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IMR Press / JIN / Volume 21 / Issue 1 / DOI: 10.31083/j.jin2101037
Open Access Review
OnabotulinumtoxinA for the treatment of headache: an updated review
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1 College of Medicine, Howard University, 20059 Washington, D.C., USA
2 Department of Ophthalmology, Faculty of Medicine, Cairo University, 11956 Cairo, Egypt
*Correspondence: ayman_elnahri@cu.edu.eg (Ayman G. Elnahry)
J. Integr. Neurosci. 2022, 21(1), 37; https://doi.org/10.31083/j.jin2101037
Submitted: 24 June 2021 | Revised: 6 August 2021 | Accepted: 25 August 2021 | Published: 28 January 2022
This is an open access article under the CC BY 4.0 license.
Abstract

Botulinum toxin (BT) is a neurotoxin produced by Clostridium botulinum, a gram-positive anaerobic bacterium. Systemic human intoxication from BT following oral ingestion results in acute and life-threatening muscle paralysis called botulism. BT has a wide scope of therapeutic uses, including conditions associated with increased muscle tone, smooth muscle hyperactivity, salivation, sweating, and allergies, as well as for cosmetic purposes. Several commercial forms of BT are available for medical use, including Botox (onabotulinumtoxinA). Multiple studies have found evidence of an analgesic effect of onabotulinumtoxinA and demonstrated the benefits of its use for the treatment of various chronic pain disorders. In this review, we provide an update on the use of onabotulinumtoxinA for the treatment of headache disorders.

Keywords
Botulinum toxin
Chronic migraine
OnabotulinumtoxinA
Neurotoxin
1. Introduction

Botulinum toxin (BT) is one of the most powerful toxins encountered in nature. It is a neurotoxin protein produced by Clostridium botulinum, a gram-positive anaerobic bacterium [1]. Chemically, BT is comprised of two polypeptide chains joined by a disulfide bond. Seven antigenically distinct serotypes (A to G) have been identified so far, with types A and B able to cause disease in humans [1, 2]. Oral ingestion of BT leads to systemic human intoxication and produces acute and life-threatening muscle paralysis known as botulism [3]. BT causes dose-dependent, reversible muscle relaxation by blocking the release of acetylcholine from nerve endings at the neuromuscular junction [4]. Consequently, BT has been observed to have a wide range of therapeutic uses, including disorders associated with increased muscle tone, smooth muscle hyperactivity, sweating, salivation, allergies and pain, and for cosmetic purposes [5]. Several commercial forms of BT are offered for medical applications, including Botox (onabotulinumtoxinA, Allergan Inc., Irvine, CA, USA), Dysport/Azzalure (abobotulimumtoxinA, Ipsen, Slough, UK/Galderma, Paris, France), Xeomin/Bocouture (incobotulinumtoxinA, Merz Pharmaceuticals GmbH, Frankfurt, Germany), and Jeuveau (prabotulinumtoxinA, Evolus Inc., Newport beach, CA, USA) [1, 2, 3, 4, 5, 6]. Here, we review the use of onabotulinumtoxinA for the treatment of various types of headaches.

2. Literature search

PubMed and OVID MEDLINE were searched on 24 April 2021, using the following terms: botulinum toxin, botox, onabotulinumtoxinA, headache, migraine, tension type headache, cluster headache, cervicogenic headache, post-traumatic headache, and low-tension headache. There were no date restrictions applied and all study types were included. References contained within the included publications were also searched to identify additional relevant studies.

The Food and Drug Administration (FDA) approved BT under the product name Oculinum (onabotulinumtoxinA, Allergan Inc., Irvine, CA, USA) for treatment of blepharospasm in 1989 [10]. BT injections were first proposed as an effective treatment for headaches when it was found incidentally that individuals who suffered from chronic headaches experienced an improvement following cosmetic BT injections [11, 12]. During the 1990s, interest grew for the treatment of tension-type headache with BT due to its muscle-paralyzing actions. Oculinum was later renamed Botox, and a long-term clinical trial program was launched to test BT type A for the treatment of headaches. Subsequent studies reported benefits from the use of onabotulinumtoxinA to treat migraine. In 2002, several headache experts indicated that onabotulinumtoxinA was safe and effective for prophylactic and acute treatment of migraine [13]. In 2010, the United States FDA approved Botox® for the treatment of chronic migraine. In 2016, the American Academy of Neurology recommended onabotulinumtoxinA as a treatment option for chronic migraine patients [14]. Currently, onabotulinumtoxinA for the treatment of headache is only regulated and approved for patients with chronic migraine. Its use for other subtypes of headache is considered to be off-label treatment.

Chronic daily headache is a heterogeneous group of headache symptoms with a frequency of more than 15 days per month, and which persists for longer than three months [15]. The four common subtypes are chronic migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua [16]. The estimated prevalence in the general population of this disabling neurological condition is about 4% to 5% and it is known to have a significant negative impact on daily living and on the quality of life [16, 17].

3.1 OnabotulinumtoxinA and chronic migraine

Chronic migraine is defined as the occurrence of 15 or more headache days per month for longer than a three-month period, with at least 8 days per month showing features of migraine [18]. Approximately one-third of chronic headaches are classified as chronic migraine [19]. However, chronic migraine varies amongst patients in terms of the intensity of pain, the frequency of days with headache, allodynia, and the overall migraine-related disability [20]. Although various pharmacological treatment options are used as prophylaxis for chronic migraine, a significant proportion of patients still suffer from recurrent attacks. This has led some experts to favor surgical intervention for the treatment of chronic headaches [21]. Numerous studies have therefore been carried out to find a more efficient way to control pain in chronic headache conditions, with BT having shown good results in this context.

The FDA has approved intramuscular injection of onabotulinumtoxinA as a preventive treatment for chronic migraine headaches. Although some experts believe that extra muscular injections are just as effective as intramuscular injections, there are no peer-reviewed studies to support this contention [22]. OnabotulinumtoxinA is therefore administered to the scalp, since migraine pain is believed to come from the meninges, as well as to the forehead, bridge of the nose, the temples, the back of the head, and neck (Figs. 1,2) [21, 23]. Some studies have suggested that the optimal injection points for onabotulinumtoxinA in the treatment of chronic migraine are in the temporal region and that it should be administered $>$45 mm above the zygomatic arch to avoid injection into the tendon [24, 25]. The greater occipital nerve is derived primarily from the C2 dorsal root and is the major sensory nerve in the occipital area. The blocking of this nerve is a common method used to treat various headaches, especially occipital headaches [26]. Several studies on ultrasound-guided greater occipital nerve block using onabotulinumtoxinA have shown effectiveness in lowering both short- and long-term pain in patients with chronic headache in the occipital area.

Fig. 1.

Botulinum toxin injection to the forehead for the treatment of chronic migraine.

Fig. 2.

Botulinum toxin injection to the bridge of the nose in the corrugator supercilli muscle for the treatment of chronic migraine. The injection is performed between the medial and lateral branches of the STN, about 18 mm lateral to the facial midline at the level of the supraorbital margin. F, frontalis muscle; OOC, orbicularis oculi muscle; CS, corrugator supercilii; ML, facial midline; STN-L, lateral branch of the supratrochlear nerve; STN-M, medial branch of the supratrochlear nerve.

The Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) program consisted of two phase III randomized controlled multicenter trials (PREEMPT 1 and 2) that evaluated the effectiveness of onabotulinumtoxinA in patients with chronic migraine [27, 28, 29]. All patients in these trials received intramuscular injections of onabotulinumtoxinA at 31 injection sites in 7 head and neck muscles with a fixed-site and fixed-dose injection paradigm (5 U in 0.1 mL per injection). In addition, up to 40 units of onabotulinumtoxinA could be administered at 8 other injection sites as needed across three head and neck muscles with a “follow-the-pain” approach. This standardized treatment program is known as the PREEMPT injection paradigm [27]. The PREEMPT studies found marked improvement in several headache symptoms and showed that treatment was associated with improved patient functioning, vitality and overall quality of life, as well as reduced psychological distress.

How onabotulinumtoxinA reduces the frequency and intensity of migraine headaches remains to be determined [8]. The clinical impact of onabotulinumtoxinA on migraine is observed within the first day of injection and is much faster than the 5 or more days needed to observe clinical effects of onabotulinumtoxinA at the neuromuscular junction [30]. After the injection of onabotulinumtoxinA into the extracellular space, the heavy chain of this neurotoxin binds to receptors on the nerve terminals of C-fibers. It is then endocytosed and enters the nerve terminals inside enclosed vesicles. The light chain of the neurotoxin then dissociates from the heavy chain and enters the cell cytoplasm where it cleaves a critical protein (the synaptosomal-associated protein) necessary for fusion of neuropeptide-bearing vesicles with nerve terminal membranes, thus preventing neuropeptide release. Upon activation by stimuli, the sensory nerve endings of C-fibers in the meninges release neuropeptides. The role of onabotulinumtoxinA in blocking the release of these neuropeptides from peripheral C-fiber nerve endings is most likely the key mechanism that underlies its therapeutic action against chronic migraine [13].

Recent clinical studies have consistently shown onabotulinumtoxinA to be effective in preventing chronic migraine by reducing the frequency of headaches and their duration or intensity, and hence their functional and severity impact, including when administered in a targeted fashion [31, 32, 33, 34]. Many studies have confirmed the higher tolerability and cost-effectiveness of onabotulinumtoxinA treatment for chronic migraine [24, 31, 34, 35]. Furthermore, the REPOSE study on onabotulinumtoxinA treatment for chronic migraine found lower use of healthcare resources and related costs using the PREEMPT injection paradigm [36]. Targeted therapy may result in even better, more cost effective, and longer-term results [32, 34]. Botox was also recently found to be cost-effective for the treatment of chronic migraine in Norway and Sweden [37]. OnabotulinumtoxinA was also found to improve migraine-related disability by reducing the intensity and frequency of headache pain in patients with chronic migraine [38]. In another recent multicenter study of chronic migraine, early treatment with onabotulinumtoxinA was more likely to be associated with a sustained clinical response [39]. In the COMPEL study, treatment with onabotulinumtoxinA also led to improvements in disability and quality of life measures in daily headache, but a longer period of treatment was needed [40]. OnabotulinutoxinA was also shown to be effective and safe in patients with allodynia [41]. Additional benefits of treatment with this agent may include an improved response to acute treatment and reduced drug intake [42, 43, 44]. Well-controlled clinical trials have shown that patients with overuse of headache medication can be treated successfully with onabotulinumtoxinA and topiramate [45]. Comparative studies have shown that onabotulinumtoxinA is an effective and safe alternative for the treatment of chronic migraine in patients who discontinue topiramate treatment and can be started during the tapering of topiramate [46, 47]. It should be noted however that combining classic migraine therapy with onabotulinumtoxinA injection should be avoided in order to allow a better understanding of the efficacy of each treatment in the individual patient.

It is well known that psychiatric comorbidities including depression and anxiety are more common in patients with chronic migraine [48]. A study of patients suffering chronic daily headaches with comorbid anxiety and depression found that onabotulinumtoxinA treatment may be an effective and safe intervention in such cases [16]. OnabotulinumtoxinA was well tolerated in chronic migraine patients with comorbid depression and reduced the frequency, impact and associated disability of headaches, leading to significant improvement in the symptoms of anxiety and depression [49]. Furthermore, a study on chronic migraine patients with impulse use disorders and medication overuse found that onabotulinumtoxinA injections improved anxiety symptomatology and impulse control disorders [50].

BT in doses used for upper-face cosmetic purposes may also be helpful for the treatment of certain subtypes of migraine. In a study that evaluated the effect of Botox injections for cosmetic purposes on migraine subtypes, more improvement in headache frequency was observed in patients with imploding and ocular migraine in comparison to patients with exploding migraine [51]. This suggests that Botox doses used for cosmetic applications may be sufficient for the prevention of some types of migraine attacks.

A small study in adolescents on onabotulinumtoxinA treatment for chronic daily headaches found that all patients experienced a decrease in headache frequency and in pain intensity immediately following injection. Some cases quickly returned to regular school attendance, thus highlighting the ability of this treatment in allowing patients to resume their regular daily activities [15]. A study conducted in a large pediatric headache center reported on a possible reversal of the underlying pathology when onabotulinumtoxinA was given as an adjunct to other preventive therapies, even when the disease was at its peak [52]. OnabotulinumtoxinA injections were also found to be safe during pregnancy, with no reported adverse effects on pregnancy outcomes [53].

Many patients with chronic migraine have a high intake of pharmacological agents for relief from headaches as well as prophylaxis. It has been estimated that more than half of cases with chronic migraine who consult in headache clinics suffer from excessive use of analgesics [54]. This overuse of medication can lead to the development of headaches (medication overuse headache). A study on the use of onabotulinumtoxinA in patients with medication overuse headache showed positive results with different dose regimes [55]. Another recent study on prophylactic treatment with onabotulinumtoxinA for medication overuse headache showed that 12 weeks of therapy can significantly reduce the consumption of acute analgesics and the overall number of days with headache. The use of analgesics without serious side effects is vitally important to reduce chronic disability associated with migraine, to increase patient quality of life, and to reduce spending on health resources [56]. Another study on prophylactic treatment with onabotulinumtoxinA for medication overuse headache found that its efficacy and safety lasted for up to 3 years. This raises the possibility of long-term treatment with onabotulinumtoxinA to prevent chronic migraine [57].

In conclusion, recent clinical trials have repeatedly shown excellent benefit from onabotulinumtoxinA treatment for chronic migraine in various age groups. Therefore, the logical next question is to ask whether onabotulinumtoxinA is also beneficial for the treatment of other types of headaches.

3.2 OnabotulinumtoxinA and episodic migraine

Episodic migraine is defined as 0–14 headache days per month, in contrast to chronic migraine which is characterized by 15 or more headache days per month [58]. A study of patients with episodic migraine (mostly $<$8 headache days per month) treated with onabotulinumtoxinA found that those with a low baseline frequency were more likely to experience complete responsiveness [59]. Another study that investigated onabotulinumtoxinA treatment for episodic migraine (approximately 5 headache days per month and 1.5 days mean duration of headache) found that treated subjects experienced fewer migraines of any severity [60]. These authors also reported fewer days with migraine needing treatments, less severe attacks and reduced frequency of vomiting, together with satisfactory safety profile and good tolerability. A randomized, double-blind trial of onabotulinumtoxinA for episodic migraine found more improvement in headache frequency in the Botox group compared to the placebo group at day 180 [61]. Multiple treatments with Botox proved safe and well tolerated. However, several recent studies and a meta-analysis of clinical trials for episodic migraine found no association between onabotulinumtoxinA treatment and clinical outcome [62, 63, 64, 65, 66, 67].

Tension-type headache is the most frequent chronic recurring head pain. It occurs more frequently in women than men and has a lifetime prevalence of 30% to 78% in the global population [68]. Recent research has shown that onabotulinumtoxinA is effective in reducing tension-type headache intensity and is safe and well-tolerated [69]. A randomized, double-blind trial of onabotulinumtoxinA injection into specific myofascial trigger points found improvement in pain from chronic tension-type headache [70]. Therapy for facial spasms might contribute to the observed improvement for tension-type headache by reducing the stress from the muscle spasms, rather than from the reduced muscle stiffness [71]. Stress factors are also related to muscle exhaustion and to the release of acetylcholine from presynaptic nerve terminals in the peripheral pain mechanism. Because onabotulinumtoxinA needs to be given every 12 weeks, this is more convenient for most patients compared to taking daily analgesic drugs [69]. However, treatment results depend on the dose given, the site of injection, the number of cycles and the interval periods [68].

3.4 OnabotulinumtoxinA and new daily persistent headache

New daily persistent headache is a subtype of chronic daily headache that is challenging to treat. The 3rd edition of the International Classification of Headache Disorders classifies it as a persistent primary daily headache with a distinct and memorable onset. The pain becomes continuous and unrelenting within 24 hours and is present for $>$3 months. In a case of new daily persistent headache reported in a 67-year-old male, complete response was observed following repeated injections with BT type A [72]. A retrospective study on new daily persistent headache and onabotulinumtoxinA therapy showed a 50.0% decrease in headache frequency at 6 months, a 63.6% decrease at 12 months, a 50.0% improvement in headache severity at 6 months, and a 77.8% improvement at 12 months [73].

Cervicogenic headache can arise from several factors associated with the back of the head and neck. Typically, cervicogenic headache starts at the rear of the head, neck and ear, and subsequently spreads to the zygomatic region. Cervicogenic headache is associated with throbbing pain and is always triggered by mechanical causes [79]. Several studies have reported benefits for onabotulinumtoxinA treatment in headaches related to the neck [23]. In a case report of a patient with a 5-year history of cervicogenic headache following whiplash injury, a dramatic response was observed after a single BT injection despite being medically refractory to usual therapies [80]. The patient required repeat injections to maintain the improvement thereafter. A recent study reported significant improvement in the range of neck motion and in pain reduction at 4 weeks [79]. Compared to pre-treatment levels, BT injection significantly lowered the frequency and severity of pain at 6- and 12-week following treatment. However, a double-blind, placebo-controlled, clinical trial of onabotulinumtoxinA for the treatment of chronic whiplash syndrome found that BT was not effective against chronic neck pain [81]. Nevertheless, another double-blind, placebo-controlled, clinical trial of BT type A (Dysport) for whiplash-associated disorder did find some benefit from this form of treatment [82].

Traumatic brain injury and post-traumatic headache associated with this injury negatively impact the lives of patients and their families [83]. As originally defined in the third edition of the International Classification of Headache Disorders, post-traumatic headache begins within 7 days of a mild, moderate, or severe traumatic brain injury and continues for longer than 3 months [83]. In a study of military veterans, onabotulinumtoxinA was shown to improve the frequency and intensity of post-traumatic headache when compared to placebo [83]. In another study of active-duty military patients, onabotulinumtoxinA was beneficial for the treatment of headaches related to concussion [84]. Moreover, a case study of onabotulinumtoxinA for the treatment of post-traumatic headache showed complete absence of pain, even after 5 years with this condition [85]. Bruxism is a rhythmic grinding of teeth that can sometimes occur following traumatic brain injury and lead to headache. This condition was also successfully treated with BT type A injection [86].

3.8 OnabotulinumtoxinA and chronic post-craniotomy headache

Chronic post-craniotomy headache is localized pain over the surgical site experienced by the majority of patients with craniotomy. Some patients describe it as a mild to moderate sensation of pressure involving the entire head and being more severe at the surgical site, and/or a throbbing sensation that can be accompanied by nausea and vomiting [87]. A study on peri-incisional onabotulinumtoxinA for chronic post-craniotomy headache following traumatic brain injury concluded that onabotulinumtoxinA injections may be useful for the treatment of chronic peri-incisional head pain after remote craniotomy and without any serious adverse effects. Furthermore, onabotulinumtoxinA appears to have several important benefits over current oral analgesics for the treatment of chronic post-craniotomy headaches. Based on a recent case series, patients can enjoy an extended period of pain relief following a single administration and without experiencing any side effects such as cognitive problems or somnolence [87]. Another case series of late-onset headache in post-temporal craniotomy patients who developed temporofacial pain due to total or partial temporal muscle hypertrophy found that onabotulinumtoxinA treatment significantly reduced pain without any adverse effects [88].

Diagnosis of orthostatic low cerebrospinal fluid (CSF) pressure headaches due to reduced CSF volume is based on clinical presentation with at least one abnormal magnetic resonance imaging (MRI) finding, cisternography findings, or an opening pressure less than the normal value of 65 mm H${}_{2}$O. A case report described significantly improved outcome following onabotulinumtoxinA injections in a patient suffering from refractory low-pressure headache. The patient continued to experience daily headaches but these were of lower intensity, suggesting that onabotulinumtoxinA may be effective for low CSF pressure headaches [89].

Nummular headache is a primary headache characterized by superficial, coin-shaped pain. A recent study of this disorder found that the number of headache days per month, including intense headache, decreased following onabotulinumtoxinA injection and without any serious adverse events [90].

4. Conclusions

BT treatment using onabotulinumtoxinA is associated with clinically significant benefits in terms of reducing headache frequency, severity, and headache-related impacts, thus improving the quality of life for many patients who suffer from various types of headache disorders [91]. Patients who take daily oral medication for headache relief will benefit from the less frequent treatment with onabotulinumtoxinA, which also shows better efficacy and safety compared to the currently used pharmacological drugs.

Author contributions

JHT and AGE designed the research study. JHT searched the literature and wrote the manuscript draft. AGE searched the literature and edited the manuscript. Both authors read and approved the final manuscript.

Ethics approval and consent to participate

This report was approved by Cairo University research ethics committee and followed the tenets of the Declaration of Helsinki.

Acknowledgment

The authors would like to thank The Illustrated Book of Medicine, LLC for their assistance in creating the figures.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest.

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