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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.

The present study aimed at evaluating the effect of a gentle shampoo and a mousse containing Adelmidrol, tapioca starch and a non-prescription antimicrobial complex on seborrhoea and other clinical signs secondary to canine atopic dermatitis (cAD). Forty-six dogs with cAD-associated seborrhoea and/or pruritus > 4 cm on the pruritus visual analogue scale (P-VAS) and/or bacterial/ Malassezia overgrowth were enrolled. The mousse was applied twice daily, and dogs were evaluated at days (D)0, 7, 14 and optionally 28, by means of a skin seborrheic index (SSI), P-VAS, cAD lesion index (CADLI), and a semiquantitative cytological score. The mean SSI value improved during the first two weeks (4.1 ± 0.37 to 1.9 ± 0.30; p < 0.0001). The mean P-VAS score (cm) decreased from 6.6 ± 0.19 at D0 to 3.8 ± 0.31 at D14 ( p < 0.0001). The mean CADLI score dropped from 13.7 ± 1.24 to 8.5 ± 1.14 at D14 ( p < 0.001). The cytological score for bacteria and Malassezia decreased from 3.2 ± 0.10 and 3.2 ± 0.11, respectively, to 1.2 ± 0.19 and 1.2 ± 0.24 ( p < 0.0001). All the investigated signs further improved at D28. Altogether, these observations suggest that the tested protocol might be useful in managing cAD-associated signs., Competing Interests: G. Morelli is employed by Innovet Italia srl, and C. Noli and M.F. della Valle are consultants for Innovet Italia srl.

Pain assessment is of paramount importance for properly managing dogs with osteoarthritis (OA) pain. The aim of the present study was to develop and psychometrically validate the Italian version of the Helsinki Chronic Pain Index (I-HCPI). Owners of OA painful ( n = 87) and healthy dogs ( n = 40) were administered the I-HCPI once or twice after an eight-week meloxicam treatment. Sixty-nine owners of healthy and OA dogs also completed the Italian version of the Canine Brief Pain Inventory (I-CBPI). Pain on palpation on a 0-4 scale was assessed on all recruited dogs. Construct validity was tested both with hypothesis testing and principal component analysis, confirming the I-HCPI accurately measured chronic pain. Good convergent and criterion validity were shown through correlations with I-CBPI subscores and distribution among pain on palpation scores ( p < 0.0001). The significant difference between the pre- and post-treatment I-HCPI scores ( p < 0.0001) and Cohen's effect size (2.27) indicated excellent responsiveness. The I-HCPI was shown to be reliable through communalities (range 0.47-0.90) and Cronbach α (≥0.95). Discriminative ability and cut-off point, as tested through Receiver Operating Characteristic analysis, showed excellent diagnostic accuracy with a threshold value of 11 (specificity 0.98 and sensitivity 0.94). The I-HCPI was confirmed to be a valid, sensitive, reliable, and accurate tool to discriminate between dogs with and without pain., Competing Interests: Carlo Schievano is employees of Innovative Statistical Research SRL, and Maria Federica della Valle is employees of CeDIS (Centro di Documentazione e Informazione Scientifica). The paper reflects the views of the scientists, and not the company. The authors declare no conflicts of interest.

Weaning entails numerous modifications of the intestinal structure and microbiota composition, making puppies at high risk of sickness during this delicate life stage. The aim of this study was to investigate the effects of a four-week administration of a supplement composed of ultramicronised Palmitoylethanolamide, bovine colostrum and Bacillus subtilis (Normalia ® Extra, Innovet Italia Srl, Saccolongo, Italy) on markers of gut health and microbiome of weaning puppies. Twenty-nine four-week-old Golden Retriever puppies were randomly assigned to control (CG, n = 13) and treated (TG, n = 16) groups. During the whole experimental time, there were no differences between the groups with regard to average daily gain and faecal score. In TG, faecal calprotectin and zonulin values were statistically significantly decreased compared to CG, especially at week 8 (zonulin: 42.8 ± 1.54 ng/mL and 55.3 ± 42.8 ng/mL, and calprotectin: 2.91 ± 0.38 µg/g and 5.71 ± 0.43 µg/g, in TG and CG, respectively; p < 0.0001 for both comparisons). Bacteria belonging to phylum Campylobacterota decreased ( p = 0.04), while those referring to genera Coprococcus and Pseudomonas increased ( p = 0.01 and p = 0.04, respectively). The supplementation of the tested complementary feed can promote the intestinal health of puppies and therefore facilitate weaning by lowering gut inflammation.

Background: Osteoarthritis (OA) pain is the number one cause of chronic pain in dogs. Multimodal treatment, including combining safe and effective nutritional interventions with non-steroidal anti-inflammatory drugs (NSAIDs), is currently considered one of the most appropriate choices for managing OA pain. Palmitoyl-glucosamine is a feed material belonging to the ALIAmide family, whose parent molecule is the prohomeostatic lipid amide N-palmitoyl-ethanolamine. Curcumin is a promising plant antioxidant. The present study aimed at investigating whether 18-week dietary integration with palmitoyl-glucosamine co-micronized with curcumin was able to maintain pain relief in dogs with OA-associated chronic pain receiving meloxicam (1.5 mg/ml oral suspension) on a tapering regimen (progressive 25% decrease of the original 0.1 mg/kg/day dose, on a biweekly basis) during the first 8 weeks of treatment. Pain was assessed both by the owners and veterinary surgeons, with the first using both subjective evaluation and validated metrology instruments-i.e., Helsinki Chronic Pain Index (HCPI) and Canine Brief Pain Inventory (CBPI)-while the second rating the severity of lameness and pain on palpation on two previously used 5-point scales., Results: A total of fifty-eight dogs with OA chronic pain entered the uncontrolled study. Pain on HCPI was considered severe at baseline (range 18-39). Based on owner's assessment, 90% of dogs who responded to meloxicam at the full-dose regimen could reduce meloxicam up to 25% of the original dose without experiencing pain worsening. Moreover, 75% of dogs was assessed as having no pain increase ten weeks after meloxicam withdrawal. A statistically significant decrease of pain severity as scored by HCPI (P < 0.0001) was observed two and ten weeks after meloxicam withdrawal compared to study entry (17.0 ± 1.05 and 15.1 ± 1.02, respectively, vs 29.0 ± 0.74; mean ± SEM). After meloxicam withdrawal, no statistically significant change in the CBPI scores was recorded. Pain on palpation and lameness significantly changed to less severe distributions along the study period (P < 0.0001)., Conclusion: The findings appear to suggest that dietary integration with palmitoyl-glucosamine co-micronized with curcumin was able to maintain meloxicam-induced pain relief in dogs with severe OA chronic pain., (© 2023. The Author(s).)

Background: Assessment of the severity of pruritus is difficult in cats, because they manifest discomfort by increased licking, increased scratching or both., Hypothesis/objectives: Our objective was to develop and validate a feline-specific pruritus scale (VAScat)., Methods: The scale was designed as a double Visual Analog Scale (VAS), one VAS for licking and one for scratching, with severity and behavioural descriptors. The highest score (VAS-max) on either VAS was taken as the pruritus score for each cat. Owners of 153 cats with skin diseases and of 108 healthy cats scored their pet's pruritus using the VAScat. Ninety-six of 153 cats with skin diseases also were re-evaluated after four to eight weeks of treatment., Results: Pearson's correlation value between VAS-licking and VAS-scratching scores was r = 0.26 (p < 0.01), and Cronbach's alpha was 0.41. Both indexes indicated that the two scales measure different manifestations of pruritus and supported the use of a dual assessing system. Comparison with a numerical pruritus severity scale (0, absent; 1, mild; 2, moderate; 3, severe) suggested that VAS-licking and VAS-scratching scales taken alone are unsuitable for measuring absent to mild pruritus (grades 0-1), while VAS-max is (p = 0.001). VAS-licking, VAS-scratching and VAS-max all were suitable to assess higher levels of pruritus (grades 2-3, p < 0.01). The VAScat was able to measure pruritus improvement following therapy, as post-treatment scores were significantly decreased compared to pre-treatment ones (p < 0.0001)., Conclusions and Clinical Importance: The VAScat proved to be a useful tool to assess pruritus in cats and for monitoring the response to treatment for pruritus., (© 2022 ESVD and ACVD.)

Serum amyloid A (SAA) is a family of acute-phase reactants. The rise of SAA concentration in blood circulation during the acute-phase response is a clinical marker of active inflammation. Despite its practical and analytical advantages, SAA measurement by enzyme-linked immunosorbent assay (ELISA) has been used mainly as a research tool rather than for the routine laboratory testing. This may be partly explained by the lack of robust reference data in the literature for the different commercially available immunoassays. Using the recommended procedures for the production of reference intervals published by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), we developed the SAA reference interval for a well-defined Italian healthy population and investigated the correlation among SAA and C-reactive protein (CRP), the commonly used acute-phase marker. After data normalization, the reference cutoff was calculated as 225 ng/ml. A good correlation between SAA and CRP was found ( P < .05). No statistically significant differences was found between males and females when the means of SAA values were compared, suggesting that not gender-partitioned reference range is recommended for this analyte. This study allowed to define a widely accepted reference cutoff for the SAA detected by ELISA, responding to an unmet need of laboratory medicine.

Chronic mixed pain and orthopedic dysfunction are the most frequently associated consequences of canine osteoarthritis (OA). An unmet need remains for safe and effective therapies for OA. Palmitoyl-glucosamine (PGA) and curcumin are safe and naturally occurring compounds whose use is limited by poor bioavailability. Micronization is an established technique to increase bioavailability. The aim of this study was to investigate if the dietary supplementation with PGA co-micronized with curcumin (PGA-Cur, 2:1 ratio by mass) could limit pathologic process in two well-established rat models of inflammation and OA pain, i.e., subplantar carrageenan (CAR) and knee injection of sodium monoiodoacetate (MIA), respectively. In CAR-injected animals, a single dose of PGA-cur significantly reduced paw edema and hyperalgesia, as well as tissue damage and neutrophil infiltration. The repeated administration of PGA-Cur three times per week for 21 days, starting the third day after MIA injection resulted in a significant anti-allodynic effect. Protection against cartilage damage and recovery of locomotor function by 45% were also recorded. Finally, PGA-cur significantly counteracted MIA-induced increase in serum levels of TNF-α, IL-1β, NGF, as well as metalloproteases 1, 3, and 9. All the effects of PGA-Cur were superior compared to the compounds used singly. PGA-Cur emerged as a useful dietary intervention for OA.

Background: Osteoarthritis is increasingly recognized as the result of a complex interplay between inflammation, chrondrodegeneration, and pain. Joint mast cells are considered to play a key role in orchestrating this detrimental triad. ALIAmides down-modulate mast cells and more generally hyperactive cells. Here we investigated the safety and effectiveness of the ALIAmide N-palmitoyl-D-glucosamine (PGA) in inflammation and osteoarthritis pain., Methods: Acute toxicity of micronized PGA (m-PGA) was assessed in rats following OECD Guideline No.425. PGA and m-PGA (30 mg/kg and 100 mg/kg) were orally administered to carrageenan (CAR)-injected rats. Dexamethasone 0.1 mg/kg was used as reference. Paw edema and thermal hyperalgesia were measured up to 6 h post-injection, when also myeloperoxidase activity and histological inflammation score were assessed. Rats subjected to intra-articular injection of sodium monoiodoacetate (MIA) were treated three times per week for 21 days with PGA or m-PGA (30 mg/kg). Mechanical allodynia and motor function were evaluated at different post-injection time points. Joint histological and radiographic damage was scored, articular mast cells were counted, and macrophages were immunohistochemically investigated. Levels of TNF-α, IL-1β, NGF, and MMP-1, MMP-3, and MMP-9 were measured in serum using commercial colorimetric ELISA kits. One- or two-way ANOVA followed by a Bonferroni post hoc test for multiple comparisons was used., Results: Acute oral toxicity of m-PGA resulted in LD50 values in excess of 2000 mg/kg. A single oral administration of PGA and m-PGA significantly reduced CAR-induced inflammatory signs (edema, inflammatory infiltrate, and hyperalgesia), and m-PGA also reduced the histological score. Micronized PGA resulted in a superior activity to PGA on MIA-induced mechanical allodynia, locomotor disability, and histologic and radiographic damage. The MIA-induced increase in mast cell count and serum level of the investigated markers was also counteracted by PGA and to a significantly greater extent by m-PGA., Conclusions: The results of the present study showed that PGA is endorsed with anti-inflammatory, pain-relieving, and joint-protective effects. Moreover, it proved that particle size reduction greatly enhances the activity of PGA, particularly on joint pain and disability. Given these results, m-PGA could be considered a valuable option in the management of osteoarthritis.

Background: Oclacitinib is a Janus-kinase inhibitor that decreases interleukin-31-induced pruritus in cats. At 0.4-0.6 mg/kg/day orally, it decreased pruritus and skin lesions in <50% of allergic cats., Hypothesis/objectives: To evaluate efficacy and safety of oclacitinib in feline nonflea nonfood-induced hypersensitivity dermatitis (NFNFIHD)., Animals: Forty cats with NFNFIHD., Methods and Materials: Cats were randomly assigned to receive oclacitinib (group A, 20 cats, 0.7-1.2 mg/kg) or methylprednisolone (group B, 20 cats, 0.5-1 mg/kg) orally twice daily for 28 days. On day (D)1 and D28, lesions were evaluated using the Scoring Feline Allergic Dermatitis (SCORFAD) scale and owners assessed pruritus using a Visual Analog Scale (VAS) and quality of life (QoL) questionnaire. Results were analysed by General Linear Mixed Model (P < 0.05). Haematochemical analyses were performed on D1 and D28., Results: In both groups all parameters improved significantly, with no difference at either time point. Group A had a 61% mean SCORFAD and 54% pruritus VAS improvement, compared with 69% and 67% in group B; 70% of cats in group A and 75% in group B achieved a ≥ 50% reduction of pruritus VAS scores; with 60% and 80% of SCORFAD. There were five non-responders in group A and three in group B. The QoL score improved in both groups (25 and 21%). Four of 14 cats had mild increases in kidney function tests (oclacitinib group) and three of 12 cats had elevated alanine transferase (methylprednisolone group)., Conclusions and Clinical Importance: Oclacitinib appears to be effective for treating pruritus and lesions in cats with NFNFIHD, albeit methylprednisolone seemed to perform better., (© 2019 ESVD and ACVD.)

Background: Fibromyalgia syndrome is a chronic multifaceted disease characterized by widespread pain, muscle stiffness, fatigue, unrefreshing sleep and cognitive disorders. To date, no medication has been shown to significantly improve pain, associated symptoms and Quality of Life in fibromyalgic patients., Methods: In this retrospective observational study, we analyzed data regarding 407 patients with diagnosis of fibromyalgia syndrome who between 2013 and 2016 have been prescribed orally ultramicronized palmitoylethanolamide tablets (Normast® Epitech Group SpA, Saccolongo, Italy) regardless of the concomitant pharmacological therapy (add-on treatment)., Results: Regarding efficacy, in the 359 analyzed patients, the change over time in Visual Analogue Scale pain score was statistically significant, ranging from 75.84 (±15.15) to 52.49 (±16.73) (p<0.001). Regarding quality of life, the change over time in Fibromyalgia Impact Questionnaire score was statistically significant, ranging from 68.4 (±14.1) to 49.1 (±19.6) (p<0.001). In the treated population, only 36 patients (13,7%) reported Adverse Events predominantly of gastrointestinal type (diarrhea, dyspepsia, bloating, constipation, vomiting). Globally, 151 patients (57,63%) left the treatment due to inefficacy., Conclusion: The results of ultramicronized palmitoylethanolamide treatment in this retrospective analysis represent an important step for the development of a new and well-tolerated therapy for fibromyalgia syndrome, mostly suitable for these patients who need long-term treatments. Further methodologically stronger studies will be necessary to validate our observation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic bladder condition characterized by frequent urination, bladder inflammation and pain. It is a particular challenging disease and a clear unmet medical need in terms of identifying new therapeutic strategies. The aim of study was to evaluate the anti-inflammatory effects of intravesical Vessilen ® (a new formulation of 2% adelmidrol (the diethanolamide derivative of azelaic acid) + 0.1% sodium hyaluronate) administration in rodent models of IC/BPS and in IC/BPS patients or other bladder disorders. Acute and chronic animal models of cystitis were induced by a single or repetitive intraperitoneal injections of cyclophosphamide (CYP); patients with IC/BPS or with bladder pain syndrome associated with symptoms of the lower urinary tract treated once weekly by bladder instillation of Vessilen ® for 8 weeks. CYP instillation caused macroscopic and histological bladder alterations, inflammatory infiltrates, increased mast cell numbers, bladder pain, increased expression of nitrotyrosine, decreased expression of endothelial tight junction zonula occludens-1. Intravesical Vessilen® treatment was able to ameliorate CYP induced bladder inflammation and pain by inhibiting nuclear factor-κB pathway and inflammatory mediator levels as well as reduced mechanical allodynia and nerve growth factor levels. A significant improvement in quality of life and symptom intensity were evident in patients with IC/BPS or other bladder disorders treated with Vessilen ® . Vessilen ® could be a new therapeutic approach for human cystitis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Canine screw-worm myiasis due to Cochliomyia hominivorax or Chrysomya bezziana has traditionally been treated with extra-label use of ivermectin. The larvicidal activities of nitenpyram and spinosad/milbemycin also have been described, but there have been no reports to describe the efficacy of isoxazolines such as afoxolaner., Objectives: To evaluate and compare the efficacy of spinosad, spinosad/milbemycin, milbemycin, nitenpyram and afoxolaner for the treatment of canine screw-worm myiasis., Animals: Forty client-owned and naturally infested dogs., Methods: Cases were randomized into five groups of eight dogs, with each receiving an insecticide at the dose recommended by the manufacturer. Each case was evaluated hourly for 7 h and then again 24 h after treatment. Scores of 0 (no visualized effect), 0.5 (partial eradication) or 1 (complete kill and eradication) were recorded at each observation and compared between groups. Time to complete killing of all larvae was recorded for each dog and compared between treatment groups., Results: Nitenpyram killed all larvae at 6 h post-consumption and spinosad/milbemycin at 7 h. In groups receiving afoxolaner or spinosad, all larvae were killed within 24 h. For those receiving milbemycin, two cases were still infested with live larvae at 24 h. Shih tzus and their crosses were most commonly affected., Conclusion: Spinosad/milbemycin or nitenpyram seem to be effective drugs for the treatment of canine screw-worm myiasis. Afoxolaner and milbemycin are effective but exhibited slower larvicidal activity. Synergism between spinosad and milbemycin was observed., (© 2018 ESVD and ACVD.)

Background: Direct examination of the hair is a simple diagnostic test for the diagnosis of dermatophytosis; training is needed to use this test., Hypothesis/objectives: To evaluate whether use of modified Wright-Giemsa blue stain and/or photographic images of infected and uninfected hairs improved the user's ability to identify infected or uninfected hairs., Animals: Ten cats with, and 10 cats without, dermatophytosis due to Microsporum canis (n = 20)., Materials and Methods: Twenty unstained and 20 stained hair samples from each group (n = 40) were anonymized and examined by veterinarians using a light microscope. Participants recorded samples as "infected" or "uninfected". Participants were then shown and allowed to use photographic images while examining the same 40 samples., Results: Without staining, investigators correctly identified 12.7 ± 4 of the 20 samples (mean ± SD) and with staining 13.6 (±3). After illustrative guidelines were shown, they correctly identified a mean of 16.9 (±2.5) unstained slides and 15.8 (±2.3) stained slides. "Illustrated guidelines" and "hair infection" significantly increased the probability of a correct answer, whereas "staining" did not. Logistic regression determined that "study participant", "illustrated guidelines" (OR = 2.6) and "hair infection" (OR = 2.1) had a significant influence on the results, whereas "staining" did not. Sensitivity and specificity of direct examination were 70.5% and 56%, respectively, compared with culture status., Conclusions and Clinical Importance: When examining hairs for the presence or absence of infected dermatophyte hairs, diagnostic accuracy was improved when observers used illustrated guides compared with just examining stained slides., (© 2018 ESVD and ACVD.)

Palmitoylethanolamide (PEA) is a pleiotropic lipid mediator with established anti-inflammatory and anti-hyperalgesic activity. Ultramicronized PEA (PEA-um) has superior oral efficacy compared to naïve (non-micronized) PEA. The aim of the present study was two-fold: (1) to evaluate whether oral PEA-um has greater absorbability compared to naïve PEA, and its ability to reach peripheral and central tissues under healthy and local inflammatory conditions (carrageenan paw edema); (2) to better characterize the molecular pathways involved in PEA-um action, particularly at the spinal level. Rats were dosed with 30 mg/kg of [ 13 C] 4 -PEA-um or naïve [ 13 C] 4 -PEA by oral gavage, and [ 13 C] 4 -PEA levels quantified, as a function of time, by liquid chromatography/atmospheric pressure chemical ionization/mass spectrometry. Overall plasma levels were higher in both healthy and carrageenan-injected rats administered [ 13 C] 4 -PEA-um as compared to those receiving naïve [ 13 C] 4 -PEA, indicating the greater absorbability of PEA-um. Furthermore, carrageenan injection markedly favored an increase in levels of [ 13 C] 4 -PEA in plasma, paw and spinal cord. Oral treatment of carrageenan-injected rats with PEA-um (10 mg/kg) confirmed beneficial peripheral effects on paw inflammation, thermal hyperalgesia and tissue damage. Notably, PEA-um down-regulated distinct spinal inflammatory and oxidative pathways. These last findings instruct on spinal mechanisms involved in the anti-hyperalgesic effect of PEA-um in inflammatory pain.

Background: Ultramicronized palmitoylethanolamide (PEA-um) has been reported to reduce pruritus and skin lesions in dogs with moderate atopic dermatitis and pruritus., Hypothesis/objectives: A canine ex vivo skin model was used to investigate the ability of PEA-um to counteract changes induced by compound 48/80, a well-known secretagogue that causes mast cell degranulation., Animals: Normal skin was obtained from three donor dogs subjected to surgery for reasons unrelated to the study., Methods: Cultured skin biopsy samples in triplicate were treated with 10 and 100 μg/mL compound 48/80, without or with 30 μM PEA-um. Mast cell (MC) degranulation, histamine release into the culture medium, local microvascular dilatation, epidermal thickness, keratinocyte proliferation and epidermal differentiation markers were evaluated., Results: Exposure of the skin organ culture to PEA-um 24 h before and 72 h concomitantly to compound 48/80 resulted in a significant decrease of degranulating MCs. PEA-um also reduced the histamine content in the culture medium by half, although the effect did not reach statistical significance. PEA-um significantly counteracted vasodilation induced by 100 μg/mL compound 48/80. Finally, PEA-um alone did not induce changes in epidermal thickness, differentiation markers, keratinocyte proliferation, MC density and/or degranulation., Conclusions and Clinical Importance: Collectively, these results support the protective action PEA-um on the skin of dogs undergoing allergic changes., (© 2017 ESVD and ACVD.)

Background: Osteoarthritis (OA) is a common progressive joint disease in dogs and cats. The goal of OA treatment is to reduce inflammation, minimize pain, and maintain joint function. Currently, non-steroidal anti-inflammatory drugs (e.g., meloxicam) are the cornerstone of treatment for OA pain, but side effects with long-term use pose important challenges to veterinary practitioners when dealing with OA pain. Palmitoylethanolamide (PEA) is a naturally-occurring fatty acid amide, locally produced on demand by tissues in response to stress. PEA endogenous levels change during inflammatory and painful conditions, including OA, i.e., they are typically increased during acute conditions and decreased in chronic inflammation. Systemic treatment with PEA has anti-inflammatory and pain-relieving effects in several disorders, yet data are lacking in OA. Here we tested a new composite, i.e., PEA co-ultramicronized with the natural antioxidant quercetin (PEA-Q), administered orally in two different rat models of inflammatory and OA pain, namely carrageenan paw oedema and sodium monoiodoacetate (MIA)-induced OA. Oral treatment with meloxicam was used as benchmark., Results: PEA-Q decreased inflammatory and hyperalgesic responses induced by carrageenan injection, as shown by: (i) paw oedema reduction, (ii) decreased severity in histological inflammatory score, (iii) reduced activity of myeloperoxidase, i.e., a marker of inflammatory cell infiltration, and (iv) decreased thermal hyperalgesia. Overall PEA-Q showed superior effects compared to meloxicam. In MIA-treated animals, PEA-Q exerted the following effects: (i) reduced mechanical allodynia and improved locomotor function, (ii) protected cartilage against MIA-induced histological damage, and (iii) counteracted the increased serum concentration of tumor necrosis factor alpha, interleukin 1 beta, metalloproteases 1, 3, 9 and nerve growth factor. The magnitude of these effects was comparable to, or even greater than, those of meloxicam., Conclusion: The present findings shed new light on some of the inflammatory and nociceptive pathways and mediators targeted by PEA-Q and confirm its anti-inflammatory and pain-relieving effects in rodent OA pain models. The translatability of these observations to canine and feline OA pain is currently under investigation.

Background: Parkinson's disease (PD) is the subject of intense efforts to develop strategies that slow down or stop disease progression and disability. Substantial evidence points to a prominent role for neuroinflammation in the underlying dopaminergic cell death. Ultramicronized palmitoylethanolamide (um-PEA) is well-known for its ability to promote the resolution of neuroinflammation and exert neuroprotection. This study was designed to assess the efficacy of um-PEA as adjuvant therapy in patients with advanced PD., Method: Thirty PD patients receiving levodopa were included in the study. The revised- Movement Disorder Society/Unified Parkinson's Disease Rating Scale (MDS-UPDRS) questionnaire was used to assess motor and non-motor symptoms. Clinical assessments were carried out before and after addition of um-PEA (600 mg). MDS-UPDRS questionnaire total score for parts I, II, III, and IV was analyzed using the Generalized Linear Mixed Model, followed by the Wilcoxon signed-rank test to evaluate the difference of each item's mean score between baseline and end of um-PEA treatment., Results: Addition of um-PEA to PD patients receiving levodopa therapy elicited a significant and progressive reduction in the total MDS-UPDRS score (parts I, II, III and IV). For each item, the mean score difference between baseline and end of um-PEA treatment showed a significant reduction in most nonmotor and motor symptoms. The number of patients with symptoms at basal was reduced after one year of um-PEA treatment. None of the participants reported side effects attributable to the addition of um-PEA., Conclusion: um-PEA slowed down disease progression and disability in PD patients, suggesting that um-PEA may be an efficacious adjuvant therapy for PD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Skin disease can negatively affect the Quality of Life (QoL) of cats and of their owners., Objectives: To develop and evaluate a questionnaire on QoL of cats with skin disease and their owners., Methods: Following interviews with owners of cats with severe skin disease and elaboration of a preliminary 19 item questionnaire, a final 15 item (score 0-3) questionnaire was developed. This was administered to owners of 45 cats with allergic dermatitis and 39 healthy cats, to assess its ability to differentiate between diseased and healthy subjects. In allergic cats, owners evaluated overall disease severity (S) and pruritus with a Visual Analog Scale (VAS); veterinarians evaluated skin lesions [SCORing Feline Allergic Dermatitis (SCORFAD) and Feline Dermatitis Extent and Severity Index (FeDESI)]. The correlation with QoL was analysed by Spearman's rank test. In 31 allergic cats, SCORFAD, FeDESI, pruritus VAS, S and QoL scores were obtained before and after therapy, and their improvement evaluated statistically., Results: QoL scores in allergic cats were significantly higher than in healthy cats (P=<0.0001). Severity correlated well and significantly with both cat's and owner's QoL (r = 0.51 and 0.64, P = 0.0003 and <0.0001, respectively). Correlation of QoL with pruritus VAS was moderate and significant (r = 0.3, P = 0.03), whereas with SCORFAD and FeDESI it was low and not significant. With therapy all scores decreased significantly (P < 0.0001); however, QoL was not influenced by improvement of clinical scores. Questions related to the burden of therapy showed the smallest improvements., Conclusions: This QoL questionnaire could be a useful tool in evaluating cats with skin disease., (© 2016 ESVD and ACVD.)

Background: 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., Objective: 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., Study Design: Pooled data analysis consisting of double-blind, controlled, and open-label clinical trials., Methods: 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: 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., Limitations: Noteworthy, serious adverse events related to PEA were not registered and/or reported in any of the studies., Conclusion: These results confirm that PEA might represent an exciting, new therapeutic strategy to manage chronic and neuropathic pain associated with neuroinflammation.

Acute ischemic stroke, the most frequent cause of permanent disability in adults worldwide, results from transient or permanent reduction in regional cerebral blood flow and involves oxidative stress and inflammation. Despite the success of experimental animal models of stroke in identifying anti-inflammatory/neuroprotective compounds, translation of these putative neuroprotectants to human clinical trials has failed to produce a positive outcome. Tissue injury and stress activate endogenous mechanisms which function to restore homeostatic balance and prevent further damage by upregulating the synthesis of lipid signaling molecules, including N-palmitoylethanolamine (PEA or palmitoylethanolamide). PEA exerts neuroprotection and reduces inflammatory secondary events associated with brain ischemia reperfusion injury (middle cerebral artery occlusion (MCAo)). Here, we examined the neuroprotective potential of a co-ultramicronized composite containing PEA and the antioxidant flavonoid luteolin (10:1 by mass), nominated co-ultraPEALut. The study consisted of two arms. In the first, rats subjected to MCAo and treated with co-ultraPEALut post-ischemia showed reduced edema and brain infract volume, improved neurobehavioral functions, and reduced expression of pro-inflammatory markers and astrocyte markers. In the second arm, a cohort of 250 stroke patients undergoing neurorehabilitation on either an inpatient or outpatient basis were treated for 60 days with a pharmaceutical preparation of co-ultraPEALut (Glialia). At baseline and after 30 days of treatment, all patients underwent a battery of evaluations to assess neurological status, impairment of cognitive abilities, the degree of spasticity, pain, and independence in daily living activities. All indices showed statistically significant gains at study end. Despite its observational nature, this represents the first description of co-ultraPEALut administration to human stroke patients and clinical improvement not otherwise expected from spontaneous recovery. Further, controlled trials are warranted to confirm the utility of co-ultraPEALut to improve clinical outcome in human stroke.

Background: Palmitoylethanolamide is a naturally occurring bioactive lipid, produced on-demand by damage-exposed cells. Palmitoylethanolamide is documented to counteract inflammation, itch and pain., Objective: The aim of this 8-week study was to evaluate the efficacy of oral ultra-micronized palmitoylethanolamide (PEA-um) in dogs with moderate atopic dermatitis., Animals: Clinicians from 39 veterinary clinics enrolled 160 dogs with nonseasonal atopic dermatitis and moderate pruritus., Methods: This was a multi-centre open-label study. On days 0 (D0) and 56 (D56), owners evaluated pruritus with a Visual Analog Scale (VAS) and completed a validated Quality of Life (QoL) questionnaire. Veterinarians assessed the severity of skin lesions using the Canine Atopic Dermatitis Lesion Index (CADLI)., Results: Mean pruritus VAS score decreased from 5.7 ± 0.08 cm (range 3.8-7.9 cm) to 3.63 ± 0.19 cm (range 0.1-9.2 cm) (P < 0.0001). At D56, 58% of dogs showed a greater than 2 cm reduction from baseline and 30% showed an absent-to-very mild pruritus (VAS ≤ 2 cm). Mean total CADLI at D56 decreased significantly (P < 0.0001); in 62% of dogs this score reached a value in the remission range (≤5). Mean total QoL score was significantly decreased (P < 0.0001) with 45% of dogs reaching QoL values described for healthy animals. Tolerability was good-to-excellent with only four dogs reporting treatment associated reversible adverse events., Conclusions and Clinical Importance: PEA-um appears to be effective and safe in reducing pruritus and skin lesions, and in improving QoL in dogs with moderate atopic dermatitis and moderate pruritus., (© 2015 Innovet Italia Srl. Veterinary Dermatology published by John Wiley & Sons Ltd on behalf of the ESVD and ACVD.)

Aim: Carpal tunnel syndrome (CTS) is a medical condition in which the median nerve is compressed, leading to discomfort and pain. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, able to modulate inflammatory cell reactivity and pain. This study deals with the capability of PEA to normalize the electroneurographic alterations associated with moderate CTS., Methods: Patients displaying moderate CTS were enrolled and daily PEA (600 mg or 1 200 mg/die) was administered for 30 days. Control group received no treatment., Results: PEA treatment significantly improved the CTS-induced reduction of median nerve latency time (P<0.0004); PEA effect was dose-dependent. Tinel's sign presence and symptoms of discomfort were also reduced., Conclusion: Although further studies are needed to better characterize PEA effect, the present report represents the first evidence on the improvement of distal motor latency elicited by PEA in patients with moderate CTS. The data support the hypothesis of protection against inflammatory and neuropathic pain by PEA.