Chronification and reversibility in migraine (CHARM)

Migraine is a common, recurrent, disabling neurological disorder affecting
around 15% of the general population characterized by recurrent attacks of
headache and associated transient neurological aura symptoms in one-third of
the patients. The majority of patients experience paroxysmal migraine attacks,
ranging from a few in their lifetime to several per week (median attack
frequency 1.5/month). A minority of patients however, suffer from increasing
attack-frequencies, where headache is sometimes present chronic. According to
the ICHD-II-R criteria, chronic migraine is currently defined as headache
occurring on 15 or more days per month for more than 3 months, occurring in a
patient who has at least five attacks fulfilling the criteria for migraine
without aura, with migraineous headache on 8 or more days per month for more
than 3 months. In 25% of episodic migraineurs, migraine frequency progresses to
over 15 days per month, meeting the criteria for chronic migraine.
While knowledge is increasing on the pathophysiology of migraine aura and
headache, the mechanisms behind chronification remain poorly understood.
Several central nervous system components have been implicated in the
chronification process; dysfunctioning pain-modulating systems as well as brain
areas known to be involved in affective changes as seen in depression and
anxiety. Adding credibility to the fact that both comorbid depression and
overuse of anti-headache medication are risk factors for chronification of
migraine. The relationship between medication overuse and chronification of
migraine has been further supported by regression of symptoms after withdrawal
from medications.
The relationship between chronic migraine, medication overuse and depression is
best described as a triad, in which every component influences the other two.
Symptoms of depression are found in up to 85% percent of patients with chronic
migraine, of which up to 25% has a severe depression. Therefore, in diagnosing
and treating migraine, it is of great importance to be aware of medication
overuse and depressive symptoms, and to treat medication overuse with
withdrawal therapy before starting new drugs.

We hypothesize for the withdrawal phase, that:
1. Treatment with Botulinum toxin A (Btx) injections (at the start of the
therapy) will increase the success rate of withdrawal therapy or will improve
quality of life during the withdrawal period.
a. The presence of comorbid depressive symptoms is associated with a reduced
success rate of withdrawal of OAHM in patients with chronic migraine.
b. The support of a headache nurse during the withdrawal period will increase
the success rate of withdrawal therapy.
c. Presence of comorbid depressive symptoms, baseline migraine characteristics
(e.g. attack frequency, duration of attacks, number of medication days per
month) and baseline brain structure and function (BSF) and excitability of the
trigeminovascular system (ETVS) measures are predictors of the success rate of
withdrawal therapy.
We hypothesize for the baseline imaging phase, that:
2. Before treatment, changes in (regional) BSF and ETVS can be identified in
chronic migraineurs with medication overuse. The use of different control
groups (episodic migraineurs, depressive patients, chronic pain patients and
healthy controls) will allow to differentiate changes in (specific) structures
or functions associated with chronification of migraine from changes associated
with depression and/or chronic pain.
We hypothesize for the longitudinal imaging phase, that:
3. After withdrawal, changes in BSF and ETVS compared to baseline will point
towards transmutable structures or functions involved in and/or predisposing to
chronification of migraine.
a. Changes in BSFB and ETVS after withdrawal therapy will depend on a)
accompaniment of Btx injections and b) the presence of depressive symptoms.
b. Specific MRI markers of BSF correlate with measures of ETVS.

1. We want to study the success rate of OAHM withdrawal in patients with
chronic migraine related to support by a headache nurse, and onabotulinum toxin
A injections during the withdrawal period, and the influence of comorbid
depression.

2. We want to study changes in ETVS (as measured by blink reflex) related to
success rate of withdrawal and structural and functional changes in the brain.

3. We want to study baseline (= before treatment) structural and functional
brain differences in chronic migraineurs compared to control populations of
episodic migraineurs, depressive patients, chronic pain patients and healthy
controls.
To do so, we will:
a. assess differences in grey and white matter density, structural integrity
and functional measures in chronic migraineurs versus control groups.
b. compare findings in the different study groups, and identify changes that
are specific for either chronic pain, depression, migraine and migraine
chronification.

4. We want to study the reversibility of (regional) structural and functional
changes in chronic migraineurs after withdrawal of OAHM.
For this, we will study:
a. differences in grey and white matter density, structural integrity and
functional measures between chronic migraineurs before and 3 and 12 months
after withdrawal.
i. Correlate these to the response to withdrawal therapy
ii. Correlate these to migraine characteristics
iii. Correlate these to depression scores
b. the eventual modifying role of the accompaniment of Onabotulinum toxin A
injections in the withdrawal therapy.
c. the differences in brain changes before and after withdrawal to assess the
influence of medication overuse on structure and function of the brain.

In this study we will perform a randomized, double blind, placebo-controlled
trial in which chronic migraine patients (n=180) with medication overuse (OAHM)
will be randomized to withdrawal therapy with accessory Botulinum toxin A (Btx)
injections or with placebo-treatment, and minimal or maximal support of a
headache nurse. Stratification will be performed for depression status.

We will perform an MRI-study in the first 100 chronic migraineurs included,
before and after withdrawal of medication. MRI will also be performed in
matched control groups, consisting of patients with episodic migraine, patients
with chronic pain, patients with a depressive disorder and healthy controls
(n=20 for each control group) to correct for any bias by migraine specific,
chronic pain related- or affective changes. Magnetic resonance imaging will be
performed at baseline in all chronic migraineurs and control groups. The
imaging protocol will be repeated in chronic migraineurs after completion of
the withdrawal phase (at three months) and at one year after start of
withdrawal to study short- and long term changes in that specific group. Blink
reflexes (as a marker of excitability of the trigeminovascular system) will be
tested at baseline in both the chronic and episodic migraine patients, and at 3
and 12 months in the chronic migraine patients. At the same time points as the
blink reflex (ETVS) and MRI-scans, questionnaires will be taken and blood
samples will be drawn.

Botulinum toxin A as a treatment for chronic migraine

Botulinum toxin A and withdrawal of OAHM
Recently, some studies were published showing that treatment with Btx
injections[48-50], without withdrawing the overused acute headache medications
(OAHM), decreases the headache frequency when compared to placebo. These
studies feed the debate about whether withdrawal of OAHM is necessary in
patients with chronic migraine. Unanswered questions remain: is the effect of
starting Btx better than withdrawing, or could a combination of withdrawal and
Btx be even better? What is the role of comorbid depression in the effect of
these different therapeutic strategies? Is the outcome of withdrawal better
with or without the support of a headache nurse?

Onabotulinum toxin A
Botox® (Onabotulinum toxin A ), by Allergan© is an acetylcholine release
inhibitor and a neuromuscular blocking agent, currently registered for use in
the Netherlands in upper limb spasticity, cervical dystonia, axillary
hyperhidrosis, blepharospasms associated with dystonia and strabismus. It is
also used as a cosmetic agent, reducing facial wrinkles by relaxing local
facial muscles. Btx has not yet been registered for use in chronic migraine in
The Netherlands, although the registration process has been started.
2.5.3 Findings from CM studies
Recently, a number of studies have been published on the use of Btx for the
treatment of chronic migraine. These studies report an additional decrease in
headache days per month over placebo injections, suggesting a subtle effect on
chronic migraine. The use of Btx for the treatment of chronic headache has
been shown to be safe in humans[51].

One of the largest studies to date on the use of Btx in the treatment of
chronic migraine is the PREEMPT (Phase III REsearch Evaluating Migraine
Prophylaxis Therapy) study , performed by the Allergan®-research team. This
study consisted of two separate trials, labelled PREEMPT-1[48] and
PREEMPT-2[49]. Both included similar groups of chronic migraineurs regardless
of medication intake, which were subsequently randomized to injection with Btx
or injection with placebo (Saline). The pooled results of both trials show a
small but significant advantage of Btx above placebo which probably does not
reach the standard for clinical relevance (10%, NNT=10). However, in the Btx
treated group 12% more responders (with 50% or more reduction of headache days)
were reported compared to the placebo group (NNT=8.3). Additional analyses
showed no specific clinical characteristics to be predictors for this
response. Importantly, although there was a decrease in frequency of headache
days (both in the verum and placebo groups) there was no decrease in the intake
of acute headache pain medication. Therefore, we want to demonstrate whether
Btx therapy has a supplementary effect in the decrease in headache days in
chronic migraine patients following a withdrawal regime.

Proposed mechanism of action of Onabotulinum toxin A in chronic migraine
Despite Btx has shown improvement in chronic migraine, its mechanism of action
is not fully understood. Botulinum neurotoxin is a potent inhibitor of
neurotransmission between neurons and muscle and signalling between neurons by
preventing fusion of intracellular vesicles containing neurotransmitter with
the cell membrane[52]. This process, when occurring in motor neurons, results
in (partial) muscle paralysis. Possibly, the toxin is also internalised in
sensory neurons, leading to inhibition of the release of pro-inflammatory
mediators locally; animal studies have shown that botulinum toxins can block
stimulated release of CGRP, glutamate and substance P from trigeminal neurons
and inhibit activation of second order neurons responsible for transmission of
pain signals, demonstrating an antinociceptive effect.[53] It is hypothesized
that botulinum toxin, by decreasing release of these mediators, inhibits
sensitization of peripheral trigeminal sensory fibres, which in turn modulate
activity of central trigeminal neurons, thus indirectly leading to inhibition
of migraine headache[54-56]. Possibly and probably, botulinum toxin A exerts
the observed anti-migraine effect by multiple if not all hypothesized
mechanisms, although its exact method of action remains unclear.

Known contraindications and adverse events
Patients suffering from neuromuscular disorders or exposure to agents that
might interfere with neuromuscular function and patients suffering from
infections or skin problems at the site of injection were excluded from
clinical studies performed on Btx.[51] Also, patients were excluded if they had
received an injection of anaesthetics or steroids into the study targeted
muscles during the 30 days immediately prior to initiation of the baseline
period. Lastly, female participants during or planning pregnancy or nursing
were excluded, as were females not using and unwilling to use reliable
contraceptives, as Btx has not been tested in pregnancy.

Contraindication for use of Btx , provided by Allergan© include
hypersensitivity to any botulinum toxin preparation or to any of the components
in the formulation and infection at the proposed injection site.[57]

The most frequently reported treatment related adverse events (AE) from other
headache studies with Btx were muscular weakness in 22.0% of patients treated
with Btx, neck pain (13.3%), headache (6.9%), and blepharoptosis (6.9%)[51].
Articles reporting from the PREEMPT trials[48-50] reported any AEs in 62.4% of
the participants in the Btx group versus 51.7 in the placebo-group. Serious AEs
were reported in 4.8% of participants in the Btx group versus 2.3% in the
placebo group. Only one treatment related serious AE was reported in the Btx
group. The reported treatment related AEs in the Btx-group consisted mainly of
neck pain (6.7%), muscular weakness (5.5%), eyelid ptosis (3.3%),
musculoskeletal pain (2.2%), injection site pain (3.2%), headache (2.9%),
myalgia (2.6%) and musculoskeletal stiffness (2.3%). In total 3.8% of patients
in the Btx group and 1.2% of patients in the placebo group discontinued due to
AEs. The most frequently reported AE's leading to discontinuation in the Btx
group were neck pain (0.6%), muscular weakness (0.4%), headache (0.4%), and
migraine (0.4%).

In rare cases, injection with Btx in the lower neck region in muscles that
serve as accessory ventilation muscles, can lead to difficulty with breathing
in patients with respiratory disorders. Also, injections into the
M.sternocleidomastoidius, especially when performed bilaterally, may cause
dysphagia.[57]

Although it is clear participation in this trial is not without risk, these
risks have been established in similar trials in other countries and have been
found small enough to allow Botulinum toxin A on the market for treatment of
chronic migraine.
All patients participating in this trial have a 50% chance of receiving
placebo-treatment rather than the full botox treatment. This is inherent to the
randomised nature of such trials. However, these participants do undergoe the
same injection protocol, which is a painful 'treatment'. Therefore, all
patients who are still suffering from chronic headache at the end of the
withdrawal period, will be offered openlabel botox-therapie. This way, every
participant will be able to receive this therapy. If adding botulinum toxin to
withdrawal therapy is indeed beneficial, these patients will have all received
the most optimal care. If it is not benificial, they will still have completed
the withdrawal, which is the current treatment-strategy.
For chronic migraineurs in general, this trial is important as it is a dificult
to treat disease and existing therapy (withdrawal) is difficult. this trial
seeks to improve their outcome as well as alleviate some of the difficulties of
withdrawal therapy.