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Phantom Limb Pain: Mechanisms and Treatment Approaches

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The vast amount of research over the past decades has significantly added to our knowledge of phantom limb pain. Multiple factors including site of amputation or presence of preamputation pain have been found to have a positive correlation with the development of phantom limb pain. The paradigms of…

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Abstract

Introduction

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.

Case Reports and Assessments

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.

Case 1

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.

Case 2

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.

Method

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:

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

1. 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.

2. Preliminary baseline assessment was completed during the first appointment. This comprised a baseline of the five mentioned variables. The assessment was completed using the following semi-structured interview and questionnaires:

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.

1. 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.

2. 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.

3. 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.

Results

PLP

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.

PLS

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.

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.

SP

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.

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.

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.

Discussion

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.

Acknowledgments

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

References

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

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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].