Article topic: Chronic Migraine
Author: Abdallah Alshloul
Editor: Ahmad Abuaisheh
Reviewer: Ethar Hazaimeh

Keywords:  Chronic migraine, Etiology, Pathophysiology, Genetics and Epigenetics, Treatment

Abbreviations: CM= chronic migraine, EM= episodic migraine, CDH= chronic daily headache

Abstract

Chronic migraine is the type in which a person has at least 15 headache days a month, involving at least eight days a month with fully developed migraines ¹. CM is a common and disabling neurological disorder. Patients with less frequent migraines (episodic migraine) should be counseled on avoiding risk factors associated with transformation to chronic migraine. The treatment of (CM) involves avoidance of risk factors for (CM), avoidance of migraine attack triggers, use of prophylactic and abortive drugs, and non-drug treatment. The knowing and management of disorders that are comorbid with CM optimizes patient outcomes.

Overview

Migraine is a headache that often affects one side of the head and can be extremely painful or have a pulsating feeling. Extreme light and sound sensitivity, along with nausea and vomiting, are common side effects. A migraine episode might be so intense that it keeps a patient away from working for hours or even days.

Chronic migraine (CM), one of the most prevalent chronic daily headache (CDH) illnesses, is characterized by recurrent headache episodes and at least 15 headache days per month. People who experience chronic migraine (CM) frequently experience episodic migraine (EM), and their frequency of headaches rises over time.²

With the increasing headache frequency, CM becomes less severe and more tranquil but is associated with worse treatment responses. The undertreated headache and associated comorbidities cause a high disease burden for CM compared with EM.²

CM patients have worse socioeconomic status and health‐related quality of life. Many studies show that patients with chronic daily headaches have lower levels of education and household income. In addition, epidemiologic profiles show that CM sufferers tend to be older and have a higher body mass index (BMI).¹⁰

The switch from EM to CM is usually a gradual step, and some patients oscillate between EM and CM. The cause of migraine chronification is not fully clear. The pathogenesis has been postulated to include the development of central sensitization or increased excitability of the trigeminal nociceptive pathways.

The reason why only a minority of EM patients are chronic while the great majority do not is still not fully understood. Although there are some recognized environmental causes, such as drug usage, a genetic predisposition is still a very real potential.

Epidemiology

Approximately 12% of the population suffers from migraine, affecting significantly more women than men. Compared with the overall prevalence of migraine, chronic migraine is not as common as episodic migraine; prevalence is estimated at 0.9% to 2.2% among the general population. 

It is estimated that approximately 3% of EM patients evolve to CM per year, and a similar result was obtained in a three-month follow-up. Besides, this transformation is bidirectional with about 26% of CM patients remitting to EM in a two-year follow-up, which makes it difficult to confirm the accurate prevalence of CM. However, chronic migraine is frequently seen in headache centers. Worldwide, up to 45% of patients presenting to headache clinics have daily or near-daily headaches. Therefore, chronic migraine should be understood as a disabling, underdiagnosed, and undertreated disorder.¹¹ 

Clinical Features

Migraine-related disability, fatigue, daily sleepiness, subjective sleep quality, anxiety, and depressive symptoms.⁵

Pain location is equal in unilateral and bilateral sides, pain side is equal in right and left, in most CM with pulsating and may with pressing/tightening and both in sometimes. CM may be associated with allodynia, cephalalgiophobia. In half of the patients, CM occurs with current medication and with acute treatment overuses.¹⁵

Symptoms of EM and CM are the same. The difference is simply the increase in the frequency of the number of headaches. Typical migraine symptoms include headache, that is moderate to severe in intensity, worsened by physical activity/movement; pain on one or both sides of the head; throbbing pain or pressure-like pain; sensitivity to light, sound, and smells; nausea,  vomiting, and Dizziness.¹³

Signs of an episodic migraine transforming into a chronic migraine include having a growing number of migraine attacks and taking more medication because of the growing number of attacks.¹³

Risk Factors

Psychiatric Problems

Psychiatric disorders are very common comorbidities of migraine patients. Chronic daily headache (CDH) patients had three times the risk of anxiety disorder, depression, bipolar disorder, and panic disorder than non-migraines and they had about double the risk of psychiatric disorders than other migraines.⁸

Sleep-Related Problems

People with CDH/CM frequently exhibit sleep-related problems. Daytime drowsiness, sleep bruxism, insomnia, and frequent snoring are all thought to be risk factors for CH/CM.⁸

Caffeine Overuse

Caffeine can be both beneficial and detrimental for migraine patients. It is a potent vasoconstrictor so it is used as a component in some acute abortive medication for migraine. In contrast, a delay in the intake of caffeine can cause weak headaches. Abrupt withdrawal of caffeine evokes headaches in more than half of people who usually consume low or moderate amounts of caffeine.⁸

Obesity

In a longitudinal population-based study, the influence of obesity was more evident for new onset CDH/CM, and the relative odds of CDH were three to five times higher in overweight or obese people than in people of normal weight in the USA.⁸

Overuse of acute migraine medication

The most important risk factor for CM is the overuse of acute migraine medication, defined as intake of analgesics on >15 days per month or triptans on >10 days per month. Regular intake of acute migraine medication leads to an increasing headache frequency, which facilitates migraine progression.⁹

Ineffective treatment of acute migraine

One of the main causes of CM is inadequate acute migraine management. This fact, which could be so easily avoided, cannot be emphasized enough: recent data from the American Migraine Prevalence and Prevention Study, which included over 5,000 migraine patients, showed that ineffective acute treatment doubled the risk for migraine chronification compared to effective acute treatment.⁹

Etiology

Migraines are not well understood. Possible causes have been identified, but final answers have not been discovered yet. Some hypotheses about migraine’s root cause include:

(CNS) disorder: an underlying neurological condition that might trigger chronic migraines.

Chemical imbalances:  For the brain to operate at its best, all chemicals must be balanced and all neural pathways must be free of obstructions. Migraines may develop if any of these processes are disturbed.

Genetic factors: if a family member, such as a parent or brother, has experienced migraine headaches, your chances of having migraines increases.

Vascular irregularities: problems with the shape, size, or blood flow in vessels to or inside your brain may cause migraine.

In some cases, (CM) may be an underlying symptom of another serious condition. Conditions that could cause (CM) include traumatic brain injury; inflammation or other problems with blood vessels in the brain, including stroke; infections such as meningitis, and endocarditis; brain tumors; and intracranial pressure that’s low or high.

Pathophysiology

The pathophysiology of (CM) and the mechanisms that result in transformation are not fully cleared. However, the effects of atypical pain processing, central sensitization, cortical hyperexcitability, and neurogenic inflammation have been studied. Atypical modulation of pain might lead to transformation. Decreased inhibition of pain by regions of the descending pain modulatory pathway has been identified in (CM).

In migraines, pain-induced functional activation of pain-inhibiting brainstem regions and the functional connectivity of brainstem pain modulatory regions are atypical. Furthermore, the extent of these abnormalities correlates with the presence of cutaneous allodynia, a symptom of central sensitization.

It is postulated that recurrent migraine attacks lead to sensitization of the trigeminal system, which results in a reduced threshold for activation of this system, more frequent migraine attacks, and transformation to chronic migraine. Cortical hyperexcitability might also contribute to transformation.

Transcranial magnetic stimulation studies (figure 1) of patients with chronic migraine suggest that the occipital cortex of these patients is hyperexcitable, even more so than in patients with (EM).³ The extent to which lack of cortical inhibition versus intrinsic cortical excitability contributes to this state is not clear.

 There is evidence that the structure and function of other pain-processing regions in the brains of patients with migraine—for example, regions that participate in sensory discriminative, affective, and cognitive pain processing—are also atypical.

Several studies have found positive correlations between the extent of these abnormalities and the increasing frequency of headaches, suggesting that they are precursors to or biomarkers of transformation to chronic migraine.

Neuroimaging studies that have specifically studied patients with (CM) have found atypical pain processing and atypical structure of pain-processing brain regions in this status. Exuberant release of vasoactive neuropeptides such as calcitonin gene-related peptide (CGRP) and the resultant neurogenic inflammation might also contribute to the pathophysiology of chronic migraine.¹⁴

A recent study found increased plasma concentrations of (CGRP) in migraines through the interictal phase of migraine compared with participants without migraine. In addition, CGRP concentrations were raised in patients with chronic migraine than in those with episodic migraine. It is not known whether high CGRP concentrations are the result of more frequent migraine attacks, thus serving as a potential biomarker of (CM), or whether they are part of the process that leads to more frequent migraine attacks.¹⁴

Genetics

Genetic factors seem to be a part of determining the risk of developing EM with and without aura. However, the role of a genetic influence on the progression of EM into CM remains to be cleared. The number of studies that specifically assess genetics in CM is very low and the relevance of their findings must be interpreted with caution.

According to the rare studies published on the possible genetic link to CM, three groups of genes have been proposed:

1. Genes potentially linked to migraine or pain progression.
2. Genes potentially linked to addiction and analgesic overuse.
3. Other genes are involved in neuronal hyperexcitability or oxidative stress.

Catechol-O-methyltransferase (COMT) polymorphisms could be related to the predisposition to chronic pain conditions. Previous reports indicate that (COMT) forms are associated with susceptibility to EM, but no specific studies in CM have been conducted.

Numerous potential genes for drug addiction have been implicated in migraine chronification, particularly in individuals who abuse analgesics. It is remarkable that some of these three genes, which are implicated in the dopaminergic and serotonergic pathways, have also been identified as having a part to play in the pathophysiology of migraines.

Oxidative stress is a topic increasing in popularity regarding its relation to the pathophysiology of migraine. However, a study that scrupulous 10 polymorphisms in 8 oxidative stress-related genes in a few populations of CM patients did not detect a relationship with CM.

However, as migraine is considered a complex disease with multifactorial inheritance, Genome-Wide Association Study (GWAS) seems a more appropriate approach to studying migraine genetic background. To date, 4 (GWAS) studies and 3 meta-analyses have been performed in EM patients leading to the identification of (44) single nucleotide polymorphisms (SNPs) on 38 distinct genomic loci associated with migraine, mainly involved in vascular natural function. Although the number of (SNPs) identified as associated with (EM) has steadily increased, our information on (CM) genetics remains considerably poor.

Studies on the genetic association of several SNP tests failed to give significant genetic risk factors for the development of CM. In 1019 individuals with CM or high-frequency migraine, the first in-depth investigation on the genetic relationship between (CM) and high-frequency migraine evaluated (144) SNPs from 48 genes but failed to detect any meaningful correlations.

Given the complexity of CM and its potential polygenic origin, additional genetic variations are expected to contribute to the disease’s susceptibility, indicating that a large sample size of patients and controls is required to discover a genetic relationship with appropriate accuracy.

The importance of epigenetic processes in a wide range of multifactorial disorders, including migraine, has become abundantly obvious in recent years. There are some indications that neuronal activity during cortical spreading depression may result in epigenetic modifications related to neuronal plasticity, neuroprotection, and control of basal synaptic activity, even though there have been no particular investigations in CM patients yet.

It is therefore conceivable that increased neuronal activity in patients with high-frequency migraine may change the cerebral epigenome, thereby promoting subsequent attacks of migraine and creating a cycle in which the epigenetic programming of genes and pathways underlying excitability is changed towards a more sensitive baseline.

Genes involved in epigenetic processes and the epigenetic regulation of the Calcitonin Gene-Related Peptide (CGRP) gene are some of the (SNPs) linked to migraine. This data has highlighted the significance of epigenetic mechanisms in the pathogenesis and chronicity of migraines.⁴

Treatment

Some people with low-frequency (EM) can be treated well with acute therapy (i.e., medications administered during the early symptom or the migraine attack to stop it), whereas those with (CM) always require prophylactic therapy.

The purpose of acute treatment is to stop a migraine attack once it has begun, whereas the purpose of prophylactic therapy is to prevent attacks from occurring. This reduces the frequency, severity, and associated disability of headaches and lessens the need for acute therapy, which may help prevent concurrent medication overuse headaches (MOH). Preventing the progression of (EM) to (CM) in patients with high-frequency EM may be another objective.⁶  Patients with EM can be treated with recommended prophylactic therapy based on the number of attacks more than four and the degree of disability.

Analgesics, non-steroidal anti-inflammatory medications, and triptans should only be used as acute therapy options for headaches in individuals with (CM). Medications containing barbiturates and opioids should also be avoided due to their strong associations with (MOH).

Triptans, which are drugs specifically designed to treat migraines, activate presynaptic (5HT1) receptors to prevent the production of (CGRP). Triptans, however, should only be taken two to three days a week at most by patients in order to prevent MOH, making them unsuitable for the treatment of (CM).

Effective acute treatment of migraine attacks with triptans may assist to halt the transition from EM to CM, but the goal of therapy for CM should be migraine attack prevention rather than depending on medication to stop migraine episodes once they have begun.

Conclusion

Chronic migraine is characterized by at least 15 headache days per month, with at least 8 of those days exhibiting migraine-like symptoms, for a period of time longer than three months. Less frequent headache episodes give way to a trend of increasingly regular headaches as the chronic headache progresses.

Chronic migraine develops over time due to several factors including increased numbers of episodic headaches over time and medications that were once used to treat episodes of headaches became overused to keep the increased number of headaches under control.

 

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