Original Title: Reinervación muscular dirigida en personas con extremidades amputadas

Authors' objectives: This Health Technology Assessment aims to evaluate the effectiveness, safety, and cost-effectiveness of TMR in improving pain, prosthetic tolerance, and outcomes related to functionality in individuals who have undergone the major amputation of one or more limbs.

Authors' results and conclusions: RESULTS: EFFECTIVENESS/SAFETY: The evaluation of effectiveness and safety is based on the results of one RCT and eight controlled observational studies with a control group. Additionally, 19 observational studies without a control group have been included, making a total of 28 assessed primary studies. Most of the included observational studies with a control group were retrospective studies with historical cohorts, which did not allow for the matching of groups in baseline characteristics, follow-up time, and safety variables, presenting a high risk of selection bias. Additionally, subgroup analyses according to the amputation site (upper or lower limb), indication for amputation, type of TMR (primary or secondary), or level of amputation, among others, could not be performed. The quality of evidence for outcomes deemed critical and important for decision-making has been classified as very low (⨁◯◯◯), primarily due to the design and risk of bias in individual studies, small sample sizes, and heterogeneity in the evaluated populations. None of the included studies evaluated psychological symptoms (e.g., anxiety, depression, stress...). In general, there is inconsistency between the results of the single included RCT and the observational studies with control group, with non-significant pain reduction results in the former for most measures and significant results in the latter, with effects doubling in intensity compared to the RCT. However, both the small sample size of the RCT (N = 30) and methodological limitations of the observational studies prevent robust conclusions from these results. Specifically, regarding pain reduction, both the RCT and observational studies found a significant reduction in pain intensity (measured through a numerical pain scale at 24 hours post-intervention) in favor of TMR. However, in other pain measures (e.g., interference and behavior), the results are not consistent among studies. The identified RCT does not find significant results (despite noting a trend in favor of TMR), but in the meta-analysis of the included controlled observational studies (N = 649), a significantly favorable effect toward TMR is observed in these variables (p < 0.05). Regarding the effectiveness of TMR for preventing neuromas, the results are also limited, as only two observational studies provide comparisons between groups, concluding that the rate of symptomatic neuromas was significantly lower in major amputations with TMR compared to those without TMR. Finally, concerning improvements in functionality, defined as an increase in functionality after TMR, the evidence appears to favor TMR, although the included studies do not show statistical significance between groups. Regarding safety, there were no statistically significant differences between TMR and the control group in terms of perioperative complication rates, reinterventions, infections, rehospitalizations, or mortality. COST-EFFECTIVENESS AND ECONOMIC ANALYSIS: No evidence was identified regarding the cost-effectiveness of TMR in individuals with amputated limbs. A 'de novo' cost-effectiveness analysis for Spain could not be undertaken due to a lack of the necessary minimum information. The cost study from the hospital perspective estimated a cost of €6000 for the initial training of three healthcare professionals per hospital performing the TMR procedure, in terms of training courses. The average incremental cost per TMR intervention was estimated at €2246.83, with a potential variation between €327.66 and €5349.60, depending on the increased time needed for the TMR procedure compared to an intervention without TMR. ETHICAL, LEGAL, ORGANIZATIONAL, SOCIAL, AND ENVIRONMENTAL ASPECTS: Eight studies were included based on various methodologies: qualitative, survey-based cohort, and mixed-method approaches, all in accordance with the predefined selection criteria. The overall quality of evidence was considered moderate to low. The main results from the studies provide insights into both user and healthcare professional perspectives regarding the evaluated technology, including organizational aspects. Findings are presented based on GRADE categories: acceptability, equity, and feasibility. Studies indicate that amputees' positive expectations and perceptions, both users and non-users of current prostheses, were higher for non-invasive techniques than for invasive ones like TMR, possibly related to satisfaction with their functional abilities. Significant predictors for TMR included age, unilateral/bilateral limb loss, cause of amputation, time since limb loss, and educational level. Reluctance to consider invasive prosthetic interfaces was linked to resistance to brain retraining and fear of surgical intervention failure. Results show that TMR can alleviate much of neuroma, cavity, nerve, and phantom limb pain. Among healthcare professionals dealing with amputated patients, knowledge of TMR is still in its early stages, but there is a positive inclination toward its adoption to manage painful neuroma and phantom limb pain. Concurrent TMR with amputation requires a multidisciplinary team for a comprehensive approach from the pre-surgical stage. In oncological patients receiving TMR at the time of amputation, post-surgical recovery and prosthetic rehabilitation may be slowed due to specific aspects of their condition. In all cases, protocols include psychological support and guidance. CONCLUSIONS: • The quality of the available evidence on the effectiveness of RMD for pain reduction, prevention of neuromas, improvement of functionality, and other evaluated variables in individuals with major amputation of upper or lower limbs has been assessed as very low. Currently, it is not possible to establish solid conclusions about its effectiveness. The available results suggest that there may be an improvement in pain, the rate of symptomatic neuromas, and functionality. • Regarding safety, no significant effect was observed in perioperative complications, reinterventions, infections, rehospitalizations, or mortality related to the use of RMD. • There was no evidence available identified on the cost-effectiveness of RMD in individuals with amputated limbs. • The cost of the specific training course in the RMD procedure for each trained healthcare professional is €2000, and it is recommended to provide initial training to a neurosurgeon, neurotraumatologist, and rehabilitation physician for each hospital performing this procedure. The cost per RMD intervention depends on the increased time in the operating room compared to surgery without RMD, with an estimated average incremental cost of €2246.83, ranging from €327.66 to €5349.60. • The analysis of ethical, legal, social, organizational, and environmental aspects has allowed us to understand the importance of thoroughly selecting suitable patients for TMR and the interrelation between this intervention and the rehabilitation process from a more comprehensive perspective, addressing its complexity. • Overall, studies on experiences, assessments, and perceptions regarding TMR indicate that users of external prostheses, clinical professionals, prosthetic industry engineers, and healthcare sector managers are interested in and positively value TMR for alleviating a significant amount of pain and improving functionality, demonstrating a good predisposition to adopt TMR. However, it is evident that there is a lack of information about TMR for amputee patients and training on this technique among the involved professionals. Limitations include the moderate to low methodological quality of the analyzed studies, which do not allow for a deeper exploration of the experiences of patients with TMR and professionals applying this technique. • Attitudes towards external prostheses and emerging technologies such as TMR are dynamic and can vary depending on a range of factors, including the time elapsed since amputation, age, body impact, comorbidities, self-assessments of current functional level, previous experiences with surgical procedures, use of external prostheses, or interactions with the healthcare system. • No specific studies were found regarding research needs and standard outcome measures related to TMR in the various sources of information consulted.

Authors' recommendations: Due to the low quality of the currently available evidence, it is not possible to establish a recommendation either in favor or against TMR for the treatment of individuals who have undergone the major amputation of one or more limbs. Given the lack of robustness in the available evidence regarding potential benefits of TMR (e.g., pain reduction, prevention of neuromas, functional improvements), coupled with several ongoing randomized controlled trials (RCTs) whose results will be available in the coming years, it would be advisable to defer the decision on its inclusion in the common services portfolio of the National Health System until higher-quality scientific evidence is available.

Authors' methods: EFFECTIVENESS AND SAFETY: A systematic literature review (SR) was conducted by independent peer reviewers consulting the following databases from the year 2000 to March 2023: MEDLINE, Embase, CINAHL, CDSR/CENTRAL, and WOS. Selected studies included SRs with or without meta-analyses (MAs), randomized controlled trials (RCTs), non-randomized controlled trials (NRCTs), and prospective/retrospective observational studies, case-control studies, and case series (n ≥ 2) published in Spanish or English. These studies assessed the effectiveness and safety of TMR, whether primary or secondary, in individuals of any age with major amputation (above the ankle and/or wrist) in one or more limbs (upper and/or lower extremities), either unilateral or bilateral. The considered outcome measures included: pain; prosthetic tolerance; health-related quality of life; functional capacity; personal autonomy/self-care; psychological symptoms (e.g., anxiety, depression, stress); individual satisfaction with prosthetic use; and complications and mild or severe adverse events associated with TMR. Risk of bias was assessed using RoB-2 (RCTs), ROBINS-I (observational studies with a control group), and JBI (observational studies without a control group). Quantitative synthesis was performed when feasible using Review Manager 5.4. The evaluation of evidence quality and recommendation strength followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. COST-EFFECTIVENESS AND ECONOMIC ANALYSIS: The SR conducted to assess the previously described effectiveness and safety also incorporated a search for economic evaluations, conducted in parallel to primary studies or models, reporting any of the following outcomes: incremental cost-effectiveness ratio (ICER), costs expressed in monetary units, and benefits expressed in quality-adjusted life years (QALYs), life years gained (LYG), monetary units, or any of the effectiveness outcome measures included in the effectiveness section. Methodological quality assessment was planned using Drummond et al.'s criteria and/or the Critical Reading Sheet (FLC 3.0) from OSTEBA. Data extraction and a narrative synthesis of the results were also envisaged. Additionally, an economic analysis was conducted through a cost study from the hospital perspective, considering the resource utilization for TMR surgical interventions and the training costs associated with the TMR procedure. ETHICAL, LEGAL, ORGANIZATIONAL, SOCIAL, AND ENVIRONMENTAL ASPECTS: An adaptation of the evaluative framework from the Core Model 3.0 of EUnetHTA, along with the criteria established by the Spanish Network of Health Technology Assessment Agencies (RedETS) of the NHS, was used. Combining the analysis criteria from these models, an SR was developed, whose scope originated from the same SR of effectiveness and safety described earlier. The inclusion criteria encompassed qualitative studies, observational studies, SRs (with or without meta-analysis), scoping reviews, realistic reviews, integrative reviews, and narrative reviews with empirical basis. For consensus evaluation, the CASPe tool (for studies with qualitative methodology), the MMAT instrument (for studies with mixed methodology), and the OSTEBA critical assessment tool (for cohort studies based on surveys) were employed. A narrative synthesis was conducted considering relevance and coherence criteria. For the environmental section, a manual search was carried out.

Project Status: Completed

Year Published: 2023

URL for published report: https://sescs.es/reinervacion-muscular-dirigida-en-personas-con-extremidades-amputadas/

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Spain

Organisation Name: Canary Health Service

Contact Address: Dirección del Servicio. Servicio Canario de la Salud, Camino Candelaria 44, 1ª planta, 38109 El Rosario, Santa Cruz de Tenerife

Contact Name: sescs@sescs.es

Contact Email: sescs@sescs.es