Effect of a New Formulation of Micronized and Ultramicronized N-palmitoylethanolamine in a Tibia Fracture Mouse Model of Complex Regional Pain Syndrome

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.