Neuropsychiatry of Chronic Migraine – Pathophysiology and Treatment

PHASES OF MIGRAINE

Migraine attacks are often reported to have four phases:

• Prodromal or premonitory phase – Symptoms are often subtle and can occur in the days and hours leading up to a migraine. Symptoms can include yawning, neck stiffness, thirst, and polyuria.

• Aura phase – In 28% of migraine patients, the prodromal phase will develop into an aura phase and this can either precede or coexist with the headache phase. [2] Patients can experience visual and auditory hallucinations, feelings of physical and mental distortion and even partial loss of sight.

• Headache phase – Described as a throbbing pressure that intensifies with increased intracranial pressure leading to nausea, sensitivity to light, noise and smell.

• Postdromal phase – This phase is characterised by a diverse range of symptoms, including fatigue and poor concentration as well as cognitive issues such as poor comprehension skills and lowered mood levels, even depression.

CLASSIFICATION AND DIFFERENTIAL DIAGNOSIS

Currently, migraines are classified using the International Classification of Headache Disorders (ICHD-2 (2^nd edition)).

However, this classification (ICHD-3Beta) is currently undergoing testing and revision to improve the power of its diagnostic criteria and allow for the identification of a broader range of migraine subtypes. [3]

Episodic migraines: 

Five headaches that last from 4 to 72 hours and can be described by two of the first four criteria, and one of the last three:

• Unilateral location
• Pulsating
• Moderate-to-severe pain
• Aggravation by or causing avoidance of routine physical activity
• Nausea and/or vomiting
• Photophobia
• Phonophobia

Chronic Migraines:

Headaches (tension or migraine-like) on at least 15 days per month for more than 3 months with at least 8 headache days per month fulfilling criteria for migraine headaches.

Differential Diagnosis

• Hemicrania continua – Daily constant headache that is unilateral and responsive to indomethacin. Indomethacin is an NSAID that inhibits cyclo-oxygenase, an enzyme that is critical in how the body produces prostaglandins [4]. Prostaglandins are vasodilator compounds that are involved in inflammatory processes.

• Chronic tension-type headaches – Chronic tension-type headaches have a pressing or tightening pain that is usually bilateral in location (unilaterality does not exclude tension headaches). They do not have more than one of the following: nausea, photophobia and phonophobia. There is no severe nausea or vomiting.

• New daily persistent headache (NDPH) – A new-onset headache occurring in a person who does not have a previous history of frequent headaches and which then persists on a daily basis for more than 3 months.
• Its onset can be distinctly remembered. It has features of both chronic migraine and tension-type headaches and in most cases, will resolve without treatment.
• However, for some, NDPH can be a treatment-resistant headache disorder that can continue for years or it can be a relapsing-remitting type where there are pain-free periods. [5]

PATHOPHYSIOLOGY OF MIGRAINE

A number of genetic, hormonal and neurochemical factors interact and result in dysregulation of cortical and brainstem excitability. [6]

A concept called cortical spreading depression (CSD) is thought to be associated with migraine.

CSD is characterised by a wave of significant cortical activation followed by sustained inhibition of activity:

“The clinical symptoms of migraine aura, as well as the clinical electrophysiological and transcranial magnetic stimulation responses of migraine patients, indicate a fundamental role for changes in neuronal excitability as a basis for increased cortical excitability in migraine.” – Charles & Brennan, 2010

This excitability leads to cortical activation via neuronal and glial activation, which in turn is associated with nociceptive activation and vascular changes including enhanced blood-brain barrier permeability.

Nociceptive activation, through the release of various neurotransmitters and neuromodulators, leads to central sensitisation. Central pain sensitisation was covered previously in the article on neuropsychiatry of fibromyalgia.

The cortical activation spreads to the brain stem via trigeminal pathways further enhancing central sensitisation.

The central sensitisation increases pain perception (migraine).

CHRONIFICATION OF MIGRAINE

Migraines are often described as a threshold disorder associated with dysfunctional nociceptive processing. [6]

The increased activity in the descending pain-modulating neural networks sensitises an individual to be more susceptible to physiological and environmental factors that precipitate migraine attacks.

Susceptibility to migraine chronification is reported to be due to several genetic and non-genetic risk factors that decrease the threshold, enhance sensitivity, and increase migraine attack frequency.

Medication-related risk factors

Two of the most important risk factors are related to medication use, and both are easily modifiable.

• Ineffective acute treatment – Doubles the risk for migraine chronification because the longer the exposure to pain, the more likelihood that the threshold is lowered for future migraine attacks. [7]

• Overuse of acute migraine medication – Chronic use of medication can facilitate migraine chronification through tolerance and drug dependency. [8] Also, medication-overuse headache (MOH) is a common form of secondary chronic migraine and is a result of the regular overuse of barbiturates, analgesics, or opioids (or a combination thereof). [9]

Metabolic risk factors

Several studies have suggested that obesity and metabolic syndrome (i.e. insulin resistance) are risk factors for increased migraine severity and an increased likelihood of progression from episodic to chronic frequency. [10], [11]

The comorbidity of these disorders is possibly due to common pathophysiological mechanisms—such as shared inflammatory mediators.

It is also interesting to note that hypertension, in association with obesity, is associated with increased intracranial pressure.

This increased intracranial pressure has been observed in 10% of chronic migraine patients, and this may underpin the comorbid relationship between migraines and metabolic issues in some cases. [12]

Psychological risk factors

Chronic migraine, but not episodic migraines, are significantly associated with other neurological disorders such as epilepsy and stroke as well as psychiatric illnesses such as depression, anxiety, bipolar disorder, and PTSD. [1]

Depression, anxiety, and bipolar disorder have a bi-directional relationship with migraines and can increase the risk of chronification if left untreated.

Bipolar II disorder is associated with a higher risk of developing migraines. [13].

Bipolar disorder with migraine is thought to be a distinct subtype with a rapid cycling course, a greater prevalence in women, increased panic attacks, and an earlier age of onset. [14]

A trend in the research does show that migraines with aura are associated with suicide ideation, and this comorbidity is independent of depressive symptoms.[15], [16]

Migraine is more prevalent in patients with a history of physical, emotional, and sexual abuse. Recent studies suggest that this relationship is mediated by the development of PTSD.

Studies show that the association between migraine and substance abuse is predominantly mediated by psychiatric co-morbidities.

The relationship between migraine and psychiatric co-morbidities is likely to be complex involving the HPA axis, pain pathways, and multiple neurotransmitter pathways.

MANAGEMENT

Migraine treatments can be classified as either symptomatic therapy (aborts acute migraine attacks) or preventative therapy (reduces acute attack frequency and severity).

At present, non-specific drugs such as analgesics and NSAIDs are commonly used with almost 50% of these being non-prescription OTC medications (e.g. aspirin, paracetamol, and ibuprofen). [17], [18]

Symptomatic therapy

The majority of specific anti-migraine drugs are serotonin receptor (5-HT) agonists.

These include ergot derivatives (ergotamine tartrate and dihydroergotamine) and triptan compounds (sumatriptan, zolmitriptan, rizatiptan, naratriptan, eletriptan, frovatriptan, and almotriptan).

• Ergot derivatives – Have been mainly replaced by triptans due to their significant adverse effect profiles that are caused by their interaction with many subtypes of 5-HT receptors, α-adrenoceptors and dopamine D2 receptors. Moreover, frequent use of ergot derivatives is associated with an ergotamine-induced rebound headache.

• Triptans – A group of seven compounds that have been shown to be effective in treating migraines in numerous randomised controlled trials. [19] Each triptan has a different efficacy and safety profile as well different pharmacokinetic and pharmacodynamic properties. Therefore, an advantage of triptan therapy is that therapy can be individualised to each patient. At present, triptans are indicated for the acute treatment of moderate-to-severe migraines and are beneficial if taken at the very onset of the headache phase. [20] Research shows that triptans provided effective pain relief that can occur as quickly as two hours and can last for up to 24 hours with no significant adverse effects reported.

Preventative therapy

An appropriate preventative strategy can effectively lower the frequency of migraines as well as help prevent the severity of migraines when they occur.

• Topiramate – One of the most extensively researched pharmaceutical agent for chronic migraines. Topiramate has been shown to be very effective at significantly reducing headache days and improving the quality of life of migraineurs. [21], [22] Common side effects of Topiramate (>10% incidence) include fatigue, depression, somnolence and paraesthesia. Given the comorbidity of depression with chronic migraine, it is therefore advised that patients are closely monitored for this risk.

• Botulinum neurotoxin (BoNT-A) – Pooled analyses of the PREEMPT I and II phase III trials showed that a commercially available form of BoNT-A (onaBoNTA) resulted in a statistically significant reduction in headache frequency over placebo as well as significant reductions in headache severity and duration. [23], [24] Allergan is currently researching the long-term safety,  efficacy and tolerability of 9 cycles of repetitive BoNT-A injections every 12 weeks. (COMPEL trial). [25]

Amitriptyline (low dose) and propranolol are considered effective preventative agents in migraine with co-morbid psychiatric disorders.

Valproate sodium is effective in the prevention of migraines in bipolar disorder.

Neuromodulation techniques

Neuromodulation is a novel approach for the treatment of chronic migraines. It involves the delivery of electrical or magnetic stimulation to specific neural circuits in the brain. As a non-pharmacological treatment option, neuromodulation can avoid adverse drug reactions that are associated with medications.

There are two main types of neuromodulation techniques: peripheral and central neuromodulation.

Central neuromodulation techniques (transcranial magnetic stimulation and transcranial direct current stimulation) have not been studied sufficiently and hence we will focus on the peripheral techniques.

• Non-invasive vagus nerve stimulation (nVNS) – Previously been used to treat epilepsy and depression. [26], [27] In one study involving chronic migraine patients, two unilateral 90-second nVNS doses (separated by 15 minutes), caused 22% of chronic migraine attacks to be aborted with 43% of attacks reported to have a significant reduction in pain scores. [28]

Targeted neuromodulation of the occipital nerve and visual cortex have previously been shown to be an effective therapy for the treatment of chronic cluster headaches.

Targeted neuromodulation techniques include:

• Occipital nerve stimulation (ONS) and supraorbital nerve stimulation (SONS) – Involves the application of a mild electrical current to the occipital nerves (greater, lesser and third occipital nerves) or the supraorbital nerve, respectively. In one study, dual ONS and SONS resulted in 71% of patients to have a significant reduction in pain severity with 50% of patients returning to normal functioning. [29]

CONCLUSION

Chronic migraine is a complex and disabling disorder that has a poorly understood pathophysiology.

Current therapeutic options are inadequate however research is ongoing and it is hoped that the near future will bring novel therapeutics with greater efficacy.

QUIZ