Ultramicronized Palmitoylethanolamide Research Articles

Ultramicronized Palmitoylethanolamide and Paracetamol, a New Association to Relieve Hyperalgesia and Pain in a Sciatic Nerve Injury Model in Rat.

Inflammation is known to be an essential trigger of the pathological changes that have a critical impact on nerve repair and regeneration; moreover, damage to peripheral nerves can cause a loss of sensory function and produces persistent neuropathic pain. To date, various potential approaches for neuropathic pain have focused on controlling neuroinflammation. The aim of this study was to investigate the neuroprotective effects of a new association of ultramicronized Palmitoylethanolamide (PEAum), an Autacoid Local Injury Antagonist Amide (ALIAmide) with analgesic and anti-inflammatory properties, with Paracetamol, a common analgesic, in a rat model of sciatic nerve injury (SNI). The association of PEAum–Paracetamol, in a low dose (5 mg/kg + 30 mg/kg), was given by oral gavage daily for 14 days after SNI. PEAum–Paracetamol association was able to reduce hyperalgesia, mast cell activation, c-Fos and nerve growth factor (NGF) expression, neural histological damage, cytokine release, and apoptosis. Furthermore, the analgesic action of PEAum–Paracetamol could act in a synergistic manner through the inhibition of the NF-κB pathway, which leads to a decrease of cyclooxygenase 2-dependent prostaglandin E2 (COX-2/PGE2) release. In conclusion, we demonstrated that PEAum associated with Paracetamol was able to relieve pain and neuroinflammation after SNI in a synergistic manner, and this therapeutic approach could be relevant to decrease the demand of analgesic drugs.

Ultramicronized Palmitoylethanolamide (um-PEA) as Add-on Treatment in Fibromyalgia Syndrome (FMS): Retrospective Observational Study on 407 Patients.

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. 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). 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. 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.

Effect of dietary supplementation with ultramicronized palmitoylethanolamide in maintaining remission in cats with nonflea hypersensitivity dermatitis: a double-blind, multicentre, randomized, placebo-controlled study.

BackgroundFeline nonflea hypersensitivity dermatitis (NFHD) is a frequent cause of over‐grooming, scratching and skin lesions. Multimodal therapy often is necessary.Hypothesis/ObjectivesTo investigate the efficacy of ultramicronized palmitoylethanolamide (PEA‐um) in maintaining methylprednisolone‐induced remission in NFHD cats.AnimalsFifty‐seven NFHD cats with nonseasonal pruritus were enrolled originally, of which 25 completed all study requirements to be eligible for analysis.Methods and materialsCats were randomly assigned to PEA‐um (15 mg/kg per os, once daily; n = 29) or placebo (n = 28) while receiving a 28 day tapering methylprednisolone course. Cats responding favourably to methylprednisolone were then administered only PEA‐um (n = 21) or placebo (n = 23) for another eight weeks, followed by a four week long treatment‐free period. Cats were maintained in the study until relapse or study end, whichever came first. Primary outcome was time to relapse. Secondary outcomes were pruritus Visual Analog Scale (pVAS), SCORing Feline Allergic Dermatitis scale (SCORFAD) and owner Global Assessment Score (GAS).ResultsMean relapse time was 40.5 days (±7.8 SE) in PEA‐um treated cats (n = 13) and 22.2 days (±3.7 SE) for placebo (n = 12; P = 0.04). On Day 28, the severity of pruritus was lower in the PEA‐um treated cats compared to placebo (P = 0.03). Mean worsening of pruritus at the final study day was lower in the PEA‐um group compared to placebo (P = 0.04), whereas SCORFAD was not different between groups. Mean owner GAS at the final study day was better in the PEA‐um than the placebo‐treated group (P = 0.05).Conclusion and clinical importanceUltramicronized palmitoylethanolamide could represent an effective and safe option to delay relapse in NFHD cats.

A co-ultramicronized palmitoylethanolamide/luteolin composite mitigates clinical score and disease-relevant molecular markers in a mouse model of experimental autoimmune encephalomyelitis

BackgroundPersistent and/or recurrent inflammatory processes are the main factor leading to multiple sclerosis (MS) lesions. The composite ultramicronized palmitoylethanolamide, an endogenous N-acylethanolamine, combined with the flavonoid luteolin, PEALut, have been found to exert neuroprotective activities in experimental models of spinal and brain injury and Alzheimer disease, as well as a clinical improvement in human stroke patients. Furthermore, PEALut enhances the expression of different myelin proteins in oligodendrocyte progenitor cells suggesting that this composite might have protective effects in MS experimental models.MethodsThe mouse model of experimental autoimmune encephalomyelitis (EAE) based on active immunization with a fragment of myelin oligodendrocyte glycoprotein (MOG35-55) was used. The daily assessment of clinical score and the expression of serum amyloid A (SAA1), proinflammatory cytokines TNF-α, IL-1β, IFN-γ, and NLRP3 inflammasome, as well as TLR2, Fpr2, CD137, CD3-γ, and TCR-ζ chain, heterodimers that form T cell surface glycoprotein (TCR), and cannabinoid receptors CB1, CB2, and MBP, were evaluated in the brainstem and cerebellum at different postimmunization days (PIDs).ResultsVehicle-MOG35-55-immunized (MOG35-55) mice developed ascending paralysis which peaked several days later and persisted until the end of the experiment. PEALut, given intraperitoneally daily starting on day 11 post-immunization, dose-dependently improved clinical score over the range 0.1–5 mg/kg. The mRNA expression of SAA1, TNF-α, IL-1β, IFN-γ, and NLRP3 were significantly increased in MOG35-55 mice at 14 PID. In MOG35-55 mice treated with 5 mg /kg PEALut, the increase of SAA1, TNF- α, IL-1β, and IFN-γ transcripts at 14 PID was statistically downregulated as compared to vehicle-MOG35-55 mice (p < 0.05).The expression of TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB2 receptors showed a significant upregulation in vehicle-MOG35-55 mice at 14 PID. Instead, CB1 and MBP transcripts have not changed in expression at any time. In MOG/PEALut-treated mice, TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB2 mRNAs were significantly downregulated as compared to vehicle MOG35-55 mice.ConclusionsThe present results demonstrate that the intraperitoneal administration of the composite PEALut significantly reduces the development of clinical signs in the MOG35-55 model of EAE. The dose-dependent improvement of clinical score induced by PEALut was associated with a reduction in transcript expression of the acute-phase protein SAA1, TNF-α, IL-1β, IFN-γ, and NLRP3 proinflammatory proteins and TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB2 receptors.

OC.6- Ultra-micronized palmitoylethanolamide rescues the cognitive decline-associated loss of neural plasticity in the neuropathic mouse entorhinal cortex-dentate gyrus pathway

OC.6- Ultra-micronized palmitoylethanolamide rescues the cognitive decline-associated loss of neural plasticity in the neuropathic mouse entorhinal cortex-dentate gyrus pathway

Efficacy of ultramicronized palmitoylethanolamide in burning mouth syndrome-affected patients: a preliminary randomized double-blind controlled trial.

This preliminary randomized double-blind controlled trial was performed to test the efficacy of ultramicronized palmitoylethanolamide treatment in the burning mouth syndrome. Patients with referred burning mouth intensity greater than 4, according to the Numeric Rating Scale, were included in the study according to established inclusion and exclusion criteria. Patients were randomized into two groups and received either placebo or ultramicronized palmitoylethanolamide 600mg twice daily for 60days. Patients were assessed at baseline, 30 and 60days after treatment start, and 4months after treatment discontinuation. In order to evaluate the change in the burning mouth sensation over time, the generalized linear mixed model was employed. A total of 35 patients were considered eligible, among which 6 withdrew prior to the end of treatment. A statistically significant reduction of burning mouth sensation (p < 0.0132) was registered at the end of the active treatment in the ultramicronized palmitoylethanolamide group compared to the placebo one. Any side effect related to the active treatment was neither observed nor reported both by patients and by physicians. The significant decrease of burning sensation in the ultramicronized palmitoylethanolamide group compared to the placebo group suggests to consider this naturally occurring molecule as a viable therapy in the management of burning mouth syndrome. The use of an effective compound to manage the burning mouth syndrome, devoid of adverse effects for the patient and that does not interfere with other pharmacological therapies, could find wide employability from clinicians.

Ultra-micronized palmitoylethanolamide rescues the cognitive decline-associated loss of neural plasticity in the neuropathic mouse entorhinal cortex-dentate gyrus pathway

Chronic pain is associated with cognitive deficits. Palmitoylethanolamide (PEA) has been shown to ameliorate pain and pain-related cognitive impairments by restoring glutamatergic synapses functioning in the spared nerve injury (SNI) of the sciatic nerve in mice. SNI reduced mechanical and thermal threshold, spatial memory and LTP at the lateral entorhinal cortex (LEC)-dentate gyrus (DG) pathway. It decreased also postsynaptic density, volume and dendrite arborization of DG and increased the expression of metabotropic glutamate receptor 1 and 7 (mGluR1 and mGluR7), of the GluR1, GluR1s845 and GluR1s831 subunits of AMPA receptor and the levels of glutamate in the DG. The level of the endocannabinoid 2-arachidonoylglycerol (2-AG) was instead increased in the LEC. Chronic treatment with PEA, starting from when neuropathic pain was fully developed, was able to reverse mechanical allodynia and thermal hyperalgesia, memory deficit and LTP in SNI wild type, but not in PPARα null, mice. PEA also restored the level of glutamate and the expression of phosphorylated GluR1 subunits, postsynaptic density and neurogenesis. Altogether, these results suggest that neuropathic pain negatively affects cognitive behavior and related LTP, glutamatergic synapse and synaptogenesis in the DG. In these conditions PEA treatment alleviates pain and cognitive impairment by restoring LTP and synaptic maladaptative changes in the LEC-DG pathway. These outcomes open new perspectives for the use of the N-acylethanolamines, such as PEA, for the treatment of neuropathic pain and its central behavioural sequelae.

Effects of Add-On Ultramicronized N-Palmitol Ethanol Amide in Patients Suffering of Migraine With Aura: A Pilot Study

Background: Palmitoyl ethanol amide (PEA) is an endogenously produced substance showing anti-nociceptive effect through both receptor and non-receptor mediated effects at the level of different cellular and tissue sites. This study showed the results of a single blind study that was conducted to evaluate both the safety and the efficacy of ultramicronized PEA (umPEA; 1,200 mg/day) for up 90 days in patients suffering of Migraine with Aura (MA) treated with NSAIDs.Methods: A total of 20 patients, 8 male (33–56-years, average 41.4 ± 7.8) and 12 female (19–61-years, average 38.5 ± 11.9) with MA were admitted to our observation and diagnosed according to ICHD-3 criteria, they received umPEA (1,200 mg/day) in combination with NSAIDs for up to 90 days. They were revaluated at 30, 60, and 90 days after treatment.Results: umPEA administration induced a statistically significant and time dependent pain relief. In particular, these effects were evident at 60 days (male P = 0.01189; female P = <0.01) and they lasted until the end of the study (male P = 0.0066; female P = 0.01473).Conclusion: Although further studies are needed, our findings indicate that in patients suffering of MA treatment with umPEA had good efficacy and safety which candidate this compound as a therapeutic tool in pain migraine management.

Ultra-micronized Palmitoylethanolamide Effects on Sleep-wake Rhythm and Neuropathic Pain Phenotypes in Patients with Carpal Tunnel Syndrome: An Open-label, Randomized Controlled Study.

Patients with carpal tunnel syndrome often suffer from fragmentary sleep. This study was designed to assess the effectiveness of treatment with ultramicronized palmitoylethanolamide in reducing pain intensity and improving quality of sleep in patients with neuropathic pain due to carpal tunnel syndrome. An open, controlled study was conducted on 42 patients awaiting carpal tunnel syndrome surgery, suffering from sleep disorders and painful symptoms and randomized into two groups. One group received ultramicronized palmitoylethanolamide (600 mg twice daily) during the pre- and postsurgery periods, while the other group did not receive any treatment except surgical therapy. The primary outcome measure was sleep quality assessment by the Pittsburgh Sleep Quality Index, with secondary outcome as painful symptomatology intensity evaluated by the Numeric Rating Scale. At the end of the pre-surgery period (T1) there was a highly significant improvement (p<0.0001) in overall sleep quality with an increase of continuous sleep time and a reduction of sleep latency and disturbances as well as a significant mitigation (p<0.0001) of painful symptoms in favor of the treated group. Disturbed sleep patterns are very common in patients suffering from neuropathic pain due to carpal tunnel syndrome. Our results, albeit preliminary, suggest that ultramicronized palmitoylethanolamide administration favors a clear improvement of sleep quality, confirming a correlation between sleep disorders and pain intensity.

Ultramicronized palmitoylethanolamide rescues learning and memory impairments in a triple transgenic mouse model of Alzheimer\u2019s disease by exerting anti-inflammatory and neuroprotective effects

In an aging society, Alzheimer’s disease (AD) exerts an increasingly serious health and economic burden. Current treatments provide inadequate symptomatic relief as several distinct pathological processes are thought to underlie the decline of cognitive and neural function seen in AD. This suggests that the efficacy of treatment requires a multitargeted approach. In this context, palmitoylethanolamide (PEA) provides a novel potential adjunct therapy that can be incorporated into a multitargeted treatment strategy. We used young (6-month-old) and adult (12-month-old) 3×Tg-AD mice that received ultramicronized PEA (um-PEA) for 3 months via a subcutaneous delivery system. Mice were tested with a range of cognitive and noncognitive tasks, scanned with magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS), and neurochemical release was assessed by microdialysis. Potential neuropathological mechanisms were assessed postmortem by western blot, reverse transcription–polymerase chain reaction (RT-PCR), and immunofluorescence. Our data demonstrate that um-PEA improves learning and memory, and ameliorates both the depressive and anhedonia-like phenotype of 3×Tg-AD mice. Moreover, it reduces Aβ formation, the phosphorylation of tau proteins, and promotes neuronal survival in the CA1 subregion of the hippocampus. Finally, um-PEA normalizes astrocytic function, rebalances glutamatergic transmission, and restrains neuroinflammation. The efficacy of um-PEA is particularly potent in younger mice, suggesting its potential as an early treatment. These data demonstrate that um-PEA is a novel and effective promising treatment for AD with the potential to be integrated into a multitargeted treatment strategy in combination with other drugs. Um-PEA is already registered for human use. This, in combination with our data, suggests the potential to rapidly proceed to clinical use.

N-of-1 Randomized Trials of Ultra-Micronized Palmitoylethanolamide in Older Patients with Chronic Pain.

Ultra-micronized palmitoylethanolamide (um-PEA) represents an attractive option for chronic pain control in complex older patients at higher risk of adverse effects with traditional analgesics. The aim of this study was to determine the effectiveness of um-PEA versus placebo on chronic pain intensity and function in individual geriatric patients. We performed randomized, blinded N-of-1 trials with two 3-week um-PEA versus placebo comparisons, separated by 2-week washout periods. The study included outpatients aged≥65years with chronic, non-cancer, non-ischemic pain in the back, joints, or limbs. Patients were randomized to Um-PEA 600mg or placebo twice daily. Pain intensity was measured using an 11-point visual numeric scale. Functional impairment was measured using a Back Pain Functional Scale. Impact of each N-of-1 trial was measured on the clinician's intention to treat and confidence. Ten of 11 eligible patients consented over 7months [all female, mean age 83.2years (SD 4.6)]. Three patients interrupted the trial: one had diarrhea (under placebo), one for low adherence, and one for intercurrent pneumonia. A small statistically significant effect in favor of um-PEA was seen at the mixed method analyses in two patients (effect size equal to 8% of the baseline pain). A statistically significant impact on function was found in one patient. After the trial, um-PEA was prescribed to four patients; in two patients the clinician changed their pre-trial intention to treat; the clinician confidence in the treatment plan either increased (5) or remained the same (2). Our experience confirmed that N-of-1 trials may help make personalized evidence-based decisions in complex older patients, with special feasibility considerations. CLINICALTRIALS.GOV: NCT02699281.

The beneficial use of ultramicronized palmitoylethanolamide as add-on therapy to Tapentadol in the treatment of low back pain: a pilot study comparing prospective and retrospective observational arms

BackgroundThis pilot study was designed to compare the efficacy of ultramicronized palmitoylethanolamide (um-PEA) as add-on therapy to tapentadol (TP) with TP therapy only in patients suffering from chronic low back pain (LBP).MethodsThis pilot observational study consists in two arms: the prospective arm and the retrospective one. In the prospective arm patients consecutively selected received um-PEA as add-on therapy to TP for 6 months; in the retrospective arm patients were treated with TP only for 6 months. Pain intensity and neuropathic component were evaluated at baseline, during and after 6 months. The degree of disability and TP dosage assumption were evaluated at baseline and after 6 months.ResultsStatistical analysis performed with generalized linear mixed model on 55 patients (30 in the prospective group and 25 in the retrospective group) demonstrated that um-PEA as add-on treatment to TP in patients with chronic LBP, in comparison to TP alone, led to a significantly higher reduction in pain intensity, in the neuropathic component, the degree of disability and TP dosage assumption. No serious side effects were observed.ConclusionOverall, the present findings suggest that um-PEA may be an innovative therapeutic intervention as add-on therapy to TP for the management of chronic LBP with a neuropathic component, as well as to improve patient quality of life. Additionally, this combination treatment allowed a reduction in TP dose over time and did not show any serious side effects.

Nonsurgical lumbar radiculopathies treated with ultramicronized palmitoylethanolamide (umPEA): A series of 100 cases

In this clinical/observational study we have reported the administration of Palmitoylethanolamide (PEA) in patients suffering from radicular lumbar spinal pathology, who had no indication for surgical treatment. We analyzed a series of 100 cases retrospectively, all undergoing clinical and diagnostic investigations, which had shown the presence of abnormalities of the vertebral body and intervertebral discs, mainly degenerative, such as spondyloarthrosis, spondylo-discarthrosis, disc protrusion, excluding disc herniation, which fell within surgical cases. We then administered ultramicronized PEA (umPEA) to these patients, in combination with paracetamol and codeine, obtaining interesting results regarding the improvement of pain symptoms of the spine pathology, in the various checks carried out, through the administration of pain assessment scales. We also noted its safety due to the total absence of adverse effects. The obtained results encourage the use of PEA in degenerative spine pathologies.

Palmitoylethanolamide in the Treatment of Failed Back Surgery Syndrome.

Introduction This observational study was designed to evaluate the efficacy of ultramicronized palmitoylethanolamide (um-PEA) (Normast®) administration, as add-on therapy for chronic pain, in the management of pain-resistant patients affected by failed back surgery syndrome. Methods A total of 35 patients were treated with tapentadol (TPD) and pregabalin (PGB). One month after the start of standard treatment, um-PEA was added for the next two months. Pain was evaluated by the Visual Analogue Scale (VAS) at the time of enrollment (T0) and after one (T1), two (T2), and three (T3) months. Results After the first month with TDP + PGB treatment only, VAS score decreased significantly from 5.7 ± 0.12 at the time of enrollment (T0) to 4.3 ± 0.11 (T1) (p < 0.0001); however, it failed to provide significant subjective improvement in pain symptoms. Addition of um-PEA led to a further and significant decrease in pain intensity, reaching VAS scores of 2.7 ± 0.09 (T2) and 1.7 ± 0.11 (T3, end of treatment) (p < 0.0001) without showing any side effects. Conclusions This observational study provides evidence, albeit preliminary, for the efficacy and safety of um-PEA (Normast) as part of a multimodal therapeutic regimen in the treatment of pain-resistant patients suffering from failed back surgery syndrome.

Protective Effects of Ultramicronized Palmitoylethanolamide (PEA-um) in Myocardial Ischaemia and Reperfusion Injury in VIVO.

Myocardial infarction is the leading cause of death, occurs after prolonged ischemia of the coronary arteries. Restore blood flow is the first intervention help against heart attack. However, reperfusion of the arteries leads to ischemia/reperfusion injury (I/R). The fatty acid amide palmitoylethanolamide (PEA) is an endogenous compound widely present in living organisms, with analgesic and anti-inflammatory properties. The present study evaluated the effect of ultramicronized palmitoylethanolamide (PEA-um) treatment on the inflammatory process associated with myocardial I/R. Myocardial ischemia reperfusion injury was induced by occlusion of the left anterior descending coronary artery for 30 min followed by 2 h of reperfusion. PEA-um, was administered (10 mg/kg) 15 min after ischemia and 1 h after reperfusion. In this study, we demonstrated that PEA-um treatment reduces myocardial tissue injury, neutrophil infiltration, adhesion molecules (ICAM-1, P-selectin) expression, proinflammatory cytokines (TNF-α, IL-1β) production, nitrotyrosine and PAR formation, nuclear factor kB expression, and apoptosis (Fas-L, Bcl-2) activation. In addition to study whether the protective effect of PEA-um on myocardial ischemia reperfusion injury is also related to the activation of PPAR-α, in a separate set of experiments it has been performed myocardial I/R in PPARα mice. Genetic ablation of peroxisome proliferator activated receptor (PPAR)-α in PPAR-αKO mice exacerbated Myocardial ischemia reperfusion injury when compared with PPAR-αWT mice. PEA-um induced cardioprotection in PPAR-α wild-type mice, but the same effect cannot be observed in PPAR-αKO mice. Our results have clearly shown a modulation of the inflammatory process, associated with myocardial ischemia reperfusion injury, following administration of PEA-um.

Efficacy of ultra-micronized palmitoylethanolamide (um-PEA) in geriatric patients with chronic pain: study protocol for a series of N-of-1 randomized trials.

BackgroundChronic pain in older people is highly prevalent, often underestimated, and associated with adverse outcomes. Most available analgesic drugs are often either ineffective or not tolerated, with many side effects. Palmitoylethanolamide (PEA) is an endogenous widely distributed N-acylethanolamina involved in neuroinflammation and pain-generating processes. Formulations containing ultra-micronized palmitoylethanolamide (um-PEA) are available but their effectiveness on chronic pain in highly heterogeneous geriatric patients is not clear and probably not generalizable. We planned to adopt the N-of-1 trial approach to test the effectiveness of um-PEA objectively at the individual level in our older outpatients.Methods/DesignPersons 65 years or older referring to the Geriatric Unit of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan complaining of noncancer chronic pain of any origin will be eligible. Each trial will be a placebo-controlled randomized crossover trial including two um-PEA (600 mg twice a day) and placebo treatment pairs. The um-PEA or placebo 3-week periods will be separated by 2-week washout intervals to overcome possible carryover effects. Pain intensity, need of on-demand analgesic medications, and impact on daily activities will be evaluated. Cognitively impaired patients will be eligible as long as an expression of pain can be recognized and its frequency assessed by a caregiver. Trial results will be discussed with the patient or caregiver and the treating physician to decide whether to continue the treatment. The impact of the N-of-1 approach on the physician’s management plan and confidence will be assessed. We will secondarily meta-analyze the performed N-of-1 trials to obtain an estimate of the average effect of um-PEA compared with placebo using a frequentist and Bayesian approach.DiscussionWhile pursuing an ultimate clinical objective, i.e. to empirically and objectively decide the best treatment choice for an individual older patient with chronic pain, these series of geriatric N-of-1 trials on PEA will bring the principles of evidence-based medicine into the care of patients not usually represented in conventional randomized controlled trials, and realize a patient-centered outcome approach necessary to improve appropriate prescribing in elderly patients with multimorbidity and polypharmacy.Trial registrationClinicalTrials.gov NCT02699281. Registered on 3 March 2016.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1496-9) contains supplementary material, which is available to authorized users.

Ultramicronized palmitoylethanolamide in spinal cord injury neuropathic pain: a randomized, double-blind, placebo-controlled trial.

Neuropathic pain and spasticity after spinal cord injury (SCI) represent significant problems. Palmitoylethanolamide (PEA), a fatty acid amide that is produced in many cells in the body, is thought to potentiate the action of endocannabinoids and to reduce pain and inflammation. This randomized, double-blind, placebo-controlled, parallel multicenter study was performed to investigate the effect of ultramicronized PEA (PEA-um) as add-on therapy on neuropathic pain in individuals with SCI. A pain diary was completed and questionnaires were completed before and after the 12-week treatment with either placebo or PEA-um. The primary outcome measure was the change in mean neuropathic pain intensity from the 1-week baseline period to the last week of treatment measured on a numeric rating scale ranging from 0 to 10. The primary efficacy analysis was the intention to treat (baseline observation carried forward). Secondary outcomes included a per protocol analysis and effects on spasticity, evoked pain, sleep problems, anxiety, depression, and global impression of change. We randomized 73 individuals with neuropathic pain due to SCI, of which 5 had a major protocol violation, and thus 68 were included in the primary analysis. There was no difference in mean pain intensity between PEA-um and placebo treatment (P = 0.46, mean reductions in pain scores 0.4 (-0.1 to 0.9) vs 0.7 (0.2-1.2); difference of means 0.3 (-0.4 to 0.9)). There was also no effect of PEA-um as add-on therapy on spasticity, insomnia, or psychological functioning. PEA was not associated with more adverse effects than placebo.

Palmitoylethanolamide, a Special Food for Medical Purposes, in the Treatment of Chronic Pain: A Pooled Data Meta-analysis

A growing body of evidence suggests that neuroinflammation, which is characterized by infiltration of immune cells, activation of mast cells and glial cells, and production of inflammatory mediators in the peripheral and central nervous systems, has an important role in the induction and maintenance of chronic pain. These findings support the notion that new therapeutic opportunities for chronic pain might be based on anti-inflammatory and pro-resolving mediators that act on immune cells, in particular mast cells and glia, to mitigate or abolish neuroinflammation. Among anti-inflammatory and pro-resolving lipid mediators, palmitoylethanolamide (PEA) has been reported to down-modulate mast cell activation and to control glial cell behaviors. The aim of this study was to perform a pooled meta-analysis to evaluate the efficacy and safety of micronized and ultra-micronized palmitoylethanolamide (PEA) on pain intensity in patients suffering from chronic and/or neuropathic pain. Pooled data analysis consisting of double-blind, controlled, and open-label clinical trials. Double-blind, controlled, and open-label clinical trials were selected consulting the PubMed, Google Scholar, and Cochrane databases, and proceedings of neuroscience meetings. The terms chronic pain, neuropathic pain, and micronized and ultra-micronized PEA were used for the search. Selection criteria included availability of raw data and comparability between tools used to diagnose and assess pain intensity. Raw data obtained by authors were pooled in one database and analyzed by the Generalized Linear Mixed Model. The changes in pain over time, measured by comparable tools, were also assessed by linear regression post-hoc analysis and the Kaplan-Meier estimate. Twelve studies were included in the pooled meta-analysis, 3 of which were double-blind trials comparing active comparators vs placebo, 2 were open-label trials vs standard therapies, and 7 were open-label trials without comparators. Results showed that PEA elicits a progressive reduction of pain intensity significantly higher than control. The magnitude of reduction equals 1.04 points every 2 weeks with a 35% response variance explained by the linear model. In contrast, in the control group pain, reduction intensity equals 0.20 points every 2 weeks with only 1% of the total variance explained by the regression. The Kaplan-Meier estimator showed a pain score = 3 in 81% of PEA treated patients compared to only 40.9% in control patients by day 60 of treatment. PEA effects were independent of patient age or gender, and not related to the type of chronic pain. Noteworthy, serious adverse events related to PEA were not registered and/or reported in any of the studies. These results confirm that PEA might represent an exciting, new therapeutic strategy to manage chronic and neuropathic pain associated with neuroinflammation.

Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing-Remitting Multiple Sclerosis.

Palmitoylethanolamide (PEA) is an endogenous lipid mediator known to reduce pain and inflammation. However, only limited clinical studies have evaluated the effects of PEA in neuroinflammatory and neurodegenerative diseases. Multiple sclerosis (MS) is a chronic autoimmune and inflammatory disease of the central nervous system. Although subcutaneous administration of interferon (IFN)-β1a is approved as first-line therapy for the treatment of relapsing-remitting MS (RR-MS), its commonly reported adverse events (AEs) such as pain, myalgia, and erythema at the injection site, deeply affect the quality of life (QoL) of patients with MS. In this randomized, double-blind, placebo-controlled study, we tested the effect of ultramicronized PEA (um-PEA) added to IFN-β1a in the treatment of clinically defined RR-MS. The primary objectives were to estimate whether, with um-PEA treatment, patients with MS perceived an improvement in pain and a decrease of the erythema width at the IFN-β1a injection site in addition to an improvement in their QoL. The secondary objectives were to evaluate the effects of um-PEA on circulating interferon-γ, tumor necrosis factor-α, and interleukin-17 serum levels, N-acylethanolamine plasma levels, Expanded Disability Status Scale (EDSS) progression, and safety and tolerability after 1 year of treatment. Patients with MS receiving um-PEA perceived an improvement in pain sensation without a reduction of the erythema at the injection site. A significant improvement in QoL was observed. No significant difference was reported in EDSS score, and um-PEA was well tolerated. We found a significant increase of palmitoylethanolamide, anandamide and oleoylethanolamide plasma levels, and a significant reduction of interferon-γ, tumor necrosis factor-α, and interleukin-17 serum profile compared with the placebo group. Our results suggest that um-PEA may be considered as an appropriate add-on therapy for the treatment of IFN-β1a-related adverse effects in RR-MS.

Ultramicronized palmitoylethanolamide reduces viscerovisceral hyperalgesia in a rat model of endometriosis plus ureteral calculosis: role of mast cells.

The effects of ultramicronized palmitoylethanolamide were evaluated on pain behaviours and markers of mast cell (MC) activity in a rat model of endometriosis plus ureteral calculosis (ENDO+STONE)-induced viscerovisceral hyperalgesia (VVH). Female Sprague-Dawley rats that underwent surgical induction of endometriosis were randomly assigned to receive active (ultramicronized palmitoylethanolamide 10 mg·kg(-1)·d(-1), orally) or placebo treatment for 25 days. At day 21, they underwent ureteral stone formation and were video-recorded till day 25 to evaluate ureteral and uterine pain behaviours. At autopsy (day 25), ureteral condition and number and diameter of endometrial cysts were evaluated. The following were then measured: number and percentage of degranulating MCs, number of vessels, chymase, nerve growth factor (NGF), vascular endothelial growth factor (VEGF), and Flk-1 (VEGF receptor) in cysts, and NGF in dorsal root ganglia (DRG). Ultramicronized palmitoylethanolamide-treated vs placebo-treated rats showed significantly lower number, duration and complexity of ureteral crises, shorter duration of uterine pain, and smaller cyst diameter (0.0001 < P < 0.004); a significantly higher percentage of expelled stones (P < 0.0001); significantly lower MC number (P < 0.01), vessel number (P < 0.01), chymase (P < 0.05), NGF (P < 0.05), VEGF (P < 0.01), and Flk-1 (P < 0.01) expression in cysts and NGF expression in DRG (P < 0.01). In all animals, the global duration of ureteral crises correlated linearly and directly with cyst diameter, MC number and chymase in cysts, and NGF in cysts and DRG (0.02 < P < 0.0002). Ultramicronized palmitoylethanolamide significantly reduces VVH from ENDO+STONE, probably by modulating MC expression/activity in cysts, thus reducing central sensitization due to noxious signals from endometriotic lesions. The results suggest potential utility of the compound for VVH in clinics.