Chronic Migraine

Posted: 11/06/2009

“An ounce of prevention is worth a pound of cure” Benjamin Franklin

There is new recognition that migraine headaches are not just an episodic disorder but also a progressive disorder in many cases. [1] “There is a great necessity to prevent disease progression and recognition that in the future successful management of migraine will ideally be measured not by attack termination, but by prevention or reversal of disease progression. Thus, the role of preventative therapy will likely become more central to migraine management.” [2] Prevention thus becomes the duty of all health care providers who render service to migraine patients.

Chronic migraine is one of the varieties of chronic daily headache, which afflicts approximately 3 to 5% of the population worldwide. [3] The quality of life of subjects with chronic daily headache in the general population was studied using the Short Form-36 in 89 patients compared to 89 healthy controls with a significant decrease in each health-related concept of the Short Form-36 as compared with healthy subjects. The highest decreases were seen for role physical, bodily pain, vitality, and social functioning. [4]

Chronic daily headache is divided into primary and secondary types. Secondary headaches are those with a demonstrable cause such as brain tumor or trauma and caution dictates that secondary causes of headaches must be ruled out. The primary types of chronic daily headaches, besides chronic migraine are chronic tension-type headache, new daily persistent headache, and hemicrania continua. Overuse or medication rebound headache often complicate chronic migraine and other forms of chronic daily headache.

This review will deal with chronic migraine headaches. Chronic migraine headaches, previously called transformed migraine, were defined in 2004 by the International Headache Society (IHS) as 15 or more days per month (for a period of at least 3 months) of headache. In 2006, an appendix was published by the IHS defining chronic migraine is characterized by a pattern of headaches, experienced by the patient, rather than focusing on symptoms of individual headache attacks. [5]

This elaboration of the concept of chronic migraine produced several significant effects:

1.  Identified the potentially progressive nature of migraine with the concept that episodic migraine was not only an episodic disorder, but also a precursor to chronic migraine and that attention to the early and effective treatment of the episodic disorder might prevent progression to the chronic disorder

2.  Called attention to the fact that “migraine is a potentially chronic, progressive disease that substantially effect patients, families, work places, and society” [2]

3.  Pointed out that there was a spectrum of clinical phenotypes, ranging from IHS migraine to IHS tension-type headaches, responsive to triptans [2]

4.  Suggested that there might be a common mechanism for chronic migraine in all its phenotypes [6]

Two recent articles highlight new opportunities for patient and health care professionals to improve communication and understanding of the disease of migraine. [7, 8]

Definition, prevalence, and transformation of chronic migraine
The 2004 ICHD II criteria required 15 or more headache days per month that met the criteria for migraine without aura. Since few patients met this definition, a new definition requires migraine without aura or response to migraine specific medication eight or more days per month. Approximately 2% of the general population suffers from chronic migraine, and the rate of transformation from episodic migraine to chronic migraine is about 2.5% per year. Risk factors for the development of chronic migraine include medication overuse, headache, frequency, or obesity, allodynia, snoring, and head injury. [9]

The mechanism of migraine transformation is unknown. Possibilities include:

1.  Sensitization of peripheral nociceptors due to repeated activation with substance P, calcitonin gene-related peptide, neurotrophins, kinins, prostaglandins, and nitric oxide felt to be liberated during neurogenic inflammation and with repeated release sensitize peripheral nociception. Glutamate has been recently shown as an important mediator in central sensitization in chronic migraine with increased in cerebrospinal fluid glutamate levels found in chronic migraine patients.

2.  Central sensitization with enhanced responsiveness of the trigeminal nucleus caudalis

3.  Defective pain modulation from increased on-cell and decreased off-cell firing in the medulla. In part, this may be due to chronic medication overuse.

4.  Hypothalamic dysfunction has been implicated in chronic migraine pathophysiology

5.  Kindling with spontaneous central pain

Underutilization of preventative treatment is a significant cause of transformation. Generally, repeated migraine attacks can cause repetitive central sensitization as in other types of chronic pain. Therefore, early treatment is essential to the prevention of central sensitization, which is felt to generate free radicals that damage the periaqueductal gray matter (PAG) and facilitate migraine progression.

Characteristics of chronic migraine
Chronic migraine occurs on a daily or near-daily basis. It is characterized by persisting pain (usually of mild to moderate intensity) that lasts at least four hours a day if untreated and is usually present for much or all of the day. More severe headache pain example is accompanied by more typical migraine symptoms including throbbing pain, headache exacerbation with physical activity, associated nausea/vomiting, sonophobia and photophobia. Chronic migraine begins as episodic migraine that increases in frequency, losing some of its migraine features as it becomes chronic and almost daily.

The revised IHS criteria for chronic migraine include:

1.  Headache (tension-type or migraine) on at least 15 days or more per month for at least 3 months

2.  Occurrence in a patient with at least five attacks qualifying as migraine without aura

3.  On or more than 8 days per month for at least 3 months headache has at least two of the following criteria:

• Unilateral location of pain

• Pulsating quality

• Moderate or severe intensity

• Aggravation or avoidance of physical activity

And at least one of the following criteria:

• Nausea or vomiting

• Phonophobia and sonophobia

• Treated and relieved before the expected development of unilateral location of pain

•Pulsating quality

• Moderate or severe intensity

• Aggravation or avoidance of physical activity by triptans or ergots. This latter point is very important because chronic migraine may lose its migraine characteristics and the relief by triptans or ergots is an important diagnostic point.

The confounding effects of medication overuse
The International Classification of Headache Disorders divided the medication-overuse headaches into:

1.  Ergotamine-overuse headache (intake on 10 or more days per month on a regular basis for longer than 3 months)

2.  Triptan-overuse headache (intake on 10 or more days per month on a regular basis for longer than 3 months)

3.  Analgesic-overuse headache (intake on 15 or more days per month on a regular basis for longer than 3 months)

4.  Opioid-overuse headache (intake on 10 or more days per month on a regular basis for longer than 3 months)

5.  Combination medication-overuse headache (intake on 10 or more days per month on a regular basis for longer than 3 months).

The vast majority of chronic migraine headache patients coming to a headache clinic or pain management center have the criteria for one or more of the above medication overuse syndromes and, initially, it was required that the headaches improve after a “washout” period of one of the above pharmacological agents. Significant difficulties in weaning patients from the offending medications make the diagnostic task more difficult as well as the obvious therapeutic task.

What can be done about chronic migraine?

1.  Exclusion of secondary headache disorders is mandatory and leads to patient reassurance. A diagnosis should be made with consideration of the fact that chronic migraine may not look like the episodic migraine disorder that was transformed to chronic migraine. This requires a thorough review of the course of transformation of the original headache disorder. At some point, the original disorder must meet the criteria for episodic migraine. Comorbid medical and psychiatric conditions and exacerbating factors, especially medication overuse, should be identified and treated. Anxiety and depression were present in 80% of chronic female migraine patients and in 63% of chronic female tension-type headache. [10]

2.  Prevention of progression from episodic to chronic migraine is essential. Comorbid medical and psychiatric conditions, as well as medication overuse need to be identified. Elimination of migraine triggers is essential with establishment of a daily routine, including proper eating habits, exercise, and sleep. Behavioral therapy, which includes stress management relaxation biofeedback and counseling are useful as is physical therapy, including heat, ultrasound, and electrical stimulation. Cold packs and contrast may be beneficial. All forms of intractable chronic daily headache may be improved by treating trigger areas in the neck. Pharmacological prevention and treatment is reviewed below.

3.  Education of the patient as to his/her disorder, especially the role of medication overuse when indicated. Some patients are able to limit their symptomatic medication use after education alone.

4.  Removal of chronic medication overuse. The type and quantities of medication being overused will determine management of withdrawal. Simple analgesics and small daily amounts of butalbital-containing compounds and narcotics can be stopped in an outpatient setting. If the patient is at risk for withdrawal, then an inpatient setting is warranted.

A severe headache, nausea, vomiting, agitation, restlessness, sleep disorder, and occasionally seizures, may occur for as long as 2 weeks. Short-acting barbiturates and benzodiazepines are replaced by long-acting medications, which are tapered gradually to avoid a serious withdrawal syndrome. The “analgesic washout period” usually lasts 3 to 8 weeks, but may last for as long as 6 months. An alternative medication may be employed and then weaned. A long-acting NSAID or triptan can be substituted for the overused simple analgesic (e.g., naproxen sodium or indomethacin); naratriptan has been used in this setting. The patient can use this medication daily for approximately 1 week and then limit its use to avoid further analgesic overuse headache. A short course of corticosteroids during outpatient detoxification has been use. A neuroleptic or other rescue medication may be necessary during outpatient detoxification. Metoclopramide is a useful agent because of its antiemetic and antiheadache properties.

Withdrawal can be difficult and require hospitalization. Statistics vary widely on the success of outpatient withdrawal from 1.5% to almost 66%. Two studies [11, 12] have shown that the detoxification process can be enhanced and shortened and the patient's symptoms made more tolerable by the use of repetitive intravenous dihydroergotamine coadministered with metoclopramide, which helps control nausea and is also an effective antimigraine drug in its own right.

Patients who are not candidates for dihydroergotamine or are truly intolerant of the drug may require repetitive intravenous neuroleptics or corticosteroids. One study suggests that repetitive intravenous diphenhydramine is effective.

Prophylactic migraine [13] treatments are aimed at reducing the frequency, severity and duration of migraine attacks, as well as the disability resulting from these attacks. Use of the MIDAS scale will quantify the level of disability in migraine attacks and stratify the treatment. Agents used for prophylactic therapy include beta-blockers, calcium channel blockers, alpha-2 adrenergic agonists, serotonin antagonists, antidepressants, NSAIDs and anti-epileptic drugs. Botox can also be used. Few of the preventative agents typically used to prevent episodic migraines have been evaluated for their effectiveness in treating chronic migraine. As these agents have not been evaluated in large multicenter controlled clinical trials, there is a great need for future research to develop effective treatments. A review of some of these agents follows:

• Gabapentin: This is an anti-epileptic medication used for a variety of painful disorders. It has been demonstrated to increase the percentage of headache 3 days over placebo by 9.1% and also diminished headache severity, disability, and improved quality of life.

• Tizanidine: This alpha-adrenergic agonist inhibits the release of norepinephrine in both the brainstem in the spinal cord. It has been shown to reduce the overall headache index compared with placebo and to reduce the average number of headache, days per week of severe headache, days per week, headache intensity, and mean, headache, duration.

• Fluoxetine: This selective serotonin reuptake inhibitor has been demonstrated to be moderately effective in treating chronic daily headache.

• Amitriptyline: Amitriptyline down regulates serotonin receptors, increases the levels of synaptic norepinephrine, and enhances opioid receptor actions. It has been used to treat chronic daily headaches, but adverse effects may limit its use.

• Valproate: This anti-epileptic drug’s mechanism of action in migraine is unclear, but it has been shown to be effective in migraine prophylaxis. Fetal abnormalities make its use in women of childbearing age untenable.

• Topiramate: This drug blocks were voltage sensitive sodium channels and voltage activated calcium channels, inhibits glutamate release and increases GABA levels. A reduction in headache, days, and in the use of acute headache medicine was observed with topiramate in patients with chronic migraine. Side effects include paresthesia, fatigue, anorexia, nausea, diarrhea, weight loss, dizziness, taste, perversion, and difficulty with memory, and concentration. It has also been associated with glaucoma and kidney stones. It has been shown to be effective at higher doses, 100 mg per day, in patients with chronic migraine.

• Botulinum toxin type A: This protein inhibits the release of acetylcholine from presynaptic nerve endings and blocks the release of nociceptive mediators, such as substance P, glutamate, and calcitonin gene-related peptide. In patients without medication overuse headaches, the injection of 100 units of Botox into 5 sites using a fixed dose resulted in significant reductions in migraine episodes in the patients with chronic migraine receiving Botox. Several studies have demonstrated the efficacy of Botox. Over long periods, for example, 9 months, Botox, topiramate, and valproate produce similar relief. New and novel treatments, including closure of patent foramen ovale, peripheral nerve stimulation in the occipital region, and vagal nerve stimulation, as well as transcranial direct current stimulation are under investigation.

Conclusion
The recognition of chronic migraine as a consequence of inadequately treated, episodic migraine has been a tremendous advance. Adequate treatment of episodic migraine in the form of prophylactic and abortive medications, as well as lifestyle adjustments is indicated to prevent transformation to chronic migraine. Once chronic migraine has occurred, consideration of elimination of medication overuse must be accompanied by changes in lifestyle. Botox, anti-epileptic medications, alpha-adrenergic agonists, and physical modalities offer promise of relief, but randomized, controlled studies at multiple centers are needed to validate the efficacy of these treatments.

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