French guidelines for neuropathic pain: An update and commentary.

Neuropathic pain remains a significant unmet need. French recommendations were updated in 2020. The goal of this minireview is to provide an update on these published guidelines. Despite newer relevant studies, our proposed algorithm remains relevant. First-line treatments include serotonin-noradrenaline reuptake inhibitors (duloxetine and venlafaxine), gabapentin and tricyclic antidepressants, topical lidocaine and transcutaneous electrical nerve stimulation being specifically proposed for focal peripheral neuropathic pain. Second-line treatments include pregabalin (such position being confirmed by newer studies), tramadol, combinations and psychotherapy as add on, high-concentration capsaicin patches and botulinum toxin A being proposed specifically for focal peripheral neuropathic pain. Third-line treatments include high-frequency repetitive transcranial magnetic stimulation of the motor cortex, spinal cord stimulation and strong opioids (in the lack of alternative). Disseminating these recommendations and ensuring that they are well accepted by French practitioners will be necessary to optimize neuropathic pain management in real life.

Pharmacological and non-pharmacological treatments for neuropathic pain: Systematic review and French recommendations.

Neuropathic pain remains a significant unmet medical need. Several recommendations have recently been proposed concerning pharmacotherapy, neurostimulation techniques and interventional management, but no comprehensive guideline encompassing all these treatments has yet been issued. We performed a systematic review of pharmacotherapy, neurostimulation, surgery, psychotherapies and other types of therapy for peripheral or central neuropathic pain, based on studies published in peer-reviewed journals before January 2018. The main inclusion criteria were chronic neuropathic pain for at least three months, a randomized controlled methodology, at least three weeks of follow-up, at least 10 patients per group, and a double-blind design for drug therapy. Based on the GRADE system, we provide weak-to-strong recommendations for use and proposal as a first-line treatment for SNRIs (duloxetine and venlafaxine), gabapentin and tricyclic antidepressants and, for topical lidocaine and transcutaneous electrical nerve stimulation specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a second-line treatment for pregabalin, tramadol, combination therapy (antidepressant combined with gabapentinoids), and for high-concentration capsaicin patches and botulinum toxin A specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a third-line treatment for high-frequency rTMS of the motor cortex, spinal cord stimulation (failed back surgery syndrome and painful diabetic polyneuropathy) and strong opioids (in the absence of an alternative). Psychotherapy (cognitive behavioral therapy and mindfulness) is recommended as a second-line therapy, as an add-on to other therapies. An algorithm encompassing all the recommended treatments is proposed.

EAN guidelines on central neurostimulation therapy in chronic pain conditions.

BACKGROUND AND PURPOSE: Our aim was to update previous European Federation of Neurological Societies guidelines on neurostimulation for neuropathic pain, expanding the search to new techniques and to chronic pain conditions other than neuropathic pain, and assessing the evidence with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. METHODS: A systematic review and meta-analysis of trials published between 2006 and December 2014 was conducted. Pain conditions included neuropathic pain, fibromyalgia, complex regional pain syndrome (CRPS) type I and post-surgical chronic back and leg pain (CBLP). Spinal cord stimulation (SCS), deep brain stimulation (DBS), epidural motor cortex stimulation (MCS), repetitive transcranial magnetic stimulation (rTMS) and transcranial direct electrical stimulation (tDCS) of the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) were assessed. The GRADE system was used to assess quality of evidence and propose recommendations. RESULTS: The following recommendations were reached: 'weak' for SCS added to conventional medical management in diabetic painful neuropathy, CBLP and CRPS, for SCS versus reoperation in CBLP, for MCS in neuropathic pain, for rTMS of M1 in neuropathic pain and fibromyalgia and for tDCS of M1 in neuropathic pain; 'inconclusive' for DBS in neuropathic pain, rTMS and tDCS of the DLPFC, and for motor cortex tDCS in fibromyalgia and spinal cord injury pain. CONCLUSIONS: Given the poor to moderate quality of evidence identified by this review, future large-scale multicentre studies of non-invasive and invasive neurostimulation are encouraged. The collection of higher quality evidence of the predictive factors for the efficacy of these techniques, such as the duration, quality and severity of pain, is also recommended.

EFNS guidelines on neuropathic pain assessment: revised 2009.

BACKGROUND AND PURPOSE: We have revised the previous EFNS guidelines on neuropathic pain (NP) assessment, which aimed to provide recommendations for the diagnostic process, screening tools and questionnaires, quantitative sensory testing (QST), microneurography, pain-related reflexes and evoked potentials, functional neuroimaging and skin biopsy. METHODS: We have checked and rated the literature published in the period 2004-2009, according to the EFNS method of classification for diagnostic procedures. RESULTS: Most of the previous recommendations were reinforced by the new studies. The main revisions relate to: (i) the new definition of NP and a diagnostic grading system; (ii) several new validated clinical screening tools that identify NP components, and questionnaires which assess the different types of NP; (iii) recent high-quality studies on laser-evoked potentials (LEPs) and skin biopsy. CONCLUSIONS: History and bedside examination are still fundamental to a correct diagnosis, whilst screening tools and questionnaires are useful in indicating probable NP; QST is also useful for indicating the latter, and to assess provoked pains and treatment response. Amongst laboratory tests, LEPs are the best tool for assessing Adelta pathway dysfunction, and skin biopsy for assessing neuropathies with distal loss of unmyelinated nerve fibres.

Thermal hyperalgesia as a marker of oxaliplatin neurotoxicity: a prospective quantified sensory assessment study.

Neurotoxicity represents a major complication of oxaliplatin. This study aimed to identify early clinical markers of oxaliplatin neurotoxicity, in comparison with cisplatin, and detect predictors of chronic neuropathy. Forty-eight patients with mainly colorectal cancer were evaluated prospectively before oxaliplatin (n=28) or cisplatin (n=20) administration and then 2 weeks after the third (C3), sixth (C6) and ninth (C9) cycles. Eighteen oxaliplatin patients were re-assessed at 12+/-2 months. Evaluation included quantitative sensory testing, i.e., detection/pain thresholds for mechanical, vibration, cold and heat stimuli; pain induced by suprathreshold cold (5-25 degrees C) and heat (38-48 degrees C) stimuli and quantified assessment of symptoms (neuropathic pain symptom inventory). Symptoms of oxaliplatin neurotoxicity (cold-triggered dysesthesia of the hands; 96% of the cases) were reversible between cycles for up to C6. In contrast, thermal testing identified sustained (irreversible between cycles) neurotoxicity two weeks after C3 in the oxaliplatin group only, characterized by hyperalgesia to cold (5-25 degrees C) (F=11.4; p=0.0002 relative to cisplatin patient responses in the hand) and heat stimuli (38-48 degrees C) (F=4.1; p=0.049 for the hand). Cold-evoked symptoms lasting 4 days or more after C3 predicted chronic neuropathy (OR: 22; 95% CI: 1.54-314.74; p=0.02) whereas enhanced pain in response to cold (20 degrees C stimulus on the hand) predicted severe neuropathy (OR: 39; 95% CI: 1.8-817.8 p=0.02). Thermal hyperalgesia is a relevant clinical marker of early oxaliplatin neurotoxicity and may predict severe neuropathy.

Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia.

Non-invasive unilateral repetitive transcranial magnetic stimulation (rTMS) of the motor cortex induces analgesic effects in focal chronic pain syndromes, probably by modifying central pain modulatory systems. Neuroimaging studies have shown bilateral activation of a large number of structures, including some of those involved in pain processing, suggesting that such stimulation may induce generalized analgesic effects. The goal of this study was to assess the effects of unilateral rTMS of the motor cortex on chronic widespread pain in patients with fibromyalgia. Thirty patients with fibromyalgia syndrome (age: 52.6 +/- 7.9) were randomly assigned, in a double-blind fashion, to two groups, one receiving active rTMS (n = 15) and the other sham stimulation (n = 15), applied to the left primary motor cortex in 10 daily sessions. The primary outcome measure was self-reported average pain intensity over the last 24 h, measured at baseline, daily during the stimulation period and then 15, 30 and 60 days after the first stimulation. Other outcome measures included: sensory and affective pain scores for the McGill pain Questionnaire, quality of life (assessed with the pain interference items of the Brief Pain Inventory and the Fibromyalgia Impact Questionnaire), mood and anxiety (assessed with the Hamilton Depression Rating Scale, the Beck Depression Inventory and the Hospital Anxiety and Depression Scale). We also assessed the effects of rTMS on the pressure pain threshold at tender points ipsi- and contralateral to stimulation. Follow-up data were obtained for all the patients on days 15 and 30 and for 26 patients (13 in each treatment group) on day 60. Active rTMS significantly reduced pain and improved several aspects of quality of life (including fatigue, morning tiredness, general activity, walking and sleep) for up to 2 weeks after treatment had ended. The analgesic effects were observed from the fifth stimulation onwards and were not related to changes in mood or anxiety. The effects of rTMS were more long-lasting for affective than for sensory pain, suggesting differential effects on brain structures involved in pain perception. Only few minor and transient side effects were reported during the stimulation period. Our data indicate that unilateral rTMS of the motor cortex induces a long-lasting decrease in chronic widespread pain and may therefore constitute an effective alternative analgesic treatment for fibromyalgia.

Effects of surgery on the sensory deficits of syringomyelia and predictors of outcome: a long term prospective study.

OBJECTIVE: To quantify the effects of surgery on the thermal deficits of syringomyelia and assess the predictors for such effects. METHODS: The subjects were 16 consecutive patients (12 men, 4 women; mean (SD) duration of sensory symptoms, 5.1 (4.5) years) presenting with the typical symptoms of syringomyelia related to Chiari I malformation or trauma, and requiring surgical treatment. They were evaluated before surgery, then at six months and two years. Sensory evaluation included determination of the extent of thermal deficits and quantitative assessment of thermal, mechanical, vibration detection, and pain thresholds. Neuropathic pain intensity was evaluated on visual analogue scales. Magnetic resonance imaging was done before and after surgery to measure syrinx dimensions. RESULTS: The magnitude and extent of thermal deficits improved in a subgroup of patients and this was best predicted by the duration of sensory symptoms: patients operated on less than two years after the onset of their symptoms tended to improve, while those operated on later were stabilised or deteriorated slightly. The effect of surgery on thermal deficits was correlated with the duration of sensory symptoms. Surgery also affected vibration deficits in patients with the Chiari malformation, neuropathic pain on effort, and syrinx dimensions. CONCLUSIONS: The duration of sensory deficits is the best predictive factor of the efficacy of surgery for the thermal symptoms of syringomyelia. Early surgery is required if these deficits are to be minimised.

Long term effects of oral sustained release morphine on neuropsychological performance in patients with chronic non-cancer pain.

Morphine is increasingly used in patients with chronic non-cancer pain, but a major concern associated with chronic use relates to possible cognitive side-effects. The aim of this long-term prospective study was to evaluate the cognitive impact of oral sustained release morphine in patients with non-cancer pain. A battery of neuropsychological tests to explore attention, psychomotor speed and memory was administered. The effects of morphine on pain, quality of life, mood, subjective memory impairment and side-effects were also investigated. Evaluations were performed at baseline in patients free from opioids and then after 3, 6 and 12 months. Twenty-eight patients were included: 18 received oral sustained morphine (range 40-140 mg/day), ten patients stopped morphine prematurely because of side-effects or insufficient pain relief and were followed as a control group. There was no impairment of any neuropsychological variable over time in the morphine treated patients in comparison with the control group. Two measures of information processing speed - the Stroop interference score and the digit symbol test were improved at 6 and 12 months and there were significant correlations with the pain relief and improvement of mood. Self-reported memory impairment improved notably in responders to morphine. Morphine induced persisting effects on pain, and to a lesser extent on quality of life and mood. The visual analog scale score for side-effects increased at 12 months and essentially consisted of gastrointestinal disorders. This study demonstrates that 12 months treatment with oral morphine does not disrupt cognitive functioning in patients with chronic non-cancer pain and instead results in moderate improvement of some aspects of cognitive functioning, as a consequence of the pain relief and concomitant improvement of well-being and mood.

Opiate self-administration as a measure of chronic nociceptive pain in arthritic rats.

The study examined the validity of oral fentanyl self-administration (FSA) as a measure of the chronic nociceptive pain that develops in rats with adjuvant arthritis independently of acute noxious challenges. Arthritic rats self-administered more of a 0.008 mg/ml fentanyl solution (up to 3.4 g/rat per day) than non-arthritic controls (0.5 g/rat per day) and did so with a biphasic time course that reached peak during weeks 3 and 4 after inoculation with Mycobacterium butyricum. The time course paralleled both the disease process and the chronic pain. Continuous infusion of dexamethasone during weeks 3 and 4 via subcutaneous osmotic pumps at 0.0025-0.04 mg/rat per day disrupted the arthritic disease and decreased FSA to a level (i.e. by 65%) similar to that observed in non-arthritic rats. Continuous naloxone (2.5 mg/rat per day) decreased FSA (by 55%) in arthritic but not in non-arthritic animals. Continuous, subcutaneous infusion of fentanyl also decreased arthritic FSA in a manner that varied with dose at 0.04-0.16 mg/rat per day doses, but leveled off at 47% of controls with 0.31 mg/rat per day. The effects of continuous fentanyl on arthritic FSA occurred only with those doses and dose-dependent dynamics with which fentanyl also induced dependence in non-arthritic rats. The findings indicate that pain, rather than the rewarding or dependence-inducing action of fentanyl mediates FSA in arthritic rats. Paralleling patient-controlled analgesic drug intake, FSA offers a specific measure allowing the dynamic effects of neurobiological agents to be studied in this unique animal model of persistent nociceptive pain.

[Characterization of sensation disorders and neuropathic pain related to syringomyelia. A prospective study]. / Caractérisation des troubles sensitifs et des douleurs neuropathiques liés aux syringomyélies. Etude prospective.

The present prospective study aimed to perform quantitative sensory testing (QST) in patients with painful or painless syringomyelia before and after surgical treatment of their syrinx (at 3 and 9 months). Eighteen consecutive patients with cervical or dorso-lumbar syringomyelia completed the study and 9 underwent surgery. Twelve patients had central neuropathic pain (of whom 6 were followed up). Spontaneous pain and brush-evoked allodynia were assessed. Von Frey hairs, vibrameter and a thermotest device were used to determine the mechanical-, vibratory-, thermal-detection thresholds, and the mechanical and thermal pain thresholds. Results showed evidence of deficits in temperature and pain sensibility in 17 cases, often associated with deficits in vibration and touch sensitivity (11 cases). Magnetic resonance scan, including axial images, demonstrated good correlation between paramedian extension of the syrinx and the laterality of thermal deficits. Somatosensory evoked potentials (11 patients) were abnormal in 9 cases at level, and showed good correlation with deficits in vibration. The magnitude of the thermal and tactile deficit was similar between areas of spontaneous pain and adjacent non painful areas. Surgery induced a significant decrease of tactile deficits, and to a lesser extent, of thermal deficits. Effects on neuropathic pain were positive in 3 patients (total disappearance of pain) and negligible or negative in 3 patients, despite collapse of the syrinx (in 2 cases). These results confirm that QST are useful in clinical practice to quantify the clinical results of surgery in patients with syringomyelia, and allow some hypotheses about the mechanisms of neuropathic pain in these patients.

Behavioural pain-related disorders and contribution of the saphenous nerve in crush and chronic constriction injury of the rat sciatic nerve.

This study evaluated the pain-related behaviours induced by 2 models of peripheral sciatic nerve injuries in the rat: transient nerve crush and chronic constriction injury (CCI). Various lesions of the saphenous nerve were performed in order to investigate the role of saphenous innervation in behavioural disorders induced by these nerve injuries. Behavioural testing included assessment of responses to phasic stimulation (mechanical and thermal) and observation of 'spontaneous' pain-related behaviour. Results confirmed that the model of CCI induces marked and prolonged phasic and spontaneous pain-related disorders (up to week 7). Rats with crush injury exhibited moderate and transient hyperalgesia and allodynia to mechanical and thermal stimulation on the lesioned side (with a maximum at day 3 and a recovery by week 1). Section plus ligation of the ipsilateral saphenous nerve on the day of surgery prevented nociceptive behaviours and induced persistent mechanical and thermal anaesthesia or hypoesthesia of the lesioned paw in both models (lasting up to 3-4 weeks). Section without ligation of the saphenous nerve induced comparable results in rats with sciatic crush, but did not significantly modify nociceptive behaviours in rats with CCI. These data emphasise the role of adjacent saphenous nerve in the mechanisms of pain-related disorders induced by these peripheral nerve lesions. On the contralateral paw, pain-related modifications were also observed in both models, suggesting that unilateral nerve lesions induce remote modifications extending beyond the site of the injured nerve.

[Dementia disclosing primary Gougerot-Sjögren syndrome]. / Démence révélatrice du syndrome de Gougerot-Sjögren primitif.

Two cases of primary Sjögren's syndrome revealed by dementia are reported. The patients had progressive or subacute memory dysfunction and psychiatric disorders with depression and delirium. The diagnosis of Sjögren's syndrome was established by biopsy of the minor salivary glands. Both patients were treated with corticosteroids. The neuropsychiatric symptoms improved dramatically in one case and remained unchanged in the other case. Dementia in Sjögren's syndrome seems to be without aphasia, apraxia or agnosia, and associated with psychiatric features, particularly depressive symptoms, thus including some characteristics of subcortical dementia. Diagnosis may be difficult because, as shown in our cases, symptoms of ocular and buccal dryness can be absent. Salivary gland biopsy can be useful in the evaluation of patients with dementia of undetermined etiology.

Effects of guanethidine on sensitization to natural stimuli and self-mutilating behaviour in rats with a peripheral neuropathy.

In the present study we have used a recent rat model for neuropathic pain to investigate the effect of the sympatholytic drug guanethidine on changes in behavioural responses evoked by mechanical, heat and cold stimuli and on self-mutilating behaviour. After a unilateral peripheral mononeuropathy induced by ligatures around the right common sciatic nerve, the left side receiving just a sham wound, lesioned and non-operated control animals were treated with saline or guanethidine (30 mg/kg) for 4 consecutive days commencing 5 days before or 10 days after surgery. Behavioural parameters were followed for 4 weeks after drug treatment. Lesioned rats were found to be sensitized to the otherwise innocuous cold stimulus and showed decreased response thresholds to noxious heat and mechanical stimuli. Some lesioned animals self-mutilated. Treatment with guanethidine diminished heat and cold sensitization considerably, but had less effect on mechanical sensitization and, if administered before surgery, rather increased the severity of self-mutilating behaviour. While these results are in agreement with clinical observations on the prominence of sensitization to evoked stimuli, especially cold, and the effectiveness of guanethidine in sympathetically maintained neuropathic pain, they indicate that the mechanisms involved in sensitization to different stimuli and self mutilating behaviour differ.

The bidirectional dose-dependent effect of systemic naloxone is also related to the intensity and duration of pain-related disorders: a study in a rat model of peripheral mononeuropathy.

In an experimental model of mononeuropathy in the rat, created by 4 ligatures around the sciatic nerve, i.v. naloxone 1 week after surgery induces bidirectional effects (antinociceptive effects at very low doses, hyperalgesic effects with high doses). Using the same nociceptive test (vocalization thresholds to paw pressure), the activity of the same doses of naloxone (3 micrograms/kg, and 1 mg/kg) was investigated 2 weeks after sciatic ligation, when the behavioural pain-related disorders are at a maximum. Three micrograms/kg naloxone produced a significant antinociceptive effect on the lesioned and non-lesioned paw, which was clearly related to the degree as well as to the duration of pain-related signs in the rat. By contrast, the high dose of naloxone did not induce a mean significant effect when tested on either paw; however, it elicited a potent hyperalgesic effect in those rats which had recovered from hyperalgesia at this 2 week time point after the sciatic injury.

Further evidence for 'pain-related' behaviours in a model of unilateral peripheral mononeuropathy.

A model of experimental peripheral neuropathy producing pain-related disorders has recently been described in the rat. The present study aimed to investigate, using a different and quantifiable behavioural approach, the abnormal pain-related sensations in the animals. The neuropathy was produced by 4 ligatures tied loosely around the common sciatic nerve. 6-8 days after surgery, most of the rats exhibited pain-related disorders ipsilateral to the sciatic ligation, which became maximal 2 weeks after surgery. Mechanical noxious stimulation (pinching of the hind paw) revealed hyperalgesia in all the animals. Rats also exhibited allodynia when tested with the vocalization threshold test to paw pressure (mean vocalization thresholds were 65.5 +/- 3.6% of the preoperative control, P less than 0.01, n = 95). Tests using heat (40, 42, 44, 46 degrees C) and cold (10 degrees C) stimulation (immersion of the rat's hind paw in a bath until it was observed to struggle) indicated hyperalgesia to noxious heat (decrease of 30% in the immersion duration (ID) at a temperature of 46 degrees C), and allodynia to non-noxious heat (decrease of 30% in the temperature of the struggle threshold) and to cold stimulation (decrease by 40% in the ID). In addition, the animals showed modifications in the spontaneous postures of the affected hind paw in a natural setting, suggesting a 'spontaneous' pain-related behaviour (the mean 'pain' rating, derived from the technique used for the formalin test and numbered 0-5, was 2.8 +/- 0.4, P less than 0.01, n = 12). Lastly, sensitized responses were observed to mechanical stimulation after thermal stimulation in the non-noxious range applied to the lesioned but not the non-lesioned paw. The time course of pain-related disorders was comparable whatever the behavioural test, with recovery 2 months after surgery. These results clearly show that the neuropathy produces abnormal pain-related disorders in the rat, which are reminiscent of those observed in some human neuropathies.