Chronic Daily Headache

PRIMARY CDH

TREATMENT OPTIONS FOR CHRONIC MIGRAINE AND OTHER CHRONIC DAILY HEADACHE

CM is characterized by at least a 3-month history of headaches occurring >15 days/month, meeting criteria for migraine on >8 days/month, in the absence of medication overuse.¹ However, a diagnosis of CM can confidently be made in a patient with >15 headache days per month and a past history of migraine. According to ICHD-II, when CM is associated with MOH, only a diagnosis of probable CM and probable MOH can be made, and only after withdrawal of overused medications and the persistence of headache can a diagnosis of CM be made. Practically, withdrawing acute medications as the only therapeutic intervention is extraordinarily difficult in clinical practice. Acute MO occurs in two-thirds of patients with CM, and the use of prophylactic medications has been shown to be effective without withdrawal of acute medications. The most pragmatic approach is initiating prophylactic therapy while minimizing acute medications to 2 days/week.

Most with CM have a history of episodic migraine with gradual transition toward more frequent headaches; however, in 30% the transition can be abrupt. Controlled epidemiologic studies have identified attack frequency (>4/month), obesity (body mass index >30), MO, life stressors, snoring/sleep apnea/sleep disturbance, caffeine consumption, female gender, head injury, low education/socioeconomic status, and prior history of episodic migraine as risk factors promoting CM.³

Aggressive approaches, involving pharmacologic and nonpharmacologic options, are often required to treat CM (figure). Avoiding identifiable triggers and regulating daily activities to a schedule can help. Addressing risk factors including poor sleep, excessive caffeine intake, lack of exercise, dehydration, and anxiety and depression are all nonpharmacologic areas that can aid in successful treatment of CDH. Functional imaging studies have shown anxiety and attention to pain can inhibit central antinociceptive networks. Relaxation training, biofeedback, stress management, and cognitive-behavioral therapy allow patients to exert control over otherwise automatic physiologic responses that influence pain modulation. A recent randomized control trial involving 203 adults with CTTH demonstrated combining tricyclic antidepressants with stress management therapy was more efficacious than either alone.⁴ Well-designed trials demonstrated the efficacy of these techniques, and have been given a grade A recommendation from the United States Headache Consortium Guidelines and the American Academy of Neurology Practice Parameter in the management of migraine.⁵

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Figure Approach to the patient with chronic migraine (CM), with or without acute medication overuse

NSAID = nonsteroidal anti-inflammatory drug.

Patients with migraine with frequent, disabling, or refractory headaches, or with contraindications or overuse of acute analgesics, benefit from prophylactic treatment. Drug selection should be based on comorbid conditions, avoiding drugs that may exacerbate another condition. While a number of prophylactic medications have been evaluated for the treatment of primary CDH (table 4), the largest properly conducted placebo-controlled trials in subjects with CM have evaluated efficacy of topiramate and onabotulinumtoxinA.

A small-scale (n = 28) double-blind, placebo-controlled trial demonstrated low-dose topiramate (50 mg/day) may be effective in reducing headache frequency in patients who had CM with MO. Responder rate (≥50% improvement in monthly headache frequency) in topiramate vs placebo-treated subjects was, respectively, 71% and 7%.⁶ Two larger, randomized, double-blind, placebo-controlled, parallel-group clinical trials were performed with topiramate in patients with CM. Significant reduction in the mean monthly rate of migraine/migrainous days (6.4 ± 5.8) compared to placebo (4.7 ± 6.1; p = 0.010) and a mean reduction from baseline of migraine days per month (5.6 ± 6.0) compared to placebo (4.1 ± 6.1; p = 0.032) was observed in the United States,⁷ whereas reduction in mean monthly migraine days (−3.5 ± 6.3) was noted compared to placebo (0.2 ± 4.7 p = 0.02) in a study conducted in the European Union. In this study, patients with acute MO reported mean monthly reduction in migraine days by 3.5 ± 7.1 days, which was significant compared to placebo with an increase of 0.8 ± 4.8 days (p = 0.03). Similar data on MO were unavailable from the US trial, but secondary analysis was performed and showed a trend toward significance (p = 0.059). The European trial responder rate of at least 50% reduction of migraine days was significant for topiramate (22% vs 0% p = 0.012), but not in the US trial.

Systematic series of exploratory controlled trials failed to show superiority of onabotulinumtoxinA over placebo in subjects with migraine, CDH, and CTTH. Efficacy of onabotulinumtoxinA in episodic migraine and CTTH has therefore not been established.

The PREEMPT clinical program confirmed onabotulinumtoxinA as effective, safe, and well-tolerated prophylaxis for adults with CM. Two phase 3 multicenter studies (PREEMPT 1 and 2) that each had a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week open-label phase enrolled 1,384 patients with CM.^8,9 All patients received the minimum 155 units IM of onabotulinumtoxinA in 31 sites across 7 head and neck muscles using a fixed-site, fixed-dose injection paradigm. Up to 40 additional units, administered IM to 8 injection sites across 3 head and neck muscles, was allowed using a modified follow-the-pain approach. Pooled analysis demonstrated onabotulinumtoxinA treatment significantly reduced mean frequency of headache days (−8.4 onabotulinumtoxinA, −6.6 placebo; p < 0.001) and headache episodes (5.2 onabotulinumtoxinA, −4.9 placebo; p = 0.009).¹⁰ Several other efficacy variables (migraine episodes, migraine days, moderate or severe headache days, cumulative hours of headache on headache days, and proportion of patients with severe disability) were significant favoring onabotulinumtoxinA. Results showed significant improvements in multiple headache symptom measures and demonstrated improvement in patient functioning, vitality, psychological distress, and overall quality of life.

Several other drugs have been evaluated for prophylactic treatment of undifferentiated primary CDH, but not specifically CM. However, because these medications have demonstrated efficacy in subjects with episodic migraine and given that CM is a highly disabling disorder with frequently unsatisfactory treatment outcomes, other drug options should be considered.

Gabapentin was evaluated in patients with CDH (dose of 2,400 mg per day).¹¹ After 12 weeks of treatment, the median 4-week migraine rate was 2.7 (baseline 4.2) in treatment group and 3.5 (baseline 4.1) in placebo group (p = 0.006). Additionally, 26 of 56 patients (46.4%) receiving a stable dose of 2,400 mg of gabapentin per day and 5 of 31 patients (16.1%) receiving placebo showed at least a 50% reduction in 4-week migraine rate (p = 0.008).

Tizanidine was evaluated in a 134-subject placebo-controlled single-blind study as adjunctive prophylactic treatment for CDH, demonstrating superiority to placebo comparing overall headache index (p = 0.0025), mean headache days per week (p = 0.0193), severe headache days per week (p = 0.0211), average headache intensity (p = 0.0108), peak headache intensity (p = 0.0020), and mean headache duration (p = 0.0127).¹²

Fluoxetine was evaluated in a 64-subject double-blind placebo-controlled trial with CDH (initial doses of 20 mg fluoxetine).¹³ Dosages increased up to 40 mg depending on patients' response. After 3 months, fluoxetine subjects had 1.57 fewer headache days per week compared with placebo-treated subjects who had 1.12 headache-free days per week.

Amitriptyline has been shown in clinical studies to be well-tolerated and effective as monotherapy for prevention of migraine and other CDH, most recently in a double-blind, placebo-controlled, 20-week parallel-track study involving 317 subjects which demonstrated superiority of amitriptyline at doses of 50–100 mg at 8 weeks.¹⁴ Amitriptyline is thought to act by facilitating the descending modulation of nociception within the trigeminal nucleus caudalis and spinal dorsal horn by increasing the amount of synaptic amines, enhancing the action of endogenous opiate receptors, and also, in rat models, by inhibiting cortical spreading depression.¹⁵

One randomized open study in 49 subjects with CM compared sodium valproate 750 mg/day to topiramate 75 mg/day.¹⁶ Three months after randomization, significant reduction in 30-day headache days with respect to baseline (p < 0.00001) and significant reduction in Migraine Disability Assessment (MIDAS) scores (p < 0.00001) were recorded in both groups. No significant differences in beneficial effects between the 2 medications were shown. Seventy patients with CDH (29 with CM, 41 with CTTH) were studied for efficacy and tolerability of sodium valproate in a prospective, double-blind, randomized, placebo-controlled trial. Sodium valproate and placebo were applied for 3 months to 40 and 30 subjects, respectively. Sodium valproate decreased the maximum pain visual analog score (VAS) for pain levels and pain frequency at the end of the study (p = 0.028 and p = 0.000, respectively), but did not change general pain VAS levels (p = 0.198). In subjects with CM, significant decreases in maximum pain VAS, general pain VAS, and pain frequency parameters were shown in sodium valproate–treated subjects (p = 0.006, p = 0.03, and p = 0.001, respectively).¹⁷ While these studies suggest a role for sodium valproate for treatment of CM, larger randomized controlled trials are required.

Efficacy of prophylactic medication combinations in patients not responding optimally to one medication has not thus far been demonstrated in placebo-controlled trials, though open-label studies and clinical impression have suggested that in selected patients, combination therapy may be effective.

Hospitalization for patients with CM is reserved for those who fail outpatient therapy, overuse significant amount of opioids or butalbital-containing analgesics, and in those with significant medical or psychiatric comorbidity.