Development of a painful neuroma is a distressing problem often associated with neuroma formation after limb amputation. The pain is perceived in the zone of innervation of the severed nerve although this region may no longer be anatomically present. Mechano-sensitivity and ectopic excitability of the injured axons likely play a major role in the pain process. Surgical resection of the neuroma may provide only transient pain relief until the neuroma re-forms. To prevent neuroma formation, the neuronal cell body in the dorsal root ganglion or anterior spinal cord must be destroyed resulting in Wallerian degeneration of the axon. Studies have shown that certain toxins, including adriamycin, are retrogradely transported by axons to their cell body resulting in death of the neuron (suicide transport). We hypothesize that treatment of the axons that innervate a neuroma with adriamycin will prevent reformation of the neuroma and will lead to permanent pain relief. In this proposal, we plan to test this hypothesis by performing histological and neurophysiological studies in a neuroma model. Specifically, we aim to answer the following questions: Is adriamycin transported by an axon to its cell body? Can a drug dose be determined that will result in a consistent neuronal lesion secondary to retrograde adriamycin transport? Does the axonal transport of adriamycin cause death only in those axons which were exposed to the drug? Does treatment of a neuroma with adriamycin result in the loss of mechano-sensitivity and ectopic excitability in the nerve? Does the use of suicide transport with adriamycin improve the outcome over standard surgical practice for patients suffering from painful neuromas? Using histo-pathology and teased-fiber electrophysiology recording techniques we will determine the response of neuromas to the treatment with adriamycin in a rat model and subsequently in a monkey model. The laboratory studies will optimize our technique laying the foundation for the clinical study in which amputation patients suffering from pain secondary to neuroma formation will undergo an open labelled/ended trial of neuroma resection with the addition of suicide transport of adriamycin. If the results look promising, a blinded, randomized trial will be performed in the future. We believe that treatment with suicide transport using adriamycin will prove to be an effective modality for eliminating neuroma pain such as that which can follow limb amputation.
