. Neurology 2019; 92:134-144