Surgical Treatments for Post-amputation Pain: Study Protocol for an International, Double-blind, Randomised Controlled Trial

doi:10.21203/rs.3.rs-1344117/v1

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Research Article

Surgical Treatments for Post-amputation Pain: Study Protocol for an International, Double-blind, Randomised Controlled Trial

https://doi.org/10.21203/rs.3.rs-1344117/v1

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published 02 May, 2023

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Background: Painful conditions such as neuroma pain, stump pain, and phantom limb pain (PLP) can manifest after amputation and are termed generally as post-amputation pain. The mechanisms underlying post-amputation pain are diverse and should be addressed accordingly. Different surgical treatment methods have shown potential for alleviating neuroma pain and at lesser degree stump pain and PLP. Two reconstructive surgical interventions, namely Targeted Muscle Reinnervation (TMR) and Regenerative Peripheral Nerve Interface (RPNI), are gaining popularity in post-amputation pain treatment with promising results. However, these two methods have not been directly compared in a randomised controlled trial (RCT). Here, we present a study protocol for a double-blind RCT to assess the effectiveness of TMR, RPNI, and a non-reconstructive procedure called neuroma transposition as an active control in alleviating neuroma pain, stump pain, and PLP.

Methods: Seventy-five upper and lower limb amputees suffering from post-amputation pain, are recruited, and randomly assigned to one of the surgical interventions (TMR, RPNI, or neuroma transposition) in an equal allocation ratio. Complete evaluations are performed during a baseline period prior to the surgical intervention and follow-ups are conducted in short-term (one-, three-, six-, and twelve-months post-surgery) and in long-term (three- and five-years post-surgery). After the twelve-months follow-up, the study is unblinded for the evaluator and the participants. If the participant is unsatisfied with the outcome to treatment at that time, further treatment including one of the other procedures will be discussed in consultation with the clinical investigator.

Discussion: A double-blind RCT is necessary for the establishment of evidence-based procedures, hence the motivation for this work. In addition, studies on pain are challenging due to the subjectivity of the experience and the lack of objective evaluation methods. Here, we mitigate this problem by including several different pain evaluation methods known to have clinical relevance. We decided to analyse the results using an adherence to protocol approach (per-protocol, PP), as this is more suitable than intention-to-treat (ITT) in pain studies with long-term follow-ups. This is because patients often experience initial pain relief post-surgery, but over time, gradually returns to pre-surgical levels. This could lead to misinterpretation of the clinical reality. We will instead report the actual values of pain and number of participants in each follow-up.

Trial registration: ClincialTrials.gov, NCT05009394.

neuroma pain

stump pain

phantom limb pain

targeted muscle reinnervation

regenerative peripheral nerve interfaces

randomised controlled trial

In addition to the loss of function, the amputation of extremities often results in neuropathic pain [1]. The underlaying causes of post-amputation pain are diverse and must be addressed accordingly [2]. Severed nerves generates the sprouting of axons resulting in a neuroma. A neuroma is a disorganized bulge at the distal end of the nerve comprising axons, Schawnn cells, endo- and peri-neural cells, all within a dense myofibroblast stroma [3]. Stimulation of neuromas is normally painful and can also elicit Phantom Limb Pain (PLP). The International Association for the Study of Pain (IASP) refers to PLP as painful sensations perceived in the missing limb¹, in other words, their operational definition is based on the location of perceived pain. However, PLP can be elicited by stimulation of nerve fibres that previously innervated nociceptors in the missing limb and are now trapped within the neuroma (“nociceptive PLP”), as well as due to maladaptive plastic changes in the nervous system (“neuropathic PLP”) [2]. Under IASP definition, neuroma pain is PLP because stimulation of neuromas normally results in painful sensations from the missing limb, yet the successful treatment of neuromas does not always resolve PLP [4]. Here, we make the distinction between neuroma pain (pain due to nociception perceived in the missing limb) and PLP (pain due to other sources than nociception perceived in the missing limb), as proposed by Ortiz-Catalan [2]. In addition to neuroma pain and PLP, the traumatic nature of amputations can result in stump pain [5]. Stump pain is all other types of pain perceived in the stump that are not associated with neuromas, such as pain arising from the joint or its surrounding tissue, and can also be caused by improper prosthetic fitting [6], Figure 1.

Historically, non-surgical treatments of post-amputation pain were considered more effective than surgical treatment options [7]. However, this has changed in the last decade with the development of surgical approaches that prevent the formation of neuromas by allowing severed nerves to grow into new target muscles [8]. Two reconstruction techniques have gained popularity for treatment of neuroma pain, Targeted Muscle Reinnervation (TMR) and Regenerative Peripheral Nerve Interface (RPNI). Both techniques are based on similar biological principles – reinnervation of denervated muscle – but there are important differences [9]. In TMR, the residual peripheral nerve is transferred to the stump of a nerve innervating a native muscle with a dispensable biomechanical function [10]. The RPNI procedure involves longitudinally dissecting the severed nerve into its main fascicles, which are then implanted into free muscle grafts [11, 12]. TMR was developed with the initial aim to increase the prosthetic function of a myoelectric artificial limb [13, 14]. However, in an early clinical series, it was observed that patients undergoing TMR surgery benefited from a notable pain reduction and no formation of new painful neuromas [15]. Pain reduction was later reported in a randomised controlled trial (RCT) in which a non-reconstructive active control was employed [10]. The non-reconstructive procedure (neuroma transposition) entailed dissecting the neuroma and burying the nerve into a muscle without denervating it. Similarly, in a retrospective clinical case series, patients reported decreased neuroma pain and PLP after undergoing RPNI surgery [11]. Despite the on-going widespread use of these two surgical techniques, clinical trials comparing the two procedures are lacking.

Study Objective

Here, we present the clinical study protocol for a double-blind RCT in which lower and upper extremity amputees are treated for post-amputation pain with three surgical approaches. The main objective is to assess the effectiveness of TMR and RPNI in treating. In addition to treatment with TMR or RPNI, we introduce an active control whereby severed nerves are surgically inserted into a remanent muscle that retains its original innervation (unlike TMR where the muscle is denervated from its native nerve).

Trial design

This is a double-blind RCT which takes place at Sahlgrenska University Hospital, Gothenburg, Sweden, and Rizzoli Orthopaedic Institute, Bologna, Italy. Seventy-five participants will be recruited and randomly assigned to one of three surgical treatments (TMR, RPNI, or neuroma transposition) in an equal allocation ratio (n=25 per group). Each participant will be followed-up short-term (one-, three-, six-, and twelve-month post-surgery) and long-term (three- and five-year post-surgery). After the twelve-month follow-up, the study is unblinded for the evaluator and the participants. If the participant is unsatisfied with the outcome of the treatment, they may request one of the other treatments. In this case a medical evaluation and further treatment options will be discussed in consultation with the clinical investigator. See study flowchart in Figure 2.

¹IASP global year against neuropathic pain 2014–2015, post-amputation pain, https://s3.amazonaws.com/rdcms-iasp/files/production/public/AM/Images/GYAP/Neuropathic/Postamputation%20Pain.pdf

2.1 Participants

2.1.1 Recruitment and inclusion of participants

Potential participants will be identified and recruited by healthcare professionals or among people who have had earlier contact with our research group. Clinical trial brochures will be distributed to prosthetic clinics, orthopaedic, and hand surgery departments. The trial will be advertised on social media, in local newspapers, and at national conferences in Sweden and Italy. Persons interested in participating will be provided with written information about the study and in Sweden persons will be directed to a pre-screening questionnaire via a secure platform provided by the online health system in Sweden (1177 formulärtjänst [16]). In Italy, persons will provide pre-screening answers either in paper or digital format. Answers to this questionnaire will be used to determine eligibility for the study. Those eligible, will be contacted by phone or via email within one to two weeks of submitting the questionnaire. If the potential participants are interested in participating in the study, they will be provided with an informed consent form (ICF) and invited to a screening visit. At the screening visit the principal investigator and the clinical investigator will perform a physical examination and any questions by the participant will be answered. The following is the study 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 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, Italian, 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.

During this clinical trial, participants will not be forbidden to receive other pain treatments if deem necessary by their physician. All pain treatments receive during this clinical trial will be recorded.

2.1.3 Withdrawal or termination of individual participants

Participants can discontinue their participation in the study at any time, without any consequences on their clinical treatment at their respective hospitals. The investigator can at any time terminate participation in the study for an individual if the participant’s safety can no longer be maintained due to any harmful clinical event, clinical anomalies or if other medical conditions or situations occur, or if the participant no longer fulfils the study criteria due to recently developed or not previously recognised disorders. Adverse events (AE) will be presented together with the results of the study.

We will employ the per-protocol (PP) methodology in the analysis. Missing data due to a study participant missing a follow-up appointment, withdrawal, termination, or large deviation from the study protocol will result in exclusion for the follow-up being conducted, and the number of participants at each follow-up will be indicated. Patients are known to experience a reduction of pain in the first months after surgical interventions, but this can come back after several months. To ensure the pain reappearance over time is accurately captured it is therefore important to select an appropriate study protocol. For example, an Intention to Treat (ITT) analysis may only highlight initial pain reduction if a patient is lost to follow-up, thereby skewing the data. Conversely, a study where years of follow-up is included would not lose this valuable data and so presents a more accurate representation of the outcome. Based on former studies, drop-outs are expected to be around 10%.

2.2 Interventions

The surgical interventions take approximately one to three hours each and the participant can leave the hospital the same day, unless the clinical investigator or surgeon in charge decides that the participant needs to stay overnight for observation. General pre-surgical rules apply i.e., abstaining from alcohol for four weeks before surgery and fasting from midnight the night before surgery. There are no post-surgery restrictions.

2.2.1 Targeted muscle reinnervation, TMR

The TMR procedure for pain management is described in detail in published literature [4, 15, 17]. Briefly, TMR is a surgical technique in which the residual peripheral nerve is transferred to an available muscle in the residual limb that has been denervated from its native nerve (Figure 3, left). The surgical procedure comprises three steps: firstly preparation of the residual nerve, secondly identification of the motor nerve to the targeted muscle and finally, nerve coaptation [17]. To prepare the residual nerve, the surgeon identifies the injured nerve that has developed a painful neuroma and cuts the damaged parts away leaving only healthy fascicles. Next, the surgeon identifies the motor nerve to a nearby target muscle. The native nerve to the target muscle is transected, thereby temporarily denervating the target muscle. In the final step, the previously injured nerve from which the neuroma was excised, is transferred and coapted to the newly severed motor nerve that innervates the target muscle [17].

2.2.2 Regenerative peripheral nerve interface, RPNI

Detailed description of the RPNI surgery has previously been described in the literature [9, 11, 12, 18]. Briefly, the RPNI procedure involves splitting the residual peripheral nerve into several nerve fascicles which are implanted into skeletal muscle grafts [18] (Figure 3, middle). The surgeon first identifies the injured nerve and excises the terminal neuroma [12]. Then, the terminal part of this nerve is dissected exposing several intraneural fascicles. Next, autologous muscle grafts are harvested from a healthy donor site and the transected nerve endings are placed in the middle part of each muscle graft, in parallel to the muscle fibres. The muscle graft is wrapped around the distal transected nerve ending and anchored by epimysial sutures, and an RPNI is created. This is repeated for each group of fascicles obtained from splitting a transected nerve [12].

2.2.3 Standard neuroma treatment, neuroma excision and muscle burying

The standard neuroma treatment entails excision of the terminal neuroma and then implanting the nerve into an adjacent deep muscle (Figure 3, right). The procedure begins with the surgeon finding the injured nerve and excising the terminal neuroma into healthy fascicles. Next, the surgeon identifies a nearby muscle which is not involved in joint motion and has limited output opportunities for the nerve. The nerve is then channelled inside to the deep muscle without applying any tension to it and secured by sutures [10].

2.3 Outcomes

2.3.1 Primary outcome measure

The primary outcome measure in this study is the change in neuroma pain intensity measured by the difference in NRS score (0-10) between baseline (visit zero - three) and at the one-year follow-up post-surgery visit. The NRS score for neuroma pain is included in a more extensive survey called Pain track, which is based on a survey by Lendaro et al. [19] titled “Questionnaire for Phantom Limb Pain (Q-PLPT)”.

2.3.2 Secondary outcome measures

The secondary outcome measures include stump pain and phantom limb pain intensity difference in NRS score (0-10) between baseline (visit zero to three) and at the one-year follow-up. Secondary outcomes also consider aspects such as pain frequency, duration, interference, and quality, see Table 1, and changes that can cause variations in any of the pain types, see Table 2. The information is collected by the following questionnaires.

Table 1

Questionnaires included in the study divided between neuroma, stump, phantom and general pain.
Questionnaire	Neuroma pain	Stump pain	Phantom pain	General pain
Pain track • NRS • Pain frequency • Pain rating index (PRI) • Pain localisation • Pain duration • Intrusion of pain	X X	X X X	X X X X X	X
Pain disability index (PDI)				X
EuroQoL (EQ-5D-5L)				X
Pain self-efficacy questionnaire (PSEQ-2)				X
Pain catastrophising scale-6 (PCS-6)			X	X
Patients’ global impression of change (PGIC)				X
Expectations for Complementary and Alternative medicine Treatments (EXPECT-SF)	X

Table 2

Non-painful question related topics found in the pain track, where changes can cause variations in any pain type described in Table 1.
Pain track
Phantom sensation (NRS)
Phantom motor ability
Phantom telescoping
Change in prosthetic hardware
Change in medication

2.3.3 Distinguishing neuroma pain, stump pain & phantom limb pain

Neuroma pain, stump pain, and phantom limb pain will be investigated in this study. These three types of pain will be distinguished by taking advantage of fundamental differences in their origin. Stump pain and phantom limb pain can be distinguished by the location of the pain, e.g., in the stump or residual limb and in the missing limb, respectively [2] (Figure 2). For neuroma pain, digital pressure, as physical stimulation, will be used to elicit pain where the neuroma is suspected. No physical stimulation will be used to elicit stump pain or PLP, rather, participants will be asked to close their eyes and localise the pain in order to distinguish the two types.

Pain track

The Pain track is a 21-item questionnaire divided into five sections: neuroma pain, stump pain, phantom limb pain, general pain interference and other questions. The Pain track is an extensive survey which evaluates intensity, quality and frequency of neuroma, stump, and phantom limb pain. The pain intensity and frequency are tracked as follows:

Numerical rating scale to evaluate the present intensity of pain (0 - 10 where 0 = no pain and 10 = worst imaginable pain)
Present pain intensity scale (range 0 – 5 calibrated as 0 = no pain, 1 = mild, 2 = discomforting, 3 = distressing, 4 = horrible, 5 = excruciating ) [20]
Study specific scale for evaluation of pain frequency (“constantly”, “few times per day”, “once a day”, “few times per week”, “once a week”, “few times per month”, “once a month”, “never”).

In the stump and phantom pain sections, the Short Form of the McGill Pain Questionnaire (SF-MPQ) [21] is included in order to calculate the pain rating index (PRI) by summing the descriptions in the survey. In addition, the phantom limb section monitors weighted pain distribution (range 0-5), phantom pain location, phantom telescoping, phantom sensation, and phantom motor ability.

The general pain interference questions track pain intrusion in daily activities, work ability and sleep, using a numerical rating scale (0-10 where 0 = no interference and 10 = full interference) for each activity. Adjustment in prosthetic hardware and pain medication is also assessed in Pain track.

Pain disability index (PDI)

The PDI is a seven-item questionnaire which measures the extent to which chronic pain interferes with participation in activities of daily life [22]. Each question includes a life activity and the degree to which a person’s ability to perform the task is hindered (disability) by their pain is rated from 0-10 where 0 = no disability and 10 = worst disability. The PDI score is calculated by summing the numerical ratings.

EuroQoL-5D-5L (EQ-5D-5L)

The questionnaire EQ-5D-5L (EuroQol Group) is a standardised survey used to evaluate health-related quality of life, in terms of health status and health evaluation [23]. The health status is measured and evaluated in five categories: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each category is rated by a five-item scale (no problems, slight problems, moderate problems, severe problems, and extreme problems). The health evaluation part includes the EQ Visual Analogue Scale (VAS) (0 – 100 where 0 = worst imaginable health state, 100 = best imaginable health state), the participant is asked to rate their health that particular day.

Pain self-efficacy questionnaire (PSEQ-2)

PSEQ-2 is a two-item questionnaire that rates pain self-efficacy, which is defined as the confidence held by people living with chronic pain that they can participate in certain activities and enjoy life, despite the pain they experience [24, 25]. The self-efficacy in each question is rated on a numerical rating scale (0 – 6 where 0 = not at all confidence and 6 = completely confidence).

Pain catastrophising scale (PCS-6)

PCS-6 is a six-item questionnaire designed to monitor catastrophising thinking, in a rating scale from 0 to 4 [26, 27]. Pain catastrophising implies the negative cognitive-affective reply to pain and is correlated with pain severity, disability, depressive symptoms as well as with inadequate adjustment to chronic pain [19, 28].

Patients’ global impression of change (PGIC)

PGIC is a single-item questionnaire used for identification of a significant clinical change by rating the patient’s belief about the treatment’s effectiveness on a seven-point rating scale (1 – 7 where 1 = no change and 7 = a great deal better).

Additional measurements

In addition to questionnaire answers, the participants are asked to provide background information of themselves, such as age, gender, type and dose of medication, date of amputation, amputation cause, type and usage of prosthesis, and previous treatments. Furthermore, additional survey regarding patients’ expectancy of benefit by using the Expectations for Complementary and Alternative Medicine Treatments (EXPECT-SF) [29]. The participants also take part in a physical examination; here the physician localises neuroma pain by palpation. In addition to neuroma localisation, Tinel’s sign test and phantom mapping are performed. Furthermore, the participants are asked to participate in brief, semi-structured interviews in order to understand how the participants have experienced the treatment and how it has affected their quality of life. Lastly, participants will undergo EEG recordings pre-surgery and post-surgery in order to localise differences in the brain before and after pain treatment. See Table 3 for a summary of all study specific assessments at each visit.

Table 3

Summary of study specific assessments at each session.
Session	Assessments
Pre-screening	• Patient information • Study consent • Background information
Screening, visit 0	• Physical examination • Pain track • PDI¹ • EQ5D-5L² • PSEQ-2³ • PCS-6⁴ • EXPECT-SF⁵
Baseline, visit 1-3	• NRS⁶ (0-10); neuroma pain, stump pain, PLP⁷ • Interview (visit 1) • EEG⁸ (visit 1)
Randomisation, allocation 1:1:1
Surgery, visit 4	• NRS (0-10); neuroma pain, stump pain, PLP • Surgery
Follow-up, visit 5-10 Short-term 1 month 3 months 6 months 12 months Unblinded	• Physical examination • Interview • EEG (visit 5, 7-10) • Pain track • PDI • EQ5D-5L • PSEQ-2 • PCS-6 • PGIC⁹
Long-term 3 years 5 years
¹PDI, Pain Disability Index; ²EQ5D-5L, EuroQol-5D-5L; ³PSEQ-2, two item Pain Self-Efficacy Questionnaire; ⁴PCS-6, six item Pain Catastrophising Scale; ⁵EXPECT-SF, Expectations for Complementary and Alternative Medicine Treatments Short Form; ⁶NRS, Numerical Rating Scale; ⁷PLP, Phantom limb pain; ⁸EEG, Electroencephalography; ⁹PGIC, Patients’ Global Impression of Change

2.4 Assignment of intervention

2.4.1 Sample size

Sample size calculation was based on previous studies investigating surgical treatments for neuroma pain [10, 11] and based on the limited number of available participants. To receive a minimum power of 80% from a one-way ANOVA with an effect size of 0.4 and at 5% significant level between the randomised groups, it is estimated that at least 66 participants are required. The drop-out rate is expected to be around 10%, therefore a total of 75 participants are aimed to be randomised.

2.4.2 Randomisation

Participants are assigned to either the TMR group, RPNI group or standard treatment according to the optimal allocation scheme of minimisation which aims to reduce the imbalance between the number of patients allocated to each treatment group. The randomisation proportion aiming to be 1:1:1, with the same number of major limb amputations assigned to each group. The allocation aims to minimise the imbalance of the following factors:

Level of amputation (upper and lower)
Baseline neuroma pain based on the NRS (medium 4–6 and high 7–10)
Investigation site (Sweden and Italy)

If a participant has two or several residual limbs that qualifies accordingly to the inclusion/exclusion criteria only one will be included in the study.

The clinical randomisation of the participants will be performed using MinimPy [30], an open-source desktop application, and is run by the principal investigator. When a new recruitment is made, and the participant meet the study criteria, the minimise factors of the participant are embedded in the software. The software runs a randomisation and allocate the participant to one of the treatment groups.

2.4.3 Blinding

The study is designed so that the patient and the evaluator are unaware of which surgical treatment the patient has received. The patients will undergo the same study specific assessments despite their assigned surgical treatment. The only difference between the groups will be the surgical treatment, although the patients in the RPNI group will have an extra scar on the muscle donor site (inconceivable to the patient) compared to the TMR and neuroma transposition group. The patients will not have any expectation of surgical outcome superiority since the trial is framed as a comparison between three surgical treatments formerly described in the literature. The evaluator and the patient will be unaware of which surgical treatment the patient has received up to 12 months post-surgery. Thereafter, the study will be unblinded for the patients and the evaluator. The clinical investigators in each site will be aware of treatment allocation, and they are excluded in the analyses. The raw data following the outcome assessments from each surgical treatment has the same structure, which make it unfeasible to differentiate the group assignments without having the document that links participant’s identity to their code number, thereby to the specific treatment.

2.5 Data collection, management, and analysis

2.5.1 Data collection and management

The clinical investigators and the principal investigator share the overall responsibility for the progress of the RCT. The evaluator is in charge of ensuring that the RCT is conducted, recorded, and reported according to the clinical protocols, Good Clinical Practise (GCP) and regulatory requirements. The study is monitored bi-monthly by a project independent monitor educated in GCP.

The evaluator oversees the case report forms (CRFs), and documents the data during the RCT. The data in the CRFs is identified by participant specific code numbers. Data documentation is also applicable for patients who have given written consent for participation, then underwent the baseline assessments but decided to leave the study. In the CRF, all items must be filled in, none must be empty. However, if data is missing or is unfeasible to collect, this should be documented as “not available” (NA) and an explanation(s) must be recorded in the CRF.

The clinical investigator is in charge of recording any occurrences of adverse events (AE), in discussion with the participant at each visit, and documentation of the AE in the patient’s CRF. Every AE needs to be explained by duration (start and stop dates and times), severity, outcome, treatment, and relation to the surgical treatment (related or unrelated). The clinical investigator must report any incidence of an AE to the evaluator and the monitor in timely manner (no later than three working days after the incident).

The data collected in this study will include images, sound recordings, questionnaire and interview answers, EEG data and medical data. Images and sound recordings will only be shared with the written consent of the participant. Participants will be able to choose whether images can be shown undoctored or with their face blurred or cropped out. All data will be pseudonymised with a code consisting of two letters and three digits and all collected data will be assigned the coded identify.

All data gathered within this RCT will be stored digitally in accordance with GDPR requirements, on a password-protected server with restricted access using two factor authorization. Only the researchers who are directly involved in the study will have access to the data. The principal investigator will ensure that all relevant research personnel have access to the data. The document which couples the identity of the study participant to their unique code will be password-protected and saved separately. All information will be confidential and stored in accordance with GDPR and with the study participant's written informed consent.

2.6.2 Statistical analyses

Statistical analyses will be performed within-participant and between surgical treatments for descriptive purposes (mean, median, standard deviation, range, and 95% confidence intervals for means and proportions). Sensitivity analyses will be performed to investigate differences in subgroups such as lower vs upper extremity, right vs left extremity, female vs male, reason for amputation, baseline NRS (medium 4-6, high 7-10), time since amputation and age. ANOVA analysis will be performed for group comparisons. An interim analysis will be performed by a project independent person when half of the study population has passed the one-year follow-up. The result will be discussed among relevant research personnel and the principal investigator takes the final decision if the study will continue or be terminated.

Investigation in pain related studies is challenging due to an absence of objective evaluation methods. Pain is a subjective experience that is difficult to quantify independently among participants. In our study design, we have tried to mitigate this problem by using several different protocols and questionnaires for pain tracking that have previously been used in clinical settings.

One of the main issues in this RCT is to recruit potential candidates meeting our inclusion criteria within an acceptable time. For example, it took over three years for Dumanian et al. (2019) to gather 28 participants who met their study criteria [10] and this study was performed in the United States (with a larger amputee population compared to Sweden and Italy). According to Sweden’s amputation and prothesis registry for lower extremities (SwedeAmp) yearly report in 2019, the mean age of amputation for women is 78 and for men is 72 years old. Furthermore, 61% of all amputated women and 58% of all amputated men are in the range of 70-89 years old and 84% of all Swedish amputees have either diabetes and/or a vascularise disease. We expect this to add significant challenge in the volume of participants we require. Our recruitment approach therefore includes close contact with prosthetic centres, orthopaedics, and hand surgeons in Sweden and Italy by in person visits and provide consistent information regarding the surgery procedure and the financial parts of the surgery.

The surgical treatment approach requires that the participants undergo surgery, thus general surgical risk applies including but not limited to those associated with anaesthesia, the possibility of superficial or deep bacterial infections and delayed wound healing. Even though the surgical approaches have shown good potential for post-amputation pain reduction in the literature [10, 11], there is a minor risk that the treatment results in no relief or a worse pain situation for the participant. This may lead to pain suppression medication.

The RCT is proposed as a double-blind study, where both the patients and the evaluator are unaware of which surgical treatment has been prescribed. However, since RPNI, involves a muscle graft from a donor site, the RPNI participants will have an extra scar compared to TMR and neuroma transposition group. We discounted the option to add a sham scar to participants from the other groups on ethical grounds and instead have designed the RCT such that participants will not be told the methodological differences between the surgeries and so will not know which surgical treatment they received. The participants can find out which treatment they received by searching in the literature, but even in that unlikely case they still do not know which one of the surgeries that is the active ones or the control.

Trial status

This clinical study was registered at ClinicalTrials.gov 17th of August 2021 with registration number NCT05009394. This is protocol version 3 (2021-12-01). Recruitment of participants is expected to take place in early 2022 and is expected to be completed in 2024.

AE = adverse event

CRF = case report form

GCP = good clinical practise

ICF = informed consent form

ITT = intension-to-treat

NRS = numerical rating scale

PLP = phantom limb pain

PP = per-protocol

RCT = randomised controlled trial

RPNI = regenerative peripheral nerve interface

TMR = targeted muscle reintervention

Ethics approval and consent to participate

This clinical trial was approved by the Swedish Ethics Review Authority, Etikprövningsmyndigheten, the 30^th of June 2021 with the application number 2021–02346. Written, informed consent to participate will be obtained from all participants. Participants in this trial are insured by government insurances in each country, Sweden and Italy, respectively. Important protocol modifications will be notified to the ethical committee.

Dissemination policy

Regardless of the significance, direction or magnitude of effect, the consortium will publish the findings of this study in scientific, peer-reviewed journals and conferences following the International Committee of Medical Journal Editors guidelines. Results will also be disseminated to all the participants of the study with a report. No professional writers external to the study will be used aside from conventional English proof reading. Access to the detailed clinical investigation plan, participant-level dataset and statistical code will be granted based on reasonable requests after the publication of the study.

Consent for publication

Not applicable.

Availability of data and materials

The clinical investigators and the principal investigator have full access to all study specific data, except the document including the link between patient’s identity and their code number. That document will only be accessible after the one-year follow-up analyses. They have the responsibility for correct data storing and for the accuracy of the data analysis.

Competing interests

There are no competing interests in this study.

Funding

This project was funded by the Promobilia Foundation, the IngaBritt and Arne Lundbergs Foundation, and the Swedish Research Council (Vetenskapsrådet).

Disclaimer

Neither the sponsor (Chalmers University of Technology, [email protected]) nor the funders had a role in the study design.

Authors' contributions

EP, PS, and MOC designed the study. EP drafted the manuscript. All authors gave feedback on the study design and edited the manuscript. All authors approved the final version of the manuscript.

Acknowledgements

The authors would like to thank their funders, as well as Axel Wolf for feedback regarding the study design, Jenna Anderson and Kirstin Ahmed for her help in proofreading the manuscript and Mirka Buist for creation of the illustrations.

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Surgical Treatments for Post-amputation Pain: Study Protocol for an International, Double-blind, Randomised Controlled Trial

Status:

Journal Publication

Version 1

Abstract

Figures

1 Background

Study Objective

Trial design

2 Methods/design

2.1 Participants

2.1.1 Recruitment and inclusion of participants

2.1.3 Withdrawal or termination of individual participants

2.2 Interventions

2.2.1 Targeted muscle reinnervation, TMR

2.2.2 Regenerative peripheral nerve interface, RPNI

2.2.3 Standard neuroma treatment, neuroma excision and muscle burying

2.3 Outcomes

2.3.1 Primary outcome measure

2.3.2 Secondary outcome measures

2.3.3 Distinguishing neuroma pain, stump pain & phantom limb pain

Pain track

Pain disability index (PDI)

EuroQoL-5D-5L (EQ-5D-5L)

Pain self-efficacy questionnaire (PSEQ-2)

Pain catastrophising scale (PCS-6)

Patients’ global impression of change (PGIC)

Additional measurements

2.4 Assignment of intervention

2.4.1 Sample size

2.4.2 Randomisation

2.4.3 Blinding

2.5 Data collection, management, and analysis

2.5.1 Data collection and management

2.6.2 Statistical analyses

3 Discussion

Trial status

Abbreviations

Declarations

Ethics approval and consent to participate

Dissemination policy

Consent for publication

Availability of data and materials

Competing interests

Funding

Disclaimer

Authors' contributions

Acknowledgements

References

Supplementary Files

Status:

Journal Publication

Version 1