Daniel Ciampi de Andrade

Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia

&NA; We assessed for the first time the long‐term maintenance of repetitive transcranial magnetic stimulation (rTMS)‐induced analgesia in patients with chronic widespread pain due to fibromyalgia. Forty consecutive patients were randomly assigned, in a double‐blind fashion, to 2 groups: one receiving active rTMS (n = 20) and the other, sham stimulation (n = 20), applied to the left primary motor cortex. The stimulation protocol consisted of 14 sessions: an “induction phase” of 5 daily sessions followed by a “maintenance phase” of 3 sessions a week apart, 3 sessions a fortnight apart, and 3 sessions a month apart. The primary outcome was average pain intensity over the last 24 hours, measured before each stimulation from day 1 to week 21 and at week 25 (1 month after the last stimulation). Other outcomes measured included quality of life, mood and anxiety, and several parameters of motor cortical excitability. Thirty patients completed the study (14 in the sham stimulation group and 16 in the active stimulation group). Active rTMS significantly reduced pain intensity from day 5 to week 25. These analgesic effects were associated with a long‐term improvement in items related to quality of life (including fatigue, morning tiredness, general activity, walking, and sleep) and were directly correlated with changes in intracortical inhibition. In conclusion, these results suggest that TMS may be a valuable and safe new therapeutic option in patients with fibromyalgia. The analgesic effects induced by repetitive transcranial magnetic stimulation of the motor cortex can be maintained over 6 months in patients with fibromyalgia, using monthly stimulation.

The use of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) to relieve pain

Chronic pain resulting from injury of the peripheral or central nervous system may be associated with a significant dysfunction of extensive neural networks. Noninvasive stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) may be suitable to treat chronic pain as they can act on these networks by modulating neural activities not only in the stimulated area, but also in remote regions that are interconnected to the site of stimulation. Motor cortex was the first cortical target that was proved to be efficacious in chronic pain treatment. At present, significant analgesic effects were also shown to occur after the stimulation of other cortical targets (including prefrontal and parietal areas) in acute provoked pain, chronic neuropathic pain, fibromyalgia, or visceral pain. Therapeutic applications of rTMS in pain syndromes are limited by the short duration of the induced effects, but prolonged pain relief can be obtained by repeating rTMS sessions every day for several weeks. Recent tDCS studies also showed some effects on various types of chronic pain. We review the evidence to date of these two techniques of noninvasive brain stimulation for the treatment of pain.

Alteration of cortical excitability in patients with fibromyalgia.

&NA; We assessed cortical excitability and intracortical modulation systematically, by transcranial magnetic stimulation (TMS) of the motor cortex, in patients with fibromyalgia. In total 46 female patients with fibromyalgia and 21 normal female subjects, matched for age, were included in this study. TMS was applied to the hand motor area of both hemispheres and motor evoked potentials (MEPs) were recorded for the first interosseous muscle of the contralateral hand. Single‐pulse stimulation was used for measurements of the rest motor threshold (RMT) and suprathreshold MEP. Paired‐pulse stimulation was used to assess short intracortical inhibition (SICI) and intracortical facilitation (ICF). Putative correlations were sought between changes in electrophysiological parameters and major clinical features of fibromyalgia, such as pain, fatigue, anxiety, depression and catastrophizing. The RMT on both sides was significantly increased in patients with fibromyalgia and suprathreshold MEP was significantly decreased bilaterally. However, these alterations, suggesting a global decrease in corticospinal excitability, were not correlated with clinical features. Patients with fibromyalgia also had lower ICF and SICI on both sides, than controls, these lower values being correlated with fatigue, catastrophizing and depression. These neurophysiological alterations were not linked to medication, as similar changes were observed in patients with or without psychotropic treatment. In conclusion, fibromyalgia is associated with deficits in intracortical modulation involving both GABAergic and glutamatergic mechanisms, possibly related to certain aspects of the pathophysiology of this chronic pain syndrome. Our data add to the growing body of evidence for objective and quantifiable changes in brain function in fibromyalgia.

Repetitive Transcranial Magnetic Stimulation Is Efficacious as an Add-On to Pharmacological Therapy in Complex Regional Pain Syndrome (CRPS) Type I

UNLABELLED Single-session repetitive transcranial magnetic stimulation (rTMS) of the motor cortex (M1) is effective in the treatment of chronic pain patients, but the analgesic effect of repeated sessions is still unknown. We evaluated the effects of rTMS in patients with refractory pain due to complex regional pain syndrome (CRPS) type I. Twenty-three patients presenting CRPS type I of 1 upper limb were treated with the best medical treatment (analgesics and adjuvant medications, physical therapy) plus 10 daily sessions of either real (r-) or sham (s-) 10 Hz rTMS to the motor cortex (M1). Patients were assessed daily and after 1 week and 3 months after the last session using the Visual Analogical Scale (VAS), the McGill Pain Questionnaire (MPQ), the Health Survey-36 (SF-36), and the Hamilton Depression (HDRS). During treatment there was a significant reduction in the VAS scores favoring the r-rTMS group, mean reduction of 4.65 cm (50.9%) against 2.18 cm (24.7%) in the s-rTMS group. The highest reduction occurred at the tenth session and correlated to improvement in the affective and emotional subscores of the MPQ and SF-36. Real rTMS to the M1 produced analgesic effects and positive changes in affective aspects of pain in CRPS patients during the period of stimulation. PERSPECTIVE This study shows an efficacy of repetitive sessions of high-frequency rTMS as an add-on therapy to refractory CRPS type I patients. It had a positive effect in different aspects of pain (sensory-discriminative and emotional-affective). It opens the perspective for the clinical use of this technique.

Diffuse analgesic effects of unilateral repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers

ABSTRACT We investigated the analgesic effects of unilateral repetitive transcranial magnetic stimulation (rTMS) of the motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) in two models of experimental pain in healthy volunteers. Two studies were carried out in parallel in two groups of 26 paid healthy volunteers. The effects of active or sham rTMS (frequency, 10 Hz; intensity, 80% resting motor threshold) applied to the right M1 or DLPFC were compared in a double‐blind randomized cross‐over design. In the first series of experiments, we analyzed the effects of rTMS on thermal (heat and cold) detection and pain thresholds measured on both hands and the left foot, by standardized quantitative sensory testing methods. In the second series of experiments, we measured the effects of M1 or DLPFC rTMS on the threshold and recruitment curves of the RIII nociceptive reflex evoked by ipsilateral electrical stimulation of the sural nerve and recorded on the biceps femoris of both lower limbs. In both studies, measurements were taken before and up to 60 min after the end of rTMS. Active rTMS of both M1 and DLPFC significantly increased the thermal pain thresholds, measured for both hands and the left foot, this effect being most marked for cold pain. These effects, which lasted at least 1 h after rTMS, were selective because they were not associated with changes in non‐painful thermal sensations. By contrast, the second study showed that rTMS of M1 or DLPFC had no significant effect on the threshold or recruitment curve of the nociceptive flexion RIII reflex. Our findings demonstrate that unilateral rTMS of M1 or DLPFC induces diffuse and selective analgesic effects in healthy volunteers. The lack of effect on the RIII reflex suggests that such analgesic effects may not depend on the activation of descending inhibitory systems.

Translation to Portuguese and Validation of the Douleur Neuropathique 4 Questionnaire

UNLABELLED The Douleur Neuropathique 4 (DN4) questionnaire was developed by the French Neuropathic Pain Group and is a simple and objective tool, with the ability to distinguish nociceptive from neuropathic pain. The purpose of this work was to validate the DN4 questionnaire in the Portuguese language in order to allow its use in clinical and research settings. A double-blind, accuracy study was conducted, consisting of translation, back-translation, literal evaluation, semantic equivalence, and communication with the target population. The Portuguese version of the questionnaire was applied in a sample of 101 patients with neuropathic (N = 42) or nociceptive pain (N = 59), ranked according to medical diagnosis. The reproducibility, reliability and validity of the instrument were analyzed, and showed a high diagnostic power for this version of the DN4 questionnaire. The Portuguese version of the DN4 questionnaire presented good validity and reliability, allowing it to identify neuropathic pain and neuropathic characteristics of mixed pain syndromes. PERSPECTIVE This article presents the first validated neuropathic pain questionnaire in the Portuguese language and represents a useful tool in the assessment of neuropathic pain both in the clinical setting and in population-based studies. The sensible and quick format of this instrument are key factors that will contribute to its widespread use, permitting a true recognition of patients with neuropathic pain.

Effects of deep brain stimulation on pain and other nonmotor symptoms in Parkinson disease

Objective: To prospectively evaluate the effect of subthalamic nucleus deep brain stimulation (STN-DBS) on the different characteristics of pain and other nonmotor symptoms (NMS) in patients with Parkinson disease (PD). Methods: Forty-four patients with PD and refractory motor symptoms were screened for STN-DBS. Patients were evaluated before and 1 year after surgery. The primary outcome was change in pain prevalence after surgery. Secondary outcome measures were changes in motor function (Unified Parkinsons Disease Rating Scale), characteristics of pain and other NMS using specific scales and questionnaires, and quality of life. Results: Forty-one patients completed the study. The prevalence of pain changed from 70% to 21% after surgery (p < 0.001). There were also significant improvements in pain intensity, NMS, and quality of life after STN-DBS (p < 0.05). Dystonic and musculoskeletal pain responded well to DBS, while central pain and neuropathic pain were not influenced by surgery. There was a strong correlation between the change in pain intensity and the improvement in quality of life (r = 0.708, p < 0.005). No correlation was found between pain improvement and preoperative response to levodopa or motor improvement during stimulation (r = 0.247, p = 0.197 and r = 0.249, p = 0.193, respectively) or with changes in other NMS. Conclusions: STN-DBS decreased pain after surgery, but had different effects in different types of PD-related pain. Motor and nonmotor symptom improvements after STN-DBS did not correlate with pain relief. Classification of evidence: This study provides Class IV evidence that in patients with idiopathic PD with refractory motor fluctuations, STN-DBS decreases the prevalence of pain and improves quality of life.

Subthalamic deep brain stimulation modulates small fiber–dependent sensory thresholds in Parkinson’s disease

TOC summary Subthalamic nucleus deep brain stimulation contributes to relieve pain associated with Parkinson’s disease and specifically modulates small fiber–mediated sensations. ABSTRACT The effects of deep brain stimulation of the subthalamic nucleus on nonmotor symptoms of Parkinson’s disease (PD) rarely have been investigated. Among these, sensory disturbances, including chronic pain (CP), are frequent in these patients. The aim of this study was to evaluate the changes induced by deep brain stimulation in the perception of sensory stimuli, either noxious or innocuous, mediated by small or large nerve fibers. Sensory detection and pain thresholds were assessed in 25 PD patients all in the off‐medication condition with the stimulator turned on or off (on‐ and off‐stimulation conditions, respectively). The relationship between the changes induced by surgery on quantitative sensory testing, spontaneous CP, and motor abilities were studied. Quantitative sensory test results obtained in PD patients were compared with those of age‐matched healthy subjects. Chronic pain was present in 72% of patients before vs 36% after surgery (P = .019). Compared with healthy subjects, PD patients had an increased sensitivity to innocuous thermal stimuli and mechanical pain, but a reduced sensitivity to innocuous mechanical stimuli. In addition, they had an increased pain rating when painful thermal stimuli were applied, particularly in the off‐stimulation condition. In the on‐stimulation condition, there was an increased sensitivity to innocuous thermal stimuli but a reduced sensitivity to mechanical or thermal pain. Pain provoked by thermal stimuli was reduced when the stimulator was turned on. Motor improvement positively correlated with changes in warm detection and heat pain thresholds. Subthalamic nucleus deep brain stimulation contributes to relieve pain associated with PD and specifically modulates small fiber–mediated sensations.

Safety and efficacy of repeated injections of botulinum toxin A in peripheral neuropathic pain (BOTNEP): a randomised, double-blind, placebo-controlled trial.

BACKGROUND Data from previous studies suggest that botulinum toxin A has analgesic effects against peripheral neuropathic pain, but the quality of the evidence is low. We aimed to assess the safety and efficacy of repeated administrations of botulinum toxin A in patients with neuropathic pain. METHODS We did a randomised, double-blind, placebo-controlled trial at two outpatient clinics in France (Clinical Pain Centre, Ambroise Paré Hospital, APHP, Boulogne-Billancourt, and Neurological Centre, Hôpital Dupuytren, Limoges) and one in Brazil (Neurological Department, Hospital das Clínicas da FMUSP, São Paulo). Patients aged 18-85 years with peripheral neuropathic pain were randomly assigned (1:1) by block randomisation, according to a centralised schedule, to receive two subcutaneous administrations of botulinum toxin A (up to 300 units) or placebo, 12 weeks apart. All patients and investigators were masked to treatment assignment. The primary outcome was the efficacy of botulinum toxin A versus placebo, measured as the change from baseline in self-reported mean weekly pain intensity over the course of 24 weeks from the first administration. The primary efficacy analysis was a mixed-model repeated-measures analysis in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01251211. FINDINGS Between Oct 2, 2010, and Aug 2, 2013, 152 patients were enrolled, of whom 68 were randomly assigned (34 per group), and 66 (37 [56%] men) were included in the primary analysis (34 in the botulinum toxin A group and 32 in the placebo group). Botulinum toxin A reduced pain intensity over 24 weeks compared with placebo (adjusted effect estimate -0·77, 95% CI -0·95 to -0·59; p<0·0001). Pain on injection was the only adverse effect reported, and occurred in 19 (56%) participants in the botulinum toxin A group and 17 (53%) of those in the placebo group (p=1·0). Severe pain was experienced by ten (29%) participants in the botulinum toxin A group and 11 (34%) in the placebo group (p=0·8). INTERPRETATION Two administrations of botulinum toxin A, each of which comprised several injections, have a sustained analgesic effect against peripheral neuropathic pain. Several factors, such as the presence of allodynia and a limited thermal deficit, may be useful in predicting treatment response and should be investigated further. FUNDING Institut National de la Santé et de la Recherche Médicale (INSERM) and Fondation CNP (France).

Repetitive transcranial magnetic stimulation in chronic pain: a review of the literature.

OBJECTIVE To review the literature on the analgesic effects of repetitive transcranial magnetic stimulation (rTMS) in chronic pain according to different pain syndromes and stimulation parameters. DATA SOURCES Publications on rTMS and chronic pain were searched in PubMed and Google Scholar using the following key words: chronic pain, analgesia, transcranial magnetic stimulation, neuropathic pain, fibromyalgia, and complex regional pain syndrome. STUDY SELECTION This review only included double-blind, controlled studies with >10 participants in each arm that were published from 1996 to 2014 and written in English. Studies with relevant information for the understanding of the effects of rTMS were also cited. DATA EXTRACTION The following data were retained: type of pain syndrome, type of study, coil type, target, stimulation intensity, frequency, number of pulses, orientation of induced current, number of session, and a brief summary of intervention outcomes. DATA SYNTHESIS A total of 33 randomized trials were found. Many studies reported significant pain relief by rTMS, especially high-frequency stimulation over the primary motor cortex performed in consecutive treatment sessions. Pain relief was frequently >30% compared with control treatment. Neuropathic pain, fibromyalgia, and complex regional pain syndrome were the pain syndromes more frequently studied. However, among all published studies, only a few performed repetitive sessions of rTMS. CONCLUSIONS rTMS has potential utility in the management of chronic pain; however, studies using maintenance sessions of rTMS and assessing the effects of rTMS on the different aspects of chronic pain are needed to provide a more solid basis for its clinical application for pain relief.