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Review
, 82 (4), 932-42

Palmitoylethanolamide for the Treatment of Pain: Pharmacokinetics, Safety and Efficacy

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Review

Palmitoylethanolamide for the Treatment of Pain: Pharmacokinetics, Safety and Efficacy

Linda Gabrielsson et al. Br J Clin Pharmacol.

Abstract

Palmitoylethanolamide (PEA) has been suggested to have useful analgesic properties and to be devoid of unwanted effects. Here, we have examined critically this contention, and discussed available data concerning the pharmacokinetics of PEA and its formulation. Sixteen clinical trials, six case reports/pilot studies and a meta-analysis of PEA as an analgesic have been published in the literature. For treatment times up to 49 days, the current clinical data argue against serious adverse drug reactions (ADRs) at an incidence of 1/200 or greater. For treatment lasting more than 60 days, the number of patients is insufficient to rule out a frequency of ADRs of less than 1/100. The six published randomized clinical trials are of variable quality. Presentation of data without information on data spread and nonreporting of data at times other than the final measurement were among issues that were identified. Further, there are no head-to-head clinical comparisons of unmicronized vs. micronized formulations of PEA, and so evidence for superiority of one formulation over the other is currently lacking. Nevertheless, the available clinical data support the contention that PEA has analgesic actions and motivate further study of this compound, particularly with respect to head-to-head comparisons of unmicronized vs. micronized formulations of PEA and comparisons with currently recommended treatments.

Keywords: Palmitoylethanolamide; adverse drug reactions; clinical trials; inflammation; pain; pharmacokinetics.

Figures

Figure 1
Figure 1
Structure of PEA. The compound is sometimes referred to as NAE 16:0, where 16 and 0 refer to the number of carbon atoms and double bonds, respectively, in the acyl side chain. The related compounds anandamide and oleoylethanolamide are NAE 20:4 and NAE 18:1, respectively, using this nomenclature
Figure 2
Figure 2
Plasma concentrations of PEA following oral dosing of 100 mg kg−1 to male Wistar rats (body weight 150–250 g). The data are taken from Table 2 of 28 and are shown as means ± SEM, n = 9. The time points from 0.25–8 h were fitted to a one‐phase decay model using the least squares method (GraphPad Prism 6.0 h for the Macintosh). The model returns the extrapolated plasma concentration at t = 0 (Cp(o), 913 ± 16 nM), the value to which the curve asymptotes (44 ± 1 nM, i.e. the data ≥2 h), the rate constant (3.4 ± 0.06 h−1) and hence the t 1/2 value (0.21 h). Needless to say, the large data spread at the first time point renders the values approximate
Figure 3
Figure 3
Number of patients treated with PEA in the studies summarized in Table 1 as a function of the length of treatment. The dotted lines represent the number of patients needed for a 95% likelihood of observing a single ADR at the frequency of occurrence shown 39

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