Efficacy of Palmitoylethanolamide for Pain: A Meta-Analysis.

BACKGROUND: Palmitoylethanolamide (PEA) is a cannabimimetic compound that has been investigated as an analgesic agent in animal models and clinical trials. OBJECTIVES: We conducted a meta-analysis to examine the efficacy of PEA for treating pain in randomized, controlled trials. STUDY DESIGN: Systematic review and meta-analysis. SETTING: This meta-analysis examined all randomized, controlled trials involving the effect of PEA on pain score. METHODS: We searched PubMed and Embase for randomized, active or placebo-controlled trials of PEA for the treatment of acute or chronic pain. Our primary outcome was the weighted mean difference in visual analog pain scales of PEA treatment compared to inactive controls. RESULTS: We identified 10 studies including data from 786 patients who received PEA and 512 controls for inclusion in our systematic review. Eight trials included an inactive control group and were included in the meta-analysis. PEA was associated with significantly greater pain reduction compared to inactive control conditions (WMD = 2.03, 95% CI: 1.19 - 2.87, z = 4.75, P < 0.001). Use of placebo control, presence of blinding, allowance for concomitant treatments, and duration or dose of PEA treatment did not affect the measured efficacy of PEA. All-cause dropout was non-significantly reduced in the PEA group compared to inactive control conditions (RR = 0.36, 95% CI: 0.10 - 1.26, z = -1.60, P = 0.11). LIMITATIONS: This meta-analysis relied on a relatively small number of trials across a variety of conditions causing pain with differing trial designs. Overall quality of the underlying studies and assessment of side effects were often poor. CONCLUSIONS: PEA may be a useful treatment for pain and is generally well tolerated in research populations. Further, well-designed, randomized, placebo-controlled trials are needed to provide reliable estimates of its efficacy and to identify less serious adverse events associated with this compound. KEY WORDS: PEA, palmidrol, palmitoylethanolamide, efficacy, pain, pain management, meta-analysis.

Remodeling of the actin cytoskeleton during mammalian sperm capacitation and acrosome reaction.

The sperm acrosome reaction and penetration of the egg follow zona pellucida binding only if the sperm has previously undergone the poorly understood maturation process known as capacitation. We demonstrate here that in vitro capacitation of bull, ram, mouse, and human sperm was accompanied by a time-dependent increase in actin polymerization. Induction of the acrosome reaction in capacitated cells initiated fast F-actin breakdown. Incubation of sperm in media lacking BSA or methyl-beta-cyclodextrin, Ca(2+), or NaHCO(3), components that are all required for capacitation, prevented actin polymerization as well as capacitation, as assessed by the ability of the cells to undergo the acrosome reaction. Inhibition of F-actin formation by cytochalasin D blocked sperm capacitation and reduced the in vitro fertilization rate of metaphase II-arrested mouse eggs. It has been suggested that protein tyrosine phosphorylation may represent an important regulatory pathway that is associated with sperm capacitation. We show here that factors known to stimulate sperm protein tyrosine phosphorylation (i.e., NaHCO(3), cAMP, epidermal growth factor, H(2)O(2), and sodium vanadate) were able to enhance actin polymerization, whereas inhibition of tyrosine kinases prevented F-actin formation. These data suggest that actin polymerization may represent an important regulatory pathway in with sperm capacitation, whereas F-actin breakdown occurs before the acrosome reaction.