Chronification and reversibility of migraine.

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.



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 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.

We want to unravel the role of depression and OAHM in the chronification of migraine, assess the (permanent and reversible) short- and long-term consequences of chronic migraine and OAHM on the brain, and decipher some of the underlying neurobiological mechanisms.

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;

C. Specific MRI markers of BSF correlate with measures of ETVS.

-1 month, 0, months 3, 6, 9, 12.

Addendum: The difference between maximal versus minimal support by a headache nurse, and depressive (HADS≥8) versus non-depressive chronic migraineurs will be assessed by measuring the absolute and relative reduction in migraine and headache days on time points 3, 6, 9 and 12, the number of patients achieving a 50% or more decrease from baseline (month -1) in the frequency of migraine days and migraine episodes at both time points and absolute and relative reductions of HIT-6, SF-36 CES-D and HADS-D scores at time points 3, 6, 9 and 12. The differences in baseline characteristics (i.e. headache characteristics, accompanying symptoms, depression, anxiety) between responders (≥50% reduction in headache days) versus non-responders will be examined.

Headache and medication overuse relapse rates at t=12 will be assessed and compared between Btx and placebo-treatment, minimal or maximal support by the headache nurse and depressive versus non-depressive groups. The change in reactiveness of the trigeminal blink reflex during the course of the trial will be assessed. Blink reflex will be tested at time points 0, 3 and 12.

Participants will be randomized to receive either:

1. "Verum": Withdrawal therapy with one-time concommitant botulinum toxin A injections in 31 locations according to the injection protocol by Allergan (total 155U);

2. "Placebo": Withdrawal therapy with one-time concommitant low-dose botulinum toxin A injections in the facial region and NaCl injections in the other regions according to the injection protocol by Allergan (Total 17.5U).

Withdrawal therapy is considered standard treatment for this patientgroup and takes three months. During this time, patients will be guided by a trained headache-nurse.



At the end of the three-month withdrawal period, primary outcomes will be assessed. All participants who have succesfully completed the withdrawal period, but are still suffering from chronic migraines will be offered single treatment (open-label) with botulinum toxin A. This group will consist of participants from both the verum and placebo groups, but due to blinding, initial treatment is not known at this point).