Project Summary:
Major limb amputation affects approximately 1,200-1,300 Wisconsinites each year, and similar numbers suffer minor amputations of digits and toes. These amputations represent major nerve injuries, whether performed therapeutically (e.g., vascular disease, cancer) or due to trauma. Of these amputees 67% have chronic amputation-related pain, both phantom limb pain (pain felt to originate in the amputated part) and residual stump pain (pain in the remaining limb). Chronic pain associated with amputations is debilitating, severely compromises quality of life, can prevent the use of prosthetics, and is associated with chronic opioid use.
Unfortunately, chronic pain is a risk factor for opioid abuse and like much of the nation, Wisconsin has been severely impacted by the rise in opioid overdoses. Opioids remain the leading cause of death amongst substance use related deaths in Wisconsin, with an overall rate of 17.7 per 100,000 from 2015-2022.
Until recently, there have only been moderately effective interventions for amputation related pain, and no preventative interventions for amputation related pain. Targeted muscle reinnervation (TMR), which connects amputated nerve ends to small motor nerve branches, was designed for motor input to myoelectric prosthetics. Unexpectedly, TMR performed at the time of amputation also reduces or prevents amputation-related pain. A multi-institutional cohort study showed that 49% of patients who had undergone early TMR (within 2 weeks of amputation) were completely free of residual limb pain (RLP) and 45% were free of phantom limb pain (PLP). In contrast, only 19% and 21% of standard amputation (no TMR) patients were free of RLP and PLP, respectively. The TMR patients also required significantly less opioids.
However, if the amputation is longstanding, such as in chronic amputees, TMR is less effective in reducing pain. Another study examined amputees that underwent TMR less than 1M post amputation (acute) and greater than 1M post amputation (delayed) and saw that delay significantly affected the resulting average Visual Analogue Scale pain score at final follow-up (median 10-11 months): 1.9 versus 6.2. These findings and a recent meta-analysis show that TMR is most effective when applied acutely at the time of injury, and while there may be improvement in pain with delayed treatment, it is not as effective. The research team’s our own data in a rat model of neuropathic pain reflects these findings: TMR produced significant analgesia when applied immediately at the time of nerve injury and up to a delay of three weeks; however, when applied after a delay of 12 weeks from injury, no analgesia resulted.
TMR is gradually becoming the standard of care for acute traumatic amputees at MCW; orthopedic surgeons, plastic surgeons, and PMR physicians all collaborate to provide TMR at Froedtert and the VA. However, chronic amputees are comparatively underserved as providers do not have effective therapies to offer. The origin of this problem is that providers do not know the underlying mechanisms of analgesia in TMR, and thus, it is unclear why it is not as effective in chronic amputees.
The project team hypothesizes that in chronic amputees, changes in the peripheral nerve resulting from chronic axotomy prevent TMR mediated analgesia by reducing reinnervation. Identification of these changes and further elucidating the role reinnervation in analgesia will allow for peripheral therapies in conjunction with TMR or modification to the TMR procedure that may improve analgesia in chronic amputees with amputation-related pain. TMR is a surgery that is already performed at Froedtert and the VA, which have a strong PMR group managing amputees long-term. Data from this work poses a strong capacity for translation as the clinical relationships have already been established.