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 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.

Neuropathic pain: Definition, assessment and epidemiology.

Neuropathic pain has been a very active and productive clinical research field over the last 15 years. Studies have concerned multiple aspects of these complex chronic pain syndromes including their very definition, the elaboration of new diagnostic algorithms, the development of specific tools for their screening and measurement and their epidemiology. In this review, we summarize these recent evolutions that have impacted the way these pain syndromes are conceptualized and managed both in daily practice and in the clinical research setting.

Assessment and manifestation of central sensitisation across different chronic pain conditions.

Different neuroplastic processes can occur along the nociceptive pathways and may be important in the transition from acute to chronic pain and for diagnosis and development of optimal management strategies. The neuroplastic processes may result in gain (sensitisation) or loss (desensitisation) of function in relation to the incoming nociceptive signals. Such processes play important roles in chronic pain, and although the clinical manifestations differ across condition processes, they share some common mechanistic features. The fundamental understanding and quantitative assessment of particularly some of the central sensitisation mechanisms can be translated from preclinical studies into the clinic. The clinical perspectives are implementation of such novel information into diagnostics, mechanistic phenotyping, prevention, personalised treatment, and drug development. The aims of this paper are to introduce and discuss (1) some common fundamental central pain mechanisms, (2) how they may translate into the clinical signs and symptoms across different chronic pain conditions, (3) how to evaluate gain and loss of function using quantitative pain assessment tools, and (4) the implications for optimising prevention and management of pain. The chronic pain conditions selected for the paper are neuropathic pain in general, musculoskeletal pain (chronic low back pain and osteoarthritic pain in particular), and visceral pain (irritable bowel syndrome in particular). The translational mechanisms addressed are local and widespread sensitisation, central summation, and descending pain modulation. SIGNIFICANCE: Central sensitisation is an important manifestation involved in many different chronic pain conditions. Central sensitisation can be different to assess and evaluate as the manifestations vary from pain condition to pain condition. Understanding central sensitisation may promote better profiling and diagnosis of pain patients and development of new regimes for mechanism based therapy. Some of the mechanisms underlying central sensitisation can be translated from animals to humans providing new options in development of therapies and profiling drugs under development.

Neuropathic pain in cancer: systematic review, performance of screening tools and analysis of symptom profiles.

BACKGROUND: The objectives of this study were to evaluate the methodological quality of rigorous neuropathic pain assessment tools in applicable clinical studies, and determine the performance of screening tools for identifying neuropathic pain in patients with cancer. METHODS: Systematic literature search identified studies reporting use of Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), Douleur Neuropathique en 4 (DN4) or painDETECT (PDQ) in cancer patients with a clinical diagnosis of neuropathic or not neuropathic pain. Individual patient data were requested to examine descriptor item profiles. RESULTS: Six studies recruited a total of 2301 cancer patients of which 1564 (68%) reported pain. Overall accuracy of screening tools ranged from 73 to 94%. There was variation in description and rigour of clinical assessment, particularly related to the rigour of clinical judgement of pain as the reference standard. Individual data from 1351 patients showed large variation in the selection of neuropathic pain descriptor items by cancer patients with neuropathic pain. LANSS and DN4 items characterized a significantly different neuropathic pain symptom profile from non-neuropathic pain in both tumour- and treatment-related cancer pain aetiologies. CONCLUSIONS: We identified concordance between the clinician diagnosis and screening tool outcomes for LANSS, DN4 and PDQ in patients with cancer pain. Shortcomings in relation to standardized clinician assessment are likely to account for variation in screening tool sensitivity, which should include the use of the neuropathic pain grading system. Further research is needed to standardize and improve clinical assessment in patients with cancer pain. Until the standardization of clinical diagnosis for neuropathic cancer pain has been validated, screening tools offer a practical approach to identify potential cases of neuropathic cancer pain.

[Misuse and dependence on prescription opioids: Prevention, identification and treatment]. / Mésusage et dépendance aux opioïdes de prescription : prévention, repérage et prise en charge.

Since the 1990s, the use of prescription opioids has largely spread, which has brought a real progress in the treatment of pain. The long-term use of prescription opioid is sometimes required, and may lead to pharmacological tolerance and withdrawal symptoms, i.e. pharmacological dependence on prescription opioids. Occasionally, this may also lead to misuse of prescription opioids (MPO). MPO preferentially occurs in vulnerable individuals, i.e., those with a young age, history of other addictive or psychiatric disorders, especially anxious and depressive disorders. MPO is associated with numerous complications, including an increased risk of fatal overdose. Prevention of MPO begins before the opioid prescription, with the identification of potential vulnerability factors. A planned and personalized monitoring should be systematically implemented. In vulnerable patients, contractualizing the prescription is warranted. During follow-up, the relevance of the prescription should be regularly reconsidered, according to the benefit observed on pain and the potential underlying signs of MPO. Patients with suspected MPO should be referred early to pain or addiction centers. The treatment of MPO should be based on multidisciplinary strategies, involving both the addiction and pain aspects: progressive opioid withdrawal, non-pharmacological measures against pain, or switching to medication-assisted treatment of addiction (i.e., buprenorphine or methadone).

Flight Lieutenant Peach's observations on Burning Feet Syndrome in Far Eastern Prisoners of War 1942-45.

INTRODUCTION: 'Burning Feet Syndrome' affected up to one third of Far Eastern Prisoners of War in World War 2. Recently discovered medical records, produced by RAF Medical Officer Nowell Peach whilst in captivity, are the first to detail neurological examinations of patients with this condition. METHODS: The 54 sets of case notes produced at the time were analysed using modern diagnostic criteria to determine if the syndrome can be retrospectively classed as neuropathic pain. RESULTS: With a history of severe malnutrition raising the possibility of a peripheral polyneuropathy, and a neuroanatomically plausible pain distribution, this analysis showed that Burning Feet Syndrome can now be described as a 'possible' neuropathic pain syndrome. CONCLUSION: After 70 years, the data painstakingly gathered under the worst of circumstances have proved to be of interest and value in modern diagnostics of neuropathic pain.

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.

From pulses to pain relief: an update on the mechanisms of rTMS-induced analgesic effects.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique that allows cortical stimulation. Recent studies have shown that rTMS of the primary motor cortex or dorsolateral prefrontal cortex decreases pain in various pain conditions. The aim of this review was to summarize the main characteristics of rTMS-induced analgesic effects and to analyse the current data on its mechanisms of action. DATABASES: Medline, PubMed and Web of Science were searched for studies on the analgesic effects and mechanisms of rTMS-induced analgesic effects. Studies on epidural motor cortex stimulation (EMCS) were also included when required, as several mechanisms of action are probably shared between both techniques. RESULTS: Stimulation site and stimulation parameters have a major impact on rTMS-related analgesic effects. Local cortical stimulation is able to elicit changes in the functioning of distant brain areas. These modifications outlast the duration of the rTMS session and probably involve LTP-like mechanisms via its influence on glutamatergic networks. Analgesic effects seem to be correlated to restoration of normal cortical excitability in chronic pain patients and depend on pain modulatory systems, in particular endogenous opioids. Dopamine, serotonin, norepinephrine and GABAergic circuitry may also be involved in its effects, as well as rostrocaudal projections. CONCLUSIONS: rTMS activates brain areas distant from the stimulation site. LTP-like mechanisms, dependence on endogenous opioids and increase in concentration of neurotransmitters (monoamines, GABA) have all been implicated in its analgesic effects, although more studies are needed to fill in the still existing gaps in the understanding of its mechanisms of action.

Are there different predictors of analgesic response between antidepressants and anticonvulsants in painful diabetic neuropathy?

BACKGROUND: To investigate baseline demographics and disease characteristics as predictors of the analgesic effect of duloxetine and pregabalin on diabetic peripheral neuropathic pain (DPNP). METHODS: Based on data from the COMBO-DN study, a multinational clinical trial in DPNP, the potential impact of baseline characteristics on pain relief after 8-week monotherapy with 60 mg/day duloxetine or 300 mg/day pregabalin was assessed using analyses of covariance. Subgroups of interest were characterized regarding their baseline characteristics and efficacy outcomes. RESULTS: A total of 804 patients were evaluated at baseline. A significant interaction with treatment was observed in the mood symptom subgroups with a larger pain reduction in duloxetine-treated patients having no mood symptoms [Hospital Anxiety and Depression Scale (HADS) depression or anxiety subscale score <11; -2.33 (duloxetine); -1.52 (pregabalin); p = 0.024]. There were no significant interactions between treatment for subgroups by age (<65 or ≥65 years), gender, baseline pain severity [Brief Pain Inventory Modified Short Form (BPI-MSF) average pain <6 or ≥6], diabetic neuropathy duration (≤2 or >2 years), baseline haemoglobin A1c (HbA1c) (<8% or ≥8%), presence of comorbidities and concomitant medication use. CONCLUSIONS: Our analyses suggest that the efficacy of duloxetine and pregabalin for initial 8-week treatment in DPNP was consistent across examined subgroups based on demographics and disease characteristics at baseline except for the presence of mood symptoms. Duloxetine treatment appeared to be particularly beneficial in DPNP patients having no mood symptoms.

Thermoregulation and pain perception: Evidence for a homoeostatic (interoceptive) dimension of pain.

BACKGROUND: Experimental and clinical observations of interactions between the nociceptive and thermoceptive systems have suggested that they could be part of the homoeostatic system relating to the condition of the body, described as 'interoception'. Homoeostatic physiological systems are extensively interconnected. Thus, consistent with this hypothesis, we would expect thermoregulatory challenges to be associated with changes in pain perception. METHODS: The effects of whole-body warming or cooling inducing significant changes in mean body temperature were tested in 15 healthy volunteers (29 ± 6 years old) on: (i) the paradoxical burning pain induced by the application of simultaneous non-noxious thermal stimuli with a 'thermal grill' and (ii) the 'normal' pain evoked by noxious thermal stimuli. RESULTS: Whole-body warming and cooling induced changes in opposite direction of the threshold of the paradoxical pain induced by the thermal grill, consisting of an increase by 1.2 ± 1.7 °C (p = 0.02) during the warming session and a nonsignificant decrease by 0.7 ± 2.7 °C (p = 0.15) during the cooling session. In addition, there was a correlation (r = 0.54; p = 0.002) between the magnitude of the change in mean body temperature and the magnitude of the change in the threshold of the paradoxical pain induced by the thermal grill. By contrast, the thermal challenges induced no significant change in pain evoked by noxious hot or cold stimuli. CONCLUSIONS: Our results are consistent with the notion that pain has a homoeostatic (interoceptive) dimension and showed that the thermal grill-induced pain is a unique experimental model to investigate this differentiable pain dimension.

Recommendations on practice of conditioned pain modulation (CPM) testing.

Protocols for testing conditioned pain modulation (CPM) vary between different labs/clinics. In order to promote research and clinical application of this tool, we summarize the recommendations of interested researchers consensus meeting regarding the practice of CPM and report of its results.

The analgesic efficiency of combined pregabalin and ketamine for total hip arthroplasty: a randomised, double-blind, controlled study.

Ketamine and pregabalin each provide postoperative analgesia, although the combination has yet to be evaluated. One hundred and forty-two patients undergoing total hip arthroplasty were randomly assigned to receive ketamine alone, pregabalin alone, ketamine and pregabalin combined, or placebo. Pain scores at rest and on movement, morphine consumption, side-effects, pressure pain thresholds and secondary hyperalgesia were evaluated. Mean (SD) total 48-h morphine use was reduced in patients given ketamine alone (52 (22) mg) and pregabalin alone (44 (20) mg) compared with placebo (77 (36) mg) p < 0.001. Morphine use was further reduced in patients given both ketamine and pregabalin (38 (19) mg) with an interaction between ketamine and pregabalin (ANOVA factorial; p = 0.028). Secondary hyperalgesia was reduced by ketamine. There were no differences between groups in pain scores after surgery, pressure pain thresholds or side-effects. The combination of pregabalin and ketamine has a small, beneficial clinical effect.

Early antiviral treatment fails to completely prevent herpes-related pain.

OBJECTIVES: Antiviral therapy does not completely relieve herpes zoster (HZ)-related pain, including post-herpetic neuralgia (PHN). The 12-month longitudinal prospective observational ARIZONA study was conducted in primary care in France between November 20, 2006 and September 12, 2008. The ARIZONA study included data from 1358 patients 50 years of age or more, presenting with acute eruptive HZ. This article focuses on the relationship between antiviral therapy and HZ-related pain in this large population. PATIENTS AND METHODS: Six hundred and forty-four family physicians (FPs) consecutively included all patients 50years of age or more presenting with acute HZ in the eruptive phase. The FP documented every patient's demographic and medical characteristics, HZ characteristics, and prescribed drugs at inclusion, and the presence of HZ-related pain on day 15 and at months 1, 3, 6, 9, and 12. RESULTS: One thousand two hundred and fifty-eight (92.6%) of the 1358 included patients (mean 67.7years [SD 10.7]; 62.2% female patients) were given antiviral drugs. The prevalence of HZ-related pain was 43.6%, 27.0%, 11.7%, 8.7%, 7.4%, and 6.0%, on day 15 and at months 1, 3, 6, 9, and 12, respectively. HZ-related pain was at least as frequent in patients treated by antiviral therapy within 72hours following HZ-rash onset as in patients treated later or who did not receive antiviral treatment, and more frequent in patients whose diagnosis was made within 24hours following HZ-rash onset. CONCLUSIONS: Antiviral therapy, even early, does not prevent HZ-related pain and PHN, probably because patients quickly identified and treated were those with severe forms and potentially at high risk of pain. Preventive strategies are thus needed.

Changes in the modulation of spinal pain processing are related to severity in irritable bowel syndrome.

BACKGROUND: In irritable bowel syndrome (IBS) patients can be divided in two groups according to inhibition or facilitation of the RIII nociceptive spinal reflex induced by rectal distension. We further investigated the differences in pain processes in these two groups and their relationship to clinical symptoms. METHODS: This study included 10 female IBS-C patients with facilitation (Group F) and 10 patients with inhibition (Group I) of the RIII reflex recorded on the left lower limb during slow-ramp rectal distension, and 11 healthy female volunteers. Diffuse noxious inhibitory control (DNIC)-induced inhibition was assessed by measuring the effects of noxious cold stimulation of the right hand on the RIII reflex and the concomitant sensation of pain. Functional magnetic resonance imaging (fMRI) was performed to compare the changes in brain activity induced by painful and non painful rectal distension. Irritable bowel syndrome symptom severity, mood, anxiety, and catastrophizing were also systematically assessed. KEY RESULTS: Unlike the patients of Group I and healthy volunteers, Group F patients displayed no inhibition of the RIII reflex or of concomitant pain sensation during immersion of the hand in ice-cold water. The reduction of the inhibition induced by heterotopic noxious stimuli was directly correlated with the severity of IBS symptoms, but not with psychological symptoms. The fMRI study showed that non-painful and painful rectal distension induced similar changes in brain activity in the two groups of patients. CONCLUSION & INFERENCES: Alterations of the modulation of spinal pain processing in IBS correlates with symptom severity but not with psychological factors or brain activity.

Alteration of pain recognition in schizophrenia.

BACKGROUND: Schizophrenia patients display impaired recognition of their own emotions and those of others and deficits in several domains of empathy. The first-person experience of pain and observing others in pain normally trigger strong emotional mechanisms. We therefore hypothesized that schizophrenia patients would display impaired recognition and categorization of both their own pain and the pain of others. METHODS: We studied 29 patients (18 men/11 women; 36 ± 13 years old) with paranoid schizophrenia-spectrum disorder and 27 healthy volunteers (20 men/7 women; 31 ± 9 years old) matched for age, gender, IQ and socio-cultural level. We assessed symptom severity and theory of mind. The participants' ability to detect and categorize pain in others was assessed with the sensitivity to expressions of pain (STEP) test, which is based on facial expressions, and another dynamic test involving a series of video sequences showing various pain-inducing events. The ability of patients to evaluate their own pain was assessed with the situational pain questionnaire (SPQ), which includes a series of questions assessing how one would expect to feel in different imaginary situations. Empathic tendencies were assessed with the interpersonal reactivity index. RESULTS: Patients and controls differed significantly in STEP, pain video and SPQ scores. By contrast with control subjects, the patients' pain judgements were not correlated with their affective or cognitive empathic capacities. CONCLUSIONS: Schizophrenic patients have a deficit of the identification and categorization of pain both in themselves and in others.