Pain represents one of the most common symptoms of Multiple Sclerosis (MS) that can seriously affect patient health-related quality of life.

Central neuropathic pain, the main form of pain in MS patients, represents a significant clinical problem, in consideration of its poorly responsiveness to available therapies.

Direct Current Stimulation (tDCS) is a non-invasive, well-tolerated procedure with an high and well documented neuromodulation activity at Central Nervous System (CNS) level. First evidences obtained by animal, neurophysiological and clinical studies suggested its potential efficacy in neuropathic pain treatment.

In particular spinal DCS (sDCS) has been proven to modulate Nociceptive Withdrawal Reflex (NWR), an objective and sensitive tool to explore pain processing at the Spinal Level and recommended by European Federation of Neurological Society (EFNS) to evaluate the analgesic effect of treatments. In this order of view the investigators' objective is to investigate sDCS efficacy in MS neurophatic pain treatment applying validated clinical scales, neurophysiological acquisitions and specific biological marker dosages.

The investigators plan to recruit, at the IRCCS Neurological National Institute C. Mondino, 60 consecutive patients with definite Multiple Sclerosis (MS) according to 2005 McDonald criteria in a follow-up procedure that includes a general and neurological evaluation scored according to the Expanded Disability Status Scale of Kurtzke and its functional systems.

Relapsing-remitting (RR), secondary-progressive (SP) and primary-progressive (PP) MS patients, affecting by neuropathic or nociceptive chronic pain conditions in accord to 1994 International Association for the Study of Pain (IASP)classification, will be recruited. Patients complaining any form of headache will be excluded by the study. The investigators will excluded also patients with cognitive impairment (Minimental State Examination - MMSE- <= 21) and psychiatry diseases, in particular depression (Back Depression Inventory Scale - BDI - >15).

Characteristic and intensity of pain symptoms will be collected respectively with validated Italian version of Neuropathic Pain Symptoms Inventory Scale (NPSI) and Numerical Rating Scale (NRS). Spasticity of lower legs, if present, will be clinical assessed with Ashworth Scale and Neurophysiologically evaluated with H/M ratio and Vibratory Inhibition of H-Reflex.

Health-Related Quality of Life (HRQoL) will be assessed by means of the Medical Outcome 36-item Short Form Health Survey (SF-36) whereas the presence and severity of fatigue will be assessed by means of the Fatigue Severity Scale (FSS).

RR patients will be evaluated in stationary phase of the disease that is at least two months after the last clinical relapse and at least one month after the end of a steroidal treatment.

Patients will be consecutive enrolled in the study and randomly assigned to two group: 1. Sham and 2. Anodal Spinal Direct Current Stimulation Treatment, in a double-blind, placebo controlled study design.

Before enrollment, the study protocol will be explained to each subject, and informed written consent will be obtained.

The investigators will proceed as follow:

1. Time of enrollment - T0 First Day

   • Complete clinical evaluation with administration of MMSE and BDI for exclusion criteria
   • Randomized assignment to Anodal or Sham treatment group
   • Administration of NPSI, SF-36, HRQoL e FSS
   • Evaluation of Somatosensory Evoked Potential by Posterior Tibial and Medial Nerve stimulation to investigate the somatosensory pathway involvement.
   • Clinical and Neurophysiological evaluation of Spasticity (if present): Ashworth Scale and H/M ratio and HReflex Vibratory Inhibition.
   • Collection of blood sample to evaluate activity of Fatty Acid Amide Hydrolase (FAAH) in platelets.

   Second Day

   • First Anodal or Sham Direct Current Stimulation Treatment Session (sDCS)
   • Neurophysiological acquisition of Nociceptive Withdrawal Reflex (NWR) and NWR Temporal Summation (see 'Neurophysiological Acquisition' Session for details) before and after 30 and 60 minutes the first sDCS treatment

2. sDCS Treatment After evaluation at T0 patients will undergo 10 daily sDCS treatment, 5 days a week (see sDCS treatment session for details).

3. Evaluation after 10 days of treatment - T1

   • Administration of NPSI, SF-36, HRQoL e FESS
   • Clinical and Neurophysiological evaluation of Spasticity (if present): Ashworth Scale and H/M ratio and HReflex Vibratory Inhibition.
   • Collection of blood sample to evaluate activity of Fatty Acid Amide Hydrolase (FAAH) in platelets.
   • Neurophysiological acquisition of Nociceptive Withdrawal Reflex (NWR) and NWR Temporal Summation

4. Evaluation after 1 month from the end of treatment - T2

   • Administration of NPSI, SF-36, HRQoL e FESS
   • Clinical and Neurophysiological evaluation of Spasticity (if present): Ashworth Scale and H/M ratio and HReflex Vibratory Inhibition.
   • Collection of blood sample to evaluate activity of Fatty Acid Amide Hydrolase (FAAH) in platelets.
   • Neurophysiological acquisition of Nociceptive Withdrawal Reflex (NWR) and NWR Temporal Summation

Inclusion Criteria:

• Relapsing-remitting (RR), secondary-progressive (SP) and primary-progressive (PP) MS patients, affected by neuropathic or nociceptive chronic pain conditions in accordance to 1994 IASP (International Association for the Study of Pain) classification

Exclusion Criteria:

• Any form of headache
• Cognitive impairment (Minimental State Examination <= 21)
• Psychiatry diseases, in particular depression (Back Depression Inventory Scale >15)