Eugene Hsu,1 Steven P Cohen21Johns Hopkins School of Medicine, Baltimore, MD, USA; 2Johns Hopkins School of Medicine and Uniformed Services, University of the Health Sciences, Bethesda, MD, USAAbstract: Postamputation pain (PAP) is highly prevalent after limb amputation but remains an extremely challenging pain condition to treat. A large part of its intractability stems from the myriad pathophysiological mechanisms. A state-of-art understanding of the pathophysiologic basis underlying postamputation phenomena can be broadly categorized in terms of supraspinal, spinal, and peripheral mechanisms. Supraspinal mechanisms involve somatosensory cortical reorganization of the area representing the deafferentated limb and are predominant in phantom limb pain and phantom sensations. Spinal reorganization in the dorsal horn occurs after deafferentation from a peripheral nerve injury. Peripherally, axonal nerve damage initiates inflammation, regenerative sprouting, and increased "ectopic" afferent input which is thought by many to be the predominant mechanism involved in residual limb pain or neuroma pain, but may also contribute to phantom phenomena. To optimize treatment outcomes, therapy should be individually tailored and mechanism based. Treatment modalities include injection therapy, pharmacotherapy, complementary and alternative therapy, surgical therapy, and interventions aimed at prevention. Unfortunately, there is a lack of high quality clinical trials to support most of these treatments. Most of the randomized controlled trials in PAP have evaluated medications, with a trend for short-term efficacy noted for ketamine and opioids. Evidence for peripheral injection therapy with botulinum toxin and pulsed radiofrequency for residual limb pain is limited to very small trials and case series. Mirror therapy is a safe and cost-effective alternative treatment modality for PAP. Neuromodulation using implanted motor cortex stimulation has shown a trend toward effectiveness for refractory phantom limb pain, though the evidence is largely anecdotal. Studies that aim to prevent PAP using epidural and perineural catheters have yielded inconsistent results, though there may be some benefit for epidural prevention when the infusions are started more than 24 hours preoperatively and compared with nonoptimized alternatives. Further investigation into the mechanisms responsible for and the factors associated with the development of PAP is needed to provide an evidence-based foundation to guide current and future treatment approaches.Keywords: phantom pain, stump pain, residual limb pain