Mobile Health App and Web Platform (eDOL) for Medical Follow-Up of Patients With Chronic Pain: Cohort Study Involving the French eDOL National Cohort After 1 Year.

Background: Chronic pain affects approximately 30% of the general population, severely degrades quality of life and professional life, and leads to additional health care costs. Moreover, the medical follow-up of patients with chronic pain remains complex and provides only fragmentary data on painful daily experiences. This situation makes the management of patients with chronic pain less than optimal and may partly explain the lack of effectiveness of current therapies.

The TREK-1 potassium channel is involved in both the analgesic and anti-proliferative effects of riluzole in bone cancer pain.

Background: The metastasis of tumors into bone tissue typically leads to intractable pain that is both very disabling and particularly difficult to manage. We investigated here whether riluzole could have beneficial effects for the treatment of prostate cancer-induced bone pain and how it could influence the development of bone metastasis.

Methods: We used a bone pain model induced by intratibial injection of human PC3 prostate cancer cells into male SCID mice treated or not with riluzole administered in drinking water.

An Updated Review on the Metabolite (AM404)-Mediated Central Mechanism of Action of Paracetamol (Acetaminophen): Experimental Evidence and Potential Clinical Impact.

Paracetamol remains the recommended first-line option for mild-to-moderate acute pain in general population and particularly in vulnerable populations. Despite its wide use, debate exists regarding the analgesic mechanism of action (MoA) of paracetamol. A growing body of evidence challenged the notion that paracetamol exerts its analgesic effect through cyclooxygenase (COX)-dependent inhibitory effect.

Identification of a human estrogen receptor α tetrapeptidic fragment with dual antiproliferative and anti-nociceptive action.

The synthetic peptide ERα17p (sequence: PLMIKRSKKNSLALSLT), which corresponds to the 295-311 region of the human estrogen receptor α (ERα), induces apoptosis in breast cancer cells. In mice and at low doses, it promotes not only the decrease of the size of xenografted triple-negative human breast tumors, but also anti-inflammatory and anti-nociceptive effects. Recently, we have shown that these effects were due to its interaction with the seven-transmembrane G protein-coupled estrogen receptor GPER.

Role of T CD4 cells, macrophages, C-low threshold mechanoreceptors and spinal Ca 3.2 channels in inflammation and related pain-like symptoms in murine inflammatory models.

Background And Purpose: T-type calcium channels, mainly the Ca 3.2 subtype, are important contributors to the nociceptive signalling pathway. We investigated their involvement in inflammation and related pain-like symptoms.

Practice guidelines for the treatment of acute migraine and chronic knee osteoarthritis with paracetamol: an expert appraisal on evolution over time between scientific societies.

Background: Paracetamol is the commonest analgesic worldwide in primary care. Despite evidence-based recommendations for management of acute and chronic pain with paracetamol, practices seem to vary considerably in its modalities of use, with or without restrictions, between renowned scientific societies and over time.

Objective: Qualitative assessment of similarities, differences, and changes over time in guidelines for paracetamol use in acute and chronic pain.

eDOL mHealth App and Web Platform for Self-monitoring and Medical Follow-up of Patients With Chronic Pain: Observational Feasibility Study.

Background: Chronic pain affects approximately 30% of the general population, severely degrades quality of life (especially in older adults) and professional life (inability or reduction in the ability to work and loss of employment), and leads to billions in additional health care costs. Moreover, available painkillers are old, with limited efficacy and can cause significant adverse effects. Thus, there is a need for innovation in the management of chronic pain.

In-Depth Characterization of Somatic and Orofacial Sensitive Dysfunctions and Interfering-Symptoms in a Relapsing-Remitting Experimental Autoimmune Encephalomyelitis Mouse Model.

Among the many symptoms (motor, sensory, and cognitive) associated with multiple sclerosis (MS), chronic pain is a common disabling condition. In particular, neuropathic pain symptoms are very prevalent and debilitating, even in early stages of the disease. Unfortunately, chronic pain still lacks efficient therapeutic agents.

Fine Detection of Human Motion During Activities of Daily Living as a Clinical Indicator for the Detection and Early Treatment of Chronic Diseases: The E-Mob Project.

Methods to measure physical activity and sedentary behaviors typically quantify the amount of time devoted to these activities. Among patients with chronic diseases, these methods can provide interesting behavioral information, but generally do not capture detailed body motion and fine movement behaviors. Fine detection of motion may provide additional information about functional decline that is of clinical interest in chronic diseases.

The Class I HDAC Inhibitor, MS-275, Prevents Oxaliplatin-Induced Chronic Neuropathy and Potentiates Its Antiproliferative Activity in Mice.

Oxaliplatin, the first-line chemotherapeutic agent against colorectal cancer (CRC), induces peripheral neuropathies, which can lead to dose limitation and treatment discontinuation. Downregulation of potassium channels, which involves histone deacetylase (HDAC) activity, has been identified as an important tuner of acute oxaliplatin-induced hypersensitivity. MS-275, a class I histone deacetylase inhibitor (HDACi), prevents acute oxaliplatin-induced peripheral neuropathy (OIPN).

Neuropathic pain-alleviating activity of novel 5-HT receptor inverse agonists derived from 2-aryl-1H-pyrrole-3-carboxamide.

The diverse signaling pathways engaged by serotonin type 6 receptor (5-HTR) together with its high constitutive activity suggests different types of pharmacological interventions for the treatment of CNS disorders. Non-physiological activation of mTOR kinase by constitutively active 5-HTR under neuropathic pain conditions focused our attention on the possible repurposing of 5-HTR inverse agonists as a strategy to treat painful symptoms associated with neuropathies of different etiologies. Herein, we report the identification of compound 33 derived from the library of 2-aryl-1H-pyrrole-3-carboxamides as a potential analgesic agent.

A new clinically-relevant rat model of letrozole-induced chronic nociceptive disorders.

Among postmenopausal women with estrogen receptor-positive breast cancer, more than 80% receive hormone therapy including aromatase inhibitors (AIs). Half of them develop chronic arthralgia - characterized by symmetric articular pain, carpal tunnel syndrome, morning stiffness, myalgia and a decrease in grip strength - which is associated with treatment discontinuation. Only a few animal studies have linked AI treatment to nociception, and none to arthralgia.

The Antitumor Peptide ERα17p Exerts Anti-Hyperalgesic and Anti-Inflammatory Actions Through GPER in Mice.

Persistent inflammation and persistent pain are major medical, social and economic burdens. As such, related pharmacotherapy needs to be continuously improved. The peptide ERα17p, which originates from a part of the hinge region/AF2 domain of the human estrogen receptor α (ERα), exerts anti-proliferative effects in breast cancer cells through a mechanism involving the hepta-transmembrane G protein-coupled estrogen receptor (GPER).

Epigenetics Involvement in Oxaliplatin-Induced Potassium Channel Transcriptional Downregulation and Hypersensitivity.

Peripheral neuropathy is the most frequent dose-limiting adverse effect of oxaliplatin. Acute pain symptoms that are induced or exacerbated by cold occur in almost all patients immediately following the first infusions. Evidence has shown that oxaliplatin causes ion channel expression modulations in dorsal root ganglia neurons, which are thought to contribute to peripheral hypersensitivity.

Cross-Sectional Study of Prevalence, Characterization and Impact of Chronic Pain Disorders in Workers.

Chronic pain prevention and treatment constitute a challenge for occupational health The aim of this study was to provide data on workers in a variety of jobs and multiple contexts to determine the prevalence and characteristics of different chronic pain disorders, in view to highlighting possible new targets for preventive actions. 1,008 participants working in 14 French IKEA stores were analyzed in this observational study on the basis of their responses to surveys on their sociodemographic characteristics, psychosocial factors, lifestyle, and pain disorders. The prevalence of chronic pain, moderate-to-severe chronic pain and high-impact chronic pain were 49%, 30%, and 11%, respectively.

Paracetamol analogues conjugated by FAAH induce TRPV1-mediated antinociception without causing acute liver toxicity.

Paracetamol, one of the most widely used pain-relieving drugs, is deacetylated to 4-aminophenol (4-AP) that undergoes fatty acid amide hydrolase (FAAH)-dependent biotransformation into N-arachidonoylphenolamine (AM404), which mediates TRPV1-dependent antinociception in the brain of rodents. However, paracetamol is also converted to the liver-toxic metabolite N-acetyl-p-benzoquinone imine already at therapeutic doses, urging for safer paracetamol analogues. Primary amine analogues with chemical structures similar to paracetamol were evaluated for their propensity to undergo FAAH-dependent N-arachidonoyl conjugation into TRPV1 activators both in vitro and in vivo in rodents.

TREK1 channel activation as a new analgesic strategy devoid of opioid adverse effects.

Background And Purpose: Opioids are effective painkillers. However, their risk-benefit ratio is dampened by numerous adverse effects and opioid misuse has led to a public health crisis. Safer alternatives are required, but isolating the antinociceptive effect of opioids from their adverse effects is a pharmacological challenge because activation of the μ opioid receptor triggers both the antinociceptive and adverse effects of opioids.

Prevalence of chronic pain in opioid-maintained patients using the capture-recapture method: a nationwide population-based study.

Few studies all based on classical surveys have provided prevalence estimates of chronic pain (CP) in opioid-maintained patients (OMPs) but often had a limited patient sample size and a great variability in the prevalence estimates. This study sought to assess the prevalence of CP in the exhaustive population of OMPs using the capture-recapture method applied to the French nationwide health care database. Capture-recapture methods are increasingly used to estimate the prevalence of chronic conditions but have never been used in the specific context of CP in OMPs.

mTOR activation by constitutively active serotonin6 receptors as new paradigm in neuropathic pain and its treatment.

Chronic neuropathic pain is a highly disabling syndrome that is poorly controlled by currently available analgesics. Here, we show that painful symptoms and associated cognitive deficits induced by spinal nerve ligation in the rat are prevented by the administration of serotonin 5-HT receptor inverse agonists or by the mTOR inhibitor rapamycin. In contrast, they are not alleviated by the administration of 5-HT receptor neutral antagonists.

Testosterone-androgen receptor: The steroid link inhibiting TRPM8-mediated cold sensitivity.

Recent studies have revealed gender differences in cold perception, and pointed to a possible direct action of testosterone (TST) on the cold-activated TRPM8 (Transient Receptor Potential Melastatin Member 8) channel. However, the mechanisms by which TST influences TRPM8-mediated sensory functions remain elusive. Here, we show that TST inhibits TRPM8-mediated mild-cold perception through the noncanonical engagement of the Androgen Receptor (AR).

Replacement of current opioid drugs focusing on MOR-related strategies.

The scarcity and limited risk/benefit ratio of painkillers available on the market, in addition to the opioid crisis, warrant reflection on new innovation strategies. The pharmacopoeia of analgesics is based on products that are often old and derived from clinical empiricism, with limited efficacy or spectrum of action, or resulting in an unsatisfactory tolerability profile. Although they are reference analgesics for nociceptive pain, opioids are subject to the same criticism.

c-Jun/p38MAPK/ASIC3 pathways specifically activated by nerve growth factor through TrkA are crucial for mechanical allodynia development.

Mechanical allodynia is a cardinal sign of several inflammatory pain disorders where nerve growth factor, a prototypic neurotrophin, plays a crucial role by binding to TrkA receptors. Here, we took the advantage of our generated knock-in mouse model expressing a chimeric TrkA/TrkC receptor that seems to not specifically develop mechanical allodynia after inflammation, to identify the TrkA downstream pathways involved in this phenomenon. We confirmed and extended that disrupting TrkA-specific pathways leads to a specific deficit in mechanical hypersensitivity development after somatic (systemic nerve growth factor administration and paw incision) and, to a lesser extent, visceral injuries.

Ethosuximide improves chronic pain-induced anxiety- and depression-like behaviors.

Chronic pain is a heavy burden disease. Current treatments are generally weakly effective or associated with adverse effects. New therapeutic approaches are therefore needed.

Paracetamol is a centrally acting analgesic using mechanisms located in the periaqueductal grey.

Background And Purpose: We previously demonstrated that paracetamol has to be metabolised in the brain by fatty acid amide hydrolase enzyme into AM404 (N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide) to activate CB receptors and TRPV1 channels, which mediate its analgesic effect. However, the brain mechanisms supporting paracetamol-induced analgesia remain unknown.

Experimental Approach: The effects of paracetamol on brain function in Sprague-Dawley rats were determined by functional MRI.

Risk assessment of using off-label morphine sulfate in a population-based retrospective cohort of opioid-dependent patients.

Aims: Several addictovigilance studies have described the off-label use of morphine sulfate (MS) for nonchronic pain in opioid use disorder (OUD) patients as an alternative to conventional opioid substitution treatments (OSTs). This study primarily sought to compare the incidence of unintentional opioid-related overdose in the year following the prescription initiation in off-label MS users, compared to OST-maintained patients.

Methods: Sequential cohorts of OUD patients who were regularly dispensed MS, buprenorphine, or methadone, between 1 April 2012 and 31 December 2014, were retrospectively identified using the French nationwide healthcare data system.