Results of Nerve Surgery to Treat PostAmputation Pain

Official title

Results of Nerve Surgery to Treat PostAmputation Pain (TreatPAP): a Prospective Study

Overview

Rationale: Postamputation pain (PAP) is frequently seen after amputations and is a severe lifelong disabling condition affecting quality of life (QoL). Different nerve surgical techniques are available to treat PAP if non-surgical treatment options are not sufficient. Multiple techniques have been described for treatment of symptomatic neuromas with varying results. Techniques described include traction neurectomy with/without implantation, nerve grafting, nerve capping, regenerative peripheral nerve interface, and targeted muscle reinnervation (TMR). In the Leiden University Medical Center (LUMC), the most common techniques to treat painful neuromas include TMR and fascicular split (FS). TMR involves coaptating the transected mixed nerve to functional motor nerves, showing promising results in recent studies. FS is a technique closely related to neurectomy with implantation in a functional muscle. The difference is that with FS, the nerve is split into fascicles before implantation to allow for better distribution of nerve fibers. These techniques have not yet been compared. In this study, the investigators will compare both these techniques in a prospective setting for the treatment of PAP. The hypothesis is, that after 12 months, pain will be diminished and QoL will be increased in all patients versus the pre-operative status. There will be little to no difference in outcome between the surgical techniques used. Objective: To evaluate limb pain in patients with intractable postamputation pain (residual limb pain and phantom limb pain) one year after nerve embedding surgery following the standardized workup of the LUMC. Study design: Prospective study Study population: Patients 18 years of age or older, with a history of more than 6 months of intractable postamputation neuropathic limb pain, with no history of previous surgical intervention for pain treatment, referred to the Leiden Nerve Center. Main study parameters/endpoints: The mean difference in pain scores for phantom limb pain and residual limb pain one year postoperatively. An average pain score from the past 7 days is used for PLP and RLP individually, on the 11-point (0-10) numerical rating scale (NRS). Additionally, the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Behavior and Interference Questionnaire Short Forms (7a and 8a, respectively) are used one year postoperatively. Nature and extent of the burden and risks associated with participation, benefit, and group relatedness: Both techniques are currently used in the Leiden University Medical Center (LUMC) and considered standard of care. The decision to perform either technique is solely dependent on the personal preference of the treating nerve surgeon. The results of this trial will improve the understanding of the treatment effect of both surgical techniques with a minimal patient burden. Participation requires patients to complete 3-4 non-invasive questionnaires about pain, quality of life, depression and anxiety, and mobility over a period of 2 years. The pre-operative (if applicable) and 12-month postoperative questionnaire will each take approximately 15 minutes to complete. The other two questionnaires at 18 and 24 months postoperative will take approximately 3-4 minutes to complete. Additionally, participants will fill out a daily questionnaire consisting of one to three questions about pain for 7 consecutive days at 12 months.

Detailed description

Postamputation pain (PAP) is a common sequela after major lower limb amputation, with an estimated incidence of 61%. PAP can be divided into two major categories: phantom limb pain (PLP) and residual limb pain (RLP, 'stump pain'). Both RLP and PLP are predominantly driven by the cut nerve endings during the amputation, that form terminal-neuromas. PAP is known to compromise prosthetic rehabilitation and profoundly diminishes the quality of life after amputation. When PAP develops, it is extremely difficult to treat. When non-surgical treatment fails, or side effects of medication dominate patients' lives, surgery for PAP is occasionally undertaken. Nerve surgical techniques that are then applied differ widely and lack any solid scientific base. In general, secondary surgery for PAP includes resection of the neuroma and transposition of the freshened nerve into a more favorable environment, such as muscle, bone, vessels, or fat. This nerve implantation technique has been described since 1918 to treat painful neuromas, showing good results ranging from 64 to 82% of pain relief. Based on the vast experience gained over a 25-year period in the Leiden Nerve Center in treating painful neuromas, an adaptation of the nerve implantation method was developed called the Fascicular Split (FS) technique to treat PAP. In the FS technique, after transecting the neuroma, the nerve is first split into multiple fascicles before implanting the nerve in the muscle. This allows for better distribution of the nerve in the muscle, resulting in less neuroma formation. The strength of FS is its relative simplicity, which is crucial for the wider implementation in routine care. Promising results were observed applying this technique in a small series (n=8) of patients with PAP yielding a long-lasting, life-changing effect in all but one patient. In some cases, FS was performed years after the initial amputation and after previous failed neuroma surgeries. Other nerve handling techniques to treat symptomatic neuroma include centro-central neurorrhaphy, End-to-Side neurorrhaphy, Graft to Nowhere, Targeted Muscle Reinnervation (TMR), and Regenerative Peripheral Nerve Interface. TMR is, after simply embedding the nerve in healthy tissue, the best studied and most promising technique to treat PAP. Several cohort studies and a recent randomized trial in secondary surgery for PAP show that a nerve surgical technique called Targeted Muscle Reinnervation (TMR) is effective in treating PAP. However, the main disadvantage of TMR is that it is a time-consuming procedure.

To date, there are no studies that compare both techniques for the treatment of PAP. The investigators believe that the treatment FS yields similar results to TMR. Moreover, in terms of clinical applicability, the FS technique is easier to learn, does not require extensive nerve surgical skills, and does not take much time to perform.

Few papers have been published on TMR as a treatment for postamputation pain. Despite issues with the validity of the articles, results of PLP and RLP were consistently in favor of TMR as a technique regarding all outcome measures, including intensity and interference with daily activities. FS, although not mentioned in the literature, has many similarities with nerve implantation, which showed similarly good results for the treatment of painful neuromas. However, there have been no studies to date that directly compare the two techniques.

PAP is a lifelong disabling condition profoundly affecting quality of life. Nerve embedding surgical techniques (simple, FS, and TMR) have proven to be effective to treat postamputation pain. Preliminary results show that simple embedding, TMR, and FS are potentially good techniques to treat invalidating PAP. However, no comparative studies have been performed.

The investigators hypothesize that FS will show equally good results compared to TMR in the surgical treatment of intractable PAP, reducing pain, and improving quality-of-life (QoL) and mobility.

The investigators propose a prospective observational cohort study evaluating outcomes after various nerve embedding techniques following a standardized selection protocol in patients with intractable post-amputation pain after a major limb amputation.

Interventions

• Procedure Fascicular split
  Fasicular split surgical technique: 1. Painful nerve is identified and the neuroma is resected. 2. Split the nerve into its constituent multiple nerve fascicles 3. Create a deep muscle pocket for each individual fascicle 4. Plant each fascicle into a separate muscle compartment and fixate the fascicle in place with tissue glue.
• Procedure Targeted Muscle Reinnervation
  Targeted Muscle Reinnervation surgical technique 1. Painful nerve is identified and the neuroma is resected. 2. 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 3. End-to-end nerve coaptation is performed between the amputated nerve and the transected motor nerve branch.

Primary outcome measures

• Phantom limb pain measured on the 11-point (0-10) numeric rating scale. [Time frame: 1 year postoperatively]
• Residual limb pain measured on the 11-point numeric rating scale [Time frame: 1 year postoperatively]
• PROMIS pain behavior short form 7a [Time frame: 1 year postoperatively]
• PROMIS pain interference short form 8a [Time frame: 1 year postoperatively]

Secondary outcome measures (12)

• Phantom limb pain using the 11-point (0-10) numeric rating scale [Time frame: From enrolment until 24 months post-operatively]
• Residual limb pain using the 11-point (0-10) numeric rating scale [Time frame: From enrolment until 24 months postoperatively]
• PROMIS pain behavior 7a short form in Dutch-Flemish [Time frame: From enrolment until 24 months postoperatively]
• PROMIS pain interference 8a short form in Dutch-Flemish [Time frame: From enrolment until 24 months postoperatively]
• Quality of life (EQ-5D-5L) [Time frame: From enrolment until 24 months postoperatively]
• Pain type using the ICAN localization map [Time frame: From enrolment until 12 months postoperatively]
• Neuropathic pain using the PainDetect [Time frame: From enrolment until 12 months postoperatively]
• Hospital anxiety and depression using the HADS [Time frame: From enrolment until 12 months postoperatively]
• Perceived treatment effect using the GPE-DV [Time frame: at 12 months postoperativley]
• Prosthetic rehabilitation using the PLUS-M [Time frame: From enrolment until 12 months postoperatively]
• Changes in sensory quality in the amputated stump using quantitative sensory testing (QST) [Time frame: at enrolment until 12 months postoperative]
• Quantified neuroma perfusion using near-infrared fluorescence using indocyanine green [Time frame: Peri-operatively]

Eligibility criteria

Inclusion criteria

• Age older than or equal to 18 years
• Intractable postamputation pain

Exclusion criteria

• Cognitive impairment or delirium at the time of inclusion
• Having received previous radiotherapy on the affected limb
• Patients who are unable to comprehend the informed consent form or the questionnaires used in the current study
• Unfit for general anesthesia

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

Healthy volunteers: No

Study design

Observational model

Case-control

Study locations

Netherlands · 1 center

• Leiden University Medical Center — Leiden

Publications

• Anné C, de Laat FA, Hafner BJ, et al. "Dutch-Flemish translation of the Prosthetic Limb Users Survey of Mobility (PLUS-M)". Poster tijdens het PROMIS congres Praag. 2022.
• Hudak PL, Wright JG. The characteristics of patient satisfaction measures. Spine (Phila Pa 1976). 2000 Dec 15;25(24):3167-77. doi: 10.1097/00007632-200012150-00012. PMID 11124733
• Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983 Jun;67(6):361-70. doi: 10.1111/j.1600-0447.1983.tb09716.x. PMID 6880820
• Freynhagen R, Baron R, Gockel U, Tolle TR. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin. 2006 Oct;22(10):1911-20. doi: 10.1185/030079906X132488. PMID 17022849
• Gomez-Eslava B, Raasveld FV, Hoftiezer YAJ, McCarty JC, Daddario JL, Valerio IL, Heng M, Eberlin KR. Pain Sketches to Predict Pain following Primary Targeted Muscle Reinnervation in Amputees. Plast Reconstr Surg. 2024 May 1;153(5):1162-1171. doi: 10.1097/PRS.0000000000010762. Epub 2023 May 26. PMID 37252909
• Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, Badia X. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011 Dec;20(10):1727-36. doi: 10.1007/s11136-011-9903-x. Epub 2011 Apr 9. PMID 21479777
• Harden RN, Weinland SR, Remble TA, Houle TT, Colio S, Steedman S, Kee WG; American Pain Society Physicians. Medication Quantification Scale Version III: update in medication classes and revised detriment weights by survey of American Pain Society Physicians. J Pain. 2005 Jun;6(6):364-71. doi: 10.1016/j.jpain.2005.01.350. PMID 15943958
• Terwee CB, Roorda LD, de Vet HC, Dekker J, Westhovens R, van Leeuwen J, Cella D, Correia H, Arnold B, Perez B, Boers M. Dutch-Flemish translation of 17 item banks from the patient-reported outcomes measurement information system (PROMIS). Qual Life Res. 2014 Aug;23(6):1733-41. doi: 10.1007/s11136-013-0611-6. Epub 2014 Jan 9. PMID 24402179

Identifiers

NCT: NCT07605754 · 25-3058

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗