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Surgical Treatments for Postamputation Pain

Primary Purpose

Residual Limb Pain, Amputation Neuroma, Phantom Limb Pain

Status
Recruiting
Phase
Not Applicable
Locations
International
Study Type
Interventional
Intervention
Targeted Muscle Reinnervation (TMR)
Regenerative Peripheral Nerve Interface (RPNI)
Standard neuroma treatment, neuroma excision, and muscle burying
Sponsored by
Center for Bionics and Pain Research
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Residual Limb Pain

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • The participant must have a major limb amputation.
  • The participant is ≥ 18 years old at the time of consent.
  • The participant must be in generally good health to undergo a surgical treatment, as per the clinical investigator's opinion.
  • The post-operative amputation follow-up is greater than one year at time of consent.
  • The participant must be diagnosed with neuroma pain, stump pain, or phantom limb in their residual limb, at latest the time of screening visit.
  • The participant must have an average pain score (of neuroma pain, sump pain or PLP) greater than three on the Numerical Rating Scale (NRS, 0-10) after the baseline period.
  • If the participant is prescribed pharmacological treatments for pain, there must be no variations in dosage (steady consumption) for at least one month before the screening visit.
  • If the participant is prescribed non-pharmacological treatments for pain, such as spinal cord stimulation, transcutaneous electrical nerve stimulation or mirror therapy, the treatment must have ended at least one month before the screening visit.
  • The participant has sufficient understanding of Swedish or English to be able to participate in all study assessments, as per the principal investigator's opinion.

Exclusion Criteria:

  • Neurological or other conditions that affect nerve regeneration.
  • Active infection in the residual limb.
  • Smokers or less than six weeks of smoking cessation at inclusion.
  • Mental inability, reluctance or language difficulties that result in difficulty understanding the meaning of study participation, as per the principal investigator's discretion.
  • Ongoing participation in a clinical study that the clinical investigator deems detrimental to participation in this study.

Sites / Locations

  • Northwestern Memorial Hospital
  • Massachusetts General Hospital
  • University of Michigan Health System
  • Dandenong Hospital, Monash Health
  • University of Alberta Hospital
  • Worker Hospital
  • Rizzoli Orthopedic Institute
  • Sahlgrenska University HospitalRecruiting
  • NHS Lothian, NHS Clyde & Greater Glasgow, and NHS Grampian

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Active Comparator

Arm Label

Targeted Muscle Reinnervation (TMR)

Regenerative Peripheral Nerve Interface (RPNI)

Standard neuroma treatment, neuroma excision, and muscle burying

Arm Description

The surgical procedure comprises three steps: preparation of the donor nerve, identification of a motor branch to the targeted muscle, and nerve coaptation. To prepare the donor nerve, the surgeon will identify the nerve with a painful neuroma and resect the neuroma up to healthy fascicles. Next, the surgeon will identify a motor branch to a nearby target muscle and will confirm muscle contraction using a hand-held nerve stimulator. The motor branch to the target muscle will be transected as close as possible to its entry point without tension. In the final step, the previous nerve stump from which the neuroma was resected will be transferred and coapted to the newly severed motor branch that innervates the target muscle and secured by 2-3 non-resorbable monofilament sutures. The surgery time is approximately 2-3 hours and it takes place in the hospital.

The RPNI procedure involves construction of a residual peripheral nerve split into several nerve fascicles and implanted into free skeletal muscle grafts. First, the surgeon identifies the nerve with a painful neuroma and resect the neuroma up to healthy fascicles. Then, a longitudinal intraneural dissection will be performed exposing its fascicles. Next, autologous muscle grafts will be harvested from a healthy donor site, and the dissected nerve stumps will be placed parallel to the muscle fibers. The nerve stump will be secured to the muscle graft, thereafter the graft will be wrapped around the nerve stump and anchored in the folded graft, thus creating an RPNI. This will be repeated for each fascicle obtained from splitting the transected nerve. Lastly, the RPNIs will be placed in a protected area. The surgery time is approximately 2-3 hours and it takes place in the hospital.

The standard neuroma treatment, also called neuroma transposition, includes excision of the terminal neuroma and burying the nerve into an adjacent deep muscle.The standard neuroma treatment entails the excision of the terminal neuroma and then implanting the nerve into an adjacent muscle. Firstly, the surgeon will identify the nerve with a painful neuroma and thereafter resect the neuroma up to healthy fascicles. Next, the surgeon will identify a nearby muscle which is not involved in joint motion and has limited output opportunities for the nerve. The nerve will then be channeled at least 1 cm inside the muscle without applying any tension to it and secured by 1-2 non-resorbable monofilament sutures. The identified nerve with the painful neuroma will not be treated with any additional therapy than the resection (e.g., diathermy, pharmacotherapy, crushing, etc.). The surgery time is approximately 1-2 hours and it takes place in the hospital.

Outcomes

Primary Outcome Measures

Residual limb pain intensity
Difference in residual limb pain intensity will be measured by numerical rating scale (NRS, 0-10), where 0 - no pain and 10 - worst imaginable pain, between baseline period and at the 12-month follow-up visit.

Secondary Outcome Measures

Neuroma pain intensity
Difference in neuroma pain intensity will be measured by numerical rating scale (NRS, 0-10), where 0 - no pain and 10 - worst imaginable pain, between baseline period and at the 12-month follow-up visit.
Phantom limb pain intensity
Difference in phantom limb pain intensity will be measured by numerical rating scale (NRS, 0-10), where 0 - no pain and 10 - worst imaginable pain, between baseline period and at the 12-months follow-up visit.

Full Information

First Posted
July 12, 2021
Last Updated
September 27, 2023
Sponsor
Center for Bionics and Pain Research
Collaborators
Vastra Gotaland Region, Göteborg University, Chalmers University of Technology, Istituto Ortopedico Rizzoli, Hospital del Trabajador de Santiago, NHS Lothian, NHS Greater Clyde and Glasgow, NHS Grampian, Northwestern Memorial Hospital, University of Michigan, Massachusetts General Hospital, Dandenong Hospital, The Bionics Institute of Australia, University of Alberta
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1. Study Identification

Unique Protocol Identification Number
NCT05009394
Brief Title
Surgical Treatments for Postamputation Pain
Official Title
Surgical Treatments for Postamputation Pain
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 20, 2023 (Actual)
Primary Completion Date
June 2025 (Anticipated)
Study Completion Date
June 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Center for Bionics and Pain Research
Collaborators
Vastra Gotaland Region, Göteborg University, Chalmers University of Technology, Istituto Ortopedico Rizzoli, Hospital del Trabajador de Santiago, NHS Lothian, NHS Greater Clyde and Glasgow, NHS Grampian, Northwestern Memorial Hospital, University of Michigan, Massachusetts General Hospital, Dandenong Hospital, The Bionics Institute of Australia, University of Alberta

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a double-blind randomised controlled trial (RCT) which compares the effectiveness of three surgical techniques for alleviating residual limb pain (RLP), neuroma pain and phantom limb pain (PLP). The three surgical treatments are Targeted Muscles Reinnervation (TMR), Regenerative Peripheral Nerve Interface (RPNI), and an active control (neuroma excision and muscle burying). Patients will be follow-up for 4 years.
Detailed Description
Residual limb pain (RLP), neuroma pain, and phantom limb pain (PLP) can develop after the loss of a body part and fall within the umbrella term postamputation pain. However, the underlaying causes to postamputation pain are diverse and must be addressed accordingly. Surgical treatments for RLP have become a popular approach and have shown great potential for successful outcomes. The two surgical interventions, Targeted Muscle Reinnervation (TMR) and Regenerative Peripheral Nerve Interface (RPNI), are globally used in pain management therapies. This is a multi-centre, double-blind, superiority RCT which takes place at 9 hospitals in 7 countries:the Sahlgrenska University Hospital in Gothenburg, Sweden; the Rizzoli Orthopaedic Institute in Bologna, Italy; the University of Alberta Hospital in Edmonton, Canada; Worker Hospital in Santiago, Chile; the NHS Lothian, NHS Clyde & Greater Glasgow, and NHS Grampian, UK; Dandenong Hospital, Monash Health in Melbourne, Australia; the Northwestern Memorial Hospital in Chicago, USA; the University of Michigan Health System in Ann Arbor, Michigan, USA; and within the Massachusetts General Hospital in Boston, USA. One hundred ten participants will be recruited and randomly assigned to one of three surgical treatments (TMR, RPNI, or control) in an equal allocation ratio (n = 37 per group). Each participant will be followed up short term (1, 3, 6, and 12 months post-surgery) and long term (2 and 4 years post-surgery). After the 12-month follow-up, the study will be unblinded for the evaluator and the participants. If the participants are unsatisfied with the outcome of the treatment, they may request one of the other treatments. In such a case, a medical evaluation and further treatment options will be discussed in consultation with the clinical investigator at the site. The study design is chosen to be able to follow RLP, neuroma pain and PLP intensity before and after surgical treatment as well as to investigate how pain develops up to four years post-surgery. The evaluation methods in the study are based on previously used methods in the literature for RLP-, neuroma- and PLP-related pain research. The questionnaires are previously used in clinical settings.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Residual Limb Pain, Amputation Neuroma, Phantom Limb Pain, Pain, Neuropathic, Pain, Nerve

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantOutcomes Assessor
Allocation
Randomized
Enrollment
110 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Targeted Muscle Reinnervation (TMR)
Arm Type
Active Comparator
Arm Description
The surgical procedure comprises three steps: preparation of the donor nerve, identification of a motor branch to the targeted muscle, and nerve coaptation. To prepare the donor nerve, the surgeon will identify the nerve with a painful neuroma and resect the neuroma up to healthy fascicles. Next, the surgeon will identify a motor branch to a nearby target muscle and will confirm muscle contraction using a hand-held nerve stimulator. The motor branch to the target muscle will be transected as close as possible to its entry point without tension. In the final step, the previous nerve stump from which the neuroma was resected will be transferred and coapted to the newly severed motor branch that innervates the target muscle and secured by 2-3 non-resorbable monofilament sutures. The surgery time is approximately 2-3 hours and it takes place in the hospital.
Arm Title
Regenerative Peripheral Nerve Interface (RPNI)
Arm Type
Active Comparator
Arm Description
The RPNI procedure involves construction of a residual peripheral nerve split into several nerve fascicles and implanted into free skeletal muscle grafts. First, the surgeon identifies the nerve with a painful neuroma and resect the neuroma up to healthy fascicles. Then, a longitudinal intraneural dissection will be performed exposing its fascicles. Next, autologous muscle grafts will be harvested from a healthy donor site, and the dissected nerve stumps will be placed parallel to the muscle fibers. The nerve stump will be secured to the muscle graft, thereafter the graft will be wrapped around the nerve stump and anchored in the folded graft, thus creating an RPNI. This will be repeated for each fascicle obtained from splitting the transected nerve. Lastly, the RPNIs will be placed in a protected area. The surgery time is approximately 2-3 hours and it takes place in the hospital.
Arm Title
Standard neuroma treatment, neuroma excision, and muscle burying
Arm Type
Active Comparator
Arm Description
The standard neuroma treatment, also called neuroma transposition, includes excision of the terminal neuroma and burying the nerve into an adjacent deep muscle.The standard neuroma treatment entails the excision of the terminal neuroma and then implanting the nerve into an adjacent muscle. Firstly, the surgeon will identify the nerve with a painful neuroma and thereafter resect the neuroma up to healthy fascicles. Next, the surgeon will identify a nearby muscle which is not involved in joint motion and has limited output opportunities for the nerve. The nerve will then be channeled at least 1 cm inside the muscle without applying any tension to it and secured by 1-2 non-resorbable monofilament sutures. The identified nerve with the painful neuroma will not be treated with any additional therapy than the resection (e.g., diathermy, pharmacotherapy, crushing, etc.). The surgery time is approximately 1-2 hours and it takes place in the hospital.
Intervention Type
Procedure
Intervention Name(s)
Targeted Muscle Reinnervation (TMR)
Intervention Description
Surgical procedure used to rewire injured proximal nerves to motor nerves directly innervating an otherwise redundant target muscle.
Intervention Type
Procedure
Intervention Name(s)
Regenerative Peripheral Nerve Interface (RPNI)
Intervention Description
Surgical procedure where the the nerve is split into fascicles and wrapped in free muscle grafts.
Intervention Type
Procedure
Intervention Name(s)
Standard neuroma treatment, neuroma excision, and muscle burying
Intervention Description
Surgical procedure where the neuroma is excised and the nerve stump is buried in an adjacent deep muscle.
Primary Outcome Measure Information:
Title
Residual limb pain intensity
Description
Difference in residual limb pain intensity will be measured by numerical rating scale (NRS, 0-10), where 0 - no pain and 10 - worst imaginable pain, between baseline period and at the 12-month follow-up visit.
Time Frame
Baseline to 12-month post-surgery
Secondary Outcome Measure Information:
Title
Neuroma pain intensity
Description
Difference in neuroma pain intensity will be measured by numerical rating scale (NRS, 0-10), where 0 - no pain and 10 - worst imaginable pain, between baseline period and at the 12-month follow-up visit.
Time Frame
Baseline to 12-month post-surgery
Title
Phantom limb pain intensity
Description
Difference in phantom limb pain intensity will be measured by numerical rating scale (NRS, 0-10), where 0 - no pain and 10 - worst imaginable pain, between baseline period and at the 12-months follow-up visit.
Time Frame
Baseline to12-month post-surgery

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: The participant must have a major limb amputation. The participant is ≥ 18 years old at the time of consent. The participant must be in generally good health to undergo a surgical intervention, as per the clinical investigator's opinion. Time since the last amputation must be over a year at the time of consent. The participant must have an average residual limb pain score equal or greater than 4 on the Numerical Rating Scale (NRS, 0-10) after the baseline period. If the participant has been prescribed pharmacological treatments for pain, there must be no variations in dosage (steady consumption) for at least 1 month before the screening visit. If the participant has been prescribed non-pharmacological treatments for pain, such as spinal cord stimulation, transcutaneous electrical nerve stimulation, and mirror therapy, the treatment must have ended at least 1 month before the screening visit. The participant must have a stable prosthetic fitting for at least a month before the screening visit. The participant has a sufficient understanding of the language in which the assessments will be conducted, as per the clinical investigator's opinion. Exclusion Criteria: Neurological or other conditions that affect nerve regeneration for the nerve to be treated. Active infection in the residual limb. Prior RPNI or TMR surgery of the nerve to be treated (with painful neuroma) to address postamputation pain. Mental disorders (e.g., schizophrenia, paranoia, psychosis, etc.), reluctance, or language difficulties that result in difficulty understanding the meaning of study participation. Ongoing participation in a clinical study that the clinical investigator deems detrimental to participation in this study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Emily Pettersen, MSc
Phone
+46764026503
Email
emily.pettersen@vgregion.se
First Name & Middle Initial & Last Name or Official Title & Degree
Max Ortiz Catalan, PhD
Email
maxortizc@outlook.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Max Ortiz Catalan, PhD
Organizational Affiliation
Center for Bionics and Pain Research
Official's Role
Principal Investigator
Facility Information:
Facility Name
Northwestern Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jason Ko, MD, PhD
Email
jason.ko@nm.org
First Name & Middle Initial & Last Name & Degree
Jason Ko, MD, PhD
First Name & Middle Initial & Last Name & Degree
Gregory Dumanian, MD, PhD
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ian Valerio, MD, PhD
Email
IVALERIO@mgh.harvard.edu
First Name & Middle Initial & Last Name & Degree
Ian Valerio, MD, PhD
First Name & Middle Initial & Last Name & Degree
Kyle Eberlin, MD, PhD
Facility Name
University of Michigan Health System
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Paul Cederna, MD, PhD
Email
cederna@med.umich.edu
First Name & Middle Initial & Last Name & Degree
Paul Cederna, MD, PhD
First Name & Middle Initial & Last Name & Degree
Theodore Alexander Kung, MD, PhD
Facility Name
Dandenong Hospital, Monash Health
City
Melbourne
Country
Australia
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michael Lo, MD, PhD
Email
mlo@bigpond.net.au
First Name & Middle Initial & Last Name & Degree
Michael Lo, MD, PhD
First Name & Middle Initial & Last Name & Degree
Michael Leung, MD, PhD
Facility Name
University of Alberta Hospital
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
AB T6G 2B7
Country
Canada
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Adil Ladak, MD, PhD
Email
aladak@ualberta.ca
First Name & Middle Initial & Last Name & Degree
Adil Ladak, MD, PhD
First Name & Middle Initial & Last Name & Degree
Hollie Power, MD, PhD
First Name & Middle Initial & Last Name & Degree
Jacqueline Hebert, MD, PhD
Facility Name
Worker Hospital
City
Santiago
Country
Chile
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Juan Manuel Breyer, MD, PhD
Email
jmbreyer@hotmail.com
First Name & Middle Initial & Last Name & Degree
Juan Manuel Breyer, MD, PhD
Facility Name
Rizzoli Orthopedic Institute
City
Bologna
State/Province
Emilia-Romagna
ZIP/Postal Code
40136
Country
Italy
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Paolo Sassu, MD, PhD
Email
sassupaolo@gmail.com
First Name & Middle Initial & Last Name & Degree
Paolo Sassu, MD, PhD
First Name & Middle Initial & Last Name & Degree
Francesca Pedrini, MD
Facility Name
Sahlgrenska University Hospital
City
Mölndal
State/Province
Västra Götaland
ZIP/Postal Code
431 80
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Max Ortiz Catalan, PhD
Email
maxortizc@outlook.com
First Name & Middle Initial & Last Name & Degree
Emily Pettersen, MSc
Email
emily.pettersen@vgregion.se
First Name & Middle Initial & Last Name & Degree
Carina Reinholdt, MD, PhD
First Name & Middle Initial & Last Name & Degree
Hannes Granberg, MD
Facility Name
NHS Lothian, NHS Clyde & Greater Glasgow, and NHS Grampian
City
Edinburgh
Country
United Kingdom
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Aidan Roche, MD, PhD
Email
aidan.roche@ed.ac.uk
First Name & Middle Initial & Last Name & Degree
Aidan Roche, MD, PhD
First Name & Middle Initial & Last Name & Degree
Andrew Hart, MD, PhD
First Name & Middle Initial & Last Name & Degree
Lorraine Harrington, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
30371518
Citation
Dumanian GA, Potter BK, Mioton LM, Ko JH, Cheesborough JE, Souza JM, Ertl WJ, Tintle SM, Nanos GP, Valerio IL, Kuiken TA, Apkarian AV, Porter K, Jordan SW. Targeted Muscle Reinnervation Treats Neuroma and Phantom Pain in Major Limb Amputees: A Randomized Clinical Trial. Ann Surg. 2019 Aug;270(2):238-246. doi: 10.1097/SLA.0000000000003088.
Results Reference
background
PubMed Identifier
24562875
Citation
Souza JM, Cheesborough JE, Ko JH, Cho MS, Kuiken TA, Dumanian GA. Targeted muscle reinnervation: a novel approach to postamputation neuroma pain. Clin Orthop Relat Res. 2014 Oct;472(10):2984-90. doi: 10.1007/s11999-014-3528-7.
Results Reference
background
PubMed Identifier
28293490
Citation
Woo SL, Kung TA, Brown DL, Leonard JA, Kelly BM, Cederna PS. Regenerative Peripheral Nerve Interfaces for the Treatment of Postamputation Neuroma Pain: A Pilot Study. Plast Reconstr Surg Glob Open. 2016 Dec 27;4(12):e1038. doi: 10.1097/GOX.0000000000001038. eCollection 2016 Dec.
Results Reference
background
PubMed Identifier
37131180
Citation
Pettersen E, Sassu P, Reinholdt C, Dahm P, Rolfson O, Bjorkman A, Innocenti M, Pedrini FA, Breyer JM, Roche A, Hart A, Harrington L, Ladak A, Power H, Hebert J, Ortiz-Catalan M. Surgical treatments for postamputation pain: study protocol for an international, double-blind, randomised controlled trial. Trials. 2023 May 2;24(1):304. doi: 10.1186/s13063-023-07286-0. Erratum In: Trials. 2023 Oct 9;24(1):654.
Results Reference
background
PubMed Identifier
34398088
Citation
Chang BL, Mondshine J, Attinger CE, Kleiber GM. Targeted Muscle Reinnervation Improves Pain and Ambulation Outcomes in Highly Comorbid Amputees. Plast Reconstr Surg. 2021 Aug 1;148(2):376-386. doi: 10.1097/PRS.0000000000008153.
Results Reference
background
PubMed Identifier
37063502
Citation
Bjorklund KA, Alexander J, Tulchin-Francis K, Yanes NS, Singh S, Valerio I, Klingele K, Scharschmidt T. Targeted Muscle Reinnervation for Limb Amputation to Avoid Neuroma and Phantom Limb Pain in Patients Treated at a Pediatric Hospital. Plast Reconstr Surg Glob Open. 2023 Apr 13;11(4):e4944. doi: 10.1097/GOX.0000000000004944. eCollection 2023 Apr.
Results Reference
background
PubMed Identifier
31461024
Citation
Kubiak CA, Kemp SWP, Cederna PS, Kung TA. Prophylactic Regenerative Peripheral Nerve Interfaces to Prevent Postamputation Pain. Plast Reconstr Surg. 2019 Sep;144(3):421e-430e. doi: 10.1097/PRS.0000000000005922.
Results Reference
background
PubMed Identifier
30634038
Citation
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.
Results Reference
background

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Surgical Treatments for Postamputation Pain

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