Objective
To review the literature on the mechanism of action of onabotulinumtoxinA in chronic migraine.
Background
OnabotulinumtoxinA is a chronic migraine preventive treatment that significantly ...reduces headache frequency. The traditional mechanism described for onabotulinumtoxinA – reducing muscle contractions – is insufficient to explain its efficacy in migraine, which is primarily a sensory neurological disease.
Methods
A narrative literature review on the mechanism of action of onabotulinumtoxinA in chronic migraine.
Results
Following injection into tissues, onabotulinumtoxinA inhibits soluble N‐ethylmaleimide‐sensitive fusion attachment protein receptor (SNARE)‐mediated vesicle trafficking by cleaving one of its essential proteins, soluble N‐ethylmaleimide‐sensitive fusion attachment protein (SNAP‐25), which occurs in both motor and sensory nerves. OnabotulinumtoxinA inhibits regulated exocytosis of motor and sensory neurochemicals and proteins, as well as membrane insertion of peripheral receptors that convey pain from the periphery to the brain, because both processes are SNARE dependent. OnabotulinumtoxinA can decrease exocytosis of pro‐inflammatory and excitatory neurotransmitters and neuropeptides such as substance P, calcitonin gene‐related peptide, and glutamate from primary afferent fibers that transmit nociceptive pain and participate in the development of peripheral and central sensitization. OnabotulinumtoxinA also decreases the insertion of pain‐sensitive ion channels such as transient receptor potential cation channel subfamily V member 1 (TRPV1) into the membranes of nociceptive neurons; this is likely enhanced in the sensitized neuron. For chronic migraine prevention, onabotulinumtoxinA is injected into 31‐39 sites in 7 muscles of the head and neck. Sensory nerve endings of neurons whose cell bodies are located in trigeminal and cervical ganglia are distributed throughout the injected muscles, and are overactive in people with migraine. Through inhibition of these sensory nerve endings, onabotulinumtoxinA reduces the number of pain signals that reach the brain and consequently prevents activation and sensitization of central neurons postulated to be involved in migraine chronification.
Conclusion
OnabotulinumtoxinA likely acts via sensory mechanisms to treat chronic migraine.
Background
OnabotulinumtoxinA is approved for the prevention of headache in those with chronic migraine (CM); however, more clinical data on the risk-benefit profile for treatment beyond one year is ...desirable.
Methods
The
C
hronic Migraine
O
nabotulinu
M
toxinA
P
rolonged
E
fficacy open
L
abel (COMPEL) Study (
ClinicalTrials.gov
, NCT01516892) is an international, multicenter, open-label long-term prospective study. Adults with CM received 155 U of onabotulinumtoxinA (31 sites in a fixed-site, fixed-dose paradigm across 7 head/neck muscles) every 12 weeks (±7 days) for 9 treatment cycles (108 weeks). The primary outcome was headache day reductions at 108 weeks; secondary outcomes were headache day reductions at 60 weeks and change in the 6-item Headache Impact Test (HIT-6) score. Safety and tolerability were assessed by reviewing the frequency and nature of adverse events (AEs). AEs were determined at each visit through patient self-report, general non-directed and, for specific AEs, directed questioning, and physical examination. Subgroup analyses for safety and efficacy included, but were not limited to, patients with/without concomitant oral preventive treatment and acute medication overuse at baseline.
Results
Enrolled patients (
N
= 716) were 18–73 years old and most were female (
n
= 607, 84.8%). At baseline, patients reported an average 22.0 (SD = 4.8) headache days per month. 52.1% of patients (
n
= 373) completed the study. By 60 and 108 weeks, a significant reduction in headache days (− 9.2 days and − 10.7 days, respectively,
P
< 0.0001) was observed. Significant improvements (
P
< 0.0001) in HIT-6 scores (− 7.1 point change at week 108) were also demonstrated. 131 patients (18.3%) reported ≥1 treatment-emergent adverse events; most frequently reported was neck pain (
n
= 29, 4.1%). One patient reported a serious treatment-related adverse event (rash). No deaths were reported.
Conclusions
The COMPEL Study provides additional clinical evidence for the consistency of the efficacy and for the long-term safety and tolerability of onabotulinumtoxinA for the prevention of headache in those with CM who have been treated with onabotulinumtoxinA every 12 weeks over 2 years (9 treatments) with the fixed-site, fixed-dose injection paradigm.
Trial registration
Trial registration number:
NCT01516892
. Name of registry:
clinicaltrials.gov
. Date of registration: January 20 2012. Date of enrollment of first patient: December 2011.
Objective
To assess the effects of migraine on important life domains and compare differences between respondents with episodic and chronic migraine and between sexes.
Background
Migraine is ...associated with a substantial personal and societal burden and can also affect the interpersonal dynamics, psychological health and well‐being, and financial stability of the entire family of the person with migraine.
Methods
The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study is a prospective, longitudinal, Web‐based survey study undertaken between September 2012 and November 2013 in a systematic U.S. sample of people meeting modified International Classification of Headache Disorders, 3rd edition migraine criteria: 19,891 respondents were invited to complete the Family Burden Module, which assessed the perceived impact of migraine on family relationships and life, career and finances, and overall health. Respondents were stratified by episodic migraine (<15 headache days/month) and chronic migraine (≥15 headache days/month) and sex for comparisons.
Results
A total of 13,064 respondents (episodic migraine: 11,944 91.4%; chronic migraine: 1120 8.6%) provided valid data. Approximately 16.8% of respondents not currently in a romantic relationship (n = 536 of 3189) and 17.8% of those in a relationship but not living together (n = 236 of 1323) indicated that headaches had contributed to relationship problems. Of those in a relationship and living together (n = 8154), 3.2% reported that they chose not to have children, delayed having children or had fewer children because of migraine (n = 260; episodic migraine: n = 193 of 7446 2.6%; chronic migraine: n = 67 of 708 9.5%; P < .001). Of individuals responding to career/finance items (n = 13,061/13,036), 32.7% indicated that headaches negatively affected ≥1 career area (n = 4271; episodic migraine: n = 3617 of 11,942 30.3%; chronic migraine: n = 654 of 1119 58.4%), and 32.1% endorsed worry about long‐term financial security due to migraine (n = 4180; episodic migraine: n = 3539 of 11,920 29.7%; chronic migraine: n = 641 of 1116 57.4%).
Conclusions
Migraine can negatively affect many important aspects of life including marital, parenting, romantic and family relationships, career/financial achievement and stability, and overall health. Reported burden was consistently greater among those with chronic migraine than among people with episodic migraine; however, few differences were seen between the sexes.
Objective
This analysis assessed migraine‐related burden and treatment decisions in Chronic Migraine Epidemiology and Outcomes (CaMEO) Study survey respondents who stopped taking acute prescription ...medications for migraine.
Background
Migraine is a common yet underdiagnosed and undertreated neurological disease often associated with significant disability. Acute prescription medications are underused, in part because patients discontinue treatment. Rates and reasons for discontinuing acute prescription medications require exploration.
Methods
The CaMEO Study is a longitudinal, Internet‐based survey that identified and followed people who met modified ICHD‐3 migraine criteria. For this analysis, eligible respondents had used acute prescription medication for migraine in the past but no longer used or kept these treatments on hand (discontinued users). Respondents who reported discontinuing acute prescription treatment answered questions about length of time since last use and reasons for stopping. Reasons for discontinuing were thematically summarized. Monthly headache day frequency, Migraine Disability Assessment (MIDAS), Patient Health Questionnaire 9‐item depression screener, Generalized Anxiety Disorder 7‐item screener, and the 12‐item Allodynia Symptom Checklist were also assessed.
Results
Of 13,624 respondents with migraine, 4840 (35.5%) had ever used acute prescription medications and 1719 (35.5%) of those were discontinued users. Discontinued users had a mean (SD) age of 42.1 (14) years, and 1348/1719 (78.4%) were female. Monthly headache frequency of 0‐4 days was reported by 1073/1719 (62.4%) of respondents, 5‐9 days by 322/1719 (18.7%), 10‐14 days by 135/1719 (7.9%), and ≥15 days by 189/1719 (11.0%). Two‐thirds (1160/1719 67.5%) of discontinued users reported a receiving migraine (or chronic migraine) diagnosis from a doctor or other health professional in the past. Although all had spoken to a doctor about their headaches, 1504/1719 (87.5%) had stopped having their headaches managed or treated by a doctor for at least 12 months. Only 1 in 5 discontinued users reported being able to work or function normally with a headache, and 717/1719 (41.7%) had moderate to severe disability (MIDAS). Among the most commonly reported reasons for prescription medication discontinuation were switching to non‐prescription pain medication (782/1719 45.5%), as well as concerns about prescription medication efficacy (484/1719 28.2%) and tolerability (428/1719 24.9%). Nearly half of respondents who reported either efficacy or tolerability concerns had moderate to severe disability.
Conclusions
People with migraine who discontinue acute prescription medication have a high level of unmet treatment need. The majority cannot work or function normally with headaches, with 646/1719 (37.6%) of discontinued users reporting 5 or more headache days per month.
To assess the effects of onabotulinumtoxinA treatment for chronic migraine (CM) on comorbid symptoms of depression, anxiety, fatigue and poor sleep quality.
The Chronic Migraine OnabotulinuMtoxinA ...Prolonged Efficacy open-Label (COMPEL) study is a multicentre, open-label, prospective study assessing the long-term safety and efficacy of onabotulinumtoxinA 155 U over nine treatments (108 weeks) in adults with CM. The Patient Health Questionnaire (PHQ-9) and Generalised Anxiety Disorder (GAD-7) scales were used to assess the effects of onabotulinumtoxinA on comorbid symptoms of depression and anxiety, respectively. A clinically meaningful improvement was assessed by the percentage of patients experiencing a ≥1 severity category reduction in PHQ-9 and GAD-7. The effects of onabotulinumtoxinA on associated sleep quality and fatigue were assessed using the Pittsburgh Sleep Quality Index and Fatigue Severity Scale, respectively.
OnabotulinumtoxinA treatment was associated with sustained reduction in headache days and PHQ-9 and GAD-7 scores in the analysis population (n=715) over 108 weeks. PHQ-9 and GAD-7 scores were significantly reduced at all time points in patients with clinically significant symptoms of depression and/or anxiety at baseline. By week 108, 78.0% and 81.5% had clinically meaningful improvement in depression and anxiety symptoms, respectively. Sleep quality and symptoms of fatigue also improved; however, less is understood about clinically meaningful changes in these measures. No new safety concerns were identified.
In addition to reducing headache frequency, onabotulinumtoxinA treatment for CM was associated with clinically meaningful reduction in symptoms of depression and anxiety, and improved associated symptoms of poor sleep quality and fatigue.
NCT01516892.
We examined the cross-sectional association of sleep apnea and indices of sleep quality with both episodic migraine (EM) and chronic migraine (CM).
Sleep apnea and abnormal patterns of sleep, such as ...insomnia, were associated with migraine onset, severity, and progression in previous research.
The Chronic Migraine Epidemiology & Outcomes Study, a longitudinal study, used a series of web-based surveys to assess migraine symptoms, burden, and patterns of health care utilization. Quota sampling was used from September 2012 to November 2013 to generate a representative sample of the US population. Persons who screened positive for sleep apnea on the Berlin Questionnaire are said to be at "high risk" for sleep apnea. Respondents indicated if they believed that they had sleep apnea, if a physician had diagnosed it, and if and how they were treated. Other aspects of sleep quality were assessed using the Medical Outcomes Study (MOS) Sleep Measures.
Of 12,810 eligible respondents with migraine and data on sleep, 11,699 with EM (91.3%) and 1111 with CM (8.7%) provided valid data for this analyses. According to the Berlin Questionnaire, 4739/12,810 (37.0%) were at "high risk" for sleep apnea, particularly persons with CM vs EM (575/1111 51.8% vs 4164/11,699 35.6%), men vs women (1431/3220 44.4% vs 3308/9590 34.5%), people with higher body mass index, and older people (all P < .001). Among respondents to the MOS Sleep Measures, persons with CM were more likely to report poor sleep quality than those with EM, including sleep disturbance (mean SD values: 53.2 26.9 vs 37.9 24.3), snoring (38.0 33.9 vs 31.0 32.1), shortness of breath (34.9 29.8 vs 15.3 20.6), somnolence (44.1 23.4 vs 32.2 21.2), and less likely to report sleep adequacy (34.0 24.2 vs 39.2 22.1).
Compared with respondents with EM, a larger proportion of those with CM were at "high risk" for sleep apnea and reported poor sleep quality. This reflects an association between CM vs EM and sleep apnea and poor sleep quality; the potential relationships are discussed.
Objective
To compare effectiveness of onabotulinumtoxinA and topiramate for chronic migraine (CM) prevention.
Background
The efficacy* of onabotulinumtoxinA and topiramate has been established in ...placebo‐controlled randomized clinical trials (*defined as the benefit of treatment under ideal conditions). The effectiveness* of the 2 preventive treatments, however, has not been established (*the benefit of treatment under real‐world conditions, representing a blend of efficacy and tolerability).
Methods
In this multicenter, randomized, parallel‐group, post‐authorization, open‐label prospective study (FORWARD; ClinicalTrials.gov, NCT02191579), we randomized adults with CM (1:1) to onabotulinumtoxinA 155 U every 12 weeks for 3 cycles or topiramate “immediate release” 50‐100 mg/day to week 36. Primary outcome measure was proportion of patients achieving ≥50% reduction in headache days (weeks 29‐32). Missing values were imputed using baseline observation carried forward (BOCF) methodology. After 12 weeks, patients initially randomized to topiramate could cross over to onabotulinumtoxinA treatment. We monitored and recorded all adverse events (AEs).
Results
We enrolled 282 patients (onabotulinumtoxinA, n = 140; topiramate, n = 142) and 148 patients completed randomized treatment (onabotulinumtoxinA, n = 120 86%; topiramate, n = 28 20%). Primary reasons for withdrawal were ineffective treatment (onabotulinumtoxinA, n = 7 5%; topiramate, n = 27 19%) and AEs (onabotulinumtoxinA, n = 5 4%; topiramate, n = 72 51%). Eighty topiramate patients crossed over to onabotulinumtoxinA.
In the BOCF analysis, a significantly higher proportion of patients randomized to onabotulinumtoxinA experienced ≥50% reduction in headache frequency compared with those randomized to topiramate (40% 56/140 vs 12% 17/142, respectively; adjusted OR, 4.9 95% CI, 2.7‐9.1; P < .001). OnabotulinumtoxinA was superior to topiramate in meeting secondary endpoints. In a post hoc analysis using observed data, the 50% responder rates at week 12 were 45.6% for onabotulinumtoxinA (n = 125) and 29.4% for topiramate (n = 109) (P = .015). AEs were reported by 48% (105/220) of onabotulinumtoxinA and 79% (112/142) of topiramate patients. Results were similar in those who crossed over to onabotulinumtoxinA.
Conclusions
While using imputation methods of accounting for differences in discontinuation rates, we found onabotulinumtoxinA to have greater clinical utility than topiramate, largely because of tolerability issues associated with the latter and a relatively higher number of onabotulinumtoxinA patients remaining on treatment.
Background
Longitudinal migraine studies have rarely assessed headache frequency and disability variation over a year.
Methods
The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study is a ...cross-sectional and longitudinal Internet study designed to characterize the course of episodic migraine (EM) and chronic migraine (CM). Participants were recruited from a Web-panel using quota sampling in an attempt to obtain a sample demographically similar to the US population. Participants who passed the screener were assessed every three months with the Core (baseline, six, and 12 months) and Snapshot (months three and nine) modules, which assessed headache frequency, headache-related disability, treatments, and treatment satisfaction. The Core also assessed resource use, health-related quality of life, and other features. One-time cross-sectional modules measured family burden, barriers to medical care, and comorbidities/endophenotypes.
Results
Of 489,537 invitees, we obtained 58,418 (11.9%) usable returns including 16,789 individuals who met ICHD-3 beta migraine criteria (EM (<15 headache days/mo): n = 15,313 (91.2%); CM (≥15 headache days/mo): n = 1476 (8.8%)). At baseline, all qualified respondents (n = 16,789) completed the Screener, Core, and Barriers to Care modules. Subsequent modules showed some attrition (Comorbidities/Endophenotypes, n = 12,810; Family Burden (Proband), n = 13,064; Family Burden (Partner), n = 4022; Family Burden (Child), n = 2140; Snapshot (three months), n = 9741; Core (six months), n = 7517; Snapshot (nine months), n = 6362; Core (12 months), n = 5915). A total of 3513 respondents (21.0%) completed all modules, and 3626 (EM: n = 3303 (21.6%); CM: n = 323 (21.9%)) completed all longitudinal assessments.
Conclusions
The CaMEO Study provides cross-sectional and longitudinal data that will contribute to our understanding of the course of migraine over one year and quantify variations in headache frequency, headache-related disability, comorbidities, treatments, and familial impact.
To assess rates of and factors associated with traversing fundamental barriers to good medical outcomes and pharmacologic care in individuals with episodic migraine (EM) and chronic migraine (CM), ...including socioeconomic status and race.
Barriers to good outcomes in migraine include the lack of appropriate medical consultation, failure to receive an accurate diagnosis, not being offered a regimen with acute and preventive pharmacologic treatments (if indicated), and not avoiding medication overuse.
The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study was a longitudinal Internet-based survey. Respondents who met criteria for migraine consistent with the International Classification of Headache Disorders, 3rd edition, had a Migraine Disability Assessment score ≥ 6, and provided health insurance coverage status were included in this analysis. Successfully traversing each barrier to care and the effects of sociodemographic characteristics were examined.
Among 16,789 respondents with migraine, 9184 (54.7%; EM: 7930; CM: 1254) were eligible. Current headache consultation was reported by 27.6% (2187/7930) of EM and 40.8% (512/1254) of CM respondents. Among consulters, 75.7% (1655/2187) with EM and 32.8% (168/512) with CM were accurately diagnosed. Among diagnosed consulters, 59.9% (992/1655) with EM and 54.2% (91/168) with CM reported minimally appropriate acute and preventive pharmacologic treatment. Among diagnosed and treated consulters, in the EM group 31.8% (315/992) and in the CM group 74.7% (68/91) met medication overuse criteria. Only 8.5% (677/7930) of EM and 1.8% (23/1254) of CM respondents traversed all four barriers. Higher income was positively associated with likelihood of traversing each barrier. Blacks and/or African Americans had higher rates of consultation than other racial groups. Blacks and/or African Americans and multiracial people had higher rates of acute medication overuse.
Efforts to improve care should focus on increasing consultation and diagnosis rates, improving the delivery of all appropriate guideline-based treatment, and avoidance of medication overuse.
Objective
To examine the influences of depression and anxiety on headache‐related disability in people with episodic migraine or chronic migraine.
Background
Depression and anxiety are common ...comorbidities in people with migraine, especially among those with chronic migraine.
Methods
This cross‐sectional analysis of data from the longitudinal, internet‐based Chronic Migraine Epidemiology and Outcomes Study assessed sociodemographic and headache features, and headache‐related disability (Migraine Disability Assessment Scale). Four groups were defined based on scores from validated screeners for depression (9‐item Patient Health Questionnaire) and anxiety (7‐item Generalized Anxiety Disorder Scale): depression alone, anxiety alone, both, or neither.
Results
Respondents (N = 16,788) were predominantly women (74.4% 12,494/16,788) and white (84.0% 14,044/16,788); mean age was 41 years. Depression was more likely in persons with chronic migraine vs episodic migraine (56.6% 836/1476 vs 30.0% 4589/15,312; P < .001), as were anxiety (48.4% 715/1476 vs 28.1% 4307/15,312; P < .001) and coexisting depression and anxiety (42.0% 620/1476 vs 20.8% 3192/15,312; P < .001). After controlling for headache frequency and other covariates, depression alone, and anxiety alone were associated with 56.0% (rate ratio RR, 1.56; 95% confidence interval CI, 1.46‐1.66) and 39.0% (RR, 1.39; 95% CI, 1.30‐1.50) increased risks of moderate/severe migraine‐related disability (both P < .001), respectively; the combination had an even greater effect on risk of moderate/severe disability (79.0% increase; RR, 1.79; 95% CI, 1.71‐1.87; P < .001).
Conclusions
Depression alone and anxiety alone are associated with greater headache‐related disability after controlling for sociodemographic and headache features. Coexisting depression and anxiety are more strongly associated with disability than either comorbidity in isolation. Interventions targeting depression and anxiety as well as migraine itself may improve headache‐related disability in people with migraine.
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