|Year : 2015 | Volume
| Issue : 3 | Page : 103-110
Treatment of phantom pain with contralateral injection into tender points: a new method of treatment
Alaa A El Aziz Labeeb PhD 1, Roberto Casale2
1 Department of Physical Medicine and Rehabilitation, Menoufia University, Menoufia, Egypt
2 Pain Unit, Department of Neurorehabilitation, Scientific Institute of Montescano, Salvatore Maugeri Foundation, Montescano, Pavia, Italy
|Date of Submission||30-Jan-2015|
|Date of Acceptance||06-Jul-2015|
|Date of Web Publication||31-Aug-2015|
Alaa A El Aziz Labeeb
Department of Physical Medicine and Rehabilitation, Menoufia University, Menoufia
Source of Support: None, Conflict of Interest: None
The aim of this study was to ascertain the existence of contralateral painful muscle areas mirroring phantom pain and to evaluate the short-term effects of anaesthetics versus saline, injected contralaterally to control phantom and phantom limb pain.
This was a double-blinded cross-over study.
This study included eight lower-limb amputees with phantom limb pain in the past 6 months.
Either 1 ml of 0.25% bupivacaine or 0.9% saline was injected alternately in each point with a 28-G needle, with 72 h between injections. The main outcomes measured were phantom sensation modification and the intensity of phantom limb pain (visual analogue scale) before and after injections.
Painful muscle areas in the healthy limb do not mirror the topographical distribution of phantom limb pain. At 60 min after the injection, a statistically significantly greater relief of phantom limb pain was observed after using a local anaesthetic compared with that when using saline injection (P = 0.003). Bupivacaine consistently reduced/abolished the phantom sensation in six out of eight patients. These effects on phantom sensation were not observed after saline injections.
Contralateral injections of 1 ml of 0.25% bupivacaine in the myofascial hyperalgesic areas attenuated phantom limb pain and affected phantom limb sensation. Our study gives a basis of a new method of management of that kind of severe pain to improve the method of rehabilitation of amputee. However, further longitudinal studies with larger number of patients are needed to confirm our study.
Keywords: hyperalgesic areas, phantom pain, phantom sensations
|How to cite this article:|
El Aziz Labeeb AA, Casale R. Treatment of phantom pain with contralateral injection into tender points: a new method of treatment. Egypt Rheumatol Rehabil 2015;42:103-10
|How to cite this URL:|
El Aziz Labeeb AA, Casale R. Treatment of phantom pain with contralateral injection into tender points: a new method of treatment. Egypt Rheumatol Rehabil [serial online] 2015 [cited 2020 Aug 8];42:103-10. Available from: http://www.err.eg.net/text.asp?2015/42/3/103/163929
| Introduction|| |
Phantom limb pain has been reported to occur in up to 90% of limb amputees  . Despite such a high prevalence of this problem and a wide variety of treatment approaches that have been used, mechanism-based specific treatment guidelines are yet to evolve , . The nonpharmacological or local modalities used for treating phantom pain range from invasive procedures such as spinal surgery , to less invasive treatments such as electrotherapy  , acupuncture  and the use of local anaesthetics  .
To alleviate phantom pain, acupuncture needs to engage the nervous system to override the response to mismatched information. Acupuncture to the intact limb sends a normal afferent input to the nervous system, eliciting an analgesic effect. Acupuncture stimulation of points in the ear, stump, scalp and contralateral limb has been reported to help alleviate symptoms in individuals with phantom limb syndrome ,, .
Moreover, contralateral painful muscle areas (i.e. in the intact limb) and a phenomenon called synchiria have been reported. Contralateral painful muscle area is related to the areas of pain felt in the phantom  , whereas synchiria is defined as the perception of touch on the phantom on the reflected intact limb  .
These clinical observations suggested the idea that to treat these painful spots in the healthy limb by means of other physical treatments such as transcutaneous electrical nerve stimulation (TENS)  , as well as with locally injected anaesthetics, would influence the phantom pain sensation of the contralateral ones. As far as we know, although positive results were obtained using anaesthetic injection on contralateral muscle painful areas, there are only a few case reports dealing with this possible treatment ,,, .
Experimental observations support the hypothesis of a potential central origin of these seemingly heterolateral and reciprocal responses. The functional bilaterality at the spinal and higher supraspinal levels would then lead to mixed short-term responses both in the sensory and in the motor compartments , .
Treatment of phantom pain can be classified as medical, nonmedical and surgical. Medical treatment is the most effective. Numerous medical interventions have been proposed over the years, but tricyclic antidepressants and sodium channel blockers are currently considered to be the drug treatments of choice for neuropathic pain  .
Selective serotonin reuptake inhibitors  and benzodiazepine clonazepam have been reported to have a beneficial effect  . However, there is a general clinical impression that benzodiazepines do not produce substantial pain relief. Carbamazepine, an anticonvulsant drug, has been reported to be effective in the treatment of phantom pain  . Novel anticonvulsants such as lamotrigine and gabapentin may also prove to be effective in phantom pain  .
Nonmedical treatment can be combined with medical treatment and various noninvasive techniques such as TENS, vibration therapy, acupuncture, hypnosis, biofeedback and electroconvulsive therapy. Despite the widespread use of some of these techniques, clear evidence of effect is limited  .
Surgical treatments in the form of stump revision or neurectomy, cordotomy, thalamotomy and sympathectomy for phantom pain has been attempted for decades, but the results have generally been unfavourable  .
The aim of this study was to verify the existence of these contralateral painful muscle areas mirroring the painful areas of the phantom and evaluate, in the short-term, the effects of anaesthetics versus saline injection in the contralateral painful muscle areas in the control of phantom and phantom pain.
| Patients and methods|| |
After the approval of the protocol from our ethical committee and after providing detailed information to the patients as regards the aim and procedures of the study, eight lower-limb amputees affected by phantom limb pain lasting for more than 6 months gave their consent and were then enrolled in this study. Demographic features of the study group are described in [Table 1]. Exclusion criteria were the presence of stump pain, nonhealed early surgical scars or ulcers of the stump and the concomitant presence of polyneuropathy. The aetiology of amputation was traumatic (three cases) and vascular (five cases).
Patients were requested to draw on a paper their phantom and the painful sites within the phantom. Thereafter, on the healthy limb, painful muscle areas were searched by palpation on the corresponding topographical areas, according to Travell's manual semeiology  . Painful muscle sites to palpation were reported on paper and also marked on the skin of the patients ([Figure 1]).
|Figure 1: Representation of painful areas, level of amputation and phantom pain areas. Numbers from 1 to 8 represent the patients. Transverse striations above the knee represent levels of amputations. Striated areas at the knee and below represent painful areas on the amputated side.|
Click here to view
The same physician who performed the basal clinical examination, blinded to the type of treatment performed, visited the patient collecting the number of painful muscle areas present within 1 h after the injection. The intensity of the phantom pain was evaluated before and after treatments by means of visual analogue scale from 0 (no pain) to 10 (worst pain ever experienced).
In a double-blind cross-sectional way, a saline or a long-lasting anaesthetic (bupivacaine 2.5 mg/ml) was prepared in a separate room by a nurse by filling syringes of the same size (10 ml), attached to 28-G needles, to allow the injection of the same volume of 1 ml of saline or anaesthetic at each point. An independent doctor performed the injection of all signed points by injecting 1 ml of the given solute, blinded to the contents of the syringe and on the aim of the study.
All patients were injected with both saline and anaesthetics with a cross-over design ([Table 2]). Treatments lasted from each other not less than 72 h.
| Results|| |
No statistically significant differences were found on comparing the basal values of phantom pain before treatments (saline-basal vs. bupivacaine-basal; P = NS). In addition, no statistically significant difference was found in phantom pain values in the two groups between the first and the second treatment ([Table 2] and [Figure 2]).
|Figure 2: Comparison of basal phantom pain values (visual analogue scale). BUP, bupivacaine; SAL, saline.|
Click here to view
At 1 h after bupivacaine treatment, a significant reduction in the phantom pain versus basal values (P < 0.0005) was found. Saline also induced a significant decrease in the phantom pain versus basal values, with a lower level of significance (P < 0.05). Decrease in pain after bupivacaine is significantly more compared with that after saline (P < 0.005) ([Table 3] and [Figure 3]).
|Figure 3: Pain variation 1 h after treatment. BUL-AFT, bupivacaine after treatment; BUL-B, bupivacaine-basal values; SAL-AFT, saline after treatment; SAL-BS, saline-basal values.|
Click here to view
[Figure 2] shows no statistically significant differences on comparing basal values of phantom pain before treatments (saline-basal vs. bupivacaine-basal; P = NS), as well as in phantom pain values in the two groups between the first and the second treatment.
Bupivacaine consistently reduced/abolished the phantom sensation in six out of eight patients. These effects were not observed after saline injections.
[Figure 3] shows significant reduction in the phantom pain versus basal values. Saline also induced a significant decrease in the phantom pain versus basal values, with a lower level of significance (P < 0.05). Decrease in pain after administration of bupivacaine was significantly greater compared with that after administration of saline (P < 0.005).
| Discussion|| |
The presence of continuous intractable pain is a serious bias to the rehabilitation of amputees, and it affects the outcome of these patients in terms of speed of recovery, prosthesis fitting and quality of life , . From the literature emerges a new landscape where almost all of the 68 methods of treatment mentioned in a review of the 80s are reported as successful by some authors and unsuccessful by the others  . Unfortunately, until now there is no clear consensus about the efficacy of phantom limb pain treatment  and the situation seems to be very much the same as that critically described by Sunderland  that any operation selected for phantom pain seems to be more likely to fail than to succeed.
A part of the therapy focused on the amputated limb (mainly on the stump pain). The obvious lack of a physical area where we can locally apply physical treatments has forcefully directed the attention of clinicians to the possible utilization of the contralateral healthy limb to apply physical therapies. This possibility has found some other justification in the observations that hyperalgesic muscle areas are present in the healthy limb and that cutaneous stimuli applied to one limb can evoke simultaneous sensation in the other limb: both phenomena have been described in amputees , .
The aims of our work were to determine the extent to which the presence of areas of myofascial hyperalgesia could mirror phantom pain localization and to determine whether their infiltration with an anaesthetic could relieve both myofascial hyperalgesia to static mechanical stimulation and the phantom pain.
In our small series, the most affected parts in the healthy limb were the proximal lateromedial part of the thigh and the anterior compartment (tibialis anterior) in the calf, whereas the areas of major phantom pain representation were essentially related to the foot and ankle. This is in agreement with the clinical data presented in the literature on the prevalent distribution of the phantom and phantom pain to distal areas of limbs  . Thus, the presence of myofascial hyperalgesic areas in the healthy limb and their distribution did not seem to exactly mirror the phantom pain areas.
However, notwithstanding this substantial mismatch between phantom pain localization and the presence of myofascial hyperalgesic areas, their treatment was able to reduce the phantom pain in all patients and induce modification in the phantom perception in six of them. It is worth to mention the fact that, as described previously by others  , saline was also able to partially reduce pain but did not affect the phantom except in a case in which a transient telescopic sensation was reported.
As expected, the anaesthetic injection into the myofascial hyperalgesic areas in the healthy limb completely relieved the pain.
Possible mechanism of phantom pain relief
The mechanism by which contralateral injection of anaesthetic is able to influence (reduce) phantom pain has not yet been established because until now the real nature of the phantom pain has not been clearly illustrated. A possible pragmatic approach could also take into account other physical modalities applied contralaterally in these patients to find out possible similarities of mechanism of action that can be used as a model of understanding.
Only few contralateral physical treatments are described in the literature. They are TENS [7, 9, 14] and contralateral local anaesthetic injections , . All of them have been reported to be highly effective.
TENS has been used by applying high-frequency/low-intensity currents. Its efficacy has been assumed to be related to a gating mechanism and theoretically limited to segmental short-lasting effects  . This view has been recently enlarged (expanded) by the observation of bilateral changes in thermal threshold induced by unilateral application of high-frequency TENS (100 Hz) in a group of healthy individuals and related these changes to a central segmental mechanism of TENS , . The fact that thermal sensations are carried by fibres histologically similar to pain fibres carrying nociceptive information (namely A-delta and C fibres) can give some support to the theory of contralateral antinociceptive effect of TENS. This hypothesis has also supported the use of electrical stimulation in the clinical battlefield either ipsilateral or contralateral to the amputation, with some success.
Traditional, as well as western, acupuncture, has been encountered into the so-called counter-irritative therapies  exerting their analgesic effects by means of hyperstimulations  . Its efficacy is related to the activation of antinociceptive systems such as endorphins  . Therefore, from a therapeutical point of view acupuncture or electroacupuncture acting on opiatergic systems can be accounted for inducing a decrease in pain and phantom pain sensation even when contralaterally applied to the painful site ,, .
The use of anaesthetics differs from the above-mentioned mechanisms (i.e. the spinal gating and the opiatergic systems) as it is mainly based on the inhibition of afferent inputs at the site of origin, or on the blockade of nociceptive fibres along a peripheral nerve  . A possible systemic effect of bupivacaine does not seem to be sustained, as the phantom pain completely disappeared in patient VII in whom only few muscle hyperpathic areas were found and a few millilitres of bupivacaine were used. Moreover, the recorded effect was too fast to be mediated by a systemic diffusion of the drug.
The blockade of afferent inputs, especially if pathological, and the consequent reduction of abnormal sensory barrages to the spinal cord could be taken into account to justify its action. Phantom pain, however, is not influenced by a peripheral blockade and it often persists even after dorsal rhizotomy  .
Another intriguing hypothesis is that the phantom and the phantom pain are sustained by a dramatic lack of inputs from the amputated limb. A variation of this is that the lack of inputs should be time locked with the huge surge of sensory inputs due to the amputation. In these cases the systemic blockade of all hyperalgesic contralateral areas should theoretically increase the pain rather than reduce it, as seen after lumbar plexus blockade  . Moreover, in the light of that, a 'normal phantom' is usually felt after local anaesthetic blockade of a peripheral nerve  . All these do not help in understanding how a contralateral blockade can influence the phantom pain.
A possible explanation of the efficacy of the blockade of sensory and nociceptive inputs to the spinal cord contralaterally to the phantom is the positive sensory phenomenon, called synchiria  , seen in a clinic, in which a cutaneous stimulus that is applied to one limb evokes sensation simultaneously in both limbs. This phenomenon, as well as referred sensations, has been described following stroke, complex regional pain syndrome, and in amputees with phantom limb pain  .
In dysynchiria, touch to the asymptomatic limb evokes the sensation of touch in that limb and pain and dysaesthesia on the affected limb  . Neither synchiria nor dysynchiria has been reported in healthy individuals or in patients with minor nerve damage such as acute localized or radicular pain  . The mechanisms underlying synchiria and dysynchiria are the positive aspects we observed and used in our study as using anaesthetic: a blockade of muscle hyperpathic areas in the healthy side (i.e. a reduction of inputs) is able to influence the phantom sensation and painful phantom on the contralateral side. The mechanisms underlined these effects both the positive, synchiria, and the negative, the reduction of phantom and pain sensation, could include any of the followings working alone or in combination:
- Changes in spinal dorsal horn function including central sensitization  , bilateral sensory interneurons or ganglia  , spinal cord or brainstem commissural interneurons  , or glial cell activation , .
- Changes in subcortical structures, including changes in thalamic function , , associative somatosensory cortices, the insula, frontal cortices or the anterior cingulate cortex ,,,,.
Most of the recent studies are focused on the changes recorded at suprasegmental cortical level following the original idea of a distortion of the neuromatrix ,, . However, the concept of a 'neuromatrix' for pain processing has scanty evidence for any particular regional or circuit dysfunction during clinical pain  .
At the spinal level, many data support a mutual connectivity between the two sides of the cord. For instance, the neurochemical modulation of one side provokes rapid responsivity changes on the corresponding contralateral side , . In pathological models of peripheral neuropathy, the centrally induced sensitization of dorsal horn neurons facilitates heterolateral inputs. Sensitization would allow for direct responses of ipsilateral wide dynamic range neurons, accounting for lowered threshold to contralateral stimulations  . Neurodynamic events such as sensitization and lowered threshold values are the final outcome of many metabolic and neurochemical events modifying often permanently the responsive features of sensory neurons and driving to the lowered discharge and stimulus thresholds. On the basis of a delicate AMPA and NMDA receptor interaction, sensitization shares many markers with widespread phenomena in the CNS, such as long-term potentiation and memory storages , . Bilateral input weighing is functionally operative even at higher supraspinal levels. For instance, early reports have already provided evidence on mutual connections in rat somatosensory thalamus  , as well as on instances of cortical transcallosal connections in humans  . This evidence would come along with those fast responses we observed in our patients.
Bilaterality is a far diffused phenomenon both in the sensory and in the motor compartments. For instance, as it has been shown in rats with a peripheral neuropathy, the stimulation of the uninjured paw promoted evoked potentials in the ventral root on the injured side  .
The dynamic properties induced by the bilateral sensorimotor image of lateralized inputs seem the heritage of strong developmental anatomic design where robust bilateral interactions between the developing neural systems on each side are important for achieving connectivity balance between the two sides of the neuraxis  .
The fast relief of pain in the patient, as shown in our data, even with few numbers of patients, would match with the speed of signal transition due to paucisynaptic connections between the two sides of the system. These characteristics would explain many of the data here and elsewhere reported, even if obvious pending problems remain - for instance, the strength, the distribution level of the mutual connections and the very role they would play on the clinical stage.
| Conclusion|| |
Contralateral injections of 1 ml 0.25% bupivacaine in myofascial hyperalgesic areas attenuated phantom limb pain and affected phantom limb sensation. Our study gives a basis of a new method of management of that kind of severe pain to improve the method of rehabilitation of amputee. However, further longitudinal studies with larger number of patients are needed to confirm our study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Hsu E, Cohen SP. Postamputation pain: epidemiology, mechanisms, and treatment. J Pain Res 2013; 6
Casale R, Maini M, Bettinardi O, Labeeb A, Rosati V, Damiani C, Mallik M. Motor and sensory rehabilitation after lower limb amputation: state of art and perspective of change. G Ital Med Lav Ergon 2013; 35
Subedi B, Grossberg GT. Phantom limb pain: mechanisms and treatment approaches. Pain Res Treat 2011; 2011
Zheng Z, Hu Y, Tao W, Zhang X, Li Y. Dorsal root entry zone lesions for phantom limb pain with brachial plexus avulsion: a study of pain and phantom limb sensation. Stereotact Funct Neurosurg 2009; 87
Viswanathan A, Phan PC, Burton AW. Use of spinal cord stimulation in the treatment of phantom limb pain: case series and review of the literature. Pain Pract 2010; 10
Mulvey MR, Radford HE, Fawkner HJ, Hirst L, Neumann V, Johnson MI. Transcutaneous electrical nerve stimulation for phantom pain and stump pain in adult amputees. Pain Pract 2013; 13
Davies A. Acupuncture treatment of phantom limb pain and phantom limb sensation in a primary care setting. Acupunct Med 2013; 31
Ilfeld BM, Moeller-Bertram T, Hanling SR, Tokarz K, Mariano ER, Loland VJ, et al.
Treating intractable phantom limb pain with ambulatory continuous peripheral nerve blocks: a pilot study. Pain Med 2013; 14
Bradbrook D. Acupuncture treatment of phantom limb pain and phantom limb sensation in amputees. Acupunct Med 2004; 22
Jacobs M, Niemtzow R. Treatment of phantom limb pain with laser and needle auricular acupuncture: a case report. Med Acupunct 2011; 23
Mannix S, O'Sullivan C, Kelly G. Acupuncture for managing phantom-limb syndrome: a systematic review. Med Acupunct 2013; 25
Gross D. Contralateral local anaesthesia in the treatment of postamputation pain. In: Siegfried J, Zimmermann M, editors Phantom and stump pain
Berlin: Springer-Verlag 1981;107-107.
Moseley GL, Gallace A, Spence C. Bodily illusions in health and disease: physiological and clinical perspectives and the concept of a cortical 'body matrix'. Neurosci Biobehav Rev 2012; 36
Carabelli RA, Kellerman WC. Phantom limb pain: relief by application of TENS to contralateral extremity. Arch Phys Med Rehabil 1985; 66
Gross D. Contralateral local anaesthesia in the treatment of phantom limb and stump pain. Pain 1982; 13
Gross D. Contralateral local anesthesia in stump, phantom and post-traumatic pain. Reg Anaesth 1984; 7
Flöter T. Pain management by contralateral local anaesthesia. Acupunct Electrother Res 1983; 8
Koltzenburg M, Wall PD, McMahon SB. Does the right side know what the left is doing? Trends Neurosci 1999; 22
Dostrovsky JO. Ascending spinal and trigeminal nociceptive pathways. In: Justins DM, editor Pain 2005 - an updated review: refresher course syllabus
. Seattle: IASP Press; 2005. 43-48.
Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999; 83
Iacono RP, Sandyk R, Baumford CR, Awerbuch G, Malone JM. Post-amputation phantom pain and autonomous stump movements responsive to doxepin. Funct Neurol 1987; 2
Bartusch SL, Sanders BJ, D'Alessio JG, Jernigan JR. Clonazepam for the treatment of lancinating phantom limb pain. Clin J Pain 1996; 12
Elliott F, Little A, Milbrandt W. Carbamazepine for phantom-limb phenomena. N Engl J Med 1976; 295
Patterson JF. Carbamazepine in the treatment of phantom limb pain. South Med J 1988; 81
Rasmussen KG, Rummans TA. Electroconvulsive therapy for phantom limb pain. Pain 2000; 85
Saris SC, Iacono RP, Nashold BS Jr. Successful treatment of phantom pain with dorsal root entry zone coagulation. Appl Neurophysiol 1988; 51
Travell J. Myofascial trigger points: a clinical view. In: Bonica JJ, Albe-Fessard D, editors Advances in pain research and therapy
New York: Raven Press 1976;919-26.
Kazemi H, Ghassemi S, Fereshtehnejad SM, Amini A, Kolivand PH, Doroudi T. Anxiety and depression in patients with amputated limbs suffering from phantom pain: a comparative study with non-phantom chronic pain. Int J Prev Med 2013; 4
Kooijman CM, Dijkstra PU, Geertzen JH, Elzinga A, van der Schans CP. Phantom pain and phantom sensations in upper limb amputees: an epidemiological study. Pain 2000; 87
Malavera Angarita M, Carrillo Villa S, Gomezese Ribero O, García R, Silva Sieger F. Pathophysiology and treatment of phantom limb pain. Colomb J Anesthesiol 2014; 42
Sunderland S. The treatment of pain and related abnormal sensory phenomena associated with amputation stump. In: Sunderland S, editors. Nerves and nerve injuries.
2nd ed. Baltimore: William & Wilkins 1978; 448-458.
Henderson WR, Smyth GE. Phantom limbs. J Neurol Neurosurg Psychiatry 1948; 11
Frost FA, Jessen B, Siggaard-Andersen J. A control, double-blind comparison of mepivacaine injection versus saline injection for myofascial pain. Lancet 1980; 1
Tashani O, Johnson M. Transcutaneous electrical nerve stimulation (TENS). A possible aid for pain relief in developing countries?. Libyan J Med 2009; 4
DeSantana JM, Walsh DM, Vance C, Rakel BA, Sluka KA. Effectiveness of transcutaneous electrical nerve stimulation for treatment of hyperalgesia and pain. Curr Rheumatol Rep 2008; 10
Buonocore M, Camuzzini N, Cecini M, Dalla Toffola E. High-frequency transcutaneous peripheral nerve stimulation induces a higher increase of heat pain threshold in the cutaneous area of the stimulated nerve when confronted to the neighbouring areas. Biomed Res Int 2013; 2013
Pfab F, Kirchner MT, Huss-Marp J, Schuster T, Schalock PC, Fuqin J, et al
. Acupuncture compared with oral antihistamine for type I hypersensitivity itch and skin response in adults with atopic dermatitis: a patient- and examiner-blinded, randomized, placebo-controlled, crossover trial. Allergy 2012; 67
Gorenberg M, Schwartz K. Imaging-guided hyperstimulation analgesia in low back pain. J Pain Res 2013; 6
Saris SC, Iacono RP, Nashold BS Jr. Dorsal root entry zone lesions for post-amputation pain. J Neurosurg 1985; 62
Martin G, Grant SA, Macleod DB, Breslin DS, Brewer RP. Severe phantom leg pain in an amputee after lumbar plexus block. Reg Anesth Pain Med 2003; 28
Nathan PW, Noordenbos W, Wall PD Ongoing activity in peripheral nerve: interactions between electrical stimulation and ongoing activity. Exp Neurol 1973; 38
Acerra NE, Souvlis T, Moseley GL. Stroke, complex regional pain syndrome and phantom limb pain: can commonalities direct future management?. J Rehabil Med 2007; 39
Acerra NE, Moseley GL. Dysynchiria: watching the mirror image of the unaffected limb elicits pain on the affected side. Neurology 2005; 65
Bausbaum A, Bushnell MC, Devor M. Pain: basic mechanisms. In: Justins DM, editor Pain 2005 - an updated review
. Seattle: IASP Press 2005; 3-9.
McLachlan EM, Janig W, Devor M, Michaelis M. Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia. Nature 1993; 363
Milligan ED, Twining C, Chacur M, Biedenkapp J, O'Connor K, Poole S, et al.
Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci 2003; 23
Watkins LR, Maier SF. Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev 2002; 82
Fukumoto M, Ushida T, Zinchuk VS, Yamamoto H, Yoshida S. Contralateral thalamic perfusion in patients with reflex sympathetic dystrophy syndrome. Lancet 1999; 354
Flor H, Elbert T, Knecht S, Wienbruch C, Pantev C, Birbaumer N, et al.
Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature 1995; 375
Grüsser SM, Mühlnickel W, Schaefer M, Villringer K, Christmann C, Koeppe C, Flor H. Remote activation of referred phantom sensation and cortical reorganization in human upper extremity amputees. Exp Brain Res 2004; 154
Ramachandran VS. A brief tour of human consciousness: from impostor poodles to purple numbers
. New York: PI Press; 2004.
Knecht S, Henningsen H, Elbert T, Flor H, Höhling C, Pantev C, Taub E Reorganizational and perceptional changes after amputation. Brain 1996; 119
Gandevia SC, Phegan CM. Perceptual distortions of the human body image produced by local anaesthesia, pain and cutaneous stimulation. J Physiol 1999; 514
Melzack R. Evolution of the neuromatrix theory of pain. The Prithvi Raj lecture: presented at the third world congress of world institute of pain, Barcelona 2005. Pain Pract 2005; 5
Giummarra MJ, Gibson SJ, Georgiou-Karistianis N, Bradshaw JL. Central mechanisms in phantom limb perception: the past, present and future. Brain Res Rev 2007; 54
Iannetti GD, Mouraux A. From the neuromatrix to the pain matrix (and back). Exp Brain Res 2010; 205
Derbyshire SW. Exploring the pain 'neuromatrix'. Curr Rev Pain 2000; 4
Bileviciute-Ljungar I, Biella G, Bellomi P, Sotgiu ML. Contralateral treatment with lidocaine reduces spinal neuronal activity in mononeuropathic rats. Neurosci Lett 2001; 311
Sotgiu ML, Biella GE. NMDA and strychnine diversely modulate spinal dorsal horn noxious responsiveness in normal rats: potential significance to sensory disorders in neuropathic pain. Somatosens Mot Res 2002; 19
Sotgiu ML, Biella G. Contribution of central sensitization to the pain-related abnormal activity in neuropathic rats. Somatosens Mot Res 2000; 17
Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci 2003; 26
Collingridge GL, Isaac JTR, Wang YT. Receptor trafficking and synaptic plasticity. Nat Rev 2004; 5
Verley R. Reorganization of the somatosensory cerebral cortex after peripheral damage. NIPS 1986; 1
Frot M, Mauguière F. Dual representation of pain in the operculo-insular cortex in humans. Brain 2003; 126
Won R, Jung SJ, Park YG, Chung SS, Lee BH. Crossed-withdrawal reflex in a rat model of neuropathic pain: implications in neural plasticity. Neurosci Lett 369
Friel KM, Martin JH. Bilateral activity-dependent interactions in the developing corticospinal system. J Neurosci 2007; 27
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]