Clinical trial NCT02639533: Brain Response to Single Dose of Pregabalin in Fibromyalgia
Official title: Pregabalin Acute Effects on Cortical Excitability, Psychophysical Parameters, and Serum Markers of Neuroplastic Processes in Fibromyalgia: a Placebo Controlled, Double Blinded, Randomized, Crossover Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Fibromyalgia
Keywords: fibromyalgia
pregabalin
cortical excitability
functional near infrared spectroscopy
Lead sponsor: Hospital de Clinicas de Porto Alegre
Sponsor class: OTHER
Collaborators: name: Conselho Nacional de Desenvolvimento Científico e Tecnológico
name: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior.
name: Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul, Brazil
First posted: 2015-12-24
Enrollment: 27
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief 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.

Eligibility criteria: Inclusion Criteria:

* Fulfill ACR 2010 criteria for fibromyalgia diagnosis.
* Literate.
* Mean VAS for pain higher than 6 in the last 3 months.

Exclusion Criteria:

* Pregnancy or inadequate use of validated contraceptive method.
* Contraindications for Transcranial Magnetic Stimulation.
* Alcohol of drugs abuse in the last 6 months.
* Any severe neurological, neurosurgical, cardiac, endocrinological, or oncological disease (current or past).
* Decompensated chronic systemic disease.
* Previous use of Pregabalin.

Primary outcomes:
measure: Cortical Excitability: Intracortical Inhibition.
timeFrame: 1 hour after intervention
measure: Cortical hemodynamics: Oxy-hemoglobin concentration (mM/L)
timeFrame: 1 hour after intervention
Secondary outcomes:
measure: Pain
timeFrame: 1 hour after intervention
measure: Heat Pain Threshold
timeFrame: 1 hour after intervention
measure: Pressure Pain Threshold
timeFrame: 1 hour after intervention
measure: Maximal Heat Pain Tolerance
timeFrame: 1 hour after intervention
measure: Conditioned pain modulation
timeFrame: 1 hour after intervention
measure: Serum Brain Derived Neurotrophic Factor (BDNF)
timeFrame: Baseline and 2 hours after intervention
measure: Serum Protein S100B
timeFrame: Baseline and 2 hours after intervention
Other outcomes:
Locations:
Study officials:
affiliation: HCPA
name: Wolnei Caumo, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Deitos A, Soldatelli MD, Dussan-Sarria JA, Souza A, da Silva Torres IL, Fregni F, Caumo W. Novel Insights of Effects of Pregabalin on Neural Mechanisms of Intracortical Disinhibition in Physiopathology of Fibromyalgia: An Explanatory, Randomized, Double-Blind Crossover Study. Front Hum Neurosci. 2018 Nov 19;12:406. doi: 10.3389/fnhum.2018.00406. eCollection 2018.