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ABSTRACT & COMMENTARY
By Dara Jamieson, MD
Assistant Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Jamieson reports no financial relationships relevant to this field of study.
SYNOPSIS: A pooled analysis of four clinical trials concluded that treatment with onabotulinumtoxinA at doses of 75-260 U administered every 12 weeks for up to five treatment cycles was efficacious, safe, and well tolerated for the prophylaxis of headache in adults with chronic migraine.
SOURCE: Diener HC, et al. Pooled analysis of the safety and tolerability of onabotulinumtoxinA in the treatment of chronic migraine. Eur J Neurol 2014;21:851-859.
Injection of onabotulinumtoxinA, causing inhibition of the release of acetylcholine at the neuromuscular junction, is an effective treatment for the prophylaxis of headache in patients with chronic migraine (CM). But patients want to know that it is safe and without problem side effects. Diener et al assessed the safety and tolerability of onabotulinumtoxinA in CM prophylaxis in men and women, aged 18-65 years, using data from two exploratory Phase 2 and two Phase 3 (PREEMPT: Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy) double-blind, placebo-controlled trials. The studies shared similar dosing intervals (approximately 12 weeks) with doses between 75 and 260 U. In the PREEMPT 1 and 2 multicenter trials, patients were randomized to either onabotulinumtoxinA (155-195 U) or placebo. Treatments were 31 fixed-site, fixed-dose intramuscular injections across seven specific head/neck muscle areas. An additional 40 U of onabotulinumtoxinA or placebo could be administered using a "follow-the-pain" injection paradigm that varied across treatment visits. The maximum dose was 195 U across 39 sites per treatment cycle. Patients who completed the double-blind phase entered an open-label phase, where they received 155-195 U of onabotulinumtoxinA at 12-week intervals. The majority of patients in the pooled analysis of the four studies received doses between 150-200 U, with an average of 163 U per treatment cycle.
Safety assessments included adverse events (AEs), physical examination, and clinical laboratory tests. OnabotulinumtoxinA was safe and well tolerated, with a low discontinuation rate (3.4%) due to AEs. Approximately 73% of patients who were injected with onabotulinumtoxinA reported at least one AE, most frequently neck pain (13.8% vs 2.4% with placebo). Other AEs that occurred in the pooled analysis more frequently with onabotulinumtoxinA treatment than with placebo were head, neck, or shoulder/upper arm muscular weakness (8.0%); headache (8.0%); facial paresis (8%); musculoskeletal stiffness (6.1%); and eyelid ptosis (4.6%). Weakness generally involved injected or adjacent muscles, but an effect on nearby muscles can occur due to local diffusion. However, distant effects of the intramuscular injection were not reported. Serious AEs (most commonly migraine, pneumonia, uterine leiomyoma, and headache) were infrequent, occurring in 5.4% of patients who received any onabotulinumtoxinA treatment (n = 1997) and 3.0% of patients receiving placebo (n = 1052), and did not appear to be treatment related. The incidence of AEs potentially associated with hypersensitivity was also not considered to be treatment related (2.2% with onabotulinumtoxinA and 2.0% with placebo). The dosing and injection paradigm used in the PREEMPT clinical program (155-195 U) resulted in fewer individual AEs and demonstrated robust long-term (up to 56 weeks) efficacy.
CM, as defined by the third beta edition of the International Classification of Headache Disorders (ICHD-3 beta), is characterized by headache occurring on ≥ 15 days per month for at least 3 months and the features of migraine headache on at least 8 days per month. Any effective treatment that can decrease the personal and economic disability of CMs has very significant individual and societal benefit. There are very limited prophylactic treatment options for the 1.4-2.2% of the population who suffer specifically from CM; although medications used to decrease the frequency and severity of episodic migraine are commonly used to prevent CM. Topiramate, commonly used for migraine prophylaxis in episodic migraine, was shown in a small pilot study to have more treatment-related AEs, with a higher discontinuation rate, as compared to treatment with onabotulinumtoxinA. The benefit of onabotulinumtoxinA in the prevention of CM has been proven in randomized, double-blind, placebo-controlled trials, with most patients deriving benefit to varying degrees. Any CM trial has logistical challenges, because of the variable nature of the disease itself, with added study design difficulties when using a muscle paralytic agent. True blinding of onabotulinumtoxinA injections is problematic, as lack of the ability to wrinkle the forehead is characteristic of the treatment. However, this potential unblinding of the treatment arm in clinical trials does not negate the clear benefit enjoyed by many patients, both before and after the treatment was approved by the FDA.
Physicians who inject this medication for CM realize the unique aspects of this treatment and may tweak the FDA-recommended injection protocol. The physician’s individual injection technique is perfected with experience and patient feedback. After years of treating patients with onabotulinumtoxinA, I inject fewer units into the neck and shoulders of small, thin individuals in order to decrease the risk of neck weakness and pain. Injection higher in the corrugator muscles above the brows, with a small extra dose injected laterally, eliminates cosmetic complaints about asymmetric eyebrows. Some returning patients are adamant about the benefit of their "follow-the-pain" injections, which may be offered when the injections can be performed safely in painful areas of the face and head. Although the treatment is not approved for use in children under the age of 18, I have found efficacy and tolerability with onabotulinumtoxinA injections for chronic migraine in adolescents. The usual experience of neurologists who inject onabotulinumtoxinA is that the treatment is safe and effective, providing a significant measure of relief to many patients suffering from this disabling neurological disorder.