Diagnosis and Management of Chronic Daily Headache

Ivan Garza, M.D.; Todd J. Schwedt, M.D.


Semin Neurol. 2010;30(2):154-166. 

In This Article

Chronic Migraine

Chronic migraine, which affects ~2% of the world population, places a substantial burden on individuals and societies.[10] Chronic migraine results in poorer quality of life and causes significant disability.[11 12] The World Health Organization considers chronic migraine to cause disability on par with the disability secondary to quadriplegia, dementia, and active psychosis.[13] Direct and indirect costs from migraine are estimated at more than $20 billion annually in the United States, much of which is due to chronic migraine.[4] The average annual cost per person with chronic migraine is more than four times that associated with episodic migraine ($7750 versus $1757).[14]

Progression from episodic migraine (<15 headache days/month) to chronic migraine is referred to as "transformed migraine." In population studies, 3% of those with infrequent episodic headaches transform to CDH each year; 6% transform to frequent episodic headaches.[1,15] In clinic-based studies, 14% of those with episodic migraine transform to chronic migraine each year. Modifiable and nonmodifiable risk factors for this transformation have been described.[15a]

A detailed discussion of migraine pathophysiology is discussed in the article by Dr. Cutrer in this issue. Interictal (between migraine) and longitudinal studies of chronic migraine will hopefully lead to an improved understanding of the pathophysiology and effects of transformation from episodic migraine to chronic migraine. Elevated concentrations of vasoactive neuropeptides in the cerebrospinal fluid of chronic migraine patients suggest persistent activation of the trigeminovascular system.[16] Neurogenic inflammation may lead to central sensitization, a process implicated in the chronification of migraine. Functional and structural brain changes have been identified in migraine and are positively associated with increasing headache frequency and duration.[17] Chronic migraine sufferers have increased iron deposition in the periaqueductal gray, putamen, globus pallidus, and red nucleus.[18,19] They have reductions in gray and white matter density and volume in multiple regions of the brain.[20–22] Migraine sufferers have inferior executive function and abnormal visual motion perception even when headache free.[23,24]


Chronic migraine patients tend to have mild to moderate headaches associated with mild migrainous features (e.g., photophobia, phonophobia) with superimposed more-severe headaches associated with more prominent migraine features ("full-blown" migraines). In some patients, environmental hypersensitivities persist even during headache-free periods.[25] This may include mild photophobia, phonophobia, motion-sensitivity, and cutaneous hypersensitivity/allodynia. Patients with chronic migraine have an increased frequency of comorbid psychiatric disorders, sleep disorders, fatigue, other pain, and gastrointestinal complaints. Recognition and treatment of these comorbidities can result in improved health, greater quality of life, and may potentially result in higher migraine treatment success rates. The following are the recently revised diagnostic criteria for chronic migraine:[26]

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

  2. Occurring in a patient who has had at least five attacks fulfilling criteria for migraine without aura

  3. On ≥8 days per month for at least 3 months, headache has fulfilled criteria for pain and associated symptoms of migraine without aura (Criteria a and b below) or was treated and relieved by triptan(s) or ergot before the expected development of symptoms listed in Criteria a and b.

    1. Has at least two of the following:

      1. Unilateral location

      2. Pulsating quality

      3. Moderate or severe pain intensity

      4. Aggravation by or causing avoidance of routine physical activity

    2. Has at least one of the following:

      1. Nausea and/or vomiting

      2. Photophobia and phonophobia

  4. No medication overuse and not attributed to another causative disorder


The treatment of chronic migraine focuses on prophylactic therapies, which may include avoidance of migraine triggers, pharmacotherapy, physical therapy, biobehavioral therapy, and others. Simultaneous use of these different therapeutic modalities may be needed. Identification and treatment of comorbid disorders is also required for true treatment success. Acute headache medication use needs to be limited to avoid medication overuse headache. Although complete headache eradication is not a realistic expectation, significant reductions in headache frequency and/or severity are the goal of prophylactic therapy.

Pharmacologic Prophylaxis Prophylactic medications used to treat episodic migraine are also used for the prevention of chronic migraine. Thus, first-line prophylactic medications are from the following classes: antidepressants, antiepileptics, and antihypertensives. The prophylactic medications that have been specifically studied in clinical trials of patients with chronic migraine are illustrated in Table 2. Once an effective prophylactic medication is found, it is typically continued for 3 to 6 months prior to attempting discontinuation. An effective prophylactic medication is one that decreases headache frequency by at least 50%.

Topiramate Two randomized, double-blind, placebo-controlled studies are available.[27,28] The larger of the two studies randomized 153 subjects to topiramate 100 mg daily and an equal number to placebo.[27] Those in the topiramate group experienced a reduction of 6.4 ± 5.8 headache days per month from a baseline of 17.1 ± 5.4 days, as compared with a reduction of 4.7 ± 6.1 days from a baseline of 17.0 ± 5.0 days in the placebo group (p = 0.10). In the smaller of the two studies, 32 subjects were randomized to topiramate 100 mg daily and 27 were randomized to placebo.[28] Among all subjects, topiramate significantly reduced the mean number of monthly migraine days during the third month of therapy as compared with placebo (p = 0.02).

Gabapentin Gabapentin has been studied as a prophylactic medication for chronic daily headache in a multicenter randomized placebo-controlled crossover study of 133 subjects (~85% with migraine).[29] Gabapentin 2400 mg per day was associated with a greater percentage of headache-free days (mean 26.6% vs. 17.5%, p < 0.001) and reductions in headache duration, severity, and analgesic use.

Tizanidine Tizanidine has been studied as an adjunctive prophylactic for chronic daily headache in a multicenter, randomized, blinded, placebo-controlled study.[30] One hundred thirty-six subjects (~3/4 with chronic migraine) were randomized to placebo or to tizanidine titrating up from 2 mg each night to the maximum tolerated dose, or 24 mg divided among three daily doses. The median tizanidine dosage was 20 mg per day. Subjects in the tizanidine group had significant reductions in headache index as compared with the placebo group.

Fluoxetine Sixty-four subjects with chronic migraine were randomized in a 16-week double-blind trial of fluoxetine.[31,32] Subjects were treated with 20 mg daily and then increased to 40 mg daily if needed and as tolerated. Fluoxetine-treated subjects had significant improvements as compared with the placebo group in overall headache status, mood, and headache frequency.

Amitriptyline Thirty-nine transformed migraine subjects participated in a prospective double-blind study of amitriptyline versus amitriptyline plus fluoxetine.[32] Although there were not significant differences in outcomes between the two treatment groups, subjects treated with amitriptyline (8–40 mg/day) and those treated with amitriptyline plus fluoxetine (8–20 mg/day) both had reductions in headache frequency and intensity.

Levetiracetam An open-label study of 36 transformed migraine subjects, with or without medication overuse, investigated the effect of levetiracetam.[33] At 3 months, levetiracetam-treated subjects had reductions in headache frequency (24.9 days/month to 16.2 days/month; p < 0.001), disability (MIDAS dropped from 62.8 to 40.8; p = 0.01), and HIT-6 score (63.4 to 59.4; p ≤ 0.01).

Valproate Two studies suggest valproate may be useful in the prophylaxis of chronic migraine. In an open-label study of 30 patients with intractable transformed migraine, patients were maintained on dosages between 1000 to 2500 mg.[34] A 50% or greater reduction in headache index was found in 67% of the subjects, headache-free days per month increased from 5.5 to 17.7, and days with significant disability declined from 22 per month to 8.5 per month. The second study was a chart review of 138 chronic daily headache patients (49 with transformed migraine) being treated with divalproex sodium monotherapy.[35] In the migraine patients, the mean decrease in migraine frequency was 65.2%.

Botulinum Toxin Although botulinum toxin type A appears to benefit a subset of patients with chronic migraine, no consistent or strong evidence is available yet to permit drawing conclusions on its efficacy in CDH (mainly transformed migraine).[36] Further study results are required and pending.

Memantine Memantine was recently reported to induce remission of chronic migraine.[37]An open-label study further suggests this drug may play a role in chronic migraine management.[38] Double-blind studies are required to establish memantine's role in chronic migraine treatment.

Nonpharmacologic Therapy Biofeedback, relaxation therapy, cognitive-behavioral therapy, and physical therapy may be useful as adjunctive treatments for chronic migraine. A controlled study of biofeedback showed associated decreases in oxidative stress and disability from migraine.[39] Cognitive-behavioral therapy may provide short-term and long-term reductions in headache burden.[40] Physical therapy is associated with significant reductions in migraine burden in some studies.[41] Furthermore, a combination of physical therapy and biofeedback has been shown to provide greater relief than physical therapy alone.[42]


Patients with chronic migraine may revert back to episodic migraine. Reversion rates at one year range from 56 to 70% in population-based and specialty headache clinic-based samples, respectively.[9,43] Predictors of reversion include withdrawal of overused medications, compliance with prophylactic medications, and regular physical exercise.


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