Chronic pain is a major source of morbidity for which there are limited effective treatments. Palmitoylethanolamide (PEA), a naturally occurring fatty acid amide, has demonstrated utility in the treatment of neuropathic and inflammatory pain. Emerging reports have supported a possible role for its use in the treatment of chronic pain, although this remains controversial. We undertook a systematic review and meta-analysis to examine the efficacy of PEA as an analgesic agent for chronic pain. A systematic literature search was performed, using the databases MEDLINE and Web of Science, to identify double-blind randomized controlled trials comparing PEA to placebo or active comparators in the treatment of chronic pain. All articles were independently screened by two reviewers. The primary outcome was pain intensity scores, for which a meta-analysis was undertaken using a random effects statistical model. Secondary outcomes including quality of life, functional status, and side effects are represented in a narrative synthesis. Our literature search identified 253 unique articles, of which 11 were ultimately included in the narrative synthesis and meta-analysis. Collectively, these articles described a combined sample size of 774 patients. PEA was found to reduce pain scores relative to comparators in a pooled estimate, with a standard mean difference of 1.68 (95% CI 1.05 to 2.31, p = 0.00001). Several studies reported additional benefits of PEA for quality of life and functional status, and no major side effects were attributed to PEA in any study. The results of this systematic review and meta-analysis suggest that PEA is an effective and well-tolerated treatment for chronic pain. Further study is warranted to determine the optimal dosing and administration parameters of PEA for analgesic effects in the context of chronic pain.

Summary: Acute postoperative pain remains a critical treatment priority and has prompted a search for technologies and techniques to assist with intra‐operative analgesic monitoring and management. Anaesthetists traditionally rely on clinical judgement to guide intra‐operative analgesia, but several emerging technologies such as the nociception level index herald the possibility of routine intra‐operative analgesia monitoring. However, the impact of devices like nociception level index on postoperative outcomes has not been proven. We undertook a systematic review and meta‐analysis of articles which compared nociception level index‐guided analgesia to standard care. The primary outcomes were pain intensity and opioid consumption during the first 60–120 min after surgery. Secondary outcomes were the incidence of postoperative nausea and vomiting and duration of stay in the post‐anaesthesia care unit. Ten studies, collectively including 662 patients and published between 2019 and 2023, met inclusion criteria for both the qualitative systematic review and quantitative meta‐analysis. Risk of methodological bias was generally low or unclear, and six studies reported a significant conflict of interest relevant to their findings. Our meta‐analysis was performed using a random‐effects model. It found statistically significant benefits of nociception level index‐guided analgesia for early postoperative pain (mean (95%CI) difference ‐0.46 (‐0.88 to ‐0.03) on an 11‐point scale, p = 0.03), and opioid requirement (mean (95%CI) difference ‐1.04 (‐1.94 to ‐0.15) mg intravenous morphine equivalent, p = 0.02). Our meta‐analysis of the current literature finds that nociception level index‐guided analgesia statistically significantly reduces reported postoperative pain intensity and opioid consumption but fails to show clinically relevant outcomes. We found no evidence that nociception level index‐guided analgesia affected postoperative nausea and vomiting nor duration of stay in the post‐anaesthesia care unit.

Palmitoylethanolamide (PEA) is marketed as a “dietary food for special medical purposes”. Its broad-spectrum analgesic, anti-inflammatory, and neuroprotective effects make PEA an interesting substance in pain management. However, the underlying analgetic mechanisms have not yet been investigated in humans. The aim of our study is to provide a deeper understanding of the involved mechanisms, which is essential for differentiating therapeutic approaches and the establishment of mechanism-based therapeutic approaches. In this randomized, placebo-controlled, double-blinded crossover trial, 14 healthy volunteers were included. PEA (3 × 400 mg per day) or placebo were taken for 4 weeks. Our study investigated the mode of action of PEA using an established pain model, “Repetitive phasic heat application”, which is well-suited to investigate analgesic and anti-hyperalgesic effects in healthy volunteers. Parameters for peripheral and central sensitization as well as for pain modulation were assessed. Repetitive heat pain was significantly decreased, and the cold pain tolerance was significantly prolonged after the PEA treatment. The pressure pain tolerance and the conditioned pain modulation were increased after the PEA treatment. The wind-up ratio and the average distance of allodynia were significantly decreased after the PEA treatment. The heat pain tolerance was significantly higher after the PEA treatment. The present study has demonstrated that PEA has clinically relevant analgesic properties, acting on both peripheral and central mechanisms as well as in pain modulation.

Background: Web-based analysis of search queries has become a very useful method in various academic fields for understanding timely and regional differences in the public interest in certain terms and concepts. Particularly in health and medical research, Google Trends has been increasingly used over the last decade. Objective: This study aimed to assess the search activity of pain-related parameters on Google Trends from among the most populated regions worldwide over a 3-year period from before the report of the first confirmed COVID-19 cases in these regions (January 2018) until December 2020. Methods: Search terms from the following regions were used for the analysis: India, China, Europe, the United States, Brazil, Pakistan, and Indonesia. In total, 24 expressions of pain location were assessed. Search terms were extracted using the local language of the respective country. Python scripts were used for data mining. All statistical calculations were performed through exploratory data analysis and nonparametric Mann–Whitney U tests. Results: Although the overall search activity for pain-related terms increased, apart from pain entities such as headache, chest pain, and sore throat, we observed discordant search activity. Among the most populous regions, pain-related search parameters for shoulder, abdominal, and chest pain, headache, and toothache differed significantly before and after the first officially confirmed COVID-19 cases (for all, P<.001). In addition, we observed a heterogenous, marked increase or reduction in pain-related search parameters among the most populated regions. Conclusions: As internet searches are a surrogate for public interest, we assume that our data are indicative of an increased incidence of pain after the onset of the COVID-19 pandemic. However, as these increased incidences vary across geographical and anatomical locations, our findings could potentially facilitate the development of specific strategies to support the most affected groups.

Klivinyi C, et al. Korean J Pain. 2018 Jan;31(1):3-9. https://doi.org/10.3344/kjp.2018.31.1.3