Migraine in focus

Migraine is the second most prevalent neurological disorder (after tension-type headache) with a female-to-male ratio of 2:1. The term migraine has a Greek origin and originates from the word ‘haemicranias’ which means ‘half the head’. This is a characteristic feature of the disease, as the pain occurs unilaterally in most individuals, However, bilateral pain is also common and takes place at the front and the back of the head. Although headache is the cardinal symptom of migraine, it is not necessarily always the most bothersome for all patients. An acute migraine attack is defined as unilateral, throbbing, severe headache lasting longer than four hours associated with nausea and/or vomiting, phonophobia and photophobia and worsened with exertion or movement.

Epidemiology

The global prevalence of migraine is approximately 14.4 per cent in the general population with more than one billion individuals being afflicted by this disorder worldwide. The prevalence peaks between the ages of 35 and 39 years, and approximately 75 per cent of affected persons report the onset of migraine before the age of 35 years.

Before puberty, females and males are equally affected, however, after puberty, the occurrence of migraine is two-to-three times commoner in females than in males. Men suffering from migraine generally have less severe attacks and disabilities than women.

When it comes to the burden of disease, migraine is responsible for 4.9 per cent of global ill health, quantified as disability-adjusted life-years (DALYs). It has an impact on the individual’s family relationships, economic situation, direct medical costs, work, and school performance.

Classification

The International Classification of Headache Disorders (third edition)provides diagnostic criteria for the three main categories of migraine: Migraine without aura, migraine with aura, and chronic migraine.

Chronic migraine refers to headaches (suggestive of migraine or tension headaches) on 15 days or more per month for greater than three months and affects approximately 5-to-8 per cent of persons with migraine, whereas episodic migraine, which is defined as fewer than 15 migraine days per month with or without aura, accounts for more than 90 per cent of patients with migraine. Among individuals with migraine, episodic migraine is more prevalent than chronic migraine

The estimated rate of progression from episodic migraine to chronic migraine is 2.5 per cent per year. The predisposing factors for this progression include high frequency of migraine attacks, medication overuse, obesity, and comorbid pain syndromes.

An aura is experienced by approximately 20-to-30 per cent of patients with migraines, with visual aura being the most common, occurring in over 90 per cent of patients with migraine with aura.

There are a number of rare or specific-trigger types of migraine.

Basilar migraine: This is a rare form of migraine that can feature double-vision, blurred vision, loss of balance, possible fainting, and speaking difficulties. Also known as ‘migraine with brainstem aura’, it is characterised by symptoms such as dysarthria, vertigo, or ataxia, without evidence of motor weakness.

Hemiplegic: Another rare form of migraine that features the pain that usually accompanies other types of migraine, but with numbness, weakness and in some cases temporary paralysis on one side of the body. This is one of the more challenging migraines to diagnose, as the symptoms can often mimic the effects of a stroke.

Ophthalmoplegic: Another very rare form of migraine, this mainly occurs in younger people and is often accompanied by muscle weakness in the eye, as well as other eye manifestations.

Abdominal migraine: Abdominal migraine is quite a common condition that affects four-in-100 children and also some adults. Symptoms are usually nausea- and stomach-related rather than headache. Children usually stop experiencing abdominal migraine by the time they reach adulthood, but often develop migraine headache later in life.

Menstrual migraine: Affecting women, migraine attacks caused by menstruation (hormonal) are typically more severe and last longer than migraine attacks at other times of the month. 

Migraine aura without headache: This occurs in only around 1 per cent of migraineurs, where the sufferer experiences aura, but without the accompanying headache.

Migraines may be further divided into two categories, these being resistant and refractory migraines.

Resistant migraines are described as migraines which have failed at least three classes of migraine preventatives and individuals suffering from at least eight debilitating headache days per month for a minimum of three consecutive months without any improvement whatsoever.

‘The International Classification of Headache Disorders’ (third edition) provides diagnostic criteria for the three main categories of migraine: Migraine without aura, migraine with aura, and chronic migraine’

Refractory migraines are migraines which have failed all of the available preventatives and individuals suffer from at least eight debilitating headache days monthly for at least six consecutive months.

Phases of migraine

A migraine can last anywhere from a few hours to days. Migraine is defined as a cyclic disorder characterised by a series of four key phases which often overlap: The prodromal stage, aura, headache pain, and post-drome stage.

The prodromal or premonitory phase can precede the headache of a migraine attack by 72 hours and this phase may consist of a combination of fatigue, neck stiffness, difficulty with concentration, sensitivity to light and/or sound, blurred vision, nausea, yawning, and pallor amongst others. Most of these symptoms continue, and may worsen, in the headache phase.

The aura phase occurs in about 20-to-30 per cent of migraines. (Migraine without aura does not include this stage.) The aura part of migraine includes a wide range of neurological symptoms usually before the headache stage. These symptoms include changes in sight (visual disturbances) such as dark spots, coloured spots, sparkles or ‘stars’, and zigzag lines; numbness or pins and needles – weakness; dizziness or vertigo (sensation of spinning and poor balance); speech and hearing changes; and some people experience memory changes, feelings of fear and confusion, and more rarely, partial paralysis or fainting.

The headache phase may last from four-to-72 hours and can cause moderate-to-severe head pain. The headache is typically throbbing and is made worse by movement. It is usually on one side of the head, especially at the start of an attack.

Following resolution of the migraine, there may be a postdromal phase that may last hours/days. The most common symptoms described to occur in this ‘hangover’ phase include tiredness/sleepiness, neck stiffness, difficulty with concentration, and mild residual head discomfort.

Causes/risk factors

Various general and individual risk factors for migraine have been identified and these include head trauma, advanced age, lower socioeconomic status, medication overuse, diet, increased caffeine and alcohol intake, sleep problems, increased body weight and obesity, stress, weather changes, pain, and pro-thrombotic and pro-inflammatory states. Triggers are very individual and a diary should be kept which can help identify hormonal, emotional, physical, dietary, environmental, and medicinal triggers.

Migraine is considered to have a strong genetic component and studies have shown that migraine can run in families.

Pathophysiology

Despite some progress in understanding migraine pathogenesis over the past decade, many aspects of this complex disorder remain poorly understood.

The underlying mechanism appears to be a possibly complex, genetic predisposition in combination with environmental and behavioural conditions causing a modification of sensory brain processing, which subsequently results in increased sensory susceptibility. This process results in normal sensory inputs being perceived as disturbing in individuals who suffer from migraines

Neurotransmitters, such as serotonin, play major roles in the pathophysiology of migraine.

During the pro-dromal phase, there is activation of the hypothalamus and thalamus along with increased blood flow to the hypothalamus and in circuits connecting the thalamus-cortex.

In the aura phase, there is depolarisation of the cortex along with creation of a transient wave – collectively known as cortical spreading depression.

It has been suggested that the postdromal phase might be a result of persistent activation of the brainstem and diencephaly during and after processing the pain stimuli.

Diagnosis

For an accurate diagnosis of migraine, there must be a recognition of the pattern of headaches and of the migraine phases. Additionally, the diagnostic process requires a thorough history of the condition. Any medical history of anxiety, depression, or sleep issues should be sought along with a history of allergy, current and past medications, family and social history, diet (mainly coffee and alcohol intake), smoking, and occupation. A physical examination should also be carried out in order to identify any issues which may be exacerbating the patient’s tendency for developing migraine. Inspection, fundoscopy, and palpation of the head and neck structures could be performed along with brief cardiovascular and neurological screening examinations.

Diagnosis of migraine does not require any specific investigations – it is mainly diagnosed by the typical history. However, blood investigations and imaging modalities, mainly CT and MRI may be used to exclude other possible causes of headache.

Management of migraine – acute and preventive

The primary aim of treatment for migraine is to reduce the duration and severity of the migraine attack. Other aspects of management include the restoration of functional ability, reduction of the usage of rescue medications, and promotion of overall management with minimal or no adverse effects. Preventive treatment is recommended for patients that have frequent or severe migraines, causing significant disability, and reduced quality-of-life.

Pharmacological treatment

1. Paracetamol:

• It is a non-opioid analgesic and an antipyretic agent, which acts to relieve pain and for the treatment of fever.

• It is commonly used as a single agent to treat both mild and moderate forms of migraine.

• It is considered to act by inhibition of COX (cyclooxygenase) enzyme, an enzyme which works by inhibiting prostaglandins. Prostaglandins usually act as mediators of the inflammatory response. 

• Severe liver pathology and hypersensitivity to paracetamol are contraindications.

2. Non-steroidal anti-inflammatory drugs:

Naproxen:

• This drug is used as an anti-inflammatory, antipyretic and analgesic agent.

• It is used preferably for its analgesic properties and is usually reserved for the early treatment of
  migraines.

• The half-life of naproxen is between 12 and 17 hours, exceeding that of ibuprofen. 

• The contraindications for its use include ulceration and hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin.

Ibuprofen:

• Ibuprofen has anti-pyretic, analgesic, and anti-inflammatory effects on migraine.

• This drug inhibits both COX-1 and COX-2 enzymes, both of which play an imperative role in prostaglandin synthesis.

Aspirin:

• This drug is used either alone or in combination with other drugs to treat chronic headache.

• Aspirin is also an inhibitor of both the COX enzymes.

• As aspirin is also used as an antiplatelet therapy, it increases the risk of bleeding.

3. Combination therapy:

• In the early treatment of headaches during an acute migraine attack, a combination of paracetamol and caffeine may be considered.

• Caffeine works by further enhancing the analgesic effect of other medications such as paracetamol
  and aspirin.

• A combination of paracetamol, aspirin, and caffeine is used as triple analgesic therapy when treating chronic migraines.

4. Melatonin:

• Melatonin is a hormone which acts on hypothalmic receptors in order to promote sleep.

• It is used as a short-term medication in the treatment of insomnia and the prevention of migraine.

• Contraindications for this drug include pregnancy and breastfeeding.

Triptans

• These drugs are used as first-line treatment in acute attacks of moderate-to-severe migraine, especially in those individuals in which pain is not relieved by analgesics such as NSAIDs. They should be taken as early as possible during a migraine.

• Triptans are selective serotonin agonists. They work by binding to serotonin receptors (5-HT1B) in dilated intracranial vessels during a migraine attack and produce vasoconstriction. This binding in the neurogenic and central systems results in an inhibition of substance P and CGRP release and blocks pain signals to the brain via nociceptor inhibition.

• Contraindications to the use of triptans include severe hepatic and renal impairment, coronary artery disease, poorly controlled hypertension, hemiplegic migraine, and basilar migraine.

• Long-term use of triptans, ie, for longer than 10 days monthly, may cause ‘triptan-overuse headache’.  Triptans are available as tablets, injections, and nasal sprays. All triptans available in Ireland are prescription-only, apart from sumatriptan.

5. Monoclonal antibodies targeting the CGRP pathway:

• The calcitonin gene-related peptide (CGRP) has become the target for the prevention and management of migraine in view of its critical role in the pathophysiology of migraines.

• These drugs have been recommended as long-term and effective preventive drugs for migraine. They have been associated with a reduction in the frequency of migraines and also with improvements in the quality-of-life.

• The CGRP monoclonal antibodies (MABs) erenumab, fremanezumab, and galcanezumab are available through the HSE under the High Tech Arrangement and eptinezumab is available under hospital pricing approval. A Managed Access Protocol is in place for the CGRP MABs. This outlines the criteria that must be satisfied in order for a patient to be recommended for reimbursement of erenumab, fremanezumab, or galcanezumab under the High Tech Arrangement, or eptinezumab under hospital pricing approval.

• The prescribing of erenumab, fremanezumab, and galcanezumab under the High Tech Arrangement and eptinezumab under hospital pricing approval is confined to consultant neurologists who have agreed to the terms of the HSE-Managed Access Protocol and have been approved by the HSE-Medicines Management Programme. Full information is available here: www.hse.ie/eng/about/who/cspd/medicines-management/managed-access-protocols/cgrp-mabs/.

6. Gepants:

• This new class of specific migraine drugs are small-molecule CGRP receptor antagonists.

• These drugs can be used in both the prevention and treatment of migraine and include rimegepant, ubrogepant and atogepant (oral tablets), and zavegepant (nasal spray). Compared to conventional acute treatments, the gepants do not seem to cause rebound or medication overuse headache. While gepants are available in the UK through the NHS, they are yet to be reimbursed by the HSE.

7. Ditans:

• Ditans are a new emerging class of oral drugs for the acute treatment of migraines. They are highly selective to the 5-HT1F receptor and lasmiditan was the first drug in this class to be approved. Ditans are yet to be reimbursed in Ireland or the UK.

8. Antiemetics:

• Management of nausea is imperative in the management of migraine, as it may impair absorption.

• Additional administration of antiemetics with analgesics aids in the management of this condition.

• Oral metoclopramide at a dose of 10mg is commonly used to treat migraine-related nausea.

• Prochlorperazine 10mg is an alternative option, but this has a higher risk of extrapyramidal effects.

• Furthermore, domperidone 10mg may also be used, but this is less efficient than metoclopramide.

Other options

• There are various other medications which may be used in order to prevent migraine and these include betablockers, angiotensin-receptor blockers, and the anticonvulsant topiramate (not suitable in women of childbearing age due to teratogenic effects) as first-line medications followed by tricyclic antidepressants, calcium antagonists, and the anticonvulsant sodium valproate (not suitable in women of childbearing age due to teratogenic effects) as second-line.

• Botulinum toxin is another well-established treatment option for patients with chronic migraine. In Ireland, Botox is approved for the treatment of adults fulfilling the criteria for chronic migraine (defined as having at least 15 headache days a month, with at least eight of those featuring migraine symptoms) who are intolerant of/have not responded adequately to prophylactic migraine medications.

• Greater occipital nerve blocks have been demonstrated to be effective for migraine. They involve an injection of a steroid and local anaesthetic around the greater and lesser occipital nerves that are located on the back of the head just above the neck area, which reduces inflammation, and thus pain and migraine, and the effects may last up to a few months.

Neuromodulatory devices

• Neuromodulatory devices have been shown to be effective in reducing the frequency and intensity
  of headaches.

• These work by using an electric current or a magnetic field in order to stimulate the nervous system centrally or peripherally, which in turn modulates pain mechanisms involved in headache.

• Several neuromodulatory devices are available for the treatment of migraine and these include single-pulse transcranial magnetic stimulation, external trigeminal nerve stimulation, non-invasive vagus nerve stimulation, and remote electrical neuromodulation.

Non-pharmacological measures

Lifestyle modifications are an important aspect of migraine management and can help to reduce both the frequency and severity of migraine attacks. Triggers that may precipitate migraine attacks should be identified and avoided. These may include certain foods, caffeine, stress, alcohol, smoking, bright lights, and strong odours. Establishing a good sleep pattern is important in preventing migraines and patients should be encouraged to practice good sleep hygiene habits.

Physical activity is also important. Exercise has an effect on the severity, duration, and total amount of days of migraine attacks. Studies have proven that aerobic exercise reduces the frequency of migraine attacks.

Stress management to help avoid migraine can include relaxation activities, yoga, meditation, and mindfulness.

Cognitive behavioural therapy is a commonly used treatment that uses cognitive factors in order to improve mental disorders and psychological distress.

These stress avoidance/management techniques have proven effective in reducing the frequency of migraine attacks and related disorders.

Advice and support

The Migraine Association of Ireland offers useful advice and support for people with migraines, and information and training for healthcare professionals – www.migraine.ie.

References on request

Authors: Dr Francesca Briffa, MD (Melit), BSc (Hons) Pod, Letterkenny University Hospital; and
Dr Mark Emanuel Debono, MD (Melit), PGDip Endo (USW), Letterkenny University Hospital

Supported by Abbvie