Evaluation of the Potentiating Effect of tDCS on Opioid Analgesia of Pain Threshold in Humans

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the potential additive effect of tDCS compared to placebo-sham in opioid analgesia on pain thresholds in nociceptive experimental model in healthy volunteers .

Detailed Description
-----------------
Pain is a prevalent symptom in medicine and the role of various opioids is valuable in the treatment of moderate to severe pain. Several technologies of brain stimulation , including transcranial direct current stimulation ( tDCS) are emerging as therapeutic options for many pain conditions. The effect of tDCS was demonstrated in sensory perception , decreasing the threshold for acute pain in healthy volunteers and in various chronic pain conditions . There is evidence about the use of tDCS with the participation through many mechanisms in cortical modulation , including the regulation of neurotransmitters, including opioids. In the context of neurostimulation, opioidergic system and cortical pain modulation, emerge the hypothesis of a possible potentiating effect of tDCS on clinical application of opioid analgesia.

Official Title
-----------------
Evaluation of the Potentiating Effect of Transcranial Direct Current Stimulation (tDCS) on Opioid Analgesia of Pain Threshold in Humans

Conditions
-----------------
Acute Pain

Intervention / Treatment
-----------------
* Drug: Remifentanil
* Device: Active tDCS
* Device: Sham tDCS
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male Healthy Without medication Sign the informed consent Exclusion Criteria: Patients who did not understand the Portuguese Acute or chronic pain conditions Medical or psychiatric disorders History of sleep disorders (apnea, hypersomnia, somnambulism…) History of alcohol or substance abuse Neurological disorder Use of anti-inflammatory drugs, steroids and non-steroids, opioid and non-opioid analgesics, psychiatric medications, anticonvulsants, alpha and beta blockers Traumatic brain injury Neurosurgery Metallic implant in the brain

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remifentanil + Active tDCS<br>tDCS session: the procedure will initiate by placing an anode electrode on the primary motor cortex (contralateral to the dominant cortex) and the cathode electrode on the contralateral supra-orbital region. The current employed is 2mA of transcranial direct-current stimulation administered for 20 minutes. Remifentanil - 0,06mcg.kg.min - Infusion 10min before the tDCS session, during the tDCS session and after the tDCS session, until the end of pain tests. | Drug: Remifentanil<br>* Remifentanil (IV infusion): 0,06mcg.kg.min. The infusion starts 10min before tDCSThe infusion will be stopped in the event of: a decrease in respiratory rate below 7 breaths / min, a peripheral oxygen saturation below 85%, a lower heart rate of 40 beats per minute, a lower mean arterial pressure of 60 mmHg, sedation causing inadequate management switch stimuli tests and occurrence of vomiting.<br>Device: Active tDCS<br>* The stimulation will be administered with a pair of surface electrodes, sponge coated, soaked in saline. A battery-powered constant current stimulator will be used for this purpose (tDCS device). The stimulation is performed by placing the anodal electrode in the primary motor cortex (M1) and the cathodal one in the contralateral supraorbital area and it will use a 2 mA (milliampere) current.<br>* Other names: transcranial direct current stimulation;|
| Other: Placebo + Active tDCS<br>tDCS session: the procedure will initiate by placing an anode electrode on the primary motor cortex (contralateral to the dominant cortex) and the cathode electrode on the contralateral supra-orbital region. The current employed is 2mA of transcranial direct-current stimulation administered for 20 minutes. Placebo: Saline infusion - Infusion 10min before the tDCS session, during the tDCS session and after the tDCS session, until the end of pain tests. | Device: Active tDCS<br>* The stimulation will be administered with a pair of surface electrodes, sponge coated, soaked in saline. A battery-powered constant current stimulator will be used for this purpose (tDCS device). The stimulation is performed by placing the anodal electrode in the primary motor cortex (M1) and the cathodal one in the contralateral supraorbital area and it will use a 2 mA (milliampere) current.<br>* Other names: transcranial direct current stimulation;Drug: Placebo<br>* Saline infusion - Infusion 10min before the tDCS session, during the tDCS session and after the tDCS session, until the end of pain tests.<br>|
| Other: Remifentanil + Sham tDCS<br>Sham tDCS: consists in the same montage of the active tDCS, but the device is turned off 30 seconds after starting stimulation (without letting the patient notice it). The rest of the montage is kept identical to the active one during the 20 minutes session. Remifentanil - 0,06mcg.kg.min - Infusion 10min before the tDCS session, during the tDCS session and after the tDCS session, until the end of pain tests. | Drug: Remifentanil<br>* Remifentanil (IV infusion): 0,06mcg.kg.min. The infusion starts 10min before tDCSThe infusion will be stopped in the event of: a decrease in respiratory rate below 7 breaths / min, a peripheral oxygen saturation below 85%, a lower heart rate of 40 beats per minute, a lower mean arterial pressure of 60 mmHg, sedation causing inadequate management switch stimuli tests and occurrence of vomiting.<br>Device: Sham tDCS<br>* The sham tDCS consists in the same montage of the active tDCS, but the device is turned off 30 seconds after starting stimulation (without letting the patient notice it). The rest of the montage is kept identical to the active one during the 20 minutes session.<br>* Other names: Sham - transcranial direct current stimulation;|
| Other: Placebo + Sham tDCS<br>Sham tDCS: consists in the same montage of the active tDCS, but the device is turned off 30 seconds after starting stimulation (without letting the patient notice it). The rest of the montage is kept identical to the active one during the 20 minutes session. Placebo: Saline infusion - Infusion 10min before the tDCS session, during the tDCS session and after the tDCS session, until the end of pain tests. | Device: Sham tDCS<br>* The sham tDCS consists in the same montage of the active tDCS, but the device is turned off 30 seconds after starting stimulation (without letting the patient notice it). The rest of the montage is kept identical to the active one during the 20 minutes session.<br>* Other names: Sham - transcranial direct current stimulation;Drug: Placebo<br>* Saline infusion - Infusion 10min before the tDCS session, during the tDCS session and after the tDCS session, until the end of pain tests.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Thresholds of pain to the cold pressor test (CPT) |  | 20min | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum levels of BDNF |  | 20min | 
| Intensity of electrical brain activity in the bi-spectral index (BIS) |  | 60min | 
| Sedation level in the visual analogue scale (VAS) |  | 60min | 
| Temperature of tolerance to the thermal stimulus (TTTS) |  | 20min | 
| Conditioned pain modulation (CPM) | A nociceptive tonic conditioning stimulus - immersion of the non-dominant hand in cold water (0°C for 1 minute) - will be applied concomitant to the progressive thermal stimulus in the dominant forearm as applied in the QST pattern until it reaches the 6/10 pain temperature previously determined by the participant. | 20min | 
| Threshold of pain to the thermal stimulus (TT) |  | 20min | 
| Hemodynamic changes of brain using fNIRSNear-infrared spectroscopy (NIRS) | The vascular response will be assessed using functional near infrared spectroscopy (fNIRS). Emerging technique that allows the functional mapping of the brain, with a better understanding of the neuro-vascular coupling, the neurophysiological fluctuations and cerebral hemodynamics. | 60 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
tDCS, Opioid, Pain, Pain threshold