Botulinum Neurotoxin Reduces Headache Frequency and Disability in Chronic Migraine

Daniel M. Keller, PhD

September 16, 2009

September 16, 2009 (Philadelphia, Pennsylvania) — Pooled results of 2 large, randomized, phase 3, placebo-controlled trials show that onabotulinumtoxinA (BT) is an effective, safe, and well-tolerated treatment for the prevention of headache for patients with chronic migraine. Up to now, few preventive treatments have been investigated for chronic migraine, and none is approved specifically for this condition, lead investigator David Dodick, MD, told the attendees here at the 14th International Headache Congress.

Dr. Dodick, who is associate professor of neurology at the Mayo Clinic in Scottsdale, Arizona, and president-elect of the American Headache Society, presented the pooled results of 2 parallel, double-blind, placebo-controlled trials for the prevention of headache in adults with chronic migraine. The studies were the Phase 3 Research Evaluating Migraine Prophylaxis Therapy With Botulinum Toxin Type A-1 and -2 (PREEMPT-1 and PREEMPT-2).

During a 4-week baseline period, patients (n = 1384) recorded headaches and associated symptoms in electronic daily diaries. They were then randomly assigned to receive BT (n = 688) or placebo (n = 696) in a double-blind fashion on day 0 and at week 12. In an open-label phase of the studies, patients received injections at weeks 24, 36, and 48, with follow-up out to week 56. Injections consisted of either 155 to 195 units of BT at 31 to 39 sites or placebo. Most of the BT group received the lowest dose, but investigators could inject 3 muscles with an additional 40 units for pain at their discretion.

The study was conducted at 122 sites in North America and Europe and could include men and women ages 18 to 65 years (mean age, 41 years; 87.6% and 85.2% women in the BT and placebo groups, respectively). Subjects could not have used any prophylactic headache medication 4 weeks before baseline, nor could they have had previous exposure to any form of botulinum toxin.

The 2 groups were well balanced for baseline characteristics. About 90% in each group were white and had a mean of 20 headache days and 19 migraine days per 4-week period, of which they classified 18 days as moderate or severe.

Patients in the BT group had slightly more cumulative hours of headache per 4-week period (295.9 vs 281.2; P = .021), but the placebo group had more mean headache and mean migraine episodes than did the BT group (13.0 vs 12.2; 12.2 vs 11.4 episodes, respectively; P = .004 for both). The mean Headache Impact Test (HIT-6) score did not differ between the groups, and about 93% in each group were highly disabled according to this measure (HIT-6 score ≥ 60). Two-thirds of patients in each arm were overusing medications, judging by established criteria.

Dr. Dodick reported results from the primary time point at 24 weeks. Patients in the active treatment group experienced a reduced frequency of headache days and episodes, reduced frequency of migraine days and episodes, fewer moderate or severe headache days, and a lower cumulative number of hours of headache on headache days. They also experienced a significant improvement in their functioning and less disability. All efficacy analyses used the intent-to-treat population and included all randomized patients, Dr. Dodick said.

Outcomes With BT vs Placebo

Outcome BT Placebo P
Frequency of headache days −8.4 −6.6 <.001
Frequency of migraine days −8.2 −6.2 <.001
Frequency of moderate/severe headache days −7.7 −5.8 <.001
Total cumulative headache hours −119.7 −80.5 <.001
Reduction in HIT-6 score −4.8 −2.4 <.001
Severe HIT-6 score (≥60) 67.6% 78.2% <.001

Similarly, the frequencies of headache or migraine episodes were less in the BT group (P = .009 and P = .004, respectively). The BT group also experienced a significantly greater reduction in the mean number of headache days at every 4-week time point out to 24 weeks vs the placebo group.

There was no significant difference in the frequency of acute headache medication intake. Dr. Dodick said this finding mirrors the results of 2 studies using topiramate for chronic migraine — in neither of which was consumption of acute medications decreased.

"However, when we went back and looked at the frequency of triptan use, we showed that both in PREEMPT-1 and PREEMPT-2...there was a statistically significant reduction of the consumption of triptans in the botulinum toxin group compared to placebo but not [of] other analgesics or pain medications," he reported. In PREEMPT-1, triptan use decreased by 3.3 occurrences in the BT group vs 2.5 in the placebo group (P = .023), and in PREEMPT-2 it decreased by 3.0 vs 1.7, respectively (P <.001).

Adverse events (AEs) were more frequent in the BT group (62.4%) than in the placebo group (51.7%), as were treatment-related AEs (29.4% vs 12.7%, respectively) and serious AEs (4.8% vs 2.3%). No treatment-related AE occurred in the placebo group, but 1 migraine requiring hospitalization occurred in the BT group. Discontinuations related to AEs were more frequent for patients receiving BT (3.8%) than for patients receiving placebo (1.2%). No deaths occurred.

Population With Highest Need

BT has been studied for episodic migraine with mixed efficacy results. PREEMPT is the largest randomized, placebo-controlled study for chronic migraine. Elizabeth Loder, MD, MPH, chief of the division of headache and pain at the Brigham and Women's Hospital in Boston, Massachusetts, and cochair of the session at which Dr. Dodick spoke, told Medscape Neurology, "It's really heartening to see randomized trials done in that population because it's the population with the highest need that we see all the time in headache centers, and up until recently there has been very little attention paid to that particular segment of the population.

"What we see clinically is that there is a subset of patients who experience significant and sustained relief from botulinum toxin and who remain very interested in getting repeated injections," Dr. Loder said. However, she cautioned that it does not work for everyone and that there is no easy way to predict who will respond other than trying the medication. In her experience, she said, she finds it well tolerated and has not seen serious AEs. Nonetheless, she said it is difficult to generalize from the results of any single study, and although these results are encouraging, "I would withhold judgment until we have some confirmatory studies."

The study was sponsored by Allergan. Dr. Dodick has disclosed that he receives research support from Advanced Neuromodulation Systems, Inc; Mayo Clinic; Medtronic, Inc; National Institute of Neurological Disorders and Stroke; and St. Jude Medical, Inc. He receives honoraria and is a consultant for Alexza Pharmaceutical, Inc; Allerga, Inc; Almirall; Coherex Medical Inc; Eli Lilly and Company; Endo Pharmaceuticals Inc; GlaxoSmithKline; H. Lundbeck/Kowa Company Ltd; MAP Pharmaceuticals, Inc; Medtronic, Inc; Merck & Co, Inc; Minster Pharmaceuticals; Neuralieve Inc; NeurAxon; Novartis; NuPathe Inc; and Pfizer Inc. Dr. Loder has disclosed no relevant financial relationships.

14th International Headache Congress: Abstract LBOR 01. Presented September 12, 2009.

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