Botulinum Toxin Type A Versus Local Anesthetic Injection for Chronic Neuroma Pain After Combat-Related Amputation (NEUROQUIET)

Botulinum Toxin Type A Versus Local Anesthetic Injection for Chronic Neuroma Pain After Combat-Related Amputation: A Multicenter Randomized Double-Blind Trial

Patients with combat-related amputations frequently experience persistent neuroma pain that may interfere with rehabilitation, prosthesis use, sleep, mobility, and quality of life. Current treatment options often provide only temporary relief. This study aims to compare two ultrasound-guided injection approaches for chronic neuroma pain after combat-related amputation: botulinum toxin type A and local anesthetic injection.

Participants will be randomly assigned to receive one of the two treatments. Pain intensity, neuropathic pain symptoms, phantom limb pain, prosthesis tolerance, and functional outcomes will be evaluated during follow-up visits over a 24-week period.

The goal of the study is to determine whether botulinum toxin type A provides longer-lasting pain reduction and improved functional recovery compared with local anesthetic injection in patients with chronic neuroma pain after combat-related amputation.

Study Overview

• Status: Not yet recruiting
• Conditions: Neural Injury; Chronic Pain Due to Injury; Combat Related Symptoms; Neuroma of Upper Limb; Neuroma of Lower Limb
• Intervention / Treatment: Drug: Botulinum Toxin Type A (BoNT-A); Drug: Local Anesthetic Solution

Detailed Description

Neuroma pain is a common and disabling complication after combat-related limb amputation. Persistent neuroma pain may contribute to residual limb pain, phantom limb pain, impaired prosthesis tolerance, sleep disturbance, reduced mobility, and decreased quality of life. Conventional treatment strategies, including local anesthetic injections, often provide only temporary pain relief.

Botulinum toxin type A has emerged as a potential treatment option because of its ability to modulate peripheral nociceptive signaling, reduce neurogenic inflammation, and decrease peripheral sensitization. However, evidence regarding its efficacy in patients with combat-related amputations remains limited.

The NEUROQUIET Trial is a multicenter, randomized, double-blind clinical trial designed to compare ultrasound-guided botulinum toxin type A injection versus ultrasound-guided local anesthetic injection for persistent neuroma pain after combat-related amputation.

Eligible participants with ultrasound-confirmed painful neuroma will be randomized in a 1:1 ratio to receive either botulinum toxin type A or local anesthetic injection under ultrasound guidance. Participants, outcome assessors, and data analysts will remain blinded to treatment allocation.

Patients will undergo longitudinal follow-up for 24 weeks. Outcomes will include pain intensity, neuropathic pain characteristics, phantom limb pain, residual limb pain, prosthesis tolerance, analgesic consumption, sleep disturbance, and patient-reported global improvement.

The study aims to determine whether botulinum toxin type A provides greater and longer-lasting analgesia compared with local anesthetic injection in patients with chronic neuroma pain following combat-related amputation.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Dmytro Dmytriiev, PhD.Professor; Phone Number: +380674309449; Email: mddmytriiev@gmail.com

Study Locations

• Ukraine
  • Vinnitsa, Ukraine, 21000
    • Vinnitsya university hospital
    • Contact: Dmytro Dmytriiev, Phd; Phone Number: 0674309449; Email: mddmytriiev@gmail.com
  • Vinnytsia Oblast
    • Kyiv, Vinnytsia Oblast, Ukraine, 03143
      • Feofaniya Clinical Hospital
      • Contact: Andrii Khomenko, MD; Phone Number: +380937635858; Email: farmen@ukr.net

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥18 years
• Combat-related limb amputation
• Persistent neuroma pain lasting ≥3 months
• Ultrasound-confirmed neuroma
• Positive Tinel sign over the neuroma
• Average pain intensity ≥4/10 on the Numeric Rating Scale (NRS)
• Stable analgesic regimen for at least 14 days before enrollment
• Ability to provide written informed consent

Exclusion Criteria:

• Active infection at the injection site
• Previous botulinum toxin injection within 6 months
• Previous neuroma surgery within 3 months
• Severe uncontrolled psychiatric disorder
• Coagulopathy or anticoagulant therapy contraindicating injection
• Known allergy to botulinum toxin or local anesthetics
• Severe uncontrolled systemic disease
• Inability to complete study follow-up or questionnaires

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Botulinum Toxin Type A; Ultrasound-guided perineuroma injection of botulinum toxin type A for persistent neuroma pain after combat-related amputation.	Drug: Botulinum Toxin Type A (BoNT-A); Ultrasound-guided perineuroma injection of botulinum toxin type A for treatment of persistent neuroma pain after combat-related amputation.
Active Comparator: Local Anesthetic; Ultrasound-guided perineuroma injection of local anesthetic for persistent neuroma pain after combat-related amputation.	Drug: Local Anesthetic Solution; Ultrasound-guided perineuroma injection of local anesthetic for treatment of persistent neuroma pain after combat-related amputation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in neuroma pain intensity measured	Assessment of change in average neuroma pain intensity using an 11-point Numeric Rating Scale (0 = no pain, 10 = worst imaginable pain) following ultrasound-guided injection treatment.	Baseline to 12 weeks after intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Residual Limb Pain Intensity Assessed Using the Numeric Rating Scale (NRS)	Residual limb pain intensity will be assessed using the 11-point Numeric Rating Scale (NRS). Participants will rate their average residual limb pain during the previous 7 days on a scale from 0 to 10, where 0 indicates "no pain" and 10 indicates "worst imaginable pain." Higher scores indicate greater pain intensity and a worse clinical outcome. Scale Information: Numeric Rating Scale (NRS) Minimum Value: 0 Maximum Value: 10 Interpretation: Higher scores indicate worse residual limb pain intensity.	Baseline to 24 weeks
Pain Catastrophizing	Pain catastrophizing will be assessed using the Pain Catastrophizing Scale (PCS), a validated 13-item self-report questionnaire designed to measure catastrophic thinking related to pain. The PCS evaluates three domains: rumination, magnification, and helplessness. Total scores range from 0 to 52, with higher scores indicating greater levels of pain catastrophizing and a worse psychological pain profile. Scale Information: Pain Catastrophizing Scale (PCS) Minimum Value: 0 Maximum Value: 52 Interpretation: Higher scores indicate greater pain catastrophizing and worse pain-related psychological outcomes.	Baseline, 3 months, 6 months, and 12 months after amputation.
Prosthesis Tolerance Assessed Using the Prosthesis Evaluation Questionnaire (PEQ) - Utility and Satisfaction Domains	Prosthesis tolerance will be assessed using selected domains of the Prosthesis Evaluation Questionnaire (PEQ), a validated instrument evaluating comfort, utility, satisfaction, and functional use of the prosthesis. Scores range from 0 to 100, with higher scores indicating better prosthesis tolerance and satisfaction. Scale Information: Prosthesis Evaluation Questionnaire (PEQ) Minimum Value: 0 Maximum Value: 100 Interpretation: Higher scores indicate better prosthesis tolerance, comfort, and prosthetic adaptation.	Baseline to 24 weeks
Analgesic Consumption	Analgesic consumption will be assessed by calculating the total daily analgesic use and converting opioid medications into Oral Morphine Equivalent Daily Dose (OMEDD). Non-opioid analgesics (e.g., acetaminophen, NSAIDs, gabapentinoids) will also be recorded. Higher opioid consumption indicates greater analgesic requirements and potentially more severe pain. Measurement: Oral Morphine Equivalent Daily Dose (OMEDD), expressed in milligrams per day (mg/day) Minimum Value: 0 mg/day Maximum Value: No predefined maximum value Interpretation: Higher values indicate greater analgesic consumption and higher pain management requirements.	Baseline to 24 weeks
Patient Global Impression of Change (PGIC)	Overall perceived improvement will be assessed using the Patient Global Impression of Change (PGIC) scale. The PGIC is a validated patient-reported outcome measure that evaluates a participant's perception of change in pain, function, and overall health status since the beginning of treatment. Participants rate their overall improvement on a 7-point scale ranging from "Very much worse" to "Very much improved." Scale Information: Patient Global Impression of Change (PGIC) Minimum Value: 1 (Very much worse) Maximum Value: 7 (Very much improved) Interpretation: Higher scores indicate greater perceived improvement and better overall clinical outcomes. Scale Categories: = Very much worse; = Much worse; = Minimally worse; = No change; = Minimally improved; = Much improved; = Very much improved	Week 12 and Week 24
Adverse Events	Adverse events will be assessed by recording the occurrence, type, severity, and relationship to treatment throughout the study period. Events may include medication-related adverse effects, prosthesis-related complications, falls, skin breakdown, residual limb complications, infections, hospitalizations, and other clinically significant events. Severity will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0, when applicable. Measurement: Number of participants experiencing one or more adverse events. Minimum Value: 0 participants Maximum Value: Number of participants enrolled in the study Interpretation: Higher values indicate a greater incidence of adverse events and worse safety outcomes. Additional Safety Assessment: Severity of adverse events will be categorized as Grade 1 (Mild) to Grade 5 (Death related to adverse event) according to CTCAE v5.0.	Baseline to 24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sleep Disturbance	Sleep disturbance will be assessed using the Pittsburgh Sleep Quality Index (PSQI), a validated 19-item questionnaire that evaluates subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication, and daytime dysfunction during the previous month. The global PSQI score ranges from 0 to 21, with higher scores indicating poorer sleep quality and greater sleep disturbance. Scale Information: Pittsburgh Sleep Quality Index (PSQI) Minimum Value: 0 Maximum Value: 21 Interpretation: Higher scores indicate worse sleep quality and greater sleep disturbance. Clinical Interpretation: A global PSQI score >5 is commonly considered indicative of clinically significant sleep disturbance.	Baseline to 24 weeks
Functional Mobility	Functional mobility will be assessed using the Amputee Mobility Predictor (AMP), a validated performance-based instrument designed to evaluate ambulatory potential, balance, transfers, gait, and functional mobility in individuals with lower-limb amputation. The scale assesses the patient's ability to perform a series of mobility tasks and predicts prosthetic functional potential. Scale Information: Amputee Mobility Predictor (AMP) Minimum Value: 0 Maximum Value: 47 Interpretation: Higher scores indicate better functional mobility, greater ambulatory capacity, and improved rehabilitation outcomes. Clinical Interpretation: Higher AMP scores are associated with higher functional levels and greater potential for successful prosthetic use.	Baseline to 24 weeks
Need for Repeat Intervention	he need for repeat intervention will be assessed by recording the number of participants who require additional pain-related interventions following the initial treatment. Repeat interventions may include repeat nerve blocks, cryoneurolysis, radiofrequency ablation, neuroma surgery, revision procedures, additional injections, or other clinically indicated pain-management procedures. Measurement: Number of participants requiring one or more additional pain-related interventions during follow-up. Minimum Value: 0 participants Maximum Value: Number of participants enrolled in the study Interpretation: Higher values indicate a greater need for additional interventions and may reflect reduced durability or effectiveness of the initial treatment. Additional Analysis: Time to first repeat intervention (days) may also be recorded and analyzed as a secondary outcome.	Up to 24 weeks
Patient Satisfaction	Patient satisfaction will be assessed using the Client Satisfaction Questionnaire (CSQ-8), a validated 8-item patient-reported outcome measure evaluating satisfaction with treatment, services received, and overall care experience. Total scores range from 8 to 32, with higher scores indicating greater satisfaction with treatment outcomes and care. Scale Information: Client Satisfaction Questionnaire (CSQ-8) Minimum Value: 8 Maximum Value: 32 Interpretation: Higher scores indicate greater patient satisfaction and better perceived treatment outcomes.	Week 12 and Week 24
Neuroma Maximum Diameter Measured by High-Resolution Ultrasound	Neuroma size will be assessed using high-resolution ultrasound. The maximum neuroma diameter will be measured in the longitudinal or transverse plane and recorded in millimeters (mm). The largest measured diameter will be used for analysis. Unit of Measure: Millimeters (mm) Minimum Value: 0 mm Maximum Value: No predefined maximum value Interpretation: Higher values indicate larger neuroma size and greater structural abnormality.	Baseline and Week 24

Collaborators and Investigators

• Sponsor: Ukrainian Society of Regional Anesthesia and Pain Therapy

Publications and helpful links

General Publications

• Climent JM, Mondejar-Gomez F, Rodriguez-Ruiz C, Diaz-Llopis I, Gomez-Gallego D, Martin-Medina P. Treatment of Morton neuroma with botulinum toxin A: a pilot study. Clin Drug Investig. 2013 Jul;33(7):497-503. doi: 10.1007/s40261-013-0090-0.

Study record dates

Study Major Dates

• Study Start (Estimated): May 30, 2026
• Primary Completion (Estimated): December 15, 2026
• Study Completion (Estimated): December 15, 2026

Study Registration Dates

• First Submitted: May 23, 2026
• First Submitted That Met QC Criteria: May 30, 2026
• First Posted (Actual): June 4, 2026

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: May 30, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Neuropathic pain; Botulinum toxin type A; Phantom limb pain; Residual limb pain; Ultrasound-guided injection; Ultrasound-guided pain intervention; Local anesthetic injection; Military trauma; Neuroma pain; Combat-related amputation; Chronic post-amputation pain
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Nervous System Diseases; Postoperative Complications; Pathologic Processes; Neuromuscular Diseases; Peripheral Nervous System Diseases; Neurobehavioral Manifestations; Perceptual Disorders; Pain, Postoperative; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Neuralgia; Phantom Limb; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Hydrolases; Enzymes; Enzymes and Coenzymes; Botulinum Toxins; Metalloendopeptidases; Endopeptidases; Peptide Hydrolases; Metalloproteases; Bacterial Proteins; Bacterial Toxins; Toxins, Biological; Botulinum Toxins, Type A; incobotulinumtoxinA
• Other Study ID Numbers: 2205v0123052026; UARA-NEUROQUIET (Other Identifier: UARA-NEUROQUIET)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data including demographic characteristics, pain intensity scores, neuropathic pain assessments, phantom limb pain measures, prosthesis tolerance outcomes, adverse events, and follow-up assessments collected during the study will be available for sharing. The study protocol and statistical analysis plan may also be shared upon reasonable request.
• IPD Sharing Time Frame: Beginning 6 months after publication of the primary study results and ending 5 years after publication.
• IPD Sharing Access Criteria: De-identified individual participant data and supporting documents will be available to qualified researchers upon reasonable request to the study investigators. Requests will be reviewed for scientific validity and compliance with institutional and ethical requirements.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

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