Brain Response to Single Dose of Pregabalin in Fibromyalgia
Condition: Fibromyalgia
MeSH terms: Fibromyalgia; Myofascial Pain Syndromes
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Fibromyalgia syndrome represents a "spectrum disorder" characterized by widespread chronic
      pain, fatigue, sleep disturbances, mood and cognitive alterations. The most accepted models
      explaining the causes of the disease have focused on the reduced pain inhibitory systems
      activity, that allow low intensity stimuli to be processed easier, and that finally amplify
      pain stimuli. One of the interventions approved for Fibromyalgia is Pregabalin, which
      demonstrated to be effective reducing pain. Different studies in animals have shown that it
      works reducing the liberation of neuronal messengers, which slow the conduction of pain
      signals. Although studies in humans have confirmed Pregabalin clinical benefits, there are
      still few studies aiming to explain how it actually works in patients with fibromyalgia,
      though.

      A better understanding of the mechanisms by which Pregabalin reduces pain in patients with
      fibromyalgia would allow designing new interventions to enhance its clinical effects. Thus,
      the investigators propose to study in real-time the electrical, vascular and hormonal
      response of the brain of patients with fibromyalgia who receive a single dose of Pregabalin.
      The vascular response will be assessed using functional near infrared spectroscopy (fNIRS)
      neuroimaging techniques. The electrical response will be assessed using Transcranial Magnetic
      Stimulation (TMS). The hormonal response will be assessed in blood, measuring neurotrophins
      (Brain Derived Neurotrophic Factor) and inflammatory mediators (Tumor Necrosis Factor). These
      responses will be studied in consideration of the patients' characteristics that will be
      assessed using validated scales.

      Taken into account the above considerations, a crossover, double-blinded randomized clinical
      trial is proposed. In the investigators' study, patients and healthy volunteers will be asked
      to visit the investigators' laboratory in three opportunities: one for a baseline assessment,
      and the other two to test the effects of either Pregabalin 150 mg PO or Placebo. All
      participants will eventually receive both, Pregabalin and Placebo. In each visit a brain
      hemodynamic, electrical, hormonal and clinical evaluation will be performed.
    

Detailed description: 
      A crossover, double-blinded randomized clinical trial is proposed. The investigators will
      recruit literate adult females aging 18 to 65 years old; fulfilling the diagnosis criteria
      for fibromyalgia according to the American College of Rheumatology 2010; with mean pain ≥6 in
      the verbal analog scale; who speak Brazilian Portuguese; and were able to perform the three
      visits. Female adult participants without chronic pain will also be recruited. Participants
      with severe psychiatric disorders that would limit consenting; neurologic deficits;
      decompensated systemic disease or chronic inflammatory disorders (Systemic Erythematous Lupus
      or Rheumatoid arthritis); contraindications for TMS; and those with previous use of
      Pregabalin will be excluded.

      In the investigators' study, participants will be asked to visit the investigators'
      laboratory in three opportunities: one for a baseline assessment, and the other two to test
      the effects of either Pregabalin 150 mg PO or Placebo. All participants will eventually
      receive both, Pregabalin and Placebo. In each visit a brain hemodynamic, electrical, hormonal
      and clinical evaluation will be performed.

      In the first visit, after explaining the research, solving doubts and signing the informed
      consent, participants will be randomized to an allocation sequence (either Pregabalin in the
      second or in the third visit). Then, a blood sample will be gathered and participants will be
      asked to fill some questionnaires to understand better their pain, and its impact on their
      quality of life (Fibromyalgia Impact Questionnaire), Anxiety (State/Trait Anxiety Inventory),
      Depressive symptoms (Beck Depression Inventory II), Catastrophizing thinking (Pain
      Catastrophizing Scale - PCS), Sleep (Pittsburgh Sleep Quality Index), and resiliency. Then, a
      fingertapping task will be performed while assessing hemodynamic changes using fNIRS. After
      that, heat perception will be tested using quantitative sensory testing (QST) and Conditioned
      Pain Modulation (CPM) with cold. Also, the pain pressure threshold (PPT) using a digital
      algometer will be evaluated. Finally, cortical excitability parameters (motor evoked
      potentials, intracortical facilitation and inhibition, and cortical silent period) will be
      determined using paired pulsed TMS.

      In the second visit, according to the randomized allocation participants will receive either
      Pregabalin 150 mg PO or Placebo. Then, the M.I.N.I. International Neuropsychiatric Interview
      will be performed. One hour after taking the medication, the fNIRS, QST, CPM, PPT and TMS
      evaluations will be repeated, and a new blood sample will be collected. In the third visit, a
      blood sample will be gathered, followed by administration of the corresponding intervention
      according to the randomized allocation. Then, the pain level, PCS, STAI and International
      Physical Activity Questionnaire (IPAQ) will be asked again. One hour after taking the
      medication, the fNIRS, QST, CPM, PPT and TMS evaluations will be repeated, and a final blood
      sample will be collected. Participants' guess about blinding will be assessed after each
      intervention. All evaluators will remain blind to the allocation.
    

Intervention name(s): Pregabalin; Placebo
Intervention type(s): Drug; Other
Intervention description(s): Pregabalin 150 mg PO, single dose.; Pill of same physical characteristics as the one used for the intervention, containing starch only. Administered PO in single dose.
Intervention MeSH terms: Pregabalin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: fibromyalgia; pregabalin; cortical excitability; functional near infrared spectroscopy