Efficacy of OnabotulinumtoxinA in Migraine
Condition: Migraine
MeSH terms: Migraine Disorders
Study type: Interventional
Phase: Phase 2

Summary: 
      Population studies estimate that patients who have episodic migraine transition to chronic
      migraine at a rate of about 2.5% per year.

      CM is a devastating disorder associated to severe disability. Patients with CM frequently
      overuse symptomatic medications in the attempt to control their disease, which adds up to the
      high costs associated to the disorder In this frame, it seems of the outmost importance to
      strive at preventing the transition from EM to CM.

      At the moment Onabotulinum toxin A (BoNT-A) represents the only drug specifically approved
      for CM prophylaxis.

      The aim of the present study was to evaluate the efficacy of BoNT-A in reducing the number of
      migraine days in a population of migraineurs with a high frequency of migraine attacks over a
      12-month period.
    

Detailed description: 
      Episodic migraine (EM) is a common type of disabling headache that affects up to 15% of the
      general population. In a minority of patients, migraine progressively increase in frequency,
      until it becomes chronic. According to the criteria of the International Headache Society
      chronic migraine (CM) is characterized by a headache that is present on at least 15 days per
      month over at least three months period, with migraine characteristics on at least 8
      days/month. Population studies estimate that patients who have episodic migraine transition
      to chronic migraine at a rate of about 2.5% per year.

      CM is a devastating disorder associated to severe disability. Patients with CM frequently
      overuse symptomatic medications in the attempt to control their disease, which adds up to the
      high costs associated to the disorder In this frame, it seems of the outmost importance to
      strive at preventing the transition from EM to CM.

      Transition to CM rarely is a rapid phenomenon. Most often it occurs over several months or
      years during which the frequency of attacks progressively increases as does the intake of
      acute medications. High monthly headache frequency is a risk factor for the progression of
      episodic migraine to chronic migraine. Compelling evidence from clinical and pre-clinical
      studies suggests that the transformation into CM is associated to, and probably brought about
      by, plastic changes in the peripheral and central nervous system induced by the repetitive
      occurrence of pain attacks. These changes configure a condition of chronic sensitization,
      usually associated to a reduced response to treatments.

      In this frame, it is noteworthy that the investigators previously showed that patients with
      CM overusing acute medications bear a condition of enhanced facilitation of spinal cord pain
      processing that is detectable with specific neurophysiological evaluations. The situation
      normalizes, i.e. pain facilitation is reduced, 60 days after successful treatment. Similarly,
      the Danish group showed that patients with chronic headache associated to medication overuse
      (most of whom were suffering from CM) are sensitized to pain, and pain perception continues
      to normalise over a period of at least 12 months when patients are successfully treated.

      At the moment Onabotulinum toxin A (BoNT-A) represents the only drug specifically approved
      for CM prophylaxis.

      Seven different subtypes of botulinum toxin (A-G) are known. A highly-diluted preparation of
      botulinum toxin type A was introduced in clinical practice in the 1970s and 1980s to treat
      squint and blepharospasm. Since then, it has found uses in other areas of medicine including
      dystonia (including writer's cramp), post-stroke spasticity, and hyperhidrosis but in the
      mid-1990s a number of people reported improvement in headaches in patients receiving
      botulinum toxin for other reasons. Finally, in the first decade of 2000 two trials, the Phase
      3 Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) recruited 1384 patients with
      chronic migraine, and randomised them to treatment with BoNT-A (Botox® by Allergan
      Industries) or placebo. These patients were suffering on average 20 days of headache each
      month, of which 18 were moderate or severe. Those randomised to Botox®® received fixed-site,
      fixed dose injections every 12 weeks over 56 weeks. These injections covered seven specific
      areas of the head and neck, with a total dose of between 155-195 units. At six months, after
      two cycles of treatment, those treated with Botox® had on average eight less days of headache
      each month. After 12 months, 70% of those treated had ≤50% the number of headaches that they
      had done originally. Botox® was well-tolerated, the commonest side effects being neck pain
      (6.7%), muscular weakness (5.5%), and drooping of the eyelid (3.3%). No serious irreversible
      side effects have ever been reported in trials of Botox® in headache.

      These studies led in 2013 to the approval by AIFA of Botox® as a drug form CM prophylaxis.

      An increasing body of evidence suggests that BoNT-A acts on peripheral trigeminal endings by
      inhibiting the release of nociceptive neuropeptides - such as calcitonin gene-related peptide
      (CGRP) - and glutamate, as well as the expression of the transient receptor potential
      vanilloid 1, thereby reducing directly peripheral sensitization, and, indirectly, central
      sensitization. It is noteworthy that preclinical data also suggest a central antinociceptive
      action for BoNT-A, probably associated with an enhanced opioidergic and GABA-ergic
      transmission.

      Taken together, these observations provide the rationale of this study, which is to evaluate
      whether BoNT-A treatment is effective in reducing the number of migraine days in migraineurs
      with a high monthly frequency of migraine attacks.

      This study is a phase II, single group, non-randomized, non-controlled, open label trial
      performed at a single centre: Mondino Foundation.

      Patients affected by migraine with high frequency of attacks per month were enrolled at the
      Headache Science Centre of IRCCS C. Mondino in Pavia. After the screening visit, selected
      patients were evaluated with a headache daily diary for a period of 1 month. If the diagnosis
      of episodic migraine with high frequency of attacks per month was confirmed, the patient were
      enrolled and received the treatment with BoNT-A at the centre every 3 months for 4 cycles (at
      visit V2-V5-V8-V11). At the first administration of the treatment (V2), 155 UI of Botox were
      injected according to the approved PREEMPT protocol, in 31 sites. From visit 5, the PREEMPT
      'follow-the-pain' paradigm will be applied in patients falling in the 'non-responder' or
      'partial responder' classes after the 1st BoNT-A injection, with the possibility to increase
      the doses up to 195 UI in maximum 39 sites.

      Every 3 month the patients were asked to fill in 3 validated questionnaires for the
      quantification of disability (Migraine Disability Assessment Score Questionnaire - MIDAS),
      quality of life (Mental Status Questionnaire - MSQ), anxiety and depression (Hospital Anxiety
      and Depression Scale - HADS). Every month the patient also received a phone call from the
      site personnel in order to be updated on the clinical conditions.

      During all the study period the patient was asked to complete a daily headache diary in order
      to evaluate the clinical condition and the medications use.
    

Intervention name(s): OnabotulinumtoxinA
Intervention type(s): Drug
Intervention description(s): BOTOX contains onabotulinumtoxinA, an acetylcholine release inhibitor and a neuromuscular blocking agent available in the lyophilized form of purified clostridium botulinum toxin type A, suitable for injection, for intramuscular, intradetrusor, or intradermal use. The recommended dilution is 100 Units/2 mL, with a final concentration of 5 Units per 0.1 mL. The recommended dose for treating chronic migraine is 155 Units administered intramuscularly using a sterile 30-gauge, needle as 0.1 mL (5 Units) injections per each site.
Other intervention name(s): BonT-A (Botox®)
Intervention MeSH terms: Botulinum Toxins, Type A; abobotulinumtoxinA
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Migraine; OnabotulinumtoxinA