Joint European Academy of Neurology-European Pain Federation-Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines on neuropathic pain assessment.

BACKGROUND AND PURPOSE: In these guidelines, we aimed to develop evidence-based recommendations for the use of screening questionnaires and diagnostic tests in patients with neuropathic pain (NeP). METHODS: We systematically reviewed studies providing information on the sensitivity and specificity of screening questionnaires, and quantitative sensory testing, neurophysiology, skin biopsy, and corneal confocal microscopy. We also analysed how functional neuroimaging, peripheral nerve blocks, and genetic testing might provide useful information in diagnosing NeP. RESULTS: Of the screening questionnaires, Douleur Neuropathique en 4 Questions (DN4), I-DN4 (self-administered DN4), and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) received a strong recommendation, and S-LANSS (self-administered LANSS) and PainDETECT weak recommendations for their use in the diagnostic pathway for patients with possible NeP. We devised a strong recommendation for the use of skin biopsy and a weak recommendation for quantitative sensory testing and nociceptive evoked potentials in the NeP diagnosis. Trigeminal reflex testing received a strong recommendation in diagnosing secondary trigeminal neuralgia. Although many studies support the usefulness of corneal confocal microscopy in diagnosing peripheral neuropathy, no study specifically investigated the diagnostic accuracy of this technique in patients with NeP. Functional neuroimaging and peripheral nerve blocks are helpful in disclosing pathophysiology and/or predicting outcomes, but current literature does not support their use for diagnosing NeP. Genetic testing may be considered at specialist centres, in selected cases. CONCLUSIONS: These recommendations provide evidence-based clinical practice guidelines for NeP diagnosis. Due to the poor-to-moderate quality of evidence identified by this review, future large-scale, well-designed, multicentre studies assessing the accuracy of diagnostic tests for NeP are needed.

Cortical stimulation for chronic pain: from anecdote to evidence.

Epidural stimulation of the motor cortex (eMCS) was devised in the 1990's, and has now largely supplanted thalamic stimulation for neuropathic pain relief. Its mechanisms of action involve activation of multiple cortico-subcortical areas initiated in the thalamus, with involvement of endogenous opioids and descending inhibition toward the spinal cord. Evidence for clinical efficacy is now supported by at least seven RCTs; benefits may persist up to 10 years, and can be reasonably predicted by preoperative use of non-invasive repetitive magnetic stimulation (rTMS). rTMS first developed as a means of predicting the efficacy of epidural procedures, then as an analgesic method on its own right. Reasonable evidence from at least six well-conducted RCTs favors a significant analgesic effect of high-frequency rTMS of the motor cortex in neuropathic pain (NP), and less consistently in widespread/fibromyalgic pain. Stimulation of the dorsolateral frontal cortex (DLPFC) has not proven efficacious for pain, so far. The posterior operculo-insular cortex is a new and attractive target but evidence remains inconsistent. Transcranial direct current stimulation (tDCS) is applied upon similar targets as rTMS and eMCS; it does not elicit action potentials but modulates the neuronal resting membrane state. tDCS presents practical advantages including low cost, few safety issues, and possibility of home-based protocols; however, the limited quality of most published reports entails a low level of evidence. Patients responsive to tDCS may differ from those improved by rTMS, and in both cases repeated sessions over a long time may be required to achieve clinically significant relief. Both invasive and non-invasive procedures exert their effects through multiple distributed brain networks influencing the sensory, affective and cognitive aspects of chronic pain. Their effects are mainly exerted upon abnormally sensitized pathways, rather than on acute physiological pain. Extending the duration of long-term benefits remains a challenge, for which different strategies are discussed in this review.

Stimulation of the motor cerebral cortex in chronic neuropathic pain: the role of electrode localization over motor somatotopy.

BACKGROUND: Previous studies have reported the pain-relieving effect of chronic electrical motor cortex stimulation (eMCS) in various types of neuropathic pain. The study aimed to explore the potential relationship between the clinical efficacy of eMCS for the treatment of chronic neuropathic pain and the precise localization of the contacts over the motor cortex somatotopic representation of the painful area. METHODS: A total of 22 patients with neuropathic pain were implanted with eMCS electrodes. Implantation of the electrodes was performed using intraoperative 1) anatomical identification by neuronavigation software using 3D-MRI; 2) monitoring of somesthetic evoked potentials to check the potential reverse over the central sulcus; and 3) electrical stimulations through the dura to identify the motor responses and its somatotopy. Image fusion of postoperative 3D-CT and preoperative MRI images allowed postoperative location of the electrodes. RESULTS: Analgesic effects were obtained in 18 (81.81%) out of 22 patients. Postoperative 3D-CT analysis showed a correspondence between localization of the contacts and the motor cerebral cortex somatotopy in the patients with postoperative good analgesic effects. No correspondence was found between localization of the contacts and the motor cerebral cortex somatotopy in the four patients with no analgesic effects. In three out of these four patients, analgesic effects were obtained after new surgery allowed repositioning of the electrode over the motor cortex somatotopy of the painful area. CONCLUSIONS: The findings of this study suggest that eMCS provides analgesic effects when the stimulated cortex corresponds to the somatotopy of the painful area.

Transcranial direct current stimulation of 3 cortical targets is no more effective than placebo as treatment for fibromyalgia: a double-blind sham-controlled clinical trial.

ABSTRACT: Transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) and the dorsolateral prefrontal cortex seem to improve pain and other symptoms of fibromyalgia (FM), although the evidence on the effectiveness of tDCS and the optimal stimulation target is not robust enough. Our main objective was to establish the optimal area of stimulation, comparing the 2 classical targets and a novel pain-related area, the operculo-insular cortex, in a sham-controlled trial. Using a double-blind design, we randomly assigned 130 women with FM to 4 treatment groups (M1, dorsolateral prefrontal cortex, operculo-insular cortex, and sham), each receiving fifteen 20-minute sessions of 2 mA anodal tDCS over the left hemisphere. Our primary outcome was pain intensity. The secondary outcomes were the other core symptoms of FM (fatigue, mood, cognitive and sleep disorders, and hyperalgesia measured by the pressure pain threshold). We performed the assessment at 3 time points (before, immediately after treatment, and at 6 months follow-up). The linear mixed-model analysis of variances showed significant treatment effects across time for clinical pain and for fatigue, cognitive and sleep disturbances, and experimental pain, irrespective of the group. In mood, the 3 active tDCS groups showed a significantly larger improvement in anxiety and depression than sham. Our findings provide evidence of a placebo effect, support the use of tDCS for the treatment of affective symptoms, and challenge the effectiveness of tDCS as treatment of FM.

Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS).

A group of European experts was commissioned by the European Chapter of the International Federation of Clinical Neurophysiology to gather knowledge about the state of the art of the therapeutic use of transcranial direct current stimulation (tDCS) from studies published up until September 2016, regarding pain, Parkinson's disease, other movement disorders, motor stroke, poststroke aphasia, multiple sclerosis, epilepsy, consciousness disorders, Alzheimer's disease, tinnitus, depression, schizophrenia, and craving/addiction. The evidence-based analysis included only studies based on repeated tDCS sessions with sham tDCS control procedure; 25 patients or more having received active treatment was required for Class I, while a lower number of 10-24 patients was accepted for Class II studies. Current evidence does not allow making any recommendation of Level A (definite efficacy) for any indication. Level B recommendation (probable efficacy) is proposed for: (i) anodal tDCS of the left primary motor cortex (M1) (with right orbitofrontal cathode) in fibromyalgia; (ii) anodal tDCS of the left dorsolateral prefrontal cortex (DLPFC) (with right orbitofrontal cathode) in major depressive episode without drug resistance; (iii) anodal tDCS of the right DLPFC (with left DLPFC cathode) in addiction/craving. Level C recommendation (possible efficacy) is proposed for anodal tDCS of the left M1 (or contralateral to pain side, with right orbitofrontal cathode) in chronic lower limb neuropathic pain secondary to spinal cord lesion. Conversely, Level B recommendation (probable inefficacy) is conferred on the absence of clinical effects of: (i) anodal tDCS of the left temporal cortex (with right orbitofrontal cathode) in tinnitus; (ii) anodal tDCS of the left DLPFC (with right orbitofrontal cathode) in drug-resistant major depressive episode. It remains to be clarified whether the probable or possible therapeutic effects of tDCS are clinically meaningful and how to optimally perform tDCS in a therapeutic setting. In addition, the easy management and low cost of tDCS devices allow at home use by the patient, but this might raise ethical and legal concerns with regard to potential misuse or overuse. We must be careful to avoid inappropriate applications of this technique by ensuring rigorous training of the professionals and education of the patients.

Is Life better after motor cortex stimulation for pain control? Results at long-term and their prediction by preoperative rTMS.

BACKGROUND: A positive effect of motor cortex stimulation (MCS) (defined as subjective estimations of pain relief ≥ 30%) has been reported in 55 - 64% of patients. Repetitive magnetic cortical stimulation (rTMS) is considered a predictor of MCS effect. These figures are, however, mostly based on subjective reports of pain intensity, and have not been confirmed in the long-term. OBJECTIVES: This study assessed long-term pain relief (2 - 9 years) after epidural motor cortex stimulation and its pre-operative prediction by rTMS, using both intensity and Quality of Life (QoL) scales. STUDY DESIGN: Analysis of the long-term evolution of pain patients treated by epidural motor cortex stimulation, and predictive value of preoperative response to rTMS. SETTING: University Neurological Hospital Pain Center. PATIENTS: Twenty patients suffering chronic pharmaco-resistant neuropathic pain. INTERVENTION: All patients received first randomized sham vs. active 20 Hz-rTMS, before being submitted to MCS surgery. MEASUREMENT: Postoperative pain relief was evaluated at 6 months and then up to 9 years post-MCS (average 6.1 ± 2.6 y) using (i) pain numerical rating scores (NRS); (ii) a combined assessment (CPA) including NRS, drug intake, and subjective quality of life; and (iii) a short questionnaire (HowRu) exploring discomfort, distress, disability, and dependence. RESULTS: Pain scores were significantly reduced by active (but not sham) rTMS and by subsequent MCS. Ten out of 20 patients kept a long-term benefit from MCS, both on raw pain scores and on CPA. The CPA results were strictly comparable when obtained by the surgeon or by a third-party on telephonic survey (r = 0.9). CPA scores following rTMS and long-term MCS were significantly associated (Fisher P = 0.02), with 90% positive predictive value and 67% negative predictive value of preoperative rTMS over long-term MCS results. On the HowRu questionnaire, long-term MCS-related improvement concerned "discomfort" (physical pain) and "dependence" (autonomy for daily activities), whereas "disability" (work, home, and leisure activities) and "distress" (anxiety, stress, depression) did not significantly improve. LIMITATIONS: Limited cohort of patients with inhomogeneous pain etiology. Subjectivity of the reported items by the patient after a variable and long delay after surgery. Predictive evaluation based on a single rTMS session compared to chronic MCS. CONCLUSIONS: Half of the patients still retain a significant benefit after 2 - 9 years of continuous MCS, and this can be reasonably predicted by preoperative rTMS. Adding drug intake and QoL estimates to raw pain scores allows a more realistic assessment of long-term benefits and enhance the rTMS predictive value. The aims of this study and its design were approved by the local ethics committee (University Hospitals St Etienne and Lyon, France).

Does the insula tell our brain that we are in pain?

Current knowledge on pain-related cerebral networks has relied so far on stimulus-induced brain responses, but not on the analysis of brain activity during spontaneous pain attacks. In this case report, correlation between intracerebral field potentials and online sensations during spontaneously painful epileptic seizures suggests a crucial role of the insula in the development of subjective pain. Attacks originated from a very limited dysplasia located in the posterior third of the right insula and propagated to other areas of the pain matrix, including the parietal operculum and the midcingulate gyrus. Concomitant painful symptoms started on the left hand or the left foot and extended in a few seconds to the whole left side of the body, sparing the head. Continuous during the first seconds of the attack, the painful feeling evolved to throbbing and remained so until it progressively vanished, together with the spike discharge. Stimulation of the insula, but not of other pain matrix regions, induced pain identical to that of seizures. After thermocoagulation of the insular epileptic focus, a short, transient exacerbation of seizures with same painful features but different location was observed before a long-lasting and complete remission of the attacks. Although these preliminary data need to be confirmed, they strongly suggest that if the full pain experience involves the pain matrix network, the posterior insula seems to play a leading role in the triggering of this network and the resulting emergence of subjective pain experience.

Motor cortex stimulation for refractory neuropathic pain: four year outcome and predictors of efficacy.

Thirty-one patients with medically refractory neuropathic pain were included in a prospective evaluation of motor cortex stimulation. The long-term outcome was evaluated using five variables: (a) rate (percentage) of pain relief, (b) pain scores as assessed on VAS, (c) postoperative decrease in VAS scores, (d) reduction in analgesic drug intake, (e) a dichotomic (yes/no) response to the question whether the patient would accept, under similar circumstances, to be operated on again. Pain relief was rated as excellent (>70 % pain relief) in 10 % of cases, good (40-69 %) in 42 %, poor (10-39 %) in 35 % and negligible (0-9 %) in 13 %. Intake of analgesic drugs was decreased in 52 % of patients and unchanged in 45 % (unavailable data in 3 %), with complete withdrawal of analgesic drugs in 36 % of patients. Twenty-one patients (70 %) declared themselves favourable to re-intervention if the same beneficial outcome could be guaranteed. Neither preoperative motor status, pain characteristics, type or localisation of lesions, quantitative sensory testing, Somatosensory Evoked Potentials, nor the interval between pain and surgery were found to predict the efficacy of MCS. The level of pain relief, as evaluated in the first month following implantation was a strong predictor of long-term relief (regression analysis, R=0.744; p<0.0001). These results confirm that MCS can be a satisfactory and durable alternative to medical treatments in patients with refractory pain, and suggest that the efficacy of MCS may be predicted in the first month of therapy.

Capillary electrophoresis combined with microdialysis in the human spinal cord: a new tool for monitoring rapid peroperative changes in amino acid neurotransmitters within the dorsal horn.

A method originally developed for the separation of the three neurotransmitters gamma-aminobutyric acid (GABA), glutamate (Glu) and L-aspartate (L-Asp) in microdialysis samples from rat brain (Sauvinet et al., Electrophoresis 2003, 24, 3187-3196) was applied to human spinal dialysates obtained during peroperative microdialysis from patients undergoing surgery against chronic pain. Molecules were tagged on their primary amine function with the fluorogene agent, naphthalene-2,3-dicarboxaldehyde (NDA), and, after separation by capillary electrophoresis (CE, 75 mmol/L borate buffer, pH 9.2, containing 70 mmol/L sodium dodecyl sulfate and 10 mmol/L hydroxypropyl-beta-cyclodextrin, + 25 kV voltage), were detected by laser-induced fluorescence detection (LIFD) using a 442 nm helium-cadmium laser. The complete method, including microdialysis sampling and analysis by CE-LIFD, has been validated for the analysis of human spinal microdialysates. The analytical detection limits were 1, 3.7 and 17 nmol/L for GABA, Glu and L-Asp respectively. This method allows an accurate measurement of the three amino acid neurotransmitters during an in vivo monitoring performed as rapidly as every minute in the human spinal dorsal horn. In addition, the effect of a brief peroperative electrical stimulation of the dorsal rootlets was investigated. The results obtained illustrate the advantages of combining microdialysis with CE-LIFD for studying neurotransmitters with such a high sampling rate.

Flexion reflexes following anterolateral cordotomy in man: dissociation between pain sensation and nociceptive reflex RIII.

Nociceptive flexion reflexes (RIII response) of the lower limbs were recorded after unilateral cervico-thoracic anterolateral cordotomy (ALC) in 7 patients. Pre-operative recordings were also obtained in 1 patient and follow-up observations in 3 patients. Flexion reflexes ipsilateral to cordotomy remained normal after surgery. Conversely, responses contralateral to the cordotomy exhibited two consistent postoperative changes: first, the RIII reflex was always dissociated from subjective pain, i.e., it appeared in the absence of any pain sensation, and, second, the RIII was depressed in the limb contralateral to ALC in 5 of 7 patients. RIII attenuation ranged from slight reduction to total abolition, and proved to be reversible in 2 of 3 patients tested during the follow-up. The reappearance of withdrawal reflexes was never accompanied by a recovery of pain sensation in the stimulated limb. We conclude that the dissociation between flexion reflexes and pain sensation, which was evidenced even in case of depressed RIII responses, should be attributable to the surgical lesion of spinothalamic fibers. Dissociation between RIII and subjective pain is a landmark indicating a lesion of the spinothalamic fibers, and may be used for the clinical assessment of spinothalamic dysfunction. Conversely, RIII depression after ALC does not depend upon the surgical lesion to the spinothalamic axons, but may be secondary to interruption of ascending spinoreticular fibers in the anterolateral quadrant, and/or of descending excitatory axons in the ventral cord.