Mechanisms of Neurodynamic Treatments (MONET)

Mechanisms of Neurodynamic Treatments (MONET)

INTRODUCTION: Carpal tunnel syndrome (CTS) is a relatively common condition caused by compression of one of the main nerves at the wrist, the median nerve. Non-surgical treatments, like steroid injections and physiotherapy, are the first line of treatment for patients with carpal tunnel syndrome. The investigators have previously shown that specific physiotherapeutic exercises (neurodynamic exercises) can reduce the need for carpal tunnel surgery in some patients. Experimental studies in animal models demonstrate that these exercises have an anti-inflammatory effect and can help the nerve to regenerate. However, the exact mechanisms of action of these exercises are not well understood in patients. A better understanding of the mechanisms of action of physiotherapeutic exercises would help clinicians to better target these treatments to those patients who may benefit from them.

AIM: To investigate the mechanisms of action of 6 weeks' neurodynamic treatments on nerve function and structure as well as patient-reported outcome measures in patients with CTS compared to a positive control intervention (routine care steroid injection) and a negative control intervention (advice).

METHODS AND ANALYSIS: In this single-blind randomised mechanistic trial, patients with confirmed mild to moderate CTS (n=78) and age and gender-matched healthy controls (n=30) will be included. Patients will be randomly allocated to a 6-week neurodynamic exercise group, steroid injection, or advice group. Outcome measures will be explored at baseline (patients and controls), post-intervention (patients), and 6-month follow-up (patients). Outcomes include diffusion-weighted and anatomical MRI of the median nerve at the wrist, quantitative sensory testing, nerve conduction studies, inflammatory markers in blood and skin biopsies, and validated questionnaires for pain, function, and psychological factors. Two-way repeated measures ANCOVAs (factors time and intervention, adjusted for baseline measurements as a continuous covariate) will be performed to identify differences in MRI parameters, clinical assessment, and inflammatory markers between patients in different groups and healthy controls.

Study Overview

• Status: Recruiting
• Conditions: Carpal Tunnel Syndrome; Physiotherapy; Neurodynamic Treatment; Nerve Mobilisation; Diffusion MRI; Mechanistic Trial
• Intervention / Treatment: Other: Neurodynamic exercises; Drug: Steroid injection (Depomedrone 40mg); Other: Advice

Detailed Description

Follow-up at 6 months will only include outcome measures from questionnaires.

Details on enrollment:

Pilot testing of healthy participants who consented to our ethics but will not be included in the study was on 13-April-2023.

• First healthy participant enrolled: 17-May-2023.
• First patient participant enrolled: 1-June-2023.

Details on amendment:

• Amendment SA2_BPOR on 3/Aug/2023 to expand recruitment through registries of patients
• Amendment SA3_REC on 22/Aug/2023 to add Thames Valley Primary Care Research Partnership, musculoskeletal clinics, and media advertisement to help with recruitment of participants.

• Study Type: Interventional
• Enrollment (Estimated): 108
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Annina Schmid, PhD; Phone Number: +44 (0) 1865 223254; Email: annina.schmid@ndcn.ox.ac.uk
• Study Contact Backup: Name: Eva Sierra-Silvestre, PhD; Phone Number: +44 (0) 1865 234821; Email: eva.sierra@ndcn.ox.ac.uk

Study Locations

• United Kingdom
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 9DU
      • Recruiting
      • Nuffield Department of Clinical Neurosciences, University of Oxford
      • Contact: Eva Sierra-Silvestre, PhD; Phone Number: +44 (0) 1865 234821; Email: eva.sierra@ndcn.ox.ac.uk

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria

Patients:

1. Patients who have a diagnosis of mild to moderate carpal tunnel syndrome based on a clinical assessment and confirmed with nerve conduction studies.
2. Male or Female, aged 18 years or above.
3. Patient is willing and able to give informed consent for participation in the study.

Healthy participants:

1. Male or female aged 18 years or above.
2. Participant is willing and able to give informed consent for participation in the study.
3. No history of hand or arm symptoms
4. No history of neck pain in the past 3 months
5. No systemic medical condition
6. No strong anticoagulant medication or altered coagulation (e.g., hemophilia) preventing skin biopsies
7. Severe anxiety or depression
8. Participants are required to be age- & sex-matched to patient participants
9. No contraindications for magnetic resonance scanning at 3T
10. Sufficient command of the English language

Exclusion Criteria

Patients:

1. Patients who already had surgery for their carpal tunnel syndrome (CTS) or are planning to undergo surgery in the next 6 weeks (patients with unilateral surgery who have unoperated CTS on the other hand are eligible to participate)
2. Patients who had a steroid injection for their CTS in the 6 months prior to the study enrolment or who had already more than 1 steroid injection into the study wrist.
3. Patients who have a diagnosis of severe carpal tunnel syndrome based on a clinical assessment and confirmed with electrodiagnostic testing
4. Electrodiagnostic testing revealing abnormalities other than CTS
5. Any other upper limb or neck problem for which they have sought treatment in the past 3 months
6. History of significant trauma to the upper limb or neck
7. Diabetes
8. Hypothyroidism
9. Severe anxiety or depression
10. Patient who is pregnant, lactating, or planning pregnancy during the study.
11. Patients on strong anticoagulant medication or altered coagulation preventing skin biopsies.
12. Contraindications for magnetic resonance imaging (assessed with MRI safety screening questionnaire).
13. Contraindications for steroid injections
14. Insufficient command of the English language

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neurodynamic exercises; 6-weeks home exercise programme of nerve and tendon gliding exercises	Other: Neurodynamic exercises; The neurodynamic exercises will consist of a home-based exercise programme performed over a period of 6 weeks. Patients will attend a single session with an investigator who will instruct them the home exercise programme consisting of nerve and tendon gliding exercises which will be adjusted with pre-specified progressions over the 6 weeks intervention period. Patients will receive a leaflet and a video link detailing these exercises.
Active Comparator: Steroid injection Steroid injection (Depomedrone 40mg); Single steroid injection into Carpal Tunnel (positive control group)	Drug: Steroid injection (Depomedrone 40mg); Steroid injection (Depomedrone 40mg) into the carpal tunnel as per standard practice in patients with carpal tunnel syndrome
Other: Advice; The advice group will receive advice but no additional intervention during the 6 week intervention period (negative control group)	Other: Advice; Group receiving advice but no additional treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median nerve fractional anisotropy as determined on diffusion weighted imaging	Fractional anisotropy will be extracted from regions-of-interest in the median nerve and compared to healthy control group	Baseline
Change in median nerve fractional anisotropy as determined on diffusion weighted imaging	Change in fractional anisotropy extracted from regions-of-interest in the median nerve at post-intervention (after 6-weeks) compared to baseline	From baseline to post-intervention (after 6-weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nerve markers on diffusion weighted imaging: water diffusivity (mm2/s)	Measured at the median nerve and cervical dorsal root ganglia. mm2/s; continuous data	Baseline
Change to nerve markers on diffusion weighted imaging: water diffusivity (mm2/s)	Measured at the median nerve and cervical dorsal root ganglia. mm2/s; continuous data	From baseline to post-intervention (after 6-weeks)
Nerve markers on anatomical MRI	Measured at the median nerve and cervical dorsal root ganglia. ratio/mm2; continuous data	Baseline
Change in nerve markers on anatomical MRI	Measured at the median nerve and cervical dorsal root ganglia. ratio/mm2; continuous data	From baseline to post-intervention (after 6-weeks)
Median nerve MRI T2 mapping	ms; continuous data	Baseline
Changes in median nerve MRI T2 mapping	ms; continuous data	From baseline to post-intervention (after 6-weeks)
Median nerve MRI magnetisation transfer ratio (MTR)	ratio; continuous data	Baseline
Changes in median nerve MRI magnetisation transfer ratio (MTR)	ratio; continuous data	From baseline to post-intervention (after 6-weeks)
Changes in median nerve conduction velocities from electrodiagnostic studies (m/s)	m/s; continuous data	From baseline to post-intervention (after 6-weeks)
Changes in median sensory nerve action potentials (SNAPs) and compound muscle action potentials (CMAPs): amplitudes (mV)	mV; continuous data	From baseline to post-intervention (after 6-weeks)
Thermal detection thresholds as assessed in Quantitative Sensory testing - warm and cold detection threshold; thermal sensory limen	Thermal detection thresholds will be assessed using a thermode over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger). Data is measured in degrees celsius (point at which cold or warm is detected)	Baseline
Change in thermal detection thresholds as assessed in Quantitative Sensory testing- warm and cold detection threshold; thermal sensory limen	Thermal detection thresholds will be assessed using a thermode over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger). Data is measured in degrees celsius (point at which cold or warm is detected)	From baseline to post-intervention (after 6-weeks)
Thermal pain thresholds as assessed in Quantitative Sensory testing- warm and cold painful threshold	Pain thermal thresholds will be assessed using a thermode over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger) and over the contralateral lower limb (tibial anterior). Data is measured in degrees celsius (point at which cold or warm is initially detected as painful)	Baseline
Change in thermal pain thresholds as assessed in Quantitative Sensory testing- warm and cold painful threshold	Pain thermal thresholds will be assessed using a thermode over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger) and over the contralateral lower limb (tibial anterior). Data is measured in degrees celsius (point at which cold or warm is initially detected as painful)	From baseline to post-intervention (after 6-weeks)
Mechanical detection thresholds as assessed in Quantitative sensory testing	Mechanical detection thresholds will be assessed using a standardised set of von Frey filaments (mN) over the index finger. Geometric mean will be calculated	Baseline
Change in mechanical detection thresholds as assessed in Quantitative sensory testing	Mechanical detection thresholds will be assessed using a standardised set of von Frey filaments (mN) over the index finger. Geometric mean wil be calculated	From baseline to post-intervention (after 6-weeks)
Mechanical pain thresholds as assessed in Quantitative sensory testing	Mechanical pain thresholds will be assessed using a series of weighted pin prick stimulators (mN). They will be assessed over the index finger and over the contralateral lower limb (tibial anterior).	Baseline
Change in mechanical pain thresholds as assessed in Quantitative sensory testing	Mechanical pain thresholds will be assessed using a series of weighted pin prick stimulators (mN). They will be assessed over the index finger and over the contralateral lower limb (tibial anterior).	From baseline to post-intervention (after 6-weeks)
Mechanical pain sensitivity as assessed in Quantitative sensory testing	Mechanical pain sensitivity will be assessed using a series of weighted pin prick stimulators (mN) over the index finger. Pain rating for each stimulus on a 0-100 numerical rating scale ('0' indicating "no pain", and '100' indicating "most intense pain imaginable"). Geometric mean of all numerical ratings for pinprick stimuli will be calculated	Baseline
Change in mechanical pain sensitivity as assessed in Quantitative sensory testing	Mechanical pain sensitivity will be assessed using a series of weighted pin prick stimulators (mN) over the index finger. Pain rating for each stimulus on a 0-100 numerical rating scale ('0' indicating "no pain", and '100' indicating "most intense pain imaginable"). Geometric mean of all numerical ratings for pinprick stimuli will be calculated	From baseline to post-intervention (after 6-weeks)
Dynamic mechanical allodynia as assessed in Quantitative sensory testing	Pain rating for each stimulus on a 0-100 numerical rating scale ('0' indicating "no pain", and '100' indicating "most intense pain imaginable"). Geometric mean (compound measure) of all numerical ratings across light touch stimulators over the index finger	Baseline
Change in dynamic mechanical allodynia as assessed in Quantitative sensory testing	Pain rating for each stimulus on a 0-100 numerical rating scale ('0' indicating "no pain", and '100' indicating "most intense pain imaginable"). Geometric mean (compound measure) of all numerical ratings across light touch stimulators over the index finger	From baseline to post-intervention (after 6-weeks)
Wind-up ratio as assessed in Quantitative sensory testing	Wind-up ration will be assessed using a pin prick (mN) over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger). Ratio, continous data	Baseline
Change in wind-up ratio as assessed in Quantitative sensory testing	Change in wind-up ration will be assessed using a pin prick (mN) over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger). Ratio, continuous data	From baseline to post-intervention (after 6-weeks)
Vibration detection thresholds as assessed in Quantitative sensory testing	Vibration detection thresholds will be assessed using a tuning fork (64 Hz, 8/8 scale) over a bony prominence over (e.g., palmar side of the distal end of the second metacarpal)	Baseline
Change in vibration detection thresholds as assessed in Quantitative sensory testing	Change in vibration detection thresholds will be assessed using a tuning fork (64 Hz, 8/8 scale) over a bony prominence over (e.g., palmar side of the distal end of the second metacarpal)	From baseline to post-intervention (after 6-weeks)
Pressure pain thresholds as assessed in Quantitative sensory testing	Pressure pain thresholds will be assessed using an algometer (kg) on the thenar eminence and over the contralateral lower limb (tibialis anterior)	Baseline
Change in pressure pain thresholds as assessed in Quantitative sensory testing	Change in pressure pain thresholds will be assessed using an algometer (kg) on the thenar eminence and over the contralateral lower limb (tibialis anterior)	From baseline to post-intervention (after 6-weeks)
Pinch strength test - maximum isometric strength	Pinch grip dynamometry. Continuous data, kg	Baseline
Change in pinch strength test - maximum isometric strength	Pinch grip dynamometry. Continuous data, kg	From baseline to post-intervention (after 6-weeks)
Nerve mechanosensitivity- upper limb neurodynamic test (median nerve)	Evaluation of nerve mechanosensitivity in response to mechanical load (increased tension) applied to the nerve. Range of elbow extension at point of symptoms (degrees)	Baseline
Change in nerve mechanosensitivity- upper limb neurodynamic test (median nerve)	Change in nerve mechanosensitivity in response to mechanical load (increased tension) applied to the nerve. Range of elbow extension at point of symptoms (degrees)	From baseline to post-intervention (after 6-weeks)
Nerve mechanosensitivity - positive upper limb neurodynamic tests	Upper limb neurodynamic tests will be assessed to determine the presence of increased mechanosensitivity. The neurodynamic test will be graded as 'positive', when there is at least partial reproduction of symptoms plus when symptoms can be modified with structural differentiation. Otherwise, the neurodynamic test will be graded as 'negative'	Baseline
Change in nerve mechanosensitivity - positive upper limb neurodynamic tests	Upper limb neurodynamic tests will be assessed to determine the presence of increased mechanosensitivity. The neurodynamic test will be graded as 'positive', when there is at least partial reproduction of symptoms and when symptoms can be modified with structural differentiation. Otherwise, the neurodynamic test will be graded as 'negative'	From baseline to post-intervention (after 6-weeks)
Symptom severity and limitations in hand function as assessed by the Boston carpal tunnel syndrome questionnaire	Patient reported symptoms and limitations on the Boston carpal tunnel syndrome questionnaire	Baseline, post-intervention (after 6 weeks), 6-months follow up
Symptom intensity levels on a Visual Analogue Scale (VAS)	Patient reported average intensity of pain, paraesthesia and numbness on 10cm visual analogue scales, ranging from no symptoms to worst symptoms ever	Baseline, post-intervention (after 6 weeks), 6-months follow up
Location of symptoms in a body and a hand diagram	Patient reported location of symptoms in a body diagram and a hand diagram.	Baseline, post-intervention (after 6 weeks)
Presence of central sensitisation as assessed with the Central Sensitisation Inventory	Patient reported central sensitisation on the Central Sensitisation Inventory	Baseline, post-intervention (after 6 weeks), 6-months follow up
Functional deficits- Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire	Participant reported outcomes on ability to perform activities as per quick DASH questionnaire	Baseline, post-intervention (after 6 weeks), 6-months follow up
Functional deficits- Patient specific functional scale (PSFS)	Participant reported outcomes on the patient specific functional scale	Baseline, post-intervention (after 6 weeks), 6-months follow up
Presence of neuropathic pain - DN4	Patient screened for neuropathic pain using DN4	Baseline, post-intervention (after 6 weeks), 6-months follow up
Presence of neuropathic pain - pain DETECT	Patient screened for neuropathic pain using pain DETECT	Baseline, post-intervention (after 6 weeks), 6-months follow up
Neuropathic pain symptoms - Neuropathic Pain Symptom Inventory	Patient reported outcomes on neuropathic pain symptoms as assessed on Neuropathic Pain Symptom Inventory.	Baseline, post-intervention (after 6 weeks), 6-months follow up
Presence of psychological co-morbidities - The Depression, Anxiety, and Positive Outlook Scale (DAPOS)	Participant reported outcomes on depression and anxiety as per DAPOS	Baseline, post-intervention (after 6 weeks), 6-months follow up
Presence of psychological co-morbidities - short-form Pain Anxiety Symptoms Scale (PASS-20)	Participant reported outcomes on depression and anxiety as per short-form Pain Anxiety Symptoms Scale (PASS-20)	Baseline, post-intervention (after 6 weeks), 6-months follow up
Presence of psychological co-morbidities - pain catastrophizing scale (PCS)	Participant reported outcomes on depression and anxiety as per pain catastrophising scale (PCS)	Baseline, post-intervention (after 6 weeks), 6-months follow up
Assessment of quality of life - EQ-5D-5L	Participant reported outcomes on quality of life as per EQ-5D-5L questionnaire	Baseline, post-intervention (after 6 weeks), 6-months follow up
Assessment of sleep interference - Insomnia Severity Index	Participant reported outcomes on sleep interference with the Insomnia Severity Index.	Baseline, post-intervention (after 6 weeks), 6-months follow up
Adverse and serious adverse events	Patient self-reported adverse events	From start of intervention until end of intervention (6 weeks)
Exercise adherence to the neurodynamic home-based intervention - number of sessions	Patient self-reported number of sessions per day throughout the intervention in an exercise diary	From start of intervention until end of intervention (6 weeks)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood samples - DNA	Blood samples coupled with detailed phenotype data will investigate potential gene associations in CTS and recovery	Baseline
Change in blood samples - DNA	Change in blood samples coupled with detailed phenotype data will investigate potential gene associations in CTS and recovery	From baseline to post-intervention (after 6-weeks)
Concentration of serum inflammatory markers - metabolomics	Concentrations of inflammatory markers in serum	Baseline
Change in the concentration of serum inflammatory markers - metabolomics	Change in the concentrations of inflammatory markers in serum	From baseline to post-intervention (after 6-weeks)
Pro-inflammatory cytokine levels	Proinflammatory cytokine assay (pg/ml); continuous data	Baseline
Change in pro-inflammatory cytokine levels	Change in proinflammatory cytokine assay (pg/ml); continuous data	From baseline to post-intervention (after 6-weeks)
Concentration of inflammatory markers in serial skin biopsies	Concentration of inflammatory markers in skin biopsies. Baseline biopsy will be performed in the most distal part of the ventrolateral side of the proximal phalanx of the index finger. The 6-weeks biopsy will be performed proximally, avoiding the primary biopsy site	Baseline
Change in concentration of inflammatory markers in serial skin biopsies	Change in concentration of inflammatory markers in skin biopsies. Baseline biopsy will be performed in the most distal part of the ventrolateral side of the proximal phalanx of the index finger. The 6-weeks biopsy will be performed proximally, avoiding the primary biopsy site	From baseline to post-intervention (after 6-weeks)

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: Wellcome Trust
• Investigators: Principal Investigator: Eva Sierra-Silvestre, PhD, University of Oxford

Study record dates

Study Major Dates

• Study Start (Actual): May 17, 2023
• Primary Completion (Estimated): February 1, 2025
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: April 20, 2023
• First Submitted That Met QC Criteria: May 4, 2023
• First Posted (Actual): May 16, 2023

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 3, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Wounds and Injuries; Neuromuscular Diseases; Mononeuropathies; Peripheral Nervous System Diseases; Median Neuropathy; Nerve Compression Syndromes; Cumulative Trauma Disorders; Sprains and Strains; Carpal Tunnel Syndrome; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate
• Other Study ID Numbers: 313200

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPDs that underlie results in a publication.
• IPD Sharing Time Frame: IPD that underlie results of a publication will be shared upon the final publication of the main manuscripts of this study.
• IPD Sharing Access Criteria: IPD will be shared upon reasonable request and in line with ethical approval with authors contacting the study investigators.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

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