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

Abstract

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.

Keywords: Anandamide; FAAH; N-acylethanolamines; NAAA; Neuroinflammation; Oleoylethanolamide; Pain.

Fig. 1

Ultramicronized palmitoylethanolamide (PEA) treatment reduces pain perception but not erythema at interferon (IFN)-β1a injection site. (A) Pain perception at the injection site of IFN-β1a was assessed using the visual analog scale at month 1, and at 6 and 12 months after starting PEA treatment (600 mg/day, p.o.). A significant effect of the treatment was found both at 6 and 12 months. Data are expressed as mean ± SEM; *p < 0.05 versus the placebo group. (B) The diameter of the erythema consequent to IFN-β1a injections was measured at 1 month, and after 6 and 12 months of PEA treatment. PEA had no effect on the erythema width

Fig. 2

Ultramicronized palmitoylethanolamide (PEA) treatment reduces proinflammatory cytokine serum levels. (A) Interferon (IFN)-γ, (B) interleukin (IL)-17, and (C) tumor necrosis factor (TNF)-α serum levels were measured by enzyme-linked immunosorbent assay at 1 month, and after 3, 6, and 12 months of treatment with either placebo or um-PEA (600 mg/day, p.o.). Similar cytokine levels between groups were found at 1 month, whereas at the subsequent time points PEA treatment reduced the cytokine levels compared with the placebo group. Data are expressed as mean ± SEM; ***p < 0.001, **p < 0.01, *p < 0.05 versus the placebo group

Fig. 3

Ultramicronized palmitoylethanolamide (PEA) treatment increases plasma N-acylethanolamine levels. (A) PEA, (B) anandamide (AEA), and (C) oleoylethanolamide (OEA) plasma levels were measured by ultra performance liquid chromatography–mass spectrometry at 1 month, and after 3, 6, and 12 months of treatment with either placebo or um-PEA (600 mg/day, p.o.). At treatment onset, similar levels were found between the 2 treatment groups. After 3 months of treatment PEA, AEA, and OEA levels were increased and remained higher for the duration of the study. Data are expressed as mean ± SEM; ***p < 0.001, **p < 0.01 versus the placebo group

Fig. 4

mRNA expression of the hydrolytic enzymes of N-acylethanolamines, fatty acid amide hydrolase (FAAH) and N-acylethanolamine- hydrolyzing acid amidase (NAAA) in peripheral blood mononuclear cells (PBMCs). FAAH and NAAA mRNA expression in PBMCs was measured by quantitative reverse transcription using RPL19 as housekeeping gene. (A) Expression of FAAH and NAAA at 1 month of treatment showing a higher expression of NAAA than FAAH, as evidenced by the smaller ΔCt numbers (the smaller the ΔCt number the higher the expression). (B) FAAH and (C) NAAA mRNA expression during the study. Data are expressed as mean ± SEM versus the placebo group. *p < 0.05 versus the placebo group

Fig. 5

Cluster analysis of patients after 12 months of treatment. Hierarchical cluster analysis of patients based on their circulating tumor necrosis factor (TNF)-α, interleukin (IL)-17, and interferon (IFN)-γ levels measured at 12 months of treatment. The patients that received placebo are represented in blue and those treated with um-PEA are represented in red