Prevention of PostAmputation Pain with Targeted Muscle Reinnervation

Not Applicable

Recruiting

• Conditions: Amputation, Surgical; Phantom Limb Pain; Surgery; Neuroma Amputation

• Registration Number: NCT06719245
• Lead Sponsor: Leiden University Medical Center

Brief Summary

The goal of this study is to compare postamputation pain (phantom limb pain and residual limb pain) one year postoperatively in patients who received a lower extremity amputation (LEA) with standard nerve handling (neurectomy) versus those who received Targeted Muscle Reinnervation (TMR).

Patients between 18 and 75 years old, scheduled for an LEA (transfemoral to transtibial) as a primary or secondary sequela of vascular disease, are randomized into standard neurectomy or TMR. TMR is a frequently studied surgical technique and prevents neuroma formation by rerouting a cut mixed nerve end to a functional motor nerve.

The investigators hypothesize that TMR during amputation surgery will significant improve PostAmputation Pain (PAP), quality of life, participation in family life and society, and reduction of health-related costs. Participants will be asked to complete multiple online questionnaires postoperatively regarding these outcomes at five evaluation moments (at 2 weeks, and at 3, 6, 9, and 12 months).

Detailed Description

Rationale: In the Netherlands, approximately 3300 lower extremity amputations (sacroiliac to forefoot) are performed each year. In current amputation practice, the nerves are simply cut, without employing any nerve surgical techniques to prevent the development of chronic pain due to neuroma formation. Around 61% of these patients develop postamputation pain (PAP). PAP is a severe lifelong disabling condition profoundly affecting quality of life.

Microsurgical nerve handling can prevent the formation of a painful neuroma and its sequelae. In recent years, targeted muscle reinnervation (TMR) has been the most frequently studied technique with promising results. TMR prevents neuroma formation by rerouting a cut mixed nerve end to a functional motor nerve.

The expected benefit of the implementation of TMR during amputation surgery is a significant reduction in the incidence of PAP. Prevention of this chronic pain syndrome will lead to a significant improvement in quality of life, participation in family life and society, and reduction of health-related costs for thousands of amputation patients every year. To achieve this, a transformation of nerve handling during amputation is needed.

Objective: To compare postamputation pain (phantom limb pain and residual limb pain) one year postoperatively in patients who received a lower extremity amputation (LEA) with standard nerve handling (neurectomy) versus those who received TMR.

Study design: A national, multicenter, randomized, sham-controlled superiority trial, comparing standard neurectomy with TMR in amputations of the lower extremities.

Study population: Patients between 18 and 75 years old, scheduled for an LEA (transfemoral to transtibial) as a primary or secondary sequela of vascular disease.

Intervention: Patients with an LEA are randomized into standard neurectomy or TMR. TMR in short: each transected nerve is identified after amputation and is dissected proximally for length. A nerve stimulator is used to identify functional motor nerve branches. Near the point where the motor branch enters the muscle, the motor nerve branch is transected, and an end-to-end coaptation is performed with a nearby amputated nerve.

Main study parameters: The mean difference in pain scores for phantom limb pain and residual limb pain one year postoperatively. Pain is measured for 30 consecutive days (Pain Diary) on the 11-point (0-10) numerical rating scale (NRS) and according to the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Behavior and Interference Questionnaire Short Forms (7a and 8a, respectively).

Nature and extent of the burden and risks associated with participation, benefit, and group relatedness: The additional risks of performing TMR during amputation are negligible. TMR can be performed at any level of the lower extremities with a standardized technique. For TMR to be possible, in upper leg amputations, an additional incision (ca 10 centimetres) has to be made on the dorsal side of the leg, medial tot the sartorius muscle. In our experience this will not result in more postoperative pain or difficulty in sitting. To properly blind study participants this additional incision for upper leg amputations must also be superficially performed in the control group. Another factor that will differ from current standards is that the procedure will take 30 to 90 minutes longer. The extra time investment will depend on technical aspects related to the level of amputation and surgeon experience. Although an increase in surgical time of this length is associated with a slightly higher risk of infection, studies have not found more complications in patients undergoing acute TMR compared to those receiving standard care. The burden of the study is minimal, as participation only requires patients to fill out multiple online questionnaires at five evaluation moments (at 2 weeks, and at 3, 6, 9, and 12 months). Prophylactic TMR results in a reduction of the chance to develop PAP. The risks and the burden for patients are negligible.

Study Timeline

• Study First Submitted: 2024-07-12
• Study First Submitted QC: 2024-12-02
• Study First Posted: 2024-12-05
• Study Start: 2024-12-31
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-26
• Last Update Posted: 2025-02-27
• Primary Completion: 2028-01-01
• Study Completion: 2028-01-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 203

Inclusion Criteria

• Patients scheduled for a lower extremity amputation (transfemoral to transtibial) as a primary or secondary sequela of vascular disease.

Exclusion Criteria

• Less than 18 years of age
• Over 75 years of age
• Other reasons for amputation besides a primary or secondary sequela of vascular disease (i.e., traumatic or neoplasms)
• Insensate limbs at the level of amputation
• CRPS (Complex Regional Pain Syndrome)
• Existing neuroma or prior neuroma surgery in the affected limb
• Physiologically unstable patients at the time of amputation
• Cognitive impairment, delirium
• Undergoing radiotherapy on the affected limb
• Unfit for general anesthesia
• No nerve surgeon available to perform TMR

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Postoperative residual limb pain	at 12 months	Postoperative residual limb pain will be scored on the 11-point (0-10) Numeric Rating Scale (NRS) for 30 consecutive days in a pain diary. A higher score indicates more pain.
Postoperative phantom limb pain	at 12 months	Postoperative phantom limb pain will be scored on the 11-point (0-10) Numeric Rating Scale (NRS) for 30 consecutive days in a pain diary. A higher score indicates more pain.
Postoperative pain behavior	at 12 months	Postoperative pain behavior will be scored using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Behavior Short Form 7a. The results will be scored on a scale from 7 to 35 points, with a higher score indicating that pain has a greater influence on behavior.
Postoperative pain interference	at 12 months	Postoperative pain interference will be scored using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference Short Form 8a. The results will be scored on a scale from 8 to 40 points, where a higher score indicates greater interference of pain with daily life

Secondary Outcome Measures

Name	Time	Method
Pain medication use	at 3, 6, 9, and 12 months	The Medication Quantification Scale measures the extent of pain medication use. A higher score indicates an increased use or dosage of pain medication.
Type of pain	at 3, 6, 9 and 12 months	Type of pain (local, diffuse, radiating) will be reported using the pain sketches from the Interdisciplinary Care for Amputees Network (ICAN).
Postoperative residual limb pain	at 3, 6, and 9 months	Postoperative residual limb pain will be scored on the 11-point (0-10) Numeric Rating Scale (NRS) at one timepoint. A higher score indicates more pain.
Postoperative phantom limb pain	at 3, 6, and 9 months	Postoperative phantom limb pain will be scored on the 11-point (0-10) Numeric Rating Scale (NRS) at one timepoint. A higher score indicates more pain.
Postoperative pain behavior	at 3, 6, and 9 months	Postoperative pain behavior will be scored using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Behavior Short Form 7a. The results will be scored on a scale from 7 to 35 points, with a higher score indicating that pain has a greater influence on behavior.
Postoperative pain interference	at 3, 6, and 9 months	Postoperative pain interference will be scored using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference Short Form 8a. The results will be scored on a scale from 8 to 40 points, where a higher score indicates greater interference of pain with daily life
Neuropathic pain	at 12 months	Using the Neuropathic pain component in chronic pain syndromes (PainDetect) questionnaire. The results will be scored on a scale from 0 to 38. A higher score indicates a greater likelihood of experiencing neuropathic pain
Hospital anxiety	at 12 months	Using the Hospital Anxiety and Depression Scale (HADS). The results will be scored on a scale from 0 to 21. A higher score indicates a greater likelihood of experiencing anxiety
Depression	at 12 months	Using the Hospital Anxiety and Depression Scale (HADS). The results will be scored on a scale from 0 to 21. A higher score indicates a greater likelihood of experiencing depression.
Global perceived effect	at 12 months	Using the Global Perceived effect (GPE-DV) questionnaire to evaluate the patients' view on recovery and satisfaction of the treatment.
Prosthetic rehabilitation	at 12 months	Measured with the Prosthetic Limb Users Survey of Mobility (PLUS-M, seven items short form). The results will be scored on a scale from 7 to 35. A higher score indicates a better prosthetic rehabilitation.
EuroQol-5D-5L	at 2 weeks, and at 3, 6, 9 and 12 months	Quality of life using the EuroQol-5D-5L questionnaire. A higher score indicates worse quality of life.
Medical consumption costs	at 3, 6, 9, and 12 months	Cost effectiveness analysis with a trial-based cost-utility analysis from a societal perspective (i.e., cost per QALY). Using the Medical Consumption Questionnaire (iMCQ)
Productivity costs	at 3, 6, 9, and 12 months	Cost effectiveness analysis with a trial-based cost-utility analysis from a societal perspective (i.e., cost per QALY). Using the Productivity Costs Questionnaire (iPCQ)
Budget impact analysis (BIA).	at 12 months	Budget impact analysis using the ZonMW BIA tool to estimate the financial impact of different implementation scenarios at the national level

Trial Locations

Locations (7)

Amsterdam University Medical Center; 🇳🇱 Amsterdam, North Holland, Netherlands

Isala Zwolle; 🇳🇱 Zwolle, Overijssel, Netherlands

Leiden University Medical Center; 🇳🇱 Leiden, South Holland, Netherlands

Alrijne Zorggroep; 🇳🇱 Leiderdorp, South Holland, Netherlands

Erasmus Medical Center; 🇳🇱 Rotterdam, South Holland, Netherlands

Haaglanden Medisch Centrum; 🇳🇱 The Hague, South Holland, Netherlands

University Medical Center Utrecht; 🇳🇱 Utrecht, Netherlands