Non-Invasive Brain Stimulation for the Treatment of Parkinson´s Disease-related Pain

NCT04651699 | Completed

• 1 other identifier: PainPD-tDCS
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

Pain is an under-reported but prevalent symptom in Parkinson´s Disease (PD), impacting patients' quality of life. Both pain and PD conditions cause cortical excitability reduction, but non-invasive brain stimulation is thought to be able to counteract it, resulting also effective in chronic pain conditions. The investigators in the present project aim to evaluate the efficacy of a novel brain stimulation protocol in the management of pain in PD patients during the ON state. The investigators hypothesize that active transcranial direct current stimulation (a-tDCS) over the Primary Motor Cortex (M1) can improve clinical pain and its central processing features.

Conditions

Parkinson Disease; Pain

Keywords

Parkinson Disease; Pain; tDCS

Outcome Measures

Primary Outcomes (10)

• Change in King´s Parkinson´s Disease Pain Scale score

  Parkinson´s Disease specific scale that evaluates the localization, frequency, and intensity of pain. It has 14 items distributed in 7 domains: 1. Musculoskeletal Pain; 2. Chronic Pain; 3. Fluctuation-related Pain; 4. Nocturnal Pain; 5. Oro-facial Pain; 6. Discoloration, Oedema/Swelling Pain; 7. Radicular Pain. Each item is scored by severity (0, none to 3, very severe) multiplied by frequency (0, never to 4, all the time) resulting in a subscore of 0 to 12, the sum of which gives the total score with a theoretical range from 0 to 168, with higher scores indicating more severity and frequency of pain.

  From Baseline at 2 weeks

• Change in King´s Parkinson´s Disease Pain Scale score

  Parkinson´s Disease specific scale that evaluates the localization, frequency, and intensity of pain. It has 14 items distributed in 7 domains: 1. Musculoskeletal Pain; 2. Chronic Pain; 3. Fluctuation-related Pain; 4. Nocturnal Pain; 5. Oro-facial Pain; 6. Discoloration, Oedema/Swelling Pain; 7. Radicular Pain. Each item is scored by severity (0, none to 3, very severe) multiplied by frequency (0, never to 4, all the time) resulting in a subscore of 0 to 12, the sum of which gives the total score with a theoretical range from 0 to 168, with higher scores indicating more severity and frequency of pain.

  From Baseline at 1 month

• Change in Brief Pain Inventory score

  It contains 15 items, including 2 multi-item scales to measure the intensity of pain and its impact on the function and welfare of patients. It also presents open questions to assess the localization of pain and the treatment used for its management, just as its effectiveness. Scores oscillate from 0 to 110, with higher scores indicating more pain and more impact on function and welfare of patients.

  From Baseline at 2 weeks

• Change in Brief Pain Inventory score

  It contains 15 items, including 2 multi-item scales to measure the intensity of pain and its impact on the function and welfare of patients. It also presents open questions to assess the localization of pain and the treatment used for its management, just as its effectiveness. Scores oscillate from 0 to 110, with higher scores indicating more pain and more impact on function and welfare of patients.

  From Baseline at 1 month

• Change in Conditioned Pain Modulation

  Assesses the descending pain modulatory system. The Pain Pressure Threshold will be assessed in the middle of the 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 at 2 weeks

• Change in Conditioned Pain Modulation

  Assesses the descending pain modulatory system. The Pain Pressure Threshold will be assessed in the middle of the 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 at 1 month

• Change in Temporal Summation

  Represents excitatory modulation processes. It will be generated through the application of 10 pulses of the handheld pressure algometer over the middle of the distal phalanx of the thumb with the intensity of the Pain Pressure Threshold, previously calculated. In each pulse, pressure intensity will be increasing at a rate of 2 kg/s over the previously determined Pain Pressure Threshold intensity, leaving an interstimulus interval of one second according to the optimal method reported for inducing Temporal Summation with pressure pain. Before the first pressure pulse, subjects were taught to use a verbal numeric pain rating scale to rate the pain intensity of the first, fifth, and 10th pressure pulses. The verbal numeric pain rating scale ranged from 0 ("no pain") to 10 ("the worst possible pain").

  From Baseline at 2 weeks

• Change in Temporal Summation

  Represents excitatory modulation processes. It will be generated through the application of 10 pulses of the handheld pressure algometer over the middle of the distal phalanx of the thumb with the intensity of the Pain Pressure Threshold, previously calculated. In each pulse, pressure intensity will be increasing at a rate of 2 kg/s over the previously determined Pain Pressure Threshold intensity, leaving an interstimulus interval of one second according to the optimal method reported for inducing Temporal Summation with pressure pain. Before the first pressure pulse, subjects were taught to use a verbal numeric pain rating scale to rate the pain intensity of the first, fifth, and 10th pressure pulses. The verbal numeric pain rating scale ranged from 0 ("no pain") to 10 ("the worst possible pain").

  From Baseline at 1 month

• 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 them will be performed, taking the average as Pain Pressure Threshold.

  From Baseline at 2 weeks

• 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 them will be performed, taking the average as Pain Pressure Threshold.

  From Baseline at 1 month

Secondary Outcomes (21)

• Beck Depression Inventory

  Baseline

• Beck Depression Inventory

  At 2 weeks from Baseline

• Beck Depression Inventory

  At 1 month from Baseline

• State-Trait Anxiety Inventory

  Baseline

• State-Trait Anxiety Inventory

  At 2 weeks from Baseline

Study Arms (2)

Active Transcranial Direct Current Stimulation

EXPERIMENTAL

Active Transcranial Direct Current Stimulation (a-tDCS) will be applied over the Primary Motor Cortex during 10 sessions of 20 minutes at 2 milli amps.

Device: Active Transcranial Direct Current Stimulation

Sham Transcranial Direct Current Stimulation

SHAM COMPARATOR

Sham Transcranial Direct Current (s-tDCS) will be applied over the Primary Motor Cortex during 10 sessions of 20 minutes.

Device: Sham Transcranial Direct Current Stimulation

Interventions

Active Transcranial Direct Current Stimulation DEVICE

The Starstim tDCS® stimulator will be used by an experienced physical therapist to transfer direct current by a saline-soak pair of surface sponge electrodes (35cm2). The anode electrode will be placed over C3 (EEG 10/20 system) and the cathode electrode over the contralateral supraorbital area (Fp2), in order to enhance the excitability of M1 (32). Regarding the stimulated hemisphere, contralateral M1 will be stimulated in patients with asymmetric pain and the dominant (contrary to the dominant hand determined by the Edinburgh Handedness Inventory) in patients with symmetric pain, due to the widespread changes induced by tDCS in other cortical areas, including contralateral M1. A constant current of 2 milli amps intensity (subthreshold intensity) will be applied for 20 min, with 30 seconds of ramp-up and 30 seconds of ramp-down.

Active Transcranial Direct Current Stimulation

Sham Transcranial Direct Current Stimulation DEVICE

The electrodes will be placed in the same positions as for M1 stimulation, but only applying ramping active current for 30 seconds in the beginning and at the end of the procedure for a reliable blinding.

Sham Transcranial Direct Current Stimulation

Eligibility Criteria

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

You may qualify if:

• Neuroimaging study without previous pathologies.
• Score \> 5 in transfers (bed to chair and back) item in Barthel Index.
• Score = or \> 24 in Mini-Mental State Examination.
• Tolerability for the application of electrotherapy.
• Able to provide informed consent to participate in the study.

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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• Gonzalez-Zamorano Y, Jose Sanchez-Cuesta F, Moreno-Verdu M, Arroyo-Ferrer A, Fernandez-Carnero J, Chaudhuri KR, Fieldwalker A, Romero JP. TDCS for parkinson's disease disease-related pain: A randomized trial. Clin Neurophysiol. 2024 May;161:133-146. doi: 10.1016/j.clinph.2024.01.011. Epub 2024 Feb 28.

  PMID: 38479239 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 Muñoz, MD PhD

  Universidad Francisco de Vitoria, Facultad de Ciencias Experimentales

  PRINCIPAL INVESTIGATOR

• Josué Fernandez Carnero, PT PhD

  Universidad Rey Juan Carlos

  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 groups 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 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 full treatment, patients will be asked whether they received active or sham stimulation, to assess the blinding success. Patients recruited will not meet in waiting rooms to avoid them to comment on their experience during the protocol. The statistician will be also blinded through the mentioned neutral numbers. Unblinding will be permissible when any event could suppose a risk for the patient's health.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This study will be a triple-blinded experimental longitudinal prospective randomized controlled trial with a parallel design. The randomization will be realized 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: active-tDCS (a-tDCS) or sham-tDCS (s-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 intervention.

Study Record Dates

• First Submitted: November 19, 2020
• First Posted: December 3, 2020
• Study Start: May 3, 2021
• Primary Completion: June 30, 2022
• Study Completion: January 23, 2023
• Last Updated: January 26, 2023

Record last verified: 2021-03

Data Sharing

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

Locations

ES (1)