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Article Contents

Introduction, case reports and assessments, acknowledgments.

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Contralateral Stimulation, Using TENS, of Phantom Limb Pain: Two Confirmatory Cases

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Orazio Giuffrida, Lyn Simpson, Peter W. Halligan, Contralateral Stimulation, Using TENS, of Phantom Limb Pain: Two Confirmatory Cases, Pain Medicine , Volume 11, Issue 1, January 2010, Pages 133–141, https://doi.org/10.1111/j.1526-4637.2009.00705.x

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Objectives. This study aims to evaluate the effectiveness of trans-electric nerve stimulation (TENS) for phantom limb pain applied to contralateral limb (nonamputated limb).

Design. Two detailed single case studies using TENS on the contralateral limb are reported in a longitudinal study with one-year follow-up. Five variables were measured across this period. The study comprised of five sequential stages (Pre-assessment, Preliminary baseline, Start of intervention, Extended assessment, One-year follow-up).

Setting and Patients. Patients were identified at the Rookwood Hospital in Cardiff. They subsequently received regular home visits. The first patient was a 24-year-old male who had suffered a left below-elbow amputation following a car crash. The second patient was a 38-year-old male who had a transfemoral right amputation further to a viral infection.

Measures. The following semistructured interview and questionnaires were used: McGill Comprehensive pain questionnaire part A and B; The Cambridge Phantom Limb Profile; The Groningen Questionnaire: Problems after Arm Amputation; and 13 Visual Analog Scales.

Conclusions. Both patients showed a significant improvement in their perception of phantom limb pain and sensations that was maintained at one-year follow-up.

A randomized blinded controlled trial to confirm these positive outcomes is required.

Following amputation, most subjects (60–80%) experience phantom limb phenomenon [1] , a constellation of painful and nonpainful sensations localized in or around the phantom limb [2] . Although phantom pain decreases with time [3] , the occurrence of phantom pain is deeply debilitating and independent of age in adults, gender and level, or side of amputation [1] . The etiology of phantom limb pain (PLP) remains unclear, however, painful sensations have been reported in 70% of amputees within the first 2 years [4] and typically persist for years or even decades [5] . Over the past century, many different interventions have been used for PLP, many with little success [6–8] . Recently, following the studies by Ramachandran [9] using of mirror visual feedback (MVF), several clinical studies have confirmed [10,11] striking beneficial effects of MVF on phantom pain.

Another intervention, however, that has shown promise but is less well known is trans-electric nerve stimulation (TENS). This intervention has the benefits of being easy to self-administer, relatively inexpensive, noninvasive, few side effects, and no drug interactions. Several studies highlight the benefits of TENS for post-amputation pain [12,13] , though not all [14] . One interesting but neglected permutation of applying TENS for PLP involves stimulating the contralateral limb (i.e., the healthy limb) rather than the more conventional application to the stump or healthy areas of the affected limb. A systematic review of the literature revealed a small number of published studies, all of which reported the relatively successful outcome of PLP using contralateral TENS stimulation.

The first study [15] to employ contralateral stimulation for PLP involved 46 patients suffering with 13 different chronic pain chronic conditions including five patients with PLP. All clinical conditions were treated with TENS. The intervention consisted of both ipsilateral and contralateral application, but only the latter was used for the five PLP patients reviewed. In this study [15] , 19 patients (41%) showed a significant reduction of the pain (including some with complete extinction), 17 (37%) showed a mild reduction of pain, and in 10 (22%), the stimulation was ineffective. Critically, the patients who benefited most were the five PLP patients. A 9-month follow-up showed that the intervention with the PLP patients demonstrated the greatest improvement for all conditions.

Four years later [16] , a similar study reported 100 patients suffering with chronic pain of various sources including two PLP patients where TENS was applied to the contralateral part of the body. One of these patients reported an excellent response to the treatment and showed a clear reduction in the frequency and intensity of their pain. The second described a moderate reduction in the frequency and intensity of pain.

Another study [17] again produced an encouraging response using TENS applied only to the contralateral limb and resulted in the complete elimination of PLP in three adult patients (aged 48–64 years) with chronic pain originating from various sites of the amputated extremity. The results at 6-month follow-up showed no pain recurrence of PLP such that that all patients were able to avail of prosthetic training.

In 1985 [18] , a similar treatment for PLP in a group of amputees using cutaneous electrical stimulation applied to the contralateral limb was reported. The 10 subjects aged between 28 years and 63 years had PLP following amputation of a lower limb. The results were impressive; in 8 of the 10 patients, PLP disappeared after 1 minute or 2 minutes typically at the beginning of the session. Two patients reported partial reduction of PLP.

Finally, in 1989 [19] , a detailed case study of TENS applied to the contralateral lower leg in a case of PLP was described. This is the only study in which the placebo effect was compared directly with contralateral TENS stimulation to study the efficacy of this treatment for PLP. In this experiment, the researchers alternated and combined baseline (placebo) with bilateral ear (auricular) stimulation and contralateral TENS. During the placebo session, no stimulation was carried out. This session was performed in such a way that the participant believed that electric stimulation was delivered using a very low intensity. The results showed that TENS applied to the contralateral limb was significantly more effective than placebo in helping to reduce the intensity of phantom sensations. Stimulation of the outer ears did not produce a significant decrease in phantom sensations.

Although differing in details and follow-up, the five mentioned previous studies employed similar methodology with promising results. None, however, differentiated among PLP, phantom limb sensation (PLS), and stump pain (SP), and no distinction was made among frequency, intensity, and duration of the different pains. Finally, minimal theoretical explanation was provided to explain the potential mechanisms underpinning the intervention.

To replicate and extend previous studies by including improved controlled conditions, two new patients with chronic PLP were evaluated. The aims were to 1) establish the effectiveness of TENS when applied to those selective areas on the intact contralateral limb that mirrored the felt location on the phantom limb; 2) characterize the frequency, intensity, and duration of the pain throughout the intervention period; and, finally, 3) document the differential effectiveness of the intervention on PLS, PLP, and SP at follow-up.

Although several patients were considered, only two patients were considered, given the inclusion/exclusion criteria. Inclusion criteria: Patients had to have PLP for a minimum period of 1 year with little or minimal improvement in the perception of PLP since amputation. In terms of exclusion criteria, subjects had to be adults (aged between 18 and 60) without psychiatric diagnosis and no previous psychiatric history. Eight patients with PLP were originally identified, but only four of these met the inclusion/exclusion criteria. Two of these subsequently agreed to participate in the study.

Same assessment methods were used with both patients. However, as the first participant (FG) had suffered upper limb amputation and the second (SL) suffered above-knee amputation, the Gronigen Questionnaire [20] was adapted for use with a lower limb amputation. The adaptation was carried out by simply substituting the word “arm” with the word “leg.” Moreover, as SL had never reported SP, these were not recorded.

FG was a 24-year-old man who had suffered a left below-elbow amputation following a car crash. FG reported PLP for a period of 12 months, at which time the current interventions began. His pain started soon after the amputation of his arm and had not changed significantly. FG reported a number of symptoms that accompanied his phantom pain including blurred vision, dizziness, excessive sweating, fatigue, nausea, and skin temperature change. The pain was located in his left phantom hand, extending to the tip of his phantom thumb.

As first assessment, FG was coping with his pain by using painkillers (6 doses of gabapentin—mg 300—a week and 6 doses of tramadol—mg 300—a week). The initial assessment also discovered that physical factors such as cold, heat, massage, and changes in the weather increased his pain as did emotional events such as anger, fatigue, and frustration.

SL was a 38-year-old male who had a transfemoral right amputation further to a viral infection. SL suffered a motorbike accident 10 years before the amputation. Three years after the accident, he had a fused knee, and 7 years later, amputation of the leg was necessary due to viral infection. He reported that his PLP started soon after the amputation, which had been carried out 23 months before this study. During that period of time, he claimed that the pain, while diminished, was uncontrolled. The degree of pain relief improvement, however, was minimal (and hence, in accordance with our inclusion criteria).

Pains were localized in the phantom muscle and/or skin. He also described it as continuous, steady, and constant. SL described several locations where he felt pain in his phantom right leg, with the most painful points being the top of the shin just below the knee and the top of his right foot matching the area of the extensor digitorum brevis muscle.

The intervention period consisted of 3 months of contralateral TENS stimulation, using five variables that were monitored before, during, and after the trial. Patients were instructed to apply four rubber electrodes connected to the TENS stimulator to their contralateral limb at precise point(s) corresponding to the maximum pain each time they felt pain for a period not exceeding 60 minutes. Each machine delivered a constant source of electric stimulation with a frequency of 80 Hz and a pulse width of 50. The intensity (ampere) of the stimulation was regulated by each participant individually. Patients were instructed to regulate the machine until they experienced strong, but not painful, stimulation. The variables measured before, during, and after the trial period were:

Overall use of prostheses (measured in hours), and

Number of coping strategies used.

PLP, PLS, and SP were measured for intensity, duration, and frequency. The study design comprised five sequential different stages.

Pre-assessment—involving a preliminary questionnaire (McGill Comprehensive Pain Questionnaire—part A only) [21] sent to the participant before first formal appointment; this assessment was carried out to collect important screening information such as the quality and quantity of PLP and PLS, the location of their pain, etc.

The Comprehensive Pain Questionnaire interview guide—part B [21] ;

The Cambridge Phantom Limb Profile (CPLP) [22] ; this is a questionnaire concerning PLP, PLS, and SP. For each variable, intensity, frequency, and duration of the phenomenon were assessed using rating scales varying from 0 to 5;

The Groningen Questionnaire: Problems after Arm Amputation (GQPAA) [20] , a questionnaire assessing PLS, PLP, SP, the use of prostheses, and also rating the intensity, duration, and frequency of those variables;

The 13 visual analog scales (VAS), measuring PLP, PLS, SP, the use of prostheses, and coping strategies. This offered the possibility to measure those same variables using a continuous scale moving from 0 to 10.

Further screening information was also obtained. As part of this assessment, we provided participants with the opportunity to report any changes regarding the quality and quantity of their PLP since amputation.

Start of intervention that lasted 3 months—TENS treatment. This treatment stage started a week after the baseline assessment was obtained. Participants used TENS on their contralateral limb. Training was provided. Patients were instructed to apply the TENS each time the pain occurred to the contralateral sites where the phantom pain was experienced on the amputated limb for a period not exceeding 60 minutes. During the period of the active intervention, the subjects met with the researcher four times, where the CPLP [22] , GQPAA [20] , and 13 VAS were completed. The assessments carried out during this stage were administrated at regular intervals of 3 weeks. However, as the treatment stage started a week after the baseline measures were completed, the time interval between baseline and first treatment assessment was 4 weeks.

Extended assessment at the end of the 3 months treatment period; the assessments described in stages 1 and 2 were repeated. During this assessment, further information regarding how PLP, PLS, and SP changed in time were also collected.

Follow-up: 1 year following end of intervention, participants were contacted for a follow-up interview. During the interview, the CPLP, GQPAA, and 13 VAS were completed.

PLP was evaluated at six different stages and involved evaluations of frequency, intensity, and duration . The first assessments served as a stable baseline, three assessments were carried out during the treatment, an interim assessment at the end of the 3 months intervention, and finally, the last assessment 1 year from the end of the intervention (follow-up). Frequency of the PLP involved a combined measure of the following three measures: VAS (0–10); CPLP (0–4); and GQPAA (0–6). This aggregate score was generated by transforming the results of the two rating scales to a continuous variable score using proportional mathematical transformations and adding these to the VAS score. These scores were subsequently averaged to obtain a more reliable measure of the variable under observation. Similar results were obtained for intensity of PLP. As CPLP and GQPAA did not contain rating scales to estimate the duration of each episode, duration was measured using a VAS only.

Figure 1 shows how both patients rated frequency, intensity, and duration of their PLP (dashed lines = patient SL; solid lines = patient FG). In the case of FG, the ratings for frequency, intensity, and duration of PLP consistently decreased during intervention and 1-year follow-up. This figure also shows that the frequency and duration of PLP for SL had also clearly decreased by comparison with the original baseline. Moreover, these changes were maintained at the 1-year follow-up. Although the intensity of PLP for SL showed decreases in comparison with the original baseline, the changes reported were marginal. In the case of SL, all three measures consistently decreased prior to their complete elimination during the third planned assessment.

Changes on the three different indexes of phantom limb pain (PLP) in time. Point 1 shows the pretreatment baseline. Points 2, 3, 4, and 5 show the perception of PLP across the 3 months treatment stage (an assessment every 3 weeks). The time interval between baseline and assessment 1 was, however, 4 weeks. Point 6 shows the perception of PLP at 1-year follow-up. The top graph shows data regarding the intensity of PLP, the middle graph shows the duration, and the bottom graph shows the frequency. Dashed lines show the performance of SL. Solid lines show the performances of FG.

Changes on the three different indexes of phantom limb pain (PLP) in time. Point 1 shows the pretreatment baseline. Points 2, 3, 4, and 5 show the perception of PLP across the 3 months treatment stage (an assessment every 3 weeks). The time interval between baseline and assessment 1 was, however, 4 weeks. Point 6 shows the perception of PLP at 1-year follow-up. The top graph shows data regarding the intensity of PLP, the middle graph shows the duration, and the bottom graph shows the frequency. Dashed lines show the performance of SL. Solid lines show the performances of FG.

To better understand changes in PLS, four different measures were employed: 1) frequency, 2) intensity, 3) duration, and 4) the number of describing words used. Frequency was assessed using the same procedure as PLP. Intensity was measured by combining the results of the rating scale in GQPAA with the results of a new VAS, whereas duration of PLS was simply assessed using a single rating scale. Finally, the number of words used to describe PLS was measured by asking the participant to select some of the words from a list presented in the GQPAA.

Figure 2 charts the changes for PLS during the 3-month treatment and at the 1-year follow-up. For patient FG (solid lines), the graph shows that the frequency, intensity, and duration of PLS had significantly decreased. These changes were maintained at 12 months. There were no changes in the number of words (“itching,”“abnormal shape,” and “cold”) selected to describe PLS across assessments, suggesting that the quality of sensations has not changed.

Changes on the three different indexes of phantom limb sensations (PLS) in time. Point 1 shows the pretreatment baseline. Points 2, 3, 4, and 5 show the perception of PLS across the 3 months treatment stage (an assessment every 3 weeks). The time interval between baseline and assessment 1 was, however, 4 weeks. Point 6 shows the perception of PLS at 1-year follow-up. The top graph shows data regarding the intensity of PLS, the middle graph shows the duration, and the bottom graph shows the frequency. Dashed lines show the performance of SL. Solid lines show the performances of FG.

Changes on the three different indexes of phantom limb sensations (PLS) in time. Point 1 shows the pretreatment baseline. Points 2, 3, 4, and 5 show the perception of PLS across the 3 months treatment stage (an assessment every 3 weeks). The time interval between baseline and assessment 1 was, however, 4 weeks. Point 6 shows the perception of PLS at 1-year follow-up. The top graph shows data regarding the intensity of PLS, the middle graph shows the duration, and the bottom graph shows the frequency. Dashed lines show the performance of SL. Solid lines show the performances of FG.

In the case of SL (dashed lines), the results show a constant continuous decrement in the perception of PLS. Although intensity, duration, and frequency continuously decreased across time, these changes are relatively small when compared with changes showed by the same participants for PLP. Again, the words used by SL to describe the PLS did not change across time.

As with the previous two variables, frequency, intensity, and duration of each episode were measured. To rate the frequency and intensity of SP, the GQPAA and two different VAS (one for intensity and the other for frequency) were used. The two rating scales were transformed and averaged as previously described for other variables. To measure duration of the episodes of SP, a single VAS was used. Figure 3 shows the changes during the 3-month treatment and at the 1-year follow-up for FG (solid lines). SL never reported SP. Data regarding SL SP is not consequently reported in this graph. The graph clearly shows that FG's frequency, intensity, and duration of SP had decreased and were maintained at the 1-year follow-up.

Changes on the three different indexes of stump pain (SP) in time. Point 1 shows the pretreatment baseline. Points 2, 3, 4, and 5 show the perception of SP across the 3 months treatment stage (an assessment every 3 weeks). The time interval between baseline and assessment 1 was, however, 4 weeks. Point 6 shows the perception of SP at 1-year follow-up. The top graph shows data regarding the intensity of PLS, the middle graph shows the duration, and the bottom graph shows the frequency. This graph shows only the data regarding FG as SL never reported SP.

Changes on the three different indexes of stump pain (SP) in time. Point 1 shows the pretreatment baseline. Points 2, 3, 4, and 5 show the perception of SP across the 3 months treatment stage (an assessment every 3 weeks). The time interval between baseline and assessment 1 was, however, 4 weeks. Point 6 shows the perception of SP at 1-year follow-up. The top graph shows data regarding the intensity of PLS, the middle graph shows the duration, and the bottom graph shows the frequency. This graph shows only the data regarding FG as SL never reported SP.

Overall Use of Prostheses

No changes regarding overall use of the prostheses was recorded for both patients during the trial and at 1-year follow-up.

Number of Coping Strategies

Finally, the numbers of coping strategies used by participants across the trial and at 1-year follow-up were evaluated. Three VAS were used, for PLP, PLS, and SP consecutively. Figure 4 shows the changes during the 3-month intervention and at 1-year follow-up.

The graph shows the number of coping strategies used by each participant in a daily scale moving from 0 to 10. Coping strategies were calculated separately for phantom limb pain, phantom limb sensation, and stump pain. Point 1 shows the pretreatment baseline. Points 2, 3, 4, and 5 show the number of coping strategies across the 3 months treatment stage (an assessment every 3 weeks). The time interval between baseline and assessment 1 was, however, 4 weeks. Point 6 shows the number of coping strategies at 1-year follow-up. Dashed lines show the performance of SL. Solid lines show the performances of FG. SL never reported stump pain. SL often reported not using any conscious coping strategy.

The graph shows the number of coping strategies used by each participant in a daily scale moving from 0 to 10. Coping strategies were calculated separately for phantom limb pain, phantom limb sensation, and stump pain. Point 1 shows the pretreatment baseline. Points 2, 3, 4, and 5 show the number of coping strategies across the 3 months treatment stage (an assessment every 3 weeks). The time interval between baseline and assessment 1 was, however, 4 weeks. Point 6 shows the number of coping strategies at 1-year follow-up. Dashed lines show the performance of SL. Solid lines show the performances of FG. SL never reported stump pain. SL often reported not using any conscious coping strategy.

For FG (solid lines), it can be seen that while the overall use of coping strategies did not change across time for PLP and PLS, the use of coping strategies for SP decreased, keeping with the continuous decrement in frequency, intensity, and duration of SP. In the case of SL (dashed lines), the graph shows that the number of coping strategies did not change over time, and one can assume that coping strategies did not play any significant role in relation to the previous mentioned changes in PLP and PLS.

Overall, observation on the five key factors showed that FG experienced a functional improvement in both the experience and management of PLP, PLS, and SP, despite initial reporting that his PLP was stable in the year prior to intervention. These improvements were unrelated to the use of prostheses and/or the use of coping strategies, which remained largely unchanged. At the end of the 3-month intervention trial, FG decided to keep the TENS equipment and to continue to use it when pain occurred. However, at the 1-year follow-up, he reported that he had stopped using the equipment 6 months previously. Although FG showed a substantial improvement, PLP, PLS, and SP were not completely eliminated. These single-case results support those previously reported [16,19,20] , all of which found a significant improvement in patients treated with contralateral TENS.

SL also showed that contralateral TENS had contributed to decreasing his perception of PLP and PLS. While SL showed a greater improvement in PLP (decreased in frequency, intensity, and duration), the improvements in PLS were more marginal. However, the improvement achieved was maintained at the 1-year follow-up. SL kept the TENS machine at the end of the 3-month trial as he considered it beneficial. However, at the 1-year follow-up, he reported having ceased to use the machine systematically.

Although the current case studies show that both participants improved following contralateral TENS treatment, we cannot rule out the contribution played by an inadvertent placebo effect, and/or paying regular attention to their phantom limb—although the latter was more likely to be associated with an increase in pain.

Contralateral Limb Stimulation and PLP

Despite limited number of studies, the current study, together with previous reports, suggests that contralateral stimulation of PLP represents a promising intervention in need of further evaluation. Working back from the clinical findings to a theoretical explanation, however, is not immediately obvious. Animal models highlight changes to the dorsal horn of the spinal cord following amputation. These changes lead to central sensitization, comprising enduring changes in the responsiveness of synapses of the dorsal horn of the spinal cord [23] . This can result in a reorganization of the spinal cord sensory map [24] such that receptive fields on the skin close to the amputated limb shift into regions of the spinal cord previously occupied by the limb. However, because spinal anesthesia does not prevent PLP [25] , it would appear that such spinal cord changes do not provide the full picture.

Supraspinal changes have been extensively employed to explain the origins and maintenance of PLP [26] . Moreover, amputation of the finger of an owl monkey produced up to 2 mm “invasion” of contiguous areas into the cortical representation of the amputated finger [26] . The most commonly studied supraspinal changes following limb amputation in humans using functional imaging and behavioral studies have shown evidence of extensive remappings of the contralateral somatosensory cortex and thalamus [27,28] . Support for remapping comes from studies using functional magnetic resonance imaging and magnetoencephalography. An investigation of cortical reorganization in 13 upper limb amputees has found evidence that the area of the brain representing an amputated part of the body could be used by the neighboring cortical areas [29] . Similarly, several cases in which, following arm amputation, a precise topographically organized map of the amputated hand was identified on the ipsi-amputational face and shoulder have been reported [27] . These findings were subsequently confirmed and extended in studies that showed that the original topographic and apparently exclusive ipsi-amputational-referred sensations could change with time [28,30] . Within a year, in patients who suffered a limb amputation, multiple areas on the contra-amputational side of the face were now able to elicit referred sensations in the phantom limb, implying that homotopic regions of primary somatosensory cortex were linked between the hemispheres [28,30] . Animal research also showed that plasticity induced in one hemisphere, in the form of receptive field expansion brought about by small peripheral denervation, was mirrored in the other hemisphere without such neurons displaying any responsiveness to stimulation of the ipsilateral body surface [31] .

It has been previously suggested [27] that this extensive cortical/subcortical remapping may affect the functionality of the gate control system for moderating pain [32] . The process of remapping could alter this, amplifying painful sensations associated to the missing limb. The theory that remapping is associated with PLP was also discussed in a study [32] in which it was argued that the lack of afferent signals caused by the amputation affects the neuromatrix triggering abnormal firing in substitution. Consequently [32] , TENS works because it replaces or substitutes for the lack of afferent signals. In the case of contralateral stimulation, topographically relevant afferent signals from the intact limb accessed through trancallosal fibers linking up homotopic parts of the brain activate cortical areas representing the de-afferenated limb. Assuming that a key source of PLP is caused by the lack of appropriate afferent signals, then it would appear that reinstating the missing lateral inhibition even for a short period might help alleviate or prevent the pain. This is realized by stimulating the relevant homotopic area of the body contralateral to the missing limb, i.e., by stimulating the areas on the intact limb that approximates to the pain felt in the phantom. This account assumes that inputs help reinstate the lateral inhibition normally generated from stimulating a homotopic ipsilateral body surface. In support of this speculation, there is literature reporting contralateral responses to unilateral lesions and/or stimulations. A review of 18 studies where a unilateral lesion(s) caused contralateral effects [33] showed that contralateral responses to unilateral neurological lesions were common between species and have been reported in rats, guinea pigs, frogs, cats, mice, and ferrets. This phenomenon was considered to be mediated via neurological mechanisms that cross through the spinal cord [33] . Although the two sides of the spinal cord have been traditionally described as being functionally independent, there are three main lines of research that suggest that this is not the case [34–36] .

In 2000 [37] , it was suggested that because phantom pain was, in part, a response to the discrepancy between vision and proprioception, MVF could act by restoring the congruence between motor output and sensory input. It is possible that contralateral stimulation works by changing previous cortical reorganization with corresponding reduction of pain. In particular, contralateral stimulation results from the way in which precise topographical activations compensate for the lack of afferent signals by reinstating (albeit temporarily) normal lateral inhibition on the ipsilateral side. Following the previously mentioned review [33] , we speculate that the stimulation caused by contralateral stimulation could initially activate the contralateral spinal cord and subsequently reinstate (even partially) the lack of afferent signals given by the amputated limb. This mechanism could then offer a feedback that would prevent the perception of PLP. Systematic research is therefore needed to test the validity of this speculation.

Our results, together with those previous studies reviewed, show that there is sufficient clinical evidence to warrant further more rigorous evaluation and suggest that in the future, this promising technique warrants a more definitive and larger randomized, observer-blinded trial of contralateral stimulation vs stump stimulation to establish its potential efficacy.

The authors acknowledge the cooperation of ALAC, Rookwood Hospital, Cardiff and Vale NHS Trust, and the Medical Research Council.

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  • Approaches to neuropathic amputation-related pain: narrative review of surgical, interventional, and medical treatments
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  • Adrian N Markewych 1 ,
  • Tolga Suvar 2 ,
  • Marco A Swanson 3 ,
  • Mateusz J Graca 2 ,
  • Timothy R Lubenow 2 ,
  • http://orcid.org/0000-0002-0966-5311 Robert J McCarthy 2 ,
  • Asokumar Buvanendran 2 and
  • David E Kurlander 4
  • 1 Rush University Medical College , Chicago , Illinois , USA
  • 2 Department of Anesthesiology , Rush University Medical Center , Chicago , Illinois , USA
  • 3 Department of Plastic & Reconstructive Surgery , Cleveland Clinic Foundation , Cleveland , Ohio , USA
  • 4 Department of Plastic & Reconstructive Surgery , Rush University Medical Center , Chicago , Illinois , USA
  • Correspondence to Dr Robert J McCarthy, Department of Anesthesiology, Rush University Medical Center, Chicago, Illinois, USA; Robert_J_McCarthy{at}rush.edu

Background/importance Neuropathic amputation-related pain can consist of phantom limb pain (PLP), residual limb pain (RLP), or a combination of both pathologies. Estimated of lifetime prevalence of pain and after amputation ranges between 8% and 72%.

Objective This narrative review aims to summarize the surgical and non-surgical treatment options for amputation-related neuropathic pain to aid in developing optimized multidisciplinary and multimodal treatment plans that leverage multidisciplinary care.

Evidence review A search of the English literature using the following keywords was performed: PLP, amputation pain, RLP. Abstract and full-text articles were evaluated for surgical treatments, medical management, regional anesthesia, peripheral block, neuromodulation, spinal cord stimulation, dorsal root ganglia, and peripheral nerve stimulation.

Findings The evidence supporting most if not all interventions for PLP are inconclusive and lack high certainty. Targeted muscle reinnervation and regional peripheral nerve interface are the leading surgical treatment options for reducing neuroma formation and reducing PLP. Non-surgical options include pharmaceutical therapy, regional interventional techniques and behavioral therapies that can benefit certain patients. There is a growing evidence that neuromodulation at the spinal cord or the dorsal root ganglia and/or peripheral nerves can be an adjuvant therapy for PLP.

Conclusions Multimodal approaches combining pharmacotherapy, surgery and invasive neuromodulation procedures would appear to be the most promising strategy for preventive and treating PLP and RLP. Future efforts should focus on cross-disciplinary education to increase awareness of treatment options exploring best practices for preventing pain at the time of amputation and enhancing treatment of chronic postamputation pain.

  • Pain Management
  • CHRONIC PAIN
  • Spinal Cord Stimulation

https://doi.org/10.1136/rapm-2023-105089

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Introduction

Neuropathic amputation-related pain can be challenging to treat. In the USA, there will be an estimated 3.6 million patients with amputations by the year 2050. 1 Neuropathic amputation-related pain may encompass phantom limb pain (PLP) or residual limb pain (RLP), with many patients having elements of both. PLP is present in 60%–80% of patients with amputation and refers to the perception of discomfort in a limb that no longer exists. 2–4 Phantom sensations are benign but potentially unsettling feeling of a limb after amputation. 5 RLP localizes to the residual extremity. RLP is often associated with symptomatic neuroma formation 6 but also can be related to an inadequate soft tissue envelope or heterotopic ossification. 7–10

Amputation-related pain, particularly PLP, is an incompletely understood pathophysiological phenomenon that includes both peripheral and central nervous system components. Changes in both the peripheral and central nervous system occur after amputation, and that these changes may likely contribute to the pathophysiology of PLP. Changes in the peripheral nerve system include deafferentation, neuroma formation and enhancing hyperexcitability of distally severed nerves. 11 12 Persistence of chronic PLP even after peripheral treatment suggests central nervous system contribution. 4 Flor et al found a correlation between PLP and extent of cortical reorganization. 13 There is also evidence that subcortical mechanisms are present as thalamic stimulation can lead to phantom sensations in amputees. 14

Central changes are present at both the level of the spinal cord and brain. Changes at the level of the spinal cord include activation of spinal wide dynamic range neurons by the increased activity of N-methyl-D-aspartate (NMDA) receptors, followed by a “windup phenomenon” that changes the firing pattern of central nociceptive neurons. There may also be decreased descending inhibitory transmission from supraspinal centers. 11 Changes at the level of the brain include cortical reorganization, largely by overgrowing areas of the somatosensory and motor cortex that neighbor the amputated limb. Changes in the medial and lateral pain systems involving limbic and thalamocortical components contribute to the localization and nociceptive of the pain. 15

The optimal treatment approach to these complex patients is yet to be defined and cross-disciplinary education of current practice standards and efficacy of treatment methods in each domain is lacking. The population of patients who undergo amputations is very heterogeneous. PLP occurs after 32% of upper extremity and 34% of lower extremity amputations. 16 17 Indication for upper extremity amputations is more likely to be oncological or related to trauma; whereas patients undergoing lower extremity amputations are more likely to have comorbidities such as diabetes and vascular insufficiency.

This narrative review will focus on prevention and treatment options for neuropathic amputation-related pain, including medical, surgical, and interventional approaches. Non-neuropathic postamputation pain related to an inadequate soft tissue envelope, heterotopic ossification, infection, or vascular insufficiency will not be covered in this review. This article presents a narrative review of the literature available for medical, surgical, and interventional, PLP therapies.

The search strategy was developed with the aid of a research librarian to identify studies of medical, surgical and interventional pain therapies for treatment of PLP. A broad search strategy was employed based on terms for PLP including PLP, RLP and amputation pain. No date, language, geographical or study design limits were applied to the strategy. The following databases were searched: MEDLINE (including Epub Ahead of Print, In-Process & Other Non-Indexed Citations, via Ovid MEDLINE Daily and via Ovid MEDLINE), and Embase via Ovid. The searches, including abstracts, were imported into Microsoft Access and structure query language tools were used to remove duplicates. The titles and abstracts were then searched for the following keywords: surgery, targeted muscle reinnervation, regenerative peripheral nerve interface, neuroma, medical therapies, neuromodulation, spinal cord stimulation, dorsal root ganglion stimulation, peripheral nerve stimulation, mirror visual therapy, behavioral therapy, epidural anesthesia, anticonvulsants, antidepressants, capsaicin, cannabis, propranolol, tramadol, opioids, NMDA receptor antagonists, botulinum toxin. Abstracts and full text were reviewed by two authors for each of the following categories; medication/behavioral related (RJM and MJG), surgical related (ANM, DEK, and MAS), interventional pain therapies and neuromodulation (TS and AB). Full articles were retrieved whenever possible.

Overall, 3040 records were retrieved from the searches. Figure 1 shows the details of the number of references excluded at each stage.

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Flow diagram of studies through the review. Full length manuscripts reviewed for this review included: RCT single center (n=29), RCT multicenter (n=4), prospective clinical study (n=46), retrospective clinical study (n=42), cross-sectional study (n=24), case reports single case (n=79), multiple cases or series (n=69), non-human subjects research (n=13), review articles general (n=68), narrative (n=6), scoping (n=3), systematic (n=15), methods or techniques (n=3), editorials (n=6), letters or correspondence (n=16), and conference proceedings (n=3). RCT, randomized clinical trial.

Medical treatments

Pathophysiological sources of PLP can be related to changes in peripheral nerves with sprouting of neuromas and spontaneous nerve activity, changes in sensitization at the spinal cord level with expansion of the neuronal receptive fields and changes at the cortical level with reorganization of the region of the amputated limb into neighboring somatosensory and motor areas. 3 Evidence of a peripheral contribution includes the finding that perineuronal stump injections of norepinephrine increase PLP, 18 while lidocaine decreased PLP when administered in a similar manner. 19 In addition to changes in the peripheral and central nervous system infection and depression can mediate PLP. The overall goal of medical management is to disrupt the cycle of abnormal signaling along the peripheral and central pathways that contribute to PLP. Pharmacological agents that are used to treat PLP target peripheral nerve firing, spinal cord wind-up, and central sensitization. By targeting neurotransmitter release, ion channel function, and neuronal excitability, these medications collectively work to modulate pain signaling at different levels of the nervous system.

Peripheral nerve firing

The use of medications in PLP often involves agents that modulate peripheral nerve firing such as anticonvulsant drugs (carbamazepine, gabapentin) and tricyclic antidepressants (amitriptyline) which act on ion channels and neurotransmitter release at the peripheral nerve endings. By stabilizing neuronal membranes and inhibiting excitatory neurotransmitter release, these medications help reduce abnormal firing of peripheral nerves. This modulation is essential for dampening the increased signaling that contributes to the generation of PLP.

Dorsal root wind-up phenomenon

Dorsal root wind-up refers to the amplification of pain signals at the spinal cord level, leading to increased sensitivity to painful stimuli. Medications that target this phenomenon often include NMDA receptor antagonists such as memantine or ketamine. By inhibiting NMDA receptors, these drugs help attenuate the wind-up phenomenon by preventing excessive activation of spinal neurons.

Central sensitization

Central sensitization is a key component of chronic pain conditions, including PLP. Medications used in the treatment of PLP often have central nervous system effects that impact the processes of central sensitization. Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) influence descending inhibitory pathways, thereby reducing hyperexcitability of central neurons. Opioids are another treatment option which modulates pain perception at the central level by acting on opioid receptors in the spinal cord and brain.

The management of PLP syndrome can be challenging, and various medications are used to alleviate symptoms. It is important to understand that responses to medications can vary among individuals and dosing is frequently limited by side effects.

Drug classes used in treating chronic PLP

Anticonvulsants.

Anticonvulsant medications have been reported to be used in the treatment of PLP. Gabapentin and pregabalin inhibit alpha 2 /delta-1 subunit of voltage-gated calcium channels and carbamazepine inhibits sodium-channel activity. Gabapentin and pregabalin are effective in treating many neuropathic pain conditions, however, evidence of their effectiveness in treating PLP is modest. 20–25 Carbamazepine has been used to treat PLP since the 1970s, but no clinical trials support it use. 26–28 Topiramate and lamotrigine have been reported to provide analgesic benefit in cases with PLP and RLP. 29 30

Antidepressants

Antidepressant medications are often useful in the treatment of most neuropathic conditions, however, their utility in PLP treatment is less clear. 31 In a randomized clinical trial, Wilder-Smith et al demonstrated the effectiveness of tramadol and amitriptyline compared with placebo for postamputation pain in naïve patients compared with placebo. 32 Tricyclic antidepressants such as amitriptyline, desipramine and nortriptyline have more evidence for treating PLP than SSRIs, such as fluoxetine, or SNRIs, such as duloxetine. 33–35

Nonsteroidal anti-inflammatory drugs

Many patients suffering from PLP regularly take non-steroidal anti-inflammatory drugs or acetaminophen for their anti-inflammatory and analgesic properties with reported decrease in pain. 36 These medications decrease prostaglandin synthesis both peripherally and centrally. While they may not directly address neuropathic pain, they can be part of a comprehensive pain management plan.

Topical agents

Topical medications such as lidocaine and capsaicin have been used to treat PLP. Capsaicin interacts with the transient receptor potential vanilloid 1 (TRPV1) receptor, which is present in peripheral sensory nerve endings. The use of this medication in patients with PLP desensitizes the nerves by activating the TRPV1 receptor. Capsaicin 8% has been shown to reduce PLP symptoms after a single application. 37 In a function MRI study, 8% capsaicin demonstrated restoration the brain map in subjects with PLP. 38 Topical formulation of lidocaine can be applied directly to the skin of the residual limb. Lidocaine has demonstrated utility in other neuropathic conditions, but no reports specifically have looked at PLP. 39 40

Cannabinoids

Cannabinoids (delta-9-tetrahydrocannabinol and cannabidiol) regulate pain perception mainly by modulating pain receptors in the central nervous system. The endocannabinoid system is involved in the regulation of pain, inflammation, and neuronal activity. Dunn and Davis reported that 4 of 10 patients with PLP reported decrease pain in response to cannabis use. 41

Beta blockers

Cases of improvement in PLP have been reported with the administration of propranolol. 42 43 Propranolol has been reported to improve PLP symptoms and reducing the intensity of PLP pain. Its mechanism in pain management is not fully understood but may involve modulation of sympathetic nervous system activity.

Opioid medications have been used to treat patients with PLP, although they are associated with significant side effects, including sedation, constipation, dependence, among others. 44 Chronic opioid use in patient with PLP is estimated to be as prevalent as 45% following lower extremity amputation. 45 The therapeutic benefit from opioids is believed to be due to the opioid-induced prevention of cortical reorganization, which is a proposed contributor to PLP. 46 47 Morphine was shown to improve PLP compared with mexiletine but with greater side effects. 48 A morphine injection followed by an infusion for demonstrated significant reductions in both stump as well as PLP, whereas lidocaine administered in both bolus and infusion only reduced stump pain. 49 Methadone and buprenorphine/naloxone have also been reported to be effective in PLP. 50 51

NMDA receptor antagonists

PLP neuroplastic changes are partly mediated by excitatory amino acids such as glutamate acting at NMDA ion channels throughout the central nervous system. Increased calcium flux has a key role in synaptic function, plasticity, learning and memory. NMDA antagonists such as ketamine, memantine and dextromethorphan have been evaluated for treatment of PLP. Ketamine has poor bioavailability as an oral formulation but has shown to reduce PLP when administered as four intravenous infusions at 0.4 mg/kg. 52 Memantine has been shown to reduce acute PLP but had limited effect in PLP that had persisted past 1 year. 53–56 In a limited number of patients, dextromethorphan demonstrated reduced acute PLP. 57 58

Botulinum toxin

Injection of botulinum toxin type A into the residual stump using electromyogram control has been shown to increase global clinical improvement in a small case series. 59 In a larger series of cases, botulinum toxin type B reduced RLP and decreased hyperhidrosis but not PLP at 3 months after treatment. 60

A synopsis of the evidence and support for use in PLP treatment are summarized in table 1 .

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Pharmacological classes and supporting evidence for treatment of chronic phantom and residual limb pain

Behavioral therapies

Psychiatric disorders such as depression, anxiety and mood disorders have an increase in the prevalence following amputation or deafferentation of a limb. 21 Behavioral therapies that have been used in treatment of PLP include sensory motor training, mirror visual therapy and virtual reality. Mirror visual therapy works by placing a mirror at the observer’s medial line and having them use the intact limb to produce voluntary movements. The reflection of the movements creates a visual illusion of non-painful movement of the phantomlimb. 21 It is believed that this helps to restore the original organization of the somatosensory and motor cortex. A systematic review of mirror visual therapy from four studies found significant improvements in pain following lower limb amputation, but there are inadequate data to compare with other interventions. 61 Virtual reality gaming is like mirror visual training but uses a virtual gaming environment to simulate non-painful movements of the limbs. 62

Surgical treatments

Traditional surgical approaches to chronic neuropathic PLP and RLP have generally targeted symptomatic neuromas and have attempted to “bury the neuroma” to minimize symptoms. An example of this is traction neurectomy or implantation of a transected nerve end into muscle. More recently, active treatments for amputation-related pain have been supported to give the nerve “somewhere to go and something to do”. 63 Examples of these procedures include targeted muscle reinnervation and regenerative peripheral nerve interface which targets the underlying pathophysiology behind the neuropathic pain ( figure 2 ). After axonal injury, sensory free nerve endings seek a distal connection to heal and reinnervate. When unable to reinnervate, the nerve undergoes Wallerian degeneration, resulting in neuroma formation, and neuropathic pain. 11 These interventions prevent such degeneration and can be performed at the time of amputation to prevent pain or to treat chronic amputation-related pain.

Surgical approaches to phantom limb pain (PLP) management. Targeted muscle reinnervation involves the transfer of a transected sensory or sensorimotor nerve to a nearby purposefully denervated motor branch. Regional peripheral nerve interface involves capping a transected sensorimotor nerve with a free muscle graft, providing a site for regenerating the nerve. Targeted muscle reinnervation and regional peripheral nerve interface are the leading surgical techniques for reducing PLP neuroma formation and improving postoperative options for future myoelectric prostheses control.

Traditional surgical treatments

At the time of amputation, traction neurectomy is traditionally performed for major nerves. 64 In traction neurectomy, the nerve is divided under distal traction allowing for retraction of the nerve into the more proximal soft tissues, and the surrounding soft tissue acts as a cushion to physically protect the neuroma from mechanically induced trauma and depolarization. 65 For patients with chronic neuroma pain, the neuroma can be excised, and the residual nerve treated with traction neurectomy, nerve cap, implantation into bone or muscle, or neurolysis. 12 The evidence for these passive treatments is mixed. Poppler et al completed a meta-analysis of 54 articles and found that the surgical treatment of neuroma pain was effective in 77% of patients. 66 The study did not find a significant difference in pain reduction between the passive surgical techniques. Sehirlioglu et al retrospectively assessed 75 patients who experienced war-related traumatic amputations. 67 Each patient underwent traction neurectomy for neuroma pain and was pain-free at a mean follow-up of 2.8 years. In a retrospective cohort study of 38 patients and 63 nerves, Pet et al found persistence or recurrence of neuroma-type pain in 42% of patients who underwent traction neurectomy. 65

A retrospective study of 35 patients assessed implantation of transected nerves into muscle. This study found that 92% of patients who underwent implantation into muscle at the time of amputation and 87% who underwent implantation into muscle for neuroma treatment were free of neuroma pain. 68 Rungprai et al expanded on these results with a retrospective analysis of 99 patients, two-thirds receiving traction neurectomy and one-third receiving implantation into muscle. The results support significantly better pain outcomes for muscle implantation compared with traction neurectomy. 69

Nerve grafting surgical treatments

Targeted muscle reinnervation was initially conceived as nerve transfers to power a myoelectric prosthesis. 70 This same technique is now used widely to treat and prevent chronic amputation-related pain. Targeted muscle reinnervation is a technique in which transected sensory or mixed nerves are formally transferred to nearby motor branch nerves. An example of a targeted muscle reinnervation to treat chronic pain would be the excision of a tibial nerve neuroma and transfer to a motor branch of the soleus. This differs from the passive technique of implanting the nerve into nearby muscle, which buries the nerve adjacent to innervated muscle. Due to the transection of the recipient motor nerve in targeted muscle reinnervation, the adjacent muscle is inherently denervated, facilitating “reinnervation”. Prospective and randomized controlled trials support the advantages of targeted muscle reinnervation over traditional muscle implantation to reduce pain and improve quality of life measures. 71 72 The targeted muscle reinnervation ability to prevent neuroma formation is also supported in animal models. 73 74

The effect of targeted muscle reinnervation on neuroma formation and chronic pain was evaluated in a meta-analysis of 5 studies that included 149 patients found that almost all experienced a near-complete resolution of neuroma pain. 75 Pet et al found that of 12 prophylactic targeted muscle reinnervation procedures, 92% had no neuroma pain at 22 months follow-up. Further, for those who had existing neuromas and underwent targeted muscle reinnervation, 87% had no neuroma pain at follow-up. 65 In a retrospective study, Souza et al reviewed their experience with targeted muscle reinnervation for upper extremity improved prosthetic control. None of the patients treated developed symptomatic neuromas and 14 of the 15 with preoperative neuromas experienced symptom resolution. 76 Valerio et al further supported targeted muscle reinnervation efficacy: 49% of patients who underwent targeted muscle reinnervation were free of RLP relative to only 19% in the controls. 45% who underwent a targeted muscle reinnervation were free of PLP compared with only 21% in the controls. 77 Bowen et al focused on targeted muscle reinnervation in below knee amputations: of the 22 patients treated with a targeted muscle reinnervation, none developed symptomatic neuromas. This study elucidated a timeline of phantom limb recovery that included 72% of patients experiencing PLP in the first month, with an abrupt decline to 19% at the third month and 13% at 3 months. 78 A targeted muscle reinnervation has also been effective in decreasing or eliminating need for chronic opiate use. 79 80 Additionally, a retrospective series from Chang et al demonstrates the value of a targeted muscle reinnervation in highly comorbid patients to decrease risk of chronic pain and improve rates of ambulation. 80 Advancement of the targeted muscle reinnervation techniques continues with adjunct use of a peripheral nerve stimulator to reduce pain and provide improve prosthetic use and quality of life for these patients. 81

Creating a regenerative peripheral nerve interface is another active nerve reconstruction technique that involves capping a sensory or mixed nerve with a free muscle graft. The free muscle graft is, by definition, denervated and provides recipient for the regenerating nerve. This technique can reduce neuroma formation, increase prosthetic control, and reduce amputation-related pain. 82 83 Kubiak et al conducted a retrospective review of ninety patients; half received major limb amputation alone, while half received major limb amputation with a regenerative peripheral nerve interface. 13% of controls developed symptomatic neuromas compared with no patients treated with a regenerative peripheral nerve interface. The regenerative peripheral nerve interface group also experienced a significant reduction in PLP. 32 There is little literature comparing the efficacy of versus a regenerative peripheral nerve interface, but the techniques have been combined to reduce neuropathic pain. 84

From the perspective of surgical treatments, both targeted muscle innervation and a regenerative peripheral nerve interface both show promise as techniques to reduce PLP and RLP. 85 Mechanistically, both techniques target the free distal nerve endings to allow a recipient end-organ for transected axons. This minimizes risk of neuroma formation, thus preventing a primary peripheral mechanism of PLP. Clinical trials are ongoing to compare these two techniques.

Interventional pain therapies

Neuraxial anesthesia and analgesia.

Karanikolas et al reported that optimizing perioperative analgesia using epidural analgesia and or anesthesia or combined with patient-controlled intravenous analgesia resulted in minimal clinically important RLP when started 48 hours preoperatively and continued for 48 hours postoperatively. 86 87 Two additional randomized trials failed to support these findings 88 ; whereas two non-randomized trials demonstrated the benefit of neuraxial anesthesia and analgesia for preventing PLP following amputation. 89 90 Although ketamine is commonly used as a perioperative analgesic adjunct, intravenous ketamine has not been shown to independently contribute to a reduction in PLP incidence. 91 92 Similarly, perioperative gabapentin administration has not been shown to reduce the incidence of PLP. 93

Continuous peripheral nerve blocks

Peripheral nerve blocks using perineural catheters with continued local anesthetic infusions postoperatively have been evaluated as a method for reducing PLP. A 2016 systematic review of this method concluded that although opioid use was decreased, there were no differences in incidence of PLP 94 ; however, a more recent study by Ilfeld et al , found clinically important decreases in worst and average pain at 4 weeks following a 6-day ropivacaine infusion. 95 It is difficult to ascertain whether these perioperative regional anesthesia techniques independently reduce the incidence of PLP, or whether they simply provided adequate perioperative analgesia which has been shown to reduce the incidence of PLP. 87

Prospective clinical trials and case series have reported the benefits of neurolysis using phenol and alcohol for RLP and PLP. 96–98 Cryoneurolysis, or utilization of cold temperatures to ablate peripheral nerves, suggested positive results in treating PLP in two small retrospective case series. 99 100 A randomized control trial assessing ultrasound-guided percutaneous cryoneurolysis did not demonstrate significant reductions in PLP when compared with sham therapy. 101

Neuromodulation

There are case reports of the effectiveness of both central and peripheral neuromodulation for treating PLP. While the mechanisms of action of spinal cord stimulation are not fully elucidated, it was originally postulated that spinal cord stimulation of larger sensory nerve fibers blocks peripheral ascending nociceptive impulses at the level of the spinal cord ( figure 3 ). There are as many as 15 case series and small sample prospective and retrospective studies of the use of spinal cord stimulation of the dorsal column for treatments of PLP, but a systematic review of this method concluded that the level of certainty of the evidence of efficacy is inconclusive as the data are limited and the risk of bias is high in many of these studies. 102

Comparison of electrode implantation and localization for spinal cord stimulation and DRG stimulation neuromodulation. Spinal cord stimulation lead implantation; axial (A) and posterior (B) views. Spinal cord stimulation implantation involves the insertion of electrode nerve stimulators into the epidural space and positioned over the dorsal spinal column. The electrodes stimulate physiological changes in the dorsal spinal column. There is mixed evidence on the efficacy of spinal cord stimulation in reducing PLP. Dorsal root ganglion lead implantation; axial (C) and posterior (D) views. DRG stimulation can reduce chronic neuropathic pain through modulation of the peripheral nerve impulses that pass through the DRG. This technique passes an electrode through the epidural space and spinal foramen to the DRG. DRG, dorsal root ganglion; PLP, phantom limb pain.

Dorsal root ganglion (DRG) neuromodulation is a technique where the electrode is placed through the epidural space and targeted neural foramen to stimulate the DRG, a structure that is important in the expansion of the wide dynamic range at the spinal cord level leading to central sensitization. The DRG evolved as a target for neuromodulation about a decade ago when it was recognized that its stimulation can decrease neuronal transmission beyond the primary sensory afferent neuron. 103 DRG stimulation has since become a highly successful analgesic therapy for patients suffering from a variety of neuropathic pain pathologies. 104 While the level of evidence for the use of DRG neuromodulation is limited to case reports, DRG stimulation potentially offers more promising results for the treatment of PLP. 103 105 106

Peripheral nerve stimulation (PNS) is a less invasive neuromodulation modality that has reported to treat cases of PLP. 107 PNS involves the placement of an electrode near a peripheral nerve identified to be a source of neuropathic pain. A temporary (adhered to skin) or a permanent (implanted) pulse generator continuously sends electrical patterns eliciting waveform stimulations of the nerve at the site of the electrode to disrupt pathological nerve signal transmission. A summary of evidence for neuraxial and peripheral nerve blocks, neurolysis and neuromodulation methods for the treatment of PLP is shown in table 2 .

Evidence for interventional neuraxial and peripheral nerve blocks and neuromodulation methods for the treatment of postamputation pain

There is no consensus as to the optimal combinations of therapies to treat PLP. In addition, the treatment will likely be driven by multiple factors including pathology and pathophysiology of the injury along with psychological and social circumstances of the patient. Treatment modalities that target both central and peripheral mechanisms of PLP are available and range from minimally invasive to surgical intervention. Medical treatments for chronic PLP are generally suboptimal and limited by side effects. Infusion therapies and intradermal injections may provide temporary but rarely long-lasting relief. Treatment paradigms including prolonged nerve blocks, catheters, spinal cord stimulation, and dorsal root ganglion stimulation have all become increasingly popular as interventional treatments, but their role in PLP has yet to be defined.

Given the limited effectiveness of pharmacological treatments, there has been recent increased attention to the prevention and treatment of amputation-related pain. Surgical techniques including targeted muscle reinnervation and regenerative peripheral nerve interface go beyond the traditional “traction neurectomy” to prevent and treat amputation-related pain and improve quality of life. In addition to refined surgical techniques, specific regional and general anesthesia protocols in the perioperative period may reduce the risk of chronic PLP and be more effective than pharmacological therapies with fewer side effects. Finally, behavioral and psychological management are important components of effective therapy for many patients.

Treatment for amputation-related pain is poorly protocolized and often guided by referral patterns, institutional biases, and training backgrounds. Comparison between treatment modalities is limited by a lack of standardized outcome measures and a lack of high-quality evidence. Patient-guided multimodal approaches with a combination of pharmacotherapy, surgery and invasive procedures could provide the most benefit but protocol designed to optimize these individual therapies have not been extensively studied. Future efforts should focus on cross-disciplinary education to increase awareness of treatment options and exploring best practices for preventing pain at the time of amputation and comparative studies of treating chronic PLP.

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Contributors ANM made substantial contributions to the conception and design of the study; the acquisition, and interpretation of data; drafting the manuscript; and approved the submitted version. TS made substantial contributions to the conception and design of the study; the acquisition, and interpretation of data; drafting and revising the manuscript; and approved the submitted version. MJG made substantial contributions to the conception and design of the study; the acquisition, and interpretation of data; drafting the manuscript; and approved the submitted version. MAS made substantial contributions to the conception and design of the study; creating the illustrations, drafting the manuscript; and approved the submitted version. TRL made substantial contributions to the conception and design of the study; the acquisition, and interpretation of data; drafting the manuscript; and approved the submitted version. RJM made substantial contributions to the conception and design of the study; drafting the manuscript; and approved the submitted version. AB made substantial contributions to the conception and design of the study; drafting the manuscript; and approved the submitted version. DEK made substantial contributions to the conception and design of the study; the acquisition, and interpretation of data; drafting the manuscript; and approved the submitted version.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests TRL reports financial support was provided by Abbott Laboratories. TRL reports a relationship with Abbott Laboratories that includes consulting or advisory; a relationship with Boston Scientific Corp that includes consulting or advisory; a relationship with Nevro Corp that includes consulting or advisory; a relationship with Medtronic that includes consulting or advisory; a relationship with Avanos Medical that includes consulting or advisory; and a relationship with Flowonix Medical Inc that includes consulting or advisory.

Provenance and peer review Not commissioned; externally peer reviewed.

Read the full text or download the PDF:

Mirror Therapy and Transcutaneous Electrical Nerve Stimulation for Management of Phantom Limb Pain in Amputees - A Single Blinded Randomized Controlled Trial

Affiliation.

  • 1 Christian Medical College, Vellore, 632002, India.
  • PMID: 25832306
  • DOI: 10.1002/pri.1626

Background and purpose: Phantom limb pain (PLP) can be disabling for nearly two thirds of amputees. Hence, there is a need to find an effective and inexpensive treatment that can be self administered. Among the non-pharmacological treatment for PLP, transcutaneous electrical nerve stimulation (TENS) applied to the contralateral extremity and mirror therapy are two promising options. However, there are no studies to compare the two treatments. The purpose of this study is to evaluate and compare mirror therapy and TENS in the management of PLP in subjects with amputation.

Methods: The study was an assessor blinded randomized controlled trial conducted at Physiotherapy Gymnasium of Physical Medicine and Rehabilitation Department, Christian Medical College, Vellore. Twenty-six subjects with PLP consented to participate. An initial assessment of pain using visual analogue scale (VAS) and universal pain score (UPS) was performed by a therapist blinded to the treatment given. Random allocation into Group I-mirror therapy and Group II-TENS was carried out. After 4 days of treatment, pain was re-assessed by the same therapist. The mean difference in Pre and Post values were compared among the groups. The change in pre-post score was analyzed using the paired t test.

Results: Participants of Group I had significant decrease in pain [VAS ( p = 0.003) and UPS ( p = 0.001)]. Group II also showed a significant reduction in pain [VAS ( p = 0.003) and UPS ( p = 0.002)]. However, no difference was observed between the two groups [VAS ( p = 0.223 and UPS ( p = 0.956)].

Discussion: Both Mirror Therapy and TENS were found to be effective in pain reduction on a short-term basis. However, no difference between the two groups was found. Substantiation with long-term follow-up is essential to find its long-term effectiveness. Copyright © 2015 John Wiley & Sons, Ltd.

Keywords: mirror therapy; phantom limb pain; transcutaneous electrical nerve stimulation.

Copyright © 2015 John Wiley & Sons, Ltd.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Amputees / rehabilitation*
  • Follow-Up Studies
  • Imagery, Psychotherapy / methods*
  • Middle Aged
  • Pain Measurement*
  • Phantom Limb / psychology
  • Phantom Limb / rehabilitation*
  • Risk Assessment
  • Single-Blind Method
  • Transcutaneous Electric Nerve Stimulation / methods*
  • Treatment Outcome

Physical Therapy Guide To Phantom Limb Pain

Physical Therapy Guide To Phantom Limb PainPhysical Therapy Guide To Phantom Limb Pain

For many people, phantom limb pain (PLP) is a debilitating symptom that can make everyday tasks difficult. For some, PLP is so severe that it can lead to physical therapy appointments and even surgery. In this blog post, we will provide you with a comprehensive guide to phantom limb pain, including tips on how to treat it and what you can do to prevent its development in the first place.

  • 1 What Is Phantom Limb Pain?
  • 2 Physical Therapy For Phantom Limb Pain
  • 3.1 Transcutaneous Electrical Nerve Stimulation (TENS)
  • 3.2 Acupuncture 
  • 4 Reasons To Choose Physical Therapy For Phantom Limb Pain
  • 5 Preparing For Physical Therapy For Phantom Limb Pain
  • 6 Conclusion

What Is Phantom Limb Pain?

What Is Phantom Limb Pain?

Phantom limb pain (PLP) is a widespread and difficult-to-treat condition that can occur after an amputation, tumor removal or another injury to the limb. PLP can be extremely frustrating and debilitating, causing people to feel as if their missing limb is still present.

This disease is also a  common cause of sleep deprivation. A lack of adequate sleep can worsen the symptoms of PLP and make it harder to cope with the pain.

There’s no one cause for PLP, but it can often be caused by a complex mix of physical, psychological, and neurological factors. Treatment typically involves addressing the underlying causes of the condition, including trauma to the nerves and muscles controlling the phantom limb.

If you’re experiencing PLP and don’t see improvement with standard treatments, talk to your doctor about other options. Some people successfully achieve relief through surgery or medical implants that stimulate nerve endings in the stump.

Physical Therapy For Phantom Limb Pain

There is no one-size-fits-all approach to treating phantom limb pain, as the severity and type of injury will vary. However, physical therapy can be very effective in alleviating this type of pain.

In general, physical therapy for phantom limb pain will focus on restoring function to the affected extremity. This may involve exercises that help improve strength and mobility, as well as treatments such as heat and ice packs. Additionally, some patients may require surgery to remove or reduce pressure on the nerve endings in the stump.

One of the most important factors in achieving long-term relief from phantom limb pain is ongoing therapy. If symptoms improve but physical therapy is discontinued, the pain may return later on. Thus, it is important to seek regular treatment to maintain progress.

Types of Physical Therapy For Phantom Limb Pain

There are many types of physical therapy for phantom limb pain, each person may be choosing other types of therapy based on their personal experience, symptoms, and goals.

Transcutaneous Electrical Nerve Stimulation (TENS)

Transcutaneous Electrical Nerve Stimulation (TENS) is a type of electrical stimulation therapy that is used to treat various types of pain. TENS works by sending small electrical pulses through the skin to the affected area. These pulses cause pain relief by activating nerve cells in the area. TENS can be used to treat pain from conditions such as phantom limb pain, back pain , neck pain , and migraine headaches.

TENS is a safe and effective treatment option for many patients. Some common side effects of TENS include mild tingling or warmth, temporary relief of symptoms, and an increased feeling of well-being. Patients should consult with their physician before starting TENS therapy, as there are certain contraindications (such as severe heart problems) that should not be treated with this type of therapy.

Acupuncture 

In acupuncture , tiny needles are inserted into specific points on the body to relieve pain. Acupuncture is said to work by affecting the body’s energy flow, which can help relieve pain. Acupuncture can also be used in conjunction with other treatments, such as physical therapy.

According to the National Center for Complementary and Integrative Health (NCCIH), acupuncture stimulates the flow of Qi, which can help to reduce inflammation and pain. Additionally, acupuncture has been shown to improve sleep quality and function, increase feelings of well-being, and decrease stress levels. If you’re considering acupuncture as a potential treatment for PLP, be sure to discuss your goals with your physical therapist .

Reasons To Choose Physical Therapy For Phantom Limb Pain

Reasons To Choose Physical Therapy For Phantom Limb Pain

There are many reasons to choose physical therapy for phantom limb pain. Physical therapists have a deep understanding of the neurology of the body and can provide targeted treatment to help reduce or resolve the pain. They also have expertise in treating conditions that can cause phantom limb pain, such as peripheral nerve damage or other nerve injuries.

Some of these reasons why people may use physical therapy for phantom limb pain:

Cost-Effective

One of the main benefits of physical therapy for phantom limb pain is that it is often very affordable. This is due in part to the fact that physical therapists have access to a wide range of treatments and therapies, as well as equipment and resources needed to help treat this condition.

Targeted Treatment

Physical therapy for phantom limb pain typically takes a targeted approach, which means that the therapist will work with you individually to identify the source of your pain and develop a treatment plan specific to your needs. This can be a crucial step in resolving the pain and improving your overall quality of life.

Experience & Expertise

Physical therapists are experts in treating conditions that can cause phantom limb pain, such as peripheral nerve damage or other nerve injuries. They have years of experience working with patients who suffer from this type of pain, which means they are likely to provide you with the best possible treatment options.

Effectiveness

Another benefit of physical therapy for phantom limb pain is that it is often very effective in resolving the pain. This is because physical therapists have a deep understanding of the neurology of the body and can target specific areas of the body where the pain is originating from.

Physical therapy for phantom limb pain can be an effective treatment option for those who suffer from this type of pain. If you are looking for an affordable and reliable solution, physical therapy may be a good option for you.

Preparing For Physical Therapy For Phantom Limb Pain

Preparing For Physical Therapy

Physical therapy can help people with phantom limb pain by teaching them exercises and strategies to reduce the sensation of pain. Many people find that physical therapy helps manage their phantom limb pain. Physical therapists will typically begin by assessing your current level of pain and disability. They will then work with you to create a personalized treatment plan.

There are many tips for preparing for physical therapy for phantom limb pain. Here are a few:

Discuss Your Expectations

One of the main goals of physical therapy for phantom limb pain is to help you regain mobility and function. Before starting therapy, it is important to discuss your expectations with your therapist. This will help ensure that you are targeting the right areas and making progress.

Physical therapy can be strenuous, so it is important to prepare yourself mentally and physically. Make a list of the exercises and stretches that you will be doing, and make sure that you have adequate clothing and gear available. If possible, schedule sessions at a time when you are least likely to be interrupted.

Take Advantage Of Support Groups

Many people find support groups helpful in managing their phantom limb pain. Groups allow individuals to share experiences and strategies, which can help increase understanding and support. There are many groups available across the country, so it is best to consult with your therapist or local community resources to find one that fits your needs.

Try Medications

Many people find that medications help manage their phantom limb pain. Depending on the severity of your condition, your therapist may recommend medications such as ibuprofen or opioids. Discussing medication options with your therapist is an important step in treating your condition.

Be Patient and Persistent

Physical therapy for phantom limb pain is a long-term process. It is important to be patient and persistent in achieving your goals. If you are unable to complete an exercise or stretch, do not be discouraged. Try again later or with a different therapist. Remember, progress is always possible with dedication and effort.

Photo limb pain is a condition in which you feel pain in your limbs even though they no longer exist.

If you’re experiencing phantom limb pain, it’s important to see a physical therapist. A physical therapist can help you understand your condition, find solutions, and put in place the necessary treatment plan. In addition to providing support during the acute phase of phantom limb pain (the first few weeks after losing a limb), physical therapy can also prolong the time until the sensation returns to the area. If you are suffering from phantom limb pain, don’t hesitate to seek out professional help.

Physical Therapy  help patients recover from pain. If you’re experiencing  Back pain ,  Shoulder pain ,  Knee pain ,  Neck pain ,  Elbow pain ,  Hip pain , or  Arthritis pain , a physical therapist at MantraCare can help:  Book a physiotherapy session .

Mantra Care aims at providing affordable, accessible, and professional health care treatment to people across the globe.

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electrical stimulation for phantom limb pain

What if electrical stimulation could treat phantom limb pain?

Most people who have had a limb amputated will experience some form of phantom limb pain. Unfortunately, currently available drug treatments have varying success. Dr Katharine Polasek , at Hope College in the US, is investigating ways to use electrical stimulation to treat this painful phenomenon

TALK LIKE A NEURAL ENGINEER

AMPUTATION – the surgical removal of part of the body, such as an arm or leg

CENTRAL NERVOUS SYSTEM – consisting of the brain and spinal cord

EEG – abbreviation of electroencephalogram, which is a recording of brain activity using a special machine. Small sensors are attached to the scalp to pick up the electrical signals produced when brain cells send messages to each other

ELECTRODE – a small piece of metal or other substance that is used to take an electric current to or from a source of power, a piece of equipment, or a living body

NEUROPLASTICITY – the ability of the brain to form and re-organise synaptic connections, especially in response to learning, experiences or following injury

PERIPHERAL NERVOUS SYSTEM – consisting mainly of nerves, which are enclosed bundles of fibres connecting the central nervous system to every part of the body

REFERRED SENSATIONS – sensations felt in parts of the body far away from the site receiving the electrical stimulation

SOMATOSENSORY SYSTEM – the part of the sensory system concerned with the perception of sensations such as touch, pain, pressure and vibration

SURFACE ELECTRICAL STIMULATION (SES) – a non-invasive method of electrical stimulation which involves placing electrodes on the skin

Imagine losing your left arm, but months later you experience pain in your left hand, even though it is no longer there. This is known as phantom limb pain, the painful sensations amputees feel in their missing limbs. Even though the word ‘phantom’ might suggest otherwise, phantom limb pain is a very real and painful phenomenon, often described as throbbing, burning or stabbing in the part of the body that has been removed. It usually starts soon after the amputation surgery, and its duration and intensity vary from person to person.

Phantom limb pain is estimated to affect up to 80 percent of amputees and can be a long-term problem, so it is essential to find ways of managing and treating the pain. Unfortunately, finding a treatment to relieve phantom limb pain can be difficult, and there are no medications that are specifically aimed at this condition.

Dr Katharine (Katie) Polasek is an associate professor of engineering at Hope College in the US. Katie and her team are using their engineering skills to find innovative ways to relieve phantom limb pain.

WHAT CAUSES PHANTOM LIMB PAIN?

Scientists are still not certain about the exact mechanisms behind phantom limb pain, despite extensive research into the topic. It is most likely due to the brain and spinal cord continuing to send signals down to the nerves of the missing limb. However, no neural signals return and so the brain gets confused. It could be that the pathway (nerve to spinal cord to brain) that used to connect to the missing limb sends signals randomly, which causes confusion in the brain that is interpreted as pain.

“Some people have shown changes in their brain after an amputation where the area of the brain that used to connect to the amputated limb now responds to another nearby body location. For example, if you touch their face, a person with an amputated hand may feel the touch in their face AND in their phantom hand,” says Katie. “It’s not clear if this is a cause of phantom limb pain, but people who have more of this overlap often have pain.”

HOW IS PHANTOM LIMB PAIN CURRENTLY TREATED?

Current treatments for this condition have varying levels of success and do not directly address the neural changes mentioned above. Drugs for nerve pain are commonly prescribed to mask the pain, but these are covering up the issue rather than solving it and can have many negative side effects. Other options include acupuncture, massage and distraction techniques, but again, none of these really address the root of the problem.

HOW CAN ELECTRICAL STIMULATION BE USED AS A TREATMENT METHOD?

When small electric currents are passed through our skin, they activate sensors within the skin, producing a buzzing or tingly sensation that we can feel. This sending of electric currents is known as electrical stimulation. Sometimes electrical stimulation is used to turn on muscles after an injury in an athlete or to help people who are paralysed perform tasks such as grasping a fork or holding a toothbrush. It can also be used to evoke referred sensations, where the sensation is felt away from the site of stimulation. For example, Katie can place electrodes by someone’s elbow and use electrical currents to turn on fibres in the median nerve near the electrodes. The signal then travels up to the brain where it is interpreted. “If we activate the right fibres in the right way, we can make it feel like someone is tapping your hand!” says Katie.

The aim of these surface electrical stimulations is to give individuals with amputated limbs the very real impression that a non-painful sensation is happening in the missing body part. This is achieved by activating nerve fibres that used to come from the missing hand or foot, which Katie believes may help counteract phantom limb pain. “We think that allowing amputees to feel non-painful sensations in their phantom hand will reduce or eliminate phantom limb pain,” she explains.

electrical stimulation for phantom limb pain

Download the article

Reference https://doi.org/10.33424/FUTURUM180

electrical stimulation for phantom limb pain

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electrical stimulation for phantom limb pain

HOW FAR IS THE TEAM INTO THIS RESEARCH?

Having investigated effective ways to activate referred sensations, Katie’s team carried out further investigations to find out how to best evoke a ‘natural’ sensation in subjects with an amputation. They stimulated different areas of the skin at different frequencies and asked the subjects questions about what they felt.

Katie and her team have successfully developed a technique to electrically stimulate on the skin at the elbow or knee, but for the participant to feel the sensation in their hand or foot. This occurs in people both with and without amputations.

The team is aiming to evoke a ‘natural’ sensation, meaning that the sensation felt by the amputee matches a common feeling. A tap on the skin is a good example, says Katie. “It’s very common to feel a tingling sensation or pins and needles due to electrical stimulation, however it’s hard to do something to someone that looks like pins and needles. We don’t like it when our sensations don’t match!” Tapping is something that I can do on someone’s hand or prosthesis as part of the therapy.

The researchers are investigating what happens in the brain when an amputee experiences an actual touch versus an electrically stimulated touch. So far, they have studied the brain by looking at EEG signals in people without amputations to see how they respond to different types of touch. Katie’s team is working to make the referred sensation as realistic as possible. After this, the researchers will begin testing their electrical stimulation therapy on people with amputations, recording their brain signals during therapy and seeing whether their brain begins to respond differently. This will help us learn more about the causes of phantom limb pain.

WHAT ARE THE FUTURE IMPLICATIONS OF USING ELECTRIC CURRENTS TO TREAT PHANTOM LIMB PAIN?

Katie hopes that her work will lead to customised therapies for phantom limb pain. She also aims to develop a tool for patients to use at home, making it far easier for people to access treatment. “I would hope that we can provide an inexpensive, at-home treatment for people suffering from phantom limb pain to do on their own. I would like the therapy to be effective and maybe a little fun, so that people will actually do it,” she says. Moreover, by exploring ways to tap into our nervous system and target pain without invasive treatment or drugs, this research could pave the way for therapies for many other neurological conditions.

electrical stimulation for phantom limb pain

FIELD OF RESEARCH: Neural Engineering

RESEARCH PROJECT: Treating phantom limb pain with electrically induced somatosensation

FUNDER: National Science Foundation

electrical stimulation for phantom limb pain

ABOUT NEURAL ENGINEERING

Did you know that fully functional bionic arms have been developed for amputees that respond to signals from the brain? The user only has to think about moving their hand, and signals from the brain will be detected by electrodes in the bionic arm, causing it to move! This life changing invention is all due to the work of neural engineers.

Neural engineering is a discipline within biomedical engineering. It focuses on using engineering techniques and skills to understand, interface with and manipulate the nervous system. Neural engineers are interested in understanding how the brain functions, and often create computer models of neural systems to better understand them and how they interact.

WHY DO WE NEED NEURAL ENGINEERS?

Neural engineers are essential for many medical-related technologies and therapies. They might design heart devices such as pacemakers or defibrillators, or develop brain devices to help people with Parkinson’s disease or epilepsy, or work on therapies to help people who have suffered from a stroke or spinal cord injury.

DOES KATIE RECOMMEND A CAREER IN NEURAL ENGINEERING?

“Neural engineering is a pretty narrow field, but I love learning about how the different parts of the body communicate and work together to allow us to do all of the amazing things that we can do,” she says. “As a neural engineer, I have to understand what the body is doing so that I can use my engineering skills to restore function that was lost, or take pain away.”

EXPLORE A CAREER IN NEURAL ENGINEERING

• You can read more about neural engineering on the IEEE Engineering in Medicine & Biology Society website: www.embs.org/about-biomedical-engineering/our-areas-of-research/neural-engineering/

• The Royal Academy of Engineering also has a handy guide: www.raeng.org.uk/publications/reports/neuralengineering-briefing

• Neural engineering is a specialised field, so it is useful to read up on the more general field of biomedical engineering. UCAS provides a great summary: www.ucas.com/ucas/after-gcses/find-career-ideas/explore-jobs/job-profile/biomedical-engineer

• Practical experience is a good way to find out whether neural engineering, biomedical engineering or engineering in general is the career for you. Hope College hosts ExploreHope which, as Katie says, “runs awesome engineering camps for older kids.” Research the engineering departments of universities near you to see if they hold similar camps or outreach activities for schools and students.

• Katie recommends finding a neural engineer and shadowing them, if possible. “Once you get to engineering school, apply for an internship or research experience so that you can start doing real science and/or engineering,” she says. “The best way to know if you like something is to try it out!”

• According to Indeed, the average salary for a neural engineer in the US ranges from $91,000 – $150,000, though this will vary depending on your qualifications and whether you work for a company or at a university.

HOW DID KATIE BECOME A NEURAL ENGINEER?

WHAT WERE YOUR INTERESTS WHEN YOU WERE YOUNGER?

As a child, I always loved to let my imagination take over, using toys and dolls to create new worlds, and I have many happy memories of playing with siblings and friends that way. I loved reading fantasy books, especially those of Madeline L’Engle. As I grew older, I enjoyed playing piano and trombone, and running track and cross-country. I’ve also loved jigsaw puzzles all of my life.

DID YOU ALWAYS KNOW YOU WANTED TO BE AN ENGINEER?

My father is a civil engineer, so I was exposed to engineering at a young age. I didn’t really have an interest in designing bridges or cars, so I didn’t plan on becoming an engineer initially. When I was 4, I wanted to be a monkey doctor. This progressed to baby doctor, then veterinarian, so I guess I was mostly focused on the medical field. It was in my junior year at high school that I first heard about biomedical engineering, and it sounded perfect for someone like me who was definitely interested in how the body worked but also liked math and solving problems.

YOU HAVE A BSE IN MECHANICAL ENGINEERING AND A PHD IN BIOMEDICAL ENGINEERING. WHY DOES BIOMEDICAL ENGINEERING FASCINATE YOU?

When I was in high school, I remember being fascinated with how muscles produced movement. My favourite muscle was the zygomaticus major – the smiling muscle! In my anatomy and physiology class, I learned the secrets to how muscles contract and create complex movements. Once I started studying engineering, I wanted to learn more.

HOW WOULD YOU DESCRIBE YOURSELF?

I like to solve problems and am very practical and hands on. I have trouble visualising things that people tell me verbally, so I like to see the problem or draw it, based on a description. Seeing the problem helps me to find a solution.

WHAT DO YOU ENJOY OUTSIDE OF RESEARCH?

I love my work but I also love coming home at the end of the day to my husband Greg and my three boys, Isaac, Teddy and Sam. We also have two dogs and two cats who are always available for pets and snuggles. For my hobbies, I still keep up with running and playing the trombone but I added hockey as an interest when I was in graduate school. Hockey is fun and social, and a great way to exhaust myself and be part of a team.

KATIE’S TOP TIPS

01 Don’t expect getting into a specific career to be a straight path, and don’t worry if you’re not sure what you want to do.

02 At each stage in your career, make the best decision for you at that time. It’s good to have a long-term plan but life often doesn’t work out exactly as you planned!

Do you have a question for Katie? Write it in the comments box below and Katie will get back to you. (Remember, researchers are very busy people, so you may have to wait a few days.)

Katie Holzheimer

Hi Katie Are you aware of any research using electrical stimulation and ALS patients? Your research is very impressive, my son has ALS and I would be interested in exploring that. By the way I remember you from our trips to Honduras !!!

Katie Polasek

Hi Katie! I’m sorry to hear about your son’s diagnosis, ALS is hard. I know people have looked at electrical stimulation for slowing the progression of ALS but I don’t know the details. Restoring function electrically and getting assistive devices is especially difficult since ALS is a progressive disease. Once you get things set up, the disease changes and the device no longer works. My first personal contact with someone with ALS was with one of the Honduras trip leaders when I first started going. Lots of Honduras memories!

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Neuromodulation Techniques in Phantom Limb Pain: A Systematic Review and Meta-analysis

Kevin pacheco-barrios.

Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Boston, Massachusetts, USA

Universidad San Ignacio de Loyola, Vicerrectorado de Investigación, Unidad de Investigación para la Generación y Síntesis de Evidencias en Salud, Lima, Peru

Xianguo Meng

Shandong First Medical University & Shandong Academy of Medical Sciences, College of Sport Medicine and Rehabilitation, Jinan, Shandong Province, P.R. China

Felipe Fregni

Associated data.

To evaluate the effects of neuromodulation techniques in adults with phantom limb pain (PLP).

A systematic search was performed, comprising randomized controlled trials (RCTs) and quasi-experimental (QE) studies that were published from database inception to February 2019 and that measured the effects of neuromodulation in adults with PLP. Hedge’s g effect size (ES) and 95% confidence intervals were calculated, and random-effects meta-analyses were performed.

Fourteen studies (nine RCTs and five QE noncontrolled studies) were included. The meta-analysis of RCTs showed significant effects for i) excitatory primary motor cortex (M1) stimulation in reducing pain after stimulation (ES = −1.36, 95% confidence interval [CI] = −2.26 to −0.45); ii) anodal M1 transcranial direct current stimulation (tDCS) in lowering pain after stimulation (ES = −1.50, 95% CI = −2.05 to 0.95), and one-week follow-up (ES = −1.04, 95% CI = −1.64 to 0.45). The meta-analysis of noncontrolled QE studies demonstrated a high rate of pain reduction after stimulation with transcutaneous electrical nerve stimulation (rate = 67%, 95% CI = 60% to 73%) and at one-year follow-up with deep brain stimulation (rate = 73%, 95% CI = 63% to 82%).

Conclusions

The evidence from RCTs suggests that excitatory M1 stimulation—specifically, anodal M1 tDCS—has a significant short-term effect in reducing pain scale scores in PLP. Various neuromodulation techniques appear to have a significant and positive impact on PLP, but due to the limited amount of data, it is not possible to draw more definite conclusions.

Introduction

Phantom limb pain (PLP) is a chronic pain condition that is perceived in a limb that no longer exists [ 1 ]. PLP is a serious public health problem that can affect the physical, psychological, and functional health of amputees [ 2 ]. After limb amputation, 50–80% of patients experience PLP [ 2–6 ], which deteriorates their quality of life [ 3 , 7 , 8 ]. The occurrence of long-term PLP can lead to comorbidities, such as depression, sleep disturbances, and substance abuse, and affect the use of prostheses [ 5 , 9 , 10 ].

The current treatment options (pharmacological and behavioral) for PLP are not entirely effective [ 11 ]. The pathophysiology of PLP is related to cortical reorganization [ 11 , 12 ]. Nevertheless, no existing PLP treatment targets these maladaptive brain modifications.

Neuromodulation is a potential treatment option for chronic pain [ 13 , 14 ], which could alter maladaptive neuroplasticity and enhance descending inhibitory pathways [ 15 , 16 ]. Such methods include invasive central (deep brain stimulation [DBS], motor cortex stimulation [MCS], and spinal cord stimulation [SCS]) and peripheral (dorsal root ganglion stimulation [DRGS]) interventions and noninvasive central (transcranial magnetic stimulation [rTMS], transcranial direct current stimulation [tDCS]) and peripheral (transcutaneous electrical nerve stimulation [TENS], neuromuscular electrical stimulation [NMES], and peripheral nerve stimulation [PNS]) techniques.

Systematic reviews have attempted to evaluate these options but have encountered several limitations: They analyzed the efficacy of noninvasive brain stimulation without comparing invasive or peripheral techniques [ 17 , 18 ] focused on chronic pain conditions in general, including PLP patients, but failed to target PLP specifically [ 17 ]. Therefore, the efficacy of neuromodulation in PLP and the ideal option for treating PLP are unknown.

This study systematically reviewed the evidence on the efficacy and safety of neuromodulation techniques in the treatment of PLP to provide initial data on the type of neuromodulation that has significant effect sizes for further research and future clinical applications.

Study Design

We performed a systematic review. The study protocol was registered at PROSPERO, number CRD42018117998. This study follows the Cochrane handbook [ 19 ] and PRISMA guidelines [ 20 ] ( Supplementary Data ).

Eligibility Criteria

Our inclusion criteria were as follows: i) studies that evaluated any beneficial or adverse effect of the use of neuromodulation techniques in the treatment of adults (>18 years old) with a PLP diagnosis. We included i) invasive central nervous system (CNS) stimulation (DBS, MCS, and SCS), noninvasive CNS stimulation (rTMS and tDCS), and peripheral nervous system stimulation—TENS, PNS, and NMES; ii) randomized controlled trials (RCTs), including parallel-group and crossover designs, and quasi-experimental (QE) studies, including noncontrolled and nonrandomized studies; iii) studies with pain scales (visual analog scale [VAS], numeric rating scale [NRS], McGill Pain Questionnaire, or universal pain score [UPS]) as the primary outcome (and this information had to include mean and standard deviation before and after the intervention); iv) without language restriction. We excluded case–control studies, cohort studies, case series, review articles, conference abstracts, case reports, letters, and editorials. We excluded the studies with full text not available after trying to contact the authors. The most recent or the largest sample size publication was included when the authors published several studies using the same database.

Literature Search and Study Selection

We performed a literature search using five databases: Medline, Central Cochrane Library, Embase, Scopus, and Web of Science. The last updating search was run in February 2019. No additional filters (e.g., language or publication year) were set. The complete search strategy is available in the Supplementary Data . A manual search was also conducted to find other potential articles based on identified references in the individual articles.

Before titles and abstract screening, two reviewers (XM and KP-B) agreed on a standard approach. Two random samples of 50 search results were selected for training purposes. Reviewers screened these titles and abstracts, and inter-rater agreement and kappa estimator were computed, aiming for an inter-rater agreement of at least 90% ( Supplementary Data ). After this standardization process, duplicate records were removed, and two reviewers (XM and KP-B) screened all titles and abstracts following the prespecified framework and selection criteria. Discrepancies were resolved by a third reviewer independently (FF). After the title and abstract selection, full texts of selected reports were sought and analyzed; differences were resolved by consensus between all authors. These selection processes—titles and abstracts as well as full texts—were conducted using Endnote software. The complete list of excluded articles and the reasons for exclusion at this full-text stage is available in the Supplementary Data .

Data Extraction

Two authors systematically extracted data from each included study using a standardized form. The form used for data extraction documented the most relevant items, including sample characteristics, study design, and intervention characteristics. The PLP intensity (visual analog scale), quality of life, anxiety and depression scales, and adverse events were extracted to evaluate the efficacy and safety of the use of neuromodulation techniques.

Risk of Bias Assessment

To assess the risk of bias (RoB) of RCTs, we used the Jadad Scale [ 21 ] following the standard score system from 0 to 5 (high number means low risk of bias). To assess the risk of bias of QE studies, we used the Methodological Index for Non-Randomized Studies (MINORS) tool [ 22 ]. For QE controlled studies, the MINORS tool was scored from 0 to 2; 0 for not reported information, 1 for inadequately reported information, and 2 for well-reported information. We considered a low risk of bias when the information was well reported, a high risk of bias when it was not reported, and an unclear risk of bias when it was reported inadequately [ 22 ]. The RoB evaluation was assessed by two reviewers (XM and KP-B), and discrepancies were solved by a third reviewer independently (FF).

Data Synthesis

First, we reported the articles in a narrative approach. We decided to present results separately according to study design (RCTs vs QE studies), given the differences in the quality of evidence between these two types of studies.

Interventions were categorized into one of four groups: i) excitatory noninvasive CNS stimulation, ii) inhibitory noninvasive CNS stimulation, iii) invasive CNS stimulation, iv) PNS stimulation. Pain outcome was categorized according to time, based on a previous study [ 17 ], in three groups: i) short term (end of intervention or less than one week), ii) medium term (more than one week to less than six weeks), and iv) long term (more than six weeks).

Then, with the RCT data, we performed an exploratory meta-analysis using Hedge’s g for pain intensity. Although within the treatment categories are interventions with different parameters, we decided to do an exploratory synthesis to compare across the spectrum of the available neuromodulation techniques. When possible, we used pre and post scores of the pain analog scales for each outcome to calculate the mean difference between groups. The difference was then converted to an effect size (ES). Given that Cohen’s d has a slight bias to overestimate in small sample sizes, we adjusted Cohen’s d to Hedge’s g by applying a correction factor.

With the QE data, we pooled the rate of pain reduction per individual study by implementing a proportions meta-analysis approach. Briefly, we estimated 95% confidence intervals (CIs) using the exact binomial method and incorporated the Freeman-Tukey double arcsine transformation for computation of pooled proportions [ 23 ].

We assessed heterogeneity using the I 2 statistic, and we considered low heterogeneity I 2 < 40% [ 24 ]. We considered it appropriate to use random-effects models due to the overall heterogeneity of the evaluation (in population and intervention) [ 25 ]. Metaregression and publication bias were not assessed, as the number of studies pooled for each meta-analysis was <10 [ 26 ]. The data were processed using Stata, version 15.0.

Management of Missing Data

When the primary outcome data (i.e., PLP visual analog scale) were missing or unclear, we contacted the authors. We used Web Plot Digitizer, version 3.11, to extract data from relevant graphs. If we could not reach the authors or obtain the data graphically, we excluded the study from the quantitative analysis.

Search Results

The search retrieved 1,573 results. After removing duplicates, 865 titles and abstracts were screened, and of these, 776 were excluded. Seventy-two studies were evaluated in full text, and 14 were included ( Figure 1 ) [ 27–40 ].

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Prism flowchart (study selection).

Studies Characteristics

Regarding the included studies, nine were RCTs [ 27–31 , 33 , 35 , 36 , 38 ], including five crossover RCTs [ 28–30 , 33 , 36 ], and five were noncontrolled QE studies [ 32 , 34 , 37 , 39 , 40 ]. We included 236 PLP patients in this review. The number of participants ranged from eight to 54 in RCTs, and from three to 10 in QE studies.

Regarding the interventions, they consisted of invasive or noninvasive neuromodulation techniques:

  • Three studies used tDCS: All were RCTs and used anodal primary motor cortex (M1)/cathodal supraorbital [ 29 , 30 , 33 ]. Also, one used anodal posterior parietal cortex (PPC)/cathodal supraorbital as a part of the experimental arms [ 30 ].
  • Three studies used rTMS: All were RCTs and used excitatory frequencies (20 Hz, 10 Hz, 5 Hz) with intensities from 80% to 95% of the motor threshold [ 27 , 28 , 31 ]. Additionally, one used an inhibitory frequency (1 Hz) [ 28 ]. All of the studies targeted the primary motor cortex (M1).
  • Two studies used DBS: Both were noncontrolled QE studies. One used contralateral ventroposterior-lateral nucleus (VPL) stimulation [ 34 ], and the other used contralateral periventricular gray stimulation [ 39 ].
  • Four studies used TENS: Two were RCTs [ 36 , 38 ], and two were noncontrolled QE studies [ 37 , 40 ]. Two used stimulation in the PLP location on the nonamputated limb [ 37 , 38 ]; one study used the stump location [ 40 ], and the other used auricular TENS stimulation [ 36 ].
  • One QE study used PNS (femoral nerve and sciatic nerve trunk stimulation on the amputee side) [ 32 ], and one QE study used NMES (stimulation of quadriceps muscles of both legs) [ 35 ].

Intervention Characteristics

Interventions were heterogeneous in terms of stimulation parameters (area of stimulation, current intensity, pulse frequency, duration of the session, frequency, and the number of sessions) ( Table 1 ). Regarding the control group, most of the studies used sham stimulation as a comparator, and the other few studies used, respectively, 2-Hz TMS [ 28 ], mirror therapy [ 38 ], and placebo (TENS device off) [ 36 ]. One study reported the use of phantom hand movements during brain stimulation (anodal tDCS) [ 33 ]; no other intervention combinations in the active group were reported.

Study characteristics of individual studies

BKN = below knee; C = control; DBS = deep brain stimulation; EEG = electroencephalography; I = intervention; F = female; M = male; MARP = military amputee rehabilitation program; NMES = neuromuscular electrical stimulation; NR = not reported; NRS = numeric rating scale; PLP = phantom limb pain; PVG = ; QE = quasi-experimental; RCT = randomized controlled trial; rTMS = transcranial magnetic stimulation; tDCS = transcranial direct current stimulation; TENS = transcutaneous electrical nerve stimulation; VAS = visual analog scale.

Risk of Bias

The RoB for nine RCTs was assessed using the Jadad scale. The range of points was from 2 to 5 (TMS studies had low RoB, tDCS studies had low to moderate RoB, and the other techniques had moderate to high RoB). Five studies (56%) did not report the blinding procedures or reported incomplete information about the blinded personnel. Three studies (33.3%) did not report how they generated the randomization sequence and allocation concealment, even though they specified that the allocation of the subjects was done randomly ( Figure 2a ). The risk of bias for the five QE studies was assessed using the MINORS tool. The studies have a moderate to high RoB. All studies did not report the sample size calculation and the procedure and personnel in charge to assess the primary outcome. Also, all the studies included consecutive patients ( Figure 2b ).

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Risk of bias assessment. a) Risk of bias of randomized controlled trials using the Jadad scale. b) Risk of bias of quasi-experimental studies using Methodological Index for Non-Randomized Studies scale.

Neuromodulation Effects on Pain

We first evaluated the pooled effect of noninvasive excitatory M1 stimulation (including high-frequency rTMS and anodal tDCS). We found a significant and large effect size for short-term pain reduction (immediately after the end of stimulation sessions—six RCTs, two parallel and four crossover studies, N = 123, ES = −1.36, 95% CI = −2.26 to −0.45) ( Figure 3.1a ). We also found a significant medium-term pain reduction after one week to one month of stimulation (four RCTs, two parallel and two crossover studies, N = 106, ES = −1.24, 95% CI = −2.18 to −0.31) ( Figure 3.2b ).

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Forest plots on excitatory M1 noninvasive brain stimulation effects in phantom limb pain patients. a) Short-terms effects. b) Medium-term effects.

Considering the tDCS studies only, we found also a significant and large effect size of anodal tDCS in M1 for pain reduction immediately after the end of stimulation sessions (three crossover RCTs, N = 33, ES = −1.50, 95% CI = −2.05 to 0.95) ( Figure 3.2a ) and a significant pain reduction at one-week follow-up (two RCTs, N = 25, ES = −1.04, 95% CI = −1.64 to 0.45) ( Supplementary Data ). On the other hand, we found no significant pooled effect of anodal or cathodal tDCS in PPC on pain reduction immediately after the end of the stimulation sessions (one crossover RCT, N = 8, ES = −0.80, 95% CI = −1.82 to 0.22, ES = −0.40, 95% CI = −1.39 to 0.59) ( Supplementary Data ). These studies did not report any adverse effects related to tDCS stimulation.

Considering the rTMS studies only, we found no significant pooled effect of rTMS in M1 on pain reduction immediately after the end of the stimulation sessions (three RCTs, one parallel and two crossover, performed excitatory rTMS, N = 90, ES = −1.25, 95% CI = −3.05 to 0.56; one RCT performed inhibitory rTMS, N = 9, ES = −0.07, 95% CI = −1.00 to 0.85) ( Supplementary Data ) or pain reduction at one-month follow-up (two RCTs performed excitatory rTMS, N = 81, ES = −1.46, 95% CI = −3.79 to 0.86) ( Supplementary Data ). These studies do not report any adverse effects related to rTMS stimulation.

For the QE studies, we calculated a pooled response rate of TENS after stimulation sessions and found a significant pooled response rate (two studies, N = 20, pooled response rate = 67%, 95% CI = 60% to 73%) ( Supplementary Data ) and similar results for DBS after one year of follow-up (two studies, N = 8, rate = 73%, 95% CI = 63% to 82%) ( Supplementary Data ).

Our review comprised 14 studies (nine RCTs and five QE studies) that measured the effects of neuromodulation techniques (tDCS, rTMS, DBS, PNS, NMES, TENS) in patients with PLP. These studies were heterogeneous with regard to stimulation parameters and had small sample sizes and variable risk of bias (RCTs: low to moderate; QE: moderate to high). The pooled effects showed that PLP patients who underwent excitatory M1 stimulation, especially anodal tDCS, experienced a significant reduction in pain scale scores at the short-term and midterm time points. Motor cortex rTMS effected no significant difference between the active and sham groups. DBS and TENS elicited a significant decrease in PLP (noncontrolled QE studies).

Effects of tDCS and rTMS

Our exploratory meta-analysis of tDCS included three RCTs [ 29 , 30 , 33 ], demonstrating a significant decline in visual analog scale (VAS) scores for pain at the short-term and midterm end points with anodal M1 tDCS. Only cathodal tDCS to PPC decreased nonpainful phantom sensations [ 30 ]. There was no benefit for stump pain or telescoping. These results implicate a separation between the effects on painful and painless phantom sensations, likely due to the different neural circuits that are involved. None of the three trials reported moderate to severe side effects, confirming the safety of and tolerance to this technique [ 41 ].

The tDCS stimulation parameters were homogeneous; all studies targeted the motor cortex using excitatory polarization with a low current intensity (1–2 mA). Also, the session duration was 15–20 minutes. The main difference was the number of sessions [ 1–5 ]; the study with more sessions [ 33 ] reported a larger effect size, but due to the small number of included studies, we cannot suggest a potential dose response of this intervention, necessitating further studies to determine the influence of the number of sessions in PLP patients. Only one study [ 33 ] used a concomitant task (imaginary movements of the amputated limb) during tDCS stimulation, reporting a large effect on pain, indicating that the inclusion of concomitant motor tasks in the tDCS protocol may help to reactivate the deafferented motor cortex (amputated side) [ 42 ].

All of the studies on rTMS were RCTs [ 27 , 28 , 31 ]. Although Ahmed et al. [ 31 ] noted benefits of rTMS in reducing PLP, the exploratory pooled effect showed no significant difference between the active and sham groups.

One explanation of this negative result is the frequencies in these three rTMS experiments vs tDCS. Yet, all of the studies targeted the motor cortex; the forest plot results ( Supplementary Data ) showed a clear effect of stimulation frequency, with 1 Hz and 5 Hz showing no effect, 10 Hz having a marginal effect, and 20 Hz eliciting a significant result, suggesting that higher frequencies should be examined in future studies. This heterogeneity of the intervention makes it difficult to determine the reference stimulation parameters and might be a source of variability in the clinical effects.

This variability of parameters contrasts with the tDCS studies that had more homogeneous stimulation parameters (M1 anodal tDCS, cathoda l supraorbital, 2 mA, 20 minutes). Further, the baseline characteristics of the rTMS studies included patients who had undergone amputation less than three months earlier, which is not the best time to begin treating PLP. Conversely, more than three months had passed after amputation in most of the patients in the TDCS studies.

These trials were limited by their small sample sizes and short follow-up periods. Only well-powered trials with longer follow-ups can determine the true potential of tDCS and rTMS for PLP.

Effects of Invasive Neuromodulation Techniques

There are four reviews on DBS in patients with chronic pain, including small studies with PLP patients; three studies noted pain relief [ 43–45 ], but one showed no significant reductions in pain scores [ 46 ]. However, most of these reports were small mixed studies or case series. All available evidence has come from small trials, especially noncontrolled QE studies, and there is no consensus on how to perform DBS surgery or the parameters of stimulation [ 47 ], hampering the studies’ comparability. Although the pooled effect of the QE studies is significant in the short term and at follow-up, uncontrolled research results are inherently unreliable, and the certainty of the results should be considered low. Moreover, the risk for complications of invasive neuromodulation surgery is high; it is usually used only for severe PLP and is often chosen as a late treatment option, likely rendering it unsuitable for widespread use.

We could not include any study on DRG or SCS, for which there are only case reports, case series, and small retrospective cohorts ( Supplementary Data ). There are limited data on invasive neuromodulation (DBS, DRG, and SCS), and further research is needed.

TENS Effects

Three reviews on TENS [ 48–50 ] in mixed chronic pain populations, including few PLP patients, have been unable to judge the effectiveness of TENS for this condition. The main problem of TENS studies is the difference in stimulation site, including auricular areas [ 36 ], the contralateral leg [ 37 , 38 ], and above the stump [ 40 ]. All of these studies reported a significant reduction in PLP, based on the VAS, McGill Pain Questionnaire, universal pain score (UPS), and numerical rating scale (NRS). We pooled the results of the two quasi-experiments with the same stimulation parameters (contralateral to the site at which PLP was experienced on the amputated leg), and a significant reduction was found immediately after stimulation. However, the limitations of the noncontrolled QE designs prevented us from making a definitive conclusion.

Neurophysiological Hypothesis of Motor Cortex Stimulation in PLP

An important finding of this meta-analysis is that excitatory (anodal) primary motor cortex (M1) tDCS stimulation elicits a statistically and clinically significant reduction in pain intensity (by 1.5 points on the VAS) in patients with PLP [ 51 ]. The most frequently accepted hypothesis states that after amputation, PLP is associated with maladaptive reorganization of the sensory–motor cortex [ 52 ] and lower cortical inhibition [ 53 ], based on functional magnetic resonance imaging and TMS studies. Thus, PLP could be associated with decreased afference to M1, resulting in maladaptive plasticity in this area [ 54 ].

The resulting pain relief can be explained by the potential effects of tDCS on central pathophysiological mechanisms of pain that is associated with PLP [ 11 , 16 ]. It has been suggested that anodal M1 tDCS regulates in a top-down manner, sending signals toward the thalamocortical connections, prefrontal cortex, cingulate gyrus, and periaqueductal gray [ 55–57 ]. Based on this assumption, Lang et al. [ 58 ] reported significant activation of cortical and subcortical pain-related areas with anodal stimulation in healthy subjects. Further, one study on M1 anodal tDCS noted an increase in endogenous opioid release in the thalamus, insula, cingulate, and nucleus accumbens in a chronic pain patient [ 59 ].

Based on animal models, we hypothesized that the motor cortex not only is a passive target but also could be actively involved in the modulation of pain networks through disinhibition of the periaqueductal gray, enhancing the endogenous pain modulation system and the pain pathway of the dorsal horn in the spinal cord [ 60 , 61 ]. This phenomenon could result in the widespread modulation of other pain-related neural areas, such as the thalamus, thus modulating the upstream nociceptive signaling pathway. However, more mechanistic human studies are needed to truly understand the function of motor cortex stimulation as a target in the treatment of PLP patients and its influence on pain perception.

Limitations and Strengths

Due to the heterogeneity in stimulation parameters in the studies that were analyzed, it can be argued that meta-analyses do not compare similar interventions. These techniques are too heterogeneous to pool into a single unique meta-analysis; thus, we performed separate meta-analyses for similar techniques (mechanism of action and similar stimulation parameters) to reduce heterogeneity. The range in the variability of parameters was evaluated carefully to avoid a meta-analysis of opposing mechanistic effects (such as excitatory vs inhibitory stimulation, central vs peripheral intervention, and invasive vs noninvasive). For instance, the main pooled estimate in our study included noninvasive excitatory M1 stimulation. In addition, because effect estimates are needed for decision-making to guide future research and clinical applications, we found meta-analyses to be useful in providing a better overview of the results. Further, our meta-analysis recognizes the limitations in the primary studies, such as insufficient detail on the evaluation of the outcome, concomitant interventions, and the treatment that was received by the control group.

However, this study has important strengths. It followed the PRISMA guidelines and was registered in the PROSPERO database. In addition, we performed a comprehensive search strategy using multiple databases, without any language restrictions and across the articles that were cited by each of the identified studies, allowing us to retrieve all articles in previous systematic reviews [ 17 , 18 ] and others that were not found in these reviews. These strengths allowed us to report the state of the art in RCTs and QE controlled research on neuromodulation interventions in PLP and examine the efficacy and safety of these interventions.

The evidence from RCTs suggests that excitatory M1 stimulation—specifically, anodal M1 tDCS—significantly reduces pain scale scores in PLP patients after the stimulation sessions and at the midterm follow-up (one week). There are limited data on the efficacy of invasive neuromodulation techniques (DBS, DRG, and SCS). More RCTs are needed to evaluate the benefits and risks of neuromodulation techniques in patients with PLP. These studies need to be well powered, with longer follow-up (more than six weeks), and adequately reported (stimulation parameters and co-intervention description) to provide a definitive conclusion.

Supplementary Material

Pnaa039_ssupplementary_material, acknowledgments.

We thank the “Principle and Practice of Clinical Research” (PPCR) program from Harvard T.H. Chan School of Public Health for feedback on the initial version of this manuscript.

Authors’ Contributions

All authors designed the study. KP-B and XM collected the data. KP-B and XM performed statistical analyses. All authors participated in the interpretation of the results and the writing of the manuscript and approved the final version.

Contributor Information

Kevin Pacheco-Barrios, Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Boston, Massachusetts, USA. Universidad San Ignacio de Loyola, Vicerrectorado de Investigación, Unidad de Investigación para la Generación y Síntesis de Evidencias en Salud, Lima, Peru.

Xianguo Meng, Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Boston, Massachusetts, USA. Shandong First Medical University & Shandong Academy of Medical Sciences, College of Sport Medicine and Rehabilitation, Jinan, Shandong Province, P.R. China.

Felipe Fregni, Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Boston, Massachusetts, USA.

Funding sources: This study was supported by an National Institutes of Health (NIH) RO1 grant (1R01HD082302-01A1 to Felipe Fregni).

Conflicts of interest: The authors declare that they have no compelling interests related to this article.

Protocol registration number: PROSPERO 2018 CRD42018117998.

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    Phantom limb pain (PLP) can be disabling for nearly two thirds of amputees. Hence, there is a need to find an effective and inexpensive treatment that can be self administered. Among the non-pharmacological treatment for PLP, transcutaneous electrical nerve stimulation (TENS) applied to the contralateral extremity and mirror therapy are two ...

  21. Phantom Limb Pain

    Phantom limb pain (PLP) is a widespread and difficult-to-treat condition that can occur after an amputation, tumor removal or another injury to the limb. ... (TENS) is a type of electrical stimulation therapy that is used to treat various types of pain. TENS works by sending small electrical pulses through the skin to the affected area. These ...

  22. What if electrical stimulation could treat phantom limb pain?

    SURFACE ELECTRICAL STIMULATION (SES) - a non-invasive method of electrical stimulation which involves placing electrodes on the skin Imagine losing your left arm, but months later you experience pain in your left hand, even though it is no longer there. This is known as phantom limb pain, the painful sensations amputees feel in their missing limbs.

  23. Neuromodulation Techniques in Phantom Limb Pain: A Systematic Review

    The meta-analysis of noncontrolled QE studies demonstrated a high rate of pain reduction after stimulation with transcutaneous electrical nerve stimulation (rate = 67%, 95% CI = 60% to 73%) and at one-year follow-up with deep brain stimulation (rate = 73%, 95% CI = 63% to 82%). Conclusions