Prevention of PostAmputation Pain With Targeted Muscle Reinnervation

Official title

Prevention of PostAmputation Pain With Targeted Muscle Reinnervation: A National, Multicenter, Randomized, Sham-controlled Superiority Trial, Comparing Standard Neurectomy With Targeted Muscle Reinnervation in Amputations of the Lower Extremities

Overview

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.

Interventions

• Procedure Targeted Muscle Reinnervation (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.
• Procedure Standard neurectomy
  During the amputation a standard neurectomy will be performed based on the surgeons preference. Standard neurectomy will include cutting of the nerve, with or without traction, with or without coagulation, and with or without infiltration with a local anesthetic (i.e., ropivacaine) or phenol. Ligation of the nerve will not be allowed.

Primary outcome measures

• Postoperative residual limb pain [Time frame: at 12 months]
• Postoperative phantom limb pain [Time frame: at 12 months]
• Postoperative pain behavior [Time frame: at 12 months]
• Postoperative pain interference [Time frame: at 12 months]

Secondary outcome measures (12)

• Postoperative residual limb pain [Time frame: at 3, 6, and 9 months]
• Postoperative phantom limb pain [Time frame: at 3, 6, and 9 months]
• Postoperative pain behavior [Time frame: at 3, 6, and 9 months]
• Postoperative pain interference [Time frame: at 3, 6, and 9 months]
• Neuropathic pain [Time frame: at 12 months]
• Hospital anxiety [Time frame: at 12 months]
• Depression [Time frame: at 12 months]
• Global perceived effect [Time frame: at 12 months]
• Prosthetic rehabilitation [Time frame: at 12 months]
• EuroQol-5D-5L [Time frame: at 2 weeks, and at 3, 6, 9 and 12 months]
• Medical consumption costs [Time frame: at 3, 6, 9, and 12 months]
• Productivity costs [Time frame: at 3, 6, 9, and 12 months]

Eligibility criteria

Inclusion criteria

• Patients aged between 18 and 75 years old.
• Scheduled for a transtibial, through-knee, or transfemoral amputation as a primary or secondary sequela of vascular disease.

Exclusion criteria

• Insensate limbs at the level of amputation.
• Complex Regional Pain Syndrome.
• Existing neuroma or prior neuroma surgery in the affected limb.
• Undergoing radiotherapy on the affected limb.
• Cognitive impairment, or delirium at the time of consent.
• Patients who are unfit for general anesthesia.
• No nerve surgeon trained in the TMR procedure is available

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Prevention

Study locations

Netherlands · 7 centers

• Amsterdam University Medical Center — Amsterdam
• Isala Zwolle — Zwolle
• Leiden University Medical Center — Leiden
• Alrijne Zorggroep — Leiderdorp
• Erasmus Medical Center — Rotterdam
• Haaglanden Medisch Centrum — The Hague
• University Medical Center Utrecht — Utrecht

Publications

• Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole MR. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001 Nov;94(2):149-158. doi: 10.1016/S0304-3959(01)00349-9. PMID 11690728
• Mioton LM, Dumanian GA, Shah N, Qiu CS, Ertl WJ, Potter BK, Souza JM, Valerio IL, Ko JH, Jordan SW. Targeted Muscle Reinnervation Improves Residual Limb Pain, Phantom Limb Pain, and Limb Function: A Prospective Study of 33 Major Limb Amputees. Clin Orthop Relat Res. 2020 Sep;478(9):2161-2167. doi: 10.1097/CORR.0000000000001323. PMID 32452928
• Dal-Re R, Janiaud P, Ioannidis JPA. Real-world evidence: How pragmatic are randomized controlled trials labeled as pragmatic? BMC Med. 2018 Apr 3;16(1):49. doi: 10.1186/s12916-018-1038-2. PMID 29615035
• Torrance N, Lawson KD, Afolabi E, Bennett MI, Serpell MG, Dunn KM, Smith BH. Estimating the burden of disease in chronic pain with and without neuropathic characteristics: does the choice between the EQ-5D and SF-6D matter? Pain. 2014 Oct;155(10):1996-2004. doi: 10.1016/j.pain.2014.07.001. Epub 2014 Jul 11. PMID 25020004
• Parsons B, Schaefer C, Mann R, Sadosky A, Daniel S, Nalamachu S, Stacey BR, Nieshoff EC, Tuchman M, Anschel A. Economic and humanistic burden of post-trauma and post-surgical neuropathic pain among adults in the United States. J Pain Res. 2013 Jun 17;6:459-69. doi: 10.2147/JPR.S44939. Print 2013. PMID 23825931
• Groffen AJ, Klapwijk T, van Rootselaar AF, Groen JL, Tijssen MA. Genetic and phenotypic heterogeneity in sporadic and familial forms of paroxysmal dyskinesia. J Neurol. 2013 Jan;260(1):93-9. doi: 10.1007/s00415-012-6592-5. Epub 2012 Jun 30. PMID 22752065
• Valerio IL, Dumanian GA, Jordan SW, Mioton LM, Bowen JB, West JM, Porter K, Ko JH, Souza JM, Potter BK. Preemptive Treatment of Phantom and Residual Limb Pain with Targeted Muscle Reinnervation at the Time of Major Limb Amputation. J Am Coll Surg. 2019 Mar;228(3):217-226. doi: 10.1016/j.jamcollsurg.2018.12.015. Epub 2019 Jan 8. PMID 30634038
• Frantz TL, Everhart JS, West JM, Ly TV, Phieffer LS, Valerio IL. Targeted Muscle Reinnervation at the Time of Major Limb Amputation in Traumatic Amputees: Early Experience of an Effective Treatment Strategy to Improve Pain. JB JS Open Access. 2020 May 6;5(2):e0067. doi: 10.2106/JBJS.OA.19.00067. eCollection 2020 Apr-Jun. PMID 33123667

Identifiers

NCT: NCT06719245 · NL87196.058.24

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗