Efficacy of Botulinum Toxin-A Treatment in Chronic Migraine – Kuwait Experience

Research Article

Austin J Clin Neurol 2015;2(6): 1052.

Efficacy of Botulinum Toxin-A Treatment in Chronic Migraine – Kuwait Experience

Al-Hashel JY1,2*, Nagarajan V¹ and Ahmed SF1,3

¹Department of Neurology, Ibn Sina Hospital, Kuwait

²Neurologist, Kuwait University, Kuwait

³Department of Neurology, Minia University, Egypt

*Corresponding author: Jasem Yousef Al-Hashel,Department of Neurology, Ibn Sina Hospital, P.O. Box 25427, Safat 13115, Kuwait

Received: April 13, 2015; Accepted: May 08, 2015; Published: May 19, 2015


Background: Botulinum toxin-A (BoNT-A) is approved for prophylactic treatment of chronic migraine (CM). We aimed to assess the efficacy and safety of BoNT-A in the treatment of CM.

Methods: This open-label prospective study included 40 CM patients. Each patient received 100 units of BoNT-A following fixed site fixed dose protocol. Patient’s headache was assessed by their headache dairy and recording Headache Impact test (HIT-6) at baseline and 4th, 8th and 12th weeks following BoNT-A injection. Adverse events (AEs) were monitored to assess the safety of BoNT-A. For willing patients, BoNT-A injection was given and they were assessed at 3 months interval.

Results: After BoNT-A treatment, there were reduction in all parameters (headache frequency and severity, analgesic consumption and HIT-6 score) by 40% at 4th week, 45% at 8th weeks and 42% at 12th week post treatment. At 4th week, 62.5% of patients achieved good response while, 37.5% indicated no alteration in their headache frequency and severity. At 8th week and 12th week post treatment 30%, 25% respectively were found to have no response to treatment. Five patients (12.5%) experienced mild and short lasting AEs. There was 70% improvement of variables after repeated injections at 3 months interval.

Conclusions: BoNT-A is effective and well tolerated therapy in the prophylaxis of CM.

Keywords: Chronic Migraine; Migraine; Botulinum Toxin-A; Botox; Kuwait; Middle East


Chronic migraine (CM) is a disabling, underdiagnosed, and undertreated neurological disorder [1]. Currently, CM is defined as Headache occurring on 15 or more days per month for more than 3 months, which has the features of migraine headache on at least 8 days per month meeting criteria for migraine without aura or demonstrating response to migraine-specific treatment [2]. It is estimated that about 2% of general population meets the criteria for chronic migraine with or without analgesic overuse [3]. Chronic migraine is important not only on account of its great frequency, but also because it significantly reduces the quality of life of the patients [4].

Chronic migraine is very difficult to treat even by the experts. Currently there are no agent approved for CM prophylaxis and whatever available symptomatic medications have significant adverse effects (AEs) with limited benefit. So there is always a demand for useful alternative preventive therapies with limited AEs among CM sufferers [5]. Despite advances in headache therapies, there remains a group of sufferers with refractory (intractable, treatment-resistant) headache who fail to respond to or cannot tolerate current evidencebased treatments [6]. Refractory chronic migraine is often associated with disability and a low quality of life (QOL) [7].

Since 2010, based on the two PREEMPT-studies (Phase III Research Evaluating Migraine

Prophylaxis Therapy), Botulinum toxin A (BoNT-A) is registered for the indication chronic migraine in the USA and since 2011 in Great Britain and the European Community [8].

BoNT-A mediates its postulated mechanism of action in migraine by inhibiting the release of neurotransmitters in the cholinergic (motor and autonomic) and nociceptive (sensory) nerve endings such as glutamate, substance P, calcitonin gene-related peptide and acetylcholine so, it temporarily relieve the muscle spasm, regulate the exocrine secretions and reduce the neurogenic inflammation responsible for pain [9]. The advantages of a treatment with BoNT-A are the good tolerability, the lack of side-effects and the therapeutic effect over three to six months. The success rate varies between 30% and 50% [8]. Thus, BoNT-A may be an ideal prophylactic agent for use in patients with CM.

The purpose of our prospective, open-label study was to assess the efficacy and safety of BoNT-A in the treatment of CM patients in Kuwait.

Material and Methods

Study design

This is open-label prospective study that was conducted in Ibn Sina hospital, Kuwait which is a tertiary neurology care centre that having regular Headache clinic run by an expert headache specialist. Patients were evaluated neurologically and underwent imaging and other investigations if indicated to rule out secondary forms of headache. The CM patients were referred from the headache clinic to our Botox clinic.

Patient identification

Both males and females over the age of 18 years with a history (one year or more) of chronic migraine meeting the diagnostic criteria listed in ICHD-III beta [10] were eligible to participate in our study.

Patients were excluded from the study if they had other forms of primary headache disorder, had any neuromuscular junction disorders that might put them at risk with BoNT-A exposure, had uncontrolled systemic disease, abnormal brain or spinal cord pathology contributing to headaches, had concurrent infection at proposed injection sites, or were pregnant, planning for pregnancy or breast-feeding. Patients were also excluded if they were currently using any drugs that might interfere with neuromuscular function, had undergone any pericranial injection for headache within a month time prior to enrollment, or had previously received BoNT-A injection for any reason. Patients were also excluded if had suspected hypersensitivity to BoNTA, or had known or suspected drug or alcohol abuse, or those on narcotics.

Treatment schedule and protocol

On first visit to Botox clinic, the referred patients who satisfy the inclusion and exclusion criteria were enrolled for the study after obtaining an informed consent. They were trained to keep a headache diary thereafter at least 1 month before the injection. They were instructed to note down the headache parameters like type, duration, number of headache days, severity including associated symptoms and number of days on medications and the total amount of pain killers consumed. Treatment with symptomatic medication was allowed “when needed” basis for treatment of break through headaches.

On the second visit, patient’s headache dairies were verified, clarified and documented. First assessment using headache impact test (HIT–6; version 1.1) [11]. It was carried out at baseline to find out the level of limitation of patient’s social life and activities of daily life because of the headache. All the patients were briefed about the number, sites and possible side effects of BoNT-A injection. They were injected with 100 U BoNT-A (Botox; Allergan, Irvine, USA) dissolved in 2 ml of normal saline using 30G insulin needle. Following “fixed sites fixed doses” (FSFD) protocol (8), BoNT-A was injected at 27 sites pericranially - procerus (5U – 1 site), corrugator (10U – 2 sites) frontalis (10U – 2 sites), temporalis (40U – 8 sites), suboccipitalis (10U – 4 sites), trapezius (10U – 4 sites) and neck muscles (15U – 6 sites). The injection was given by the first investigator. Patients were observed for 10-15 minutes following the injection and advised not to rub or massage the injected areas for 24 hours. Patients were informed that the improvement of headache will not be immediate and might take few weeks.

Efficacy and Safety Measures

Patients were evaluated at baseline, and at 4th, 8th and 12th week after the injection. Patients were advised to report any adverse side effects any time during the study period. Investigators also probed for any adverse events by direct questioning and also examining the patients’ headache diaries during each visit. The effectiveness of BoNT-A treatment was evaluated subjectively by noting down total number of headache days, migraine days among them (primary end-point of the study), as well as amount of analgesic medications required (secondary end point) in the past 4 weeks. Health related quality of life (HRQoL) of the headache patient was evaluated objectively by recording HIT-6 at 4th, 8th and 12th week post injection. Patient who had more than 30% reduction in the above parameters was considered as responder.

At the end of 12 weeks all the patients were offered if they are willing to repeat BoNT-A treatment every 3 months and their headache dairy and HIT 6 score were assessed every 3 months during repeated injections.

Data analysis

All the effect related variables were computed during every visit. Simple descriptive statistical tests (mean and standard deviation) are used to describe the numerical values of the sample. Comparisons of values before and after treatment were evaluated using Student’s paired t-test. Ordinal measures (e.g., age, age of onset, medications intake) were compared between responders and non-responders, male and female gender, and those taking regular prophylaxis versus those not on medications using Mann-Whitney U test. The difference between their characteristics was analysed using repeated measures ANOVA to account for both between and within patient variable. A p value of less than 0.05 was considered to be statistically significant.


Demographic and baseline headache characteristics

Overall 40 patients (33 female and 7 male) between 24 and 73 (mean 44) years of age were enrolled for the study. Half of them were professionally active in their job and only 4 out of them were single. Among the 33 females 5 attained menopause and 7 had disorganized menstrual cycle. Average age of onset of headache was 25. 25 years and in one person it started at 3 years of age and in another at 56 years. Most of them, the headache start in frontal (17/40) or temporal (13/40) region. Some of them (17/40) the headache was almost continuous and in most of them it last for 2 to 3 days at a stretch.

Efficacy results

After BoNT-A treatment, there were reduction in all parameters by 35-40% at 4th weeks, 41-45% at 8th weeks and 39-42% at 12th weeks post treatment. At 4th week, 62.5% (25/40) of patients achieved good response while, 37.5% (15/40) indicating no alteration in their headache frequency and severity. At 8th weeks and 12th weeks post treatment 30% (12/40), 25% (10/40) respectively were found to have no response to treatment.

Over the 12 weeks study period, there was a significant reduction in the frequency of headache and the use of acute migraine medications per month at 4th, 8th and 12th weeks compared to baseline. We found significant reduction in the total number of moderate to severe headache days at 4th, 8th and 12th weeks (14.03 ± 6.39, P = .0017; 11.9 ± 6.63, P = .0001; 12.6 ± 7.56, P = .0008, respectively, versus 21.73 ± 6.03 at baseline), number of migraine days at 4th, 8th and 12th weeks post injection. (6.63 ± 3.47, P = .0001; 5.85 ± 3.39, P = .0001; 6.1 ± 3.89, P = .0001, respectively versus of 10.40 ± 2.72 at baseline) and the analgesic consumption at 4, 8 and 12 weeks post injection. (8.78 ± 6.46, P = .00867; 8.53 ± 5.90, P = .006; 10.38 ± 6.71, P = .0429, respectively versus 14.53 ± 136.50 at baseline) (Figure 1). HIT-6 total scores were also significantly improved at 4th, 8th and 12th weeks compared to baseline. (55.83 ± 10.68, P = .0001; 48.05 ± 10.30, P = .00002; 47.64 ± 11.79, P = .000019, respectively versus 74.33 ± 5.24 at baseline) (Figure 1).