There are currently 1.6 million people in the U.S. living with limb loss. More than 185,000 people undergo amputations in the U.S. alone each year, and the total number of amputees is expected to be nearly 3.6 million people by 2050. Moreover, there have been approximately 1,700 combat Service-related amputations between 2001 and 2015 resulting from recent U.S. military operations. Almost one-third of these individuals will form painful neuromas as a result of nerve injury that occurs at the time of amputation. This pain can be extremely debilitating, reduces functionality, and can lead to disability and poor quality of life. Once a neuroma is symptomatic, analgesic medication is used to alleviate pain, and surgical intervention is performed to remove the neuroma from the end of the affected nerve. The Regenerative Peripheral Nerve Interface (RPNI) is a novel treatment strategy for the alleviation of pain associated with neuroma following amputation. Once the neuroma has been removed, the RPNI is created by surgically implanting the end of the nerve into a small piece of the patient’s own muscle. In this study, we seek to assess the viability of RPNI surgery as a novel treatment strategy to prevent pain once the neuroma is removed and to prevent neuroma formation altogether at the time of lower-limb amputation.

This proposal addresses the “Post-Operative Pain Management” Fiscal Year 2016 Peer Reviewed Orthopaedic Research Program Rehabilitation Focus Area. The proposed research will evaluate the efficacy of using RPNI surgery to treat symptomatic neuromas and also to prevent these neuromas from forming in major lower-extremity amputees. Patients who have suffered lower-limb loss, and those who are about to undergo lower-limb amputations, will be recruited to participate and receive RPNI surgery to treat existing neuromas or to prevent neuroma formation at the time of amputation, respectively. Patients will be evaluated for pain symptoms before and after RPNI treatment at regular intervals for 1 year using validated survey instruments designed to assess patient-reported outcomes. These scores will be compared with amputees who do not receive RPNI surgery. In addition, a group of patients who undergo RPNI surgery will undergo functional magnetic resonance imaging (fMRI) in order to assess whether pain receptors in the brain are less active once the RPNI surgery has been performed and to evaluate the health and development of those nerves that received RPNI treatment following neuroma removal using both MR neurography and diffusion tensor imaging (DTI).

Aim 1 of the study will determine the ability of RPNI surgery to treat existing painful neuromas in major lower-limb amputees. Aim 2 of the study will assess the efficacy of RPNI surgery to prevent the formation of painful neuromas in patients undergoing major lower-limb amputation. Validated survey instruments will be utilized to assess the severity of patient’s neuroma and phantom pain pre-operatively and post-operatively. Functional assessments and clinical evaluations will also be used to evaluate the effectiveness of RPNI treatment. Aim 3 will assess both peripheral and central nervous system changes and responses to RPNI treatment. Peripheral changes will be assessed using MR neurography and DTI. Central brain changes in response to neuroma treatment will be analyzed using fMRI. We expect to have all three aims completed within the 4-year funding period.

The outcomes of this study will provide much needed insight into the effectiveness of RPNI surgery to treat the debilitating effects of painful neuromas on lower-limb amputees. The results will also direct the future surgical standard of care for these individuals, potentially revolutionizing the standard of care for the millions of amputees who suffer from neuroma pain and subsequently changing current clinical practice. This will directly enhance both the productivity and quality of life for individuals suffering from painful neuromas while decreasing the medical costs associated with treatment. This will be extremely beneficial to both active Service members and Veterans who have had amputations following combat injuries and will allow them to return to active duty and/or civilian work.