Tar g e t e d M u s c l e

Reinnervation for
Treatment of Neuro pathic Pain
Ava G. Chappell, MD, Sumanas W. Jordan, MD, PhD,
Gregory A. Dumanian, MD*

KEYWORDS
 Neuropathic pain  Neuroma  Targeted muscle re innervation  Chronic postoperative pain
 Phantom limb pain

KEY POINTS
 Targeted muscle reinnervation (TMR) is a reproducible technique for effective treatment and pre-
vention of neuropathic pain.
 The fundamental concept of TMR is to give severed nerve endings a place to go and something to
do, which facilitates healing of these severed peripheral nerves.
 Methods to encourage normal healing of severed peripheral nerves instead of burying the nerve
ending in surrounding tissue, will lead to improved outcomes of neuroma treatment.
 Neuropathic pain is a surgically treatable condition.

INTRODUCTION perineural injection with alcohol or corticosteroids,

regional blocks, spinal cord stimulation, transcuta-
Chronic pain after surgery leads to significant neous electrical nerve stimulation, and direct oper-
disability worldwide. Although there are numerous ative handling of the injured nerves.7–11
established causes of chronic postsurgical pain, Whenever possible, nerve injuries should be
neuropathic pain due to peripheral nerve injury is repaired. When this is not feasible, such as in the
a known contributor. In some proportion of periph- case of an absent distal nerve stump or in the
eral nerve injuries, symptomatic neuromas—disor- case of a failed reconstruction, direct operative
ganized axons encased in scar—form and may handling of the injured nerve is preferred. For de-
be exquisitely painful to light touch, pressure, vi- cades, the standard surgical approach for symp-
bration, and extreme temperatures or even at tomatic neuroma has been neuroma excision and
rest. Many management strategies have been relocation to a more favorable position, commonly
proposed, yet symptomatic neuromas remain a buried into bone or muscle, with the hope that the
challenge.1 Pharmacologic therapy with antide- recurrent neuroma would be hidden and asymp-
pressants, anticonvulsants, opioids, and topical tomatic.12,13 In contrast, more recent strategies
anesthetics have variable efficacy and places are based on the concept of providing severed
patients at risk for opioid dependence.2–5 Behav- axons an end organ—somewhere to go and some-
ioral strategies include desensitization protocols, thing to do. One such technique is targeted muscle
cognitive behavioral therapy, and group psycho- reinnervation (TMR), a nerve transfer procedure
therapy.6 Interventional methods for neuropathic that treats pain via direct nerve to nerve healing.
plasticsurgery.theclinics.com

pain include minimally invasive treatments of the First performed by the senior author G.A. Duma-
injured nerve with radiofrequency ablation, nian in 2002, TMR is defined as the coaptation of

Division of Plastic Surgery, Department of Surgery, Northwestern Feinberg School of Medicine, 675 North
Street Clair, Suite 19-250, Chicago, IL 60611, USA
* Corresponding author.
E-mail address: gdumania@nm.org
Twitter: @gregdumanian (G.A.D.)

Clin Plastic Surg - (2020) -–-

https://doi.org/10.1016/j.cps.2020.01.002
0094-1298/20/Ó 2020 Elsevier Inc. All rights reserved.
2 Chappell et al

Table 1
Classifications of peripheral nerve injury

Seddon Sunderland Mackinnon

(1947)38 (1951)39 (1988)40 Summary
Neuropraxia 1 Local conduction block with possible
segmental demyelination. No injury to
axons, so no regeneration. Remyelination
and complete recovery by 12 wk postinjury.
Axonotmesis 2 Axonal injury occurs. Intact endoneurium,
perineurium, and epineurium. Distal
segment undergoes wallerian
degeneration. Proximal nerve fibers
regenerate at 1mm/day. Full recovery
possible unless distance of injury from
motor end plate far and prolonged
denervation of the receptor prevents motor
recovery.
3 Axonal injury occurs. Wallerian degeneration
combined with fibrosis of endoneurium.
Perineurium and epineurium intact.
Incomplete recovery likely, due to scar
within endoneurium hinders regenerating
fibers interaction with correct end organs.
4 Nerve-in-continuity but injury causes
complete scar block. Only epineurium
intact. Recovery only possible if scar is
surgically removed and nerve repaired or
grafted.
Neurotmesis 5 Nerve completely divided and must be
surgically repaired before regeneration can
occur.
6 Mixed nerve injury. Combination of any of the
types of injuries 1–5, and different levels of
injury occur at different regions of the
nerve.

cut peripheral nerves to a newly divided nearby outcomes from nonamputees with neuroma pain
motor nerve branch.14 The fascicles of the prox- who were treated with TMR are better than those
imal nerve grow into motor end plates, and likely who were treated with standard neuroma excision
into proprioceptors and other sensory end organs, and hiding.18–20 There is growing acceptance for
to reinnervate the target muscle.15,16 TMR has TMR as an effective surgical strategy for manage-
evolved from a technique to improve intuitive pros- ment of neuropathic pain. TMR may be performed
thesis control in amputees to a technique to treat by any surgeon with knowledge of peripheral nerve
and prevent neuropathic pain from peripheral anatomy and nerve dissection experience.
neuroma. A recent randomized clinical trial in the
treatment of chronic postamputation pain demon- PATHOPHYSIOLOGY
strated that healing a nerve ending with TMR had
better patient-reported outcomes for residual limb Traumatic neuromas are regions of nerve swelling/
pain and phantom limb pain at 18 months of inflammation that can occur in any part of the body
follow-up, compared with neuroma excision and after nerve injury. Nerve injury can be direct—tran-
muscle burying.17 Furthermore, a cohort study of section during dissection, or indirect—stretched
patients who underwent TMR at the time of amputa- or crushed during retraction. The physiologic
tion compared with unselected amputees from the response to axonal injury is axon sprouting and
general population demonstrated significantly fewer regeneration from the proximal segment and wal-
TMR patients with moderate to severe residual limb lerian degeneration of the distal segment. Sed-
and phantom limb pain by multiple measures.9 don’s classification distinguishes types of nerve
Additional clinical data have shown that pain injury in terms of neuropraxia, axonotmesis, and
 TMR for Neuropathic Pain 3

Fig. 1. TMR nerve transfers for BKA. Under loupe magnification (2.5), the tibial nerve was divided and coapted
to the motor nerve to the soleus with 6-0 Prolene interrupted sutures (yellow background). The common pero-
neal nerve was transposed medial to lateral gastrocnemius tendon and coapted to the lateral gastrocnemius mo-
tor nerve and the motor nerve to the lateral gastrocnemius (vessel loops at the top). The 2 components of the
sural nerve were coapted to 2 separate motor nerves to the medial gastrocnemius muscle. The total tourniquet
time was 45 minutes.

neurotmesis.21 Sunderland further grades nerve Histologically, TMR restores axon count, size,
injury based on expected recovery. With intact and myelination in a rabbit amputation model.23 In
or repaired perineurium and epineurium, sprout- the authors’ clinical experience, reestablishment
ing axons find a distal target and eventually of muscle function can be detected clinically in
prune excess axons. For Sunderland grade 4 or more than 95% of nerve transfers.23 Electromyog-
greater, however, sprouting axons fail to connect raphy after transhumeral TMR has demonstrated
to a distal segment or target organ and become physiologic synaptic inputs to reinnervated mus-
encased in scar, thus forming neuromas, specif- cles.24 What is unclear is the fascicles that fail to
ically neuroma-in-continuity in axonotmesis or find a distal target after nerve transfer due to
end neuroma in neurotmesis (Table 1).21 obvious mismatch in size and fascicle numbers be-
Within the neuroma bulb, the authors’ data have tween donor and recipient nerves. This size
shown that the axons are sensory, with no motor mismatch undoubtedly led to the slow adoption
staining found.22 The model is that the sensory of TMR as a surgical technique. It is hypothesized
nerves continue to seek a distal nerve attempting that the large denervated block of muscle near
to heal and reinnervate, whereas without Schwann the nerve coaptation site is a source of additional
cells and other trophic factors, the motor axons end organs to soak up escaping axons.
recede back toward the spine.22 This is consistent
with clinical peripheral nerve surgery that motor PRESENTATION AND DIAGNOSIS
outcomes tend to be less successful than sensory
recoveries for mixed nerve repairs. Furthermore, it A typical patient presenting with a symptomatic
has been the authors’ experience that cut pure neuroma may describe the pain as electric, shoot-
motor nerves do not form neuromas, a key to TMR. ing, or burning. The pain may be associated with
4 Chappell et al

light touch or pressure or changes in weather and For the patient who presents with intolerable
temperature or be without any provocation at all. symptomatic neuroma, the clinician must address
Neuropathic pain may affect sleep quality, such the nerve injury. Symptomatic neuromas by defini-
as the common complaint of night waking in carpal tion are associated with injury to a mixed or sen-
tunnel syndrome; mood; ambulation; and, for the sory nerve. The clinical diagnosis is made as a
amputee, prosthetic use. Patients may present combination of the chief complaint as chronic
with high opioid tolerances. For the amputee, pain postamputation/surgery/injury and a focused
postamputation pain may include residual limb physical examination. The clinician asks patients
(or stump) pain, phantom limb pain, back pain, to point to a location on their extremity where the
and hip pain.25,26 To clarify distinctions between pain is the greatest, and the patients can quickly
pain syndromes, residual limb pain is defined as identify this painful spot. There likely is a Tinel
pain local to the residual limb, often due to a neu- sign when this spot is tapped by the clinician, or
roma27; phantom limb pain is defined as unpleas- patients may experience severe acute pain when
ant or painful sensations perceived in the missing this region is palpated. The nerve leading to this
limb, thought to be a complex interplay between neuroma often is excitable to palpation along its
the neuroma and several levels of the central ner- length. Imaging typically is not necessary or rec-
vous system28–30; and chronic pain is defined as ommended for the work-up of intolerable neuro-
pain lasting greater than 6 months and causing pathic pain.
physical debilitation and decreased quality of Injections with local anesthesia may be per-
life.31 A simple history for pain includes an assess- formed to confirm that treatment of the injured
ment of intensity on an 11-point numerical rating nerve will lead to a change in symptoms. An
scale (0 is no pain and 10 is the worst pain imagin- inability to improve symptoms temporarily with
able) and an assessment of frequency. an anesthetic injection should give both surgeon

Fig. 2. Case example, a 68-year-old woman one year post op left below knee amputation presented with persis-
tent left leg pain in the common peroneal nerve distribution. Despite medical treatment with hydrocodone and
gabapentin, her residual limb pain and phantom limb pain were severe, and she was unable to tolerate wearing a
prosthesis. After discussion of risks and benefits, she wished to pursue with TMR surgery for her chronic postam-
putation pain and phantom limb pain. Prior to nerve transfers from a midline posterior incision, donor nerves are
prepared (right, from top of figure to bottom): the common peroneal nerve, the peroneal component of the su-
ral nerve, and the tibial component of sural nerve. The tibial nerve in the center of the field has not undergone
neurotomy. Recipient motor branches are shown with vessel loops (from top to bottom): motor nerve to the
lateral gastrocnemius, motor nerve to the flexor hallucis longus (FHL), and 2 motor branches to the medial
gastrocnemius. The motor nerve to the soleus is in the center of the field.
 TMR for Neuropathic Pain 5

and patient pause before beginning surgery. A few Table 3

patients have centralization of their pain, with a Donor nerves and potential motor nerve
complete lack of pain reduction after neuroma targets for acute below-knee amputation
treatment. Fortunately, these completely central- (supine)
ized pain patients are infrequent but may be
more common as the time from amputation or Nerve Primary Muscle Target
injury increases over decades. Diagnostic nerve Deep peroneal Tibialis anterior
blocks are even more important as the surgeon at-
Superficial peroneal Peroneus longus
tempts to localize neuromas of the head and neck,
Tibial Soleus, or flexor
trunk, or in nonamputees. Injections can be
digitorum longus
done for thin patients in the office, but heavier pa-
tients may require interventional radiology for an Medial surala Medial gastrocnemius
ultrasound-guided procedure. Lateral surala Lateral gastrocnemius
a
Indicated when significant soft tissue dissection is not
SURGICAL TECHNIQUE required.
Targeted Muscle Reinnervation for the
Amputee (ie, Treatment of End Neuroma)
Surgical, Cleveland, Ohio). These nerve stimula-
The procedural method of TMR has been well tors are recommended becuase they do not
described in the literature for the various levels of exhaust motor nerves, can locate intramuscular
upper and lower extremity amputation.22,32–34 motor points, and enable stimulation of motor
The fundamental technical steps of TMR are (1) nerves at more than 45 minutes tourniquet time.
nerve identification and preparation to healthy fas- These motor points serve as potential recipients
cicles, (2) recipient motor nerve identification, and of TMR nerve transfer. Sometimes, finding motor
(3) tension-free coaptation. Common nerve trans- points involves intramuscular dissection. The mo-
fers are listed in Tables 2–8 for convenience. tor nerve branches are divided 1 mm to 2 mm
In the preoperative area, the location of painful from the muscle entry point. The mixed nerve
Tinel signs are marked. In amputees or patients proximal segment is coapted to the surgically
who have undergone previous peripheral nerve divided distal segment of the motor nerve branch
manipulation, the locations of the neuromas may using standard technique, under loupe magnifica-
not be intuitive from anatomy alone. Although neu- tion with 2 to 3 6-0 or 7-0 polypropylene epineural
roma excision is not necessary because the sutures. The coaptation should be under no ten-
nerves are treated proximally, the trajectory of sion with minimal redundancy. Size mismatch is
the nerve toward the Tinel sign can be helpful dur- common. If encountered, pure sensory nerves
ing nerve identification. Smooth Gerald forceps are treated in the similar manner.
work well for handling larger nerves and microsur- In the acute setting, the major peripheral nerves
gical forceps are used for small motor branches. have been exposed and divided by the resecting
Once the donor nerves are identified, nearby mo- team. It is important to communicate to the resect-
tor nerve branches are identified via anatomy ing team not to perform a traction neurectomy if
and/or a handheld nerve stimulator (Checkpoint that is their standard practice. Access to known
motor nerves may require a position change, or
intramuscular dissection may be performed to
Table 2 identify nearby motor points, which is a term
Donor nerves and potential motor nerve
targets for delayed below-knee amputation
(prone, 1-incision approach, posterior midline Table 4
only) Donor nerves and potential motor nerve
targets for above-knee amputations
Nerve Primary Muscle Target
Nerve Primary Muscle Target
Common peroneal, Lateral gastrocnemius
possible sparing Saphenous Vastus medialis
of motor nerve Peroneal component Biceps femoris
to anterior tibial of sciatic
Tibial Soleus Tibial component Semitendinosus/
Medial sural Soleus, or medial of sciatic semimembranosus
gastrocnemius Posterior femoral Biceps femoris
Lateral sural Flexor hallucis longus cutaneous (distal motor branch)
6 Chappell et al

Table 5 Table 7
Donor nerves and possible motor nerve targets Donor nerves and possible motor nerve targets
for shoulder disarticulation nerve transfer for transradial nerve transfer

Nerve Primary Muscle Target Donor Nerve Primary Muscle Target

Radial Thoracodorsal Median Flexor digitorum superficialis
Musculocutaneous Superior pectoral Flexor digitorum profundus
to clavicular head Brachioradialis
Median Middle pectoral Ulnar Flexor carpi ulnaris
Ulnar Lateral pectoral Radial nerve: Pronator quadratus
superficial Flexor digitorum profundus
branch
used to describe tiny excitable nerve fascicles
found within a muscle. The decision to stay within
the wound to perform TMR or to perform a position neuroma pain is an underrecognized condition.
change and to use a new incision is left to the Whereas the standard procedure is ilioinguinal
discretion of the TMR surgeon, with pros and neurectomy, an alternative approach is to treat
cons to both strategies (Fig. 1 and 2). the injured nerve by giving the nerve somewhere
to go and something to do. Recently, the use of
Targeted Muscle Reinnervation for the processed nerve allograft has been described to
Nonamputee (ie, Treatment of End Neuroma serve as interposition graft after neuroma excision
and Unreconstructable Neuroma-in- when the neuroma can be located.17 When the
Continuity) nerve cannot be reconstructed, the ilioinguinal
nerve is dissected proximally toward the spine
TMR for the nonamputee is indicated for patients
and coapted to a motor nerve to the internal obli-
with neuroma formation and failed prior recon-
que and transversus abdominis, that is, TMR.
struction or nerve gaps greater than 3 cm to
This procedure has shown excellent pain out-
5 cm. Again, the neuroma is located by palpation
comes in the authors’ hands (see Fig. 3 for clinical
with the assistance of the patient preoperatively.
photograph of abdominal wall TMR).
The injured nerves are exposed proximally, and
nearby motor targets are identified, as described
previously. For the lower leg, for example, the au- POSTOPERATIVE CARE
thors recommend TMR to the extensor digitorum For patients presenting for chronic pain or pros-
longus for nerves in the lateral compartment and thetic control, patients typically are observed over-
the lateral gastrocnemius in the superficial poste- night for pain control and discharged to home.
rior compartment.34 Because the deep posterior Postoperative blocks may be performed at the
compartment is inaccessible in the nonamputee discretion of the regional anesthesia team. If a pa-
patient, this is not used as a motor target for TMR. tient’s pain is well controlled on oral pain medica-
Further illustrating the utility and principles of tion and the patient wishes to be discharged on
TMR to treat symptomatic neuroma, the authors the same day of surgery, there is no contraindica-
have performed TMR to treat chronic abdominal tion. Postoperative swelling is minimized with
wall pain due to ilioinguinal nerve injury after
inguinal hernia repair. Chronic abdominal wall
Table 8
Table 6 Donor nerves and possible motor nerve targets
Donor nerves and possible motor nerve targets for the nonamputee with an unreconstructable
for transhumeral nerve transfer neuroma

Nerve Primary Muscle Target Donor Sensory Nerve Primary Muscle Target
Median Medial head of biceps Deep peroneal Extensor digitorum
Ulnar Brachialis longus
Radial Lateral head of triceps Superficial Peroneus longus
peroneal
Medial antebrachial Any local muscles
cutaneous/lateral Lateral sural Lateral gastrocnemius
antebrachial Medial sural Lateral or medial
cutaneous gastrocnemius
 TMR for Neuropathic Pain 7

Fig. 3. TMR for treatment of recurrent ilioinguinal neuroma. The neuroma is excised and the freshened ending of
the ilioinguinal nerve coapted to a freshly divided motor nerve to the internal oblique.

compressive dressings. A splint or other additional between 50% and 90% of amputees.25,26 Symp-
form of immobilization is not needed. Patients can tomatic neuromas are a major driver of residual
restart wearing their original prosthesis when their limb pain and phantom limb pain.36 Moreover,
surgical incisions are healed and postoperative symptomatic neuromas may occur with any injury
edema has resolved, at approximately 4 weeks to mixed and sensory peripheral nerves. Funda-
to 6 weeks after surgery.35 It is important that pa- mentally, the injured sensory axons are sprouting
tients are informed prior to surgery that after sur- in an attempt to find an end organ. Modern tech-
gery they may experience numbness in the niques, including nerve repair, nerve autografts
residual limb, dysesthesia, and even transfer and allografts, regenerative peripheral nerve inter-
sensation in the skin over reinnervated muscles. faces, and TMR, all aim to satisfy the need for an
Additionally, for patients with phantom limb pain, end organ.8,10,18 TMR resolves sprouting and
some may have an exacerbation of symptoms associated painful symptoms by direct nerve-to-
lasting up to 4 weeks to 6 weeks after surgery until nerve healing.
new nerve connections have formed.32 Internal Recent studies have shown that TMR can
data support the improvement in established address the chronic postamputation pain prob-
phantom limb pain approximately 6 months after lem. TMR results in clinically meaningful improve-
TMR. ment in residual limb and phantom limb pain by an
For patients presenting for TMR at the time of average of 3.7 and 3.6 of 10 points, respectively, at
amputation, postoperative care and discharge last follow-up.17 TMR has shown improvement in
planning are dictated by needs related to the postamputation neuroma pain even months to
amputation itself. No special instructions are years after the initial amputation, although learned
necessary because of the TMR portion of the behaviors from chronic pain are difficult to
case. Once evidence of muscle reinnervation has reverse.17,37 As a prophylactic measure, TMR per-
occurred, the patient may practice contracting formed at the time of initial amputation leads to
the reinnervated muscles. significantly lower residual limb and phantom
limb pain scores (1 of 10 for both) compared with
DISCUSSION the general amputee population (4 of 10 and 5 of
10, respectively).9 TMR more than doubled the
Postamputation pain syndromes may include re- proportion of amputees reporting zero pain and
sidual limb pain, phantom limb pain, back pain, nearly halved the proportion of amputees report-
and hip pain and are a significant concern for the ing severe pain (7–10 of 10).9 Thus, the indication
amputee population, with prevalence ranging for TMR extends beyond prosthesis control for
8 Chappell et al

upper extremity amputees and includes the treat- 7. Bittar RG, Otero S, Carter H, et al. Deep brain stim-
ment and prevention of symptomatic neuroma ulation for phantom limb pain. J Clin Neurosci 2005;
pain in amputees and nonamputees. 12(4):399–404.
8. Kubiak CA, Kemp SWP, Cederna PS. Regenerative
SUMMARY peripheral nerve interface for management of post-
amputation neuroma. JAMA Surg 2018;153(7):
Postoperative neuropathic pain causes chronic 681–2.
disability to many people globally. As access to 9. Valerio IL, Dumanian GA, Jordan SW, et al. Preemp-
surgical care increases, clinicians must be aware tive treatment of phantom and residual limb pain
of the potential postoperative pain complications. with targeted muscle reinnervation at the time of ma-
Chronic neuroma pain frequently is misdiagnosed, jor limb amputation. J Am Coll Surg 2019;228(3):
overlooked, or masked with opioids. Surgical 217–26.
techniques and principles from TMR can apply to 10. Woo SL, Kung TA, Brown DL, et al. Regenerative pe-
successfully treat neuroma pain at sites of ampu- ripheral nerve interfaces for the treatment of postam-
tation as well as other postsurgical sites. putation neuroma pain: a pilot study. Plast Reconstr
Surg Glob Open 2016;4(12):e1038.
CODING 11. Kung TA, Langhals NB, Martin DC, et al. Regenera-
tive peripheral nerve interface viability and signal
transduction with an implanted electrode. Plast Re-
International D36.10 Neuroma
constr Surg 2014;133(6):1380–94.
Classification
of Diseases, Tenth 12. Mackinnon SE, Dellon AL, Hudson AR, et al. Alter-
Revision ation of neuroma formation by manipulation of its
Current Procedural 64905 Nerve pedicle microenvironment. Plast Reconstr Surg 1985;76(3):
Terminology transfer, first stage 345–53.
64910 Neuroma excision 13. Boldrey E. Amputation neuroma in nerves implanted
in bone. Ann Surg 1943;118(6):1052–7.
14. hijiawi JKT, Lipschutz. An improved brain-machine
interface accomplished using multiple nerve trans-
fers. Plast Reconstr Surg 2006;118:1573–8.
DISCLOSURE 15. Kuiken TA, Dumanian GA, Lipschutz RD, et al. The
Dr G.A. Dumanian has consulted for the Check- use of targeted muscle reinnervation for improved
point Surgical Company and has received support myoelectric prosthesis control in a bilateral shoulder
for his teaching course for Targeted Muscle Rein- disarticulation amputee. Prosthet Orthot Int 2004;
nervation. Dr S.W. Jordan and Dr A.G. Chappell 28(3):245–53.
have nothing to disclose. 16. Kuiken TA, Miller LA, Lipschutz RD, et al. Targeted
reinnervation for enhanced prosthetic arm function
in a woman with a proximal amputation: a case
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