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Palmitoylethanolamide, a naturally occurring disease-modifying agent in neuropathic pain

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Persistent pain affects nearly half of all people seeking medical care in the US alone, and accounts for at least $80 billion worth of lost productivity each year. Among all types of chronic pain, neuropathic pain stands out: this is pain resulting from damage or disease of the somatosensory nervous system, and remains largely untreatable. With few available treatment options, neuropathic pain represents an area of significant and growing unmet medical need. Current treatment of peripheral neuropathic pain involves several drug classes, including opioids, gabapentinoids, antidepressants, antiepileptic drugs, local anesthetics and capsaicin. Even so, less than half of patients achieve partial relief. This review discusses a novel approach to neuropathic pain management, based on knowledge of: the role of glia and mast cells in pain and neuroinflammation; the body's innate mechanisms to maintain cellular homeostasis when faced with external stressors provoking, for example, inflammation. The discovery that palmitoylethanolamide, a member of the N-acylethanolamine family which is produced from the lipid bilayer on-demand, is capable of exerting anti-allodynic and anti-hyperalgesic effects by down-modulating both microglial and mast cell activity has led to the application of this fatty acid amide in several clinical studies of neuropathic pain, with beneficial outcome and no indication of adverse effects at pharmacological doses. Collectively, the findings presented here propose that palmitoylethanolamide merits further consideration as a disease-modifying agent for controlling inflammatory responses and related chronic and neuropathic pain.
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... The analgesic and anti-inflammatory effects of PEA have been widely researched [16] and supported by several pain studies [12,[17][18][19][20][21][22]. PEA is reported to down-regulate multiple proinflammatory and nociceptive pathways and is known to inhibit mast and glial cell activity [16,17,22]. ...
... The analgesic and anti-inflammatory effects of PEA have been widely researched [16] and supported by several pain studies [12,[17][18][19][20][21][22]. PEA is reported to down-regulate multiple proinflammatory and nociceptive pathways and is known to inhibit mast and glial cell activity [16,17,22]. Recently, a double-blind randomized placebo-controlled study assessed the efficacy of PEA for symptoms of knee osteoarthritis and found that PEA may be a novel treatment for attenuating pain and reducing other associated symptoms of knee osteoarthritis [23]. ...
... As previously mentioned, PEA exerts its analgesic and anti-inflammatory effects by down-regulating multiple proinflammatory and nociceptive pathways and is known to inhibit mast and glial cell activity [14,16,17,22]. The commonly prescribed pharmaceuticals for pain relief generally provide symptomatic relief, without resolving the underlying mechanism of pain [11]. ...
... Furthermore, PEA may be considered a natural disease-modifying agent instead of a symptoms-reducing one, as it modulates the inflammatory processes and immune system. When PEA endogenous synthesis is low, PEA exogenous supplementation improves the molecule's effectiveness [32]. Many studies have shown its pivotal role in several downregulating mechanisms dealing with pain modulation [33], hyperalgesia [34], edema formation [35], activation of C-fibers [36], sensory neuropeptides release [37], and activation of IL1-β in preclinical tests [38]. ...
... The size of natural PEA is about 100-700 µm, while its micronized (m-PEA) form is 6-10 µm and its ultramicronized form (um-PEA) contains particles between 1 and 10 µm. The smaller particle size (with higher surface-to-volume ratio) contributes to better solubility and, thus, to a better distribution in tissues and a higher biological efficacy [32,44,45]. ...
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Ultramicronized palmitoylethanolamide (um-PEA), a compound with antioxidant, anti-inflammatory and neuroprotective properties, appears to be a potential adjuvant treatment for early stages of Coronavirus disease 2019 (COVID-19). In our study, we enrolled 90 patients with confirmed diagnosis of COVID-19 that were randomized into two groups, homogeneous for age, gender and BMI. The first group received oral supplementation based on um-PEA at a dose of 1800 mg/day for a total of 28 days; the second group was the control group (R.S. 73.20). At baseline (T0) and after 28 days of um-PEA treatment (T1), we monitored: routine laboratory parameters, inflammatory and oxidative stress (OS) biomarkers, lymphocytes subpopulation and COVID-19 serological response. At T1, the um-PEA-treated group presented a significant reduction in inflammation compared to the control group (CRP p = 0.007; IL-6 p = 0.0001; neutrophils to lymphocytes ratio p = 0.044). At T1, the controls showed a significant increase in OS compared to the treated group (FORT p = 0.05). At T1, the um-PEA group exhibited a significant decrease in D-dimer levels (p = 0.0001) and higher levels of IgG against SARS-CoV-2 (p = 0.0001) compared to the controls. Our data demonstrated, in a randomized clinical trial, the beneficial effects of um-PEA in both asymptomatic and mild-symptomatic patients related to reductions in inflammatory state, OS and coagulative cascade alterations.
... In this framework, particular attention is currently devoted to endocannabinoids and related lipid compounds, such as NAEs and more particularly PEA [106][107][108][109]. As detailed below, PEA and similar endocannabinoids are locally released on demand during injury to counterbalance the effects of pro-algesic mediators [110,111]. ...
... Before dealing with the effectiveness of PEA in chronic pain, a key formulation question must be addressed. PEA is a highly lipophilic compound and tends to aggregate in large particles (up to 2000 microns)-a big pharmaceutical issue since absorption rate is inversely related to particle size [46,108,168]. ...
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The management of chronic pain is an integral challenge of small animal veterinary practitioners. Multiple pharmacological agents are usually employed to treat maladaptive pain including opiates, non-steroidal anti-inflammatory drugs, anticonvulsants, antidepressants, and others. In order to limit adverse effects and tolerance development, they are often combined with non-pharmacologic measures such as acupuncture and dietary interventions. Accumulating evidence suggests that non-neuronal cells such as mast cells and microglia play active roles in the pathogenesis of maladaptive pain. Accordingly, these cells are currently viewed as potential new targets for managing chronic pain. Palmitoylethanolamide is an endocannabinoid-like compound found in several food sources and considered a body’s own analgesic. The receptor-dependent control of non-neuronal cells mediates the pain-relieving effect of palmitoylethanolamide. Accumulating evidence shows the anti-hyperalgesic effect of supplemented palmitoylethanolamide, especially in the micronized and co-micronized formulations (i.e., micro-palmitoylethanolamide), which allow for higher bioavailability. In the present paper, the role of non-neuronal cells in pain signaling is discussed and a large number of studies on the effect of palmitoylethanolamide in inflammatory and neuropathic chronic pain are reviewed. Overall, available evidence suggests that there is place for micro-palmitoylethanolamide in the dietary management of chronic pain in dogs and cats.
... Likewise, increasing the levels of PEA in LPS-challenged microglial cells through the inhibition of its hydrolysis significantly reduces microglial activation [70]. On the other hand, administration of PEA significantly relieves neuroinflammatory-associated disorders [32], and counteracts neuroinflammation at the cellular level, provided the compound is formulated in bioavailable forms [71]. The highly lipophilic nature of PEA, in fact, limits its dissolution and absorption as well as the bioavailability for achieving health benefits by oral route. ...
... The highly lipophilic nature of PEA, in fact, limits its dissolution and absorption as well as the bioavailability for achieving health benefits by oral route. Bioavailable formulations of PEA, i.e., micronized PEA (PEA-m) and ultra-micronized PEA (PEA-um) with a particle size distribution in the 2-10 µm and 0.8-6 µm range, respectively, have been developed accordingly [71,75]. After oral administration, PEA-m and PEA-um have repeatedly shown higher bioavailability and superior effects compared to naïve PEA [75,76]. ...
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Neuroinflammation is a physiological response aimed at maintaining the homodynamic balance and providing the body with the fundamental resource of adaptation to endogenous and exogenous stimuli. Although the response is initiated with protective purposes, the effect may be detrimental when not regulated. The physiological control of neuroinflammation is mainly achieved via regulatory mechanisms performed by particular cells of the immune system intimately associated with or within the nervous system and named “non-neuronal cells.” In particular, mast cells (within the central nervous system and in the periphery) and microglia (at spinal and supraspinal level) are involved in this control, through a close functional relationship between them and neurons (either centrally, spinal, or peripherally located). Accordingly, neuroinflammation becomes a worsening factor in many disorders whenever the non-neuronal cell supervision is inadequate. It has been shown that the regulation of non-neuronal cells—and therefore the control of neuroinflammation—depends on the local “on demand” synthesis of the endogenous lipid amide Palmitoylethanolamide and related endocannabinoids. When the balance between synthesis and degradation of this bioactive lipid mediator is disrupted in favor of reduced synthesis and/or increased degradation, the behavior of non-neuronal cells may not be appropriately regulated and neuroinflammation exceeds the physiological boundaries. In these conditions, it has been demonstrated that the increase of endogenous Palmitoylethanolamide—either by decreasing its degradation or exogenous administration—is able to keep neuroinflammation within its physiological limits. In this review the large number of studies on the benefits derived from oral administration of micronized and highly bioavailable forms of Palmitoylethanolamide is discussed, with special reference to neuroinflammatory disorders.
... Micronized and ultramicronized palmitoylethanolamide (m-PEA and um-PEA) have been used for preclinical and clinical studies to overcome the concern of PEA bioavailability. Both m-PEA and um-PEA are constituted by a crystalline form with a particle size between 100 and 700 μm [15] characterized by a high surface-volume ratio that allows a better diffusion, distribution, and higher biological efficacy compared to nonmicronized PEA [16,17]. In 2016, however, Gabrielsson et al. [9] suggested to cautiously interpret the available literature on PEA because of a conflict of interest issue and poorquality clinical trials. ...
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Background: Palmitoylethanolamide is reported to solve pain and neuroinflammation in different models of chronic and neurodegenerative diseases. Some concerns have been illustrated for cautiously interpreting the available literature on the topic. Specifically, there is a lack of evidence about palmitoylethanolamide and female chronic pelvic pain. Concerns will be best solved by randomized trials. The present study was aimed at finding the best responders to micronized palmitoylethanolamide in female patient with chronic pelvic pain, using the existing literature at individual patient level, to help further randomized trial planning. Methods: After a systematic research, eligible studies (the ones enrolled female patients treated for chronic pelvic pain or for dyspareunia, dysuria, dyschezia, and dysmenorrhea with or without chronic pelvic pain) were assessed at individual patient data level. Conditional probabilities were calculated to assess variables conditioning the rates of good responders (pain score points more or equal to 3 reduction), poor responders (2 pain score reduction), and nonresponders at a three-month follow-up. Results: Only cases treated with palmitoylethanolamide comicronized with polydatin for a short period can be assessed. Good responders are more than 50%. In chronic pelvic pain, there is a 19.0% conditional probability to find good responders among patients with pain score at enrolment of 6 to 8 and of 6.8% to find poor responders among patients with a pain score at enrolment of 6 to 8. Painful disease does not matter on responders' rates. Conclusion: Best responders to comicronized palmitoylethanolamide/polydatin are patients with pain score higher than 6 at enrolment, irrespective of other variables.
... Additionally, it preserves the peripheral nerve morphology. 6 The most recent clinical studies have demonstrated PEA to be a promising analgesic and effective in treating neuralgia, [7][8][9] carpal tunnel syndrome, 10,11 postoperative pain, 12 endometriosis, 13 osteoarthritis, anxiety, sleep, 5 autism spectrum disorder, 14,15 and cognition. 14 It has also been helpful in restoring gut microbiota changes in gut-brain axis 13 and as an adjunct therapy in Parkinson disease. ...
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Palmitoylethanolamide (PEA) is an endogenous ethanolamine playing a protective and homeodynamic role in animals and plants. Prenatal developmental toxicity of PEA was tested following oral administration to pregnant female Wistar rats, from days 0 to 19 of gestation, at dosage of 250, 500, or 1,000 mg/kg body weight, according to Organisation for Economic Co-operation and Development Test Guideline No. 414. On gestation day 20, cesarean sections were performed on the dams, followed by examination of their ovaries and uterine contents. The fetuses were further examined for external, visceral, and skeletal abnormalities. Palmitoylethanolamide did not cause any alterations at any of the given dosages in the measured maternal parameters of systemic toxicity (body weight, food consumption, survival, thyroid functions, organ weight, histopathology), reproductive toxicity (preimplantation and postimplantation losses, uterus weight, number of live/dead implants and early/late resorptions, litter size and weights, number of fetuses, their sex ratio), and fetal external, visceral, or skeletal observations. Any alterations that were recorded were "normal variations" or "minor anomalies," which were unrelated to treatment with PEA. Under the condition of this prenatal study, the no-observed-adverse-effect level of PEA for maternal toxicity, embryotoxicity, fetotoxicity, and teratogenicity in rats was found to be >1,000 mg/kg body weight/d. It indicates that PEA is well tolerated by and is safe to pregnant rats even at a high dose of 1,000 mg/kg body weight/d, equivalent to a human dose of greater than 9.7 g/d. This prenatal developmental toxicity study contributes greatly in building a robust safety profile for PEA.
... To obtain these results, natural nutraceutical molecules represent a family of naturally occurring lipid amides acting through the so-called autacoid local injury antagonism ALIA mechanism, and PEA is the most well-known and has been studied since 1950. PEA has emerged as a disease-modifying agent in several pathological conditions, such as inflammatory and neuropathic pain, in experimental and naturally occurring conditions in both humans and animals [20]. PEA's mechanism of action is peculiar and involves interactions with several biological pathways, such as the endocannabinoid system, and the multitarget mechanisms of PEA exhibit a fascinating pharmacological strategy that acts according to the natural biomodulation of body responses to different stimuli and injury [21]. ...
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Background: Four show jumping horses were evaluated for non-responsive lameness, which caused their withdrawal from show jumping competitions. The clinical evaluation was performed by radiographic examination, flexion tests, diagnostic anesthesia and lameness evaluation using the American Association of Equine Practitioners (AAEP) scale. The diagnoses were a case of navicular syndrome, a complicated case of chronic navicular syndrome and arthrosis of the distal interphalangeal joint of the right anterior limb and two cases of distal intertarsal joint arthritis. Nutraceuticals are often an important management strategy or coadjutant of pharmacological therapies in joint disease. Ultramicronized Palmitoylethanolamide (PEA-um) is an endogenous fatty acid amide that is well-known for its anti-inflammatory and analgesic proprieties widely used in human medicine and small animal veterinary medicine. Although it includes a small number of cases, our study describes for the first time the efficacy of the use of PEA-um in horses. The four horses with non-responsive lameness and significant impairment in athletic performance were daily treated with PEA-um into their normal diet. After four months of PEA-um supplementation, all horses showed remissions of lameness that led to their reintroduction into showjumping competitions without disease recurrence. Therefore, despite the small number of cases included in this study, these observations suggest a good prospective for developing a controlled experiment to test PEA in a larger cohort of horses.
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Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication of antineoplastic drugs, particularly paclitaxel (PTX). It can affect the quality of patients’ lives and increase the risk of developing mood disorders. Although several drugs are recommended, they yielded inconclusive results in clinical trials. The aim of the present work is to investigate whether the palmitoylethanolamide (PEA) would reduce PTX-induced CIPN and associated mood disorders. Moreover, the role PPAR-α and the endocannabinoid system will also be investigated. CIPN was induced by intraperitoneally injection of PTX (8 mg/kg) every other day for a week. PEA, 30 mg/kg, was orally administrated in a bioavailable form (i.e., ultramicronized PEA, um-PEA) one hour after the last PTX injection, for 7 days. In the antagonism experiments, AM281 (1 mg/kg) and GW6471 (2 mg/kg) were administrated 30 min before um-PEA. Our results demonstrated that um-PEA reduced the development of hypersensitivity with the effect being associated with the reduction in spinal and hippocampal pro-inflammatory cytokines, as well as antidepressive and anxiolytic effects. Moreover, the PPAR-α and CB1 receptor antagonists blocked the behavioral and antinociceptive effects of um-PEA. Our findings suggest that um-PEA is a promising adjunct in CIPN and associated mood disorders through the activation of PPAR-α, which influences the endocannabinoid system.
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BACKGROUND The aim of this study was to determine the efficacy and tolerability of treatment with a Palmitoylethanolamide (PEA)-based nutraceutical in patients with episodic migraine. METHODS A pilot, prospective, open-label experimental study was designed in which patients with episodic migraine with and without aura seen in the general practice office of a tertiary centre during a period of 6 month were offered the possibility to participate. No control group was included. All included patients were treated with nutraceutical Calmux® taken every 12 hours for 3 months. Monthly attack frequency, attack intensity, impact of migraine (HIT-6 and MIDAS scales) and quality of sleep at baseline and after 3 months of treatment were compared. RESULTS Twenty-five patients (22 women and 3 men) were included, with a mean age of 36.3±12 years. Headache days per month decreased from 10±2.1 days to 6.6±3.6 days (p<0.00001). Days of analgesic use decreased from 9.2±2.6 days to 4.1±2.1 (p<0.0001). None of the patients included suffered from adverse events attributable to treatment. Pain intensity showed a mean reduction of 3.1 points, from 8.1 at baseline to 5 at 3 months of treatment (p<0.005). CONCLUSIONS PEA nutraceuticals could be useful in migraine prevention. Further studies are necessary, but we consider that PEA-based nutraceutical could be a new approach in the treatment of migraine patients.
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Background: Neuropathic pain is a condition caused by a lesion or disease of the somatosensory nervous system. It may present as debilitating pain with a sensation of burning and electric-like symptoms and is often difficult to manage effectively. Although pharmacological medications are the first line of treatment, multidisciplinary teams are sometimes required to provide appropriate treatment to improve quality of life and overall wellbeing. Aim: The aim of this study is to present a case of post herpetic neuralgia relieved successfully by the compound palmitoylethanolamide (PEA) - a natural alternative to pharmacological pain relief. Methods: We present the case of a 67 year-old male with ongoing post-herpetic neuralgia, over a 3-year period, as a result of complications from shingles (herpes zoster). Previous studies on the relationship between PEA and neuropathy were reviewed, with an attempt to discuss the possible underlying mechanism of PEA on neuropathic pain. Results: PEA demonstrated effective pain relief within 48 hours at an administered daily dose of 900 mg (10 mg/kg). Conclusions: PEA may offer a valid nutraceutical treatment for practitioners.
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The present study evaluated the effectiveness of micronized palmitoylethanolamide (PEA-m) treatment in reducing the painful symptoms experienced by diabetic patients with peripheral neuropathy. PEA-m, a fatty acid amide of the N-acylethanolamine family, was administered (300 mg twice daily) to 30 diabetic patients suffering from painful diabetic neuropathy. Before treatment start, after 30 and 60 days the following parameters were assessed: painful symptoms of diabetic peripheral neuropathy using the Michigan Neuropathy Screening instrument; intensity of symptoms characteristic of diabetic neuropathic pain by the Total Symptom Score; and intensity of different subcategories of neuropathic pain by the Neuropathic Pain Symptoms Inventory. Hematological and blood chemistry tests to evaluate metabolic control and safety were also performed. Statistical analysis (ANOVA) indicated a highly significant reduction in pain severity ( P < 0.0001 ) and related symptoms ( P < 0.0001 ) evaluated by Michigan Neuropathy Screening instrument, Total Symptom Score, and Neuropathic Pain Symptoms Inventory. Hematological and urine analyses did not reveal any alterations associated with PEA-m treatment, and no serious adverse events were reported. These results suggest that PEA-m could be considered as a promising and well-tolerated new treatment for symptomatology experienced by diabetic patients suffering from peripheral neuropathy.
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INTRODUCTION AND AIMS: Interleukin-1β (IL-1β) is an important inflammatory mediator of immune complex-induced glomerulonephritis (GN). As IL-1β is activated by Caspase 1 in an inflammasome-dependent intracellular process, we examined the functional role of the inflammasome components Nlrp3 and its adapter molecule Asc in autologous murine nephrotoxic serum nephritis (NTN), a model of immune complex-mediated GN. METHODS: NTN was induced in wild-type, Nlrp3- and Asc-deficient C57BL/6 mice after preimmunisation with rabbit IgG. After 21 days functional parameters (serum urea, total serum protein, serum cholesterol, albuminuria), renal histology and renal leukocyte infiltrates were compared between the three groups. Moreover, cellular and humoral immune responses against rabbit IgG were analysed. RESULTS: In comparison to wild-type, Nlrp3 knockout mice revealed significantly lower serum urea levels and developed a less pronounced nephrotic syndrome (less hypoproteinemia, hypercholesterolemia, and albuminuria). Consistently, renal leukocyte infiltrates were significantly decreased in Nlrp3-deficient mice compared to wild-type. The reductions in renal leukocyte counts were 45% for CD45+ leukocytes, 50% for CD4+ T-cells, 40% for CD8+ T-cells, 39% for CD11c+ dendritic cells, and 50% for F4/80+ mononuclear phagocytes. The reduced accumulation of renal leukocytes correlated with a significantly decreased expression of renal mRNA for inflammatory chemokines and cytokines like Ccl2, Ccl5, Cxcl10, Ccr6, Tnf, Inf-γ, and IL-1β. In contrast, NTN was not attenuated in Asc-deficient mice. Functional parameters and leukocyte infiltration were comparable between Asc knockout mice and wild-type controls. Analysis of systemic immune responses revealed a decreased cellular activation of Nlrp3-deficient splenocytes after re-stimulation with rabbit-IgG (reduced surface expression of CD69 on CD4+ T-cells, less secretion of Inf-γ). However, humoral immunity was exacerbated in Nlrp3-deficient mice, as indicated by increased autologous anti rabbit-IgG serum titers. Asc knockout mice also demonstrated an attenuated cellular immune response, with humoral immune responses being comparable to those of wild-type controls. CONCLUSIONS: In summary, these results identify Nlrp3 as an important pro-inflammatory mediator of immune complex glomerulonephritis. Surprisingly, we could demonstrate an inflammatory function of Nlrp3 independently of its adapter molecule Asc. Thus, therapeutic blockade of Nlrp3 receptors, but not Asc may be a new strategy in the treatment of immune complex nephritis.
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Palmitoylethanolamide (PEA) is an endogenous fatty acid amide displaying anti-inflammatory and analgesic actions. To investigate the molecular mechanism responsible for these effects, the ability of PEA and of pain-inducing stimuli such as capsaicin (CAP) or bradykinin (BK) to influence intracellular calcium concentrations ([Ca2+]i) in peripheral sensory neurons, has been assessed in the present study. The potential involvement of the transcription factor PPARα and of TRPV1 channels in PEA-induced effects was also studied. [Ca2+]i was evaluated by single-cell microfluorimetry in differentiated F11 cells. Activation of TRPV1 channels was assessed by imaging and patch-clamp techniques in CHO cells transiently-transfected with rat TRPV1 cDNA. In F11 cells, PEA (1–30 μM) dose-dependently increased [Ca2+]i. The TRPV1 antagonists capsazepine (1 μM) and SB-366791 (1 μM), as well as the PPARα antagonist GW-6471 (10 μM), inhibited PEA-induced [Ca2+]i increase; blockers of cannabinoid receptors were ineffective. PEA activated TRPV1 channels heterologously expressed in CHO cells; this effect appeared to be mediated at least in part by PPARα. When compared with CAP, PEA showed similar potency and lower efficacy, and caused stronger TRPV1 currents desensitization. Sub-effective PEA concentrations, closer to those found in vivo, counteracted CAP- and BK-induced [Ca2+]i transients, as well as CAP-induced TRPV1 activation. Activation of PPARα and TRPV1 channels, rather than of cannabinoid receptors, largely mediate PEA-induced [Ca2+]i transients in sensory neurons. Differential TRPV1 activation and desensitization by CAP and PEA might contribute to their distinct pharmacological profile, possibly translating into potentially relevant clinical differences.
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Unlabelled: SUMMARY Aims: To investigate the effectiveness of N-palmitoylethanolamide (PEA) in the treatment of neuropathic pain due to lumbosciatica. Materials & methods: Patients with neuropathic pain were assigned to standard treatment plus PEA (600 mg/day) or standard treatment for 30 days. Changes in visual analog scale, and score on Oswestry Disability Index and SF-12® Health Survey were assessed at baseline and follow-up. Results: The mean age of the 118 patients evaluated was 48.4 years, and 47 (40.9%) were women. In the group comparison, significantly larger improvements were seen in the PEA group for visual analog scale and the physical component of the SF-12 Health Survey. Conclusion: The addition of PEA to standard treatment shows an improvement in pain relief in patients with neuropathic pain due to lumbosciatica. PEA was well tolerated. Future investigations of the role of PEA in the treatment of neuropathic pain might help to define novel therapeutic strategies for the treatment of this kind of neuropathic pain.