Chronic Migraine: An Update on Diagnosis and Management
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.315972
Source of Support: None, Conflict of Interest: None
Keywords: CGRP, chronic migraine, onabotulinumtoxin A
Chronic migraine (CM) is a primary headache disorder that can be diagnosed when patients experience fifteen or more headache days per month for more than 3 months, with at least eight headaches per month having migrainous features. It affects approximately 2% of the population worldwide and has significant associated morbidity. The disorder occurs more commonly in women than in men and has the highest prevalence between 18 and 50 years of age. In addition to poorer quality of life, CM has a significant socioeconomic cost, with loss of working days and productivity in paid and unpaid work. Healthcare costs alone are three times higher for patients with CM compared to episodic migraine (EM) and psychiatric comorbidities are also more common in CM than EM. Epidemiological data for south Asia are sparse but some data suggest that women and those living in rural areas have the highest burden of disease.
The burden of CM is frequently underestimated by health professionals. A greater awareness that CM is a treatable condition could have a significant clinical and economic impact. However, there are a number of barriers that can prevent patients from receiving the correct diagnosis and subsequent treatment for CM. A greater understanding of the pathophysiology of migraine over the last decade has led to the development of the first targeted treatments for CM and therefore it is now more important than ever that neurologists recognize and treat this debilitating disorder.
The pathophysiology of migraine is complex, and a detailed discussion is beyond the remit of this review and there are excellent reviews on this subject within the literature., Nonetheless, it is important to acknowledge that great advances have been made in understanding the pathophysiology of migraine over the last decade which has led to the development of targeted treatments.
In brief, patients with migraine may have an underlying vulnerability to this disorder, in part determined by genetic predisposition interacting with environmental influences. Although three genetic mutations coding for calcium and sodium channels have been found in the rare familial hemiplegic migraine cohorts, the genetic susceptibilities in most patients with episodic and CM are likely to be more complex.
Migraine is caused by activation and sensitization of the trigeminovascular system. Migraine aura may be mediated by cortical spreading depression which is a slow-moving wave of depolarization that spreads across the cortex then to the thalamus, and brainstem nuclei. Activation of the trigeminovascular system results in the release of neuropeptides substance P, vasoactive intestinal peptide (VIP), and calcitonin gene-related peptide (CGRP). These cause neurogenic inflammation in the neurovascular system – mast cell degranulation and vasodilation, which are associated with the pain of migraine.
Much recent research has focused on CGRP as a target for treating migraine. This neuropeptide is found in the central and peripheral nervous systems and acts differently at these sites. In the central nervous system, it mediates transmission of pain and regulatory mechanisms, whereas in the peripheral nervous system it mediates vasodilation. Interictal CGRP levels in the blood are higher in patients with CM compared to both EM patients and Nonheadache patients.
The pathophysiological events leading to CM from EM are unclear, but amongst other factors, central sensitization resulting from dysfunction of the descending pain modulation pathways is likely to play a role. Functional imaging studies have shown altered patterns of activation in the brain stem and hypothalamus in patients with migraine, supporting this hypothesis. For example, neurons in the periaqueductal grey matter (PAG), the center of descending pain modulation, show increased activity during migraine attacks. It has been hypothesized that repeated migraine attacks may enhance central sensitization, increasing the risk of CM. Optimal management of EM is therefore vital.
There are a number of recognized risk factors for the transformation of EM to CM. In addition to genetic susceptibility, female sex, obesity, depression, and stressful life events increase the likelihood of progression to CM. Conversely, stress management, physical exercise and adequate preventative treatment can aid in preventing CM. [Figure 1]
The concept of chronic migraine
It has long been recognized that patients with infrequent migraine could start to experience more frequent migraine and this was termed “transformed migraine”. This term, along with “chronic daily headache” is no longer used. “Chronic migraine” was first added in the International Classification of Headache Disorders 2 (ICHD-2) but had the requirement that medication overuse was addressed. This was further revised in ICHD-2R and the 3rd ed.ition (ICHD-3) and a diagnosis of CM can now be made even with ongoing medication overuse.
CM is defined as headaches on at least fifteen days per month for three months, with eight of those days having headaches with migrainous features. Not all the attacks need to be typical of the patient's migraines as it is recognized that milder attacks can lack the hallmark features of more severe migraines. The migraine attacks can occur with or without aura. In contradistinction to CM, patients with migraine who have less than fifteen headache days per month are defined as having EM.
The concept of CM is clinically important since patients have higher morbidity and disability compared to EM. However, it is recognized that there are imperfections to clinical criteria––some patients cycle between high-frequency EM and CM. Those with ten to fourteen migraine days per month do not fulfill the criteria for CM but may have similar levels of disability.
The ICHD-3 outlines clear diagnostic criteria for migraine with or without aura [Table 1] and [Table 2] and CM [Table 3]. The headache of migraine is characteristic – unilateral or bilateral pain, which is often throbbing, of moderate to severe intensity, aggravated by activity, and typically associated with photophobia, phonophobia, and nausea. The headache history should be focused and on one hand, should specifically seek positive features of migraine, whilst simultaneously trying to identify symptoms suggestive of secondary causes of headaches. A group for the British Association for the Study of Headache (BASH) looked at clinical features of patients presenting to primary care with headache and divided these into red, orange, and yellow flags, to identify features that had a higher likelihood of being a brain tumor presentation [Table 4].
Headache diaries are very helpful in assessing the effectiveness of treatments for CM. Diaries can range from simple to very detailed. In addition to headache days and severity, patients can include information about what medication they took and lifestyle factors such as sleep, diet, and stress.
Neurological examination including fundoscopy will identify any focal deficits that warrant further investigation. Blood pressure should be measured as malignant hypertension is a medical emergency that requires prompt treatment. Blood tests have little role in the diagnosis of headache in a systemically well patient. The exception is in those over 50 years of age, in whom erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) should be measured if giant cell arteritis is suspected.
The clinical history can identify any orange or red flags that suggest the need for further investigation [Table 4]. If cranial imaging is required, we prefer magnetic resonance imaging (MRI) to computed tomography (CT) as it has the advantage of providing detailed images whilst avoiding exposure to ionizing radiation. Conversely, if the history is classical of migraine, cranial imaging is not required as the likelihood of a brain tumor, in the absence of red flags, is extremely low. Unnecessary imaging should be avoided as incidental benign findings are common, especially with MRI, and can be a source of anxiety for patients. Those offered a scan for reassurance may have an initial improvement in anxiety, but this is not sustained at 12 months. However, they may have lower healthcare costs due to less frequent utilization of services.
As discussed, the history and examination should aim to identify patients for whom investigations should be performed to exclude causes of secondary headache. In addition, the clinician should determine how the headache started. Unlike CM, new daily persistent headache (NDPH) is daily from onset and patients can usually recall the precise time of onset. It becomes continuous within 24 h and is present persistently for more than three months. Differentiating NDPH from CM is important because patients presenting with NDPH may require investigation to exclude secondary causes.
It is important to consider a diagnosis of idiopathic intracranial hypertension (IIH) in patients with the characteristic phenotype, which includes female patients with elevated body mass index. The features of headache in IIH can overlap with those of migraine, the headache can also be throbbing, and can be either intermittent or continuous. Examination for papilloedema is therefore crucial if this diagnosis is not to be missed. The headache of spontaneous intracranial hypotension can also present with a throbbing headache but usually presents with either an orthostatic headache or a headache that appears later in the day. It is important to exclude features of giant cell arteritis in patients of around 50 years or older, and specifically ask about jaw claudication and scalp tenderness, assess for temporal artery tenderness, and detect elevated CRP and elevated ESR.
Distinguishing migraine from other primary headaches is usually straightforward. Patients with cluster headaches typically describe restlessness and agitation during attacks which tend to be shorter (typically less than 3 h), and often occurring multiple times per day. If a continuous headache is side-locked with autonomic symptoms, although they can sometimes be minimal, one should always consider hemicrania continua as this is highly responsive to indomethacin. Chronic tension-type headache is typically not severe, and there should be no more than one of photophobia, phonophobia, or mild nausea.
The aim of preventive treatment of CM is a reduction in the frequency of episodes, with a subsequent improvement in the quality of life for the patient. Managing expectations and providing reassurance is important as is ensuring that the patient feels empowered to manage their condition. Advice regarding the importance of lifestyle measures and trigger management is important before embarking on treatments for CM. The most common triggers are sleep disruption and hormonal changes in women, but these vary between individuals and a migraine diary is helpful in identifying these. Headaches diaries are also useful to assess preventive treatments objectively. The use of structured patient disability tools should also be considered. The most commonly used are HIT (Headache impact test) and MIDAS (Migraine disability assessment questionnaire). Prescribing decisions should be made with reference to the patient's current status and also their future plans, particularly in women of childbearing age. The choice of preventive treatment depends primarily upon the side effect profile of the drug and coexisting morbidities.
Management of acute migraine attacks in patients with CM is the same as in EM patients. Acute treatments can be prescribed in a stepwise approach – starting with simple analgesics and if ineffective, a triptan could be tried. Alternatively, a stratified approach could be used based on attack severity. The stratified approach is associated with better health-related outcomes and lower healthcare costs. An antiemetic should be added, not just for associated nausea and vomiting but as it may also increase the efficacy of the acute treatment by increasing gastric motility and hence drug absorption [Table 5].
The triptans are 5-HT agonists that were developed specifically for the management of EM and are most effective when taken early in the headache phase of the migraine. There are seven different triptans, with differences in oral bioavailability and plasma half-life. If a particular triptan is considered to be ineffective for an individual, an alternative triptan should be considered for future attacks. Lack of response to one triptan does not predict the response to other triptans and trials of different triptans should be considered. Advice regarding the development of medication overuse headaches (MOH) must always be provided when prescribing acute treatments for migraine as all acute treatments are associated with the condition. Patients must be advised that restricting their acute headache medications to no more than two days a week minimizes the potential of developing MOH. Triptans are contraindicated in patients with vascular disease.
MOH occurs when taking headache treatments for more than 10-15 days per month. This is most likely to occur with opiates and triptans but can also occur with simple analgesics like paracetamol and Nonsteroidal anti-inflammatory drugs. MOH occurs primarily in individuals with migraine or tension-type headache and is usually of the same phenotype. It is important to identify MOH as otherwise treatments for migraine are less likely to be effective. Education is paramount in the management of MOH, particularly as the headache will likely worsen initially after stopping regular analgesia and unless the information is provided, patients would revert back to overusing the acute medications. Patients must be advised that MOH is less likely to improve unless the offending medication is withdrawn. The outcome is similar if medications are withdrawn abruptly or in a gradual manner. However, if opiates are being overused then a gradual reduction is advisable. Withdrawal headache can occur for up to ten days following withdrawal and appropriate management of that with simple analgesia and antiemetics should be undertaken.
The majority of the drug treatments used for CM are based on the experience of their use in EM. Some of these drugs are not licensed for use in migraine and licensing varies between countries. As the majority of oral drugs for CM are primarily used for another indication, the patient's background can be used to select one. All oral medications should be trialed for at least 6-8 weeks at a therapeutic dose before they are deemed ineffective. The use of headache diaries is encouraged to be able to assess the response objectively.
A large number of oral medications have been used for the preventive treatment of migraine, however randomized controlled trials have not been carried out for all of these treatments. Oral treatments that are supported by randomized placebo-controlled trials include Propranolol, candesartan, flunarizine, topiramate, and amitriptyline. There are very few head-to-head trials comparing oral migraine preventative treatments. A trial comparing topiramate with amitriptyline in patients with EM concluded that the least square mean (LSM) change from baseline in the mean monthly migraine episodes was not significantly different between the topiramate and amitriptyline groups (–2.6 and –2.7 respectively, 95% CI–0.6 to 0.7). There is no clear difference in terms of efficacy between these treatments and the medication should be selected following discussion with patients regarding the side effect profile and existing comorbidities. For example, propranolol may be a preferred treatment in patients with anxiety whereas candesartan may be more appropriate with coexisting hypertension. Topiramate could be considered if the patient is obese and amitriptyline if low mood coexists.
Topiramate is the only oral medication with several randomized controlled trials supporting its use in CM. In a randomized, placebo-controlled, parallel-group multicenter study consisting of 16 weeks of double-blind treatment in adults with CM, topiramate in a dose of 100 mg per day resulted in a statistically significant mean reduction of migraine days (topiramate -6.4 vs placebo -4.7 P = 0.010) relative to baseline. In a further randomized, double-blind placebo-controlled trial to evaluate the efficacy and tolerability of topiramate in adults with CM, topiramate significantly reduced the mean number of monthly migraine days by 3.5 days compared to -2 days with placebo (P < 0.05). The migraine disability score (MIDAS) also showed improvement with the topiramate treatment group (P = 0.042 vs. placebo). 78% of the patient group had acute medication overuse at baseline. Side effects were reported by 75% of topiramate-treated patients versus 37% in the placebo group. The most common side effects were paresthesia, nausea, dizziness, dyspepsia, fatigue, anorexia, and disturbance in attention.
Most oral treatments are associated with side effects and the occurrence of these, in addition to lack of efficacy, is a reason that most patients with migraine do not persist with taking their prescribed preventative medications. In patients with migraine, the persistence of the initial oral migraine preventative medication was 25% at six months and 14% at 12 months.
Onabotulinumtoxin A is an effective treatment for CM. It is given as an intramuscular injection to 31 predefined sites across the head and neck, with each injection delivering five units of the toxin. Repeat injections are carried out at 12 weekly intervals. In two multicenter, pivotal trials in the PREEMPT (Phase 3 Research Evaluating Migraine Prophylaxis Therapy) clinical program, a total of 1384 adults with CM were randomized to receive onabotulinumtoxinA or placebo. Each trial included a 24-week randomized, double-blind phase followed by a 32-week open-label phase. Pooled analyses demonstrated a statistically significant between-group difference favoring onabotulinumtoxinA over placebo at week 24 (–8.4 vs –6.6; P < 0.001) in the frequency of headache days when compared to baseline. This trial also confirmed that onabotulinumtoxinA treatment results in significant improvements when compared with placebo in multiple headache symptom measures and a significant reduction in headache-related disability with improved functioning and overall health-related quality of life.
The nature and frequency of adverse events were similar in both groups. The only adverse events reported with an incidence of >5% were neck pain (8.7%) and muscle weakness (5.5%). The most common side effects experienced are neck pain, headache, injection site pain, and eyelid and eyebrow ptosis.
The exact mechanism of onabotulinumtoxinA in CM is unclear but the most accepted theory is that it reduces peripheral and central sensitization of the trigeminovascular system. OnabotulinumtoxinA and topiramate have been demonstrated to have similar efficacy in small trials.
OnabotulinumtoxinA is an effective treatment with few side effects but it requires administration by a trained healthcare professional, which adds to healthcare costs. In the United Kingdom, which has a predominantly public healthcare system, a trial of at least three oral preventative treatments for CM is generally undertaken prior to treatment with onabotulinumtoxinA. A trial period of two cycles of onabotulinumtoxinA administered 12 weeks apart is then undertaken. If the treatment results in improvement, defined as a more than 30% reduction in the number of headache days compared to baseline, then the treatment is continued.
A greater understanding of the role of CGRP in the pathophysiology of migraine has led to the first targeted preventive treatments for CM. Oral CGRP antagonists were very effective in clinical trials and studies of telcagepant for the acute treatment of EM demonstrated it to be more effective than placebo and as effective as zolmitriptan for pain freedom at 2 h. When investigated for CM however the trial had to be terminated early for safety reasons, due to significant hepatic dysfunction in 2.5% of patients. The development of CGRP antagonists was then halted for a number of years.
However recently small molecule oral CGRP antagonists namely rimegepant, atogepant, and ubrogepant – have been in the process of development and clinical trials for patients with migraine. Atogepant has been shown to be effective for the preventative treatment of EM. All five doses of atogepant, ranging from 10 mg once daily to 60 mg twice daily, showed significant LSM change from baseline in mean monthly migraine days vs placebo.
Ubrogepant was studied in a randomized trial for the acute treatment of migraine. 19.2% of patients in the 50 mg ubrogepant group were free from pain at 2 h when compared to 11.8% in the placebo group. In a phase-3 trial, rimegepant 75 mg oral was compared to placebo for the treatment of a single migraine attack. 19.6% patients in the rimegepant group were pain-free at 2 h compared to 12% in the placebo group.
Clinical trials on the oral small molecule CGRP antagonists are being conducted for the preventive treatment of episodic and CM and these treatments look promising for this indication.
The CGRP monoclonal antibodies have been developed for the preventative treatment of migraine. These are large molecules, do not cross the blood-brain barrier, have long half-lives and need to be given parenterally as their gastrointestinal absorption is poor. They have a low rate of immunogenicity which does not impact safety or efficacy.
There are four CGRP monoclonal antibodies. Erenumab is directed at the CGRP receptor and Fremanezumab, Galcanezumab and Eptinezumab are directed at the CGRP ligand [Figure 2]. Eptinezumab is given intravenously whereas all others are administered as subcutaneous injections. Each antibody needs to be given at 1-3 monthly intervals. These are the first treatments that have been designed and developed specifically for the preventative treatment of migraine and can be used in both migraine with and without aura. The clinical trials confirm their effectiveness across the spectrum of migraine and also their favorable safety profile.
Erenumab was the first CGRP monoclonal antibody that was licensed for the preventive treatment of migraine. This drug was studied in a pivotal clinical trial comparing a subcutaneous injection of either 70 mg or 140 mg of erenumab with placebo, each given monthly for 6 months in patients with EM with between 4 and 14 migraine days a month. The mean number of migraine days was reduced by 3.2 in the 70 mg Erenumab group and by 3.7 days in the 140 mg Erenumab group as compared with 1.8 days in the placebo group (P < 0.001 for each dose vs placebo). A 50% or greater reduction in the mean number of migraine days per month was achieved in 43.3% of patients in the 70 mg erenumab group and 50% in the 140 mg erenumab group as compared with 26.6% in the placebo group (P < 0.001 for each dose v placebo). Similar results were obtained in the clinical trials of Fremanezumab, Galcanezumab, and Eptinezumab for the preventive treatment of EM.,,
Erenumab, Fremanezumab and Galcanezumab have also been shown to be effective treatments in patients who have migraine refractory to other preventive treatments., Most trials included patients with medication overuse and the treatments continued to show effectiveness in this group of patients as well. Long term data emerging from post-marketing data and from open-label studies also confirm the long-term effectiveness and safety of these treatments.
Each trial demonstrates that a high proportion of patients achieve not just a 50% reduction in migraine frequency but also a 75% and even 100% reduction in migraine occurrence. Improvement in migraine-related disability and in the health-related quality of life is also consistently reported in each trial.
Each CGRP monoclonal antibody has been trialed for the preventive treatment of CM with positive results reported consistently and with each dose of every drug.
The effectiveness of the CGRP monoclonal antibodies in CM is replicated in every trial as described in [Table 6]. Each trial met the primary endpoint of statistically significant reduction in mean monthly migraine days when compared to baseline. Additionally, reduction in the number of headache days when compared to baseline, reduction in the monthly average number of days of use of any acute headache medication and a reduction in disability due to migraine was demonstrated in each trial.,,,
The long -term effectiveness of Erenumab in CM patients has been reported. Efficacy was sustained over a 52-week open-label extension study of Erenumab in patients with CM who had participated in a 12-week double-blind treatment phase study. Achievement of >50%, >75%, and 100% reductions from the double-blind treatment phase baseline in monthly migraine days at week 52 were reported by 59%, 33.2% and 8.9% of patients respectively.
In a clinical trial comparing a monthly and a quarterly dose of fremanezumab with placebo in adult patients with CM, adverse events were reported in 64% of the patients receiving placebo, in 70% of those receiving fremanezumab quarterly (P = 0.06 versus placebo) and in 71% of those receiving fremanezumab monthly (P = 0.03 versus placebo). Injection site reactions, pain induration, or erythema, were reported in 40% of the patients receiving placebo and in 47% of those receiving fremanezumab. Nasopharyngitis, dizziness, and nausea were also reported. No participants had anaphylaxis and possible trial agent-induced liver injury was similar in all three groups. Overall, the dropout rates in the trial were between 1 and 2% and the drug was well tolerated. The adverse events in trials of all other subcutaneous CGRP monoclonal antibodies are similar to those observed in the fremanezumab trial. In clinical practice, constipation seems to be a fairly commonly reported adverse event but one which does not lead to discontinuation of treatment and which can be easily managed.
One of the major exclusions in all the CGRP trials was of patients with any form of active vascular disease. Owing to the vascular effects of CGRP, which is a vasodilator, there are concerns that this group of drugs may predispose to hypertension, and real-world data should be collected to assess this.
Although real work experience is still accumulating, this class of drugs is effective and well-tolerated and their development is a major advancement in the management of migraine. These drugs are expensive and as with Onabotulinumtoxin A they should perhaps only be considered when oral treatments are ineffective, contraindicated, or lead to unacceptable side effects.
Greater occipital nerve blocks have been used for the preventive treatment of CM. Open-label trials report a reduction of headache severity in 35-68% of patients with the effect lasting for up to 4 weeks. Blinded trials are few and the methodology, techniques, and time points for assessing outcomes are different. The injection sites differ as do the constituents of the injection with no clear results to guide efficacy. The cost-effectiveness of this treatment may be attractive in certain healthcare systems and this could also be considered in patients who may have comorbid conditions where standard migraine preventive treatments cannot be used.
Noninvasive neuromodulation therapies are an interesting development for the management of CM as they provide more options for patients who cannot tolerate medications due to side effects or have contraindications such as other health conditions and pregnancy. Evidence from clinical trials into these devices is limited by small patient numbers and difficulties with blinding.
Transcutaneous stimulation of the supraorbital nerve, a branch of the ophthalmic division of the trigeminal nerve, has been studied in CM and the Cefaly device is approved for use in many countries. In an RCT of 67 patients with episodic, the 50% responder rate after three months was 38.2% in the treatment group compared to 12.1% in the sham group. The device was well tolerated and had positive feedback from patients. The most common adverse effects are local skin irritation and paresthesia. There has only been one study in patients with CM, an open-label pilot trial. Headache days decreased by 3.12 days per month and use of acute medication reduced by 30%, compared to the months prior to the study.
Single-pulse transcranial magnetic stimulation has also been studied for the acute treatment of migraine, however, the trial did not achieve the primary end point. Transcutaneous vagal nerve stimulation has also been trialed for the treatment of CM with negative results.
CM is an under-recognized and under-treated disorder. Prompt diagnosis and appropriate management can have a significant improvement in the quality of life and lead to socioeconomic benefits. There are a large number of options for the preventative treatment of migraine. Oral treatments should generally be trialed before considering injectable treatment options such as Onabotulinumtoxin A. The wider availability of injectable CGRP monoclonal antibodies heralds a new era of migraine management and the development of oral CGRP antagonists promises to widen the treatment options available to patients.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]