Chronic Migraine

Chronic migraine is defined as headache on more than 15 days per month in patients with migraine. Chronic migraine is difficult to treat and requires a multidisciplinary approach. Only two pharmacological treatments have been shown to be effective in placebo-controlled randomized trials: topiramate and local injection of botulinum toxin.

The International Headache Society separates primary headaches into episodic and chronic headache. Chronic headache is defined as more than 15 headache days per month for a time period of more than 3 months. Chronic migraine may be complicated by the frequent or regular use of symptomatic treatment with analgesics including opioids or specific migraine drugs (eg, ergots or triptans). This condition is termed chronic migraine with medication overuse. Medication overuse is defined as intake of simple analgesics (eg, aspirin, acetaminophen, or ibuprofen) on more than 15 days per month or the intake of combination analgesics, opioids, ergots, or triptans on more than 10 days per month.

Epidemiology

It has been estimated that chronic migraine may affect 1.3% to 5.1% of the global population. Chronic migraine is a disabling, underdiagnosed, under-recognized, and undertreated disorder; data demonstrate that it is significantly more disabling than episodic migraine. Compared to episodic migraine, patients from chronic migraine are significantly more likely to be female, disabled from employment, depressed, anxious, suffering with other forms of chronic pain, and overusing acute pain medications. Acute pain medication overuse or overuse of specific migraine medication is reported in about 66% to 75% of adults with chronic migraine.

Pathophysiology

The pathophysiology of chronic migraine is not clear. Sensitization of central trigeminothalamic pathways is considered one possibility. Dysmodulation from impaired descending inhibition or enhanced descending facilitation of nociception are possibilities. The frequent overuse of acute pain medications also may play a major role in the development of chronic migraine. Both acute pain medication overuse and migraine headache often are accompanied by cutaneous allodynia, which begins on the side of the head ipsilateral to the headache and may spread to involve the contralateral side of the head, upper torso, and extremities.

Management of chronic migraines

The management of chronic migraine requires identifying and managing risk factors (eg, sleep apnea, caffeine consumption), establishing limits on acute pain medications to less than 10 days per month, initiating nonpharmacologic treatment if appropriate, initiating preventive treatment, and assessing and treating neuropsychiatric disorders and other comorbid conditions that could contribute to increased attack frequency (eg, obesity).

Preventative treatment

The primary goals of preventive migraine therapy are to reduce the frequency and severity of attacks, to reduce reliance upon acute medications, and to improve the migraine patients’ quality of life. Reduction of attack frequency and reliance on acute medications may be particularly important in reducing the risk of the development of chronic migraine. Preventive treatment, even in the presence of acute pain medication overuse, has been shown to effectively reduce migraine frequency and disability. Drug selection should be individualized based on comorbid or coexistent illness/disorders, specifically avoiding drugs that may exacerbate another underlying condition. The choice of preventive drug should be based on evidence, though few clinical trials have investigated preventive medications over the long term or specifically for patients with chronic migraine.

Several recent randomized controlled trials evaluating the efficacy of topiramate and onabotulinumtoxin A have confirmed efficacy of these treatments for the prophylaxis of headaches in patients with CM.

Topiramate

Preventive treatment with topiramate in patients with episodic migraine may reduce the risk of developing chronic forms of headache. Low-dose topiramate may be effective in reducing headache frequency in patients experiencing chronic migraines with acute medication overuse.

Botulinum toxin injections

Boulinumtoxin A has been reported to relieve pain associated with a variety of conditions, including migraine headache. Unlike its function at the neuromuscular junction, the mechanism of action of boulinumtoxin A in nociception and migraine relief is not clear. It is postulated that boulinumtoxin A inhibits the sensitization of peripheral trigeminal sensory fibers, which modulate the activity of central trigeminal neurons, and thus, indirectly leads to the inhibition of migraine headache.

The PREEMPT trial confirmed botulinumtoxin A as an effective, safe, and well-tolerated headache prophylaxis treatment of adults with chronic migraines.

Other treatment options in chronic migraine

  • Gabapentin
  • Pregabalin
  • Amitriptyline

Anti-CGRP monoclonal antibodies

In 2018, the US Food and Drug Administration approved for migraine prevention 3 new monoclonal antibodies that target CGRP or its receptorerenumab, fremanezumab, and galcanezumab. CGRP antagonists represent the first class of medications to target specifically the pathophysiologic processes implicated in migraine. Thus far, clinical trial data indicate that these 3 agents have comparable efficacy, are well tolerated, and are not associated with safety issues.

Calcitonin Gene-Related Peptide (CGRP)

CGRP is a neuropeptide widely distributed in the nervous system, where it is thought to play a role in several processes, including vasodilation of cerebral and dural vessels, release of inflammatory mediators and transmission of nociceptive signals to the central nervous system.

The underlying pathophysiology of migraine is largely unknown, but calcitonin gene-related peptide (CGRP) most likely plays an important role. The first time CGRP was hypothesized to be involved in migraine was in 1985. This hypothesis was later supported by the finding of CGRP release during acute migraine attacks and the subsequent demonstration of normalization of CGRP levels in migraine patients after efficacious sumatriptan treatment.

Several lines of evidence support the role of CGRP in migraine:

  • In the absence of triggers or during treatment, it has been noted that migraine patients’ CGRP levels remain lower.
  • Elevations in serum and salivary CGRP have been observed in both spontaneous migraine attack and nitric oxide-induced attack.
  • Intravenous CGRP can induce a migraine attack in a matter of hours in migraine patients. This was not observed in people who do not suffer from migraine.

Two Kinds of Anti-CGRP Medications (Oral VS mAbs):

Oral anti-CGRP medications called ‘gepants’ were initially developed and tested in the early 2000s but the discovery of liver toxicity with its use caused many drug companies to stop pursuing this class of drugs. With many drug companies halting the development of gepants, the use of monoclonal antibodies (mAbs) to target CGRP molecules and its receptors were developed. Monoclonal antibodies are proteins that use the immune system to target specific molecules inside your body. Currently, there are four anti-CGRP mAbs that have been developed, galcanezumab, eptinezumab, erenumab, and fremanezumab.

Aimovig (Erenumab)

The first calcitonin-gene receptor peptide (CGRP) drug for treating migraines has been approved by the FDA this year with the introduction of Aimovig by Amgen and Novartis. Erenumab binds to the CGRP receptor and blocks the CGRP receptor function. The administration is monthly subcutaneous injections. The recommended dose of erenumab is 70 mg once monthly. Some patients may benefit from a higher dose of 140 mg once monthly, which is administered as two consecutive subcutaneous injections of 70 mg each.

The FDA’s approval for Aimovig was based on results obtained from a Phase IIIb clinical study known as LIBERTY. It was a multi-centre, double-blind, placebo-controlled study that enrolled 246 patients with episodic migraine who had between two and four unsuccessful treatments. The patients were randomised to receive either 140mg Aimovig or placebo for 12-weeks. The primary endpoint of the study was the percentage of patients with at least a 50% reduction of monthly migraine days from baseline over the last four weeks of the study. The most common adverse reactions found in patients treated with Aimovig were injection site reactions and constipation.

Patients treated with Aimovig showed significant reductions in the number of migraine days each month during the extensive clinical programme that involved the participation of 2,600 patients. The safety and tolerability profile of the drug was found to be similar to placebo.

Aimovig is now licensed for use in the UK. It has been approved for prophylaxis of migraine in adults who have 4 or more migraine days per month. It is not yet available on the formulary in most NHS hospitals but Dr. Krishna is able to prescribe it privately. Please contact us if you need further information.

Summary

Chronic migraines is a highly disabling disease and treatment options are limited. Up to now, only topiramate and local injection of botulinum toxin have shown efficacy in large placebo controlled randomized trials. Both therapies are effective in patients with chronic migraines with and without medication overuse. In many patients, treatment results are unsatisfactory and other prophylactic drugs are needed.

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