Extremity amputations are common operations both in the United States and other areas of
the world. It is estimated that there are nearly 2 million adults living in the United
States alone. Etiologies for extremity amputation are diverse but the most common
indications include complications of type 2 diabetes, non-diabetic peripheral vascular
disease, trauma, and oncologic conditions. Given the increasing prevalence of several of
these pathologies, conservative estimates suggest that the population of people living
with an amputated limb will likely double within the next several decades.
Patients who undergo limb amputation are at significant risk of developing chronic
neuropathic pain as a result of symptomatic neuroma formation, due in large part to the
abundance of sizeable nerves within the extremities that are necessarily transected as
part of the procedure. There are two distinct forms of pain experienced by patients who
have undergone major extremity amputations. Residual limb pain is the more
straightforward form of post-amputation pain attributable to neuroma formation within the
amputation stump. Following peripheral nerve transection, axons regenerating from the
proximal stump tend to form aggregates of disorganized neural growth called neuromas.
Some neuromas will produce severe, intractable pain causing significant impairment in
prosthetic fit and function, activities of daily living, and quality of life. Some
estimates place the prevalence of residual limb pain attributable to neuroma formation as
high as 75%. The other form of pain is known as phantom limb pain. While the
underpinnings of phantom limb pain are the subject of ongoing debate, it is thought by
many to arise from chronic stimulation of the cerebral cortex with painful inputs from
peripheral neuromas, leading to unpredictable and poorly characterized reorganization of
the cortex. Informed estimates of phantom limb pain prevalence as high as 85% have been
reported. Successful prevention and treatment of symptomatic neuromas in the setting of
limb amputation is therefore of paramount importance given the central role in the
pathogenesis of chronic post-amputation limb pain encompassing both residual limb pain
and phantom limb pain.
Treatment options for chronic post amputation pain caused by symptomatic neuromas are
diverse. Medical options for both phantom limb pain and residual limb pain have been met
with limited success. Despite the widespread use, the utility of neuromodulating
medications, such as gabapentin, has been called into question by recent large scale
meta-analyses that failed to demonstrate meaningful improvements. Neurotoxins, such as
botulinum toxin, have also been studied and found to offer limited, if any, pain
resolution.
One of the most commonly used surgical approaches to treat and prevent symptomatic
neuromas involves burying the proximal nerve stump into nearby muscle. There is a
widely-held misconception that burying a proximal nerve stump into muscle will prevent a
neuroma from forming. However, elegant animal studies have proven that regeneration of a
neuroma is virtually guaranteed because innervated muscle will not accept additional
innervation from regenerating neurons.
In the past decade, two other surgical treatments for chronic post-amputation limb pain
have come into vogue. Targeted muscle reinnervation (TMR) was initially pioneered as a
means of providing intuitive control of advanced prostheses and only later observed to
reduce neuroma pain. TMR involves transferring the proximal nerve stump of the injured
nerve into a nearby distal motor branch. Early results are promising. A recently
published randomized, controlled trial demonstrated the superiority of the TMR approach
over the 'bury in muscle' approach, so much so that the trial concluded prematurely due
to the superiority of the TMR compared to the historical technique.
The other recently developed and widely popularized option for surgical treatment of
chronic post-amputation limb pain involves creation of a regenerative peripheral nerve
interface (RPNI). Similar to TMR, the RPNI was initially conceived as a method to provide
an interface with an advanced neuroprosthetic prior to being employed as a treatment
strategy for neuromas. RPNIs are muscle grafts that are coapted to the ends of severed
proximal nerve stumps. This technique has gained popularity because of its technical
simplicity and promising early clinical data. In contrast to the 'bury in muscle'
approach, RPNIs are denervated at the time of harvest and have been shown to accept
reinnervation via direct neurotization from the proximal nerve stump.
To address possible limitations of the strategies described above, the investigators
propose using muscle targets similar to RPNIs but maintaining vascularity - a
vascularized, denervated muscle target (VDMT). This is accomplished by raising a portion
of muscle on a vascular leash in proximity to the transected nerve. Perforating branches
from larger blood vessels that perfuse adjacent muscle can be found in abundance
throughout the extremities. Any nerves traveling with the vascular leashes will be
divided to ensure complete denervation of the muscle. Therefore, VDMTs will be receptive
to reinnervation from the implanted proximal nerve stump, maintain vascularity such that
the VDMTs can be large enough to supply an abundance of sensory receptors (spindle cells,
Golgi apparati, etc) to accept regenerating axons, and avoid the use of a nerve
coaptation. In short, the VDMT offers possible enhancements to the surgical techniques
currently in use.
In terms of surgical outcomes, there is a robust body of data surrounding the TMR and
RPNI operations, with some more recent reports providing pre- and post-operative pain
scores for the individual operations. With the exception of one study that prospectively
compared TMR to the historical gold standard of neuroma excision and implantation into
surrounding tissue, there is a startling lack of prospective data on pain outcomes.
Furthermore, the investigators are not aware of prospective, head-to-head comparative
data for RPNI vs TMR. Robust, prospective, comparative data is now needed to validate the
VDMT approach and assess its efficacy in comparison to the other established techniques.
It is of prime importance to surgeons who perform extremity amputations (eg orthopedic
surgeons, vascular surgeons, trauma surgeons, plastic surgeons, and podiatrists) as well
as those who perform salvage procedures for post-amputation extremity pain to understand
the potential of these operations in treating this pain. Physicians are still lacking
evidence-based treatment guidelines. With the generation of this data, surgeons and
patients can make more informed decisions about which operative intervention provides the
highest likelihood of durable, significant pain relief.