Indian Journal of Pain

REVIEW ARTICLE
Year
: 2022  |  Volume : 36  |  Issue : 1  |  Page : 10--17

Postamputation pain: A narrative review


Samridhi Nanda1, Debesh Bhoi2, Virender Kumar Mohan2,  
1 Department of Anesthesia, Critical Care and Pain Medicine, Sawai Man Singh Hospital, Jaipur, Rajasthan, India
2 Department of Anaesthesia, Critical Care and Pain Medicine, All India Institute of Medical Sciences, New Delhi, India

Correspondence Address:
Dr. Debesh Bhoi
Department of Anaesthesia, Critical Care and Pain Medicine, All India Institute of Medical Sciences, New Delhi
India

Abstract

Postamputation phenomenon is commonly encountered in more than 80% of amputees. Due to the increasing burden of trauma and associated amputations, disability due to postamputation pain becomes rampant. In this review, we aim to describe the history, epidemiology, types and mechanisms of postamputation phenomenon, factors affecting its development, and the currently available treatment modalities – both pharmacological and nonpharmacological.



How to cite this article:
Nanda S, Bhoi D, Mohan VK. Postamputation pain: A narrative review.Indian J Pain 2022;36:10-17


How to cite this URL:
Nanda S, Bhoi D, Mohan VK. Postamputation pain: A narrative review. Indian J Pain [serial online] 2022 [cited 2022 Jul 5 ];36:10-17
Available from: https://www.indianjpain.org/text.asp?2022/36/1/10/343836


Full Text



 Introduction



The word amputation finds its roots in the Latin word “amputation” meaning “to cut around.” Amputations have been practiced since Neolithic times, with crude weapons such as stone knives, axes, and saws.[1] Ten percent of the world population faces disability. Trauma and vascular causes are the two main culprits of amputation-related disability in the world and vascular causes are at the top of the chart; however, Pooja et al. reported trauma as the most important cause of amputation in India.[2] Postamputation pain (PAP), also called phantom pain, is described as the patient's experience of pain in parts of the body separated from the body either surgically or as a result of trauma. Interestingly, this kind of phenomenon has been described not only after limb but also from tooth, breast, rectum, or other part removal[3],[4],[5] This has also been seen in patients with denervation conditions like brachial plexus injuries,[6] post stroke. or after regional anesthesia[7],[8] This narrative aims to elaborate the epidemiology, classification, possible mechanisms, predictive factors, and currently available pharmacological and nonpharmacological treatment.

 History



PAP, described as a debilitating, chronic pain in the parts that were removed from the body, was first observed by French Surgeon Ambroise Paré in 1551.[9] Serving the military, he removed many of soldiers' shattered limbs, inspired by which he began designing the earliest prostheses. These early artificial limbs, although less advanced, were scientifically built.[10] However, the term “Phantom limb” was coined in 1871, at the time of the American Civil War, by Silas Weir Mitchell (1829–1914), one of the fathers of American neurology.[11] Regardless of the development, the amputees even in the post-World War-II times were considered socially outcast and the PAP was attributed to psychopathology.[12]

 Epidemiology



The prevalence of PAP has shown significant variability ranging from 49% to 83% owing to different research techniques. Allami et al., in their study on 247 veterans below-knee amputations, concluded that the prevalence of stump pain, phantom sensations (PS), and phantom pain was 84.2%, 77.3%, and 73.7%, respectively.[13] The males outnumber females by nearly 2.5 times. The mean age of amputees presenting with postamputation syndrome was nearly 61 years. PAP was described as being present in 41% of upper limb amputees and 80% in lower limb amputees.

In a multivariate analysis, trauma was found to be the leading cause of upper limb amputations, whereas, for lower limb amputations, trauma, followed by vascular diseases and diabetes mellitus, was found to be causative mostly.[14] The risk factors associated with the development of phantom limb pain (PLP) are uncontrolled preamputation pain[15],[16] Diabetes,[17] presence of bilateral amputation or lower limb amputations.[14] PLP intensity rises with higher phantom limb sensations and age, whereas residual pain (RP) intensity relates with pre amputation pain and level of amputation.[18] Moreover, the severity of PS, PLP, and RP at 12 months after amputation could be predicted by preamputation scores of depression and anxiety.[19] Most studies claim that the early introduction of prosthesis in the amputees leads to lesser incidence of PS and PLP[20],[21] The authors also recommend at least 9 h a day of usage of prosthesis to prevent development of pain.[20] Some authors refute the concept entirely.[22]

 Types of Postamputation Phenomenon



Different kinds of phenomenon are experienced after amputation in an amputee. These entail specific pathogenesis. It is imperative to know the specific type for better management. The following are commonly seen.

Phantom sensations

PSs are defined as the nonpainful sensations arising from the deafferentated/amputated part of the body. These may begin as early as in the postoperative period, within 24 h. These sensations can range from kinetic, kinesthetic to exteroceptive sensations. Sensations of voluntary or spontaneous movement of amputated body parts exemplify kinetic sensations. Kinesthetic sensations are perceptions of altered size, shape, or position of the amputated body part, for example, feelings that the amputated hand is in flexed position. Exteroceptive sensations, on the other hand, are perceived sensations of tingling, temperature, touch, pressure, itch, or vibration. PS is a phenomenon appreciated in those regions of the body which have a larger representation in the cortex.

Phantom limb pain

PLP is a painful or an unpleasant sensation in the amputated/deafferentated part of the body. It may be neuropathic, nociceptive or neuroplastic type, or most often mixed. In an interesting observation, the PLP exhibited characteristics of prickling (23.4%), electrification (21%), tingling (20.4%), cramp (15.3%) or burning (13.6%) in that order.[23]

Telescoping

In nearly 20% amputees, telescoping can be seen.[24] Compared to the lower limb, upper limb amputees show almost double the incidence of telescoping.[24] Telescoping is the perception of progressive shortening of the phantom parts. The sensations gradually get more proximal and finally, the amputated hand may feel almost joined to the end of the residual limb. The PAP patients experiencing this phenomenon often are benefitted lesser from mirror therapy (MT) than those not experiencing it.[25] Illusions of telescoping have been experimentally induced in healthy subjects using mannequins.[26]

Residual pain

Nearly 10% of the amputees have persistent RP 6 months after amputation.[27] Also known as stump pain, it is typically described as severe, sharp, and aching in quality. It is mostly nociceptive but may also be neuropathic owing to the nerve damage. There may be several causes of the this kind of pain, viz-a-viz, infection of the stump (especially in diabetics), wound breakdown, arterial insufficiency, osteomyelitis, bony spurt, hematoma, insufficient myoplasty covering, and ill-fitting prosthesis.[28] At times, a neuroma forms at the stump, wherein the free nerve endings of the pain-specific neurons (A-delta and C) get knotted and form an area of hyperpathia at the stump. Neuromas are usually formed late in the course and present as focal point on the stump.

Secondary pain

An amputee may present with a host of other pains that may develop as a result of altered body mechanics owing to the nonuniform distribution of the body weight and overuse of the remaining limb. Chief among them are osteoporosis, osteoarthritis, back pain, and other musculoskeletal conditions.[29] In a study by Hungerford and Cockin, it was concluded that a higher incidence of patellofemoral degeneration is seen in intact limb of amputees over that nonamputees. Backache occurs in 50% of the amputees.[30] Even after the use of prosthesis, the body weight is often not distributed evenly as prosthesis lacks sensory input.[31] As a matter of fact, there are alignment changes in gait even with prosthesis use.[32]

 Mechanisms for Postamputation Pain



Both central and peripheral mechanisms have been purported in the causation of PAP [Figure 1]. The most commonly acceptable theory is that of cortical remapping.[33] Earlier studies implicated neuroma formation as the most frequent underlying mechanism, despite evidence of pain shortly after the surgery.[34]{Figure 1}

Cortical re-organization theory

This theory has been thought of as the neurophysiological basis of PAP. It is based on the premise that each bodily body represented within the cortex. After amputation, this representation remains intact, while the limb is missing. This leads to disconnect between the sensory input from the missing limb and the cortex, thus generating pain. Researchers have studied the malleability of the neuromatrix through the rubber-hand phenomenon.[35],[36] In due course of time, the area of the cortex corresponding to the amputated limb responds to stimulation at a nearby somatosensory region due to its expansion and invasion into the neighboring area that has stopped receiving sensory input.[37] Several examples of the same are cited in the literature, for example, removal of digit began responding to the adjacent digit and sensations from a denervated arm felt in the ipsilateral ear[6]. In a radiological study, the researchers discovered that the medial border of the lip area in the somatosensory cortex, contralateral to the amputated side, shifted.[38] The evoked PS were found on both sides in the somatosensory and the intraparietal sulcus, correlating with the intensity of the stimulus.[39] These evidences suggest that there may be unraveling of the normally dormant synapses along with new connection formation. Chemically, the neurotransmitter involved in such an unmasking is the depletion of GABA.[40] Thus, improving GABA stores might potentially suppress cortical reorganization. In the same context, there are other studies that contradict the above theory.[41] These authors posit no concrete evidence of such a cortical rearrangement, and the occurrence of PLP may be multifactorial. However, if this were true, the effect of transcranial magnetic stimulation in PAP could not have been explained.

Subcortical theory

The subcortical areas, especially the thalamus, may also be reorganized and may be an independent pain generator. Possibly, the thalamic reorganization may be the result of the cortical rearrangement through its efferent connections,[42] bringing changes in the thalamus or it may also be the cause of cortical changes.[43]

Proprioceptive memory theory

It is proposed that the brain has memory of limb position, for both voluntary and involuntary movements. This helps us achieve learned tasks rapidly and efficiently. After amputation, the memory regarding the movement remains, despite the absence of the visual stimulus. It appears that this memory overrides the sensory information of the limb absence. Thus, PSs continue to be felt, long after the part is gone. Both visual input and proprioceptive memory play a part in reducing PAP.[25],[44],[45]

Peripheral nervous system theory

There are some theories emphasizing that a peripheral mechanism of pain generation may be involved. Most notable is the theory around neuroma formation. Since the dorsal horn and dorsal root ganglion (DRG) are the hub of somatic, sensory input, injury to the distal neurons leads to severing of the input to the DRG. Resultantly, new neural connections begin sprouting at the amputation stump. This aberrant arrangement leads to ectopic, hyperexcitable locus of neural activity causing spontaneously originating and stimulus-dependent heightened pain response. If this were the only mechanism of PAP, denervation of the part through anesthesia should result in eliminating the PAP experience. However, since it is not true, a complex interplay of both the central and peripheral mechanism can be deduced.[43]

Factors predicting postamputation pain

Preamputation pain – It is believed that the intensity/presence of preamputation pain predicted its presence in the postoperative period[46],[47] Regardless of the type of anesthesia, effective acute pain management reduces the prevalence of chronic pain at 6 months[48]Use of prosthesis – The daily use of prosthesis may lead to less motor re-organization because of the activation of the residual limb muscles. Lesser the motor reorganization, lower are the chances of PAP[49]Level of amputation – Compared to above-knee amputations, through-knee amputations resulted in better physical quality of life[50]Others:

The cause of amputation, laterality (bilateral vs unilateral), and upper limb amputations[51]all appear to be important risk factors in development of PAP.[52] In a multivariate analysis, years of education and increased self-efficacy to return to normalcy[53] and use of early and aggressive narcotics appear protective, while high alcohol use in months preceding the injury was the risk factor to chronicity of pain.[54] Other factors such as acute pain intensity at 3 months and anxiety, depression, sleep, and rest irregularities were strong predictors of chronic pain at the end of 7 years.[54]

 Currently Available Treatments



PAP, though a very difficult-to-treat pain, however, an individualized and interdisciplinary approach provides better outcomes. The medical management focuses on multimodal pain management. Both pharmacological and nonpharmacological treatments have been suggested for the management of PAP.

 Pharmacological



Many classes of pharmacological drugs have been proposed for the management of PAP. Most commonly used drugs are antidepressants, anticonvulsants, opiates, and NMDA antagonists. In some cases, however, botulinum toxin and hormones such as calcitonin have also been tried. There are very few studies on the efficacy of the above-mentioned drugs in PAP. The drugs are summarized in [Table 1].{Table 1}

Anticonvulsants such as gabapentin and opioids are the cornerstone of pharmacological management of PAP. Anticonvulsants are effective in bringing down the frequency of pain as well as overall severity of the attacks.[69] Opioids are also efficacious, but one should be mindful of the effects of long-term opioid therapy and opioid-induced hyperalgesia in higher doses.

 Nonpharmacological Management



Due to the refractory nature of the disease, the nonpharmacological management ranges from noninvasive to invasive surgical management. Various modalities have been attempted based on the altered neurophysiology in phantom limb patients.

Mind–body interventions

These are basically noninvasive, nonpharmacological modalities that deal with PAP. Chief among them are MT, virtual reality, mental imagery, biofeedback, hypnosis,[70] and meditation. Distinct advantages of the above therapies over pharmacological or invasive management are that these are noninvasive, lack side effects, and can be executed through self-delivery.[71]

Mirror therapy

First described by Ramachandran and Rogers,[72] MT is by far the most efficacious. The underlying concept of the therapy is that of creating an illusion in the brain that the amputated limb responds to the motor commands, thereby decreasing the pain. Through MT, a visual impression of both healthy limbs is created, leading to reversal of the learned paralysis. In a systematic review of 115 publications, it was concluded that MT was effective in reducing the intensity and duration of daily episodes of pain.[73] The duration of treatment in these studies was between 5 and 30 min daily. MT also showed a positive effect on muscle tone and motor function during lower limb rehabilitation after stroke.[74] When compared to conventional rehabilitation, MT showed better results in upper limb functioning in acute and chronic stroke patients.[75] The trajectory of effectiveness of MT in PLP in terms of duration is pain relief after 7 days for low levels, 14 days for medium, and 21 days for high levels of pain. Moreover, the throbbing, shooting, stabbing, sharp, cramping, aching, etc., decreased with treatment, while gnawing, hot/burning, sickening, and fearful do not.[76] However, if the patient is experiencing telescoping phenomenon, this therapy offers less benefit than in those not experiencing it. This has been depicted diagrammatically in [Figure 2].{Figure 2}

Virtual reality

Based on the same concept of MT, virtual reality (VR) simulates the same mechanism in an artificial setting. VR offers presence, interactivity, customization, social interaction, and embodiment, thus making it desirable for children and adolescents alike.[77] Its use appears promising.

Graded motor imagery

It is a three-step, gradual process, wherein the amputees progressively go through lateralization, motor imagery, and MT in a graded, step-wise manner [Figure 3]. It was found to be more effective than routine physiotherapy of the amputees.[78]{Figure 3}

Neurostimulation

Therapies such as transcutaneous electrical nerve stimulation,[79] peripheral nerve stimulation,[80] DRG stimulation,[81] spinal cord stimulation,[82] transcranial direct current stimulation, transcranial magnetic stimulation, motor cortex stimulation, and parietal cortex stimulation have been tried with varying success. An interesting observation in a study done by Bolognini et al. is that the stimulation of M1 Cortex through anodal transcranial direct current reduces PLP, whereas cathodal stimulation of the posterior parietal cortex mitigates PS.[83]

Peripheral nerve stimulation

Several studies have evaluated the use of peripheral nerve stimulations for managing chronic PLP.[80],[84],[85],[86],[87] In as small pilot study, with surgically implanted peripheral nerve stimulators, 85% achieved significant pain relief using high-frequency alternating current block.[84] In a study on 28 lower extremity amputees, who underwent ultrasound-guided peripheral nerve stimulations, 67% patients had ≥50% pain relief compared to 14% in placebo at the end of 8 weeks therapy.[85]

Acupuncture

Acupuncture may be an effective tool for management of PAP.[88] Scalp acupuncture is posited to be effective in treating phantom limb, RP, and complex regional pain syndrome.[89] Commonly, ear/body/electronic acupuncture may be used.

Prosthetic use

It is known that amputation of a body part leads to re-organization of the somatosensory cortex, and secondarily, the motor cortex. Since there is a direct relationship of the degree of motor cortex re-organization after amputation and the level of postamputation pain, the early use of prosthesis has been postulated as being preventive.[49] The cause-and-effect relationship has still to be established. Another evidence supporting prosthetic use comes from the study done by PrieBler et al., who found that PLP rates inversely correlated with time spent in using prosthesis.[90] Few studies evaluated the use of Electromagnetically Shielded Limb Liner that protected the nociceptive nerve endings in the amputated limb from the environmental electromagnetic-induced influx of calcium. A positive effect was noted in those who could tolerate its use.[91],[92]

 Surgical Management



This review would be incomplete if the surgical options of PAP are not mentioned. The surgical indications are bony exostosis, wound infections, poorly healed wounds, or neuroma formation. Surgeries may range from debridement, revision of the stump to neuroma excision. Recently, targeted muscle re-innervation surgery that approximates the sensory nerve ends to motor end plates has been developed to reduce the incidence of PAP in both oncologic and limb salvage amputees.[93],[94],[95]

In summary, there is a high prevalence of postamputation pain in amputees, with stump pain leading the chart, followed by phantom pain and RP. Different pathogenetic mechanisms have been proposed for its development. Cortical reorganization theory is the most acceptable one. Factors predicting PAP are presence of preamputation pain, use of prosthesis, coexistent depression, laterality, upper limb amputations, etc., Among the pharmacological agents, most agents such as anticonvulsants, SNRIs, and botulinum toxins have weak to very weak evidence of effect. In fact, tricyclic antidepressants have no effect on pain. Opioid use has shown good efficacy in reduction of pain for short to intermediate term. Other agents such as NMDA antagonists, sodium channel blockers, and calcitonin have inconclusive evidence in reduction of pain. Among the nonpharmacological treatments, MT and its upgraded version Graded Motor Imagery appear to be, by far the most efficacious in reducing pain. Early use of prosthetics is also advised. Although there is a wide range of treatment options available, its management is still a big challenge. Hopefully, with advent of newer discoveries, like that of peripheral nerve stimulation, dorsal root stimulation, deep brain stimulation, etc., the burden of PAP reduces further in future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Padula PA, Friedmann LW. Acquired amputation and prostheses before the sixteenth century. Angiology 1987;38:133-41. doi: 10.1177/000331978703800207. PMID: 3548491.
2Pooja GD, Sangeeta L. Prevalence and aetiology of amputation in Kolkata, India: A retrospective analysis. Hong Kong Physiother J 2013;31:36-40.
3Marbach JJ. Is phantom tooth pain a deafferentation (neuropathic) syndrome? Part I: Evidence derived from pathophysiology and treatment. Oral Surg Oral Med Oral Pathol 1993;75:95-105.
4Krøner K, Knudsen UB, Lundby L, Hvid H. Long-term phantom breast syndrome after mastectomy. Clin J Pain 1992;8:346-50.
5Ovesen P, Krøner K, Ørnsholt J, Bach K. Phantom-related phenomena after rectal amputation: Prevalence and clinical characteristics. Pain 1991;44:289-91.
6Pazzaglia M, Galli G, Lucci G, Scivoletto G, Molinari M, Haggard P. Phantom limb sensations in the ear of a patient with a brachial plexus lesion. Cortex 2019;117:385-95.
7Russell HG, Tsao JW. Phantom sensations following brachial plexus nerve block: A case report. Front Neurol 2018;9:436.
8Shrestha GS, Koirala Sabin. Exacerbation of phantom limb pain following spinal anaesthesia: A case report and review of the literatures. Ains Shams Journal of Anaesthesiology 2016; 9:309-10. Available from: http://asja.eg.net/article.asp?issn=1687-7934;year=2016;volume=9;issue=2;spage=309;epage=310;aulast=Shrestha. [Last accessed on 2020 Sep 18].
9Hernigou P. Ambroise Paré IV: The early history of artificial limbs (from robotic to prostheses). Int Orthop 2013;37:1195-7.
10The Civil War Doctor Who Proved Phantom Limb Pain Was Real – HISTORY. Available from: https://www.history.com/news/the-civil-war-doctor-who-proved-phantom-limb-pain-was-real. [Last accessed on 2020 Oct 08].
11Nathanson M. Phantom limbs as reported by S. Weir Mitchell. Neurology 2011;77:475.
12Ewalt JR, Randall GC, Morris H. The phantom limb. Psychosom Med 1947;9:118-23.
13Allami M, Faraji E, Mohammadzadeh F, Soroush MR. Chronic musculoskeletal pain, phantom sensation, phantom and stump pain in veterans with unilateral below-knee amputation. Scand J Pain 2019;19:779-87.
14Dijkstra PU, Geertzen JH, Stewart R, van der Schans CP. Phantom pain and risk factors: A multivariate analysis. J Pain Symptom Manage 2002;24:578-85.
15Richardson C, Glenn S, Horgan M, Nurmikko T. A prospective study of factors associated with the presence of phantom limb pain six months after major lower limb amputation in patients with peripheral vascular disease. J Pain 2007;8:793-801.
16Yin Y, Zhang L, Xiao H, Wen CB, Dai YE, Yang G, et al. The pre-amputation pain and the postoperative deafferentation are the risk factors of phantom limb pain: A clinical survey in a sample of Chinese population. BMC Anesthesiol 2017;17:69.
17Noguchi S, Saito J, Nakai K, Kitayama M, Hirota K. Factors affecting phantom limb pain in patients undergoing amputation: Retrospective study. J Anesth 2019;33:216-20.
18Münger M, Pinto CB, Pacheco-Barrios K, Duarte D, Enes Gunduz M, Simis M, et al. Protective and risk factors for phantom limb pain and residual limb pain severity. Pain Pract 2020;20:578-87.
19Larbig W, Andoh J, Huse E, Stahl-Corino D, Montoya P, Seltzer Z, et al. Pre- and postoperative predictors of phantom limb pain. Neurosci Lett 2019;702:44-50.
20Casale R, Alaa L, Mallick M, Ring H. Phantom limb related phenomena and their rehabilitation after lower limb amputation. Eur J Phys Rehabil Med 2009;45:559-66.
21Giummarra MJ, Moseley GL. Phantom limb pain and bodily awareness: Current concepts and future directions. Curr Opin Anaesthesiol 2011;24:524-31.
22Hunter JP, Katz J, Davis KD. Stability of phantom limb phenomena after upper limb amputation: A longitudinal study. Neuroscience 2008;156:939-49.
23Kern U, Busch V, Rockland M, Kohl M, Birklein F. Prevalence and risk factors of phantom limb pain and phantom limb sensations in Germany. A nationwide field survey. Schmerz 2009;23:479-88.
24Giummarra MJ, Georgiou-Karistianis N, Nicholls ME, Gibson SJ, Chou M, Bradshaw JL. Corporeal awareness and proprioceptive sense of the phantom. Br J Psychol 2010;101:791-808.
25Foell J, Bekrater-Bodmann R, Diers M, Flor H. Mirror therapy for phantom limb pain: Brain changes and the role of body representation. Eur J Pain 2014;18:729-39.
26Schmalzl L, Ehrsson HH. Experimental induction of a perceived 'telescoped' limb using a full-body illusion. Front Hum Neurosci 2011;5:34.
27Jensen TS, Krebs B, Nielsen J, Rasmussen P. Phantom limb, phantom pain and stump pain in amputees during the first 6 months following limb amputation. Pain 1983;17:243-56.
28Neil MJ. Pain after amputation. BJA Educ 2016;16:107-12.
29Gailey R, Allen K, Castles J, Kucharik J, Roeder M. Review of secondary physical conditions associated with lower-limb amputation and long-term prosthesis use. J Rehabil Res Dev 2008;45:15-29.
30Burke MJ, Roman V, Wright V. Bone and joint changes in lower limb amputees. Ann Rheum Dis 1978;37:252-4.
31Petrofsky JS, Khowailed IA. Postural sway and motor control in trans-tibial amputees as assessed by electroencephalography during eight balance training tasks. Med Sci Monit 2014;20:2695-704.
32Jonkergouw N, Prins MR, Buis AW, van der Wurff P. The effect of alignment changes on unilateral transtibial amputee's gait: A systematic review. PLoS One 2016;11:e0167466.
33Phantom-Limb Pain as a Perceptual Correlate of Cortical Reorganization Following Arm Amputation,Nature. Available from: https://www.nature.com/articles/375482a0. [Last accessed on 2020 Oct 27].
34Available from: https://livingston1945.pdf. [Last accessed on 2020 Oct 27].
35Botvinick M, Cohen J. Rubber hands 'feel' touch that eyes see. Nature 1998;391:756.
36Ehrsson HH. The experimental induction of out-of-body experiences. Science 2007;317:1048.
37Wall JT, Xu J, Wang X. Human brain plasticity: An emerging view of the multiple substrates and mechanisms that cause cortical changes and related sensory dysfunctions after injuries of sensory inputs from the body. Brain Res Brain Res Rev 2002;39:181-215.
38Lotze M, Flor H, Grodd W, Larbig W, Birbaumer N. Phantom movements and pain. An fMRI study in upper limb amputees. Brain 2001;124:2268-77.
39Andoh J, Diers M, Milde C, Frobel C, Kleinböhl D, Flor H. Neural correlates of evoked phantom limb sensations. Biol Psychol 2017;126:89-97.
40Chen R, Cohen LG, Hallett M. Nervous system reorganization following injury. Neuroscience 2002;111:761-73.
41Makin TR, Scholz J, Henderson Slater D, Johansen-Berg H, Tracey I. Reassessing cortical reorganization in the primary sensorimotor cortex following arm amputation. Brain 2015;138:2140-6.
42Ergenzinger ER, Glasier MM, Hahm JO, Pons TP. Cortically induced thalamic plasticity in the primate somatosensory system. Nat Neurosci 1998;1:226-9.
43Flor H. Phantom-limb pain: Characteristics, causes, and treatment. Lancet Neurol 2002;1:182-9.
44Barbin J, Seetha V, Casillas JM, Paysant J, Pérennou D. The effects of mirror therapy on pain and motor control of phantom limb in amputees: A systematic review. Ann Phys Rehabil Med 2016;59:270-5.
45Herrador Colmenero L, Perez Marmol JM, Martí-García C, Querol Zaldivar ML, Tapia Haro RM, Castro Sánchez AM, et al. Effectiveness of mirror therapy, motor imagery, and virtual feedback on phantom limb pain following amputation: A systematic review. Prosthet Orthot Int 2018;42:288-98.
46Nikolajsen L, Ilkjaer S, Krøner K, Christensen JH, Jensen TS. The influence of preamputation pain on postamputation stump and phantom pain. Pain 1997;72:393-405.
47Jensen TS, Krebs B, Nielsen J, Rasmussen P. Immediate and long-term phantom limb pain in amputees: Incidence, clinical characteristics and relationship to pre-amputation limb pain. Pain 1985;21:267-78.
48Karanikolas M, Aretha D, Tsolakis I, Monantera G, Kiekkas P, Papadoulas S, et al. Optimized perioperative analgesia reduces chronic phantom limb pain intensity, prevalence, and frequency: A prospective, randomized, clinical trial. Anesthesiology 2011;114:1144-54.
49Karl A, Mühlnickel W, Kurth R, Flor H. Neuroelectric source imaging of steady-state movement-related cortical potentials in human upper extremity amputees with and without phantom limb pain. Pain 2004;110:90-102.
50Penn-Barwell JG. Outcomes in lower limb amputation following trauma: A systematic review and meta-analysis. Injury 2011;42:1474-9.
51Davidson JH, Khor KE, Jones LE. A cross-sectional study of post-amputation pain in upper and lower limb amputees, experience of a tertiary referral amputee clinic. Disabil Rehabil 2010;32:1855-62.
52Ferraro F, Jacopetti M, Spallone V, Padua L, Traballesi M, Brunelli S, et al. Diagnosis and treatment of pain in plexopathy, radiculopathy, peripheral neuropathy and phantom limb pain. Evidence and recommendations from the Italian consensus conference on pain on neurorehabilitation. Eur J Phys Rehabil Med 2016;52:855-66.
53Wegener ST, Mackenzie EJ, Ephraim P, Ehde D, Williams R. Self-management improves outcomes in persons with limb loss. Arch Phys Med Rehabil 2009;90:373-80.
54Castillo RC, MacKenzie EJ, Wegener ST, Bosse MJ; LEAP Study Group. Prevalence of chronic pain seven years following limb threatening lower extremity trauma. Pain 2006;124:321-9.
55Robinson LR, Czerniecki JM, Ehde DM, Edwards WT, Judish DA, Goldberg ML, et al. Trial of amitriptyline for relief of pain in amputees: Results of a randomized controlled study. Arch Phys Med Rehabil 2004;85:1-6.
56Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ. Amitriptyline for neuropathic pain in adults. Cochrane Database Syst Rev 2015;2015:CD008242.
57Bone M, Critchley P, Buggy DJ. Gabapentin in postamputation phantom limb pain: A randomized, double-blind, placebo-controlled, cross-over study. Reg Anesth Pain Med 2002;27:481-6.
58Smith DG, Ehde DM, Hanley MA, Campbell KM, Jensen MP, Hoffman AJ, et al. Efficacy of gabapentin in treating chronic phantom limb and residual limb pain. J Rehabil Res Dev 2005;42:645-54.
59Huse E, Larbig W, Flor H, Birbaumer N. The effect of opioids on phantom limb pain and cortical reorganization. Pain 2001;90:47-55.
60Wu CL, Tella P, Staats PS, Vaslav R, Kazim DA, Wesselmann U, et al. Analgesic effects of intravenous lidocaine and morphine on postamputation pain: A randomized double-blind, active placebo-controlled, crossover trial. Anesthesiology 2002;96:841-8.
61Hocking G, Cousins MJ. Ketamine in chronic pain management: An evidence-based review. Anesth Analg 2003;97:1730-9.
62Nikolajsen L, Hansen CL, Nielsen J, Keller J, Arendt-Nielsen L, Jensen TS. The effect of ketamine on phantom pain: A central neuropathic disorder maintained by peripheral input. Pain 1996;67:69-77.
63Wu CL, Agarwal S, Tella PK, Klick B, Clark MR, Haythornthwaite JA, et al. Morphine versus mexiletine for treatment of postamputation pain: A randomized, placebo-controlled, crossover trial. Anesthesiology 2008;109:289-96.
64Briand MM, Boudier-Réveret M, Rodrigue X, Sirois G, Chang MC. A moving residual limb: Botulinum toxin to the rescue. Transl Neurosci 2020;11:34-7.
65Kern U, Martin C, Scheicher S, Müller H. Does botulinum toxin A make prosthesis use easier for amputees? J Rehabil Med 2004;36:238-9.
66Eichenberger U, Neff F, Sveticic G, Björgo S, Petersen-Felix S, Arendt-Nielsen L, et al. Chronic phantom limb pain: The effects of calcitonin, ketamine, and their combination on pain and sensory thresholds. Anesth Analg 2008;106:1265-73.
67Jaeger H, Maier C. Calcitonin in phantom limb pain: A double-blind study. Pain 1992;48:21-7.
68Yousef AA, Aborahma AM. The preventive value of epidural calcitonin in patients with lower limb amputation. Pain Med 2017;18:1745-51.
69Levendoglu F, Ogün CO, Ozerbil O, Ogün TC, Ugurlu H. Gabapentin is a first line drug for the treatment of neuropathic pain in spinal cord injury. Spine (Phila Pa 1976) 2004;29:743-51.
70Niraj S, Niraj G. Phantom limb pain and its psychologic management: A critical review. Pain Manag Nurs 2014;15:349-64.
71Darnall BD. Self-delivered home-based mirror therapy for lower limb phantom pain. Am J Phys Med Rehabil 2009;88:78-81.
72Ramachandran VS, Rogers-Ramachandran D. Synaesthesia in phantom limbs induced with mirrors. Proc Biol Sci 1996;263:377-86.
73Campo-Prieto P, Rodríguez-Fuentes G. Effectiveness of mirror therapy in phantom limb pain: A literature review. Neurologia (Engl Ed) 2018. S0213-9. doi: 10.1016/j.nrl.2018.08.003. Epub ahead of print. PMID: 30447854.
74Broderick P, Horgan F, Blake C, Ehrensberger M, Simpson D, Monaghan K. Mirror therapy for improving lower limb motor function and mobility after stroke: A systematic review and meta-analysis. Gait Posture 2018;63:208-20.
75Pérez-Cruzado D, Merchán-Baeza JA, González-Sánchez M, Cuesta-Vargas AI. Systematic review of mirror therapy compared with conventional rehabilitation in upper extremity function in stroke survivors. Aust Occup Ther J 2017;64:91-112.
76Griffin SC, Curran S, Chan AW, Finn SB, Baker CI, Pasquina PF, et al. Trajectory of phantom limb pain relief using mirror therapy: Retrospective analysis of two studies. Scand J Pain 2017;15:98-103.
77Won AS, Bailey J, Bailenson J, Tataru C, Yoon IA, Golianu B. Immersive virtual reality for pediatric pain. Children (Basel) 2017;4:52.
78Limakatso K, Madden VJ, Manie S, Parker R. The effectiveness of graded motor imagery for reducing phantom limb pain in amputees: A randomised controlled trial. Physiotherapy 2020;109:65-74.
79Johnson MI, Mulvey MR, Bagnall AM. Transcutaneous electrical nerve stimulation (TENS) for phantom pain and stump pain following amputation in adults. Cochrane Database Syst Rev 2015;8:CD007264.
80Gilmore CA, Ilfeld BM, Rosenow JM, Li S, Desai MJ, Hunter CW, et al. Percutaneous 60-day peripheral nerve stimulation implant provides sustained relief of chronic pain following amputation: 12-month follow-up of a randomized, double-blind, placebo-controlled trial. Reg Anesth Pain Med 2019. m-100937. doi: 10.1136/rapm-2019-100937. Epub ahead of print. PMID: 31740443.
81Harrison C, Epton S, Bojanic S, Green AL, FitzGerald JJ. The efficacy and safety of dorsal root ganglion stimulation as a treatment for neuropathic pain: A literature review. Neuromodulation 2018;21:225-33.
82Aiyer R, Barkin RL, Bhatia A, Gungor S. A systematic review on the treatment of phantom limb pain with spinal cord stimulation. Pain Manag 2017;7:59-69.
83Bolognini N, Olgiati E, Maravita A, Ferraro F, Fregni F. Motor and parietal cortex stimulation for phantom limb pain and sensations. Pain 2013;154:1274-80.
84Soin A, Fang ZP, Velasco J. Peripheral neuromodulation to treat postamputation pain. Prog Neurol Surg 2015;29:158-67.
85Gilmore C, Ilfeld B, Rosenow J, Li S, Desai M, Hunter C, et al. Percutaneous peripheral nerve stimulation for the treatment of chronic neuropathic postamputation pain: A multicenter, randomized, placebo-controlled trial. Reg Anesth Pain Med 2019;44:637-45.
86Cohen SP, Gilmore CA, Rauck RL, Lester DD, Trainer RJ, Phan T, et al. Percutaneous peripheral nerve stimulation for the treatment of chronic pain following amputation. Mil Med 2019;184:e267-74.
87Rauck RL, Cohen SP, Gilmore CA, North JM, Kapural L, Zang RH, et al. Treatment of post-amputation pain with peripheral nerve stimulation. Neuromodulation 2014;17:188-97.
88Trevelyan EG, Turner WA, Summerfield-Mann L, Robinson N. Acupuncture for the treatment of phantom limb syndrome in lower limb amputees: A randomised controlled feasibility study. Trials 2016;17:519.
89The Treatment of Phantom Limb Pain by Scalp Acupuncture; 2006. Available from: https://www.acupuncturetoday.com/mpacms/at/article.php?id=30431. [Last accessed on 2020 Nov 09].
90Preißler S, Dietrich C, Blume KR, Hofmann GO, Miltner WH, Weiss T. Plasticity in the visual system is associated with prosthesis use in phantom limb pain. Front Hum Neurosci 2013;7:311.
91Kern U, Altkemper B, Kohl M. Management of phantom pain with a textile, electromagnetically-acting stump liner: A randomized, double-blind, crossover study. J Pain Symptom Manage 2006;32:352-60.
92Fisher K, Oliver S, Sedki I, Hanspal R. The effect of electromagnetic shielding on phantom limb pain: A placebo-controlled double-blind crossover trial. Prosthet Orthot Int 2016;40:350-6.
93Vincitorio F, Staffa G, Aszmann OC, Fontana M, Brånemark R, Randi P, et al. Targeted muscle reinnervation and osseointegration for pain relief and prosthetic arm control in a woman with bilateral proximal upper limb amputation. World Neurosurg 2020;143:365-73.
94Miller LA, Stubblefield KA, Lipschutz RD, Lock BA, Kuiken TA. Improved myoelectric prosthesis control using targeted reinnervation surgery: A case series. IEEE Trans Neural Syst Rehabil Eng 2008;16:46-50.
95Alexander JH, Jordan SW, West JM, Compston A, Fugitt J, Bowen JB, et al. Targeted muscle reinnervation in oncologic amputees: Early experience of a novel institutional protocol. J Surg Oncol 2019;120:348-58.