Interventional procedure overview of targeted muscle reinnervation for managing limb amputation pain

Alexander JH, Jordan SW, West JM et al. (2019) Targeted muscle reinnervation in oncologic amputees: Early experience of a novel institutional protocol. Journal of Surgical Oncology 120: 348–58

Retrospective cohort study

Upper and lower limbs.

Primary TMR.

n=85 (27 TMR)

Follow-up: mean 14.7 months

TMR reduced patient-reported PLP and RLP behaviour and interference compared to unselected general oncologic amputee controls beyond the clinically meaningful threshold for this population.

More recent studies with a larger population or longer follow up are included.

Study is included in systematic review by Tham et al. (2023).

Bascone CM, Sulkar RS, McGraw JR et al. (2023) Bringing the below-knee amputation out of the Civil War era: Utilization of the neurovascularized lateral compartment flap, TMR, and RPNI. Orthoplastic Surgery 13: 10–16

Retrospective cohort study

n=25

Below-knee amputations with TMR or RPNI

The potential use of TMR and RPNI, which have both shown to be effective in preventing neuroma formation and associated neuropathic pain, will be a contributing factor in decreasing opioid dependency in this population. Additionally, the use of these reconstructive techniques may enable patients to take advantage of new advances in myoelectric prosthetics.

Studies with more people or longer follow up are included.

Berger LE, Shin S, Haffner ZK et al. (2023) The application of targeted muscle reinnervation in lower extremity amputations: A systematic review. Microsurgery 43: 736–47

Systematic review

n=318 limbs (11 articles)

Lower limb

Primary or secondary TMR

The application of TMR to lower limb amputations is effective in reducing PLP and RLP with limited complications. Quantifying standardised patient reported pain and functional outcomes stratified by amputation indication and anatomic location are warranted to better realise this potential.

No meta-analysis.

Bishay J, Yeap I, Wang T (2024) The effectiveness of targeted muscle reinnervation in reducing pain and improving quality of life for patients following lower limb amputation. Journal of Plastic, Reconstructive & Aesthetic Surgery: JPRAS; 92: 288–98

Systematic review

n=778 limbs (20 studies)

Primary or secondary TMR

This systematic review highlights TMR's capacity to significantly reduce both residual and PLP, reduce opioid dependency, increase ambulation rates as well as enhance the use of prosthetic devices. However, further research is needed to address the limitations and challenges associated with TMR and to establish standardised protocols for patient selection, surgical techniques, and postoperative rehabilitation.

No meta-analysis.

Bowen JB, Ruter D, Wee C et al. (2019) Targeted muscle reinnervation technique in below-knee amputation. Plastic and Reconstructive Surgery 143: 309–12

Case series

n=22

Below-knee amputations

Primary or secondary TMR

Follow-up: 6 months

TMR may be a reliable technique for the treatment and prevention of below-knee amputation PLP at all amputation levels, without additional morbidity to the traditional below-knee amputation procedure.

Studies with more people or longer follow up are included.

de Lange JWD, Hundepool CA, Power DM et al. (2022) Prevention is better than cure: Surgical methods for neuropathic pain prevention following amputation - A systematic review. Journal of plastic, reconstructive & aesthetic surgery: JPRAS; 75: 948–59

Systematic review

5 articles on TMR

For major limb amputation, TMR and RPNI are beneficial techniques to prevent neuropathic pain and PLP. Based on the current literature, considering what the results of the techniques were on the treatment of symptomatic neuroma, the authors conclude that during amputation, techniques to prevent neuropathic pain and PLP should be performed.

Review includes a variety of techniques for preventing neuropathic pain and there is no meta-analysis.

ElAbd R, Dow T, Jabori S et al. (2024) Pain and functional outcomes following targeted muscle reinnervation: A systematic review. Plastic and Reconstructive Surgery 153: 494–508

Systematic review

n=1,165 (449 TMR)

39 studies

Upper and lower limbs

Primary or secondary TMR

The current evidence in the literature suggests that TMR is a promising novel therapeutic strategy for improving pain, prosthesis use, and functional outcomes following major limb amputation when performed as an immediate or delayed procedure.

No meta-analysis.

Frantz TL, Everhart JS, West JM et al. (2020) Targeted muscle reinnervation at the time of major limb amputation in traumatic amputees. JBJS Open Access 5: e0067

Prospective case series

n=25

Upper and lower limbs

Primary TMR

Follow-up: mean 14.1 months

The data suggest that TMR for orthopaedic trauma amputees was associated with low overall pain scores at follow-up, decreased overall opioid and neuromodulator medication use, and an overall high rate of daily prosthetic use.

Studies with more people or longer follow up are included.

Study is included in systematic review by Tham et al. (2023).

Fulton ZW, Boothby BC, Phillips SA (2022) Targeted muscle reinnervation for trauma-related amputees: a systematic review. Cureus 14: e28474

Systematic review

n=125

6 studies

Upper or lower limbs

Primary or secondary TMR

In this systematic review of TMR in the trauma-related amputee population, there was a high rate of neuroma pain prevention, reduction, and resolution. There was a high rate of overall pain resolution or reduction. No differences were seen between TMR as a primary or secondary procedure for either of these outcomes. Prosthetic wear rates were also high, while post-TMR opioid use was low. All these data points indicate that TMR is a promising procedure that deserves wider consideration in the traumatic amputee population.

A more recent systematic review with more papers is included.

Hagiga A, Aly M, Gumaa M et al. (2023) Targeted muscle reinnervation in managing post-amputation related pain: A systematic review and meta-analysis. Pain Practice 23: 922–32

Systematic review and meta-analysis

n=127 5 studies

Upper and lower limbs

Primary or secondary TMR

There is limited evidence of good quality favouring TMR in reducing postamputation PLP and RLP pain compared with standard care. Randomised clinical trials are encouraged to compare the efficacy of different surgical techniques.

The same studies are included in the systematic review by Tham et al. (2023).

Hoyt B, Gibson J, Potter B et al. (2021) Practice patterns and pain outcomes for targeted muscle reinnervation: an informed approach to targeted muscle reinnervation use in the acute amputation setting.

Journal of Bone and Joint Surgery 103: 681–87

Retrospective cohort study

n=74

TMR, RPNI or both

Lower limbs

Primary or secondary

Follow-up: median 14 months

The data suggest that a targeted approach featuring concurrent use of TMR and RPNI in the acute setting can be safely used to prevent neuroma pain and avoid revision surgical procedures.

Studies with more people or longer follow up are included.

Study is included in systematic review by Tham et al. (2023).

Lambie CJ, Moura SP Eftekari SC et al. (2024) Social media analysis of pain outcomes following targeted muscle reinnervation. Journal of Plastic, Reconstructive & Aesthetic Surgery 91: 236–40

Social media survey

n=43

Forty-three individuals commented on their TMR experience. Among them, 31 had favourable surgical outcomes, 7 felt that the surgery worsened their pain or there was no notable change in their pain levels, and 5 commented during the initial postoperative period. Among the 28 people who commented on overall reduction in chronic pain, 24 reported that TMR reduced their pain, whereas 4 reported no change or worsened pain.

Social media review with small sample size.

Mauch JT, Kao DS, Friedly JL et al. (2023) Targeted muscle reinnervation and regenerative peripheral nerve interfaces for pain prophylaxis and treatment: A systematic review. PM & R: The Journal of Injury, Function, and Rehabilitation 15: 1457–65

Systematic review

n=441

17 studies

TMR or RPNI

Upper or lower limbs

Primary or secondary

Follow-up: range 4 to 27.6 months

Both TMR and RPNI may be beneficial for preventing and treating pain originating from peripheral nerve dysfunction compared to traditional techniques. Randomised trials with longer term follow-up are needed to directly compare the effectiveness of TMR and RPNI with traditional nerve management techniques.

No meta-analysis.

McNamara CT, Iorio ML (2020) Targeted muscle reinnervation: outcomes in treating chronic pain secondary to extremity amputation and phantom limb syndrome. Journal of Reconstructive Microsurgery 36: 235–40

Systematic review

n=149

5 articles

Upper or lower limbs

Primary or secondary TMR

For TMR at the time of amputation, all studies reported a minimal development of symptomatic neuromas (27%). For secondary TMR, near-complete resolution of previous pain was found (90%). Phantom pain was noted to improve over time with both primary (average drop of 3.5 out of 10 points on the numerical rating scale) and secondary (diminishing from 72% of patients to 13% over 6 months) operations.

A more recent systematic review is included.

Mioton LM, Dumanian GA, Shah N et al. (2020) Targeted muscle reinnervation improves residual limb pain, phantom limb pain, and limb function: a prospective study of 33 major limb amputees. Clinical Orthopaedics and Related Research 478: 2161–67

Prospective case series

n=33

Upper or lower limbs

Secondary TMR

Follow-up: 1 year

Targeted muscle reinnervation demonstrates improvement in RLP and PLP parameters in major limb amputees. It should be considered as a first-line surgical treatment option for chronic amputation-related pain in patients with major limb amputations. Additional investigation into the effect on function and quality of life should be performed.

Studies with more people or longer follow up are included.

The main results from this study are included in the meta-analysis by Tham et al. (2023).

O'Brien AL, Jordan SW, West JM et al. (2021) Targeted muscle reinnervation at the time of upper-extremity amputation for the treatment of pain severity and symptoms. The Journal of Hand Surgery 46: 72e1–e10

Retrospective non-randomised comparative study

n=71 (16 TMR)

Upper limbs

Primary TMR

Follow-up: mean 23.1 months

62% of those who had early TMR were without PLP compared with 24% of controls. Half were free of RLP compared with 36% of controls. The median PROMIS PLP intensity score for the general sample was 47 versus 38 in the early TMR sample. Patients who had early TMR reported reduced pain behaviours and interference specific to PLP (50 versus 53 and 41 versus 50, respectively). The PROMIS RLP intensity score was lower in patients with early TMR (36 versus 47).

Studies with more people or longer follow up are included.

The main results from this study are included in the meta-analysis by Tham et al. (2023).

Pet MA, Ko JH, Friedly JL et al. (2014) Does targeted nerve implantation reduce neuroma pain in amputees? Clinical Orthopaedics and Related Research 472: 2991–3001

Retrospective cohort study

n=35 (12 primary targeted nerve implantation)

Upper or lower limbs

Follow-up: mean 22 months

Targeted nerve implantation performed either primarily at the time of acute amputation or secondarily for the treatment of established symptomatic neuroma is associated with a low frequency of neuroma-related pain. By providing a distal target for regenerating axons, the procedure may offer an effective strategy for the prevention and treatment of neuroma pain in amputees.

More recent studies are included.

Reid RT, Johnson CC, Gaston RG et al. (2024) Impact of timing of targeted muscle reinnervation on pain and opioid intake following major limb amputation. Hand 19: 200–205

Prospective registry data

n=43 (44 limbs)

Primary or secondary TMR

TMR is an effective procedure to reduce pain following major limb amputation. Patients with TMR performed acutely had significantly lower VAS pain scores at both intermediate and final follow-up than patients with TMR performed in a delayed setting.

Studies with more people or longer follow up are included.

Roubaud MS, Hassan AM, Shin A et al. (2023) Outcomes of targeted muscle reinnervation and regenerative peripheral nerve interfaces for chronic pain control in the oncologic amputee population. Journal of the American College of Surgeons 237: 644–54

Retrospective cohort study

n=63 (28 TMR alone, 4 RPNI alone, 31 combined TMR and RPNI)

Upper and lower limbs

Primary

Follow-up: mean 11 months

At final follow-up, patients had an average NRS score of 1.3 for RLP and 1.9 for PLP. The final average raw PROMIS measures were pain intensity 6.2 (T-score 43.5), pain interference 14.6 (T-score 55.0), and pain behaviour 39.0 (T-score 53.4). Patient opioid use decreased from 86% to 38% and morphine milligram equivalents decreased from a mean of 52.4 preoperatively to 20.2 postoperatively.

Studies with more people or longer follow up are included.

Salminger S, Sturma A, Roche AD et al. (2019) Outcomes, challenges, and pitfalls after targeted muscle reinnervation in high-level amputees: is it worth the effort? Plastic and Reconstructive Surgery 144: 1037e–1043e

Cohort study

n=30

Upper limbs

Follow-up: at least 6 months

Targeted muscle reinnervation has improved prosthetic control and revolutionised neuroma treatment in upper limb amputees. Still, the rate of abandonment even after targeted muscle reinnervation surgery has been high, and several advances within the biotechnological interface will be needed to improve prosthetic function and acceptance in these patients.

Studies with more people or longer follow up are included.

Souza JM, Cheesborough JE, Ko JH et al. (2014) Targeted muscle reinnervation: a novel approach to postamputation neuroma pain. Clinical Orthopaedics and Related Research 472: 2984–90

Retrospective cohort study

n=26

Upper limbs

All patients had TMR to improve myoelectric control.

None of the 26 patients who had TMR demonstrated evidence of new neuroma pain after the procedure, and all but 1 of the 15 patients who had preoperative neuroma pain experienced complete relief of pain in the distribution of the transferred nerves.

Studies with more people or longer follow up are included.

Valentine L, Weidman AA, Foppiani J et al. (2024) A national analysis of targeted muscle reinnervation following major upper extremity amputation. Plastic and Reconstructive Surgery doi: 10.1097/

PRS.0000000000011439

Retrospective database survey (US)

n=8,945 upper extremity amputations (310 TMR)

Primary TMR

The proportion of people who had TMR was low (3.5%). Length of stay was statistically significantly shorter for patients who had TMR compared to those who did not (10.6 versus 14.8, p=0.012).

Other studies with more relevant outcomes are included.

Valerio IL, Dumanian GA, Jordan SW et al. (2019) Preemptive treatment of phantom and residual limb pain with targeted muscle reinnervation at the time of major limb amputation. Journal of the American College of Surgeons 228: 217–26

Cohort study

n=489 (51 TMR)

Upper or lower limbs

Primary TMR

Follow-up: at least 3 months

Patients who had TMR had less PLP and RLP compared with untreated amputee controls, across all subgroups and by all measures. Median "worst pain in the past 24 hours" for the TMR cohort was 1 out of 10 compared to 5 (PLP) and 4 (RLP) out of 10 in the control population (p=0.003 and p<0.001, respectively).

Median PROMIS t‑scores were lower in TMR patients for both PLP (pain intensity [36.3 versus 48.3], pain behaviour [50.1 versus 56.6], and pain interference [40.7 versus 55.8]) and RLP (pain intensity [30.7 versus 46.8], pain behaviour [36.7 versus 57.3], and pain interference [40.7 versus 57.3]). Targeted muscle reinnervation was associated with 3.03 (PLP) and 3.92 (RLP) times higher odds of decreasing pain severity compared with general amputee participants.

The main results from this study are included in the meta-analysis by Tham et al. (2023).

Vonu PM, Shekouhi R, Crawford K et al. (2024) Targeted muscle reinnervation: factors predisposing to successful pain score reduction. Annals of Plastic Surgery 92: 426-s431

Retrospective cohort study

n=40 (47 limbs)

Upper or lower limbs

Primary or secondary TMR

TMR demonstrated favourable pain score reduction across all studied groups in the cohort. Patients younger than 50 years and females had more dramatic improvements in pain score reduction. This study adds to the existing published literature supporting TMR as the standard of care in neuroma mitigation following major limb amputation.

Small retrospective study.

Walsh AR, Lu J, Rodriguez E et al. (2023) The current state of targeted muscle reinnervation: a systematic review. Journal of Reconstructive Microsurgery 39: 238–44

Systematic review

n=338 (341 limbs)

13 articles

Upper or lower limbs

Primary or secondary TMR

Follow-up: mean 22.3 months

There is a substantial body of evidence that supports the use of TMR to maximise quality of life for limb amputees. Once a novel approach with the potential to ameliorate pain, the evidence suggests that TMR should now be standard of care for patients at the time of amputation or thereafter.

No meta-analysis.

Yuan M, Gallo M, Gallo L et al. (2024) Targeted muscle reinnervation and regenerative peripheral nerve interfaces versus standard management in the treatment of limb amputation: a systematic review and meta-analysis. Plastic Surgery 32 (2) 253–64

Systematic review and meta-analysis

n=1,419 (418 TMR or RPNI); 11 studies

Primary

Observational study evidence suggests that TMR or RPNI results in a statistically significant reduction in incidence, pain scores and PROMIS scores of PLP and RLP. Decreased incidence of neuromas favoured primary TMR or RPNI, but this did not achieve statistical significance (p=0.07). Included studies had moderate to critical risk of bias.

Review includes RPNI as well as TMR. There is some study overlap with the systematic review by Tham et al. (2023).