Novel drug treatments for pain in advanced cancer and serious illness: a focus on neuropathic pain and chemotherapy-induced peripheral neuropathy.

Drugs that are commercially available but have novel mechanisms of action should be explored as analgesics. This review will discuss haloperidol, miragabalin, palmitoylethanolamide (PEA), and clonidine as adjuvant analgesics or analgesics. Haloperidol is a sigma-1 receptor antagonist. Under stress and neuropathic injury, sigma-1 receptors act as a chaperone protein, which downmodulates opioid receptor activities and opens several ion channels. Clinically, there is only low-grade evidence that haloperidol improves pain when combined with morphine, methadone, or tramadol in patients who have cancer, pain from fibrosis, radiation necrosis, or neuropathic pain. Miragabalin is a gabapentinoid approved for the treatment of neuropathic pain in Japan since 2019. In randomized trials, patients with diabetic neuropathy have responded to miragabalin. Its long binding half-life on the calcium channel subunit may provide an advantage over other gabapentinoids. PEA belongs to a group of endogenous bioactive lipids called ALIAmides (autocoid local injury antagonist amides), which have a sense role in modulating numerous biological processes in particular non-neuronal neuroinflammatory responses to neuropathic injury and systemic inflammation. Multiple randomized trials and meta-analyses have demonstrated PEA's effectiveness in reducing pain severity arising from diverse pain phenotypes. Clonidine is an alpha2 adrenoceptor agonist and an imidazoline2 receptor agonist, which is U.S. Federal Drug Administration approved for attention deficit hyperactivity disorder in children, Tourette's syndrome, adjunctive therapy for cancer-related pain, and hypertension. Clonidine activation at alpha2 adrenoceptors causes downstream activation of inhibitory G-proteins (Gi/Go), which inhibits cyclic Adenosine monophosphate (AMP) production and hyperpolarizes neuron membranes, thus reducing allodynia. Intravenous clonidine has been used in terminally ill patients with poorly controlled symptoms, in particular pain and agitation.

Corrigendum: Oral ultramicronized palmitoylethanolamide: plasma and tissue levels and spinal antihyperalgesic effect.

[This corrects the article DOI: 10.3389/fphar.2018.00249.].

Palmitoylethanolamide-Incorporated Elastic Nano-Liposomes for Enhanced Transdermal Delivery and Anti-Inflammation.

Palmitoylethanolamide (PEA) exhibits multiple skincare functions such as anti-nociceptive and anti-inflammatory effects. However, its topical application is limited due to its difficulty in bypassing the stratum corneum barrier, relatively low bioavailability, and low stability. Herein, elastic nano-liposomes (ENLs) with excellent deformability and elasticity were utilized as a novel drug delivery system to encapsulate PEA to overcome the abovementioned issues and enhance the biological effects on the skin. ENL was prepared with phosphatidylcholine, cholesterol, and cetyl-PG hydroxyethyl palmitamide with a molar ratio mimicking skin epidermal lipids, and PEA was loaded. The PEA-loaded ENL (PEA-ENL) demonstrated efficient transdermal delivery and enhanced skin retention, with negligible cytotoxicity toward HaCaT cells and no allergic reaction in the human skin patch test. Notably, PEA-ENL treatment increased cell migration and induced significant regulation in the expression of genes associated with anti-nociceptive, anti-inflammatory, and skin barrier repair. The mechanism of the anti-nociceptive and anti-inflammatory effects of PEA was further investigated and explained by molecular docking site analysis. This novel PEA-ENL, with efficient transdermal delivery efficiency and multiple skincare functionalities, is promising for topical application.

Effect of Palmitoylethanolamide Compared to a Placebo on the Gut Microbiome and Biochemistry in an Overweight Adult Population: A Randomised, Placebo Controlled, Double-Blind Study.

This study investigates the effects of palmitoylethanolamide (PEA) on the gut microbiome of overweight adults. Fifty-eight participants (twenty males, thirty-eight females) aged 18-65 years with a BMI range of 30-40 kg/m2 were recruited. Participants were randomised to receive PEA (n = 36) or a placebo (n = 22) for 12 weeks. Microbiota composition, richness, diversity, and metabolic functions, faecal short chain fatty acids and calprotectin, pathology markers, and health-related questionnaires were analysed throughout the 12 weeks of supplementation. PEA supplementation significantly reduced triglyceride levels and IL-2 concentrations. No significant differences were found in the overall microbiota composition between the groups, and microbiota richness and diversity remained consistent for both groups. Functional analysis demonstrated no differences in functional richness and diversity, but specific pathways were modified. PEA supplementation resulted in a decrease in the abundance of pathways related to aromatic compound degradation, NAD interconversion, and L-glutamate degradation, while pathways associated with molybdopterin biosynthesis and O-antigen building blocks exhibited increased abundance. Increased production of O-antigen results in smooth LPS associated with reduced pathogenic stealth and persistence. PEA supplementation may influence specific microbial species, metabolic pathways, and reduce serum triglyceride and IL-2 concentration, shedding light on the intricate relationship between PEA, the microbiome, and host health.

From Molecular Mechanisms to Clinical Therapy: Understanding Sepsis-Induced Multiple Organ Dysfunction.

Sepsis-induced multiple organ dysfunction arises from the highly complex pathophysiology encompassing the interplay of inflammation, oxidative stress, endothelial dysfunction, mitochondrial damage, cellular energy failure, and dysbiosis. Over the past decades, numerous studies have been dedicated to elucidating the underlying molecular mechanisms of sepsis in order to develop effective treatments. Current research underscores liver and cardiac dysfunction, along with acute lung and kidney injuries, as predominant causes of mortality in sepsis patients. This understanding of sepsis-induced organ failure unveils potential therapeutic targets for sepsis treatment. Various novel therapeutics, including melatonin, metformin, palmitoylethanolamide (PEA), certain herbal extracts, and gut microbiota modulators, have demonstrated efficacy in different sepsis models. In recent years, the research focus has shifted from anti-inflammatory and antioxidative agents to exploring the modulation of energy metabolism and gut microbiota in sepsis. These approaches have shown a significant impact in preventing multiple organ damage and mortality in various animal sepsis models but require further clinical investigation. The accumulation of this knowledge enriches our understanding of sepsis and is anticipated to facilitate the development of effective therapeutic strategies in the future.

Trajectory of Change in the Severity of Symptoms in Patients with Fibromyalgia over 24 Months: Exploratory Analyses of a Combination Pharmacological Intervention.

Symptoms of fibromyalgia (FM) fluctuate and vary in severity. The current study aimed to evaluate the efficacy of palmitoylethanolamide (PEA) and acetyl-L-carnitine (ALC) in FM patients over a 24-month period and to investigate the mediating function of pain catastrophizing subdomains in unfavorable relationships with disease severity levels in patients with FM. Patients were evaluated at baseline, after 12 months, and after 24 months, using different patient-reported measures (FIQR, FASmod, PSD, and PCS) to distinguish different levels of FM disease severity. A reduction of 30% or more from baseline was considered clinically important ("markedly improved"). A multivariate analysis was performed to identify the variables predictive of an FIQR reduction. Twenty-two patients (28.6%) were classified as "markedly improved", 16 patients (20.8%) as "slightly/moderately improved", and 39 patients (50.6%) as "not improved." The FIQR, FASmod, and PSD scores were significantly reduced at 24 months. The pain magnification domain score of the PCS was the only variable predictive of worse FIQR scores (Wald coefficient: -2.94; p = 0.047). These results suggest a potential long-term therapeutic role for the PEA + ALC combination, with pain magnification being the primary predictor of poor efficacy.

Ultramicronized Palmitoylethanolamide and Luteolin: Drug Candidates in Post-COVID-19 Critical Illness Neuropathy and Positioning-Related Peripheral Nerve Injury of the Upper Extremity.

Coronavirus disease 2019 (COVID-19) is the most dramatic pandemic of the new millennium and patients with serious infection can stay in intensive care unit (ICU) for weeks in a clinical scenario of systemic inflammatory response syndrome, likely related to the subsequent development of critical illness polyneuropathy (CIP). It is in fact now accepted that COVID-19 ICU surviving patients can develop CIP; moreover, prone positioning-related stretch may favor the onset of positioning-related peripheral nerve injuries (PNI). Therefore, the urgent need to test drug candidates for the treatment of these debilitating sequelae is emerged even more. For the first time in medical literature, we have successfully treated after informed consent a 71-year-old Italian man suffering from post-COVID-19 CIP burdened with positioning-related PNI of the left upper extremity by means of ultramicronized palmitoylethanolamide 400 mg plus ultramicronized luteolin 40 mg (Glìalia), two tablets a day 12 hours apart for 6 months. In the wake of our pilot study, a larger clinical trial to definitively ascertain the advantages of this neuroprotective, neurotrophic, and anti-inflammatory therapy is advocated.

The Effect of Palmitoylethanolamide (PEA) on Skeletal Muscle Hypertrophy, Strength, and Power in Response to Resistance Training in Healthy Active Adults: A Double-Blind Randomized Control Trial.

BACKGROUND: Palmitoylethanolamide (PEA) has analgesic/anti-inflammatory properties that may be a suitable alternative to over-the-counter (OTC) non-steroidal analgesics/anti-inflammatories. While OTC pain medications can impair strength training adaptations, the mechanism of action of PEA is distinct from these and it may not negatively affect skeletal muscle adaptations to strength training. METHODS: The primary aim of this study was to investigate the effects of daily PEA supplementation (350 mg Levagen + equivalent to 300 mg PEA) combined with 8-weeks of resistance training on lean body mass with secondary aims addressing strength, power, sleep, and wellbeing compared to placebo (PLA) in young, healthy, active adults. In a randomized, controlled, double-blinded trial, 52 untrained, recreationally active participants aged 18-35 y were allocated to either the PEA or PLA groups. Participants consumed either 2 × 175 mg Levagen + PEA or identically matched maltodextrin capsules during an 8-week period of whole-body resistance training. This trial assessed the pre- to post- changes in total and regional lean body mass, muscular strength (1-RM bench, isometric mid-thigh pull), muscular power [countermovement jump (CMJ), bench throw], pain associated with exercise training, sleep, and wellbeing compared with the PEA or PLA condition. RESULTS: 48 Participants were included in the final intention to treat (ITT) analysis and we also conducted per protocol (PP) analysis (n = 42). There were no significant between-group differences for total or regional lean muscle mass post-intervention. There was a significantly higher jump height (CMJ) at week 10 in the PEA group compared to the PLA (Adjusted mean difference [95% CI] p-value; ITT: - 2.94 cm [- 5.15, - 0.74] p = 0.010; PP: - 2.93 cm [- 5.31, - 0.55] p = 0.017). The PLA group had higher 1-RM bench press post-intervention compared with the PEA group (ITT: 2.24 kg [0.12, 4.37] p = 0.039; PP: 2.73 kg [0.40, 5.06] p = 0.023). No significant treatment effects were noted for any of the other outcomes. CONCLUSION: PEA supplementation, when combined with 8 weeks of strength training, did not impair lean mass gains and it resulted in significantly higher dynamic lower-body power when compared with the PLA condition. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR: ACTRN12621001726842p).

Altered levels of phospholipases C, diacylglycerols, endocannabinoids, and N-acylethanolamines in patients with hereditary angioedema due to FXII mutation.

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disorder characterized by local, self-limiting edema due to temporary increase in vascular permeability. HAE with normal C1 esterase inhibitor (C1INH) activity includes the form with mutations in the F12 gene encoding for coagulation factor XII (FXII-HAE) causing an overproduction of bradykinin (BK) leading to angioedema attack. BK binding to B2 receptors (BK2R) leads to an activation of phospholipase C (PLC) and subsequent generation of second messengers: diacylglycerols (DAGs) and possibly the endocannabinoids (eCBs), 2-arachidonoylglycerol (2-AG) and anandamide (AEA), and eCB-related N-acylethanolamines [palmitoylethanolamide (PEA) and oleoylethanolamide (OEA)]. To date, there are no data on the role of these lipid mediators in FXII-HAE. METHODS: Here, we analyzed plasma levels of PLC, DAGs, and eCBs in 40 patients with FXII-HAE and 40 sex- and age-matched healthy individuals. RESULTS: Plasma PLC activity was increased in FXII-HAE patients compared to controls. Concentrations of DAG 18:1-20:4, a lipid second messenger produced by PLC, were higher in FXII-HAE compared to controls, and positively correlated with PLC activity and cleaved high molecular kininogen (cHK). Also the concentrations of the DAG metabolite, 2-AG were altered in FXII-HAE. AEA and OEA were decreased in FXII-HAE patients compared to controls; by contrast, PEA, was increased. The levels of all tested mediators did not differ between symptomatic and asymptomatic patients. Moreover, C1INH-HAE patients had elevated plasma levels of PLC, which correlated with cHK, but the levels of DAGs and eCBs were the same as controls. CONCLUSIONS: BK overproduction and BKR2 activation are linked to alteration of PLCs and their metabolites in patients with FXII-HAE. Our results may pave way to investigations on the functions of these mediators in the pathophysiology of FXII-HAE, and provide new potential biomarkers and therapeutic targets.

Palmitoylethanolamide and Luteolin for Postinfectious Olfactory Disorders: How Clinically Meaningful Is Its Effect?

INTRODUCTION: The prevalence of post-viral olfactory dysfunction has increased significantly during the COVID-19 pandemic, posing a major challenge for patients and practitioners. While olfactory training (OT) is a common approach to therapy, there has been increasing interest in supplementing therapy with a combination of palmitoylethanolamide (PEA) and luteolin (LUT), which are known for their anti-inflammatory properties. In this study, their efficacy in the treatment of patients with olfactory loss following upper respiratory tract infections, mainly COVID-19, was investigated in an outpatient clinic. METHODS: Fifty patients with persistent olfactory dysfunction were randomized to two groups: one receiving OT and PEA-LUT, the other OT alone. Olfactory function was evaluated before and after treatment. RESULTS: The study group showed significant improvements in odor discrimination and overall olfactory function (TDI score) after treatment with PEA-LUT and OT, while the control group did not. However, when clinically meaningful improvements were considered, there was no significant difference between the groups. CONCLUSION: The present study suggests that while PEA-LUT may have the potential to improve olfactory function in post-viral dysfunction, the additional benefit over OT alone may be limited. These results contrast with some previous studies.

Extended Treatment with Micron-Size Oral Palmitoylethanolamide (PEA) in Chronic Pain: A Systematic Review and Meta-Analysis.

Palmitoylethanolamide (PEA) emerged over the years as a promising approach in the management of chronic pain. Despite the fact that the efficacy of micron-size PEA formulations appears to be time-dependent, the optimal timing has not yet been elucidated. This systematic review and meta-analysis aim to estimate the possible advantage of an extended treatment in the relief of chronic pain. The literature search was conducted consulting scientific databases, to identify clinical trials in which micron-size PEA was administered for at least 60 days, and pain assessed by the Visual Analogue Scale (VAS) or Numeric Rating Scale (NRS). Nine studies matched the required criteria, for a total of 742 patients involved. The meta-analysis showed a statistically and clinically significant pain intensity reduction after 60 days of micron-size PEA supplementation, compared to 30 days (1.36 points, p < 0.01). The secondary analysis revealed a weighted NRS/VAS score decrease of 2.08 points within the first month of treatment. These two obtained scores corresponded to a 35.1% pain intensity reduction within the first month, followed by a further 35.4% during the second month. Overall, these results confirm the clinically relevant and time-depended pain-relieving effect of micron-size PEA and therefore the advantage of an extended treatment, especially in patient with incomplete pain management.

Therapeutic Potential of Palmitoylethanolamide in Gastrointestinal Disorders.

Palmitoylethanolamide (PEA) is an endocannabinoid-like bioactive lipid mediator belonging to the family of N-acylethanolamines, most abundantly found in peanuts and egg yolk. When the gastrointestinal (GI) effects of PEA are discussed, it must be pointed out that it affects intestinal motility but also modulates gut microbiota. This is due to anti-inflammatory, antioxidant, analgesic, antimicrobial, and immunomodulatory features. Additionally, PEA has shown beneficial effects in several GI diseases, particularly irritable bowel syndrome and inflammatory bowel diseases, as various studies have shown, and it is important to emphasize its relative lack of toxicity, even at high dosages. Unfortunately, there is not enough endogenous PEA to treat disturbed gut homeostasis, even though it is produced in the GI tract in response to inflammatory stimuli, so exogenous intake is mandatory to achieve homeostasis. Intake of PEA could be through animal and/or vegetable food, but bearing in mind that a high dosage is needed to achieve a therapeutic effect, it must be compensated through dietary supplements. There are still open questions pending to be answered, so further studies investigating PEA's effects and mechanisms of action, especially in humans, are crucial to implementing PEA in everyday clinical practice.

Amelioration of Dextran Sodium Sulfate-Induced Colitis in Mice through Oral Administration of Palmitoylethanolamide.

Inflammatory bowel disease (IBD) is a group of chronic disorders characterized by pain, ulceration, and the inflammation of the gastrointestinal tract (GIT) and categorized into two major subtypes: ulcerative colitis (UC) and Crohn's disease. The inflammation in UC is typically restricted to the mucosal surface, beginning in the rectum and extending through the entire colon. UC patients typically show increased levels of pro-inflammatory cytokines, leading to intestinal epithelial apoptosis and mucosal inflammation, which impair barrier integrity. Chronic inflammation is associated with the rapid recruitment and inappropriate retention of leukocytes at the site of inflammation, further amplifying the inflammation. While UC can be managed using a number of treatments, these drugs are expensive and cause unwanted side effects. Therefore, a safe and effective treatment for UC patients is needed. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide and an analog of the endocannabinoid anandamine. PEA administration has been found to normalize intestinal GIT motility and reduce injury in rodents and humans. In the current study, we examined the efficacy of PEA encapsulated in phytosomes following oral administration in experimental ulcerative colitis. Here, we showed that PEA at a human-equivalent dose of 123 mg/kg (OD or BID) attenuated DSS-induced experimental colitis as represented by the reduction in clinical signs of colitis, reduction in gross mucosal injury, and suppression of leukocyte recruitment at inflamed venules. These findings add to the growing body of data demonstrating the beneficial effects of PEA to control the acute phase of intestinal inflammation occurring during UC.

Neuropathic pain in cats: Mechanisms and multimodal management.

PRACTICAL RELEVANCE: Chronic pain is a significant welfare concern in cats, and neuropathic pain, which arises from aberrant processing of sensory signals within the nervous system, is a subcategory of this type of pain. To comprehend this condition and how multimodal pharmacotherapy plays a central role in alleviating discomfort, it is crucial to delve into the anatomy of nociception and pain perception. In addition, there is an intricate interplay between emotional health and chronic pain in cats, and understanding and addressing the emotional factors that contribute to pain perception, and vice versa, is essential for comprehensive care.Clinical approach:Neuropathic pain is suspected if there is abnormal sensation in the area of the distribution of pain, together with a positive response to trial treatment with drugs effective for neuropathic pain. Ideally, this clinical suspicion would be supported by confirmation of a lesion at this neurolocalisation using diagnostic modalities such as MRI and neuroelectrophysiology. Alternatively, there may be a history of known trauma at that site. A variety of therapies, including analgesic, anti-inflammatory and adjuvant drugs, and neuromodulation (eg, TENS or acupuncture), can be employed to address different facets of pain pathways.Aim:This review article, aimed at primary care/ general practitioners, focuses on the identification and management of neuropathic pain in cats. Three case vignettes are included and a structured treatment algorithm is presented to guide veterinarians in tailoring interventions.Evidence base:The review draws on current literature, where available, along with the author's extensive experience and research.

Ultramicronized Palmitoylethanolamide in the Management of Neuropathic Pain Related to Chronic Inflammatory Demyelinating Polyneuropathy: A Proof-of-Concept Study.

Background/Objectives: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare autoimmune disease. Neuropathic pain (NP), related to peripheral inflammation, is among its earliest manifestations. This preliminary open-label investigation aimed to evaluate the efficacy of ultramicronized Palmitoylethanolamide (umPEA) in the management of NP. Methods: A total of 14 patients with CIDP, already undergoing immunoglobulin (Ig) therapy, were divided into two groups: Group A received umPEA 600 mg twice daily in addition to Ig for 60 days, followed by Ig alone until the end of the observation (180 days); Group B received Ig alone for 120 days and subsequently umPEA + Ig in the last 60 days of the study. Painful symptom intensity and quality of life were assessed by the Numeric Rating Scale, Neuropathic Pain Symptoms Inventory, and Five Dimensions Health Questionnaire. The safety umPEA profile was evaluated. Results: UmPEA in addition to immunoglobulins allowed for a significant improvement over time in all NP symptoms intensity (p = 0.0007) and in patients' quality of life (p = 0.0036). Conclusions: This study suggests umPEA as a safe and effective treatment in addition to immunoglobulins to improve NP, ameliorating the patient's health status. These results highlight the importance of neuroinflammation modulation in the management of CIDP's painful symptoms, drawing attention to umPEA's potential use also in neuropathies of different etiologies.

Oleoylethanolamide and Palmitoylethanolamide Enhance IFNß-Induced Apoptosis in Human Neuroblastoma SH-SY5Y Cells.

Oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are endogenous lipids that act as agonists of the peroxisome proliferator-activated receptor α (PPARα). Recently, an interest in the role of these lipids in malignant tumors has emerged. Nevertheless, the effects of OEA and PEA on human neuroblastoma cells are still not documented. Type I interferons (IFNs) are immunomodulatory cytokines endowed with antiviral and anti-proliferative actions and are used in the treatment of various pathologies such as different cancer forms (i.e., non-Hodgkin's lymphoma, melanoma, leukemia), hepatitis B, hepatitis C, multiple sclerosis, and many others. In this study, we investigated the effect of OEA and PEA on human neuroblastoma SH-SY5Y cells treated with IFNß. We focused on evaluating cell viability, cell proliferation, and cell signaling. Co-exposure to either OEA or PEA along with IFNß leads to increased apoptotic cell death marked by the cleavage of caspase 3 and poly-(ADP ribose) polymerase (PARP) alongside a decrease in survivin and IKBα levels. Moreover, we found that OEA and PEA did not affect IFNß signaling through the JAK-STAT pathway and the STAT1-inducible protein kinase R (PKR). OEA and PEA also increased the phosphorylation of p38 MAP kinase and programmed death-ligand 1 (PD-L1) expression both in full cell lysate and surface membranes. Furthermore, GW6471, a PPARα inhibitor, and the genetic silencing of the receptor were shown to lower PD-L1 and cleaved PARP levels. These results reveal the presence of a novel mechanism, independent of the IFNß-prompted pathway, by which OEA and PEA can directly impair cell survival, proliferation, and clonogenicity through modulating and potentiating the intrinsic apoptotic pathway in human SH-SY5Y cells.

Inflammatory-Targeted Lipid Carrier as a New Nanomaterial to Formulate an Inhaled Drug Delivery System.

There is a pressing need for efficacious therapies in the field of respiratory diseases and infections. Lipid nanocarriers, administered through aerosols, represent a promising tool for maximizing therapeutic concentration in targeted cells and minimizing systemic exposure. However, this approach requires the application of efficient and safe nanomaterials. Palmitoylethanolamide (PEA), an endocannabinoid-like endogenous lipid, plays a crucial role in providing protective mechanisms during inflammation, making it an interesting material for preparing inhalable lipid nanoparticles (LNPs). This report aims to preliminarily explore the in vitro behavior of LNPs prepared with PEA (PEA-LNPs), a new inhalable inflammatory-targeted nanoparticulate drug carrier. PEA-LNPs exhibited a size of about 250 nm, a rounded shape, and an marked improvement in PEA solubility in comparison to naked PEA, indicative of easily disassembled nanoparticles. A twin glass impinger instrument was used to screen the aerosol performance of PEA-LNP powders, obtained via freeze-drying in the presence of two quantities of mannose as a cryoprotectant. Results indicated that a higher amount of mannose improved the emitted dose (ED), and in particular, the fine particle fraction (FPF). A cytotoxicity assay was performed and indicated that PEA-LNPs are not toxic towards the MH-S alveolar macrophage cell line up to concentrations of 0.64 mg/mL, and using coumarin-6 labelled particles, a rapid internalization into the macrophage was confirmed. This study demonstrates that PEA could represent a suitable material for preparing inhalable lipid nanocarrier-based dry powders, which signify a promising tool for the transport of drugs employed to treat respiratory diseases and infections.

Cannabinoids and Sleep: Exploring Biological Mechanisms and Therapeutic Potentials.

The endogenous cannabinoid system (ECS) plays a critical role in the regulation of various physiological functions, including sleep, mood, and neuroinflammation. Phytocannabinoids such as Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinomimimetics, and some N-acylethanolamides, particularly palmitoyethanolamide, have emerged as potential therapeutic agents for the management of sleep disorders. THC, the psychoactive component of cannabis, may initially promote sleep, but, in the long term, alters sleep architecture, while CBD shows promise in improving sleep quality without psychoactive effects. Clinical studies suggest that CBD modulates endocannabinoid signaling through several receptor sites, offering a multifaceted approach to sleep regulation. Similarly, palmitoylethanolamide (PEA), in addition to interacting with the endocannabinoid system, acts as an agonist on peroxisome proliferator-activated receptors (PPARs). The favorable safety profile of CBD and PEA and the potential for long-term use make them an attractive alternative to conventional pharmacotherapy. The integration of the latter two compounds into comprehensive treatment strategies, together with cognitive-behavioral therapy for insomnia (CBT-I), represents a holistic approach to address the multifactorial nature of sleep disorders. Further research is needed to establish the optimal dosage, safety, and efficacy in different patient populations, but the therapeutic potential of CBD and PEA offers hope for improved sleep quality and general well-being.

Palmitoylethanolamide and polydatin in pediatric irritable bowel syndrome: A multicentric randomized controlled trial.

OBJECTIVE: This study aimed to evaluate the efficacy and safety of co-micronized palmitoylethanolamide (PEA)/polydatin (PD) in the treatment of abdominal pain symptoms in pediatric patients with irritable bowel syndrome (IBS). METHODS: This was a multicenter trial conducted at three Italian pediatric gastroenterology centers, employing a double-blind, placebo-controlled, parallel-arm design. Participants were ages 10 to 17 y and met Rome IV criteria for pediatric IBS. They were randomly allocated to receive either co-micronized PEA/PD or placebo, administered three times daily in a 1:1 ratio, over a 12-wk period. The study assessed baseline severity using the IBS-Severity Scoring System (IBS-SSS) at enrollment and after 4, 8, and 12 wk of treatment. Abdominal pain frequency was assessed on a scale from 1 to 7 d/wk, while stool consistency was classified using the Bristol Stool Scale (BSS) to categorize various IBS subtypes. The primary outcome was the percentage of patients who achieved complete remission, defined as IBS-SSS score <75 points after 12 wk of therapy. RESULTS: The study involved 70 children with IBS. Of the participants, 34 received co-micronized PEA/PD, and 36 received a placebo. As compared with the placebo group, the co-micronized therapy group had significantly more patients achieving complete remission after 12 wk (P = 0.015), with particular benefit in the IBS-diarrhea subtype (P = 0.01). The treatment group also experienced a significant reduction in abdominal pain intensity and frequency compared with the placebo group. No adverse events were recorded during the study period. CONCLUSIONS: Co-micronized PEA/PD is a safe and effective treatment to treat abdominal pain symptoms in pediatric IBS.

Persistent COVID-19 parosmia and olfactory loss post olfactory training: randomized clinical trial comparing central and peripheral-acting therapeutics.

PURPOSE: Although COVID-19 anosmia is often transient, patients with persistent olfactory dysfunction (pOD) can experience refractory parosmia and diminished smell. This study evaluated four putative therapies for parosmia in patients with chronic COVID-19 olfactory impairment. METHODS: After screening nasal endoscopy, 85 patients (49 female, 58%) with pOD and treatment-refractory parosmia were randomized to: (1) ultramicronized palmitoylethanolamide and luteolin + olfactory training (OT) (umPEALUT group, n = 17), (2) alpha-lipoic acid + OT (ALA group, n = 21), (3) umPEALUT + ALA + OT (combination group, n = 28), or 4) olfactory training (OT) alone (control group, n = 23). Olfactory function was assessed at baseline (T0) and 6 months (T1) using a parosmia questionnaire and Sniffin' Sticks test of odor threshold, detection, and identification (TDI). Analyses included one-way ANOVA for numeric data and Chi-Square analyses for nominal data on parosmia. RESULTS: The umPEALUT group had the largest improvement in TDI scores (21.8 ± 9.4 to 29.7 ± 7.5) followed by the combination group (19.6 ± 6.29 to 27.5 ± 2.7), both p < 0.01. The control and ALA groups had no significant change. Patients in the combination and umPEALUT groups had significantly improved TDI scores compared to ALA and control groups (p < 0.001). Rates of parosmia resolution after 6 months were reported at 96% for combination, 65% for control, 53% for umPEALUT and 29% for ALA (p < 0.001). All treatment regimens were well-tolerated. CONCLUSIONS: umPEALUT and OT, with or without ALA, was associated with improvement in TDI scores and parosmia, whereas OT alone or OT with ALA were associated with little benefit.