NEUROPATHIC PAIN in patients with SCI is resistant to

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1 1766 ORIGINAL ARTICLE Effect of Repetitive Transcranial Magnetic Stimulation Over the Hand Motor Cortical Area on Central Pain After Spinal Cord Injury Bo Sung Kang, MD, Hyung Ik Shin, MD, PhD, Moon Suk Bang, MD, PhD ABSTRACT. Kang BS, Shin HI, Bang MS. Effect of repetitive transcranial magnetic stimulation over the hand motor cortical area on central pain after spinal cord injury. Arch Phys Med Rehabil 2009;90: Objective: To evaluate the analgesic effect of repetitive transcranial magnetic stimulation (rtms) applied on the hand motor cortical area in patients with spinal cord injury (SCI) who have chronic neuropathic pain at multiple sites in the body, including the lower limbs, trunk, and pelvis. Design: Blinded, randomized crossover study. Setting: University hospital outpatient setting. Participants: Patients (N 13) with motor complete or incomplete SCI and chronic central pain (11 completed the study). Interventions: rtms was applied on the hand motor cortical area using a figure-of-eight coil. One thousand stimuli were applied daily on 5 consecutive days. Real and sham rtms were separated by 12 weeks. Main Outcome Measures: Numeric rating scale (NRS) for average and worst pain and the Brief Pain Inventory (BPI). Results: At 1 week after the end of the rtms period, the average NRS scores changed from to with real stimulation and from to with sham stimulation, and did not differ between treatments. The interference items of the BPI also did not differ between the real and sham rtms. The effect of time on the NRS score for worst pain was significant with real stimulation but not with sham stimulation. Conclusions: The therapeutic efficacy of rtms was not demonstrated when rtms was applied to the hand motor cortical area in patients with chronic neuropathic pain at multiple sites in the body, including the lower limbs, trunk, and pelvis. However, the results for worst pain reduction suggest that further studies are required in which rtms is applied with a more intensive stimulation protocol. Key Words: Pain; Rehabilitation; Spinal cord injuries; Transcranial magnetic stimulation by the American Congress of Rehabilitation Medicine NEUROPATHIC PAIN in patients with SCI is resistant to treatment and has considerable impact on the quality of life. 1,2 Recently, studies of rtms applied to the motor cortex corresponding to the pain area suggest that it has potential as a therapeutic tool to relieve chronic neuropathic pain. 3 7 In most studies, rtms has been applied to disease conditions with unilateral upper limb or facial pain rather than lower limb pain, such as neuropathic pain associated with brachial plexus injury, complex regional pain syndrome, and trigeminal neuralgia. 4-8 This might be attributable to the following factors. First, compared with the motor cortical area corresponding to the lower limbs, the upper limb and facial motor cortical areas are nearer to the scalp, resulting in a higher intensity of the induced electrical field when magnetic stimulation is applied on the scalp. Second, the representation areas for the upper limbs and face are wider than that for the lower limbs, which makes it easy to apply magnetic stimulation accurately to the corresponding area. Thus, the effect of rtms on neuropathic pain involving the lower limbs after SCI has seldom been investigated, except in the study by Defrin et al. 3 In that study, rtms was applied to paraplegic patients with chronic neuropathic pain in their legs. The stimulation site was the vertex targeting the leg representation areas, and a figure-of-eight coil was used. Pain reduction was demonstrated in both the real and sham rtms groups, and there was no significant difference between the groups. A figure-of-eight coil is commonly used for focal stimulation, such as in cortical mapping, but is not appropriate for the stimulation of the deep structures of the brain. 9,10 With this figure-of-eight coil, the cortical area representing the lower limbs might not have been stimulated to the threshold level. The lower limb motor response could not be confirmed because of the paraplegic status of the subjects, which might have contributed to the negative results of that study. 11 However, Garcia-Larrea et al 12 recently suggested the hypothesis that the motor cortex acts as a pathway to the painrelated structures of the brain including the thalamic nuclei, From the Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul, South Korea (Kang, Bang); and Department of Rehabilitation Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea (Shin). Presented to the International Spinal Cord Society, September 1 4, 2008, Durban, South Africa. Supported by the Seoul National University Bundang Hospital (grant no ). No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. Reprint requests to Hyung Ik Shin, MD, PhD, Dept of Rehabilitation Medicine, Seoul National University Bundang Hospital, 300 Gumi-Dong, Bundang-Gu, Seongnam City, Gyenggi-Do, , South Korea, hyungik1@snu.ac.kr /09/ $36.00/0 doi: /j.apmr BPI EMG FDI MCS MEP NRS RMT rtms SCI TMS List of Abbreviations Brief Pain Inventory electromyography first dorsal interosseous motor cortical stimulation motor evoked potential numeric rating scale resting motor threshold repetitive transcranial magnetic stimulation spinal cord injury transcranial magnetic stimulation

2 MAGNETIC STIMULATION FOR PAIN AFTER SPINAL CORD INJURY, Kang 1767 anterior cingulate, and upper brainstem, and somatotopic matching between the motor cortex and the pain site might not play a crucial role in the analgesic effect of rtms. Among previous studies, the report of Passard et al 13 is, to our knowledge, the only study to apply rtms over the motor cortex, which does not correspond to the pain area. In that study, rtms was applied over the hand motor cortical area to treat the widespread chronic pain of fibromyalgia. A significant reduction in pain was demonstrated, with an effect size of 1.10 at 15 days after the first stimulation. In this study, we evaluated the analgesic effect of rtms applied to the hand motor cortical area in patients with SCI who have chronic neuropathic pain at multiple sites in the body, including the lower limbs, trunk, and pelvis. METHODS Participants Thirteen patients with SCI volunteered to participate in the study. Two patients withdrew from the study before the first session of rtms for reasons unrelated to any medical issues (too much time required to reach the laboratory). Eleven patients with SCI completed the study (mean age, y). The patients were recruited consecutively from the outpatient clinic of the Department of Rehabilitation Medicine (table 1). Six patients had paraplegia and 5 patients had tetraplegia; 5 patients had motor complete SCI, and 6 had motor incomplete SCI. All participants had characteristics of neuropathic pain (pricking, tingling, hot burning, stabbing, shooting, etc) below the level of SCI at multiple sites in their bodies, including the lower limbs, trunk, and pelvis. 14 Patients with chronic pain above or at the lesion level, including subjects with cauda equina lesions, were excluded. 14 Patients with acute pain anywhere in the body were also excluded. In patients with belowlevel pain with chronic neuropathic characteristics, musculoskeletal conditions including knee osteoarthritis and tendinitis were screened for to make sure they were not responsible for the pain. The inclusion criteria were (1) chronic neuropathic pain for 15 months or more, (2) pain that was not attributable to causes other than neuropathic pain (eg, musculoskeletal pain, pain from diabetic polyneuropathy), and (3) pain that was resistant to various types of medications or physical or complementary medicine treatment. Patients having the following conditions were excluded: any kind of metal implant in the head; heart disease, including having a cardiac pacemaker; family or personal history of epilepsy, or psychiatric illness. All patients were being treated with various medications including anticonvulsants, nonsteroidal anti-inflammatory drugs, and antidepressants. They were instructed not to change the dosages throughout the experimental and follow-up period. The study protocol and consent forms were reviewed and approved by our institution s research committee for human subjects. All subjects signed an informed consent form. Preparation Each participant sat in a comfortable chair and was asked to relax. A recording electrode was placed on the FDI muscle at the proximal edge adjacent to the first and second carpometacarpal joint using a disposable self-adhesive 19-mm-diameter surface electrode. a A reference electrode was placed on the second metacarpophalangeal joint. MEP signals were filtered (bandpassed between 50Hz and 2kHz), amplified, and displayed on a conventional EMG machine. b Because the MEP amplitude can increase when the FDI muscle is not relaxed, the appearance of sounds and waveforms on the EMG machine resulting from muscle contraction were monitored to confirm the relaxation state of the FDI muscle. The TMS of the M1 cortex was delivered through a figure-of-eight coil connected to a Magstim 200 magnetic stimulator. c The external diameter of each loop was 90mm, and the peak magnetic field was 2.2T. The coil was placed tangentially to the scalp about 45 from the midline, and the handle of the coil pointed 45 backward and laterally. To avoid uncontrolled coil displacement during the TMS session, a combination of manual handling and mechanical fixation of the coil was used. We determined the hot spot for activation of the left FDI muscle, where the stimuli evoked the motor potentials with maximal peak-to-peak amplitude. Stimuli were given over the right M1 cortex at the minimum suprathreshold intensity to identify MEP signals consistently, and the coil was moved in 5-mm steps to determine the optimal scalp position. We then measured the RMT, which was defined as the minimum stimulation intensity required to evoke MEPs of more than 50 V in at least 5 of 10 trials, to the nearest 1% of the stimulator output. Repetitive Transcranial Magnetic Stimulation This study comprised 2 separate sessions: one a real rtms session and the other a sham rtms session. In the real rtms sessions, the subjects received 20 trains of 10-Hz stimuli delivered for a duration of 5 seconds. rtms was applied at 80% of the RMT intensity with a 55-second intertrain interval. 5 This stimulation session was repeated for 5 consecutive days. 4 The figure-of-eight coil was centered over the scalp position deter- Table 1: Characteristics of the Participants and Pain Site Below the Lesion Patient Age (y) Sex SCI Level ASIA Classification Grade Time From Injury (mo) Pain Locations 1 62 M C7/C8 D 84 Frontal torso/back/both buttocks/both legs 2 60 M C6/C7 B 122 Both upper legs/lower legs 3 41 F T10/T11 A 231 Both upper legs/lower legs 4 69 M C7/C7 D 16 Both lower legs/feet 5 39 F C6/T1 C 23 Both upper legs/lower legs/genitals 6 52 F T4/T4 A 34 Both upper legs/lower legs 7 58 F T6/T10 B 18 Both upper legs/lower legs 8 33 M T5/T7 A 56 Both upper legs/lower legs 9 46 F T5/T4 D 35 Right upper leg/lower legs/genitals M T10/T8 D 32 Both lower legs/feet M C7/C7 C 15 Frontal torso/back/both buttocks/both legs NOTE. Pain locations are described according to the International Spinal Cord Injury Pain Basic Data Set. 19 Abbreviation: ASIA, American Spinal Injury Association; F, female; M, male.

3 1768 MAGNETIC STIMULATION FOR PAIN AFTER SPINAL CORD INJURY, Kang mined previously. During stimulation, the subject wore a tightly fitting cap on which the hot spot was marked to ensure accurate stimulation and consistent repositioning of the coil. The procedure was identical for the sham stimulation as for the real rtms session, but the coil was elevated and angled away from the head to produce some of the subjective sensation of rtms. 4,7 Subjects heard the clicks of the coil clearly. The real and sham rtms stimulations were separated by 12 weeks and performed in a random order according to the prepared allocation code. Outcome Measures The NRS score for average pain during the preceding 24 hours was defined as the primary outcome measure, the basis of the clinical decision rule on which the determination of efficacy was made. 15 The endpoints were set as no pain sensation (0 on the NRS) and the most intense pain sensation imaginable (10 on the NRS). Although no one scale for measuring pain intensity consistently demonstrates greater responsiveness in detecting improvements associated with intervention, the 0-to-10 NRS has been recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus group for use in pain clinical trials 16 and by the National Institute on Disability and Rehabilitation Research sponsored consensus group regarding SCI-related pain. 17 As a secondary outcome measure, we assessed the NRS score for the worst pain over the preceding 24 hours. To identify the diurnal peak in pain intensity, measurements of worst pain as well as average pain over the preceding 24 hours are included in the BPI, an instrument for the comprehensive evaluation of pain. 18 We also evaluated the interference items of the BPI to measure the degree to which pain interfered with daily life. 18 These items are also recommended by the National Institute on Disability and Rehabilitation Research sponsored consensus group regarding SCI-related pain as the outcome measure for pain interference after SCI. 17 The interference items of the BPI included general activity, mood, walking, work, sleep, relationships with others, and enjoyment of life. 18 Subjects were asked to rate how their pain interfered with these items over the previous 24 hours using the NRS. We excluded the walking item because 7 of the 11 subjects could not walk. The total BPI score ranged from 0 (no interference) to 60 (complete interference). The NRS and BPI were measured before the first session, immediately after the third and fifth stimulation sessions, and 1, 3, 5, and 7 weeks after the end of the 5-day stimulation period. To ensure that the study was performed double-blind, 1 researcher applied the magnetic stimulation and a different researcher collected the clinical data; the latter researcher was not aware of the type of rtms (real or sham) that had been used for each patient. Information about the type of rtms sessions was not given to participants until the end of the study. Data Processing Data from the 11 patients who completed the study protocol were processed with SPSS software. d Analysis of variance for repeated measures was used to evaluate the effect of rtms (real, sham) on the NRS and BPI scores. To compare the effects of real and sham stimulation within each patient, we calculated the percentage modification of the pain level using the following equation: [(Post-rTMS Pre-rTMS pain score)/ Pre-rTMS pain score] 100. Intraindividual comparison was performed using the Student paired t test. Significance was accepted at a P value less than.05. RESULTS The results of the pain measurements are summarized in table 2. Numeric Rating Scale Scores for Average Pain The effect of time was not significant for the real stimulation (P.403) or for the sham stimulation (P.345). The group by time interaction was not significant (P.104), meaning that the change in the average pain intensity was similar between the real and sham rtms treatment series (fig 1). The statistical power was 39.8%, and the estimated effect size was.932. The intraindividual comparison showed a reduction in the average NRS score after the end of the real rtms period. However, the difference in the reduction rate compared with the sham stimulation was not statistically significant (fig 2A). Numeric Rating Scale Scores for Worst Pain The worst pain scores did not differ significantly between the real and sham stimulation before the first treatment session. The effect of time was significant with the real stimulation (P.024) but not with the sham stimulation (P.109). With the real stimulation, Bonferroni adjustment for multiple comparisons revealed borderline significance (P.054) at 3 weeks after the end of the stimulation period compared with the pain score measured before the rtms session (see fig 1). The group by time interaction was significant (P.025), meaning that the change in pain intensity differed between the real and sham rtms treatment series, and the estimated effect size was.972. The intraindividual comparison showed no difference between the pain intensity with the real and sham stimulations during the rtms treatment period (fig 2B). However, at 1 week after the end of the rtms period, the pain intensity had decreased by 14.1% in the real stimulation and had increased by Table 2: NRS and BPI Scores of the Participants (n 11) NRS for Average Pain NRS for Worst Pain BPI Real Sham Real Sham Real Sham Before Day ( 3.56) ( 8.86) ( 6.11) ( 2.68) ( 5.99) (4.23) Day ( 8.47) ( 14.8) ( 5.82) ( 4.32) ( 7.23) ( 3.38) After 1 wk ( 18.2) ( 2.59) ( 14.1) (6.85) ( 11.5) (6.76) After 3 wk ( 22.9) (2.79) ( 20.7) (7.89) ( 6.98) (7.04) After 5 wk ( 14.6) (7.34) ( 13.5) (12.2) ( 16.5) (7.89) After 7 wk ( 18.8) ( 1.84) ( 12.0) (11.4) ( 8.73) (2.54) NOTE: Data are expressed as mean SD. The number values in parenthesis are % changes that were calculated with the following equation: [(Post-rTMS Pre-rTMS pain score)/pre-rtms] 100.

4 MAGNETIC STIMULATION FOR PAIN AFTER SPINAL CORD INJURY, Kang 1769 We observed changes in the NRS for worst pain after the end of, but not during the 5-day stimulation period. This delayed appearance of the analgesic effects was also observed after a single session 20 of rtms and daily repetitive sessions 3,13 of rtms. The reasons for this delay remain unclear. It has been suggested that this delayed analgesic effect is related to timeconsuming neurochemical or neuroendocrine processes, expression of secondary messengers, and synaptic plasticity. 21 Most studies that investigated the effects of rtms on neuropathic pain tried to target the motor cortical area corresponding to the painful zone. 3-8 Exceptionally, in a few studies that applied rtms on the hand motor cortical area, patients with facial pain showed more improvement than patients with upper limb pain originating Fig 1. Changes in NRS scores induced by rtms. (A) Average pain, (B) Worst pain. 6.85% in the sham stimulation (P.028). Three weeks after rtms, the difference between the real and sham stimulation was borderline significant (20.7% reduction in pain in the real stimulation and 7.89% increase in pain in the sham stimulation, P.05). Brief Pain Inventory The BPI score did not change during or after the rtms sessions with real stimulation (P.272) or with sham stimulation (P.366). The group by time interaction (P.076) and the intraindividual comparison between the real and sham stimulations were not significant. DISCUSSION The changes in the average pain intensity over the preceding 24 hours did not differ between the real and sham rtms treatments. Therefore, the therapeutic efficacy of rtms was not demonstrated in this study when it was applied on the hand motor cortical area in patients with SCI who had chronic neuropathic pain at multiple sites in the body including the lower limbs, trunk, and pelvis. Only changes in the NRS for worst pain differed between the real and sham treatments. Pain intensity can be quite variable during the course of the day, and changes in the NRS for worst pain can differ from those for average pain because the NRS is a subjective self-reported scale. 18,19 Fig 2. Percentage changes in the NRS score induced by rtms. (A) Average pain. (B) Worst pain. *Significant difference (P<.05).

5 1770 MAGNETIC STIMULATION FOR PAIN AFTER SPINAL CORD INJURY, Kang from a thalamic stroke and brachial plexus injury. 5,6 Lefaucheur et al 6 explained the discrepancy between the site of rtms (hand cortical area) and the painful zone (face rather than upper limb) by 2 theories. First, the face area may shift toward the hand area in patients with a facial lesion. Second, the fast rate of 10Hz applied in rtms over the hand area might modulate some output from the nearby face cortical representation. Thus, these 2 explanations for the discrepancy between the site of rtms and the painful zone do not contradict the notion that the efficacy of motor cortex stimulation is somatotopic. The notion that appropriate targeting of the motor cortical area corresponding to the painful zone is crucial for obtaining pain relief from the rtms application might relate to the somatotopic efficacy observed in chronic MCS with implanted epidural electrodes. 22,23 However, in the study by Nguyen et al, 23 an early study that proposed the technique of neuronavigation and cortical mapping for epidural electrode implantation, only 3 of 32 participants had lower limb pain, and the others had facial or upper limb pain. In the 3 participants with lower limb pain, the effective contact position of the epidural electrode could not be determined because the leg could not be activated by electrical stimulation. Two of the 3 participants with lower limb pain showed pain relief, and the stimulation site was the upper part of the lateral surface of the precentral cortex rather than the area corresponding to the lower limb itself. To our knowledge, no further research has been reported on the somatotopic efficacy of MCS. Most MCS studies that performed somatotopic matching for epidural electrode implantation included patients with facial or upper limb pain rather than lower limb pain resulting from various conditions. 24,25 Garcia-Larrea et al 12 proposed the thalamus to pain-related structure pathway as a mechanism of pain relief induced by motor cortex stimulation. This hypothesis suggests that the activity of projections from the primary motor cortex to the thalamic nuclei is modulated by motor cortical electrical or magnetic stimulation entailing a cascade of synaptic events in pain-related structures receiving afferent fibers from these nuclei, including the anterior cingulate and upper brainstem. The same research group has recently reported positron emission tomography imaging evidence that supports this hypothesis. 26,27 According to this hypothesis, the motor cortex acts as a pathway to the thalamic nuclei, and somatotopic matching between the motor cortex and the pain site might not play a crucial role in the analgesic effect of rtms. 28 Goto et al 29 also suggested that the thalamocortical tract plays a role in the pain reduction induced by rtms of the primary motor cortex in their study using diffusion tensor images. Study Limitations Several limitations of this study should be considered and addressed in future clinical research. First, because the sample size was small, the statistical power of the average pain NRS score is weak (39.8%), and a larger sample size is required to reduce the risk of type II error. Moreover, a more vigorous magnetic stimulation protocol than was used in this study should also be considered in future studies, together with an increased sample size, to avoid a statistically significant but clinically unimportant reduction in the pain score. For example, Fregni et al 8 suggested that the frequency of the stimulation and the number of rtms sessions are important contributors to the analgesic effects of rtms. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus group suggested that changes of approximately 2.0 points or 30% to 36% in the NRS score represent a meaningful reduction in chronic pain. 15 In this study, as shown in table 2, the maximum reductions in NRS scores for average and worst pain were 1.09 (5 weeks after the end of stimulation period) and 1.64 (3 weeks after the end of stimulation period), respectively, which are less than the clinically meaningful reduction in chronic pain according to the criteria. 15 Second, the level of depression was not measured in this study. Because there are reports about the antidepressant effects of rtms, we cannot discount the possibility that the reduction in the NRS score for worst pain was induced by a reduction in depression after rtms. 30,31 To eliminate this confounding factor, it would be necessary to monitor changes in the level of depression induced by real or sham stimulation, as well as its baseline measurement in future studies. Third, the blinding process is a general potential limitation in the interpretation of rtms effects, because the person who applies the active or sham stimulation cannot be blinded to the treatment. All participants in the present study were naïve for rtms, and the investigator who applied the stimulation coil to the participants was not involved in the recruitment or evaluation of the participants. However, we did not confirm the blinding by asking the patients which treatment they thought they had received, so the possibility of incomplete blinding cannot be ruled out. Confirmation of blinding would be helpful in overcoming this difficulty inherent in the blinding process. CONCLUSIONS The changes in the NRS score for average pain over the preceding 24 hours and the interference items of the BPI did not differ between the real and sham rtms treatments, and thus, therapeutic efficacy of rtms was not demonstrated when it was applied to the hand motor cortical area in patients with chronic neuropathic pain at multiple sites in the body including the lower limbs, trunk, and pelvis. The result for worst pain reduction suggests the need for further studies in which rtms is applied with a more intensive stimulation protocol. References 1. Jensen MP, Hoffman AJ, Cardenas DD. Chronic pain in individuals with spinal cord injury: a survey and longitudinal study. Spinal Cord 2005;43: Siddall PJ, McClelland JM, Rutkowski SB, Cousins MJ. A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury. 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