Clinical trial NCT06214377: Transcranial Direct Current Stimulation for Treating Parkinson´s Disease-related Pain in OFF State
Official title: Effects of Transcranial Direct Current Stimulation (tDCS) on Pain Modulation in Individuals With Parkinson's Disease in the Off State
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Parkinson Disease
Pain
Keywords: Parkinson Disease
Pain
tDCS
Off state
Motor fluctuations
Lead sponsor: Universidad Francisco de Vitoria
Sponsor class: OTHER
Collaborators: name: Universidad Rey Juan Carlos
name: Hospital Beata María Ana
First posted: 2024-01-19
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: 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.
Primary purpose: TREATMENT

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.

Detailed description: Parkinson's Disease (PD) is a complex progressive neurodegenerative disorder. It is the second most common neurodegenerative disease, with a prevalence of 4.1 to 4.6 million people over the age of 50. It is estimated that these numbers will increase to 8.7 to 9.3 million by the year 2030.

PD is multisystemic and include both motor and non-motor symptoms. These symptoms can fluctuate throughout the day, leading PD patients to frequently experience two distinct states: the "on" state, when dopaminergic medication is active in their system, and the "off" state, which occurs when there is no medication concentration in the body, resulting in more severe symptoms.

Pain in PD is a highly relevant symptom that significantly impacts patients' quality of life, with a prevalence of up to 85% and moderate to severe intensity reported in 42% of individuals. Additionally, in Spain, the prevalence of PD-associated pain has significantly increased following the COVID-19 pandemic, with up to 50% of PD patients reporting daily pain. Moreover, pain in PD is often underreported, emphasizing the need to investigate its mechanisms and treatment.

The pathophysiological mechanisms of pain in PD are complex. In general, PD can lead to alterations in peripheral transmission, sensory-discriminative processing, pain perception, and interpretation at multiple levels, due to neurodegenerative changes in both dopaminergic and non-dopaminergic pain-modulating pathways. This dysregulation of the dopaminergic system can impact the experience of pain directly by enhancing nociceptive signals and indirectly by influencing expectations and the interpretation of such signals. However, it is considered that there is no specific pain center in PD patients but rather a pain matrix involving various brain structures.

Given the multiple central structures affected and their consequent pathophysiological mechanisms in PD-associated pain, there is a wide variety of clinical manifestations. These include musculoskeletal pain, generalized central chronic pain, visceral pain, pain related to "on-off" fluctuations, dystonic-dyskinetic pain, nocturnal immobility-related pain or restless legs syndrome, orofacial pain, inflammation or edema-related pain, and radicular pain.

Regarding the assessment of pain in PD, there is only one specific scale that evaluates all pain phenotypes of the disease in terms of intensity and frequency, namely the King's Parkinson's Disease Pain Scale (KPPS). Therefore, due to the scarcity of objective pain assessment tools and the crucial role of the central nervous system and endogenous modulation systems in the origin of PD-associated pain, it is important to assess pain processing characteristics such as Conditioned Pain Modulation (CPM), and Pressure Pain Thresholds (PPTs). CPM assesses the descending inhibitory pain system, and PPTs assess the intensity of pressure required to elicit initial pain in a specific body area.

Dopaminergic medication is the primary treatment for PD symptoms; however, its effects on pain management have shown contradictory results according to recent systematic reviews. Moreover, there is currently a lack of robust evidence to establish guidelines for pain management in PD, which is why non-pharmacological therapies have been proposed as a safe and useful alternative with fewer side effects.

Transcranial Direct Current Stimulation (tDCS) is a non-invasive form of brain stimulation in which a relatively weak continuous current is delivered to the cortical areas through small electrodes placed on the scalp. It is a neuromodulatory intervention, and based on the assumption that the exposed tissue is polarized, tDCS would modulate neuronal excitability by depolarizing or hyperpolarizing the resting membrane potential of neurons. This modulation would result in increases or decreases in cortical excitability, depending on whether the active electrode is the anode or the cathode, respectively.

tDCS has been shown to have an effect on certain psychophysical variables of pain processing in healthy subjects. It has primarily been shown to enhance CPM and improvements have been reported in PPTs, cold and heat pain thresholds, acute pain induced by laser (26), and pain threshold after peripheral electrical stimulation. Importantly, tDCS has also demonstrated beneficial effects in patients with chronic pain. Specifically, it has shown improvements in pain processing characteristics, resulting in clinical pain improvements in other populations with chronic neuropathic pain. It is hypothesized that tDCS could be an effective alternative in the treatment of pain with central sensitization components, a process common in PD-associated pain.

The majority of the hypoalgesic effects generated by tDCS are due to its modulation of the primary motor cortex (M1). It is suggested that tDCS over M1 could reduce pain by increasing excitability not only in the stimulated area but also in other structures involved in pain processing, both sensory and emotional, through cortico-subcortical connectivity.

However, there are currently no published studies applying tDCS for the treatment of PD-associated pain, except for unpublished studies from our group confirming a favorable effect in this regard. Nonetheless, disregarding our results, its use can be considered safe as it has already been tested in PD patients for other purposes. tDCS has demonstrated an influence on Motor Evoked Potentials (MEPs) in PD patients, increasing MEPs after stimulating M1 with an active anode and decreasing MEPs with an active cathode. Furthermore, it has been observed that bilateral tDCS with an active anode leads to increases in BDNF, thus slowing down the degeneration of dopaminergic neurons. This last piece of evidence, along with other findings that demonstrate the capacity of tDCS to modulate dopaminergic transmission, is relevant for the present project, considering that part of the descending inhibitory pain system involves these pathways. Similarly, it has been demonstrated that pain causes reductions in corticomotor excitability, governed by M1, and tDCS applied to M1 has shown the ability to increase cortical excitability, which has abnormal activity in PD patients and could influence their pain.

Given the overlap between many influential areas in PD-associated pain and the areas excited by tDCS over M1, with these increases in excitability correlating with pain reduction, as well as the potential effect of tDCS on dopaminergic pathways, a hypoalgesic effect of tDCS in PD patients in their OFF state is hypothesized. Additionally, if the action is based on the activation of dopaminergic pathways, a possible enhancement of dopaminergic medication's action with better pain control during the ON period is also expected. However, there is currently no study that has specifically evaluated this effect in PD patients in the OFF state, making it pertinent to conduct a proof-of-concept trial with this objective. The objective is to determine the effect of a single session of treatment using transcranial direct current stimulation (tDCS) on the primary motor cortex (M1) on perceived clinical pain and pain processing characteristics in patients with Parkinson's disease (PD) in the OFF state (without dopaminergic medication) and after taking dopaminergic medication.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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

Primary outcomes:
measure: Change in Conditioned Pain Modulation
timeFrame: From baseline to immediately post tDCS
measure: Change in Conditioned Pain Modulation
timeFrame: From baseline to immediately post dopaminergic medication
measure: Changes in Pain Pressure Threshold
timeFrame: From baseline to immediately post tDCS
measure: Changes in Pain Pressure Threshold
timeFrame: From baseline to immediately post dopaminergic medication
measure: Changes in Visual Numeric Pain Rating Scale
timeFrame: From baseline to immediately post tDCS
measure: Changes in Visual Numeric Pain Rating Scale
timeFrame: From baseline to immediately post dopaminergic medication
measure: Changes in Global Rating of Change
timeFrame: From baseline to immediately post tDCS
measure: Changes in Global Rating of Change
timeFrame: From baseline to immediately post dopaminergic medication
Secondary outcomes:
measure: Changes in Brain Symmetry Index in electroencephalography
timeFrame: From baseline to immediately post tDCS
measure: Changes in Brain Symmetry Index in electroencephalography
timeFrame: From baseline to immediately post dopaminergic medication
measure: Changes in Unified Parkinson´s Disease Rating Scale
timeFrame: From baseline to immediately post dopaminergic medication
measure: Changes in Finger tapping task
timeFrame: From baseline to immediately post dopaminergic medication
Other outcomes:
measure: King´s Parkinson´s Disease Pain Scale score
timeFrame: Baseline
measure: Brief Pain Inventory score
timeFrame: Baseline
measure: Beck´s Depression Inventory
timeFrame: Baseline
measure: State-Trait Anxiety Inventory
timeFrame: Baseline
measure: Tampa Scale of Kinesiophobia
timeFrame: Baseline
measure: Pain Catastrophizing Scale
timeFrame: Baseline
measure: PD-specific 16-items Parkinson Fatigue Scale
timeFrame: Baseline
Locations:
city: Madrid
country: Spain
facility: Hospital Beata Maria Ana
Study officials:
affiliation: Universidad Francisco de Vitoria, Facultad de Ciencias Experimentales
name: Juan Pablo Romero, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universidad Rey Juan Carlos
name: Josué Fernández Carnero, PT, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universidad Francisco de Vitoria
name: Marcos Moreno Verdú, PT, PhD
role: PRINCIPAL_INVESTIGATOR
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