Is the Capsaicin 179 mg (8% w/w) Cutaneous Patch an Appropriate Treatment Option for Older Patients with Peripheral Neuropathic Pain?

Introduction: Capsaicin 179 mg (8% weight per weight) cutaneous patch ("capsaicin patch") is a recommended topical treatment for peripheral neuropathic pain (PNP). In older patients, topical treatments may be preferred over systemic treatments, but data specific to the older population are scarce. Methods: We conducted pooled analyses of multiple clinical trials to evaluate efficacy and safety of capsaicin patch in older patients. The analysis of efficacy included four randomized, double-blind, 12-week studies with similar trial design comparing a single treatment of capsaicin 179 mg cutaneous patch vs low-dose control patch in post-herpetic neuralgia. For the safety evaluation, data were pooled from 18 interventional studies in which capsaicin patch was used in PNP with varying etiologies. Results: Capsaicin patch had similar analgesic efficacy in elderly (n=582) and non-elderly patients (n=545) in terms of change from baseline to 2-12 weeks in the 11-point numeric pain rating scale (NPRS) score for average pain over the previous 24 hours. In both age groups, decrease in NPRS score was significantly greater with capsaicin patch vs control. Older patients treated with capsaicin patch were significantly more likely than those in the control group to achieve responder status (ie mean decrease in NPRS score from baseline to week 2-12 of at least 30% or ≥2 points): 36.1% vs 27.1% (odds ratio [OR] [95% CI] 1.52 [1.06, 2.18]; P=0.0231) and 33.1% vs 20.9% (OR [95% CI] 1.90 [1.30, 2.78]; P=0.0009) for active treatment vs control group, respectively. Similar proportions of non-elderly patients (n=2,311) and elderly patients (n=537) treated with capsaicin patch experienced treatment-emergent adverse events (TEAEs) (81.6% and 78.1%, respectively) and serious TEAEs (8.2% and 7.2%), with application-site reactions the most common TEAEs in both groups. Conclusion: The capsaicin patch was equally efficacious and well tolerated in older patients as in younger patients.

Peripheral neuropathic pain is a common challenge among the elderly, yet effective treatments for this age group remain underexplored. This research focuses on the use of a high-concentration capsaicin patch, a specialized treatment for this type of pain. The patch, which is applied directly to the affected skin area, has been shown to reduce pain significantly for up to 12 weeks. This analysis of multiple clinical trials showed that the high-concentration capsaicin patch significantly reduced pain intensity and was well tolerated in older patients with peripheral neuropathic pain.

Reduced Production of Pro-Inflammatory and Pro-Catabolic Factors by Human Serum Metabolites Derived from a Patented Saffron Extract Intake.

Safe and anti-inflammatory plant-based natural products present an increasing focus in the treatment of chronic inflammatory diseases such as osteoarthritis or inflammatory bowel diseases. Among them, saffron, a spice derived from the stigma of Crocus sativus, could have anti-inflammatory properties and would be therefore a promising therapeutic agent for the treatment of such conditions. However, the anti-inflammatory molecular mechanisms of saffron in humans are still understudied and unclear. In this study, combining human serum metabolites and cell cultures, we evaluated the effect of circulating metabolites from the consumption of a patented saffron extract (Safr'InsideTM) on the chondrocytes and colon epithelial cell responses to inflammatory stress. Parametric or non-parametric Analysis of Variance with post hoc tests was performed. We demonstrated that human serum containing metabolites from saffron intake attenuated IL-1ß-stimulated production of PGE2 and MMP-13 in chondrocyte cells and limited the increase in ICAM-1, MCP-1, iNOS, and MMP-3 in human epithelial cells following combined IL-1ß and TNF-α inflammatory stimulation. Altogether, these data provide new findings into the mechanisms underlying the beneficial effects of saffron on chondrocytes and enterocyte cells at the cellular level and in the context of chronic inflammatory disorders.

Systematic review and co-ordinate based meta-analysis to summarize the utilization of functional brain imaging in conjunction with human models of peripheral and central sensitization.

BACKGROUND AND OBJECTIVE: Functional magnetic resonance imaging, in conjunction with models of peripheral and/or central sensitization, has been used to assess analgesic efficacy in healthy humans. This review aims to summarize the use of these techniques to characterize brain mechanisms of hyperalgesia/allodynia and to evaluate the efficacy of analgesics. DATABASES AND DATA TREATMENT: Searches were performed (PubMed-Medline, Cochrane, Web of Science and Clinicaltrials.gov) to identify and review studies. A co-ordinate based meta-analysis (CBMA) was conducted to quantify neural activity that was reported across multiple independent studies in the hyperalgesic condition compared to control, using GingerALE software. RESULTS: Of 217 publications, 30 studies met the inclusion criteria. They studied nine different models of hyperalgesia/allodynia assessed in the primary (14) or secondary hyperalgesia zone (16). Twenty-three studies focused on neural correlates of hyperalgesic conditions and showed consistent changes in the somatosensory cortex, prefrontal cortices, insular cortex, anterior cingulate cortex, thalamus and brainstem. The CBMA on 12 studies that reported activation coordinates for a contrast comparing the hyperalgesic state to control produced six activation clusters (significant at false discovery rate of 0.05) with more peaks for secondary (17.7) than primary zones (7.3). Seven studies showed modulation of brain activity by analgesics in five of the clusters but also in four additional regions. CONCLUSIONS: This meta-analysis revealed substantial but incomplete overlap between brain areas related to neural mechanisms of hyperalgesia and those reflecting the efficacy of analgesic drugs. Studies testing in the secondary zone were more sensitive to evaluate analgesic efficacy on central sensitization at brainstem or thalamocortical levels. SIGNIFICANCE: Experimental pain models that provide a surrogate for features of pathological pain conditions in healthy humans and functional imaging techniques are both highly valuable research tools. This review shows that when used together, they provide a wealth of information about brain activity during pain states and analgesia. These tools are promising candidates to help bridge the gap between animal and human studies, to improve translatability and provide opportunities for identification of new targets for back-translation to animal studies.

A Phase 1 randomized, open-label clinical trial to evaluate the effect of a far-infrared emitting patch on local skin perfusion, microcirculation and oxygenation.

Far-infrared radiation (FIR) has been investigated for reduction of pain and improvement of dermal blood flow. The FIRTECH patch is a medical device designed to re-emit FIR radiated by the body. This phase 1 study was conducted to evaluate the local effects of the FIRTECH patch on local skin perfusion, microcirculation and oxygenation. This prospective, randomized, open-label, parallel designed study admitted 20 healthy participants to a medical research facility for treatment for 31 h on three anatomical locations. During treatment, imaging assessments consisting of laser speckle contrast imaging, near-infrared spectroscopy, side-stream dark-field microscopy, multispectral imaging and thermography were conducted regularly on patch-treated skin and contralateral non-treated skin. The primary endpoint was baseline perfusion increase during treatment on the upper back. Secondary endpoints included change in baseline perfusion, oxygen consumption and temperature of treated versus untreated areas. The primary endpoint was not statistically significantly different between treated and non-treated areas. The secondary endpoints baseline perfusion on the forearm (least square means [LSMs] difference 2.63 PU, 95% CI: 0.97, 4.28), oxygen consumption (LSMs difference: 0.42 arbitrary units [AUs], 95% CI: 0.04, 0.81) and skin temperature (LSMs difference 0.35°C, 95% CI: 0.16, 0.6) were statistically significantly higher in treated areas. Adverse events observed during the study were mild and transient. The vascular response to the FIRTECH patch was short-lived suggesting a non-thermal vasodilatory effect of the patch. The FIRTECH patch was well tolerated, with mild and transient adverse events observed during the study. These results support the therapeutic potential of FIR in future investigations.

Osteoporosis treatment and pain relief: A scoping review.

BACKGROUND AND OBJECTIVE: Anti-osteoporosis (OP) drugs have been suggested to contribute to pain reduction during OP management. This scoping review aimed at mapping the literature on pain relief with anti-OP drugs in OP treatment. DATABASES AND DATA TREATMENT: Medline, Pubmed and Cochrane databases were searched by two reviewers with keywords combinations. Randomized controlled and real-life English studies, pain as an endpoint, antiosteoporosis drugs were inclusion criteria. Case reports, surveys, comment letters, conference abstracts, animal studies and grey literature were excluded. Predetermined data were extracted by two reviewers and disagreement solved through discussion. RESULTS: A total of 130 articles were identified, 31 publications were included, 12 randomized clinical trials and 19 observational studies. Pain reduction was assessed by different tools: Visual Analogue Scale, Verbal Rating Scale, Facial Scale or as a domain of quality of life questionnaires including Short form 8, 36, mini-OP, Japanese OP, Qualeffo, Roland Morris Disability questionnaires. Collective data show that anti-OP drugs may display an analgesic effect that may be linked to the local mode of action of drugs on bone and consecutive modulation of pain sensitization. The methodology of the studies showed a heterogeneity of endpoints, comparators, statistical approaches and follow-up duration. CONCLUSION: Considering the limitations of the literature, there is a need for more rigorous trials and larger real-life studies taking into account the recommendations published for research in rheumatology and in pain medicine. The identification of responders, patient subtypes, and of analgesic-effect doses would allow optimization and individualization for pain relief in patients with OP. SIGNIFICANCE STATEMENT: This scoping review shows that anti-OP drugs may improve pain and quality of life of patients with OP. The heterogeneity in design, choice of endpoints, methodology, comparators and follow-up duration of included randomized clinical trials and real-life studies does not allow so far to identify a predominant antiosteoporosis drug or an optimal dosage for pain relief. These gaps need to be addressed and warrant further research in the future for optimizing pain improvement in the course of OP drug treatment.

[Ketamine in chronic pain]. / Intérêt de la kétamine dans le traitement des douleurs chroniques.

Ketamine is now frequently used in the management of chronic pain refractory to conventional treatments. However, its efficacy and adverse effects appear variable in the literature in line with heterogeneous methodologies and modes of administration, leading to controversy regarding the actual interest of ketamine for chronic pain treatment. A need for clinical trials on larger cohorts of well selected patients but also real-life studies to more accurately quantify its efficacy, refine its prescription dosages and better understand its long-term adverse effects is highlighted in the literature. Progress in this direction has been achieved in recent years with improved recommendations for use, taking into account different trajectories of analgesia with ketamine, depending on the etiology of the pain, and the psycho-affective profile of patients. A holistic approach is clearly needed with consideration of pain and depression comorbidities to optimize pain management.

Title: Intérêt de la kétamine dans le traitement des douleurs chroniques. Abstract: La kétamine est aujourd'hui fréquemment utilisée dans la prise en charge de la douleur chronique réfractaire aux traitements classiques. Selon les études, l'efficacité et les effets indésirables de la kétamine apparaissent variables, en lien avec des méthodologies et des modes d'administration hétérogènes, conduisant à des controverses sur son utilisation en clinique. Un besoin d'essais sur des cohortes plus nombreuses de patients mieux sélectionnés mais aussi d'études en « vraie vie ¼ pour mieux quantifier son efficacité, raffiner les posologies de prescription et mieux comprendre ses effets indésirables à long terme, est régulièrement souligné dans la littérature. Toutefois, au cours des dernières années, plusieurs travaux ont permis d'avancer sur les recommandations d'utilisation. Ils soulignent en particulier la nécessité de prendre en compte à la fois les trajectoires diverses d'antalgie avec la kétamine, selon l'étiologie de la douleur, et les comorbidités, en particulier la dépression, afin d'optimiser la prise en charge des patients douloureux.

Assessing brain function in stressed healthy individuals following the use of a combination of green tea, Rhodiola, magnesium, and B vitamins: an fMRI study.

Introduction: This randomized, controlled, single-blinded trial assessed the effect of magnesium (Mg)-Teadiola (Mg, vitamins B6, B9, B12, Rhodiola, and green tea/L-theanine) versus placebo on the brain response to stressful thermal stimulus in chronically stressed, but otherwise healthy subjects. Impacts on stress-related quality-of-life parameters (depression, anxiety, sleep, and perception of pain) were also explored. Methods: The study recruited a total of 40 adults (20 per group), suffering from stress for more than 1 month and scaling ≥14 points on the Depression Anxiety Stress Scale (DASS)-42 questionnaire at the time of inclusion. Individuals received oral Mg-Teadiola or placebo for 28 days (D). fMRI analysis was used to visualize the interplay between stress and pain cerebral matrices, using thermal stress model, at baseline (D0) and after D28. Results: Based on blood-oxygen-level-dependent (BOLD) signal variations during the stress stimulation (before pain perception), a significantly increased activation between D0 and D28 was observed for left and right frontal area (p = 0.001 and p = 0.002, respectively), left and right anterior cingulate cortex (ACC) (p = 0.035 and p = 0.04, respectively), and left and right insula (p = 0.034 and p = 0.0402, respectively) in Mg-Teadiola versus placebo group. During thermal pain stimulation, a significantly diminished activation of the pain matrix was observed between D0 and D28, for left and right prefrontal area (both p = 0.001), left and right insula (p = 0.008 and p = 0.019, respectively), and left and right ventral striatum (both p = 0.001) was observed in Mg-Teadiola versus placebo group. These results reinforce the clinical observations, showing a perceived benefit of Mg-Teadiola on several parameters. After 1 month of treatment, DASS-42 stress score significantly decreased in Mg-Teadiola group [effect size (ES) -0.46 (-0.91; -0.01), p = 0.048]. Similar reductions were observed on D14 (p = 0.011) and D56 (p = 0.008). Sensitivity to cold also improved from D0 to D28 for Mg-Teadiola versus placebo [ES 0.47 (0.02; 0.92) p = 0.042]. Conclusion: Supplementation with Mg-Teadiola reduced stress on D28 in chronically stressed but otherwise healthy individuals and modulated the stress and pain cerebral matrices during stressful thermal stimulus.

Comparison between pupillometry and numeric pain rating scale for pain assessments in communicating adult patients in the emergency department.

OBJECTIVE: The adequate assessment of pain in the emergency department (ED) can be challenging. Two dynamic pupillary measures used in conscious subjects after a surgical procedure were previously shown to correlate to the magnitude of ongoing pain. The objective of this study was to test the ability of dynamic measures derived from pupillometry to evaluate pain intensity in conscious adult patients admitted to the ED. METHODS: This prospective, interventional, single-centre study was performed between August 2021 and January 2022 (NCT05019898). An assessment of self-reported pain intensity was performed on ED admission by the triage nurse using a numeric rating scale (NRS). This was followed by two dynamic measures derived from pupillometry that were previously correlated with pain perception: the pupillary unrest under ambient light (PUAL) and the pupillary light reflex (PLR). RESULTS: Among the 313 analysed patients, the median age was 41 years, and 52% were women. No correlation was found between self-reported pain ratings and PUAL (r = 0.007) or PLR (baseline diameter r = -0.048; decrease r = 0.024; latency r = 0.019; slope = -0.051). Similarly, the pupillometry measures could not discriminate patients with moderate to severe pain (defined as NRS ≥4). CONCLUSIONS: Pupillometry does not appear to be an effective tool to evaluate pain in the ED environment. Indeed, too many factors influencing the sympathetic system-and thus the dynamic pupillary measures-are not controllable in the ED. SIGNIFICANCE: Pupillometry does not appear to be an effective tool to evaluate pain in the ED environment. There are several possible explanations for these negative results. The factors influencing the sympathetic system-and thus the PD fluctuations-are controllable in the postoperative period but not in the ED (e.g. full bladder, hypothermia). In addition, numerous psychological phenomena can impact pupillometry measurements such as emotional reactions or cognitive tasks. These phenomena are particularly difficult to control in the ED environment.

Assessment of Initial Depressive State and Pain Relief With Ketamine in Patients With Chronic Refractory Pain.

Importance: Repeated ketamine administration is common in treatment-refractory chronic pain, but ketamine analgesic and antidepressant effects are poorly understood in patients with chronic pain with depression symptoms. Objective: To determine clinical pain trajectories with repeated ketamine administrations, exploring whether ketamine dose and/or pretreatment depressive and/or anxiety symptoms may mediate pain relief. Design, Setting, and Participants: This nationwide, multicenter, prospective cohort study included patients in France with treatment-refractory chronic pain who received repeated ketamine administration, over 1 year, according to ketamine use in their pain clinic. Data were collected from July 7, 2016, through September 21, 2017. Linear mixed models for repeated data, trajectory analysis, and mediation analysis were performed from November 15 to December 31, 2022. Interventions: Ketamine administration in cumulative dose (milligrams) over 1 year. Main Outcomes and Measures: Primary outcome was mean pain intensity (0-10 on the Numerical Pain Rating Scale [NPRS]), assessed every month for 1 year by telephone, after inclusion in the hospital. Depression and anxiety (Hospital Anxiety and Depression Scale [HADS]), quality of life (12-item Short Form Health Survey [SF-12]), cumulative ketamine dose, adverse effects, and concomitant treatments were secondary outcomes. Results: A total of 329 patients (mean [SD] age, 51.4 [11.0] years; 249 women [75.7%] and 80 men [24.3%]) were enrolled. Repeated ketamine administration was associated with a decrease of NPRS (effect size = -0.52 [95% CI, -0.62 to -0.41]; P < .001) and an increase of SF-12 mental health (39.7 [10.9] to 42.2 [11.1]; P < .001) and physical health (28.5 [7.9] to 29.5 [9.2]; P = .02) dimension scores over 1 year. Adverse effects were in the normal range. There was a significant difference between patients without and with depressive symptoms in pain diminution (regression coefficient, -0.04 [95% CI, -0.06 to -0.01]; omnibus P = .002 for interaction of time × baseline depression [HADS score ≤7 or >7]). The mediation model showed that ketamine dose was not associated with pain diminution (r = 0.01; P = .61) and not correlated with depression (r = -0.06; P = .32), and that depression was associated with pain diminution (regression coefficient, 0.03 [95% CI, 0.01-0.04]; P < .001), whereas ketamine dose was not (regression coefficient, 0.00 [95% CI, -0.01 to 0.01]; P = .67). The proportion of reduction of pain mediated by baseline depression was 64.6%. Conclusions and Relevance: The findings of this cohort study on chronic refractory pain suggest that depression (and not ketamine dose or anxiety) was the mediator of the association of ketamine with pain diminution. This finding provides radically new insights on how ketamine reduces pain primarily by dampening depression. This reinforces the need for systematic holistic assessment of patients with chronic pain to diagnose severe depressive symptoms where ketamine would be a very valuable therapeutic option.

Circulating Human Metabolites Resulting from TOTUM-070 Absorption (a Plant-Based, Polyphenol-Rich Ingredient) Improve Lipid Metabolism in Human Hepatocytes: Lessons from an Original Ex Vivo Clinical Trial.

TOTUM-070 is a patented polyphenol-rich blend of five different plant extracts showing separately a latent effect on lipid metabolism and potential synergistic properties. In this study, we investigated the health benefit of such a formula. Using a preclinical model of high fat diet, TOTUM-070 (3 g/kg of body weight) limited the HFD-induced hyperlipemia with a reduction in triglyceride (-32% after 6 weeks; -20.3% after 12 weeks) and non-HDL cholesterol levels (-21% after 6 weeks; -38.4% after 12 weeks). To further investigate such a benefit and its underlying mechanisms in humans, we designed an ex vivo clinical approach to collect the circulating bioactives resulting from TOTUM-070 ingestion and to determine their biological activities on human hepatocytes. Human serum was obtained from healthy subjects before and after intake of TOTUM-070 (4995 mg). The presence of circulating metabolites was assessed by UPLC-MS/MS. Serum containing metabolites was further incubated with hepatocytes cultured in a lipotoxic environment (palmitate, 250 µM). RNA sequencing analyses show that lipid metabolism was one of the most impacted processes. Using histologic, proteomic, and enzymatic assays, the effects of human TOTUM-070 bioactives on hepatocyte metabolism were characterized by (1) the inhibition of lipid storage, including both (2) triglycerides (-41%, p < 0.001) and (3) cholesterol (-50%, p < 0.001) intracellular content, (4) a reduced de novo cholesterol synthesis (HMG-CoA reductase activity -44%, p < 0.001), and (5) a lowered fatty acid synthase protein level (p < 0.001). Altogether, these data support the beneficial impact of TOTUM-070 on lipid metabolism and provide new biochemical insights in human mechanisms occurring in liver cells.

A tactile pain evaluation scale for persons with visual deficiencies.

OBJECTIVE: Pain evaluation scales often rely on the sense of sight. There is so far no pain assessment scale designed specifically for persons with visual impairment. DESIGN: This study aims to validate a tactile pain evaluation scale, Visiodol (Copyright Prof Pickering), in blind or visually impaired persons, by correlation with a numeric pain scale. SETTING: The study took place at University Hospital Clermont-Ferrand, France. METHODS: Pain intensity for a range of thermal stimuli (Pathway Medoc) was evaluated with Visiodol and a numeric pain scale. Secondary outcomes, including pain thresholds, catastrophizing, emotion, and quality of life, were compared in persons who were blind or visually impaired and in sighted persons. Lin's concordance correlation coefficient was estimated. Weighted Cohen's κ accounted for degrees of disagreement between scales with 95% confidence intervals (95% CI). SUBJECTS: Sixteen healthy sighted and 21 healthy nonsighted volunteers (n = 13 congenital, n = 8 acquired) were included. RESULTS: Lin's correlation coefficient for repeated data was 0.967 (95% CI, 0.956-0.978; P < 0.001) for visually impaired participants, with a good agreement at each temperature plateau. A weighted Cohen's κ of 0.90 (95% CI, 0.84-0.92) and 92.9% percentage of agreement for visually impaired participants were satisfactory. Pain perception, psychological components, and quality of life were more impaired in persons who were blind or visually impaired than in sighted persons. CONCLUSIONS: This study validates Visiodol, a tactile scale for persons who are blind or visually impaired, and addresses health care inequalities in the context of pain evaluation. Visiodol will now be tested in a larger population of patients to give the millions of persons worldwide who are blind or visually impaired an option for pain intensity evaluation in clinical situations. TRIAL REGISTRATION: French National Agency for the Safety of Medicines and Healthcare Products (2018-A03370-55) and www.ClinicalTrials.gov (NCT03968991).

Benefits of Circulating Human Metabolites from Fish Cartilage Hydrolysate on Primary Human Dermal Fibroblasts, an Ex Vivo Clinical Investigation for Skin Health Applications.

Due to its significant exposure to stressful environmental factors, the skin undergoes a high remodeling rate over time, which alters not only its appearance but also its functionality. This alteration of the skin, namely photoaging, is characterized by dryness and a loss of elasticity that mainly originates from the dysregulation of dermal fibroblast activities. In order to overcome such tissue outcome, cosmetic products have evolved toward nutricosmetics, thus promoting beauty from within. Among bio-actives of interest, bio-peptides deriving from plant or animal sources may exert various biological activities beyond their nutritional value. However, studies remain mostly descriptive and the mode of action at the cellular level in clinic remains a concern. In a recent clinical trial, it was showed that supplementation with a fish cartilage hydrolysate (FCH) improved signs of chronological and photoaging-induced skin changes in healthy women. Here, using an original ex vivo clinical approach adapted to nutricosmetic purpose, we further demonstrated that this fish cartilage hydrolysate was absorbed and that the circulating metabolites produced in humans following FCH intake stimulate human dermal fibroblast growth, promote specific hyaluronan production, up-regulate elastin synthesis and inhibit MMP-1 and 3 expression along with the enhancement of TGF-ß release. Altogether, these data provide clues on the mechanisms likely contributing to the beneficial impact of FCH on human skin functionality by supporting hydration, elasticity and limiting the expression of catabolic factors involved in photoaging onset.

Phenotyping Post-COVID Pain as a Nociceptive, Neuropathic, or Nociplastic Pain Condition.

Pain after an acute Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) condition (post-COVID pain) is becoming a new healthcare emergency. Precision medicine refers to an evidence-based method of grouping patients based on their diagnostic/symptom presentation and then tailoring specific treatments accordingly. Evidence suggests that post-COVID pain can be categorized as nociceptive (i.e., pain attributable to the activation of the peripheral receptive terminals of primary afferent neurons in response to noxious chemical, mechanical, or thermal stimuli), neuropathic (i.e., pain associated with a lesion or disease of the somatosensory nervous system and limited to a "neuroanatomically plausible" distribution of the system), nociplastic (i.e., pain arising from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain), or mixed type (when two pain phenotypes co-exist). Each of these pain phenotypes may require a different treatment approach to maximize treatment effectiveness. Accordingly, the ability to classify post-COVID pain patients into one of these phenotypes would likely be critical for producing successful treatment outcomes. The 2021 International Association for the Study of Pain (IASP) clinical criteria and grading system provide a framework for classifying pain within a precision pain medicine approach. Here we present data supporting the possibility of grouping patients with post-COVID pain into pain phenotypes, using the 2021 IASP classification criteria, with a specific focus on nociplastic pain, which is probably the primary mechanism involved in post-COVID pain. Nociplastic pain, which is usually associated with comorbid symptomology (e.g., poor sleep quality, fatigue, cognitive-emotional disturbances, etc.) and is considered to be more difficult to treat than other pain types, may require a more nuanced multimodal treatment approach to achieve better treatment outcomes.

Paracetamol Use in Patients With Osteoarthritis and Lower Back Pain: Infodemiology Study and Observational Analysis of Electronic Medical Record Data.

BACKGROUND: Lower back pain (LBP) and osteoarthritis (OA) are common musculoskeletal disorders and account for around 17.0% of years lived with disability worldwide; however, there is a lack of real-world data on these conditions. Paracetamol brands are frequently prescribed in France for musculoskeletal pain and include Doliprane, Dafalgan, and Ixprim (tramadol-paracetamol). OBJECTIVE: The objective of this retrospective study was to understand the journey of patients with LBP or OA when treated with paracetamol. METHODS: Three studies were undertaken. Two studies analyzed electronic medical records from general practitioners (GPs) and rheumatologists of patients with OA or LBP, who had received at least one paracetamol prescription between 2013 and 2018 in France. Data were extracted, anonymized, and stratified by gender, age, and provider specialty. The third study, an infodemiology study, analyzed associations between terms used on public medical forums and Twitter in France and the United States for OA only. RESULTS: In the first 2 studies, among patients with LBP (98,998), most (n=92,068, 93.0%) saw a GP, and Doliprane was a first-line therapy for 87.0% (n=86,128) of patients (71.0% [n=61,151] in combination with nonsteroidal anti-inflammatory drugs [NSAIDs] or opioids). Among patients with OA (99,997), most (n=84,997, 85.0%) saw a GP, and Doliprane was a first-line therapy for 83.0% (n=82,998) of patients (62.0% [n=51,459] in combination). Overall, paracetamol monotherapy prescriptions decreased as episodes increased. In the third study, in line with available literature, the data confirmed that the prevalence of OA increases with age (91.5% [212,875/232,650] above 41 years), OA is more predominant in females (46,530/232,650, 20.0%), and paracetamol use varies between GPs and rheumatologists. CONCLUSIONS: This health surveillance analysis provides a better understanding of the journey for patients with LBP or OA. These data confirmed that although paracetamol remains the most common first-line analgesic for patients with LBP and OA, usage varies among patients and health care specialists, and there are concerns over efficacy.

Uncovering a Genetic Polymorphism Located in Huntingtin Associated Protein 1 in Modulation of Central Pain Sensitization Signaling Pathways.

Fibromyalgia syndrome (FMS) is characterized by widespread pain and increased sensitivity to nociceptive stimulus or tenderness. While familial aggregation could suggest a potential hereditary component in FMS development, isolation of genetic determinants has proven difficult due to the multi-factorial nature and complexity of the syndrome. Central sensitization is thought to be one of the key mechanisms leading to FMS in a subset of patients. Enhanced central pain signaling can be measured using the Nociceptive Flexion Reflex (NFR) or RIII threshold. We performed a genome-wide association study (GWAS) using an array to genotype 258,756 human genetic polymorphisms in 225 FMS patients and 77 healthy volunteers and searched for genetic variants associated with a lowered NFR threshold. We have identified a potential association between a single nucleotide polymorphism resulting in a common non-synonymous coding mutation in the Huntingtin associated protein 1 (HAP1) gene (rs4796604, MAF = 0.5) and the NFR threshold (p = 4.78E-06). The Hap1 protein is involved in trafficking and is particularly enriched in neurons. Our results suggest a possible involvement of the neuronal trafficking protein HAP1 in modulating pain signaling pathways and thus participate in the establishment of the NFR threshold.

Short-Term Magnesium Therapy Alleviates Moderate Stress in Patients with Fibromyalgia: A Randomized Double-Blind Clinical Trial.

Patients suffering from fibromyalgia often report stress and pain, with both often refractory to usual drug treatment. Magnesium supplementation seems to improve fibromyalgia symptoms, but the level of evidence is still poor. This study is a randomized, controlled, double-blind trial in fibromyalgia patients that compared once a day oral magnesium 100 mg (Chronomag®, magnesium chloride technology formula) to placebo, for 1 month. The primary endpoint was the level of stress on the DASS-42 scale, and secondary endpoints were pain, sleep, quality of life, fatigue, catastrophism, social vulnerability, and magnesium blood concentrations. After 1 month of treatment, the DASS-42 score decreased in the magnesium and placebo groups but not significantly (21.8 ± 9.6 vs. 21.6 ± 10.8, respectively, p = 0.930). Magnesium supplementation significantly reduced the mild/moderate stress subgroup (DASS-42 stress score: 22.1 ± 2.8 to 12.3 ± 7.0 in magnesium vs. 21.9 ± 11.9 to 22.9 ± 11.9 in placebo, p = 0.003). Pain severity diminished significantly (p = 0.029) with magnesium while the other parameters were not significantly different between both groups. These findings show, for the first time, that magnesium improves mild/moderate stress and reduces the pain experience in fibromyalgia patients. This suggests that daily magnesium could be a useful treatment to improve the burden of disease of fibromyalgia patients and calls for a larger clinical trial.

Effect of a Combination of Magnesium, B Vitamins, Rhodiola, and Green Tea (L-Theanine) on Chronically Stressed Healthy Individuals-A Randomized, Placebo-Controlled Study.

The effect of a combination of magnesium, vitamins B6, B9, B12, rhodiola and green tea/L-theanine (Mg-Teadiola) on stress was evaluated in chronically stressed, otherwise healthy individuals. Effects on stress-related quality-of-life parameters (sleep and perception of pain) were also explored. Adults with stress for ≥1 month, scoring ≥14 points on the Depression Anxiety Stress Scale (DASS)-42 questionnaire, were randomized (1:1) to receive oral Mg-Teadiola (n = 49) or a placebo (n = 51), for 28 days, with a follow-up assessment on Day 56 (NCT04391452). The primary endpoint was the change in the DASS-42 stress score from baseline to Day 28 with Mg-Teadiola versus placebo. The DASS-42 stress scores significantly decreased from baseline to Day 28 with Mg-Teadiola versus placebo (effect size, 0.29; 95% CI [0.01, 0.57]; p = 0.04). Similar reductions were observed on Day 14 (p = 0.006) and Day 56 (p = 0.02). A significant reduction in sensitivity to cold pain (p = 0.01) and a trend for lower sensitivity to warm pain was observed (p = 0.06) on Day 28. Improvements in daytime dysfunction due to sleepiness (Pittsburgh Sleep Quality Index-7 component score) were reported on Day 28, and were significant on Day 56 (p < 0.001). Mg-Teadiola is effective in managing stress in otherwise healthy individuals. Its beneficial effects on sleep and pain perception need further investigation.

Circulating Human Serum Metabolites Derived from the Intake of a Saffron Extract (Safr'InsideTM) Protect Neurons from Oxidative Stress: Consideration for Depressive Disorders.

Increases in oxidative stress have been reported to play a central role in the vulnerability to depression, and antidepressant drugs may reduce increased oxidative stress in patients. Among the plants exerting anti-inflammatory and anti-oxidant properties, saffron, a spice derived from the flower of Crocus sativus, is also known for its positive effects on depression, potentially through its SSRI-like properties. However, the molecular mechanisms underlying these effects and their health benefits for humans are currently unclear. Using an original ex vivo clinical approach, we demonstrated for the first time that the circulating human metabolites produced following saffron intake (Safr'InsideTM) protect human neurons from oxidative-stress-induced neurotoxicity by preserving cell viability and increasing BNDF production. In particular, the metabolites significantly stimulated both dopamine and serotonin release. In addition, the saffron's metabolites were also able to protect serotonergic tone by inhibiting the expression of the serotonin transporter SERT and down-regulating serotonin metabolism. Altogether, these data provide new biochemical insights into the mechanisms underlying the beneficial impact of saffron on neuronal viability and activity in humans, in the context of oxidative stress related to depression.

Ketamine in chronic pain: A Delphi survey.

BACKGROUND: There is no recommendation in Europe for the use of ketamine in patients with chronic pain. The heterogeneity of practice highlights the need to seek the advice of experts in order to establish a national consensus. This Delphi survey aimed to reach a national consensus on the use of ketamine in chronic pain in Pain clinics. METHODS: A collaborative four-round internet-based questionnaire was used. It was created after literature search on ketamine administration in chronic pain and included about 96 items. It discussed utility and advantages, adverse events and deleterious aspects, methods of administration, concomitant treatments and assessment of results. RESULTS: Twenty-eight experts completed all rounds of the survey with a total of 81.3% items reaching a consensual answer. Neuropathic pain represents the first indication to use ketamine, followed, with a good to moderate utility, by other situations (fibromyalgia, complex regional pain syndrome, central neuropathic pain, peripheral neuropathic pain, nociceptive pain, sensitization, opioid withdrawal, palliative care, depression). Experts agreed on the rare occurrence of adverse events. Concerning routes of administration, intravenous infusion with doses of 0.5-0.9 mg/kg/d for 4 days of treatment is preferred. Place of care is hospital, as in- or out-patient, with a quarterly administration of ketamine. Finally, ketamine effectiveness is assessed 1 month after infusion, and experts encourage combination with non-pharmacological treatment. CONCLUSIONS: This Delphi survey established a consensus of pain specialists on the use of ketamine in refractory chronic pain, thus providing a basis for future comparative trials. SIGNIFICANCE: This Delphi survey in chronic pain reached agreement on four main aspects: (1) Priority to treat neuropathic pain with evaluation of effectiveness at 1 month; (2) No deleterious effects in the majority of listed diseases/situations with the absence or <3% of suggested adverse events; (3) 0.5-0.9 mg/kg/d IV infusion; (4) Combination with non-pharmacological treatment.