Abstract
Background:
Due to its debilitating nature, refractory chronic migraine (RCM) is primarily associated with a poor quality of life. However, controversy remains regarding the efficacy and safety of botulinum toxin for treating RCM.Objectives:
The aim of this study was to investigate the efficacy of botulinum toxin type A (BTX-A) in patients with RCM.Methods:
In this retrospective cross-sectional study conducted between April 2016 and March 2021, RCM patients who were resistant to conventional therapies and received BTX-A injections were followed for 7 and 14 days after the injection. The outcome variables included the frequency, duration, and severity of migraine episodes, the need for painkillers, adverse events, and the patient's perceived improvement. Data were analyzed using SPSS.Results:
In total, 52 RCM patients with a mean age of 31.84 years participated, of whom 69.2% were female. The frequency of migraine episodes decreased from a baseline of 9.84 to 3.94 and 1.25 at 7 and 14 days after injection, respectively (P < 0.001). The duration of migraine episodes dropped from 3 hours at baseline to 1.74 and 1.17 hours at 7 and 14 days post-BTX-A injection, respectively (P < 0.001). The severity of migraines alleviated from 8.07 at baseline to 6.48 and 3.38 at the respective follow-up times (P < 0.001). The need for painkillers also decreased at follow-ups (P < 0.001). Males achieved better treatment outcomes regarding the frequency of migraine episodes and the need for medications compared to females following BTX-A treatment (P < 0.05). Frontotemporal and frontotemporal-occipital headache distributions showed fewer migraine episodes, shorter duration, less severity, and lower need for painkiller consumption compared to other migraine types (P < 0.05). The most common adverse event was localized pain (42.3%), followed by itching (25.0%). A considerable number of patients felt improvement.Conclusions:
According to our findings, BTX-A is a safe and well-tolerated treatment for patients with RCM. Validation of these results requires adequately precise studies investigating the effect of BTX-A in detail.Keywords
Botulinum Toxin Type A Refractory Chronic Migraine Treatment Headache
1. Background
Migraine is a common debilitating neurological disorder with a high prevalence in the general population. It is typically characterized by recurrent disabling attacks of headache and accompanying symptoms, including throbbing unilateral headaches, nausea, vomiting, photophobia, and phonophobia (1). Globally, migraine is considered the second largest contributor to disability-adjusted life-years (DALYs) and imposes a significant burden on an individual's economic situation, anxiety, and depression, significantly lowering their quality of life (2). It affects approximately 18% of Iranians, with a higher prevalence among middle-aged individuals and females (3). Common trigger factors include stress and sleep disturbances, biological factors such as hormonal imbalances, and metabolic factors such as obesity (2). According to the international classification of headache disorders-3 (ICHD-3), migraine presents in three types: Migraine with aura, migraine without aura, and chronic migraine (4). Chronic migraine is described as a headache occurring on 15 or more days per month for more than 3 months and at least 8 days per month with features of migraine headache, responsible for the highest levels of disability (4).
Despite significant progress in recent years in the management of migraine, some patients do not experience adequate pain relief. These patients remain “refractory” or “intractable” to standard treatment (5). Refractory chronic migraine (RCM) refers to a persistent headache that is difficult to cure or does not improve with conventional or intensive therapies (6). Refractory chronic migraine mainly leads to decreased function and quality of life despite modifications in lifestyle factors. About 5% of the migraine population fulfills the criteria for RCM (7). However, RCM remains one of the most challenging problems in headache management (8).
Botulinum toxin type A (BTX-A) is well established in the treatment of chronic migraine, with safe and effective preventive properties (9, 10). As shown in the phase 3 research evaluating migraine prophylaxis therapy (PREEMPT) trials, BTX-A can lead to shorter disease duration, reduction of allodynia, relief from medication overuse and depressive symptoms, and improved quality of life (11-14). Experimental studies indicate that BTX-A interferes with neurotransmitters and pain modulators such as substance P, bradykinin, and calcitonin gene-related peptide (CGRP) (15). Botulinum toxin type A also reduces the number of pain signals that reach the brain and further inhibits the activation and sensitization of central neurons (16). However, results from recent studies reveal a lack of consensus on the confirmation of BTX-A efficacy and tolerability in the case of RCM.
2. Objectives
In the current study, we aimed to investigate the efficacy of BTX-A in patients with refractory chronic migraine.
3. Methods
3.1. Study Population
In this retrospective cross-sectional study conducted from April 2016 to March 2021, all patients with refractory chronic migraine who did not respond to conventional treatment and were referred to plastic surgeons by neurologists were consecutively evaluated. The enrollment criteria included: Diagnosis of RCM by a neurologist according to the international classification of headache disorders, 2nd and 3rd editions (17), and prior failure of traditional therapeutic migraine agents such as anticonvulsants, beta-blockers, tricyclic antidepressants, and calcium channel blockers.
3.2. Study Protocol
The medical records and questionnaires of RCM patients were retrospectively reviewed. Each patient started BTX-A (Dysport®) treatment with a 100-unit protocol, distributed in 12 sites of the head and face, including 4 symmetric points on the face (supraorbital, supratrochlear, zygomaticotemporal, and zygomaticofacial) and 2 asymmetric points on the head (temporal and occipital). Injections were administered by an expert plastic surgeon. Demographic characteristics, including age, sex, migraine type, frequency and duration of episodes, severity of headaches in migraine episodes using a ten-point scale, and the need for painkillers, were reevaluated 7 and 14 days after BTX-A injection. Detailed information on any adverse events reported by patients was collected at follow-ups. Overall satisfaction with BTX-A treatment was measured by a questionnaire using a five-point scale from extremely satisfied to extremely dissatisfied.
3.3. Statistical Analysis
Statistical analysis was performed using repeated measures ANOVA. Qualitative variables were also analyzed by the test of within-subject effects. Statistical calculations were made using SPSS software, version 18. Statistical significance was set at P < 0.05.
4. Results
4.1. Demographic Characteristics
During the study period, the records of 52 patients with migraine who were treated with BTX-A were reviewed. All patients met the criteria for RCM. Most patients (69.2%) were female, with a median age of 31.84 ± 7.04 years (ranging between 22 and 58 years). Fifteen patients (28.8%) had frontotemporal distribution of headaches, while frontotemporal-occipital headache type was seen in 14 patients (26.9%). Ocular-temporal forehead, forehead-occipital, and other types were seen in 5 (9.7%), 4 (7.7%), and 12 (23.1%) of patients, respectively.
4.2. Outcome Measures
As shown in Table 1, the number of migraine episodes significantly decreased from a mean of 9.84 at baseline to 3.94 and 1.25 at 7 and 14 days after BTX-A injection, respectively (P < 0.001). The severity of migraines significantly alleviated from 8.07 at baseline to 6.48 and 3.38 at the respective follow-up times (P < 0.001). Botulinum toxin type A treatment reduced the duration of migraine episodes from 3 hours at baseline to 1.74 and 1.17 hours at 7 and 14 days, respectively (P < 0.001). Moreover, at both 7 and 14 days after BTX-A injection, the mean number of painkillers needed showed a marked decrease (P < 0.001).
Comparison of the Study Outcomes at Baseline and Follow-ups Upon Botulinum Toxin Type A Treatment a
| Variables | Baseline | Follow 1 | Follow 2 | P-Value |
|---|---|---|---|---|
| Migraine episodes | 9.84 ± 4.70 | 3.94 ± 4.09 | 1.25 ± 1.34 | < 0.001 |
| Migraine severity | 8.07 ± 0.68 | 6.48 ± 2.39 | 3.38 ± 2.67 | < 0.001 |
| Episodes duration (h) | 3.00 ± 0.83 | 1.74 ± 0.80 | 1.14 ± 0.90 | < 0.001 |
| Need for painkillers | 2.76 ± 0.75 | 2.03 ± 1.20 | 1.28 ± 1.17 | < 0.001 |
A considerable reduction was observed in the number of migraine episodes, duration, severity, and need for painkillers at 7 and 14 days after BTX-A injection in both male and female patients, with no difference according to age and migraine type (P < 0.001). However, males experienced a significant reduction in the number of migraine episodes and need for painkillers compared to females at follow-ups (P = 0.002 and P = 0.004, respectively). Following BTX-A injections, patients with frontotemporal and frontotemporal-occipital migraine headache distribution showed fewer migraine episodes, shorter duration, and less severity, as well as lower need for painkiller consumption compared to patients with other types of migraine (P < 0.05) (Table 2).
Change in Study Outcomes at Baseline and Follow-ups Upon Botulinum Toxin Type A Treatment According Sex, Age, and Type of Migraine a
| Variables | Migraine Episodes | P | Migraine Severity | P | Episodes Duration (h) | P | Need for Painkillers | P | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Baseline | Follow 1 | Follow 2 | Baseline | Follow 1 | Follow 2 | Baseline | Follow 1 | Follow 2 | Baseline | Follow 1 | Follow 2 | |||||
| Sex | ||||||||||||||||
| Male | 11.25 ± 5.83 | 5.87 ± 6.31 | 0.75 ± 0.77 | < 0.001 | 7.93 ± 0.85 | 7.31 ± 2.35 | 2.87 ± 2.55 | < 0.001 | 2.90 ± 0.86 | 1.65 ± 0.53 | 1.03 ± 0.86 | < 0.001 | 2.81 ± 0.83 | 2.43 ± 1.20 | 0.93 ± 0.99 | < 0.001 |
| Female | 9.22 ± 4.03 | 3.08 ± 2.20 | 1.47 ± 1.48 | < 0.001 | 8.13 ± 0.59 | 6.11 ± 2.35 | 3.61 ± 2.70 | < 0.001 | 3.05 ± 0.82 | 1.77 ± 0.90 | 1.19 ± 0.93 | < 0.001 | 2.75 ± 0.73 | 1.86 ± 1.17 | 1.44 ± 1.22 | < 0.001 |
| P | 0.002 | 0.099 | 0.985 | 0.004 | ||||||||||||
| Age category | ||||||||||||||||
| < 30 y | 9.33 ± 5.67 | 4.12 ± 5.54 | 1.25 ± 0.94 | < 0.001 | 8.12 ± 0.67 | 7.20 ± 2.08 | 4.08 ± 2.96 | < 0.001 | 2.93 ± 0.81 | 1.87 ± 0.91 | 1.29 ± 0.91 | < 0.001 | 2.75 ± 0.79 | 2.33 ± 0.96 | 1.54 ± 1.25 | < 0.001 |
| ≥ 30 y | 10.28 ± 3.72 | 3.78 ± 2.33 | 1.25 ± 1.62 | < 0.001 | 8.03 ± 0.69 | 5.85 ± 2.50 | 2.78 ± 2.25 | < 0.001 | 3.07 ± 0.85 | 1.62 ± 0.70 | 1.01 ± 0.89 | < 0.001 | 2.78 ± 0.73 | 1.78 ± 1.34 | 1.07 ± 1.08 | < 0.001 |
| P | 0.511 | 0.238 | 0.308 | 0.151 | ||||||||||||
| Type of migraine | ||||||||||||||||
| Frontotemporal-occipital and frontal cortex | 10.48 ± 5.08 | 4.75 ± 5.10 | 0.68 ± 0.76 | < 0.001 | 8.20 ± 0.61 | 6.75 ± 2.54 | 2.37 ± 2.48 | < 0.001 | 3.27 ± 0.88 | 1.79 ± 0.91 | 0.82 ± 0.86 | < 0.001 | 2.75 ± 0.83 | 1.96 ± 1.23 | 0.82 ± 1.00 | < 0.001 |
| Others | 9.04 ± 4.12 | 2.91 ± 1.92 | 1.95 ± 1.58 | < 0.001 | 7.91 ± 0.73 | 6.13 ± 2.20 | 4.65 ± 2.34 | < 0.001 | 2.67 ± 0.63 | 1.67 ± 0.66 | 1.54 ± 0.81 | < 0.001 | 2.78 ± 0.67 | 2.13 ± 1.17 | 1.86 ± 1.14 | < 0.001 |
| P | 0.002 | < 0.001 | < 0.001 | 0.003 | ||||||||||||
4.3. Adverse Events
Treatments were generally well tolerated with no systemic reactions or serious injection-related adverse events. The most common adverse event was localized pain in 22 patients (42.3%) and itching in 13 patients (25%), followed by hematoma in 6 patients (11.5%) and ptosis in 6 patients (11.5%) (Table 3). All these side effects were transitory and did not interfere with patient activity, requiring no further management.
Botulinum Toxin Type A Treatment-Related Adverse Events
| Adverse Event | No. (%) |
|---|---|
| Localized pain | 22 (42.3) |
| Itching | 13 (25.0) |
| Hematoma | 6 (11.5) |
| Ptosis | 6 (11.5) |
| Others | 7 (13.3) |
4.4. Patient Feeling of Improvement with Treatment
As shown in Table 4, the majority of patients (71.2%) expressed a full feeling of improvement (excellent/good) with BTX-A treatment. Only 4 patients (7.7%) felt no improvement.
Feeling of Relief Pain and Improvement After Botulinum Toxin Type A Treatment
| Score | No. (%) |
|---|---|
| Excellent | 21 (40.4) |
| Good | 16 (30.8) |
| Medium | 9 (17.3) |
| Low | 2 (3.8) |
| None | 4 (7.7) |
5. Discussion
Despite advances in the management of migraine headaches, patients with RCM often experience significant disability and impairment in quality of life. Although the efficacy of BTX-A treatment for migraine headaches has been reported in numerous clinical trials, real-world data from actual clinical settings have shown conflicting results (18-21). This study evaluated the efficacy and safety of BTX-A in patients with RCM in a routine clinical setting.
Botulinum toxin type A injections significantly decreased migraine headache episodes after 1 and 2 weeks compared with baseline in our 52 patients with RCM. Our results are consistent with those of Herd et al., which revealed a marked reduction in migraine episodes per month (22). Pooled data analysis from two PREEMPT 1 and 2 programs with BTX-A in chronic migraine also showed significant effectiveness regarding the number of headache days and migraine episodes (23). However, BTX-A effectiveness has been limited to 37 - 50% in RCM cases, possibly due to individual susceptibility to neutralizing antibody production (24).
In the current study, 100 units of BTX-A were used, which aligns with Rozen and Sharma's report that recent studies have used doses ranging from 15 to 100 IU (Botox) or 160 to 200 units of Dysport (25). Fabregat et al. suggested that BTX-A doses ranging from 50 - 100 units achieve optimal treatment outcomes (26). However, Zhang et al. revealed that lower doses (25 units) and higher doses (75 units) were similar in terms of short-term efficacy (27). Considering this point, Zhang et al. demonstrated that different doses (< 40 units and 40 - 70 units) of BTX-A injection did not affect short-term treatment outcomes, and higher doses of BTX-A contributed to more stable long-term control of pain due to trigeminal neuralgia (28).
We observed that BTX-A treatment also resulted in reduced headache severity and duration, as well as reduced use of migraine medications. In a randomized controlled trial by Hamdy et al., BTX-A injections significantly decreased migraine severity and the consumption of prophylactic medications in Egyptian patients with chronic tension-type headache (CCTH) (18). The advantage of their study was the inclusion of a placebo group and long-term follow-up (30 and 90 days post-injection) (18). Recent studies have reported the effectiveness of BTX-A in treating a variety of disorders such as muscle spasticity and pain and have emphasized its potential in managing different types of chronic primary headaches, including migraine (29-31).
Botulinum toxin is considered capable of reducing peripheral nociceptive afferents and inhibiting the release of inflammatory neuropeptides in the trigeminal complex, leading to a decrease in neurogenic inflammation of the vessels of the dura mater by reducing the release of glutamate, substance P, and calcitonin gene-related peptide (8, 28). Botulinum toxin may also decrease the localization of pain-sensitive ion channels such as transient receptor potential cation channel subfamily V member 1 (TRPV1) into the membranes of nociceptive neurons, enhancing neuron sensitization. In people with migraine, sensory nerve endings of overactive neurons are inhibited, reducing the number of pain signals that reach the brain and subsequently preventing the activation and sensitization of central neurons involved in migraine chronification (16).
However, to provide more comprehensive outcome results for the application of BTX-A in clinical settings, stratified analyses by age, sex, and migraine headache distribution were also performed. Our results indicated that males achieved better treatment outcomes in terms of the number of migraine episodes and the need for medications following BTX-A treatment. Females, through genetic and epigenetic mechanisms such as sex hormones, brain structure, genetic polymorphism, life events, stress, neuronal activity, and their cross-connection, are more prone to migraine headaches (32). In agreement with our findings, Zhang et al. reported that following BTX-A treatment for trigeminal neuralgia (TN), male patients exhibited better improvement with high BTX-A doses (28). We also observed a higher response rate to BTX-A injections in patients with frontotemporal and frontotemporal-occipital migraine headache distribution regarding the frequency of migraine episodes, duration, severity, and lower need for painkiller consumption compared to patients with other types of migraine. Frontotemporal localization headache is a common migraine type, affecting one half of the head (33). However, data on the impact of BTX-A on migraines with different headache localizations are scarce.
Our results showed that BTX-A could be safe and well-tolerated by patients with RCM. In the current study, there were no serious adverse events after BTX-A treatment, and all detectable side effects were transitory and mainly limited to localized pain, itching, hematoma, and ptosis. Previous studies have also confirmed the safety and tolerability of BTX-A in headache patients (18, 29, 34, 35). The main limitation of the current study was the small sample size, due to the COVID-19 pandemic. Moreover, the lack of a control group and the relatively short follow-up period were other limitations.
5.1. Conclusions
The current results suggest that treatment with BTX-A may be an effective and well-tolerated approach for patients with refractory chronic migraine who have previously failed to respond to or are intolerant of commonly prescribed medications. The study indicated that BTX-A injections induce a marked reduction in the number and duration of migraine episodes, their severity, and the need for painkillers, particularly in males. Botulinum toxin type A was well tolerated, and the majority of patients experienced a full feeling of improvement. However, validation of these results requires adequately precise studies with a larger sample size and control group to investigate the effect of BTX-A in detail.
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