Dodick, DW

A number of comorbid disorders, behavioural traits and associated risk factors in patients with migraine are known to increase the risk of complications such as ischaemic vascular events and chronic migraine, a syndrome that is more disabling and resistant to treatment with acute and preventative medications than episodic migraine. Reduction of cardiovascular risk factors, smoking cessation and use of non-oestrogen-containing oral contraceptives in female patients are beneficial strategies to reduce the risk of ischaemic events in patients with migraine (especially those with aura). Attack frequency, acute medication overuse, obesity and coexisting depression and anxiety disorders are particularly strong but potentially modifiable independent risk factors for progression to chronic migraine. Identifying and managing comorbidities and associated risk factors for complications of migraine are likely to require an integrated disease management strategy involving several disciplines and allied health services. Such a disease-oriented model of care may potentially interrupt the cycle of progression and disability and improve quality of life for patients with migraine.

Background and purpose Onabotulinumtoxin A was effective and well tolerated for prophylaxis of headache in patients with chronic migraine ( CM ) in two randomized, double‐blind, placebo‐controlled, phase 3 trials. To further assess the safety and tolerability of onabotulinumtoxin A in CM prophylaxis in adults, the pooled safety data from four double‐blind, placebo‐controlled trials were analyzed. Methods The pooled analysis included two phase 2 and two phase 3 double‐blind, placebo‐controlled trials. The safety population was 2436 patients, 1997 of whom received ≥1 dose of onabotulinumtoxinA. The studies shared similar dosing intervals (approximately 12 weeks) with doses between 75 and 260 U. Safety assessments included adverse events ( AE s), physical examination and clinical laboratory tests. Results Onabotulinumtoxin A was safe and well tolerated, with a low discontinuation rate (3.4%) due to AE s. The majority of patients in this pooled analysis received doses between 150 and 200 U, with an average of 163 U per treatment cycle. Of the 1997 patients who received any onabotulinumtoxin A injections, 1455 patients (72.9%) reported at least one AE . Neck pain (12.6%) was the most common onabotulinumtoxin A ‐associated AE , followed by muscle weakness (8.0%), musculoskeletal stiffness (6.1%) and eyelid ptosis (4.6%). Serious AE s were infrequent, occurring in 5.4% of patients who received any onabotulinumtoxin A treatment and 3.0% of patients receiving placebo. AE s were consistent with the known tolerability profile of onabotulinumtoxin A . Conclusions Multiple treatments with onabotulinumtoxinA at doses of 75–260 U administered every 12 weeks, and up to five treatment cycles, were well tolerated for the prophylaxis of headache in adults with CM .

Objectives: This is the second of a pair of studies designed to evaluate the efficacy and safety of onabotulinumtoxinA (BOTOX®) for prophylaxis of headaches in adults with chronic migraine. Methods: PREEMPT 2 was a phase 3 study, with a 24-week, double-blind, placebo-controlled phase, followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections of onabotulinumtoxinA (155U–195U; n = 347) or placebo ( n = 358) every 12 weeks for two cycles. The primary efficacy endpoint was mean change in headache days per 28 days from baseline to weeks 21–24 post-treatment. Results: OnabotulinumtoxinA was statistically significantly superior to placebo for the primary endpoint, frequency of headache days per 28 days relative to baseline (−9.0 onabotulinumtoxinA/−6.7 placebo, p < .001). OnabotulinumtoxinA was significantly favoured in all secondary endpoint comparisons. OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few patients (3.5% onabotulinumtoxinA/1.4% placebo) discontinued due to adverse events. Conclusions: The results of PREEMPT 2 demonstrate that onabotulinumtoxinA is effective for prophylaxis of headache in adults with chronic migraine. Repeated onabotulinumtoxinA treatments were safe and well tolerated.

Objectives: This is the first of a pair of studies designed to assess efficacy, safety and tolerability of onabotulinumtoxinA (BOTOX®) as headache prophylaxis in adults with chronic migraine. Methods: The Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1 (PREEMPT 1) is a phase 3 study, with a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections every 12 weeks of onabotulinumtoxinA (155 U–195 U; n = 341) or placebo ( n = 338) (two cycles). The primary endpoint was mean change from baseline in headache episode frequency at week 24. Results: No significant between-group difference for onabotulinumtoxinA versus placebo was observed for the primary endpoint, headache episodes (−5.2 vs. −5.3; p = 0.344). Large within-group decreases from baseline were observed for all efficacy variables. Significant between-group differences for onabotulinumtoxinA were observed for the secondary endpoints, headache days ( p = .006) and migraine days ( p = 0.002). OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few subjects discontinued due to adverse events. Conclusions: There was no between-group difference for the primary endpoint, headache episodes. However, significant reductions from baseline were observed for onabotulinumtoxinA for headache and migraine days, cumulative hours of headache on headache days and frequency of moderate/severe headache days, which in turn reduced the burden of illness in adults with disabling chronic migraine.

Chronic migraine has been linked to the excessive use of acute headache medications. Medication overuse (MO) is commonly considered the most significant risk factor for the progression of migraine from an episodic to a chronic condition. Managing MO is a challenge. Discontinuation of the acute medication can result in withdrawal headache, nausea, vomiting and sleep disturbances. This review summarizes the results from two similarly designed, randomized, placebo- controlled, multicentre studies of chronic migraine conducted in the USA and European Union. Both studies demonstrate the efficacy and safety of the migraine preventive medication, topiramate, for the treatment of chronic migraine in patient populations both with and without MO. These studies may have important implications for the future of chronic migraine management, suggesting that detoxification prior to initiating prophylactic therapy may not be required in all patients if MO is present.

Two identical randomized, placebo-controlled, crossover studies were conducted to evaluate consistency of response to sumatriptan/naproxen sodium 85/500 mg (S/NS) over four attacks in adults with migraine. Patients were instructed to treat within 1 h of pain onset while pain was mild. Co-primary end-points were pain-free response at 2 h (2hPF) and 24-h sustained pain-free response (24hSPF) calculated as percentages of all attacks. In Study 1, 570 patients treated 1693 attacks with S/NS and 424 with placebo. In Study 2, 565 patients treated 1678 attacks with S/NS and 422 with placebo. Compared with placebo, S/NS conferred higher 2hPF rates (Study 1: S/NS 52%, placebo 25%; Study 2: S/NS 50%, placebo 20%; both P < 0.001) and higher 24hSPF rates (Study 1: S/NS 37%, placebo 17%; Study 2: S/NS 34%, placebo 12%; both P < 0.001). 2hPF was reported in at least two of the first three S/NS-treated attacks in 55.0% of patients in Study 1 and 52.1% of patients in Study 2. 24hSPF was reported in at least two of the first three S/NS-treated attacks in 35.7% of patients in Study 1 and 32.6% of patients in Study 2. The incidences of any adverse event and of specific adverse events were low and generally similar between S/NS and placebo.