Effect of a new formulation of micronized and ultramicronized N-palmitoylethanolamine in a tibia fracture mouse model of complex regional pain syndrome

Abstract

Complex regional pain syndrome type 1 (CRPS-I) is a disabling and frequently chronic condition. It involves the extremities and is a frequent consequence of distal tibia and radius fractures. The inflamed appearance of the affected CRPS-I limb suggests that local production of inflammatory mediators may be implicated in the ensuing etiology. A rodent tibia fracture model, characterized by inflammation, chronic unilateral hindlimb warmth, edema, protein extravasation, allodynia and hyperalgesia resembles the clinical features of patients with acute CRPS-I. N-palmitoylethanolamine (PEA), a member of the family of naturally-occurring N-acylethanolamines, is well-known for its ability to modulate inflammatory processes and regulate pain sensitivity. However, the large particle size and lipidic nature of PEA may limit its bioavailability and solubility when given orally. Micronized formulations are frequently used to enhance the dissolution rate of drug and reduce its variability of absorption when orally administered. The aim of this study was to assess the effects of a formulation of micronized and ultramicronized PEA (PEA-MPS), given orally in a mouse model of CRPS-I. CD-1 male mice were subjected to distal tibia fracture and divided into two groups: control and treated with PEA-MPS (PEA micronized 300 mg/kg and ultramicronized 600 mg/kg). Sensibility to pain was monitored in all mice throughout the course of the experiment. Twenty-eight days after tibia fracture induction animals were sacrificed and biochemical parameters evaluated. The PEA-MPS-treated group showed an improved healing process, fracture recovery and fibrosis score. PEA-MPS administration decreased mast cell density, nerve growth factor, matrix metalloproteinase 9 and cytokine expression. This treatment also reduced (poly-ADP)ribose polymerase activation, peroxynitrite formation and apoptosis. Our results suggest that PEA-MPS may be a new therapeutic strategy in the treatment of CRPS-I.

Management of Traumatic Brain Injury: From Present to Future

“…PEA has no unfavorable effects at pharmacological doses [97]. In addition, several experimental works showed the beneficial effects of new PEA formulations (micronized or ultramicronized) in carrageenan-induced inflammation [98] on cognitive decline associated to neuropathic pain [99] in an Alzheimer disease model [100], tibia fracture mouse model [101], and diabetic neuropathy [102]. Recent observational clinical studies reported the beneficial use of ultramicronized PEA as an add-on therapy in patients suffering from low back pain [103] as well as in patients suffering from fibromyalgia syndrome (FMS) [104].…”

An Update of Palmitoylethanolamide and Luteolin Effects in Preclinical and Clinical Studies of Neuroinflammatory Events

“…Normalize the functional post-inflammatory accelerated intestinal transit [192] Colitis Mice Improve symptoms of colitis [191] Dermatitis Dogs Reduce pruritus and skin lesions [194] Contrast-agent-induced nephropathy Rats Prevent nephropathy in and alteration of biochemical parameters [195] Idiopathic pulmonary fibrosis Mice Reduces lung inflammation [196] Tibia fracture model Mice Decrease mast cell density, nerve growth factor, matrix metalloproteinase 9, and cytokines expression [197] Alzheimer's disease Mice Normalize astrocytic function, rebalance glutamatergic transmission, and restrain neuroinflammation [198] Joint pain Rats Reduce igeminal nerve sensitization [199] In neurological diseases, increases in PEA levels were observed in the patients liquor with schizophrenia, chronic migraine, and multiple sclerosis [200][201][202]. In multiple sclerosis, the levels of PEA also increased in plasma [203].…”

“…In the same conditions, therapy with PEA-m allows for a considerable reduction of the use of nonsteroidal anti-inflammatory drugs NSAIDs, suggesting the possibility of simultaneous use in order to reduce the use of NSAIDs, which if taken for long periods, can induce significant side effects [210]. The results obtained in patients with low back pain have also been confirmed on a large number of patients with different chronic pain pathological conditions, such as radiculopathy, osteoarthritis, joint pain, tibia fracture, spinal surgical failure, post herpetic neuropathy, diabetic neuropathy, and oncological pain [197,199,209,212,213] (Table 3). Peripheral diabetic neuropathy Reduce pain symptoms characteristic of diabetic neuropathy [213] Carpal tunnel syndrome Improve sleep quality, confirming a correlation between sleep disorders and pain intensity [208] Moreover, Evangelista et al reported that in patients affected by carpal tunnel syndrome, the oral administration of ultramicronized PEA improved sleep quality, verifying a correlation between sleep disorders and pain intensity [208].…”

“…The data, obtained with ultramicronized PEA, showed that it was also able to decrease all the inflammatory pathways that were activated during pulmonary fibrosis, as well as dermatitis, myocardial ischemia, or contrast-agent-induced nephropathy [194][195][196][197]. Furthermore, Scuderi et al showed that PEA-um was a novel and effective promising treatment for AD with the potential to be integrated into a multitargeted treatment strategy in combination with other drugs [198].…”

Correction: Effect of a new formulation of micronized and ultramicronized N-palmitoylethanolamine in a tibia fracture mouse model of complex regional pain syndrome

“…The authors would like to correct the following mistakes which were inadvertently included in the publication [ 1 ].…”