Introduction
Chronic migraine (CM) is a debilitating disease occurring in 1.4% to 2.2% of adults globally [
1]. It is a distinct primary headache disease defined as headaches occurring on ≥15 days per month for > 3 months, with migraine features on ≥8 days per month [
2]. People with CM have more allodynia and greater levels of migraine-associated disability than people with episodic migraine [
3].
In clinical practice, allodynia, a common condition among people with CM [
3,
4], has been associated with a reduced likelihood of a positive response to some acute treatments for migraine [
5]. Data from the American Migraine Prevalence and Prevention study demonstrated that individuals with allodynia (defined as a sum score ≥ 3 on the Allodynia Symptom Checklist [ASC]) were significantly more likely to have an inadequate response to triptans, nonsteroidal anti-inflammatory drugs, opioids, and barbiturates than those without allodynia [
5]. However, it remains unclear whether allodynia also influences response to preventive treatment.
The efficacy and safety of onabotulinumtoxinA for the prevention of CM was established in the double-blind placebo-controlled Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials [
6‐
8] and was further confirmed in the 32-week open-label extension phase [
9]. The Chronic Migraine OnabotulinumtoxinA Prolonged Efficacy Open-Label (COMPEL) Study was designed to gather real-world evidence on the long-term management of CM by evaluating the efficacy and safety of onabotulinumtoxinA after 9 treatments (108 weeks) [
10,
11]. The COMPEL Study demonstrated that treatment with onabotulinumtoxinA 155 U was associated with sustained reduction in headache day frequency and migraine-related disability in people with CM over 108 weeks [
11]. The COMPEL Study also sought to determine the efficacy of onabotulinumtoxinA in specific subgroups of interest that were not specifically assessed in or were excluded from the PREEMPT clinical study program. We undertook this analysis of the COMPEL Study to compare the efficacy and safety of onabotulinumtoxinA in patients with CM with and without allodynia at baseline.
Discussion
The primary analysis of the COMPEL Study data demonstrated that onabotulinumtoxinA 155 U was associated with reductions in headache day frequency and a range of patient-reported outcomes in people with CM over 9 treatment cycles and 108 weeks and with a favorable tolerability profile. These results replicate and extend the findings of the PREEMPT study [
6,
8,
9].
Chronic migraine in people with allodynia is typically considered difficult to manage [
5], particularly with acute treatments; however, little is known about the effect of allodynia on the response to preventive treatment. The COMPEL data presented herein provide the first analyses over 9 treatment cycles of the efficacy and safety of onabotulinumtoxinA in patients with allodynia. Treatment was effective and well tolerated in patients regardless of whether they had allodynia at baseline. OnabotulinumtoxinA treatment resulted in a significantly greater improvement in MIDAS scores in patients with allodynia than in those without allodynia at baseline. Improvement in headache day frequency at week 108 was significantly lower in patients with allodynia compared with those without allodynia. For most other endpoints (eg, HIT-6 and MSQ scores), differences were not significant between those individuals with and without allodynia.
Allodynia is associated with sensitization of sensory neurons, first in the trigeminal ganglion within 10 to 20 min of the onset of migraine pain (corresponding to face and scalp pain) and then in the spinal trigeminal nucleus (also known as the trigeminal nucleus caudalis or the trigeminal cervical complex) within 60 to 120 min of the onset of pain [
17,
18]. Early administration of acute treatments for migraine is reported to prevent central sensitization, but is relatively ineffective once central sensitization, as expressed by cutaneous allodynia, has occurred [
19]. Across a range of drug classes routinely used for the acute treatment of migraine attacks, the presence of allodynia was associated with a greater likelihood of inadequate 2-h (ie, triptans, nonsteroidal anti-inflammatory drugs, opioids, and ergot alkaloids) and 24-h (ie, triptans, nonsteroidal anti-inflammatory drugs, opioids, and barbiturates) pain-free responses [
5].
The prevalence of allodynia was lower in our study population (
n = 289 [40.4%]) than the prevalence reported in a large group of people with migraine (63.2%) [
16] and in a much smaller sample of people with CM (92.5%) [
3]. Regardless, in our population, the benefits observed following preventive treatment with onabotulinumtoxinA was little influenced by the presence or absence of allodynia at baseline. After onabotulinumtoxinA treatment, there was a significant improvement in all efficacy measures at 24, 60 and 108 weeks in patients with and without allodynia compared with baseline. There was a statistically significant between-group reduction in headache frequency in favor of patients without allodynia at week 108, but not at other time points. Furthermore, there was no significant difference in the effect of onabotulinumtoxinA on change in moderate to severe headache frequency at any time point, regardless of allodynia status at baseline. These findings suggest that onabotulinumtoxinA is capable of attenuating the central sensitization of the sensory neurons associated with allodynia. However, the role of allodynia on the response to treatment needs to be explored further before definitive conclusions can be drawn. A recent meta-analysis of the treatment of migraine in people presenting to emergency departments, a population that would likely include people with allodynia, proposed that intravenous metoclopramide and prochlor-perazine, and subcutaneous sumatriptan “should be offered” to patients with acute migraine [
20], suggesting that these treatments are effective, even after central sensitization of sensory neurons. Nonetheless, the availability of an effective preventive treatment will minimize the need for acute treatments in patients with CM.
Physicians and patients alike seek preventive treatment that not only reduces headache days but also improves quality of life and reduces migraine-related disability [
21]. Therefore, to assess the overall effectiveness of a treatment for CM, it is recommended that in addition to efficacy measures focused on headache frequency, disease-related disability and health-related quality of life should be assessed using validated tools [
22]. A > 5 point change in HIT-6 scores is considered clinically meaningful for people with migraine [
23]. In our study, onabotulinumtoxinA resulted in a > 5 point change from baseline in HIT-6 total scores from week 24 onward, demonstrating a clinically meaningful improvement through week 108 in patients with or without allodynia. Similarly, MIDAS scores were reduced by approximately 40 points by week 60, regardless of allodynia status at baseline. OnabotulinumtoxinA preventive treatment did result in a slightly greater improvement in MIDAS scores in patients with allodynia than in those without allodynia, which was statistically significant at week 108 (
P = 0.005); however, both subgroups experienced clinically meaningful improvements.
Clinically meaningful differences in MSQ domain scores vary by the specific domain being assessed (Role Function Restrictive domain, 5-point improvement; Role Function Preventive domain, 5- to 8-point improvement; Emotional Function domain, 8- to 10-point improvement) [
24]. In our study, regardless of allodynia status at baseline, onabotulinumtoxinA treatment was associated with a clinically meaningful increase in all MSQ domain scores. When considered with the results from the other measures of migraine-related disability and quality of life we assessed, these results suggest that the reduction in headache frequency observed in the COMPEL Study would be clinically meaningful to patients with CM and no less so for patients with allodynia at baseline.
Others have reported that the presence of allodynia may signal a phenotype resistant to acute treatment for migraine [
5,
19,
25], although the benefit of some acute treatments in patients presenting to emergency departments with migraine [
20] suggests that the correlation of allodynia with treatment resistance is not clear-cut. Although the effect of onabotulinumtoxinA on headache frequency at week 108 was significantly lower in patients with allodynia than in those without allodynia, onabotulinumtoxinA reduced moderate to severe headache frequency similarly in both groups. Furthermore, onabotulinumtoxinA was at least as effective in patients with allodynia as those without allodynia across a range of secondary efficacy outcomes, suggesting that onabotulinumtoxinA is a useful preventive treatment for those patients with CM with allodynia.
Study limitations and strengths
Open-label studies, although useful to gain additional information once the safety and efficacy profile of an intervention has been clearly established, are subject to inherent limitations, such as the lack of placebo comparison, loss to follow-up, and change in concomitant medication use over the course of the study. These limitations have been discussed more fully in a previous report [
11]. Despite the low persistency rates, the treatment benefits we observed at week 24 in this anal-ysis continued to improve up to week 108, and the lack of between-group differences typically persisted, trends that reinforce our conclusions of this subgroup analysis.
In addition, fluctuations in headache frequency over time that occur with CM can make the interpretation of results difficult [
26]. It is recommended that validated disease-specific tools be used to assess health-related quality of life and disability [
22]. Tools such as the HIT-6 and MSQ, which were used in this study, have been validated for use in CM [
27,
28], and the MIDAS questionnaire has been validated in migraine [
13] and is likely to be valid for use in CM [
22], including patients with CM with allodynia. Nonetheless, given the subjective reporting and open-label nature of the study, the results should be interpreted cautiously [
22].
Despite the potential limitations outlined previously, the reduction in headache frequency from baseline in the overall population from the COMPEL Study at week 24 parallels results from the double-blind placebo-controlled phase of the PREEMPT study (− 7.4 days vs − 8.4 days, respectively) [
8,
11]. Furthermore, results at week 24 for HIT-6 scores and week 48 for MSQ scores are similar to those reported at week 24 (HIT-6, − 4.8; Role Function Preventive, + 13.1; Role Function Restrictive, + 17.0; Emotional Function, + 17.9) after the double-blind placebo-controlled phase of the PREEMPT study [
8], supporting the relevance of the results from the COMPEL Study and, by extension, this subanalysis of COMPEL data.
Acknowledgments
This study was sponsored by Allergan plc (Dublin, Ireland). Writing and editorial assistance was provided to the authors by Lee B. Hohaia, PharmD, of Complete Healthcare Communications, LLC (North Wales, PA, USA), a CHC Group company, and was funded by Allergan plc (Dublin, Ireland). All authors met ICMJE authorship criteria. Neither honoraria nor payments were made for authorship.
The authors thank the patients for their participation in the study. Principal investigators for the COMPEL Study included Lawrence D. Robbins, MD; Jan L. Brandes, MD; Tamara A. Miller, MD; Roger K. Cady, MD; Jo H. Bonner, MD; Paul K. Winner, DO, FAAN; Marshall C. Freeman, MD; Kathleen B. Mullin, MD; Andrew M. Blumenfeld, MD; Eric J. Eross, DO; Amy A. Gelfand, MD; Ejaz A. Shamim, MD; William B. Young, MD; John F. Rothrock, MD; Stephen H. Landy, MD; J. Ivan Lopez, MD; George R. Nissan, DO; Soma Sahai-Srivastava, MD; Marcia Ribeiro, MD; Maria-Carmen Wilson, MD; Jose M. Casanova, MD, PhD; Laszlo L. Mechtler, MD; Richard J. Stark, MBBS, FRCAP; Andrew H. Evans, MD; John D. O’Sullivan, MD, MBBS; Joseph Frasca, MBBS; Min Kyung Chu, MD, PhD; Jeong-Wook Park, MD; ByungKun Kim, MD, PhD; Seong Taek Kim, DDS, MS, PhD; Kwang Soo Lee, MD, MS, PhD; Heui-Soo Moon, MD.
Competing interests
William B. Young has served on advisory boards for Alder, Allergan, Cipla, Lilly, and Supernus; has consulted for Allergan and Supernus; and has received research support from AGA, Alder, Allergan, Amgen, Autonomic Technology, Cumberland, Dr. Reddy’s Laboratories, Eli Lilly, eNeura, Merz, and St. Jude Medical. J. Ivan Lopez has no disclosures to report. John F. Rothrock has served on advisory boards and/or has consulted for Allergan, Lilly, Amgen, and Supernus. He also has received funding for travel and speaking from Supernus and has received honoraria from Allergan for participating as a speaker and preceptor at Allergan-sponsored educational programs. His parent institution has received funding from Allergan, Amgen, and Dr. Reddy’s Laboratories for clinical research he has conducted. Amelia Orejudos is an employee of Allergan. Aubrey Manack Adams is an employee of Allergan and owns stock in the company. Richard B. Lipton serves on the editorial boards of Neurology and Cephalalgia and as senior advisor to Headache. He has received research support from the National Institutes of Health. He also receives support from the Migraine Research Foundation and the National Headache Foundation. He has reviewed for the National Institute on Aging and National Institute of Neurological Disorders and Stroke, serves as consultant or advisory board member or has received honoraria from Alder, Allergan, Amgen, Autonomic Technologies, Avanir, Biohaven, Biovision, Boston Scientific, Dr. Reddy’s Laboratories, Electrocore, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Novartis, Pernix, Pfizer, Supernus, Teva, Trigemina, Vector, and Vedanta. He receives royalties from Wolff’s Headache (8th Edition, Oxford University Press), Informa, and Wiley. He holds stock options in eNeura Therapeutics and Biohaven. Andrew M. Blumenfeld has served on advisory boards for Allergan, Amgen, Alder, Teva, Supernus, Promius, Egalet, and Lilly and has received funding for speaking from Allergan, Amgen, Pernix, Supernus, Depomed, Avanir, and Promius.