In the United States (U.S.), 30,000 to 40,000 amputations are performed each year. Amputations can occur for many reasons including severe trauma, tumors, vascular disease, and infection. Pain after amputation of a limb is a common symptom and is separated into two types of pain including residual limb pain (RLP) and phantom limb pain (PLP). PLP is clinically defined as the perception of pain or discomfort in a limb that no longer exists. Although PLP most commonly presents as pathological sequelae in amputee patients, the underlying pathophysiology remains poorly understood. Furthermore, PLP can present along a wide clinical spectrum and varying severity of symptoms. The condition should be differentiated from other related but separate clinical conditions, including RLP. This latter condition, formerly known as "stump pain", is pain that originates from the actual site of the amputated limb. It is most common in the early post-amputation period and tends to resolve with wound healing. Unlike PLP, RLP is often a manifestation of an underlying source, such as nerve entrapment, neuroma formation, surgical trauma, ischemia, skin breakdown, or infection. Of note, more than half of people with PLP also have RLP. It is important to know the difference between the two because the causes and treatments for each differ, but also be aware that both of these elements can coexist at the same time.
PLP and RLP represent an important challenge in medicine, in terms of epidemiology and therapeutic difficulties. Ninety-five percent of patients, indeed, report experiencing some amputation-related pain, with 79.9% reporting phantom pain and 67.7% reporting RLP. Again, these clinical manifestations can significantly worsen the health-related quality of life (HR-QOL) and in some cases are very difficult to manage.
The exact etiology of PLP is unclear. Multiple theories have been debated, and the only agreement is that multiple mechanisms are likely responsible. The predominant theory for years involved the irritation of the severed nerve endings causing phantom pain. This was enforced by evidence that almost all amputation patients will develop neuromas in the residual limb. Over the last few decades, advances in imaging and laboratory techniques have shown evidence of central nervous system (CNS) involvement. Imaging studies such as MRI and PET scans show activity in the areas of the brain associated with the amputated limb when the patient feels phantom pain. The pain is now thought to involve many peripheral and central nervous system factors.
In 2005, there were 1.6 million people (1 in 190) living with limb loss in the U.S. This same study projected a striking increase to 3.6 million cases by 2050. The literature reports PLP affecting 60% to 85% of amputee patients. The following underlying causes are given clinical consideration:
Despite, the phantom limb sensation was described by French military surgeon Ambroise Pare (1510-1590) in the sixteenth century, even today we do not have a clear explanation of this complex phenomenon and, therefore, the pathophysiology is explained by a wide range of mechanisms. These mechanisms. which are the basis of theories, they are not necessarily mutually exclusive
Peripheral Nerve Changes
During the amputation, there is a significant amount of trauma that occurs in the nerves and surrounding tissues. This damage disrupts the normal afferent and efferent signals involved with the missing limb. The proximal portions of the severed nerves start to sprout neuromas, and the nerves become hyper-excitable due to an increase in sodium-channels and resulting in spontaneous discharges.
Spinal Cord Changes
In the spinal cord, a process called central sensitization occurs. Central sensitization is a process where neural activity increases, the neuronal receptive field expands, and the nerves become hypersensitive. This is due to an increase in the N-methyl-D-aspartate, or NMDA, activity in the dorsal horn of the spinal cord making them more susceptible to activation by substance P, tachykinins, and neurokinins followed by an upregulation of the receptors in that area. This restructuring of the neural components of the spinal cord can cause the descending inhibitory fibers to lose their target sites. The combination of increased activity to nociceptive signals as well as a decrease in the inhibitory activity from the supraspinal centers is thought to be one of the major contributors to phantom limb pain. 
Over the past few years, there has been significant research into cortical reorganization and is a commonly cited factor in phantom limb pain. During this process, the areas of the cortex that represent the amputated area are taken over by the neighboring regions in both the primary somatosensory and the motor cortex. Cortical reorganization partially explains why nociceptive stimulation of the nerves in the residual limb and surrounding area can cause pain and sensation in the missing limb. There is also a correlation between the extent of cortical reorganization and the amount of pain that the patient feels. 
Chronic pain has been shown to be multi-factorial with a strong psychological component. Phantom limb pain can often develop into chronic pain syndrome and for treatment to have a higher chance of success the patient's pain behaviors and pain processing should be addressed. Depression, anxiety, and increased stress are all triggers for phantom limb pain. 
PLP is often described as tingling, throbbing, sharp, pins/needles in the limb that is no longer there. It occurs more commonly in upper extremity amputations than lower extremity and tends to be intermittent in frequency. Pain severity varies, and onset can be immediate or years afterward. It is important to try and distinguish PLP from RLP. The goal of the physical exam is to rule out the causes of RLP. First, the skin should be carefully inspected for evidence of wounds or infection. Sensation needs to be tested, along with looking for allodynia and hyperalgesia. The joint above the amputated limb should be examined for any signs of dysfunction. in terms of pain intensity, RLP usually is not severe, and features pressing, throbbing, burning, squeezing, and stabbing sensations.
The diagnosis of PLP pain is primarily a diagnosis of exclusion and heavily dependent on the patient's history. Because of this lab tests are often not needed. A complete blood count (CBC) can help rule out infection. An ultrasound can be ordered to look for neuromas as a possible pain generator. A psychology evaluation may be indicated if the patient is having a significant amount of extrinsic triggers that may be contributing to his or her pain.
Treatment, unfortunately, for PLP has not proven to be very effective. While treatment for RLP tends to focus on an organic cause for the pain, PLP focuses on symptomatic control.
PLP is very complex and difficult to treat. It is best managed by an interprofessional team The first treatment is usually conservative and should include nonpharmacological and nonsurgical methods. The prosthetic professional should assess the stump and train the patient in the use of the prosthetic device. A mental health nurse and psychotherapist should help ease anxiety and depression. If this fails, The pharmacist should work with the clinician to select an appropriate agent, as well as educate the patient on the different pharmacological agents available, their effectiveness and adverse effects. A pain specialist should be involved as well
There is no one treatment that works reliably or consistently in all patients. Most patients are prescribed multiple agents to control pain, but tragically, this polypharmacy also has serious adverse effects that tend to lower compliance. Patients with PLP often doctor shop and try many types of conventional and non-conventional therapies to relieve the pain.
A pain referral should be ordered and the patient's HR-QOL should be improved.
Patient education is key and members of the team should communicate with each other so that the patient is provided with optimal treatment. The outcomes for most patients are guarded and the quality of life is poor.
|||Cuperus AA,Disco RT,Sligte IG,van der Kuil MNA,Evers AWM,van der Ham IJM, Memory-related perceptual illusions directly affect physical activity in humans. PloS one. 2019; [PubMed PMID: 31095650]|
|||Wittkopf PG,Lloyd DM,Coe O,Yacoobali S,Billington J, The effect of interactive virtual reality on pain perception: a systematic review of clinical studies. Disability and rehabilitation. 2019 May 8; [PubMed PMID: 31067135]|
|||Rothgangel A,Braun S,Smeets R,Beurskens A, Feasibility of a traditional and teletreatment approach to mirror therapy in patients with phantom limb pain: a process evaluation performed alongside a randomized controlled trial. Clinical rehabilitation. 2019 May 8; [PubMed PMID: 31066315]|
|||He Y,Qiu D,Zhou D,Li L,Wang B,Wang L, Treatment of Partial Traumatic Hemipelvectomy: A Study of 21 Cases. The Journal of bone and joint surgery. American volume. 2019 May 1; [PubMed PMID: 31045672]|
|||Luza LP,Ferreira EG,Minsky RC,Pires GKW,da Silva R, Psychosocial and physical adjustments and prosthesis satisfaction in amputees: a systematic review of observational studies. Disability and rehabilitation. Assistive technology. 2019 Apr 23; [PubMed PMID: 31012753]|
|||Ephraim PL,Wegener ST,MacKenzie EJ,Dillingham TR,Pezzin LE, Phantom pain, residual limb pain, and back pain in amputees: results of a national survey. Archives of physical medicine and rehabilitation. 2005 Oct [PubMed PMID: 16213230]|
|||Knotkova H,Cruciani RA,Tronnier VM,Rasche D, Current and future options for the management of phantom-limb pain. Journal of pain research. 2012 [PubMed PMID: 22457600]|
|||Jutzeler CR,Curt A,Kramer JL, Relationship between chronic pain and brain reorganization after deafferentation: A systematic review of functional MRI findings. NeuroImage. Clinical. 2015 [PubMed PMID: 26740913]|
|||Fuchs X,Flor H,Bekrater-Bodmann R, Psychological Factors Associated with Phantom Limb Pain: A Review of Recent Findings. Pain research & management. 2018 [PubMed PMID: 30057653]|
|||Smith HS, Potential analgesic mechanisms of acetaminophen. Pain physician. 2009 Jan-Feb [PubMed PMID: 19165309]|
|||Cascella M,Forte CA,Bimonte S,Esposito G,Romano C,Costanzo R,Morabito A,Cuomo A, Multiple effectiveness aspects of tapentadol for moderate-severe cancer-pain treatment: an observational prospective study. Journal of pain research. 2019; [PubMed PMID: 30613160]|
|||O'Connor AB,Dworkin RH, Treatment of neuropathic pain: an overview of recent guidelines. The American journal of medicine. 2009 Oct [PubMed PMID: 19801049]|
|||Miceli L,Bednarova R,Rizzardo A,Cuomo A,Riccardi I,Vetrugno L,Bove T,Cascella M, Opioids prescriptions in pain therapy and risk of addiction: a one-year survey in Italy. Analysis of national opioids database. Annali dell'Istituto superiore di sanita. 2018 Oct-Dec; [PubMed PMID: 30575575]|
|||Robinson LR,Czerniecki JM,Ehde DM,Edwards WT,Judish DA,Goldberg ML,Campbell KM,Smith DG,Jensen MP, Trial of amitriptyline for relief of pain in amputees: results of a randomized controlled study. Archives of physical medicine and rehabilitation. 2004 Jan; [PubMed PMID: 14970960]|
|||Jefferies K, Treatment of neuropathic pain. Seminars in neurology. 2010 Sep [PubMed PMID: 20941675]|
|||Hsu E,Cohen SP, Postamputation pain: epidemiology, mechanisms, and treatment. Journal of pain research. 2013 [PubMed PMID: 23426608]|
|||Alviar MJ,Hale T,Dungca M, Pharmacologic interventions for treating phantom limb pain. The Cochrane database of systematic reviews. 2016 Oct 14 [PubMed PMID: 27737513]|
|||McCormick Z,Chang-Chien G,Marshall B,Huang M,Harden RN, Phantom limb pain: a systematic neuroanatomical-based review of pharmacologic treatment. Pain medicine (Malden, Mass.). 2014 Feb; [PubMed PMID: 24224475]|
|||Privitera R,Birch R,Sinisi M,Mihaylov IR,Leech R,Anand P, Capsaicin 8% patch treatment for amputation stump and phantom limb pain: a clinical and functional MRI study. Journal of pain research. 2017 [PubMed PMID: 28761369]|
|||Kern KU,Baust H,Hofmann W,Holzmüller R,Maihöfner C,Heskamp ML, [Capsaicin 8 % cutaneous patches for phantom limb pain. Results from everyday practice (non-interventional study)]. Schmerz (Berlin, Germany). 2014 Aug [PubMed PMID: 24939242]|
|||Kern KU,Kohl M,Seifert U,Schlereth T, [Effect of botulinum toxin type B on residual limb sweating and pain. Is there a chance for indirect phantom pain reduction by improved prosthesis use?]. Schmerz (Berlin, Germany). 2012 Apr [PubMed PMID: 22527647]|
|||Casale R,Ceccherelli F,Labeeb AA,Biella GE, Phantom limb pain relief by contralateral myofascial injection with local anaesthetic in a placebo-controlled study: preliminary results. Journal of rehabilitation medicine. 2009 May; [PubMed PMID: 19479153]|
|||Wu H,Sultana R,Taylor KB,Szabo A, A prospective randomized double-blinded pilot study to examine the effect of botulinum toxin type A injection versus Lidocaine/Depomedrol injection on residual and phantom limb pain: initial report. The Clinical journal of pain. 2012 Feb; [PubMed PMID: 21750460]|
|||Finn SB,Perry BN,Clasing JE,Walters LS,Jarzombek SL,Curran S,Rouhanian M,Keszler MS,Hussey-Andersen LK,Weeks SR,Pasquina PF,Tsao JW, A Randomized, Controlled Trial of Mirror Therapy for Upper Extremity Phantom Limb Pain in Male Amputees. Frontiers in neurology. 2017 [PubMed PMID: 28736545]|
|||Ortiz-Catalan M,Sander N,Kristoffersen MB,Håkansson B,Brånemark R, Treatment of phantom limb pain (PLP) based on augmented reality and gaming controlled by myoelectric pattern recognition: a case study of a chronic PLP patient. Frontiers in neuroscience. 2014; [PubMed PMID: 24616655]|
|||Page DM,George JA,Kluger DT,Duncan C,Wendelken S,Davis T,Hutchinson DT,Clark GA, Motor Control and Sensory Feedback Enhance Prosthesis Embodiment and Reduce Phantom Pain After Long-Term Hand Amputation. Frontiers in human neuroscience. 2018; [PubMed PMID: 30319374]|