Transcranial Direct Current Stimulation for Treating Parkinson´s Disease-related Pain in OFF State

NCT06214377 | Completed

• 1 other identifier: ParkOFF-tDCS
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

Parkinson's Disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms. Pain is a significant symptom in PD, affecting a large percentage of patients and impacting their quality of life. The mechanisms of pain in PD involve complex changes in pain-modulating pathways, including dopaminergic and non-dopaminergic systems. To address the lack of pain management strategies, the investigators propose exploring non-pharmacological therapies like transcranial direct current stimulation (tDCS). tDCS is a safe and non-invasive technique that modulates neuronal activity. It has shown positive effects on pain processing in healthy individuals and chronic pain patients, but its potential for PD-associated pain remains largely unexplored. The primary motor cortex (M1) is a target for tDCS as it is believed to influence pain processing in other brain regions involved in sensory and emotional aspects. Initial studies suggest the benefits of tDCS in PD, including enhanced motor potentials and potential modulation of dopaminergic pathways. However, there are currently no published studies specifically investigating the effects of tDCS on PD-related pain, highlighting the need for further research. A proof-of-concept trial is proposed to examine the effects of a single tDCS session on M1 in PD patients during the OFF state (without medication) and after taking dopaminergic medication. The study aims to assess the pain-relieving effects of tDCS in PD and explore potential synergies between tDCS and dopaminergic medication. By better understanding the impact of tDCS on pain relief in PD, this research may offer insights into alternative non-pharmacological approaches for managing pain in PD.

Conditions

Parkinson Disease; Pain

Keywords

Parkinson Disease; Pain; tDCS; Off state; Motor fluctuations

Outcome Measures

Primary Outcomes (8)

• Change in Conditioned Pain Modulation

  Assesses the descending pain modulatory system. The Pain Pressure Threshold will be assessed in the middle ofthe distal phalanx of the thumb with ta handheld algometer, corresponding to the first test stimulus. Afterward, the patient will immerse the contrary hand up to the wrist into stirred ice-cold water (0-4º) maintaining it for 3 minutes, corresponding to the conditioning stimulus. If the pain is unbearable before the 3 minutes, the patient will be able to remove his/her hand. Immediately after removing the hand, a second Pain Pressure Threshold measure will be performed in the same place as the first one, corresponding to the second test stimulus. After 1-minute rest, a third Pain Pressure Threshold will be measured to assess the Conditioned Pain Modulation residual functioning.

  From baseline to immediately post tDCS

• Change in Conditioned Pain Modulation

  Assesses the descending pain modulatory system. The Pain Pressure Threshold will be assessed in the middle ofthe distal phalanx of the thumb with ta handheld algometer, corresponding to the first test stimulus. Afterward, the patient will immerse the contrary hand up to the wrist into stirred ice-cold water (0-4º) maintaining it for 3 minutes, corresponding to the conditioning stimulus. If the pain is unbearable before the 3 minutes, the patient will be able to remove his/her hand. Immediately after removing the hand, a second Pain Pressure Threshold measure will be performed in the same place as the first one, corresponding to the second test stimulus. After 1-minute rest, a third Pain Pressure Threshold will be measured to assess the Conditioned Pain Modulation residual functioning.

  From baseline to immediately post dopaminergic medication

• Changes in Pain Pressure Threshold

  Two Pain Pressure Thresholds will be measured by a handheld algometer, one over the most painful area (peripheric hyperalgesia) and the other one over the middle of the distal phalanx of the thumb (central hyperalgesia). The Pain Pressure Threshold will be applied with the algometer perpendicular to the skin increasing at a rate of 1 kg/s until the first sensation of pain. 3 measures with 30-seconds rest between pulses will be performed, taking the average as Pain. Pressure Threshold.

  From baseline to immediately post tDCS

• Changes in Pain Pressure Threshold

  Two Pain Pressure Thresholds will be measured by a handheld algometer, one over the most painful area (peripheric hyperalgesia) and the other one over the middle of the distal phalanx of the thumb (central hyperalgesia). The Pain Pressure Threshold will be applied with the algometer perpendicular to the skin increasing at a rate of 1 kg/s until the first sensation of pain. 3 measures with 30-seconds rest between pulses will be performed, taking the average as Pain. Pressure Threshold.

  From baseline to immediately post dopaminergic medication

• Changes in Visual Numeric Pain Rating Scale

  It will be used to measure pain intensity due to its high discriminatory power. The scale assesses pain intensity using numbers or words through various types of scales ranging from 0 to 10. Pain rating ranges from 0 (no pain), 1-3 (mild pain, mild discomfort or irritation, slight impairment in daily activities), 4-6 (moderate pain, significant impairment in daily activities), and 7-10 (severe pain, inability to perform daily activities).

  From baseline to immediately post tDCS

• Changes in Visual Numeric Pain Rating Scale

  It will be used to measure pain intensity due to its high discriminatory power. The scale assesses pain intensity using numbers or words through various types of scales ranging from 0 to 10. Pain rating ranges from 0 (no pain), 1-3 (mild pain, mild discomfort or irritation, slight impairment in daily activities), 4-6 (moderate pain, significant impairment in daily activities), and 7-10 (severe pain, inability to perform daily activities).

  From baseline to immediately post dopaminergic medication

• Changes in Global Rating of Change

  It will be used to measure the self-perceived change in the patient's pain state. Its main objective is to quantify the extent to which a patient has improved or worsened over a specific period of time. It involves a single question asked to the patient to rate their change compared to the pre-intervention state, and the scores will range from -7 (much worse than before), through 0 (same as before), to +7 (much better than before).

  From baseline to immediately post tDCS

• Changes in Global Rating of Change

  It will be used to measure the self-perceived change in the patient's pain state. Its main objective is to quantify the extent to which a patient has improved or worsened over a specific period of time. It involves a single question asked to the patient to rate their change compared to the pre-intervention state, and the scores will range from -7 (much worse than before), through 0 (same as before), to +7 (much better than before).

  From baseline to immediately post dopaminergic medication

Secondary Outcomes (4)

• Changes in Brain Symmetry Index in electroencephalography

  From baseline to immediately post tDCS

• Changes in Brain Symmetry Index in electroencephalography

  From baseline to immediately post dopaminergic medication

• Changes in Unified Parkinson´s Disease Rating Scale

  From baseline to immediately post dopaminergic medication

• Changes in Finger tapping task

  From baseline to immediately post dopaminergic medication

Other Outcomes (7)

• King´s Parkinson´s Disease Pain Scale score

  Baseline

• Brief Pain Inventory score

  Baseline

• Beck´s Depression Inventory

  Baseline

Study Arms (2)

Active Transcranial Direct Current Stimulation and dopaminergic medication

EXPERIMENTAL

Active Transcranial Direct Current Stimulation (atDCS) will be applied over the Primary Motor Cortex (M1) contralateral to pain if it is unilateral, or always on the left M1 if pain is bilateral. It will consist of 1 session of 20 minutes of conventional stimulation (anode over M1) at 2 mA. It will be applied in the OFF state (i.e., \>12h after the last medication intake). Lately, patients will take its usual dopaminergic medication.

Device: Active Transcranial Direct Current Stimulation; Device: Sham Transcranial Direct Current Stimulation; Drug: Dopaminergic medication

: Sham Transcranial Direct Current Stimulation and dopaminergic medication

SHAM COMPARATOR

Sham Transcranial Direct Current (s-tDCS) will be applied over the Primary Motor Cortex with the same procedure, during 1 session of 20 minutes of conventional stimulation. It will be applied in the OFF state (i.e., \>12h after the last medication intake). Lately, patients will take its usual dopaminergic medication.

Device: Active Transcranial Direct Current Stimulation; Device: Sham Transcranial Direct Current Stimulation; Drug: Dopaminergic medication

Interventions

Active Transcranial Direct Current Stimulation DEVICE

The Starstim tCS® equipment will be used, with 35 cm2 sponge electrodes. The tDCS over M1 will be performed by placing the active anode on the C3 point (10/20 EEG system) and the cathode on the contralateral supraorbital area (Fp2). Regarding the stimulated hemisphere, in cases of asymmetric pain, it will be applied to the contralateral M1, and in cases of bilateral pain, it will be applied to the M1 of the dominant hemisphere. A constant current of 2 mA (subthreshold intensity) will be applied for 20 minutes, with the first 30 seconds used as a ramp-up and the last 30 seconds as a ramp-down. Number of sessions: 1.

: Sham Transcranial Direct Current Stimulation and dopaminergic medication; Active Transcranial Direct Current Stimulation and dopaminergic medication

Sham Transcranial Direct Current Stimulation DEVICE

The Starstim tCS® equipment (Neuroelectrics Inc, Barcelona, Spain) will be used with 35 cm2 sponge electrodes. The tDCS sham over M1 will be performed by placing the electrodes in the same position as in the active tDCS protocol. However, the stimulator will automatically turn off after 30 seconds of stimulation, making it a reliable sham stimulation method. Therefore, subjects will feel the same tingling sensation but will not receive current for the remainder of the stimulation time.

: Sham Transcranial Direct Current Stimulation and dopaminergic medication; Active Transcranial Direct Current Stimulation and dopaminergic medication

Dopaminergic medication DRUG

After tDCS, the participant will take their regular dopaminergic medication in order to go from OFF state to ON state.

: Sham Transcranial Direct Current Stimulation and dopaminergic medication; Active Transcranial Direct Current Stimulation and dopaminergic medication

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of Idiopathic Parkinson´s Disease.
• Presence of Parkinson´s Disease-related pain in the off-state.
• Neuroimaging study without previous pathologies.
• Score \> 5 in transfers (bed to chair and back) item in Barthel Index.
• Score = or \> 26 in Montreal Cognitive Assessment (MoCA).
• Tolerability for the application of electrotherapy.
• Able to provide informed consent to participate in the study
• Pain intensity \>= 3 in Visual Analogue Scale or equivalent.

You may not qualify if:

• Neurologic disease different from PD.
• Pain non-related to PD.
• Dermatologic problems, wounds, or ulcers in the electrode's application area.
• Presence of implants or metal pieces in the head.
• Presence of cardiac pacemaker, vagal, brain or transcutaneous stimulators, medication pumps, ventriculoperitoneal shunts or aneurysm clips.
• Significative difficulties in language.
• History of alcohol or drugs abuse.
• Non-controlled medical problems.
• Pregnancy.
• Epilepsy

Sponsors & Collaborators

• Universidad Francisco de Vitoria: lead
• Universidad Rey Juan Carlos: collaborator
• Hospital Beata María Ana: collaborator

Study Sites (1)

Hospital Beata Maria Ana

Madrid, 28007, Spain

Location

Related Publications (11)

• Kalia LV, Lang AE. Parkinson's disease. Lancet. 2015 Aug 29;386(9996):896-912. doi: 10.1016/S0140-6736(14)61393-3. Epub 2015 Apr 19.

  PMID: 25904081 RESULT

• Silverdale MA, Kobylecki C, Kass-Iliyya L, Martinez-Martin P, Lawton M, Cotterill S, Chaudhuri KR, Morris H, Baig F, Williams N, Hubbard L, Hu MT, Grosset DG; UK Parkinson's Pain Study Collaboration. A detailed clinical study of pain in 1957 participants with early/moderate Parkinson's disease. Parkinsonism Relat Disord. 2018 Nov;56:27-32. doi: 10.1016/j.parkreldis.2018.06.001. Epub 2018 Jun 6.

  PMID: 29903584 RESULT

• Antonini A, Tinazzi M, Abbruzzese G, Berardelli A, Chaudhuri KR, Defazio G, Ferreira J, Martinez-Martin P, Trenkwalder C, Rascol O. Pain in Parkinson's disease: facts and uncertainties. Eur J Neurol. 2018 Jul;25(7):917-e69. doi: 10.1111/ene.13624. Epub 2018 Apr 18.

  PMID: 29520899 RESULT

• Lefaucheur JP, Antal A, Ayache SS, Benninger DH, Brunelin J, Cogiamanian F, Cotelli M, De Ridder D, Ferrucci R, Langguth B, Marangolo P, Mylius V, Nitsche MA, Padberg F, Palm U, Poulet E, Priori A, Rossi S, Schecklmann M, Vanneste S, Ziemann U, Garcia-Larrea L, Paulus W. Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS). Clin Neurophysiol. 2017 Jan;128(1):56-92. doi: 10.1016/j.clinph.2016.10.087. Epub 2016 Oct 29.

  PMID: 27866120 RESULT

• Fregni F, Boggio PS, Santos MC, Lima M, Vieira AL, Rigonatti SP, Silva MT, Barbosa ER, Nitsche MA, Pascual-Leone A. Noninvasive cortical stimulation with transcranial direct current stimulation in Parkinson's disease. Mov Disord. 2006 Oct;21(10):1693-702. doi: 10.1002/mds.21012.

  PMID: 16817194 RESULT

• Fregni F, Boggio PS, Lima MC, Ferreira MJ, Wagner T, Rigonatti SP, Castro AW, Souza DR, Riberto M, Freedman SD, Nitsche MA, Pascual-Leone A. A sham-controlled, phase II trial of transcranial direct current stimulation for the treatment of central pain in traumatic spinal cord injury. Pain. 2006 May;122(1-2):197-209. doi: 10.1016/j.pain.2006.02.023. Epub 2006 Mar 27.

  PMID: 16564618 RESULT

• Chaudhuri KR, Rizos A, Trenkwalder C, Rascol O, Pal S, Martino D, Carroll C, Paviour D, Falup-Pecurariu C, Kessel B, Silverdale M, Todorova A, Sauerbier A, Odin P, Antonini A, Martinez-Martin P; EUROPAR and the IPMDS Non Motor PD Study Group. King's Parkinson's disease pain scale, the first scale for pain in PD: An international validation. Mov Disord. 2015 Oct;30(12):1623-31. doi: 10.1002/mds.26270. Epub 2015 Jun 11.

  PMID: 26096067 RESULT

• Perez-Lloret S, Ciampi de Andrade D, Lyons KE, Rodriguez-Blazquez C, Chaudhuri KR, Deuschl G, Cruccu G, Sampaio C, Goetz CG, Schrag A, Martinez-Martin P, Stebbins G; Members of the MDS Committee on Rating Scales Development. Rating Scales for Pain in Parkinson's Disease: Critique and Recommendations. Mov Disord Clin Pract. 2016 Jun 24;3(6):527-537. doi: 10.1002/mdc3.12384. eCollection 2016 Nov-Dec.

  PMID: 30363588 RESULT

• Imai Y, Petersen KK, Morch CD, Arendt Nielsen L. Comparing test-retest reliability and magnitude of conditioned pain modulation using different combinations of test and conditioning stimuli. Somatosens Mot Res. 2016 Sep-Dec;33(3-4):169-177. doi: 10.1080/08990220.2016.1229178. Epub 2016 Sep 20.

  PMID: 27650216 RESULT

• Santos-Garcia D, Oreiro M, Perez P, Fanjul G, Paz Gonzalez JM, Feal Painceiras MJ, Cores Bartolome C, Valdes Aymerich L, Garcia Sancho C, Castellanos Rodrigo MDM. Impact of Coronavirus Disease 2019 Pandemic on Parkinson's Disease: A Cross-Sectional Survey of 568 Spanish Patients. Mov Disord. 2020 Oct;35(10):1712-1716. doi: 10.1002/mds.28261. Epub 2020 Sep 22.

  PMID: 32776601 RESULT

• Gonzalez-Zamorano Y, Moreno-Verdu M, Martinez-Benito A, Fernandez-Carnero J, Romero JP. Transcranial Direct Current Stimulation in Parkinson's Disease Patients in the Off State: A Randomized Controlled Crossover Trial Examining the Effects on Pain With and Without the Influence of Dopaminergic Medication. Pain Pract. 2025 Nov;25(8):e70082. doi: 10.1111/papr.70082.

  PMID: 41039704 DERIVED

MeSH Terms

Conditions

Parkinson Disease; Pain

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Juan Pablo Romero, MD, PhD

  Universidad Francisco de Vitoria, Facultad de Ciencias Experimentales

  PRINCIPAL INVESTIGATOR

• Josué Fernández Carnero, PT, PhD

  Universidad Rey Juan Carlos

  PRINCIPAL INVESTIGATOR

• Marcos Moreno Verdú, PT, PhD

  Universidad Francisco de Vitoria

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Triple-blind criteria will be achieved by identic collocation of the electrodes in both conditions and by activating the "double-blind" option in the Starstim tDCS® Software (Neuroelectrics Inc, Barcelona, Spain) that allows concealing the protocol by writing a neutral number. The evaluator, not allowed to stay in the same room while the interventions, will conceal the protocols with the neutral number and the therapist will read it in the envelope, ignoring which number coincides with each intervention. At the end of the second session, patients will be asked whether they received the order 1.active-2.sham or 1.sham-2.active, to assess the blinding success. The statistician will also be blinded through the mentioned neutral numbers. Unblinding will be permissible when any event could suppose a risk to the patient's health.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This study will be a triple-blinded experimental randomized controlled trial with a crossover design. The randomization will be conducted through the "GraphPad" software by an independent investigator. All the participants who fulfill the inclusion criteria and have none of the exclusion ones will be randomly allocated into two groups (depending on the order of the intervention allocation): 1.active-tDCS-2.shamtDCS or 1.sham-tDCS-2.active-tDCS. Allocation concealment will be ensured by the inclusion of the assigned group in closed opaque envelopes that will be opened at the time of the first intervention.

Study Record Dates

• First Submitted: November 29, 2023
• First Posted: January 19, 2024
• Study Start: July 1, 2023
• Primary Completion: March 15, 2024
• Study Completion: April 11, 2024
• Last Updated: May 8, 2024

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Four months at the end of the study
• Access Criteria: Individual anonymized participant data will be available to other researchers under request.

Locations

ES (1)