Objective: To determine whether abnormalities of peripheral and central nociceptive sensory input processing exist outside areas of spontaneous pain in patients with fibromyalgia (FM) as compared with controls, by using quantitative sensory testing (QST) and a neurophysiologic paradigm independent from subjective reports.Methods: A total of 164 outpatients with FM who were attending a self‐management program were invited to participate in the study. Data for 85 patients were available and were compared with those for 40 non‐FM controls matched for age and sex. QST was performed using thermal, mechanical, and electrical stimuli at locations of nonspontaneous pain. Pain assessment was 2‐fold and included use of subjective scales and the spinal nociceptive flexion reflex (NFR), a specific physiologic correlate for the objective evaluation of central nociceptive pathways. Questionnaires regarding quality of life and the impact of FM were available.Results: Participants were mainly middle‐aged women, with a mean disease duration of 8 years. Between‐group differences were significant for neurophysiologic, clinical, and quality of life measures. In patients with FM, peripheral QST showed significantly altered cold and heat pain thresholds, and tolerance to cold pain was radically reduced. The median NFR threshold in patients with FM (22.7 mA [range 17.5–31.7]) was significantly decreased compared with that in controls (33 mA [range 28.1–41]). A cutoff value of <27.6 mA for NFR provided sensitivity of 73% and specificity of 80% for detecting central allodynia in the setting of FM.Conclusion: Our results strongly, although indirectly, point to a state of central hyperexcitability of the nociceptive system in patients with FM. The NFR can be used to assess central allodynia in FM. It may also help discriminate patients who may benefit from use of centrally acting analgesics.

Research from JAMA Internal Medicine — Drug-Induced Long QT Syndrome in Injection Drug Users Receiving Methadone — High Frequency in Hospitalized Patients and Risk Factors

Cardiovascular disease (CVD) is the leading cause of mortality worldwide in both sexes. Despite considerable progress in better understanding the patterns of disease in women, they are still often undertreated and benefit less from evidence-based treatment. Hypertension is a key contributor to CVD and is also one of the most potent risk factors for heart failure in women. Even with the wide variety of available drugs, blood pressure control is globally suboptimal. Current guidelines do not suggest differential treatment of hypertension for women; however, a growing body of research suggests gender dimorphism in the pathophysiology of hypertension and pharmacological response to cardiovascular drugs. The clinical relevance of theses sex-divergent effects of drugs is still under investigation. Owing to the exponential relationship between blood pressure and cardiovascular mortality, even a modest decrease in blood pressure or therapeutic adhesion could be clinically \relevant. In this review, we explore the known pharmacological and pharmacokinetic sex differences with special attention to the main classes of antihypertensive treatment. Current data shows frequently higher drug exposures in women and more frequent adverse drug reactions in all antihypertensive drug groups. As far as cardiovascular prevention is concerned, sex-specific data is often lacking in clinical trials, highlighting the necessity to further study CVD and their treatment in both men and women.

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. It is now more evident that paracetamol analgesia has multiple pathways and is mediated by the formation of the bioactive AM404 metabolite in the central nervous system (CNS). AM404 is a potent activator of TRPV₁, a major contributor to neuronal response to pain in the brain and dorsal horn. In the periaqueductal grey, the bioactive metabolite AM404 activated the TRPV₁ channel‐mGlu5 receptor‐PLC‐DAGL‐CB1 receptor signaling cascade. The present article provides a comprehensive literature review of the centrally located, COX-independent, analgesic MoA of paracetamol and relates how the current experimental evidence can be translated into clinical practice. The evidence discussed in this review established paracetamol as a central, COX-independent, antinociceptive medication that has a distinct MoA from non-steroidal anti-inflammatory drugs (NSAIDs) and a more tolerable safety profile. With the establishment of the central MoA of paracetamol, we believe that paracetamol remains the preferred first-line option for mild-to-moderate acute pain for healthy adults, children, and patients with health concerns. However, safety concerns remain with the high dose of paracetamol due to the NAPQI-mediated liver necrosis. Centrally acting paracetamol/p-aminophenol derivatives could potentiate the analgesic effect of paracetamol without increasing the risk of hepatoxicity. Moreover, the specific central MoA of paracetamol allows its combination with other analgesics, including NSAIDs, with a different MoA. Future experiments to better explain the central actions of paracetamol could pave the way for discovering new central analgesics with a better benefit-to-risk ratio.