The Future of Phantom Limb Pain Management Using

Virtual and Augmented Reality Environments

Ritika Kolan

Honors 222 B: Pain

Dr. John Loeser and Dr. Jonathan Mayer

June 9th, 2020

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INTRODUCTION

In the United States, nearly 2 million people are living with limb loss and approximately

185,000 amputations are performed each year, which are largely a result of complications

relating to vascular disease, including diabetes and peripheral arterial disease, trauma, and

cancer.1 Increasing rates of diabetes and vascular disease, in particular, are expected to double the

number of individuals living with limb loss to 3.6 million by 2050.2 It is reported that the

prevalence of phantom limb pain (PLP), which is clinically defined as intense pain occurring in a

missing extremity, is 75-80% post-amputation and can persist many years after surgery,3

hindering individuals from pursuing personally meaningful activities and thus impeding their

quality of life. This indicates that the management of phantom limb pain is of immense value to

society as the number of people affected by this neuropathic pain rises to epidemic proportions.

Phantom limb pain has been a difficult condition to manage with most pharmacological and

surgical treatments lacking efficacy and producing significant side effects. While mirror-box

therapy is a non-pharmacological and non-invasive mechanism-based treatment for PLP that has

shown promise, it also has its limitations in terms of realism, its inability in treating pain in

bilateral amputees, and lack of considerable evidence in demonstrating long-lasting relief for

patients. These limitations have paved the way for more advanced and innovative technologies,

such as virtual reality/augmented reality (VR/AR) systems, that use some of the same principles

but may be applied in therapeutically more useful manners. VR/AR can provide mutable,

immersive, and life-like environments and hence interactive tasks to promote phantom motions

1
Ziegler-Graham et al., “Prevalence of Limb Loss in the United States,” 422–429; Owings and Kozak, “Ambulatory
and Inpatient Procedures in the United States,” 1-119.
2
Ziegler-Graham et al., “Prevalence of Limb Loss in the United States,” 422–429.
3
Ephraim et al.,“Phantom Pain, Residual Limb Pain, and Back Pain in Amputees,” 1910-1919.
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as well as better representations of missing extremities without reliance on a box or one’s

imagination. In order to reduce the burden of phantom limb pain, the PLP research community is

required to invest in additional randomized clinical trials to further support and evaluate the

efficacy of this type of therapy, as well as unite with virtual reality companies and insurance

companies to make virtual reality related interventions affordable and accessible to all patients.

ETIOLOGY OF PHANTOM LIMB PAIN

Although the origin of phantom limb pain remains uncertain, many hypotheses involving

central and peripheral nervous system mechanisms have been developed concerning the etiology

of the condition. A common CNS hypothesis postulates that phantom limb pain is related to and

a result of maladaptive plasticity or changes in the primary somatosensory cortex that occur in

reaction to amputation.4 A study using neuromagnetic imaging methods found that the amount of

cortical remapping is very positively correlated (r=0.93) with the degree of phantom limb pain

felt following arm amputation.4 In regard to peripheral causes, extremity amputation entails the

transection of peripheral nerves and the resultant formation of neuromas (abnormal growth of

nerve tissue) that can produce ectopic discharges that may contribute to neuropathic pain like

PLP. While there is evidence that blocking neuromata with lidocaine, a local anesthetic, has

reduced the sensation of pain in some amputees and thus supports the hypothesis, there have also

been instances where the application of the anesthetic at the residual limb did not decrease or

eliminate pain in patients.5 In addition, this hypothesis does not account for the presence of

phantom limb pain in patients who have congenital absence of limbs, suggesting that there are

4
Flor et al.,“ Phantom-Limb Pain as a Perceptual Correlate of Cortical Reorganization,” 482-484.
5
Nystrom and Hagbarth, “Microelectrode Recordings From Transected Nerves in Amputees,” 211-216; Birbaumer
et al., “Effects of Regional Anesthesia on Phantom Limb Pain,” 5503-5508.
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also CNS mechanisms for PLP at work. It is also important to note that psychological factors like

stress and depression can exacerbate many chronic pain conditions like phantom limb pain. A

cross-sectional survey found that depressive symptoms were a major predictor of the intensity of

pain.6 Overall, the different hypotheses for phantom limb pain are not mutually exclusive and

probably work in conjunction to explain the observed varied experiences among amputees with

this condition.

EXISTING TREATMENTS AND THEIR LIMITATIONS

The variances in the possible mechanisms and characteristics of phantom limb pain could

explain differences in patient response to particular therapies. While there are many PLP

treatments that have been beneficial to some patients, not a single intervention has been

recognized as largely effective. Common treatments for PLP include plasticity-based therapies,

pharmacotherapy, surgical interventions, and transcutaneous electrical nerve stimulation (TENS).

Plasticity-based therapies like motor imagery, mirror therapy, and visual reality, in particular, are

known to be more effective and of lower risk in comparison to other treatments and aim to

ameliorate the connection between expected and actual sensory feedback.

Pharmacological Options

While there are no medications specifically tailored for treating PLP, there are drugs

available to help alleviate nerve pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) and

tricyclic antidepressants are commonly used medications for treating neuropathic pain conditions

but their efficacy has mixed results for PLP.7 One survey found that NSAIDs were not as helpful

6
Ephraim et al.,“Phantom Pain, Residual Limb Pain, and Back Pain in Amputees,” 1910-1919.
7
Hanley et al., “Self-Reported Treatments Used for Lower-Limb Phantom Pain.” 270-277; Attal et al., “EFNS
Guidelines on the Pharmacological Treatment of Neuropathic Pain,” 1113-e88.
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as compared to opioids and chiropractic care in decreasing phantom limb pain intensity.8 In

regard to tricyclic antidepressants, one study reported that an average dose of 55 mg of

amitriptyline provided stable control of phantom limb pain with no major adverse effects

whereas other studies report that amitriptyline did not yield any substantial baseline differences

in pain scores relative to the active placebo treatment groups.9 Gabapentin, an anticonvulsant

medication, is another common treatment for PLP but has also shown conflicting outcomes in

terms of efficacy.10 Since studies on most pharmacological options show mixed results for

treating PLP and poor methodological quality, they should not be used as first-line treatment.

Opioids like morphine are often used to treat neuropathic pain as well and some

randomized placebo-controlled trials reveal that they have been successful at alleviating PLP by

potentially decreasing cortical remapping in the somatosensory cortex.11 Although opioid

medications have good short-term efficacy, there is insufficient evidence for demonstrating

long-term effectiveness, suggesting that they have limited usefulness in terms of managing

chronic pain conditions alone and should thus not be at the center of our efforts in treating

phantom limb pain. Furthermore, a significant disadvantage of pharmacotherapy is the risk of

addiction and overdose, especially in the United States where premature mortality rates from

drug overdose are over twice that of twelve other Organization for Economic Co-operation and

Development (OECD) member countries.12 Other common adverse side effects of opioid use are

8
Hanley et al., “Self-Reported Treatments Used for Lower-Limb Phantom Pain.” 270-277.
9
Wilder-Smith, Hill, and Laurent, “Postamputation Pain,” 619-628; Robinson et al., “Trial of Amitriptyline,” 1-6.
10
Wiffen et al., “Gabapentin for Acute and Chronic Pain,” CD005452; Nikolajsen et al., “A Randomized Study of
the Effects of Gabapentin on Postamputation Pain,” 1008-1015.
11
Wu et al., “Analgesic Effects of Intravenous Lidocaine,”841-848; Wu et al., “Morphine Versus Mexiletine,”
289,296; Huse et al., “The Effect of Opioids on Phantom Limb Pain,” 47-55.
12
Chen et al., “Premature Mortality From Drug Overdoses,” 352-354.
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constipation, nausea, sedation, dizziness, and respiratory depression.13 Despite these

consequences, some chronic pain patients build up a tolerance to these substances, leading

patients to take continuous and escalating doses of opioids in order to achieve low pain scores.

The use of opioids thus ultimately undermines the goal of treating chronic pain patients by

contributing to worsening function rather than working towards improving their health and

quality of life. As a result, non-pharmacological treatments available with minimal risk and of

greater proven efficacy for phantom limb pain should be the preferred mode of therapy over

pharmacological options.

Surgical Interventions

Surgical treatments for phantom limb pain are normally performed when other therapies

have not successfully reduced PLP intensity. A few case studies report the successfulness of the

dorsal root entry zone (DREZ) lesioning in treating PLP with brachial plexus avulsion.14 Another

case study on four patients revealed that spinal cord stimulation can provide effective pain relief

(> 80%) for PLP among particular individuals who have not acquired sufficient relief from

medical management.15 Deep brain stimulation of the periventricular grey matter and

somatosensory thalamus has also been found to reduce phantom limb pain intensity by an

average of 62% with the burning aspect of the pain completely eliminated in all three patients. 16

While these findings show promise, these interventions are case studies that are subjected to

limited data and low sample sizes, making it difficult to draw any well-founded conclusions on

their effectiveness on phantom limb pain. Since surgical interventions are also usually associated

13
Benyamin et al., “Opioid Complications,” S105-S120.
14
Zheng et al., “DREZ Lesions,” 249-255; “Tomycz and Moossy, “26 Years After DREZ,” 196-199.
15
Viswanathan, Phan, and Burton, “SCS in Treatment of Phantom Limb Pain,” 479-484.
16
Bittar et al., “Deep Brain Stimulation for Phantom Limb Pain,” 399-404.
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with higher costs and greater risks compared to non-invasive and non-pharmacological therapies,

more rigorous studies are required for these invasive procedures to be used routinely for PLP

patients. Considering non-surgical treatments have been surveyed to be more successful than
17
surgical methods in treating PLP, more research should be invested in establishing the efficacy

of those relatively cheaper, safer, and more beneficial therapies, such as virtual reality related

treatments.

Transcutaneous Electrical Nerve Stimulation (TENS)

A TENS unit is an inexpensive, low risk, and easy-to-use device that uses a low voltage

electrical current to provide pain relief and has been found to be helpful in alleviating phantom

limb pain.18 A significant short-term reduction in the intensity of PLP was achieved after

30-minute sessions of low frequency, high-intensity auricular TENS on two consecutive days in

comparison to the no stimulation placebo condition.19 However, considering that the long-term

effectiveness of this intervention on PLP remains largely unclear and that a greater degree of

evidence for other non-pharmacological treatments exists, those other treatments should receive

priority in treating phantom limb pain.

Motor Imagery

It has been reported that frequent practice of mental visualization of phantom limb

movement can relieve phantom limb pain and is associated with a decrease in cortical

remapping.20 At the same time, however, some randomized controlled trials have deduced that

17
Sherman, Sherman, and Gall, “Survey of Current PLP Treatment,” 85-89.
18
Black, Persons, and Jamieson, “Clinical Inquiries,” 155-158.
19
Katz and Melzack, “Auricular TENS Reduces Phantom Limb Pain,” 90521-5.
20
MacIver et al., “Therapeutic Effect of Mental Imagery,” 2181-2191.
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motor imagery was unsuccessful in reducing pain intensity, and, in fact, increased pain levels in

some individuals relative to baseline.21 The results of these clinical trials should be interpreted

with caution as they had small sample sizes, inadequate long-term follow-up data, and a great

probability of bias. Nevertheless, the clinical findings support the results of a different pre- and

post-therapy trial that found that motor imagery augmented pain and swelling in individuals with

chronic pain in their arm.22 Consequently, mental visualization exercises should not be used alone

as a treatment for chronic pain like phantom limb pain until there is sufficient evidence that

contradicts these findings.

Motor imagery is also used as part of a therapeutic model called graded motor imagery

(GMI), which is a three-stage treatment that consists of left/right discrimination training, then

motor imagery exercises, followed by mirror therapy. It appears that the effectiveness of GMI is

dependent on this order of increasing activity complexity due to the sequential engagement of

cortical motor networks.23 While this therapy has shown to be effective in treating PLP and

complex regional pain syndrome (CRPS) in research trials, it did not improve average pain

intensities experienced by patients in a study that applied GMI to clinical practice.24 Since motor

imagery also relies on one’s imagination to stimulate movement, the illusion may not be

compelling and long-lasting enough for some individuals who need more realistic approaches to

reap the potential benefits of this treatment. Variances in one’s imagination in addition to

conflicting reports and low-quality clinical trials on this therapy push the need for more

successfully proven treatments like mirror therapy and even more promising and reliable

21
Chan et al., “Mirror Therapy for PLP,” 2206-2207; Cacchio et al., “Mirror Therapy,” 792-799
22
Moseley et al., “Effect of Motor Imagery on Pain,” 792-799.
23
Moseley, “Successful Rehabilitation of CRPS,” 54-61.
24
Moseley, “Graded Motor Imagery,” 192-198; Johnson et al., “Using Graded Motor Imagery for CRPS,” 550-561
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treatments that use tools like virtual and augmented reality environments.

Mirror Box Therapy

The mirror box is the most frequent and cost-effective treatment in clinical use for PLP

and was developed by Dr. Vilayanur S. Ramachandran in the 1990s to alleviate phantom limb

pain through visual feedback.25 The therapy involves the use of a mirror placed between the

amputated and intact limb and manipulates the brain by providing an illusion of normal

movement in the affected limb through the reflection of a moving intact limb (Figure 1). The

same neuroplasticity that may underpin the cortical reorganization that contributes to phantom

limb pain can thus be exploited to return the brain to a “normal” state. This could potentially

allow an individual’s perception of pain to be reduced with an increasing sense of control over

their phantom limb. 26

Significant support for the therapeutic use of mirror therapy comes from case studies and

anecdotal reports, which for evident reasons, are more likely to paint a positive portrait of the

treatment. Controlled clinical trials are more reliable and have yielded conflicting support for

mirror therapy. Chen et al., for example, observed that all patients randomly allocated to use

mirror therapy for 15 minutes daily for four weeks reported a reduction in pain intensity

compared to both the controlled condition and the motor imagery groups.27 Mirror therapy in a

different randomized trial on lower limb amputees, in contrast, did not relieve phantom limb pain

or sensations relative to the control group.28 Many randomized controlled trials on mirror therapy

have been limited to a small sample size such as the Chen et al. study, which only followed 22

25
Ramachandran and Altschuler, “Mirror Visual Feedback, in Restoring Brain Function,” 1693-1710.
26
Ramachandran and Altschuler, “Mirror Visual Feedback, in Restoring Brain Function,” 1693-1710.
27
Chan et al., “Mirror Therapy for PLP,” 2206-2207.
28
Brodie, Whyte, and Niven, “Analgesia Through the Looking Glass?,” 428-436.
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PLP patients, reducing the precision estimate of the treatment effect. The same study further

impeded the reliability of their results by not acknowledging possible sources of bias in addition

to not adequately defining their pain intensity scale. A systematic review of 20 studies, including

randomized control trials, prospective studies, and case studies, on the effects of mirror therapy

on PLP and phantom limb movement in upper and lower limb amputees, has even concluded that

evidence supporting the efficacy of mirror therapy is inadequate.29 As a result, mirror therapy

should not be advised as first-line treatment for phantom limb pain until more high-quality

randomized trials are conducted and a consensus on treatment efficacy has been achieved.

Mirror therapy has some advantages in being inexpensive, noninvasive, and of minimal

risk, as well as in involving a simple procedure that patients can follow at home without

assistance. Nevertheless, the simplicity and crudeness of the treatment instrument often fails to

provide a convincing durable illusion of a moving phantom limb. Mirror therapy is also

restricted to certain movements that require an intact contralateral upper or lower extremity,

preventing bilateral amputees from participating in a potentially beneficial treatment and thus

diminishes the generalizability of the therapy. Furthermore, techniques like mirror therapy and

mental visualization demand continuous and prolonged implementation with varying levels of

durability, which may make it difficult for many patients to regularly commit to daily therapy.

These limitations along with the absence of established guidelines for protocols of particular

tasks to employ during mirror therapy make the use of virtual reality related treatments an

increasingly attractive mode of therapy for clinical use in treating phantom limb pain in the

future.

29
Barbin et al., “The Effects of Mirror Therapy on Pain,” 270-275.
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PLP MANAGEMENT USING VR/AR ENVIRONMENTS

Augmented reality uses computer-generated input to enhance the real, physical world

while virtual reality is a fully immersive computer generated simulation of an entire 3-D

environment. The application of interactive virtual and augmented reality technology in PLP

treatment has recently exhibited optimistic outcomes for relieving phantom limb pain. VR/AR

provide more realistic and diverse visuals as well as an opportunity to practice varied movements

and rehabilitation exercises that mirror therapy fails to offer. This technology can also be used

for interactive, immersive games that can challenge patients and maintain their engagement

throughout therapy. Ortiz-Catalan et al. have proposed a phantom motor execution treatment for

PLP that applies VR/AR tools based on the hypothesis that “re-engagement of central and

peripheral circuitry involved in motor execution could reduce phantom limb pain via competitive

plasticity and reversal of cortical reorganization.”30 This treatment involves a system that uses

myoelectric activity at the residual limb to predict phantom limb movements while providing

timely visual feedback to the subject in virtual and augmented reality environments (Figure 2).

This sophisticated technology additionally permits the integration of serious gaming into the

treatment, which is used to further facilitate and motivate phantom limb movement.

Clinical Findings

This phantom motor execution hypothesis was first examined in 2014 in a 72-year-old

male patient who had been resistant to many conventional PLP treatments including mirror

therapy and as a consequence had been suffering from chronic upper-limb phantom pain for 48

30
Ortiz-Catalan et al., “Phantom Motor Execution,” 2885-2894.
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years.31 Before treatment, the patient had reported the absence of control over phantom limb

movement and poor sleep conditions due to intense pain events that would often keep him awake

at night. The proposed treatment was applied over a period of 18 weeks with one session held in

the first 13 weeks and two sessions held in the last five weeks. The treatment resulted in an

overall gradual reduction in the subject’s pain intensity to the extent that he experienced episodes

of almost absent pain after each session as well as in the acquisition of control over the phantom

limb. Furthermore, the patient’s nighttime pain episodes disappeared, allowing him to improve

his sleep quality, which was described as a significant and hopeful improvement from the patient

himself and his family. The patient’s general quality of life was enhanced as he was also able to

work harder at his daily activities, which involved agricultural tasks, without being burdened by

his condition. After the treatment, the subject was supplied with his own phantom motor

execution unit, including myoelectric pattern recognition, virtual/augmented reality, and serious

gaming systems to use at home. A follow-up conducted after five years revealed that the success

of the therapy has persisted. Since this is a case study, no clinical decisions should be based on

these results. However, the significant improvement in the subject’s quality of life and both the

short-term and long-term effectiveness of this treatment where other medical and non-medical

therapies have failed serves adequate reasoning to warrant further research and conduct large

randomized, controlled clinical trials on this system in order to establish its efficacy for clinical

use.

These findings encouraged a multicenter trial across four clinics in Sweden and Slovenia

with 14 upper limb amputees between 2014-2015.32 These patients had been suffering from

31
Ortiz-Catalan et al., “Treatment of PLP Based on Augmented Reality,” 24.
32
Ortiz-Catalan et al., “Phantom Motor Execution,” 2885-2894.
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intractable chronic phantom limb pain for an average of ten years and had exhausted all

treatment options available at their designated clinic before undergoing 12 treatment sessions of

the phantom motor execution system and associated VR/AR tools.33 The patients reported a

significant reduction in phantom limb pain by about 50% from pre-treatment to the last treatment

with more than half the subjects also experiencing a decrease in pain of at least two points in the

numeric rating scale, which are both clinically significant measurements.36 Moreover, the

hindrance of phantom limb pain in daily activities and sleep was reduced by 43% and 61%,

respectively, which is consistent with the findings of the initial case study in ameliorating the

quality of life. Two out of the four patients who were on medication for PLP decreased their

intake of 1300 mg gabapentin by 81% and of 75 mg pregabalin by 33% as well, which is a

beneficial outcome in preventing overreliance on pharmacological treatments that often

contribute to worsening function and are associated with greater risks including drug abuse and

overdose. The therapy’s benefits were still observable at a six-month follow-up after the last

treatment, highlighting the clinical relevance and potential long-term effectiveness of this

treatment and associated virtual/augmented reality tools in managing if not curing phantom limb

pain in patients, especially since several pharmacological and other non-pharmacological

therapies have not yet demonstrated long-term efficacy. Despite these encouraging results, this

study has limitations that need to be recognized. Confounding variables, such as the placebo

effect, cannot be completely ignored as there were no controlled conditions in this study. The

sample size of the study, although larger than the initial case study, is still very small and

undermines the opportunity of detecting the precise effect of the particular treatment.

33
Ortiz-Catalan, “The Stochastic Entanglement and Phantom Motor Execution Hypothesis,” 748.
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Consequently, subsequent clinical trials need to address these problems before an informed

decision can be made on using this system as first-line therapy for phantom limb pain.

At the present time, a double-blind, randomized controlled multicenter trial involving

nine clinics across six European countries and Canada is being conducted in order to more

precisely evaluate the efficacy of this proposed system in treating phantom limb pain.34 The

subjects of the trial receive a total of 15 treatment sessions independent of each other lasting two

hours, including equipment setup and a blinded outcome assessment, which minimizes

evaluation bias. While the patient selects the frequency of the sessions between one, two, or five

sessions per week, two sessions of therapy per week are recommended by the authors.

Follow-ups are held at one, three, and six months after the last treatment, which will help gauge

the long-term effectiveness of the therapy. Unlike the initial studies, this trial has recruited at

least 67 patients, a much larger sample size, meaning the findings of this study will have greater

significance than the previous case studies. This trial also assesses the effect of the intervention

on both upper and lower limb amputees rather than solely upper limb amputees, strengthening

the generalizability of the therapy. The inclusion of lower limb amputees in this study follows the

verification of the feasibility of this treatment method for PLP in this population of amputees

determined by other preliminary investigations performed in 2016 that are not described in this

paper.35 The inclusion of a control group in the trial also addresses one of the major limitations of

the previous case studies. While both the experimental and control treatment groups receive the

same equipment and setup, they interact with the virtual/augmented reality environments in

different manners.36 Subjects in the control group imagine phantom movements (motor imagery)

34
Leandro et al., “Phantom Motor Execution as a Treatment for PLP,” e021039.
35
Leandro et al., “Lower-Limb Movements Using EMG,” 470.
36
Leandro et al., “Phantom Motor Execution as a Treatment for PLP,” e021039.
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rather than being allowed to execute the motions while watching them be performed by the

virtual reality environment. The myoelectric activity recorded at the residual limb for the control

group is thus being used to detect that the subject does not generate any muscular contractions

instead of being used to predict phantom limb movement. Although the outcomes of the trial

have not been published yet, the results seem encouraging based on the outcomes of prior

investigations. The full analysis of the study is expected to be finalized sometime in 2020.

Advantages of Phantom Motor Execution Aided by VR/AR Environments

The positive findings reported by Ortiz-Catalan et al. so far indicate the potential value of

the phantom motor execution system as a first-line treatment for phantom limb pain. The

intervention is further appealing as it is a non-pharmacological and non-invasive approach with

no adverse side-effects reported at the moment. Mirror therapy involves repetitive motor training

in an inattentive manner and is thus not adequate to produce purposeful reorganization of cortical

maps.37 In contrast, the phantom motor execution intervention uniquely allows for a wide range

of movements and personal control over the virtual limb, which is speculated to drive brain

plasticity and functional cortical remapping by improving dexterity and the perception of

residual limb musculature.38 Since the system also entails using myoelectric signals from the

residual limb itself to be used in a virtual reality environment rather than relying on the use of an

intact contralateral limb like in mirror therapy, the treatment can be used by bilateral amputees.

This is significant as it will improve access to potentially effective treatments for PLP to all

amputee populations. Considering that a big challenge with conventional rehabilitation exercises

for phantom limb pain is that patients do not often complete their treatment course, the exciting

37
Plautz, Milliken, and Nudo, “Effects of Repetitive Motor Training,” 27-55.
38
Ortiz-Catalan, “The Stochastic Entanglement and Phantom Motor Execution Hypothesis,” 748.
 Kolan 15

and engaging nature of the virtual/augmented reality environments including serious gaming

may serve as an enjoyable and motivating drive to fulfill the entire course of therapy. Lastly, this

treatment is not limited to only phantom limb pain patients but any type of patient that needs to

rehabilitate their mobility, including stroke survivors and individuals with spinal cord injuries.39

Clarifying VR Therapy

A common misconception about virtual reality is that it is perceived as an intervention in

itself instead of being viewed as a therapeutic tool. Any treatment that yields positive outcomes

relies more on how the technological tool is applied rather than on what tool is in operation. In

other studies that are exploring virtual reality for managing phantom limb pain, they are using

VR as a more advanced, sophisticated, and immersive version of mirror therapy.40 Since this

approach also depends on continued use of the intact limb like in mirror therapy, it is limited to

unilateral amputees and is not significantly different from undergoing mirror therapy (Figure 3).

Furthermore, this approach undermines the efforts made by the phantom limb pain patients to

make phantom movements. The use of VR in this manner consequently limits its capabilities.

When applied purposefully and used as an instrument in the design of the intervention like in the

phantom motor execution system proposed by Ortiz-Catalan et al., VR may not only help reduce

pain intensity but address the restrictions and limitations of prior treatments.

Future Steps

Despite the higher-quality randomized, controlled clinical trial currently being conducted

based on the hypothesis made by Ortiz-Catalan et al., there are still some significant challenges

39
Ortiz-Catalan et al., “Treatment of PLP Based on Augmented Reality,” 24.
40
Ortiz-Catalan et al., “Treatment of PLP Based on Augmented Reality,” 24.
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in proving the efficacy of this approach. Positive outcomes from one clinical trial will not be

enough to advocate for the use of the phantom motor execution system and its associated VR/AR

tools for clinical use. The more information and evidence that we gather, the more we can

improve the treatment of phantom limb pain. As a result, the phantom limb pain research

community needs to invest more money in advancing more formal trials for this innovative and

advanced therapy. These formal trials must include a control group, a large sample size of

patients, the randomization of patients to treatment groups to minimize allocation bias and

confounding variables, the tracking of various patient variables, and post-treatment follow-ups to

assess long-term effectiveness. The trials would preferably be double-blinded as well to

minimize additional performance and assessment bias. If all of these factors are addressed,

strong and reliable empirical evidence can be used to support the true efficacy of a treatment and

inform clinical decisions in treating phantom limb pain. High methodological quality of clinical

trials may also help prevent the mixed results that plague various pharmacological and

non-pharmacological treatments like mirror therapy for phantom limb pain. The lack of

conflicting outcomes and long-term effectiveness associated with the phantom motor execution

treatment so far is promising as these factors will not impede progress in finding a therapy that

can be generally applicable and beneficial for all types of amputees in both the short and

long-term. This treatment, which is aided by virtual/augmented reality environments, has the

potential to truly change the future of phantom limb pain management. It can prevent the

occurrence of situations like the 72-year-old chronic pain patient presented in the initial case

study done by Ortiz-Catalan et al. because no individual should have to suffer from intense pain

for 48 years.
 Kolan 17

When explaining their intervention, Ortiz-Catalan et al. repeatedly highlighted the

engaging and motivating nature of virtual reality gaming and its role in the success of the

intervention. Other investigations exploring VR related treatments have shared the same

sentiments. One case study on lower limb amputees allowed the patients to see a real-time

rendering of both intact lower limb extremities while playing games, such as Quest for Fire, Web

browser, Chess, and Checkers, using an Oculus Rift head-mounted display.41 The authors of the

study attributed the promising results of their study in reducing PLP intensity to the variety and

quality of games offered to the patients as well as to the patients’ ability to choose their game(s)

of interest. This raises the question of whether the effectiveness of virtual reality related

treatments for phantom limb pain is dependent on some portion and to what extent by patient

engagement and the interactiveness of the tasks provided. It would be worthwhile to review and

compare the success of a virtual reality environment in alleviating phantom limb pain between

using VR for more entertaining activities, such as the racing game in the Ortiz-Catalan et al. case

study on the 72-year-old patient, or using it for repetitive and straight-forward activities like a

simple reach and grasp task as implemented in other studies.42 Future research on virtual reality

systems should evaluate the possible influence of patient engagement and sense of control on the

results of a given treatment study in order to better inform how these environments should be

employed if and when they are cleared for clinical use.

While the phantom motor execution intervention has benefits in terms of being a non-

pharmacological and non-invasive and thus a minimally risky treatment, there is limited

information available on the cost-effectiveness of the approach, which will probably change if

41
Ambron et al. “Virtual Reality Treatment for Phantom Limb Pain,” 67.
42
Ichinose et al., “Virtual Visual Feedback Therapy Enhances Pain Alleviation,” 717-725.
 Kolan 18

and once the treatment comes into clinical practice. Nevertheless, it is critical to highlight the

importance of making treatments affordable for all populations, especially considering that

debilitating chronic pain conditions like phantom limb pain are often associated with loss of

work productivity in addition to substantial costs of multiple treatments. If the phantom motor

execution intervention ever adopts the use of a head-mounted display rather than a computer

screen to present the virtual/augmented reality environment and heighten the immersive

experience, the PLP research community needs to unite with virtual reality companies to make

these headsets as inexpensive as possible. While most VR headsets do not cost as much as they

once did, high-quality headsets from popular companies like Oculus VR and HTC Vive still cost

between $400-$800 with compatible computers costing around $1000.43 This cost combined with

the prices of the other equipment required for the phantom motor execution treatment like

electromyography related devices or a computer if a headset is not used would be evidently more

expensive than other treatments for phantom limb pain. As a result, amputees with PLP may

prefer to undergo user-friendly, portable, and more affordable treatments like mirror therapy,

which only requires an inexpensive mirror, or a $30-$200 TENS unit44 to alleviate their pain. If

the phantom motor execution intervention was found to be the treatment of most proven efficacy

for PLP, it would be a loss in the progress of reducing the global burden of PLP to not make this

treatment equitably accessible to all. Virtual reality companies thus need to reach an economy of

scale to drive market prices down. Many insurance companies also do not support long-term

therapy and alternative pain treatments, which often provide greater relief than pharmacological

and surgical interventions in treating neuropathic pain. In order to make these treatments even

43
Chen, “Virtual Reality Check.”
44
Palus and Witman, “The Best TENS Unit.”
 Kolan 19

more accessible to all, we need to advocate for insurance companies to cover alternative

medicine and self-management strategies and fight against those who determine which care gets

funded and which gets rejected. In the future, it would be beneficial to develop a more portable

and convenient version of the phantom motor execution system in order to strengthen clinical

appeal and facilitate the use of the treatment at home to be self-administered.

CONCLUSION

While there are more than 50 treatments that have been surveyed for phantom limb pain

in literature,45 they often lack high-quality evidence to support their efficacy. These treatments

have a limited number of randomized controlled trials to prove their success and the clinical

trials that have been conducted are frequently subjected to low sample size and poor

methodological quality, which prevent these studies from accurately representing the true effect

of the treatment. In addition, many studies are of short duration and thus do not assess the

long-term effectiveness of their intervention. This is a significant limitation of these studies as

chronic phantom limb pain persists for years and accordingly requires a therapy that is capable of

providing long-term relief. The shortfalls of surgical, pharmacological, mirror therapy, and motor

imagery interventions in treating phantom limb pain have set the scene for the use of more

sophisticated and innovative technology like virtual reality environments in the design of new

treatments for PLP.

Recent preliminary investigations have demonstrated that treatments using virtual reality

environments serve as an encouraging frontier in relieving phantom limb pain, possibly across all

populations of amputees. At present, virtual reality related treatments are not tainted with

45
Sherman, Sherman, and Gall, “Survey of Current PLP Treatment,” 85-89.
 Kolan 20

conflicting outcomes like other treatments for phantom limb pain and have been found to reduce

pain intensity at levels of clinical relevance in addition to increasing a patient’s full range of

motion, which can help improve their quality of life by increasing their ability to pursue

meaningful activities. There have also been promising indications that the effects of VR related

therapy is maintained over repeated sessions and at follow-ups post-treatment, indicating that

virtual reality environments can potentially play a pivotal role in long-term pain rehabilitation.

Despite these initial findings, larger and better-controlled randomized clinical trials are required

in the future to officially establish and strengthen VR’s efficacy. If virtual reality therapies

become more conventionally used in clinical settings, their appeal will increase if they become

more affordable and if convenient versions of the systems used in clinical trials are developed to

be used at home without guidance. Virtual and augmented reality environments offer a

potentially effective and engaging mode of therapy that makes the future of phantom limb pain

management more promising and hopeful, especially as the number of individuals living with

limb loss and consequently phantom limb pain is projected to rise.

 Kolan 21

FIGURES

Figure 1. Mirror Therapy.46

Figure 2. Phantom Motor

Execution System.47

46
Collins et al., “Current Theories and Treatment for Phantom Limb Pain” Journal of Clinical Investigation 128,
no.6 (2018): 2168-2176, figure 3-A.
47
Lendaro et al. “Phantom Motor Execution as a Treatment for Phantom Limb Pain,” BMJ Open 8, no.7 (2018):
e021039, figure 2.
 Kolan 22

Figure 3. Treatments for PLP Based on Motor Control. 48

48
Ortiz-Catalan, Max. “The Stochastic Entanglement and Phantom Motor Execution Hypotheses” Frontiers in
Neurology 9, (2018): 748, figure 4.
 Kolan 23

BIBLIOGRAPHY

Ambron, Elisabetta, Alexander Miller, Katherine J. Kuchenbecker, Laurel J. Buxbaum, and H.

Branch Coslett. “Immersive Low-Cost Virtual Reality Treatment for Phantom Limb Pain:
Evidence from Two Cases.” Frontiers in Neurology 9, (2018): 67.
https://doi.org/10.3389/fneur.2018.00067

Attal, N., G. Cruccu, R. Baron, M. Haanpää, P. Hansson, T.S. Jensen, T. Nurmikko, and
European Federation of Neurological Societies. “EFNS Guidelines on the
Pharmacological Treatment of Neuropathic Pain: 2010 Revision.” European Journal of
Neurology 17, no.9 (2010): 1113–e88. https://doi.org/10.1111/j.1468-1331.2010.02999.x

Barbin, J., V. Seetha, J.M. Casillas, J. Paysant, D. Pérennou. “The Effects of Mirror Therapy on
Pain and Motor Control of Phantom Limb in Amputees: A Systematic Review.” Annals
of Physical and Rehabilitation Medicine 59, no. 4 (2016): 270–275.
https://doi.org/10.1016/j.rehab.2016.04.001

Benyamin, Ramsin, Andrea M. Trescot, Sukdeb Datta, Ricardo Buenaventura, Rajive Adlaka,
Nalini Sehgal, Scott E. Glaser, and Ricardo Vallejo. “Opioid Complications and Side
Effects.” Pain Physician 11, no. 2 Suppl (2008): S105–S120.

Birbaumer, Niels, Werner Lutzenberger, Pedro Montoya, Wolfgang Larbig, Klaus Unertl,
Stephanie Töpfner, Wolfgang Grodd, Edward Taub, Herta Flor. “Effects of Regional
Anesthesia on Phantom Limb Pain are Mirrored in Changes in Cortical Reorganization.”
The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 17,
no. 14 (1997): 5503–5508. https://doi.org/10.1523/JNEUROSCI.17-14-05503.1997

Bittar, Richard G., Sofia Otero, Helen Carter, and Tipu Z. Aziz.“Deep Brain Stimulation for
Phantom Limb Pain.” Journal of Clinical Neuroscience: Official Journal of the
Neurosurgical Society of Australasia 12, no. 4 (2005): 399–404.
https://doi.org/10.1016/j.jocn.2004.07.013

Black, Lance M., Robert K. Persons, and Barbara Jamieson. “Clinical inquiries. What is the Best
Way to Manage Phantom Limb Pain?.” The Journal of Family Practice 58, no. 3 (2009):
155–158.

Brodie, Eric E., Anne Whyte, and Catherine A. Niven. “Analgesia Through the Looking-Glass?
A Randomized Controlled Trial Investigating the Effect of Viewing a ‘Virtual’ Limb
Upon Phantom Limb Pain, Sensation and Movement.” European Journal of Pain
(London, England) 11, no. 4 (2012): 428–436.
https://doi.org/10.1016/j.ejpain.2006.06.002

Cacchio, Angelo, Elisabetta De Blasis,Vincenzo De Blasis, Valter Santilli, and Giogio Spacca.
“Mirror Therapy in Complex Regional Pain Syndrome Type 1 of the Upper Limb in
Stroke Patients.” Neurorehabilitation and Neural Repair 23, no.8 (2009): 792–799.
 Kolan 24

https://doi.org/10.1177/1545968309335977

Chan, Brenda L., Richard Witt, Alexandra P. Charrow, Amanda Magee, Robin Howard, Paul F.
Pasquina, Kenneth M. Heilman, and Jack W. Tsao. “Mirror Therapy for Phantom Limb
Pain.” The New England Journal of Medicine 357, no. 21 (2007): 2206–2207.
https://doi.org/10.1056/NEJMc071927

Chen, Brian X. “Virtual Reality Check: Rating the HTC Vive and the Oculus Rift.” The New
York Times, April 5, 2016.
https://www.nytimes.com/2016/04/06/technology/personaltech/virtual-reality-check-ratin
g-the-htc-vive-and-the-oculus-rift.html

Chen, Yingxi, Meredith S. Shiels, David Thomas, Neal D. Freedman, and Amy Berrington de
González. “Premature Mortality From Drug Overdoses: A Comparative Analysis of 13
Organisation for Economic Co-operation and Development Member Countries With
High-Quality Death Certificate Data, 2001 to 2015.” Annals of Internal Medicine 170,
no. 5 (2019): 352–354. https://doi.org/10.7326/M18-2415

Collins Kassondra L., Hannah G. Russell, Patrick J. Schumacher, Katherine E. Robinson-

Freeman, Ellen C. O’Conor, Kyla D. Gibney, Olivia Yambem et al. “A Review of Current
Theories and Treatments for Phantom Limb Pain.” The Journal of Clinical Investigation
128, no.6 (2018): 2168-2176. https://doi.org/10.1172/JCI94003

Ephraim, Pattie L., Stephen T. Wegener, Ellen J. MacKenzie, Timothy R. Dillingham, and
Liliana E. Pezzin. “Phantom Pain, Residual Limb Pain, and Back Pain in Amputees:
Results of a National Survey.” Archives of Physical Medicine and Rehabilitation 86,
no.10 (2005): 1910–1919. https://doi.org/10.1016/j.apmr.2005.03.031

Flor, H., T. Elbert, S. Knecht, C. Wienbruch, C. Pantev, N. Birbaumer, W. Larbig, and E. Taub.
“Phantom-Limb Pain as a Perceptual Correlate of Cortical Reorganization Following
Arm Amputation.” Nature 375, no. 6531 (1995): 482–484.
https://doi.org/10.1038/375482a0

Hanley, Marisol A., Dawn M. Ehde, Kellye M. Campbell, Bridget Osborn, and Douglas G.
Smith. “Self-Reported Treatments Used for Lower-Limb Phantom Pain: Descriptive
Findings.” Archives of Physical Medicine and Rehabilitation 87, no.2 (2006): 270–277.
https://doi.org/10.1016/j.apmr.2005.04.025

Huse, Ellena, Wolfgang Larbig, Herta Flor, and Niels Birbaumer. “The Effect of Opioids on
Phantom Limb Pain and Cortical Reorganization.” Pain 90, no.1-2 (2001): 47–55.
https://doi.org/10.1016/s0304-3959(00)00385-7

Ichinose, Akimichi, Yuko Sano, Michihiro Osumi, Masahiko Sumitani, Shin-Ichiro Kumagaya,
and Yasuo Kuniyoshi. “Somatosensory Feedback to the Cheek During Virtual Visual
Feedback Therapy Enhances Pain Alleviating for Phantom Arms. Neurorehabilitation
 Kolan 25

and Neural Repair 31, no.8 (2017): 717-725. https://doi.org/10.1177/1545968317718268

Johnson, S., J. Hall, S. Barnett, M. Draper, G. Derbyshire, L. Haynes, C. Rooney, H. Cameron,

G.L. Moseley, A.C. de C. Williams, C. McCabe, and A. Goebel. “Using Graded Motor
Imagery for Complex Regional Pain Syndrome in Clinical Practice: Failure to Improve
Pain.” European Journal of Pain (London, England) 16, no. 4 (2011): 550–561.
https://doi.org/10.1002/j.1532-2149.2011.00064.x

Katz, Joel, and Ronald Melzack. “Auricular Transcutaneous Electrical Nerve Stimulation
(TENS) Reduces Phantom Limb Pain.” Journal of Pain and Symptom Management 6, no.
2 (1991): 73–83. https://doi.org/10.1016/0885-3924(91)90521-5

Lendaro, Eva, Liselotte Hermansson, Helena Burger, Corry K. Van der Sluis, Brian E. McGuire,
Monika Pilch, Lina Bunketorp-Käll, Katarzyna Kulbacka-Ortiz et al. “Phantom Motor
Execution as a Treatment for Phantom Limb Pain: Protocol of an International,
Double-Blind, Randomised Controlled Clinical Trial.” BMJ Open 8, no.7 (2018):
e021039. https://doi.org/10.1136/bmjopen-2017-021039

Lendaro, Eva, Enzo Mastinu, Bo Håkansson, and Max Ortiz-Catalan. “Real-time Classification
of Non-Weight Bearing Lower-Limb Movements Using EMG to Facilitate Phantom
Motor Execution: Engineering and Case Study Application on Phantom Limb Pain.”
Frontiers in Neurology 8, (2017): 470. https://doi.org/10.3389/fneur.2017.00470

MacIver K., D. M. Lloyd, S. Kelly, N. Roberts, and T. Nurmikko. “Phantom Limb Pain, Cortical
Reorganization and the Therapeutic Effect of Mental Imagery.” Brain 131, no. 8 (2008):
2181–2191. https://doi.org/10.1093/brain/awn124

Moseley, G. Lorimer. “Graded Motor Imagery is Effective for Long-Standing Complex Regional
Pain Syndrome: A Randomised Controlled Trial.” Pain 108, no. 1-2 (2004): 192–198.
https://doi.org/10.1016/j.pain.2004.01.006

Moseley, G. Lorimer. “Is Successful Rehabilitation of Complex Regional Pain Syndrome Due to
Sustained Attention to the Affected limb? A Randomised Clinical Trial.” Pain 114, no.
1-2 (2005): 54–61. https://doi.org/10.1016/j.pain.2004.11.024

Moseley, G. Lorimer., Nadia Zalucki, Frank Birklein, Johan Marinus, Jacobus J. van Hilten, and
Hannu Luomajoki. “Thinking About Movement Hurts: The Effect of Motor Imagery on
Pain and Swelling in People with Chronic Arm Pain.” Arthritis and rheumatism 59, no. 5
(2008): 623–631. https://doi.org/10.1002/art.23580

Nikolajsen, Lone, Nanna B. Finnerup, Steffen Kramp, Anne-Sofie Vimtrup, Johnny Keller, and
Troels S. Jensen. “A Randomized Study of the Effects of Gabapentin on Postamputation
Pain.” Anesthesiology 105, no. 5 (2006): 1008–1015.
https://doi.org/10.1097/00000542-200611000-00023
 Kolan 26

Nyström, Bo, and Karl-Erik Hagbarth. “Microelectrode Recordings From Transected Nerves in
Amputees with Phantom Limb Pain.” Neuroscience Letters 27, no.2 (1981): 211–216.
https://doi.org/10.1016/0304-3940(81)90270-6

Ortiz-Catalan, Max. “The Stochastic Entanglement and Phantom Motor Execution Hypotheses:
A Theoretical Framework for the Origin and Treatment of Phantom Limb Pain.”
Frontiers in Neurology 9, (2018): 748. https://doi.org/10.3389/fneur.2018.00748

Ortiz-Catalan, Max, Rannveig Guðmundsdóttir, Morten B. Kristoffersen, Alejandro

Zepeda-Echavarria, Kerstin Caine-Winterberger, Katarzyna Kulbacka-Ortiz, Catherine
Widehammar et al. “Phantom Motor Execution Facilitated by Machine Learning and
Augmented Reality as Treatment for Phantom Limb Pain: A Single Group, Clinical Trial
in Patients with Chronic Intractable Phantom Limb Pain.” Lancet (London, England) 388,
no. 10062(2016): 2885–2894. https://doi.org/10.1016/S0140-6736(16)31598-7

Ortiz-Catalan, Max, Nichlas Sander, Morten B. Kristoffersen, Bo Håkansson, and Ricard

Brånemark. “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 8, (2014):
24.https://doi.org/10.3389/fnins.2014.00024

Owings, M. F., and L.J. Kozak. “Ambulatory and inpatient procedures in the United States,
1996.” Vital and health statistics. Series 13, Data from the National Health Survey,
no.139 (1998):1–119.

Palus, Shannon, and Sarah Witman. “The Best TENS Unit.” The New York Times, November 11,
2019. https://www.nytimes.com/wirecutter/reviews/best-tens-unit/

Plautz, Erik J., Garrett W. Milliken, and Randolph J. Nudo. “Effects of Repetitive Motor
Training on Movement Representations in Adult Squirrel Monkeys: Role of Use Versus
Learning.” Neurobiology of Learning and Memory 74, no.1 (2000): 27–55.
https://doi.org/10.1006/nlme.1999.3934

Ramachandran, V. S., and Eric L. Altschuler. “The Use of Visual Feedback, in Particular Mirror
Visual Feedback, in Restoring Brain Function.” Brain: A Journal of Neurology 132, no. 7
(2009): 1693–1710. https://doi.org/10.1093/brain/awp135

Robinson, Lawrence R., Joseph M. Czerniecki, Dawn M. Ehde, W. Thomas Edwards, David A.
Judish, Myron L. Goldberg, Kellye M. Campbell, Douglas G. Smith, and Mark P. Jensen.
“Trial of Amitriptyline for Relief of Pain in Amputees: Results of a Randomized
Controlled Study.” Archives of Physical Medicine and Rehabilitation 85, no.1 (2004):
1–6. https://doi.org/10.1016/s0003-9993(03)00476-3

Sherman, Richard, Crystal Sherman, and Norman Gall. “A Survey of Current Phantom Limb
Pain Treatment in the United States” Pain 8, no. 1 (1980): 85–99.
 Kolan 27

https://doi.org/10.1016/0304-3959(80)90092-5

Tomycz, Nestor D., and John J. Moossy. “Follow-up 26 Years After Dorsal Root Entry Zone
Thermocoagulation for Brachial Plexus Avulsion and Phantom Limb Pain.” Journal of
neurosurgery 114, no. 1 (2011): 196–199. https://doi.org/10.3171/2010.5.JNS091520

Viswanathan, Ashwin, Philip Cuong Phan, and Allen W. Burton. “Use of Spinal Cord
Stimulation in the Treatment of Phantom Limb Pain: Case Series and Review of the
Literature.” Pain practice : the official journal of World Institute of Pain 10, no. 5 (2010):
479–484. https://doi.org/10.1111/j.1533-2500.2010.00374.x

Wiffen, Philip J., Henry J. McQuay, Jayne Edwards, and R. Andrew Moore. “Gabapentin for
Acute and Chronic Pain.” The Cochrane Database of Systematic Reviews, no. 3 (2005):
CD005452. https://doi.org/10.1002/14651858.CD005452

Wilder-Smith, Clive H., Lauren T. Hill, and Sophie Laurent. “Postamputation Pain and Sensory
Changes in Treatment-Naive Patients: Characteristics and Responses to Treatment with
Tramadol, Amitriptyline, and Placebo.” Anesthesiology 103, no. 3 (2005): 619–628.
https://doi.org/10.1097/00000542-200509000-00027

Wu, Christopher L., Prabhav Tella, Peter S. Staats, RachelVaslav, Debra A. Kazim, Ursula
Wesselmann, and Srinivasa N. Raja. “Analgesic Effects of Intravenous Lidocaine and
Morphine on Postamputation Pain: A Randomized Double-Blind, Active
Placebo-Controlled, Crossover Trial.” Anesthesiology 96, no. (2002): 841–848.
https://doi.org/10.1097/00000542-200204000-00010

Wu, Christopher L., Shefali Agarwal, Prabhav K. Tella, Brendan Klick, Michael R. Clark,
Jennifer A. Haythornthwaite, Mitchell B. Max, and Srinivasa N. Raja. “Morphine Versus
Mexiletine for Treatment of Postamputation Pain: A Randomized, Placebo-Controlled,
Crossover Trial.” Anesthesiology 109, no.2 (2008): 289–296.
https://doi.org/10.1097/ALN.0b013e31817f4523

Zheng, Z., Y. Hu, W. Tao, X. Zhang, and Y. Li. “Dorsal Root Entry Zone Lesions for Phantom
Limb Pain with Brachial Plexus Avulsion: A Study of Pain and Phantom Limb
Sensation.” Stereotactic and Functional Neurosurgery 87, no. 4 (2009): 249–255.
https://doi.org/10.1159/000225978

Ziegler-Graham, Kathryn, Ellen J. MacKenzie, Pattie L. Ephraim, Thomas G. Travison, and Ron
Brookmeyer.“Estimating the Prevalence of Limb Loss in the United States: 2005 to
2050.” Archives of Physical Medicine and Rehabilitation 89, no. 3 (2008): 422–429.
https://doi.org/10.1016/j.apmr.2007.11.005