Study of Phantom Limb Pain Using Peripheral Nerve and Spinal Cord Stimulation

Peripheral Nerve Stimulation and Spinal Cord Stimulation in Patients With Phantom Limb Pain After Upper Limb Amputation for Phantom Limb Pain Suppression and Development of the Biomarkers

The purpose of this study is to evaluate the effectiveness of neuromodulation for relief of phantom limb pain (PLP) using peripheral nerve (PNS) and spinal cord (SCS) stimulation with implantable electrodes. The researchers expect that PLP in patients with upper limb amputation will be relieved by peripheral nerve and the spinal cord stimulation. The possibility of finding EEG biomarkers for phantom pain will be explored.

Study Overview

• Status: Enrolling by invitation
• Conditions: Amputation; Phantom Limb Pain; Phantom Pain
• Intervention / Treatment: Procedure: Implantation of PNS electrodes during surgery, mapping to select sites with the best effect and pain modulation.; Procedure: SCS electrode implantation at surgery, mapping to select sites with the best effect and pain modulation.; Procedure: EEG to search for phantom pain biomarkers

Detailed Description

The purpose of this study is to evaluate the effectiveness of neuromodulation for relief of phantom limb pain (PLP) using peripheral nerve (PNS) and spinal cord stimulation (SCS) with implantable electrodes.

The study is conducted to collect information on the role of non-adaptive neuroplasticity and inhibitory descending antinociceptive influences, which determine the effect of peripheral nerve and spinal cord stimulation with implanted electrodes in patients with phantom limb pain as a result of amputation of the upper limb. Neuromodulation is a potential treatment option for chronic pain that may alter maladaptive neuroplasticity and enhance descending inhibitory pathways.

Study participants will be selected according to the inclusion criteria. Next, multichannel electrodes will be implanted in the region of the target peripheral nerves of the amputated limb and the corresponding segments of the spinal cord. The evaluation of the therapeutic effects of pain syndromes will be carried out in the mode of long-term repetitive nerve stimulation. Postoperative follow-up will be carried out from 2 weeks to 1 month. During the follow-up period, patients will complete scales and questionnaires daily.

The stimulator is turned on the day after surgery to assess pain relief. The patient is explained the rules for using the stimulator. The selection of stimulation parameters is carried out according to the generally accepted methodology (the stimulation zone should overlap the pain zone; stimulation should be in the nature of pleasant vibrations). The patient will be given a test stimulation diary to complete every day (at the end of the day) during the entire stimulation period.

The researchers expect that phantom limb pain in patients undergoing upper limb amputation will be relieved by peripheral nerve stimulation. We will explore the possibility of creating a personal phantom sensitivity map to optimize the stimulation program. We will study improving the quality of life and reducing pain.

Patients will be asked to participate in an experiment using electroencephalography (EEG) starting on the 3rd day after implantation. The purpose of this entry is to investigate the bimarkers of phantom pain. As part of the experimental procedure, we plan to sequentially turn off the stimulator until the patient returns to the preoperative pain state, and also turn on the stimulator with fixation of the moments of pain suppression to the level at the beginning of the experiment. During the entire period, the patient's EEG will be recorded. The researchers expect to see changes in alpha and theta EEG rhythms under these experimental conditions.

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Russian Federation
  • Primorsky Krai
    • Vladivostok, Primorsky Krai, Russian Federation, 690922
      • Far Eastern Federal University (FEFU)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with implanted neuromodulation devices.
• Amputation of the upper limb at the level of the forearm.
• Age ranges from 18 to 65 years old.
• The duration from the moment of amputation is from 6 months.
• The presence of persistent chronic pain syndrome is from 4 to 10 points according to the Visual Analogue Scale
• Absence of pregnancy at the time of implantation, confirmed by a pregnancy test.

Exclusion Criteria:

• The presence of severe somatic pathology
• The presence of mental illness
• The presence of a gross orthopedic deformity in the limb above the amputation level.
• The presence of oncology.
• The presence of epilepsy.
• Complications after a traumatic brain injury or stroke.
• Purulent - septic pathology.
• Drug addiction.
• Congenital malformation of the upper limb.
• Any conditions that, according to the researcher, fall under the exclusion criteria.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Patients who underwent the upper limb amputation and have phantom limb pain

Procedure: Implantation of PNS electrodes during surgery, mapping to select sites with the best effect and pain modulation.; PNS electrodes are implanted in the area of peripheral nerves of the amputated limb. During phantom pain mapping, multichannel electrodes are used to stimulate peripheral nerves at different sites in the stump. Stimulation turns on sequentially at different stimulation sites; sites are selected where pain is most effectively suppressed. These sites are assigned to the patient for daily modulation.; Procedure: SCS electrode implantation at surgery, mapping to select sites with the best effect and pain modulation.; SNS electrodes are implanted in the area of targeted peripheral nerves in the amputated limb. During phantom pain mapping, multichannel electrodes are used to stimulate the spinal cord at different sites in the cervical thickening (C5-T1). Stimulation starts at a specific site at a frequency of 1 Hz and increases by 0.1 Hz until the patient no longer feels phantom pain. Stimulation turns on sequentially at different stimulation sites; sites are selected where pain is most effectively suppressed. These sites are assigned to the patient for daily modulation.; Procedure: EEG to search for phantom pain biomarkers; This procedure uses the method of electroencephalography (EEG). EEG signals are recorded during the entire experiment. First, the patient is recorded at rest with stimulator on (PNS/SCS) with eyes open and then closed, in the stimulator off state (eyes open, then closed) when patient's pain returns to its preoperative state. The stimulation is then turned back on to the original level of pain suppression. The moments of pain suppression are fixed by marking.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determining the effectiveness of phantom pain suppression based on the Test Stimulation Diary	The patient completes a Test Stimulation Diary at the end of each day, noting the location of phantom pain and the percentage of pain reduction during stimulation.	up to 1 month
Change according to the scale of the DN4 Neuropathic Pain Questionnaire	The DN4 Neuropathic Pain Questionnaire defines the neuropathic nature of pain with a point of 4 to 10.	baseline and up to 1 month
Change according to the scale of the PainDetect questionnaire	The PainDetect questionnaire reflects all possible parameters of pain and allows us to very clearly track the picture of the pain syndrome in dynamics. The score is made in the range from 0 (best score) to 38 (worst score) points.	up to 1 month
Change in relative power of slow frequencies (alpha and theta rhythms) on the EEG with the neurostimulator on/off and eyes open/closed.	The general analysis pipeline includes the calculation of the normalized power spectral density, after which the average power of the alpha rhythm is divided by the average power of the theta rhythm.	up to 1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change according to the SF-36 scale "Quality of Life Assessment"	The SF-36 questionnaire consists of eight scales: physical functioning, role-playing, bodily pain, general health, vitality, social functioning, emotional state, and mental health. Each scale varies between 0 (worst score) and 100 (best score) points.	baseline and up to 1 month
Change according to the Trinity Amputation and Prosthetics Research Scale (TAPES-R)	TAPES-R reflects 3 aspects of psychosocial adjustment (general adjustment, social adjustment and adjustment to functional limitations) and 2 aspects (aesthetics and functionality) of prosthesis satisfaction. The answers reflect the degree of agreement with the statement indicated in the item of the questionnaire, or the degree of satisfaction, or the degree of limitation. The scores on the items of the individual subscales are summarized.	baseline and up to 1 month

Collaborators and Investigators

• Sponsor: Artur Biktimirov

Publications and helpful links

General Publications

• Tan DW, Schiefer MA, Keith MW, Anderson JR, Tyler J, Tyler DJ. A neural interface provides long-term stable natural touch perception. Sci Transl Med. 2014 Oct 8;6(257):257ra138. doi: 10.1126/scitranslmed.3008669.
• Knotkova H, Hamani C, Sivanesan E, Le Beuffe MFE, Moon JY, Cohen SP, Huntoon MA. Neuromodulation for chronic pain. Lancet. 2021 May 29;397(10289):2111-2124. doi: 10.1016/S0140-6736(21)00794-7.
• Schiefer M, Tan D, Sidek SM, Tyler DJ. Sensory feedback by peripheral nerve stimulation improves task performance in individuals with upper limb loss using a myoelectric prosthesis. J Neural Eng. 2016 Feb;13(1):016001. doi: 10.1088/1741-2560/13/1/016001. Epub 2015 Dec 8.
• Graczyk EL, Schiefer MA, Saal HP, Delhaye BP, Bensmaia SJ, Tyler DJ. The neural basis of perceived intensity in natural and artificial touch. Sci Transl Med. 2016 Oct 26;8(362):362ra142. doi: 10.1126/scitranslmed.aaf5187.
• Mekhail N, Levy RM, Deer TR, Kapural L, Li S, Amirdelfan K, Hunter CW, Rosen SM, Costandi SJ, Falowski SM, Burgher AH, Pope JE, Gilmore CA, Qureshi FA, Staats PS, Scowcroft J, Carlson J, Kim CK, Yang MI, Stauss T, Poree L; Evoke Study Group. Long-term safety and efficacy of closed-loop spinal cord stimulation to treat chronic back and leg pain (Evoke): a double-blind, randomised, controlled trial. Lancet Neurol. 2020 Feb;19(2):123-134. doi: 10.1016/S1474-4422(19)30414-4. Epub 2019 Dec 20.
• Ortiz-Catalan M, Mastinu E, Sassu P, Aszmann O, Branemark R. Self-Contained Neuromusculoskeletal Arm Prostheses. N Engl J Med. 2020 Apr 30;382(18):1732-1738. doi: 10.1056/NEJMoa1917537. Erratum In: N Engl J Med. 2022 Nov 24;387(21):2008.
• Schiefer MA, Graczyk EL, Sidik SM, Tan DW, Tyler DJ. Artificial tactile and proprioceptive feedback improves performance and confidence on object identification tasks. PLoS One. 2018 Dec 5;13(12):e0207659. doi: 10.1371/journal.pone.0207659. eCollection 2018.
• Petrini FM, Valle G, Strauss I, Granata G, Di Iorio R, D'Anna E, Cvancara P, Mueller M, Carpaneto J, Clemente F, Controzzi M, Bisoni L, Carboni C, Barbaro M, Iodice F, Andreu D, Hiairrassary A, Divoux JL, Cipriani C, Guiraud D, Raffo L, Fernandez E, Stieglitz T, Raspopovic S, Rossini PM, Micera S. Six-Month Assessment of a Hand Prosthesis with Intraneural Tactile Feedback. Ann Neurol. 2019 Jan;85(1):137-154. doi: 10.1002/ana.25384. Epub 2018 Dec 24.
• Raspopovic S, Capogrosso M, Petrini FM, Bonizzato M, Rigosa J, Di Pino G, Carpaneto J, Controzzi M, Boretius T, Fernandez E, Granata G, Oddo CM, Citi L, Ciancio AL, Cipriani C, Carrozza MC, Jensen W, Guglielmelli E, Stieglitz T, Rossini PM, Micera S. Restoring natural sensory feedback in real-time bidirectional hand prostheses. Sci Transl Med. 2014 Feb 5;6(222):222ra19. doi: 10.1126/scitranslmed.3006820.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2021
• Primary Completion (Anticipated): September 1, 2025
• Study Completion (Anticipated): November 1, 2025

Study Registration Dates

• First Submitted: November 19, 2022
• First Submitted That Met QC Criteria: December 6, 2022
• First Posted (Estimate): December 14, 2022

Study Record Updates

• Last Update Posted (Estimate): December 14, 2022
• Last Update Submitted That Met QC Criteria: December 6, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: spinal cord stimulation; neurostimulation; phantom limb pain; pain suppression; upper-limb amputation
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Postoperative Complications; Pain; Neurologic Manifestations; Neurobehavioral Manifestations; Perceptual Disorders; Pain, Postoperative; Phantom Limb
• Other Study ID Numbers: DVFU-09

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: Our institution discovers this possibilities to share the data after the study

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No