The diagnosis and treatment of chronic migraine

Abstract

Migraine is the most common disabling brain disorder. Chronic migraine, a condition characterized by the experience of migrainous headache on at least 15 days per month, is highly disabling. Patients with chronic migraine present to primary care, are often referred for management to secondary care, and make up a large proportion of patients in specialist headache clinics. Many patients with chronic migraine also have medication overuse, defined as using a compound analgesic, opioid, triptan or ergot derivative on at least 10 days per month. All doctors will encounter patients with chronic headaches. A basic working knowledge of the common primary headaches, and a rational manner of approaching the patient with these conditions, allows a specific diagnosis of chronic migraine to be made quickly and safely, and by making this diagnosis one opens up a substantial number of acute and preventive treatment options. This article discusses the current state of management of chronic migraine.

Introduction

Migraine is a common disabling brain disorder. Headache accounts for 4.4% of all consultations in general practice [Tepper et al. 2004; Kernick et al. 2008b], approximately 5% of all medical admissions to hospital [Weatherall, 2006], and approximately 20% of neurology outpatient consultations [Stone et al. 2010]. Migraine affects over 20% of people at some point in their lives; epidemiological studies have shown that 4.5% of the population of Western Europe has headache on at least 15 days per month [Welch and Goadsby, 2002]; global studies suggest that approximately 1% of the world’s population may have chronic migraine [Natoli et al. 2010]. Chronic migraine imposes a substantial economic burden on society [Buse et al. 2012]. Migraine is so common that, even though for many people it is no more than an inconvenience, the cumulative burden of the disorder caused it to rank in the top 40 conditions causing worldwide disability according to the World Health Organization’s 2012 global burden of disease figures, above all other neurological disorders other than stroke, meningitis and epilepsy; in the United Kingdom it ranks third behind stroke and the dementias, causing the loss of 230,000 DALYs (Disability-Adjusted Life Years) annually [World Health Organization, 2012].

Chronic migraine is the term that the International Classification of Headache Disorders (ICHD) uses to describe patients with frequent headaches, believed to be biologically migrainous [Headache Classification Committee of the International Headache Society, 2013] The meaning of the term ‘chronic migraine’ has evolved over the last two decades, as it has steadily replaced earlier terminology such as ‘chronic daily headache’ and ‘transformed migraine’ [Olesen et al. 2006; Zeeberg et al. 2009; Goadsby et al. 2010]. There is ongoing debate about whether a further subdivision of the diagnosis should be created to specify patients who are refractory to treatment [Martelletti et al. 2014]. The broader acceptance of the concept that migraine can be a chronic condition has led to increasing interest in the pathophysiology, epidemiology, and treatment of this condition [Diener et al. 2012].

Patients with chronic headaches have in the past experienced the adverse effects of lack of education about headaches, and therapeutic nihilism. There is now no excuse for either of these factors to impact upon the management of these patients. As this article will show, it is almost always possible to make a specific diagnosis in patients with chronic migraine, and by making this diagnosis one opens up a substantial number of treatment options.

Diagnosis of chronic migraine

Recognize the pattern

When assessing a patient with chronic headaches (that is, by definition, headaches on at least 15 days per month), it is important from the outset to ascertain how the headaches originally developed. There are two typical patterns. In one set of cases, patients with a pre-existing primary headache disorder (usually, but not exclusively migraine) have ever-increasing attacks until they reach a stage where they do not recover headache freedom in between, a pattern originally called ‘transformed migraine’ [Mathew, 1987; Silberstein et al. 1996]. In the other set of cases, patients start to have a headache one day, and it simply never goes away. This is a syndrome that goes under the name ‘new daily persistent headache’ (NDPH) [Goadsby and Boes, 2002], and is an important pattern to recognize because it is within this set of headaches that many of the serious causes lie, including those conditions which may present with a thunderclap headache (Box 1). After investigation, however, many cases of new daily persistent headache do not have an underlying cause, and are essentially chronic versions of the more familiar episodic headache disorders [Robbins et al. 2010].

Box 1.

Secondary causes for new daily persistent headache phenotype.

Thunderclap headache

Subarachnoid haemorrhage

Cerebral venous sinus thrombosis (CVST)

Reversible cerebral vasoconstriction syndrome

Carotid/vertebral artery dissection

Pituitary apoplexy

Intracerebral haemorrhage/haematoma

Hypertensive encephalopathy

Idiopathic thunderclap haemorrhage (Call–Fleming syndrome)

Persistent worsening headaches

Raised cerebrospinal fluid (CSF) pressure (tumour, abscess, CVST, idiopathic intracranial hypertension)

Low CSF volume (post-lumbar puncture, spontaneous CSF leak)

Meningitis (acute/chronic)

Hypoxia/hypercapnia

Substance abuse/withdrawal

Systemic inflammatory conditions, including temporal arteritis

Patients may be surprised that you want to know about events that happened in the past (sometimes some years previously) and what their headaches used to be like, but because chronic headaches often become steadily more featureless over time, establishing the original phenotype can be crucial in making an accurate diagnosis, without which treatment is unlikely to be successful.

Recognize the disorder

Migraine is the commonest cause of recurrent, severe headache. It is experienced at some point by over 20% of women and over 10% men. The tendency to suffer from migraine has a genetic basis, but individual attacks may be triggered by internal or external influences, or simply come by themselves for no apparent reason. The name ‘migraine’ originally comes from the Greek word hemicrania, meaning ‘half of the head’, representing one of the most striking features of the condition: that in many cases pain only affects one half of the head. Equally commonly, however, pain is felt bilaterally, at the front or the back of the head, more rarely in the face, and rarer still in the body (‘migrainous corpalgia’). The pain is generally throbbing in nature, and typically made worse by any form of movement or even modest exertion. The majority of migraine attacks are severe or at least moderately so.

The pain of migraine is typically accompanied by other features such as nausea, dizziness, extreme sensitivity to lights, noises, and smells, lack of appetite, disturbances of bowel function, and so on. The typical constellation of symptoms experienced by migraine sufferers is reflected in the ICHD criteria for the diagnosis of migraine (Box 2). It should be remembered that these criteria were originally designed for the purpose of ensuring coherent patient populations for research in headache disorders, and that not everyone’s migraine has ‘read the textbook’.

Box 2.

International Classification of Headache Disorders diagnostic criteria for migraine.

(1) At least five attacks fulfilling criteria (2)–(4)

(2) Headache attacks lasting 4–72 h (untreated or unsuccessfully treated)

(3) Headache has at least two of the following four characteristics:

(a) unilateral location

(b) pulsating quality

(c) moderate or severe pain intensity

(d) aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs)

(4) During headache at least one of the following:

(a) nausea and/or vomiting

(b) photophobia and phonophobia

(5) Not better accounted for by another ICHD-3 diagnosis.

Only about 20% of migraine sufferers experience aura, usually (but not invariably) before the headache starts. Most aura is visual, consisting of a combination of positive visual phenomena (floaters, flashes of light, moving or expanding zig-zag patterns, and so on) and negative phenomena (loss of vision causing blind spots). Many sufferers also experience sensory aura, consisting of tingling and numbness, often spreading over the hand, arm, face, lips and tongue on one side of the body. Weakness, dysphasia, and other aura symptoms are rare.

Between 10% and 20% of migraineurs experience premonitory symptoms up to 48 h before their migraines [Giffin et al. 2003]. These may include fatigue or abnormal bursts of energy, neck stiffness, yawning and frequent urination. Particular areas of the brain have now been identified that are active during the premonitory phase [Maniyar et al. 2014]. A higher proportion experience a postdrome during which they may experience grumbling headache, a bruised feeling in the head, fatigue and nausea, and a continuing sensitivity to lights, noises, smells and movement.

Take a detailed history

Accurate history taking is vitally important in the diagnosis of migraine. It is important to give patients time to describe their attacks fully (it may well be the first time that anyone has listened to them talk about their pain), and also to clarify the history with specific questions aimed at filling out the gaps in what the patient has told you spontaneously. The diagnosis of migraine lies in the history, and that the purpose of examination is primarily to look for other problems that may be exacerbating an underlying tendency to migraine. This may in most cases be restricted to fundoscopy, inspection and palpation of the head and neck structures, and a brief screening cardiovascular and neurological examination, unless, on the basis of the history, serious intracranial or systemic pathology is suspected.

As mentioned above it is useful to begin with questions about the pattern of the pain, including when, and how headaches begin; whether they are continuous, episodic or (as is often the case in chronic migraine) continuous with episodic exacerbations; the duration of episodes or exacerbations; and if there are any triggers or exacerbating factors. After this questions can be asked about the nature of the pain, such as its location, character, severity (using a verbal report scale of 0–10, where 0 is no pain and 10 is the worst imaginable). Then the presence of associated symptoms that accompany the pain should be ascertained; these include symptoms that precede attacks suggesting a prodrome or aura, such as excessive tiredness or energy, yawning, excessive urination, neck stiffness, vertigo, visual or sensory disturbances; symptoms that accompany attacks such as nausea, sensitivity to lights, noises, smells, touch, or movement; and symptoms suggesting alternative primary or secondary headache disorders such as eye watering, conjunctival injection, nasal congestion, ptosis, eyelid oedema, sweating, agitation, fever, neck stiffness or rash.

It is then useful to ascertain what treatments, current and previous, have been tried, and at what point these treatments are taken. Patients should be asked to bring a list of medications tried in the past, including doses, and be asked why these treatments were abandoned (ineffective/side effects). The use of alternative or complementary therapies should also be sought.

Finally, it is also important to ask questions about the patient’s previous medical history (including questions about depression, anxiety and sleep disorders), current nonheadache medications, allergies, family history (especially of headache), and social history (including occupation, smoking status, and levels of alcohol and caffeine consumption). It can also be helpful to ask about markers of migraine such as recurrent abdominal pain, motion sickness or a greater than expected tendency to hangovers. It is useful to know if the patient has seen other medical or nonmedical practitioners about their headaches, what conclusions were reached, and what investigations if any were carried out.

While superficially there seems to be a lot of information required, it is almost invariably the case that patients will volunteer much of this information without being specifically asked, and it usually does not take too much time to fill out the gaps if a structured approach to the history taking is followed. If there is uncertainty, then encouraging the patient to keep a headache diary can be very useful.

Investigate appropriately

Decisions on investigation of patients with chronic migraine are driven by two highly prevalent cultural myths: that headaches are commonly due to brain tumours; and that in modern medicine diagnoses can only be made on the basis of an abnormal scan or blood test result. With regard to the former, evidence shows that when a diagnosis of migraine can be made on clinical grounds, the chances of the patient having a brain tumour are 0.045% [Kernick et al. 2008a]; no investigation is indicated, therefore, not least because there is a 1–2% chance of picking up an incidental intracranial abnormality which may cause anxiety, or even have an adverse influence on life insurance applications. Imaging should be reserved for situations when clinical assessment suggests that the probability of an underlying tumour has exceeded 1%; examples include the finding of papilloedema on fundoscopy, headache with fixed abnormal neurological signs, headaches associated with new onset seizures or significant alterations in consciousness, memory or coordination, or headaches in patients with a history of cancer elsewhere in the body. In such cases magnetic resonance imaging is the modality of choice. Other investigations such as blood tests or cerebrospinal fluid analysis are only indicated in cases of diagnostic uncertainty, most typically when patients present with the NDPH phenotype.

Make a diagnosis

In cases of chronic headaches, the phenotype is often not clear. Useful a priori assumptions are that primary headache disorders (particularly migraine) present more commonly to doctors than do secondary headaches, and that it is unusual for patients to have to seek medical opinions about mild headaches, such as tension-type headache. Asking about the patient’s original headaches often elicits the story of an episodic headache disorder with migrainous features, evolving into a chronic disorder (often but not invariably driven by overuse of painkillers or caffeine [Bigal et al. 2008], psychological comorbities such as anxiety or depression, physical conditions such as sleep apnoea or significant life events), and in such cases chronic migraine is the most likely diagnosis. In some cases it may not be possible to make a definitive diagnosis (the ICHD recognizes this, including categories of ‘probable migraine’ and ‘unclassifiable’ headaches); nonetheless if the patient is experiencing chronic headaches sufficiently severe to interfere with normal everyday activities, then in the absence of an alternative cogent primary or secondary headache diagnosis, it is reasonable to treat them on the basis that chronic migraine is the most likely cause.

It is important to try to make a diagnosis, even it is only a presumptive one; explaining this to the patient, accompanied by reassurance that there is no serious underlying cause, is the first step in treatment, and may in some cases be the only intervention required.

Treatment of chronic migraine

There are three broad approaches to treating chronic migraine: lifestyle and trigger management, acute treatments (i.e. those taken during attacks or exacerbations of chronic pain), and preventive treatments (medication or other interventions designed to reduce the tendency to have attacks). While many patients find that lifestyle adjustments such as regularizing meals and sleep can reduce the frequency of their attacks, some form of medication or other treatment is almost invariably necessary in patients with chronic migraine. The National Institute for Health and Care Excellence (NICE) have recently published guidance on the diagnosis and treatment of migraine, and further consensus guidelines have been published by the British Association for the Study of Headache, the American Headache Society and American Academy of Neurology, and the European Headache Federation [Loder et al. 2012].

Lifestyle modification and trigger reduction

When patients have chronic severe headaches, it can be difficult to recognize specific triggers. Paradoxically it is often the case that as chronic headaches start to improve with treatment, triggers become more obvious. Regularity of regimen with regard to meals, hydration, sleep and stress is always helpful in reducing the tendency to migraines; recognizing that this is helpful is straightforward, but actually making the requisite changes in a modern busy life may be more difficult.

Many patients with chronic migraine will have other problems that exacerbate their tendency to headaches: these include depression, anxiety, other pain syndromes such as fibromyalgia, localized pain in head and neck structures, and conditions that create ‘metabolic’ strain such as sleep apnoea or postural orthostatic tachycardia syndrome. Proper management of these is necessary to maximize the effect of any other migraine treatments. It is particularly important to recognize and manage medication overuse (including caffeine overuse) as failure to do so will render most attempts at preventive treatment ineffective [Lipton et al. 2003].

Acute headache treatments

Patients with chronic migraine often find it difficult to know when to take acute treatments. Both patients and physicians may be concerned about the possibility of medication overuse, and in the early stages of management it may be preferable to avoid acute painkillers altogether. Once a stage is reached where there are clear ‘good days and bad days’, or a situation when there is a background headache with clearly defined exacerbations, then acute treatment can be reintroduced. The usual principles apply: attacks should be treated early, when the pain is still mild; effective doses should be used, treatments being titrated steadily up to the maximum tolerated dose before being abandoned as ineffective; associated symptoms such as nausea should also be treated; and an appropriate route of delivery should be chosen (various medications can be given by nasal spray or via a suppository). If simple analgesics are not effective, then triptans should be used and opiates avoided if possible [Ferrari et al. 2002]. Potential acute treatments are listed in Box 3. Strict limits should be set on the frequency with which acute treatments are used to avoid worsening the situation through medication overuse. Recently there has been interest in noninvasive stimulation techniques such as transcranial magnetic stimulation [Lipton et al. 2010] and vagal nerve stimulation [Goadsby et al. 2014]. Early data suggest that these may be as effective as standard analgesics in the acute treatment of migraine, and that prolonged use may start to reduce headache frequency.

Box 3.

Acute migraine treatments.

Paracetamol 1 g

Aspirin 900–1200 mg

Ibuprofen 400–800 mg

Naproxen 250–500 mg

Triptans

Sumatriptan 50–100 mg orally, 10–20 mg nasal, 6 mg subcutaneously

Almotriptan 12.5 mg

Eletriptan 40–80 mg

Frovatriptan 2.5 mg

Naratriptan 2.5–5 mg

Rizatriptan 5–10 mg, s/l melt

Zolmitriptan 5–10 mg orally, s/l melt, 5 mg nasal

Combinations

Sumatriptan 50 mg and naproxen 250–500 mg

(all of the above are taken alone or with domperidone 10 mg orally, or an alternative antiemetic)

Single-pulse transcranial magnetic stimulation

Vagal nerve stimulation

s/l, sublingual.

Preventive treatment

Preventive treatment is usually considered when headache frequency or severity increases to a point when it is significantly interfering with work, school or social life. For patients with chronic migraine this is invariably the case, and some form of preventive medication or other intervention is almost universally indicated. Evidence from the American Migraine Prevalance and Prevention study shows, however, that as many as 40% of those patients who might benefit from preventive treatment are never offered it [Lipton et al. 2007].

Numerous medications have been shown to be effective in the preventive treatment of migraine. Not all of these are licensed for this purpose in the United Kingdom. The choice of treatment can be influenced to varying degrees by the pattern of headaches, patient comorbidity, tolerability, teratogenicity, potential side effects, ease of use and patient choice. Preventive treatments should be commenced at a low dose to minimize the possibility of developing side effects. The dose should be steadily and regularly increased until the medication works, intolerable side effects occur or a maximum dose is reached, at which point it can be concluded that the medication does not work for that individual patient. Adherence should be closely monitored, as levels are known to be low [Blumenfeld et al. 2013; Hepp et al. 2014]. At this point another preventive treatment can be tried. If preventive treatment works well, it should be continued for a few months before weaning the dose down. In many cases this process can be achieved without headache frequency suddenly worsening again.

Specific trials in patients with chronic migraine are sparse, and in many cases the evidence for the use of standard preventive medications has to be extrapolated from studies in patients with high-frequency episodic migraine. Whilst NICE has recently recommended topiramate as the first-line preventive (on the basis that this medication has the most extensive high-quality clinical trial evidence on which to base the decision), most headache specialists continue to start with other older medications, probably of equivalent efficacy and certainly better tolerated, such as tricyclics (amitriptyline [Dodick et al. 2009], nortriptiline or dosulepin), β blockers (propranolol [Linde and Rossnagel, 2004], atenolol, nadolol or metoprolol). If these do not work then anticonvulsants such as topiramate [Diener et al. 2007; Silberstein et al. 2007; Mulleners et al. 2015] or sodium valproate [Yurekli et al. 2008; Mulleners et al. 2015] can be considered. The calcium channel blocker flunarizine may be helpful [Diener et al. 2002], and anecdotally is said to be the drug of choice for patients with prolonged aura, hemiplegic attack or prominent vertigo. There is also increasing evidence that angiotensin blockers such as candesartan are useful and well tolerated in migraine prevention [Tronvik et al. 2003; Stovner et al. 2013]. Details of dose regimes are given in Table 1.

Table 1.

Preventive headache treatments for chronic migraine.

First line	Starting dose	Target dose
β blockers
Propranolol	10 mg three times daily	40–80 mg three times daily
Metoprolol	25 mg twice daily	100 mg twice daily
Atenolol	25 mg once daily	100 mg once daily
Angiotensin blockers
Candesartan	4 mg once daily	12–16 mg once daily
Tricyclics
Amitriptiline	10 mg nocte	75–100 mg nocte
Nortriptiline	10 mg nocte	75–100 mg nocte
Dosulepin	25 mg nocte	75–100 mg nocte
Second line
Anticonvulsants
Topiramate	12.5 mg nocte	50–100 mg twice daily
Sodium valproate	200 mg nocte	400–800 mg twice daily
Flunarizine	5 mg once daily	5–10 mg once daily
Onabotulinum toxin A (Botox)	155 U (PREEMPT protocol)
Supplements
Riboflavin (vitamin B2)	400 mg daily
Magnesium citrate (or taurate)	600 mg daily

If first- or second-line preventives fail, the patient should be referred to a specialist headache clinic for reevaluation, and consideration of nonpharmacological interventions such as greater occipital nerve blocks (case series suggest this may be useful in reducing headache frequency and severity for a limited period in over 50% of patients [Afridi et al. 2006], though a recent double-blind randomized controlled trial casts doubt on this [Dilli et al. 2014]) or Botox (onabotulinum toxin A; Allergan, Irvine, CA) injections for chronic migraine (two successive sets of injections of 155–195 U in seven areas of the head and neck having been shown to reduce headache days by 50% over 6 months in such patients) [Aurora et al. 2011]. Ultimately neurosurgical techniques such as occipital nerve stimulation or deep brain stimulation can be considered for the rare but challenging truly intractable cases [Magis and Schoenen, 2012].

Conclusion

Chronic migraine is an important treatable cause of neurological disability. It is vital to make a diagnosis and ensure that any concomitant medical or psychological conditions are treated in parallel with interventions aimed at reducing the biological tendency to headaches. It is also important to set patients’ expectations as to what can be achieved. The tendency to migraine is genetic, and will rise and fall in people’s lives; migraine cannot be ‘cured’ in any sense. It can be managed, however, and often very successfully following the lines outlined in this article.

There are interesting times ahead for the management of chronic migraine. New acute and preventive options should become available over the next 3–6 years, including calcitonin gene-related peptide (CGRP) antagonists and antibodies, and drugs targeted at other serotonin receptor subtypes. In the meantime, however, our existing armamentarium holds plenty of possibilities for clinicians and patients to work together to improve the lives of people with chronic migraine.