Bicentre, randomized, parallel-arm, sham-controlled trial of transcranial direct-current stimulation (tDCS) in the treatment of palliative care patients with refractory cancer pain.

BACKGROUND: Pain is a common symptom in palliative care cancer patients and is often insufficiently relieved. In recent years, transcranial direct-current stimulation (tDCS) of the motor cortex has been shown to be effective to treat chronic pain, essentially neuropathic pain. We propose to test the efficacy of tDCS in patients experiencing cancer pain in the palliative care setting. METHOD/DESIGN: This article describes the protocol of a bicentre, randomized, parallel-arm, sham-controlled clinical trial evaluating tDCS in the treatment of palliative care patients with refractory cancer pain. Seventy patients between the ages of 18 and 80 years experiencing refractory pain with a pain score of 4/10 on a numerical rating scale (NRS) ranging from 0 to 10 will be enrolled in this trial. The main exclusion criteria are patients unable to fill in the various rating scales and life expectancy less than 3 weeks. Treatment consists of 5 consecutive tDCS sessions targeting the motor cortex (one daily session for 5 days) on the contralateral side to the pain. After randomization (1:1 ratio), 35 patients will receive active stimulation and 35 patients will receive sham stimulation. The primary endpoint is the NRS score and the primary objective is a significant improvement of this score between the baseline score recorded between D-3 and D-1 and the score recorded 4 days after stopping treatment (D8). The secondary objectives are to evaluate whether this improvement is maintained 16 days after stopping treatment (D21) and whether the following scores are improved on D14 and D21: Brief Pain Inventory, Edmonton Symptom Assessment System, Hospital Anxiety and Depression scale, State-Trait Anxiety Inventory and Medication Quantification Scale. DISCUSSION: Positive results of this trial would indicate that tDCS can improve pain and quality of life of cancer patients in the palliative care setting. Reduction of analgesic consumption and improvement of activities of daily living should allow many patients to return home with a decreased workload for caregivers.

Incidence and risk factors of prolonged grief in relatives of patients with terminal cancer in French palliative care units: The Fami-Life multicenter cohort study.

OBJECTIVES: Psychological consequences of grief among relatives are insufficiently known. We reported incidence of prolonged grief among relatives of deceased patients with cancer. METHODS: Prospective cohort study of 611 relatives of 531 patients with cancer hospitalized for more than 72 hours and who died in 26 palliative care units was conducted. The primary outcome was prolonged grief in relatives 6 months after patient death, measured with the Inventory Complicated Grief (ICG > 25, range 0-76, a higher score indicates more severe symptoms) score. Secondary outcomes in relatives 6 months after patient death were anxiety and depression symptoms based on Hospital Anxiety and Depression Scale (HADS) score (range 0 [best]-42 [worst]), higher scores indicate more severe symptoms, minimally important difference 2.5. Post-traumatic stress disorder symptoms were defined by an Impact Event Scale-Revised score >22 (range 0-88, a higher score indicates more severe symptoms). RESULTS: Among 611 included relatives, 608 (99.5%) completed the trial. At 6 months, significant ICG scores were reported by 32.7% relatives (199/608, 95% CI, 29.0-36.4). The median (interquartile range ICG score) was 20.0 (11.5-29.0). The incidence of HADS symptoms was 87.5% (95% CI, 84.8-90.2%) at Days 3-5 and 68.7% (95% CI, 65.0-72.4) 6 months after patient's death, with a median (interquartile range) difference of -4 (-10 to 0) between these 2 time points. Improvement in HADS anxiety and depression scores were reported by 62.5% (362/579) relatives. SIGNIFICANCE OF RESULTS: These findings support the importance of screening relatives having risk factors of developing prolonged grief in the palliative unit and 6 months after patient's death.

Repetitive transcranial magnetic stimulation for neuropathic pain: a randomized multicentre sham-controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed to treat neuropathic pain but the quality of evidence remains low. We aimed to assess the efficacy and safety of neuronavigated rTMS to the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) in neuropathic pain over 25 weeks. We carried out a randomized double-blind, placebo-controlled trial at four outpatient clinics in France. Patients aged 18-75 years with peripheral neuropathic pain were randomly assigned at a 1:1 ratio to M1 or DLPFC-rTMS and rerandomized at a 2:1 ratio to active or sham-rTMS (10 Hz, 3000 pulses/session, 15 sessions over 22 weeks). Patients and investigators were blind to treatment allocation. The primary end point was the comparison between active M1-rTMS, active DLPCF-rTMS and sham-rTMS for the change over the course of 25 weeks (Group × Time interaction) in average pain intensity (from 0 no pain to 10 maximal pain) on the Brief Pain Inventory, using a mixed model repeated measures analysis in patients who received at least one rTMS session (modified intention-to-treat population). Secondary outcomes included other measures of pain intensity and relief, sensory and affective dimensions of pain, quality of pain, self-reported pain intensity and fatigue (patients diary), Patient and Clinician Global Impression of Change (PGIC, CGIC), quality of life, sleep, mood and catastrophizing. This study is registered with ClinicalTrials.gov NCT02010281. A total of 152 patients were randomized and 149 received treatment (49 for M1; 52 for DLPFC; 48 for sham). M1-rTMS reduced pain intensity versus sham-rTMS (estimate for Group × Session interaction: -0.048 ± 0.02; 95% CI: -0.09 to -0.01; P = 0.01). DLPFC-rTMS was not better than sham (estimate: -0.003 ± 0.01; 95% CI: -0.04 to 0.03, P = 0.9). M1-rRMS, but not DLPFC-rTMS, was also superior to sham-rTMS on pain relief, sensory dimension of pain, self-reported pain intensity and fatigue, PGIC and CGIC. There were no effects on quality of pain, mood, sleep and quality of life as all groups improved similarly over time. Headache was the most common side effect and occurred in 17 (34.7%), 23 (44.2%) and 13 (27.1%) patients from M1, DLPFC and sham groups, respectively (P = 0.2). Our results support the clinical relevance of M1-rTMS, but not of DLPFC-rTMS, for peripheral neuropathic pain with an excellent safety profile.

The Fami-life study: protocol of a prospective observational multicenter mixed study of psychological consequences of grieving relatives in French palliative care units on behalf of the family research in palliative care (F.R.I.P.C research network).

BACKGROUND: Grieving relatives can suffer from numerous consequences like anxiety, depression, post-traumatic stress disorder (PTSD) symptoms, and prolonged grief. This study aims to assess the psychological consequences of grieving relatives after patients' death in French palliative care units and their needs for support. METHODS: This is a prospective observational multicenter mixed study. Relatives of adult patients with a neoplasia expected to be hospitalized more than 72 h in a palliative care unit for end-of-life issues will be included within 48 h after patient admission. End-of-life issues are defined by the physician at patient admission. Relatives who are not able to have a phone call at 6-months are excluded. The primary outcome is the incidence of prolonged grief reaction defined by an ICG (Inventory Complicate Grief) > 25 (0 best-76 worst) at 6 months after patient' death. Prespecified secondary outcomes are the risk factors of prolonged grief, anxiety and depression symptoms between day 3 and day 5 and at 6 months after patients' death based on an Hospital Anxiety and Depression score (range 0-42) > 8 for each subscale (minimal clinically important difference: 2.5), post-traumatic stress disorder symptoms 6 months after patient' death based on the Impact of Events Scale questionnaire (0 best-88 worst) score > 22, experience of relatives during palliative care based on the Fami-Life questionnaire, specifically built for the study. Between 6 and 12 months after the patient's death, a phone interview with relatives with prolonged grief reactions will be planned by a psychologist to understand the complex system of grief. It will be analyzed with the Interpretative Phenomenological Analysis. We planned to enroll 500 patients and their close relatives assuming a 25% prolonged grief rate and a 6-month follow-up available in 60% of relatives. DISCUSSION: This study will be the first to report the psychological consequences of French relatives after a loss of a loved one in palliative care units. Evaluating relatives' experiences can provide instrumental insights for means of improving support for relatives and evaluation of bereavement programs. TRIAL REGISTRATION: NCT03748225 registered on 11/19/2018. Recruiting patients.

A reappraisal of pain-paired associative stimulation suggesting motor inhibition at spinal level.

OBJECTIVES: Paired associative stimulation (PAS) can modulate motor excitability and consists of delivering repeated pairs of peripheral sensory stimulation combined with transcranial magnetic stimulation (TMS) over the contralateral motor cortex. Our objective was to evaluate the effect of a PAS protocol using a painful stimulation. METHODS: Ten healthy volunteers underwent pain-PAS protocol consisting of 90 pairs of nociceptive stimulus over the right hand followed by an image-guided navigated TMS of the contralateral motor cortex, delivered at 0.1Hz over 15minutes. Four distinct inter-stimuli intervals (ISI) were assessed: -40ms, +10ms, +30ms and +50ms with respect to the individual pain-related evoked potential (N2 latency). The impact of pain-PAS was assessed by measuring motor evoked potentials (MEPs) amplitudes before and up to 30minutes after the pain-PAS procedure. RESULTS: For the "N2 latency -40ms" ISI condition, a significant decrease of MEP amplitude was observed in the immediate post-pain-PAS period. For longer ISIs, no significant changes were observed. DISCUSSION: A motor inhibition effect was produced by repetitive pairs of painful peripheral stimulation and TMS pulse delivered to the motor cortex before the afferent volley reaches the somatosensory cortex. This short ISI falls into a period of time corresponding to the cutaneous silent period, suggesting that the motor inhibition effect produced by pain-PAS could occur at spinal level. The repeated interaction of the nociceptive afferent input and the descending motor corticospinal volley could lead to reduced excitability of homonymous spinal motoneurons.

The treatment of fatigue by non-invasive brain stimulation.

The use of non-invasive brain neurostimulation (NIBS) techniques to treat neurological or psychiatric diseases is currently under development. Fatigue is a commonly observed symptom in the field of potentially treatable pathologies by NIBS, yet very little data has been published regarding its treatment. We conducted a review of the literature until the end of February 2017 to analyze all the studies that reported a clinical assessment of the effects of NIBS techniques on fatigue. We have limited our analysis to repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). We found only 15 studies on this subject, including 8 tDCS studies and 7 rTMS studies. Of the tDCS studies, 6 concerned patients with multiple sclerosis while 6 rTMS studies concerned fibromyalgia or chronic fatigue syndrome. The remaining 3 studies included patients with post-polio syndrome, Parkinson's disease and amyotrophic lateral sclerosis. Three cortical regions were targeted: the primary sensorimotor cortex, the dorsolateral prefrontal cortex and the posterior parietal cortex. In all cases, tDCS protocols were performed according to a bipolar montage with the anode over the cortical target. On the other hand, rTMS protocols consisted of either high-frequency phasic stimulation or low-frequency tonic stimulation. The results available to date are still too few, partial and heterogeneous as to the methods applied, the clinical profile of the patients and the variables studied (different fatigue scores) in order to draw any conclusion. However, the effects obtained, especially in multiple sclerosis and fibromyalgia, are really carriers of therapeutic hope.

Effects of left DLPFC versus right PPC tDCS on multiple sclerosis fatigue.

BACKGROUND AND OBJECTIVE: Fatigue is a frequent and debilitating symptom in patients with multiple sclerosis (MS). Its classical treatments are still faced with limited benefits and numerous side effects. Hence, we aimed to evaluate the effects of transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique, on such a challenging symptom. Our secondary outcomes included the assessment of tDCS impact on mood and attentional performance. METHODS: Ten fatigued MS patients were enrolled in a double-blind, sham-controlled, and cross-over study. Each patient randomly received three anodal tDCS blocks: active stimulation over the left dorsolateral prefrontal cortex (DLPFC), active stimulation over the right posterior parietal cortex (PPC), and sham stimulation over either cortical site. Both cortical targets are key components in the MS fatigue networks. The blocks consisted of five consecutive daily sessions and were held apart by a washout interval of three weeks. RESULTS: Only active left DLPFC stimulation significantly ameliorated fatigue. Mood improvement was exclusively obtained following active right PPC stimulation. Neither intervention had effects on attention. CONCLUSION: Our study supports the role of anodal tDCS over the left prefrontal in treating MS fatigue. The lack of tDCS effects on attention might be related to the heterogeneity of the studied cohort, the relatively small sample size, the protocol design and duration. Modifying these variables and coupling tDCS with neuroimaging might improve the clinical outcomes and enhance our understanding of the tDCS mechanism of actions.

Repetitive transcranial magnetic stimulation and transcranial direct-current stimulation in neuropathic pain due to radiculopathy: a randomized sham-controlled comparative study.

No study has directly compared the effectiveness of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct-current stimulation (tDCS) in neuropathic pain (NP). In this 2-centre randomised double-blind sham-controlled study, we compared the efficacy of 10-Hz rTMS and anodal 2-mA tDCS of the motor cortex and sham stimulation contralateral to the painful area (3 daily sessions) in patients with NP due to lumbosacral radiculopathy. Average pain intensity (primary outcome) was evaluated after each session and 5 days later. Secondary outcomes included neuropathic symptoms and thermal pain thresholds for the upper limbs. We used an innovative design that minimised bias by randomly assigning patients to 1 of 2 groups: active rTMS and tDCS or sham rTMS and tDCS. For each treatment group (active or sham), the order of the sessions was again randomised according to a crossover design. In total, 51 patients were screened and 35 (51% women) were randomized. Active rTMS was superior to tDCS and sham in pain intensity (F = 2.89 and P = 0.023). Transcranial direct-current stimulation was not superior to sham, but its analgesic effects were correlated to that of rTMS (P = 0.046), suggesting common mechanisms of action. Repetitive transcranial magnetic stimulation lowered cold pain thresholds (P = 0.04) and its effect on cold pain was correlated with its analgesic efficacy (P = 0.006). However, rTMS had no impact on individual neuropathic symptoms. Thus, rTMS is more effective than tDCS and sham in patients with NP due to lumbosacral radiculopathy and may modulate the sensory and affective dimensions of pain.

Repetitive transcranial magnetic stimulation induced analgesia depends on N-methyl-D-aspartate glutamate receptors.

We investigated the role of glutamate N-methyl-d-aspartate (NMDA) receptors in the analgesic effects induced by repetitive transcranial magnetic stimulation (rTMS). In a randomized, double-blind, crossover study, we compared the effects of ketamine and placebo on the analgesic effects of motor cortex (M1) or dorsolateral prefrontal cortex/premotor cortex (DLPFC/PMC) stimulation. Three groups of 12 healthy volunteers underwent active rTMS (10Hz, 80% resting motor threshold, 1,500 pulses per session) of the right M1, active stimulation of the right DLPFC/PMC, or sham stimulation during 2 experimental sessions 2 weeks apart. Cold pain thresholds were measured on the left thenar eminence before and 1 hour after cortical stimulation, to evaluate the analgesic effects of rTMS. Ketamine (0.15 mg/kg in a 10-minute bolus followed by continuous infusion of 6 µg/kg per minute until the end of rTMS) or placebo (saline) were administered intravenously during cortical stimulation. We also systematically measured cortical excitability parameters (resting motor threshold, suprathreshold motor-evoked potentials, short intracortical inhibition, and intracortical facilitation) before and after treatment, to investigate the possible relationship between changes in cortical excitability and rTMS-induced analgesia. Ketamine injection significantly decreased the analgesic effects of both M1 and DLPFC/PMC stimulation. The decrease in the analgesic effect of rTMS was not associated with changes in cortical excitability parameters, which were not influenced by rTMS following the administration of either saline or ketamine. Thus, rTMS-induced analgesia depends on glutamate NMDA receptors and may involve long-term potentiation-like mechanisms.

Unilateral repetitive transcranial magnetic stimulation of the motor cortex does not affect cognition in patients with fibromyalgia.

Repetitive transcranial magnetic stimulation (rTMS) induces changes in neuronal activity that may affect cognition. We assessed cognitive functions, in patients with fibromyalgia participating in a sham-controlled randomized trial of rTMS for pain management. We randomly assigned 38 non depressed fibromyalgia patients (American College of Rheumatology criteria) to the active (n = 20) and sham (n = 18) rTMS treatment groups, in a double-blind manner. rTMS was applied to the left primary motor cortex (10 Hz at 80% of rest motor threshold). Neuropsychological tests were performed immediately before stimulation, to evaluate episodic memory, selective and divided attention and executive functions at baseline, week 3 (after 7 rTMS sessions) and week 11 (after 11 rTMS sessions). The actively treated and sham-treated groups were similar in terms of clinical and neuropsychological variables at baseline. No difference in overall neuropsychological performance with respect to baseline was found between these two groups, but a significant improvement over time was observed in the rTMS group, for several measurements of attention/executive function (the Symbol Digit Modalities Test and the Stroop Color Word Test). Unilateral rTMS of the motor cortex over a three-month period did not modify cognitive functions in patients with chronic pain. rTMS may have mild beneficial cognitive effects, but confirmation is required in larger groups of patients.

Neuropharmacological basis of rTMS-induced analgesia: the role of endogenous opioids.

We investigated the role of endogenous opioid systems in the analgesic effects induced by repetitive transcranial magnetic stimulation (rTMS). We compared the analgesic effects of motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) stimulation before and after naloxone or placebo treatment, in a randomized, double-blind crossover design, in healthy volunteers. Three groups of 12 volunteers were selected at random and given active stimulation (frequency 10Hz, at 80% motor threshold intensity, 1500 pulses per session) of the right M1, active stimulation of the right DLPFC, or sham stimulation, during two experimental sessions 2 weeks apart. Cold pain thresholds and the intensity of pain induced by a series of fixed-temperature cold stimuli (5, 10, and 15°C) were used to evaluate the analgesic effects of rTMS. Measurements were made at the left thenar eminence, before and 1 hour after the intravenous injection of naloxone (bolus of 0.1mg/kg followed by a continuous infusion of 0.1mg/kg/h until the end of rTMS) or placebo (saline). Naloxone injection significantly decreased the analgesic effects of M1 stimulation, but did not change the effects of rTMS of the DLPFC or sham rTMS. This study demonstrates, for the first time, the involvement of endogenous opioid systems in rTMS-induced analgesia. The differential effects of naloxone on M1 and DLPFC stimulation suggest that the analgesic effects induced by the stimulation of these 2 cortical sites are mediated by different mechanisms. Endogenous opioids are shown to be involved in the analgesic effects of repetitive transcranial magnetic stimulation of the motor cortex.

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

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.

Alteration of cortical excitability in patients with fibromyalgia.

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.

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

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, 10Hz; 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 60min 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 1h 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.