CPD: Treating Migraines with Botulinum Toxin

Treating Migraines with Botulinum Toxin

Nurse prescriber Clare Amrani explores the literature around the use of botulinum toxin as a treatment for migraines

Botulinum toxin (BoNT) is a powerful muscular paralytic agent through the inhibition of the release of acetylcholine vesicle at the pre-synaptic level.1 It is this very characteristic that allows this powerful toxin to be used in a vast array of medical conditions where an abnormal muscle activity of hyperactivity exists.2 This is the case for cervical dystonia, severe forms of lower limb spasticity and ophthalmic pathologies such as blepharospasm and strabismus.3

In aesthetic medicine, it is a cornerstone therapy for treating lines and wrinkles. In mixed pathologies such as temporal mandibular joint disorder (TMJD), bruxism and hyperhidrosis, botulinum toxin A (BoNT-A) has also demonstrated a significant efficacy.4

This article is aimed at highlighting the place of BoNT-A in the global armamentarium for migraine, as well as examining the new pathophysiological aspect, particularly with regards to the role of neuropeptide calcitonin gene-related peptide (CGRP). It will be examined whether BoNT-A has a viable role in migraine either as a stand-alone treatment or as an additional treatment.

Background Fairly recently, the beneficial effects of BoNT-A on migraine have been observed more accidentally than by design, as was the case for depression. Indeed, in the early 1990s a significant proportion of patients having undergone BoNT-A treatment for wrinkles reported a significant subsidence in migraine symptoms.2 The fact that the pathophysiology of migraines lies principally in the sensory network, the mechanism of action of acetylcholine blockage becomes a largely insufficient way to explain its effect on the nociceptive network.5

Intense research was undertaken to determine the mechanism through which BoNT-A alleviates migraine. The most recent accepted theory relates to the critical role of neuropeptides, principally CGRP.6 In parallel, research into the pathophysiology of migraine has questioned the conventional mechanisms which have classically been put forward to explain migraine.1

The search and discovery for alternative therapies for migraine is crucial for several reasons. This neurological condition, which is defined by repetitive acute attacks of headaches, can affect a large proportion of the population. Indeed, its prevalence has been reported as being as high as 15% in a Norwegian study,7 and up to 25% of women and 10% of men in the UK.8

When it occurs more than 15 days a month and for a period, it is defined as chronic migraine.3 Almost 25% of American families have at least one member suffering from migraine.9 Because of its debilitating aspect, migraine is considered to be a huge socio-economic burden.10 The main purpose of migraine therapy is to alleviate the consequence of this condition on the patient’s daily life. Practically, it aims at reducing both the rate of occurrence and the duration, hence reducing the consequent disability. Although conventional therapies are known to carry some efficiency, they are associated with significant side effects which very often lead to noncompliance or dropout.3 These range from cognitive changes, drowsiness, and nausea to alopecia, sexual dysfunction and weight gain, among many others. Although the suitability of these medications can be adapted according to the patient’s medical history, the intensity of some of the side effects is such that dropouts remain an issue so it’s no surprise that many patient seek alternative solutions.10 In addition, 20% of migraine patients are non-responders to existing therapies.11,12 For all these reasons, BoNT-A as an alternative therapy has been welcomed and widely studied. This has led to its approval by the US Food and Drug Administration (FDA) in 2010 as a therapy for chronic migraine as it has demonstrated a significant efficiency both in terms of reducing the intensity of migraine as well as the frequency.3

How botulinum toxin impacts migraines BoNT is a complex mega protein which essentially contains two subunits. When BoNT is injected, its mechanism of action involves its interaction with the complex process of neurotransmitter release.13 In normal conditions, neurotransmitters are incorporated in small vesicles at the presynaptic level, which is subsequently released in the neuromuscular junction.14 It then crosses the neuromuscular junction and acts on the receptors. This process includes different steps such as stockage and fusion within the membrane. These stages depend on the building and presence of a very large protein complex known as Soluble N-ethylmaleimide-sensitive factor

Although conventional therapies are known to carry some efficiency, they are associated with significant side effects which very often lead to noncompliance or dropout

Upper third of forehead

Orbital rim

Lateral canthus

Limbus

Medial canthus Midpupillary line Limbus line Orbital rim Tragus Tragus line Mid-helix

Hairline

Frontalis

Supraorbital notch

Corrugator

Procerus

Figure 1: The diagram shows the specific injection points as described by PREEMPT protocol for using BoNT-A to treat migraines.34

activating protein receptor (SNARE). 14 This large protein is responsible for the mechanism of vesicle formation and release of acetylcholine. BoNT-A has the ability to destroy this large mega molecule making it impossible for the vesicle to adhere and eventually release the neurotransmitters, therefore provoking a paralysis of the muscle.2

This complex pathophysiological mechanism explains the beneficial effect of BoNT-A on every condition or pathology requiring a muscle paralysis.2 However, migraine is mainly a condition that involves sensory networks. Therefore, the conventional mechanism of BoNT-A through the inhibition of acetylcholine cannot be an explanatory mechanism behind the positive effect of BoNT-A on migraine. In order to fill the gap in our comprehension, it became obvious the neurological sensory network might be affected by BoNT-A as well.2,12 The early logical hypothesis put forward was the potential ability of BoNT-A to inhibit the nociceptive pathways.5 This was brilliantly demonstrated by an experimental study in which BoNT-A injected subcutaneously was able to eliminate delayed pain reflex without affecting the muscle contraction.15

Interestingly, as early as the mid-80s, clinical research in 93 patients suffering from cervical dystonia showed that injection of BoNT-A had more effect on pain than muscle contraction.16 This observation strongly suggested a lack of association between the nociceptive aspect and muscular paralysis in cervical dystonia. Furthermore, a subsequent study concentrating on the correlation between muscular contraction and pain were unable to find a significant association between them.17 All these observations strongly support the concept that the BoNT-A beneficial effects in muscular contracture and pain are two different entities.17 Perhaps the strongest evidence supporting the beneficial effect of BoNT-A purely on pain is provided by a small randomised control trial on 18 diabetic patients suffering from peripheral neuropathy.18 In those patients, where pain is not linked to any muscular disorder, BoNT-A significantly reduced the pain. Although the observations were made on a small number of patients, the findings are extremely pertinent with regards to the effect of BoNT-A on the sensory network. All these observations put together form the strong explanatory platform behind the effect of BoNT-A in migraine.

Interestingly, as early as the mid-80s, clinical research in 93 patients suffering from cervical dystonia showed that injection of BoNT-A had more effect on pain than muscle contraction

Occipital protuberance

Helix

Nuchal ridge

Mastoid process

Inion

Figure 2: The specific injection points as described by PREEMPT.34

Crucial steps in our understanding of the mechanism of action of BoNT-A on migraine came about from pre-clinical research which demonstrated that BoNT-A was also able to inhibit the secretion of peptides like substance P and CGRP within peripheral sensory neurons.18

Recent research has highlighted that, at the presynaptic level, in addition to acetylcholine, many neurotransmitters and peptides are released using the same above-mentioned complex mechanisms involving the SNARE protein complex. This is particularly the case in cerebral areas known to be linked to migraine such as the trigeminal ganglion.18 The latter is also known to have the highest concentration of CGRP. These vesicles not only contain acetylcholine but other transmitters or neuro peptides such as substance P or more relevant CGRP.18 The ability of BoNT-A to inhibit the release of CGRP together with the crucial role of the latter in migraine explains the therapeutic action of BoNT-A and migraine.

The role of CGRP in the pathophysiology of migraine

The pathophysiology of migraine is not fully understood, although a large body of recent theories are slowly filling the gaps. The first theory that has been widely accepted and adopted up until recently is the vascular theory.19 The latter has been hypothesised by Dr Thomas Willis, an English medical doctor and pioneer in neurology, over four centuries ago and was based on the precept that migraine is due to the vasodilatation of some vessels included in the cerebral tissues and meninges.19 The vascular theory has been given a further impetus more than 100 years ago. One of the reasons behind the longevity of this theory is that drugs able to produce vasoconstriction such as Ergotamine have shown some degree of efficiency, particularly in acute migraine.20 However, with the advent of sophisticated blood flow measurement techniques, the foundation of this theory has been somehow shattered. Indeed, MRI imaging of blood flow clearly demonstrated that there is a lack of correlation between the presence of migraine and the magnitude of blood flow.21 Furthermore, in patients known to be prone to migraine, induced vasodilatation of the brain cerebral arteries using powerful vasoactive intestinal peptides (VIP), no migraine developed, highlighting again the lack of correlation between the level of blood flow and migraine.22 Therefore, after the initial observation of Dr Willis more than 400 years ago, dynamic modification of the diameter of the arteries together with the variation of blood flow became an insufficient theory to explain the genesis of migraine.

One of the theories that replaced the vascular theory was the neurohormonal theory, which supports the notion that it is the protein extravasation with the subsequent oedema which produces migraine.23 However, in the 1990s, drugs such as Bosentan, which have the characteristic of being able to inhibit plasma extravasation, did not make any changes in terms of migraine triggering.24 The role of the neuropeptide, particularly CGRP as a pathophysiological mechanism behind migraine has now been put forward.1,2,25,26,27 The crucial role of CGRP in the genesis of migraine is supported by several experimental and clinical studies. Firstly, immunocytochemistry studies clearly showed the presence of large quantities of CGRP in some key vessels supplying the cerebral loci known to be involved in migraine.1 This is particularly the case for the trigeminal ganglion.24 Further similar studies have demonstrated that 50% of the cerebral tissue in this zone have a significant amount of CGRP. Beside the mere observation of presence of CGRP in the critical cerebral area linked to migraine, it has recently demonstrated that CGRP is found in high concentrations in blood of patients known to suffer from migraine.1,2 Further convincing evidence of the role of CGRP in the pathophysiology of migraine is provided by the fact that inhibition of this neuropeptide by antagonists have been able to provide a therapeutic efficiency comparable to the classical treatment for migraine.25,26,27

The role of BoNT-A in the prevention of chronic migraine through its inhibition of CGRP is supported by basic and clinical research. Indeed, an in vitro experimental study demonstrated a significant inhibition of CGRP release by BoNT-A from peripheral neuronal sensory networks. 18 In culture medium, animal cells from trigeminal ganglion were subjected to BoNT-A. CGRP was measured and shown to be significantly reduced in the BoNT-A group when compared to the cells in the control group.28 In a clinical study involving 83 patients, BoNT-A was shown to diminish CGRP blood levels between migraine attacks in patients known to be positive responders to therapy but not in patients known to be non-responders.29 This suggests a clear relationship between the level of CGRP and pain.

With regards to the intrinsic mechanism behind the relationship between CGRP and migraine, there is no clear consensus or definitive theory. It is suggested that CGRP over expression in sensory nerves reflects a disturbance in the signalling mechanism within the trigeminal ganglion.19 Indeed, migraine can be seen as an abnormality in the filtering system of the sensory mechanism. In normal circumstances, several layers of the brain including the mid brain, the thalamus and the pons act as a control system that establish what information to filter and what information can be allowed to reach the thalamus and cortex. It is postulated that the usual migraine triggers could increase the level of CGRP and induce a high level of cerebral sensitivity.

This will lead to the anomaly in the filtering system. In turn, this allows information that is normally filtered to pass through and reach the cortex, which can trigger pain and other features of migraine such as photophobia.19,30

Is BoNT-A a viable option in the armamentarium against migraine? Over the last 20 years, studies have repeatedly demonstrated the efficacy of BoNT-A in the treatment of migraine.1-3,5,6,12,29 However, when used as a standalone treatment its efficiency has been shown to be reduced or even discontinued in some patients.12,24,29 It has recently been suggested that monotherapy of any kind, including BoNT-A aimed at targeting chronic migraine is unlikely to work in the long-term due to a variety of reasons, including the fact that migraine is a polygenic pathology which involves many peptides and neurotransmitter pathways.24,29 All of this acts in a synergetic fashion and requires a synergetic approach.

In addition, whilst BoNT-A has been clearly shown to be an efficient therapy against chronic migraine, patients having treatment can still experience migraine attacks.24,25,29 For this reason, it has very recently been advocated that CGRP monoclonal antibodies should be associated with BoNT-A.24,25,29 The rationale behind this is that the monoclonal antibodies act directly on the CGRP whereas, BoNT reduce the concentration of CGRP indirectly. Although the number of studies are limited, there is clearly a beneficial effect, particularly in those patients who are on monotherapy. Current studies suggest that conventional therapy, BoNT-A and monoclonal antibody approach have the same efficiency. Although conventional therapy demonstrates an initial higher effect, it has the highest probability of dropout.29 Therefore, direct inhibition of CGRP could have a specific place in patients who do not respond to conventional therapy of those with low compliance.25

Injection sites for migraines The specific injection site and the timing of BoNT-A has been previously described in detail, particularly the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials involving 1,384 patients.31 This subsequently led to a set of protocols. In essence, it consists of an injection into 31-39 locations involving seven muscles located in the head and neck area.33 The rationale behind this relates to the fact that the sensory nerve endings that connect to bodies found in the trigeminal and cervical ganglia are found in these areas.2 Over time, modifications have been made to the PREEMPT protocol in clinical practice making its application in practice less standardised and more patient specific.33

Summary Given the shortcomings of conventional therapies against migraine, several alternatives were considered, among which BoNT-A. The pathophysiology of migraine has remained unclear and has been based on successive theories that have been ruled out by new research. The latter has led to the development of the peptide theory, within which CGRP plays the major role. In parallel, our understanding of the mechanism of action of BoNT-A has expanded to include a specific action on the sensory/nociceptive network. This has helped elucidate the logic behind the effect of BoNT-A on migraine. Recent data suggests that combination of BoNT-A and other therapies such as monoclonal antibodies can improve the outcome.

Clare Amrani is an independent nurse prescriber and was previously a surgical care practitioner in cardiac surgery and lead tissue viability. For the last six years she has led her own medical aesthetic clinic Luvenis Aesthetics. She is a board member for the BACN and also a technical expert marker for VTCT for Level 7 in Aesthetic medicine. Amrani is currently completing her second year of a MSc in Cosmetic Medicine. Qual: RGN, INP, ANP/SCP (MSc), PG Cert, PG diploma (CosMed)

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Question

1. Regarding the mechanism of action of BoNT-A, which statement is correct?

2. BoNT-A effect is exerted via:

3. Migraine pathophysiology can be exclusively explained by:

4. The neuropeptide theory behind the physiology of migraine involves:

5. Role of BoNT-A and migraine:

Answer

a. BoNT-A exclusively inhibits acetylcholine release b. BoNT-A only acts on axons c. BoNT-A also has an action on sensory networks d. BoNT-A exclusively acts on sympathetic networks

a. Action potential b. Modification of the membrane potential c. SNARE protein complex d. Combining directly to acetylcholine molecule

a. The neurohormonal theory b. The vascular theory c. Muscular contracture d. None of the above

a. Vasoactive intestinal peptides (VIP) exclusively b. Secretion of CGRP c. Noradrenaline d. Catecholamine

a. BoNT-A always works for all forms of migraine b. As a standalone BoNT-A can work continuously and without fail c. In some instances, it is better to combine

BoNT-A with other therapies d. The site of injection is not relevant

Answers: 1C, 2C, 3D, 4B, 5C