Extended Treatment with Micron-Size Oral Palmitoylethanolamide (PEA) in Chronic Pain: A Systematic Review and Meta-Analysis

Abstract

Palmitoylethanolamide (PEA) emerged over the years as a promising approach in the management of chronic pain. Despite the fact that the efficacy of micron-size PEA formulations appears to be time-dependent, the optimal timing has not yet been elucidated. This systematic review and meta-analysis aim to estimate the possible advantage of an extended treatment in the relief of chronic pain. The literature search was conducted consulting scientific databases, to identify clinical trials in which micron-size PEA was administered for at least 60 days, and pain assessed by the Visual Analogue Scale (VAS) or Numeric Rating Scale (NRS). Nine studies matched the required criteria, for a total of 742 patients involved. The meta-analysis showed a statistically and clinically significant pain intensity reduction after 60 days of micron-size PEA supplementation, compared to 30 days (1.36 points, p < 0.01). The secondary analysis revealed a weighted NRS/VAS score decrease of 2.08 points within the first month of treatment. These two obtained scores corresponded to a 35.1% pain intensity reduction within the first month, followed by a further 35.4% during the second month. Overall, these results confirm the clinically relevant and time-depended pain-relieving effect of micron-size PEA and therefore the advantage of an extended treatment, especially in patient with incomplete pain management.

Keywords: (ultra-)micronization; chronic pain; chronic pelvic pain; micron-size PEA; neuroinflammation; palmitoylethanolamide.

Figure 1

Flowchart of the search strategy and studies selection according to PRISMA [62].

Figure 2

Robvis traffic light plot for the risk of bias of the studies included in the meta-analysis [40,42,49,50,51,52,53,54,55].

Figure 3

Robvis summary plot for the risk of bias of the studies included in the meta-analysis.

Figure 4

Forest plot of the effect of a 60-day supplementation with micron-size PEA on chronic pain intensity reduction. Positive mean values (>0) represent the additional effect after the first 30 days of supplementation. Squares display the estimate impact, the size of each square reflects the weight assigned to each study. Horizontal lines represent the 95% CI for each estimate effect. The diamond width, which indicates the total 95% CI, represents the overall effect of intervention estimate using a random statistical model. I² and τ² statistics measure the heterogeneity [40,42,49,50,51,52,53,54,55].

Figure 5

NRS/VAS score improvement during the first and the second month of micron-size PEA treatment and the corresponding percentage of pain intensity reduction after each time point compared to the previous one.