Comparative Study Between Valproate and Memantine in the Prophylactic Management of Episodic Migraine.
Condition: Migraine Headache
MeSH terms: Migraine Disorders; Headache
Study type: Interventional
Phase: Phase 3

Summary: 
      Migraine is one of the three most disabling diseases worldwide. Constituted by recurrent
      episodes of headache, characterized by unilateral location, throbbing character, moderate or
      severe intensity, worsening with physical activity, and association with nausea or
      photophobia and/or phonophobia. There are two types of drug treatment: abortifacient and
      prophylactic. The American Academy of Neurology classifies sodium valproate as level A;
      however, some patients do not obtain a satisfactory response rate and/or have adverse
      effects. Therefore, the search for new pharmacological treatments continues. In 2015, a
      double-blind, randomized clinical trial with a placebo was carried out to assess Memantine's
      efficacy in the prophylactic treatment of migraine without aura, which reported a reduction
      of 2.3 migraine attacks per month compared to the placebo group. Memantine could be a new
      effective treatment alternative, which is why we will compare the efficacy of Memantine
      against sodium valproate as a prophylactic migraine treatment.

      Main objective: To compare the efficacy of Memantine at a rate of 20mg divided into two doses
      a day against sodium valproate (VPA) at a rate of 1000mg divided into two doses a day
      prophylactic treatment of migraine for three months.

      Study design: a prospective controlled, randomized, double-blind clinical trial. Inclusion
      criteria: Men and women aged 18 to 65 years with a diagnosis at least one year before the
      study must present at least 2 to 8 migraine attacks per month and less than 15 days with
      headache per month, which should not be receiving prophylactic treatment for migraine and
      sign an informed consent

      Sample size calculation and statistical analysis:

      It is calculated using the normal distribution model, where the recommended sample size is
      196 participants. Since a pilot study will be conducted, 10% of the sample size will be taken
      to make it representative, a sample size of 20 participants is decided for each group.
    

Detailed description: 
      Migraine is a primary headache, currently one of the three most disabling diseases globally.
      It has an annual and lifetime prevalence of 18% and 33% in women, and 6 to 13% in men,
      respectively, with a predominance in women (3: 1). The age of onset with the highest
      prevalence is between 25 and 55 years.

      Migraine is described by the International Headache Society (IHS) as recurrent episodes of
      headache lasting 4 to 72 hours, characterized by unilateral location, pulsatile character,
      moderate or severe intensity, worsening with physical activity, and association with nausea
      or photophobia and phonophobia. The IHS also classifies migraine based on the frequency of
      attacks: episodic migraine when the headache occurs on less than 15 days a month, and chronic
      migraine, when the headache occurs 15 or more days a month for three months and at least
      eight days a month with characteristics of migraine headache.

      The subtypes of migraine concerning their clinical presentation are migraine with aura and
      without aura.4 Up to one-third of patients present migraine aura, with visual symptoms being
      the most frequent.

      Four phases have been identified during a migraine: prodromal phase, aura, headache, and
      postdrome. The prodromal phase is characterized by premonitory symptoms hours before the
      headache, including difficulty concentrating, irritability, fatigue, repetitive yawning,
      stiff neck, and photophobia.

      Recurrent episodes characterize the aura, lasting from 5min to 60min, with transient
      unilateral visual, sensory, or other CNS symptoms that develop progressively, usually precede
      headache and symptoms associated with migraine.4 The aura's genesis is activated by the NMDA
      (N-methyl-D-aspartate) receptor and disseminated cortical depression. Disseminated cortical
      depression is an extreme depolarization of the cell membranes of the glia and neurons that
      produce an alteration of the ionic gradient, an increase in extracellular potassium
      concentrations, glutamate release, and a transient increase followed by a decrease in
      cerebral blood flow.

      The pain phase in migraine is due to the activation and sensitization of the
      trigeminovascular pain pathway, which innervates intracranial structures, including the eye,
      the dura mater, large braincases, and the venous sinuses. It has been shown to involve
      neuronal presynaptic activation by ID serotonin receptors (5-HT 1D), resulting in the release
      of the calcitonin gene (CGRP) and pituitary adenylate cyclase-activating polypeptide
      (PACAP-38), which are neuroinflammatory peptides. The post-synaptic effect on the meninges
      includes the activation of the arachidonic acid cascade, which conditions inflammation and
      vasodilation, stimulates the nociceptive afference of pain first branch of the trigeminal
      nerve.

      The diagnosis of migraine is clinical and must meet the criteria of the IHS International
      Classification of Headaches (ICH-3), which are for migraine without aura:

      At least five crises that meet criteria B-D. A. Headache episodes are lasting 4 to 72 hours
      (untreated or unsuccessfully treated).

      B. The headache has at least two of the following four characteristics:

        1. Unilateral location.

        2. Pulsatile character.

        3. Pain of moderate or severe intensity.

        4. Made worse by or conditions the abandonment of habitual physical activity (e.g., walking
           or climbing stairs).

      C. At least one of the following during the headache:

        1. Nausea and vomiting.

        2. Photophobia and phonophobia. D. No better explanation by another diagnosis of ICHD-III.

      The non-pharmacological treatment of migraine goes hand in hand with the pharmacological one;
      one is to avoid the triggers of the migraine attacks and carry out the lifestyle
      modifications. Pharmacological treatment is divided into acute (administered at the time of
      headache) and prophylactic (administered daily to reduce the chances of migraine episodes).

      The objective of prophylactic treatment is to reduce the frequency, duration, and severity of
      migraine attacks, improve the response to acute treatment, improve functionality, and reduce
      disability.

      The American Academy of Neurology recommends initiating prophylactic treatment in patients
      with migraine with one or more of the following characteristics9

        1. Recurrent migraine, which interferes with the patient's daily life and quality of life.

        2. Frequent headaches.

        3. That they have an inadequate response or contraindication to abortive treatment.

        4. Adverse events to abortion treatment.

        5. Uncommon migraine conditions: ophthalmoplegic migraine, basilar migraine, hemiplegic,
           prolonged aura, migraine infarction.

      The IHS defines the response to treatment as a decrease equal to or greater than 50% in the
      frequency of migraine attacks compared to the baseline situation.

      The American Academy of Neurology guideline for the prophylactic drug treatment of episodic
      migraine classifies divalproex sodium, valproate sodium (VPA), topiramate, metoprolol
      propranolol as level A (Drugs with established efficacy ).

      Valproic acid (2-propylpentaenoic acid) was first synthesized in 1882 as an analog of valeric
      acid, naturally found in valerian. Anyone of Valproic acid, sodium valproate, or a mixture of
      the two (sodium valproate) has a mechanism of action characterized by increasing or improving
      GABA neurotransmission, blocking voltage-gated sodium channels, and T-type calcium channels.
      In 2013, Cochrane conducted the review: Valproate for the prophylaxis of episodic migraine
      (Linda et al.), where they evaluated ten clinical trials. Two crossover clinical trials for
      sodium valproate demonstrated a significant reduction in headache frequency than placebo (MD
      -4.31 95% CI -8.32 to -0.30), which shows us in clinical terms an approximate reduction of
      four headaches for every 28 days. Jensen 199413 showed that sodium valproate is superior to
      placebo (OR 4.67; 95% CI 1.54 - 14.14), suggesting that patients are three times more likely
      to present a reduction equal to or greater than 50% in the frequency of headaches compared to
      placebo. The recommended dose for migraine headaches is 500-1000mg per day. The most common
      adverse effects are asthenia, fatigue, dizziness/vertigo, nausea, tremor, and weight gain.

      In recent years, interest has increased in glutamate receptor antagonists for migraine
      prophylaxis, such as memantine. Within the pathophysiology of migraine, glutamate is
      implicated in disseminated cortical depression, trigeminal-vascular activation. Other studies
      corroborate its role by reporting elevated glutamate levels in the cerebrospinal fluid in
      patients with chronic migraine in the ictal period and elevated serum levels in migraine
      patients. Besides, after experimental stimulation in the dura and the ventral-posteromedial
      thalamic nucleus structures, elevated levels of glutamate in the trigeminal-cervical complex
      have been evidenced. fifteen

      In 2008 Bigal and colleagues conducted the first open clinical trial, a pilot study to
      evaluate memantine's efficacy and safety as a prophylactic treatment in patients diagnosed
      with refractory migraine. A sample of 28 participants who had a baseline frequency of
      headache days of 21.8 days per month received memantine from 10mg to 20mg per day for three
      months. A decrease in the frequency of headache days was obtained to 16.1 (P <0.01).
      Therefore, the authors concluded that memantine as a prophylactic treatment is safe and
      effective in refractory migraines. In 2015, Noruzzadeh and colleagues conducted the first
      randomized, double-blind, placebo-controlled clinical trial to evaluate memantine's efficacy
      as a prophylactic treatment of migraine without aura With a sample of 52 participants, 25
      with memantine (10 mg/day) and 27 with placebo. The memantine group had a more significant
      reduction in the frequency of migraine attacks compared to placebo, which was a difference of
      2.3 attacks per month with a P <0.001.14
    

Intervention name(s): Valproate Sodium; Memantine
Intervention type(s): Drug; Drug
Intervention description(s): Comparison between two actives; Memantine
Other intervention name(s): Diwali; Ezagun
Intervention MeSH terms: Valproic Acid; Memantine
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: A double-blind study with two groups. One using VPA and the other one using memantine in subjects with a diagnosis of episodic migraine.
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: Episodic MIgraine; Memantine; Valproate; Efficacy; Security; MIDAS; Prophylaxis