Spinal cord injury pain.

Spinal cord injury pain encompasses musculoskeletal and neuropathic pain. Its management is often multidisciplinary and involves specific drugs such as antidepressants and antiepileptics, and nonpharmacological treatment including psychotherapy, physical therapy and neuromodulation techniques. Recent progress in the diagnosis, assessment, and understanding of its mechanisms offers the perspective of a more rational therapeutic management, which should result in better therapeutic outcome.

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.

Pharmacological treatments of neuropathic pain: The latest recommendations.

We provide an up-to-date review of the pharmacological treatment of neuropathic pain with emphasis on the latest evidence-based recommendations for its pharmacological treatment. Drugs proposed as first line include tricyclic antidepressants (particularly amitriptyline), serotonin-norepinephrine reuptake inhibitors (particularly duloxetine), pregabalin and gabapentin. Second line treatments include lidocaine plasters and capsaicin high concentration patches for peripheral neuropathic pain only, and tramadol. Third line treatments include strong opioids and botulinum toxin A (for peripheral neuropathic pain). Perspectives include the development of new compounds and a more personalized therapeutic approach, which is made possible by recent progress in the assessment and understanding of neuropathic pain.

Association of the HLA-B27 antigen and the CTLA4 gene CT60/rs3087243 polymorphism with ankylosing spondylitis in Algerian population: A case-control study.

Ankylosing spondylitis (AS) is a complex inflammatory disease that represents a major health problem both in Algeria and worldwide. Several lines of evidence support that genetic risk factors play a role in AS etiology and the CTLA4 gene has attracted a considerable attention. In this study, we were interested in evaluating the HLA-B27 frequency and in exploring the CTLA4 gene in a sample of the North African population. The dataset of the current study is composed of 81 patients with AS and 123 healthy controls. All samples were genotyped by TaqMan® allelic discrimination assay. The genetic risk of the HLA-B27 specificity and the CTLA4/CT60 polymorphism were assessed by odds ratios (OR) with 95% confidence intervals (CI). High spondylitis risk was detected for HLA-B27 allele (OR= 14.62, p = 10-6 ) in addition to a significant association of the CT60*G allele (OR= 1.89, p = .002). After gender and age stratifications, the association of the CT60*G allele was still significant in females sample (OR= 2.10, p = .001) and when age up to 30 years (OR = 2.21, p = .008). Interestingly, the CT60*G allele revealed an increased spondylitis risk in the B27 negative group (OR= 2.81, p = .006). The present work showed in West Algerian population that the HLA-B27 antigen and the variation in the CTLA4 3'UTR region played an important role in the ankylosing spondylitis susceptibility. The heterogeneity of this disease is deduced by genetic difference found between B27+ and B27- groups.

[Botulinum toxin A injections in neuropathic pain : A post-hoc subgroup analysis of patients with peripheral nerve injury]. / Botulinumtoxin-A-Injektionen bei neuropathischem Schmerz : Eine Post-hoc-Subgruppenanalyse bei Patienten mit peripherer Nervenverletzung.

The randomized controlled trial (RCT) presented in this article showed significant relief in neuropathic pain following subcutaneous injections of botulinum toxin A over 24 weeks compared to placebo. This result was confirmed in a novel post-hoc analysis of the subgroup of 46 patients with peripheral nerve injury. Relevant adverse effects did not occur during the RCT.

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.

Botulinum toxin A and neuropathic pain: An update.

Botulinum toxin type A is a widely used neurotoxin for the treatment of muscle hyperactivity such as dystonia and spasticity. Several clinical trials have also reported an efficacy of subcutaneous or intradermal administrations of botulinum toxin A on various neuropathic pain conditions including idiopathic trigeminal neuralgia and found that specific sensory phenotypes were predictors of the response. This narrative review summarizes the potential mechanisms of action, efficacy and safety of botulinum toxin A in neuropathic pain as well as its place in the therapeutic algorithm of neuropathic pain.

[The 869C>T And 915G>C Polymorphisms of TGF-ß1 and Type 1 Diabetic Retinopathy in the Algerian Population]. / Polymorphismes 869C> T et 915 G>C du TGF-ß1 dans la rétinopathie du diabète de type 1 chez la population algérienne.

INTRODUCTION: Diabetic retinopathy (DR) is characterized by chronic low-grade inflammation in which the effects of genetic factors is well established. The objective of our study is to explore an association of the 869C>T and 915G>C polymorphisms of the TGF-ß1 gene with type 1 diabetic retinopathy in the Algerian population. PATIENTS AND METHODS: A case-control study was carried out in which the SNPs 869C>T and 915G>C of the TGF-ß1 gene were analysed by the PCR-SSP technique. We compared the distribution of allelic and genotypic frequencies between patients with and without retinopathy and looked for an association between these polymorphisms and certain clinical characteristics of and risk factors for diabetic retinopathy. RESULTS: A significant increase in the frequencies of the C allele (P=0.03) and GG genotype (P=0.007) of the 915 G>C polymorphism were found, respectively, in patients without and with retinopathy. However, no significant difference was found for allelic and genotypic frequencies of the 869C>T SNP (all P>0.05) or associations between genotypes and clinical characteristics or risk factors for DR. CONCLUSION: Our preliminary results suggest that the C allele of the 915 G>C polymorphism of TGF-ß1 is protective against type 1 diabetic retinopathy in the Algerian population, while the GG genotype could confer susceptibility to it.

[Therapeutic advances in pharmaceutical treatment of neuropathic pain]. / Avancées dans le traitement pharmacologique des douleurs neuropathiques.

Neuropathic pain is difficult to treat. Recommended first-line treatments include tricyclic antidepressants and alpha2delta agonists pregabalin and gabapentin for multiple neuropathic conditions, the antidepressants duloxetine and venlafaxine in diabetic painful neuropathies and lidocaine patches for postherapetic neuralgia. Therapeutic prospects include focal therapy with sustained analgesic efficacy (capsaicin patches, botulinum toxin), treatments acting on new targets (i.e., cytokine inhibitors, metabotropic glutamate inhibitors, TRPV1 antagonists). The methodology of clinical trials also tends to take better into account the symptomatic profiles of patients, which should contribute to better prediction or responders to treatment.

EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision.

BACKGROUND AND OBJECTIVES: This second European Federation of Neurological Societies Task Force aimed at updating the existing evidence about the pharmacological treatment of neuropathic pain since 2005. METHODS: Studies were identified using the Cochrane Database and Medline. Trials were classified according to the aetiological condition. All class I and II randomized controlled trials (RCTs) were assessed; lower class studies were considered only in conditions that had no top-level studies. Treatments administered using repeated or single administrations were considered, provided they are feasible in an outpatient setting. RESULTS: Most large RCTs included patients with diabetic polyneuropathies and post-herpetic neuralgia, while an increasing number of smaller studies explored other conditions. Drugs generally have similar efficacy in various conditions, except in trigeminal neuralgia, chronic radiculopathy and HIV neuropathy, with level A evidence in support of tricyclic antidepressants (TCA), pregabalin, gabapentin, tramadol and opioids (in various conditions), duloxetine, venlafaxine, topical lidocaine and capsaicin patches (in restricted conditions). Combination therapy appears useful for TCA-gabapentin and gabapentin-opioids (level A). CONCLUSIONS: There are still too few large-scale comparative studies. For future trials, we recommend to assess comorbidities, quality of life, symptoms and signs with standardized tools and attempt to better define responder profiles to specific drug treatments.

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.

Assessment of spinal somatosensory systems with diffusion tensor imaging in syringomyelia.

OBJECTIVE: The use of diffusion tensor imaging with three-dimensional fibre tracking (DTI-FT) was tested for the assessment of spinal sensory tract lesions. The relationships between tract lesions quantified with DTI-FT were systematically examined, and somatosensory dysfunction was assessed with quantitative sensory testing (QST) and laser-evoked potentials (LEP), in patients with syringomyelia. METHODS: 28 patients with cervical syringomyelia and thermosensory impairment of the hands, and 19 healthy volunteers, were studied. A DTI-FT of the spinal cord was performed, focusing on the upper segment (C3-C4) of the syrinx. Three-dimensional DTI-FT parameters (fractional anisotropy (FA) and apparent diffusion coefficient (ADC)) of the full, anterior and posterior spinal cord were individually compared with QST (thermal detection thresholds) and LEP (amplitude, latency and spinothalamic tract (STT) conduction time) of the hands. RESULTS: Patients had a significantly lower FA, but not ADC, than healthy subjects. The mean FA of the full section of the spinal cord was correlated both to sensory deficits (ie, increase in warm (rho = -0.63, p<0.010) and cold thresholds (rho = -0.72; p<0.001 of the hands)) and to changes in LEP parameters, in particular STT conduction time (rho = -0.75; p<0.010). Correlations between FA and the clinical and electrophysiological measures were higher in the anterior area (where the spinothalamic tracts are located) than in the posterior area of the spinal cord. CONCLUSIONS: The data indicate that diffusion tensor imaging with 3D-fibre tracking is a new imaging method suitable for the objective and quantitative anatomical assessment of spinal somatosensory system dysfunction.

[T-786C endothelial nitric oxide gene polymorphism and type 1 diabetic retinopathy in the Algerian population]. / Polymorphisme T-786C de l'eNOS dans la rétinopathie du diabète de type 1 chez la population algérienne.

INTRODUCTION: Diabetic retinopathy (DR) results from interactions between genetic and environmental factors. We were interested in the endothelial nitric oxide gene (eNOS), given the involvement of this enzyme in functional alterations in the retinal microvasculature in diabetes. The goal of our study was to assess the association of T-786C endothelial nitric oxide synthase (eNOS) gene polymorphism with diabetic retinopathy in the Algerian population. PATIENTS AND METHODS: Our study enrolled 110 patients with and without DR. All subjects were genotyped for the T786C eNOS polymorphism using the PCR-RFLP method. We also investigated the association between this polymorphism and certain clinical and laboratory characteristics of patients with DR. RESULTS: A significant increase in the frequency of the CC genotype is noted in subjects without DR (P=0.03). We also report a significant increase in the frequencies of the TT+TC genotypes in individuals with DR (P=0.03). However, the association between the different genotypes and clinical or laboratory profiles in patients with DR reveals that the NO level is lower in subjects carrying the TT genotype (P=0.039). CONCLUSION: Our preliminary results suggest that the CC genotype could confer protection from type 1 diabetic retinopathy in the Algerian population, while the T allele seems to confer susceptibility.

Beyond neuropathy in hereditary sensory and autonomic neuropathy type V: cognitive evaluation.

BACKGROUND AND PURPOSE: Hereditary sensory and autonomic neuropathy (HSAN) type V is a very rare disorder. It is characterized by the absence of thermal and mechanical pain perception caused by decreased number of small diameter neurons in peripheral nerves. Recent genetic studies have pointed out the aetiological role of nerve growth factor beta, which is also involved in the development of the autonomic nervous system and cholinergic pathways in the brain. HSAN type V is usually reported not to cause mental retardation or cognitive decline. However, a structured assessment of the cognitive profile of these patients has never been made. METHODS AND RESULTS: We performed a throughout evaluation of four HSAN type V patients and compared their performance with 37 normal individuals. Our patients showed no cognitive deficits, not even mild ones. DISCUSSION AND CONCLUSIONS: Although newer mutations on this and related disorders are continuously described, their clinical characterization has been restricted to the peripheral aspects of these conditions. A broader characterization of this rare disorder may contribute to better understand the mechanisms of the nociceptive and cognitive aspects of pain.

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.

Clinical variables and ethnicity may influenced by polymorphism of CAT -262C/T and MnSOD 47C/T antioxidant enzymes in Algerian type1 diabetes without complications.

The latest studies in Algeria show that the frequency of type 1 diabetes (T1D) without complications is lower than that with complications and represents a significant burden in terms of cost and treatment. For this reason, we are interested in uncomplicated type1 diabetes and risk factors that are related to polymorphisms of antioxidant enzymes in order to prevent its complications. A total of 260 blood samples of young Algerian adults were examined. The genotypic analysis of Catalase gene (CAT -262C/T, rs1001179) and the superoxide dismutase gene (MnSOD 47C/T, rs4880) was performed by real-time PCR using TaqMan technology. The genotypic distribution of the CAT -262C/T promoter gene's polymorphism showed a significant difference between control and T1D patients for the CC genotype (p = 0.009; OR = 0.30) and for the T allele (p = 0.002; OR = 2.82). In addition, the genotypic distribution of the MnSOD 47C/T gene showed an association with T1D for the CT genotype (p = 0.040; OR = 2.37). Our results revealed that polymorphisms of CAT and MnSOD may be associated with physiopathology causing the onset of T1D. Our data, suggest that the genotypic frequencies of these SNPs appear to be influenced by clinical variables and by the Arab-Berber ethnic origin of the Algerian population.

EFNS guidelines on pharmacological treatment of neuropathic pain.

Neuropathic pain treatment remains unsatisfactory despite a substantial increase in the number of trials. This EFNS Task Force aimed at evaluating the existing evidence about the pharmacological treatment of neuropathic pain. Studies were identified using first the Cochrane Database then Medline. Trials were classified according to the aetiological condition. All class I and II controlled trials (according to EFNS classification of evidence) were assessed, but lower-class studies were considered in conditions that had no top level studies. Only treatments feasible in an outpatient setting were evaluated. Effects on pain symptoms/signs, quality of life and comorbidities were particularly searched for. Most of the randomized controlled trials included patients with postherpetic neuralgia (PHN) and painful polyneuropathies (PPN) mainly caused by diabetes. These trials provide level A evidence for the efficacy of tricyclic antidepressants, gabapentin, pregabalin and opioids, with a large number of class I trials, followed by topical lidocaine (in PHN) and the newer antidepressants venlafaxine and duloxetine (in PPN). A small number of controlled trials were performed in central pain, trigeminal neuralgia, other peripheral neuropathic pain states and multiple-aetiology neuropathic pains. The main peripheral pain conditions respond similarly well to tricyclic antidepressants, gabapentin, and pregabalin, but some conditions, such as HIV-associated polyneuropathy, are more refractory. There are too few studies on central pain, combination therapy, and head-to-head comparison. For future trials, we recommend to assess quality of life and pain symptoms or signs with standardized tools.

Translational neuropathic pain research: A clinical perspective.

Neuropathic pain encompasses a broad range of conditions associated with a lesion or disease of the peripheral or central somatosensory system and its prevalence in the general population may be as high as 7-8%. The interest in the pathophysiology of neuropathic pain has increased over the last two decades with an exponential increase in the number of experimental studies. However, despite the hopes raised by scientific discoveries, there has been no rational development of a truly new class of drugs. This situation revealing the limitations of certain experimental models, also results of limitations in clinical research. One of the reasons for the therapeutic difficulties in these patients is probably due to the fact that treatments are used in a uniform fashion whatever the clinical picture, while these syndromes are in fact highly heterogeneous. Clinical advances have recently been made in this field, following the validation of new specific clinical tools and the standardization of quantitative sensory testing paradigms facilitating improvements in the clinical characterization of these syndromes. It has been clearly demonstrated that neuropathic pain is a consistent clinical entity, but it is multidimensional in terms of its clinical expression, with different sensory profiles, potentially reflecting specific pathophysiological mechanisms. This new conceptualization of neuropathic pain should improve the characterization of the responder profiles in clinical trials and provide valuable information for the development of new and more clinically sound translational approaches in experimental models in animals.

Neuropathic low back pain in clinical practice.

BACKGROUND AND OBJECTIVE: Low back pain (LBP) is one of the most common chronic pain conditions. This paper reviews the available literature on the role of neuropathic mechanisms in chronic LBP and discusses implications for its clinical management, with a particular focus on pharmacological treatments. DATABASES AND DATA TREATMENT: Literature searches were performed in PubMed, key pain congresses and ProQuest Dialog to identify published evidence on neuropathic back pain and its management. All titles were assessed for relevant literature. RESULTS: Chronic LBP comprises both nociceptive and neuropathic components, however, the neuropathic component appears under-recognized and undertreated. Neuropathic pain (NP) is challenging to manage. Many patients with chronic LBP have pain that is refractory to existing treatments. Typically, less than half of patients experience clinically meaningful analgesia with oral pharmacotherapies; these are also associated with risks of adverse effects. Paracetamol and NSAIDs, although widely used for LBP, are unlikely to ameliorate the neuropathic component and data on the use of NP medications such as antidepressants and gabapentin/pregabalin are limited. While there is an unmet need for improved treatment options, recent data have shown tapentadol to have efficacy in the neuropathic component of LBP, and studies suggest that the capsaicin 8% patch and lidocaine 5% medicated plaster, topical analgesics available for the treatment of peripheral NP, may be a valuable additional approach for the management of neuropathic LBP. CONCLUSIONS: Chronic LBP often has an under-recognized neuropathic component, which can be challenging to manage, and requires improved understanding and better diagnosis and treatment. WHAT DOES THIS REVIEW ADD?: Increased recognition and improved understanding of the neuropathic component of low back pain raises the potential for the development of mechanism-based therapies. Open and retrospective studies suggest that agents like tapentadol and topical analgesics - such as the capsaicin 8% patch and the lidocaine 5% medicated plaster - may be effective options for the treatment of neuropathic low back pain in defined patient groups.