Pain Phenotyping in Patients With Neuropathic Pain After Spinal Cord Injury

The development of neuropathic pain is one of the most debilitating sequels after a spinal cord injury (SCI). The overall aim of this study is to investigate potential underlying pathophysiological mechanisms of neuropathic pain after SCI. The functionality of the nociceptive pathway in humans as well as its plastic changes following SCI will be inferred with sophisticated sensory and pain phenotyping using quantitative sensory testing (i.e., psychophysical measures), objective neurophysiological measures of pain processing and the recording of pain-related autonomic responses (i.e., galvanic skin response, cardiovascular measures and pupil dilation). In addition, the interplay between the somatosensory and autonomic nervous system and its association with the development and maintenance of neuropathic pain after SCI will be investigated.

Study Overview

• Status: Recruiting
• Conditions: Spinal Cord Injuries; Neuropathy; Nociceptive Pain; Pain, Neuropathic
• Intervention / Treatment: Diagnostic test: Neurophysiology; Diagnostic test: Cardiovascular test; Diagnostic test: Quantitative sensory testing; Diagnostic test: Clinical pain phenotype; Diagnostic test: Experimental pain paradigms; Diagnostic test: Pupillometry

• Study Type: Observational
• Enrollment (Estimated): 300

Contacts and Locations

• Study Contact: Name: Michèle Hubli, PD Dr.; Phone Number: +41 44 510 72 03; Email: michele.hubli@balgrist.ch

Study Locations

• Switzerland
  • Canton of Zurich
    • Zurich, Canton of Zurich, Switzerland, 8008
      • Recruiting
      • Balgrist University Hospital
      • Contact: Michèle Hubli, PD Dr.; Phone Number: +41 44 510 72 03; Email: michele.hubli@balgrist.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

In- and outpatients of Balgrist University Hospital Zurich

Description

Inclusion Criteria:

• Spinal injury cohort - general inclusion criteria:
• Aged between 18-80 years
• Traumatic and non-traumatic etiology
• Para- and tetraplegic SCI
• Complete and incomplete SCI
• SCI with and without neuropathic pain
• Additional inclusion criteria for longitudinal study:
• SCI since less than one month
• Additional inclusion criteria for cross-sectional study:
• SCI since more than one year
• Control cohorts with peripheral neuropathy:
• General inclusion criteria:
• Aged between 18-80 years
• Neurological disorder affecting the peripheral nervous system (i.e., peripheral neuropathy)
• Peripheral neuropathy with or without neuropathic pain
• Additional inclusion criteria for longitudinal study:
• Peripheral neuropathy since less than one month
• Additional inclusion criteria for cross-sectional study:
• Peripheral neuropathy since more than one year
• Control cohorts without neuropathy / healthy volunteers
• General inclusion criteria:
• Aged between 18-80 years
• No medical condition affecting the peripheral and/or central nervous system (e.g., pain, systemic disease, psychological disorder)

Exclusion Criteria:

• Inability to follow study instructions
• Pregnancy
• Medically manifested psychological disorder
• Medical condition affecting the peripheral and/or central nervous system other than the desired experimental condition (e.g., additional peripheral neuropathy in the SCI cohort)

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Healthy subjects	Diagnostic test: Neurophysiology; Pain-related evoked potentials and nerve conduction studies; Diagnostic test: Cardiovascular test; Blood pressure control, orthostatic intolerance test, baro-reflex sensitivity, heart-rate variability; Diagnostic test: Quantitative sensory testing; Thermal and mechanical sensory testing; Diagnostic test: Experimental pain paradigms; Temporal summation of pain, conditioned pain modulation, offset analgesia; Diagnostic test: Pupillometry; Pupil size changes after phasic and tonic sensory stimulation
Patients with spinal cord injury with neuropathic pain	Diagnostic test: Neurophysiology; Pain-related evoked potentials and nerve conduction studies; Diagnostic test: Cardiovascular test; Blood pressure control, orthostatic intolerance test, baro-reflex sensitivity, heart-rate variability; Diagnostic test: Quantitative sensory testing; Thermal and mechanical sensory testing; Diagnostic test: Clinical pain phenotype; Pain drawings, plus and minus signs of pain; Diagnostic test: Experimental pain paradigms; Temporal summation of pain, conditioned pain modulation, offset analgesia; Diagnostic test: Pupillometry; Pupil size changes after phasic and tonic sensory stimulation
Patients with spinal cord injury but without neuropathic pain	Diagnostic test: Neurophysiology; Pain-related evoked potentials and nerve conduction studies; Diagnostic test: Cardiovascular test; Blood pressure control, orthostatic intolerance test, baro-reflex sensitivity, heart-rate variability; Diagnostic test: Quantitative sensory testing; Thermal and mechanical sensory testing; Diagnostic test: Experimental pain paradigms; Temporal summation of pain, conditioned pain modulation, offset analgesia; Diagnostic test: Pupillometry; Pupil size changes after phasic and tonic sensory stimulation
Patients with peripheral neuropathy	Diagnostic test: Neurophysiology; Pain-related evoked potentials and nerve conduction studies; Diagnostic test: Cardiovascular test; Blood pressure control, orthostatic intolerance test, baro-reflex sensitivity, heart-rate variability; Diagnostic test: Quantitative sensory testing; Thermal and mechanical sensory testing; Diagnostic test: Clinical pain phenotype; Pain drawings, plus and minus signs of pain; Diagnostic test: Experimental pain paradigms; Temporal summation of pain, conditioned pain modulation, offset analgesia; Diagnostic test: Pupillometry; Pupil size changes after phasic and tonic sensory stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Spinal cord injury patients: clinical pain phenotype including the spatial pain extent and pain intensity	Pain drawings, plus and minus signs of pain	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients: clinical pain phenotype including the spatial pain extent and pain intensity	Pain drawings, plus and minus signs of pain	Cross-sectional: once in a chronic stage (1 year post-injury)
Patients with peripheral neuropathy: clinical pain phenotype including the spatial pain extent and pain intensity	Pain drawings, plus and minus signs of pain	Cross-sectional: once in a chronic stage (1 year post-injury)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Spinal cord injury patients / healthy controls: somato-sensory evoked potentials	Amplitude in uV	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / healthy controls: somato-sensory evoked potentials	Latency in ms	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / healthy controls: contact-heat evoked potentials	Amplitude in uV	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / healthy controls: contact-heat evoked potentials	Latency in ms	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / healthy controls: N13 spinal potential	Amplitude in uV	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / healthy controls: N13 spinal potential	Latency in ms	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / healthy controls: motor neurographies	Amplitude in mV	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / healthy controls: motor neurographies	Latency in ms	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / healthy controls: motor neurographies	Nerve conduction velocity in m/s	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / healthy controls: sensory neurography	Amplitude in mV	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / healthy controls: sensory neurography	Latency in ms	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / healthy controls: sensory neurography	Nerve conduction velocity in m/s	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / healthy controls: resting blood pressure	Systolic, diastolic and mean arterial pressure all in mmHg variability	Cross-sectional: once in a chronic stage (1 year post-injury)
Patients with peripheral neuropathy / healthy controls: changes in blood pressure after a cold pressure test	Delta mmHg	Cross-sectional: once in a chronic stage (1 year post-injury)
Patients with peripheral neuropathy / healthy controls: changes in blood pressure after a Valsalva maneuvre	Delta mmHg	Cross-sectional: once in a chronic stage (1 year post-injury)
Patients with peripheral neuropathy / healthy controls: changes in blood pressure after a sit-up test	Delta mmHg	Cross-sectional: once in a chronic stage (1 year post-injury)
Patients with peripheral neuropathy / healthy controls: baro-reflex sensitivity	ms/mmHg	Cross-sectional: once in a chronic stage (1 year post-injury)
Patients with peripheral neuropathy / healthy controls: heart rate variability	RMSSD (root mean square of successive differences), high frequency/low frequency ratio	Cross-sectional: once in a chronic stage (1 year post-injury)
Spinal cord injury patients / healthy controls: temporal summation of pain after repetitive application of 12 pinprick stimuli	Change in numeric rating scale of pain from the first three to the last three pinprick stimuli	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / healthy controls: conditioned pain modulation	Changes in pressure pain threshold (measured by an algometer in delta kg) before and during a cold water bath	Longitudinal: change from 1 month up to 12 months
Patients with peripheral neuropathy / healthy controls: temporal summation of pain after repetitive application of 12 pinprick stimuli	Change in numeric rating scale of pain from the first three to the last three pinprick stimuli	Longitudinal: change from 1 month up to 12 months
Patients with peripheral neuropathy / healthy controls: conditioned pain modulation	Changes in pressure pain threshold (measured by an algometer in delta kg) before and during a cold water bath	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / healthy controls: thermal sensory testing tested with a thermode	Warm detection threshold (°C), cold detection threshold (°C), heat pain threshold (°C), cold pain threshold (°C)	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / healthy controls: mechanical sensory testing tested with von Frey monofilaments/pinpricks	Mechanical detection threshold (mN)	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / healthy controls: mechanical sensory testing tested with von Frey monofilaments/pinpricks	Mechanical pain threshold (mN)	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / healthy controls: mechanical sensory testing tested with von Frey monofilaments/pinpricks	Mechanical pain sensitivity (numeric rating scale of pain 0-10)	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / healthy controls: mechanical sensory testing tested with von Frey monofilaments/pinpricks	Vibration detection threshold (a.u.) tested with Rydel Seiffer tuning fork	Longitudinal: change from 1 month up to 12 months
Patients with peripheral neuropathy / healthy controls: thermal sensory testing tested with a thermode	Warm detection threshold (°C), cold detection threshold (°C), heat pain threshold (°C), cold pain threshold (°C)	Longitudinal: change from 1 month up to 12 months
Patients with peripheral neuropathy / healthy controls: mechanical sensory testing tested with von Frey monofilaments/pinpricks	Mechanical detection threshold (mN)	Longitudinal: change from 1 month up to 12 months
Patients with peripheral neuropathy / healthy controls: mechanical sensory testing tested with von Frey monofilaments/pinpricks	Mechanical pain threshold (mN)	Longitudinal: change from 1 month up to 12 months
Patients with peripheral neuropathy / healthy controls: mechanical sensory testing tested with von Frey monofilaments/pinpricks	Mechanical pain sensitivity (numeric rating scale of pain 0-10)	Longitudinal: change from 1 month up to 12 months
Patients with peripheral neuropathy / healthy controls: mechanical sensory testing tested with von Frey monofilaments/pinpricks	Vibration detection threshold (a.u.) tested with Rydel Seiffer tuning fork	Longitudinal: change from 1 month up to 12 months
Spinal cord injury patients / patients with peripheral neuropathy / healthy controls: pupillometry	Change in pupil size in mm after sensory input (noxious, non-noxious)	Cross-sectional: once in a chronic stage (1 year post-injury)
Spinal cord injury patients / patients with peripheral neuropathy / healthy controls: offset analgesia (pupillometry)	Change in pupil size in mm during tonic heat application (offseat analgesia paradigm)	Cross-sectional, once in a chronic stage (1 year post-injury)
Spinal cord injury patients / patients with peripheral neuropathy / healthy controls: offset analgesia (psychophysical)	Change in pain ratings during tonic heat stimulation (offet analgesia paradigm) in numeric rating scale (NRS, scale titel: offset analgesia, 0-100, higher score means better analgesia)	Cross-sectional: once in a chronic stage (1 year post-injury)

Collaborators and Investigators

• Sponsor: University of Zurich
• Collaborators: Swiss National Science Foundation
• Investigators: Principal Investigator: Patrick Freund, Prof. Dr. Dr., University of Zurich

Study record dates

Study Major Dates

• Study Start (Actual): April 17, 2024
• Primary Completion (Estimated): April 30, 2030
• Study Completion (Estimated): April 30, 2030

Study Registration Dates

• First Submitted: April 25, 2024
• First Submitted That Met QC Criteria: May 29, 2024
• First Posted (Actual): June 5, 2024

Study Record Updates

• Last Update Posted (Actual): May 15, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Neuromuscular Diseases; Peripheral Nervous System Diseases; Trauma, Nervous System; Spinal Cord Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Neuralgia; Spinal Cord Injuries; Nociceptive Pain; Musculoskeletal and Neural Physiological Phenomena; Cell Physiological Phenomena; Physiological Phenomena; Electrophysiological Phenomena; Biochemical Phenomena; Chemical Phenomena; Nervous System Physiological Phenomena; Synaptic Potentials; Membrane Potentials; Synaptic Transmission; Signal Transduction; Postsynaptic Potential Summation
• Other Study ID Numbers: 2024-00134

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No