A growing body of evidence suggests that neuroinflammation, which is characterized by infiltration of immune cells, activation of mast cells and glial cells, and production of inflammatory mediators ...in the peripheral and central nervous systems, has an important role in the induction and maintenance of chronic pain. These findings support the notion that new therapeutic opportunities for chronic pain might be based on anti-inflammatory and pro-resolving mediators that act on immune cells, in particular mast cells and glia, to mitigate or abolish neuroinflammation. Among anti-inflammatory and pro-resolving lipid mediators, palmitoylethanolamide (PEA) has been reported to down-modulate mast cell activation and to control glial cell behaviors.
The aim of this study was to perform a pooled meta-analysis to evaluate the efficacy and safety of micronized and ultra-micronized palmitoylethanolamide (PEA) on pain intensity in patients suffering from chronic and/or neuropathic pain.
Pooled data analysis consisting of double-blind, controlled, and open-label clinical trials.
Double-blind, controlled, and open-label clinical trials were selected consulting the PubMed, Google Scholar, and Cochrane databases, and proceedings of neuroscience meetings. The terms chronic pain, neuropathic pain, and micronized and ultra-micronized PEA were used for the search. Selection criteria included availability of raw data and comparability between tools used to diagnose and assess pain intensity. Raw data obtained by authors were pooled in one database and analyzed by the Generalized Linear Mixed Model. The changes in pain over time, measured by comparable tools, were also assessed by linear regression post-hoc analysis and the Kaplan-Meier estimate. Twelve studies were included in the pooled meta-analysis, 3 of which were double-blind trials comparing active comparators vs placebo, 2 were open-label trials vs standard therapies, and 7 were open-label trials without comparators.
Results showed that PEA elicits a progressive reduction of pain intensity significantly higher than control. The magnitude of reduction equals 1.04 points every 2 weeks with a 35% response variance explained by the linear model. In contrast, in the control group pain, reduction intensity equals 0.20 points every 2 weeks with only 1% of the total variance explained by the regression. The Kaplan-Meier estimator showed a pain score = 3 in 81% of PEA treated patients compared to only 40.9% in control patients by day 60 of treatment. PEA effects were independent of patient age or gender, and not related to the type of chronic pain.
Noteworthy, serious adverse events related to PEA were not registered and/or reported in any of the studies.
These results confirm that PEA might represent an exciting, new therapeutic strategy to manage chronic and neuropathic pain associated with neuroinflammation.
Aging is an inevitable process and represents the accumulation of bodily alterations over time. Depression and chronic pain are highly prevalent in elderly populations. It is estimated that 13% of ...the elderly population will suffer simultaneously from the two conditions. Accumulating evidence suggests than neuroinflammation plays a critical role in the pathogenesis of both depression and chronic pain. Apart from the common pathophysiological mechanisms, however, the two entities have several clinical links. Their management is challenging for the pain physician; however, both pharmacologic and nonpharmacologic approaches are available and can be used when the two conditions are comorbid in the elderly patients.
Objective. Neuropathic pain is a common presenting complaint of patients with peripheral neuropathy (PN) and is considered one of the most disabling neuropathic symptoms, with detrimental effects on ...patients’ quality of life (QoL). The aim of this review was to overview the current literature that focuses on QoL in painful PN of various aetiologies. We sought to clarify the direct effect of pain and its treatment on patients’ QoL. Methodology. A systematic computer-based literature search was conducted using the PubMed database to search for papers on QoL in painful PN. Information was extracted regarding prevalence, demographics, and response to treatment where relevant. Results. We identified 66 articles eligible for inclusion. The vast majority of studies (n=47) focused on patients with diabetic PN. Other aetiologies of painful PN where QoL has been studied to date include gluten, immune-mediated, HIV, chemotherapy-induced, and chronic idiopathic axonal polyneuropathy. Pharmacological treatment is the mainstay in managing pain and has a direct positive and independent effect on the overall QoL. Other nonpharmacological approaches can also be of benefit, either alone or as adjuvant treatments, and are discussed. Conclusion. The findings demonstrate that QoL is impaired in painful PN and should not be neglected in clinical practice. Patients’ pain management and subsequent impact on QoL should routinely be assessed and monitored.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Elderly patients in general exhibit a higher incidence of chronic and neuropathic pain conditions. This group poses a particular clinical challenge due to age-related pharmacokinetic and ...pharmacodynamic issues, comorbid conditions, and polypharmacy, as well as frailty and cognitive decline. Poor control of pain has consistently been identified as an issue for older people. The identification of safe and efficacious treatments for chronic pain remains a critical public health concern, especially considering the progressive increase of the world's elderly population.
This narrative review deals with the principal alterations of the somatosensory system together with changes in non-neuronal cells in the course of aging. The possibility to control chronic pain based on an innovative strategy which addresses non-neuronal cell dysregulation control will also be discussed.
Narrative review.
Peripheral nerves display functional, structural, and biochemical changes with aging that mainly involve Aδ fibers. Alteration in the responses to heat pain in the middle insular cortex and primary somatosensory cortex are also observed in the elderly. In general, pain threshold increases with age while the threshold of pain tolerance remains unchanged or decreases. Additionally, other important modifications of the pain perception system in this age group consist in a clear reduction in the descending inhibitory capacity with an associated increase in central sensitization. Furthermore, different changes concern immune system cells, such as mast cells and microglia, that with age show an increase in their sensitivity to noxious stimuli and a decreased capability to be regulated by homeostatic endogenous systems. Since these cells are the primary interlocutors for pain neurons, their alterations lead to changes that promote persistent neuroinflammation, thereby impacting pain neuronal cell functionality.
This review is not an exhaustive review for the current evidence supporting the role of immune cells in influencing pain somatosensory neuron functions. It is also important to stress the small number of studies designed to determine the efficacy and safety of anti-pain therapies in elderly patients.
Non-neuronal cells of immune system origin such as microglia and mast cells, along with astrocytes, are capable of influencing pain somatosensory neuron functions. These nervous system non-neuronal cells may thus be viewed as innovative targets for persistent pain control. Among therapies aiming at preserving the functionality of non-neuronal cells, palmitoylethanolamide, with its high efficacy/risk ratio, may be an excellent co-treatment for the ever-growing elderly population with chronic pain.
In different retrospective studies, a protective role of regional anesthetics in reducing cancer recurrence after surgery was indicated. Accordingly, it has been previously demonstrated a protective ...effect of anesthetics in breast cancer cells and in other types of cancer. On the other hand, how anesthetics influence cancer needs in‐depth investigations. For this purpose, two different human cancer cell lines, MDA‐MB‐231, triple‐negative breast cancer, and A375, melanoma, were used in this study. By means of Western blotting and immunofluorescence and terminal deoxynucleotidyl transferase dUTP nick end labeling analyses, the signal transduction pathways activated by the anesthetics, such as ropivacaine and levobupivacaine, were analyzed. The data obtained demonstrated that both anesthetics are able to counteract cell proliferation by positively modulating cell death signaling and by decreasing cell proliferation and survival pathways.
The local anesthetics are able to counteract breast cancer and melanoma cells proliferation. Local anesthetics are able to counteract cancer cell migration.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Musculoskeletal pain (excluding bone cancer pain) affects more than 30% of the global population and imposes an enormous burden on patients, families, and caregivers related to functional limitation, ...emotional distress, effects on mood, loss of independence, and reduced quality of life. The pathogenic mechanisms of musculoskeletal pain relate to the differential sensory innervation of bones, joints, and muscles as opposed to skin and involve a number of peripheral and central nervous system cells and mediators. The interplay of neurons and non-neural cells (e.g. glial, mesenchymal, and immune cells) amplifies and sensitizes pain signals in a manner that leads to cortical remodeling. Moreover, sex, age, mood, and social factors, together with beliefs, thoughts, and pain behaviors influence the way in which musculoskeletal pain manifests and is understood and assessed. The aim of this narrative review is to summarize the different pathogenic mechanisms underlying musculoskeletal pain and how these mechanisms interact to promote the transition from acute to chronic pain.
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