According to the International Association for the Study of Pain (IASP), chronic pain is defined as pain that persists or recurs for >3 months (Treede et al., 2019). Overall, the prevalence of chronic pain is estimated to be about 1 in 5 people (Breivik, Collett, Ventafridda, Cohen, & Gallacher, 2006).

The associated disease burden represented by functional impairment and disability (Breivik et al., 2006; Froud et al., 2014), emotional distress (Häuser, Schmutzer, Henningsen, & Brähler, 2014); Wang, Pu, Ghose, & Tang, 2018) and direct and indirect societal costs (Häuser, Marschall, L'Hoest, Komossa, & Henningsen, 2013; James et al., 2018), relevantly impacts on patients and society. The WHO International Classification of Diseases (ICD)-11 implemented the classification of chronic pain (developed by an international task force of IASP) in chronic primary pain which is conceived as a disease itself and is associated with significant emotional distress or functional disability, and chronic secondary pain which is regarded as a symptom of an underlying disease, like cancer-related pain, chronic postsurgical or post-traumatic pain, chronic secondary musculoskeletal pain, chronic secondary visceral pain, chronic neuropathic pain, chronic secondary headache or orofacial pain (Table 1) (ICD-11 WHO, 2019/2021; Treede et al., 2019). More recently, a third category of pain, i.e., nociplastic pain, has been introduced. It is different from nociceptive and neuropathic pain being represented by a chronic non-specific pain related to a central nervous system sensitization (Fitzcharles et al., 2021). The altered nociception occurs, in fact, without clear evidence of tissue or nerve damage (IASP, 2023).

Standard treatment of chronic pain is represented by a wide series of analgesic drugs, including COX-2 selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol (also known as acetaminophen), antidepressants, anti-seizure agents and opioids. NSAIDs are commonly used to treat mild-to-moderate pain mainly due to arthritis and muscle sprains, with COX-2 inhibitors being preferred due to their highly selective targeting and safer toxicological profile. Paracetamol represents the first-line treatment for mild-to-moderate pain, although it is sometimes indicated in combination with opioids to reduce their dosage. Antidepressants (i.e., tricyclic antidepressants and serotonin and norepinephrine reuptake inhibitors, SNRIs) are mainly used to treat neuropathic pain, chronic headaches, fibromyalgia, while anti-seizure agents, including gabapentin and pregabalin, are preferred for postherpetic neuralgia, diabetic neuropathy, and fibromyalgia (Cohen, Vase, & Hooten, 2021; Marcianò et al., 2023). Although characterized by the development of tolerance, the prolonged use of opioids is still widespread due to their potent analgesic activity, especially in chronic pain due to cancer (Cohen et al., 2021; Marcianò et al., 2023).

A less neuronocentric view of chronic pain is rapidly evolving as increasing evidence now indicates that non-neuronal cells (e.g., mast cells and microglia) play key roles in the development of pathological pain (Vanderwall & Milligan, 2019). Most of the current analgesic drugs do not address the neuroinflammatory component of chronic pain. Safe interventions targeting the non-neuronal contribution are thus desirable for a successful management of chronic pain (Skaper, Facci, Zusso, & Giusti, 2018).

N-palmitoylethanolamine (PEA) is a naturally occurring fatty acid ethanolamide (FAE) endowed with several physiological properties (e.g., anti-inflammatory, neuroprotective, immunomodulating, anti-hyperalgesic functions), mainly due to its ability to down-modulate hyperactive non-neuronal cells (Skaper, Facci, & Giusti, 2013). PEA, that belongs to the family of autacoid local injury antagonist amides (ALIAmides), is one of the most studied members of the recently termed “paracannabinoid system”, i.e., a family of naturally occurring lipid mediators known as endocannabinoid-like lipids, that are structurally related to the endocannabinoids, share similar biosynthetic and degradative pathways, but exert distinct effects and target different receptors (Piomelli & Mabou Tagne, 2022). Other endocannabinoid-like lipids are linoleoylethanolamide (LEA), oleoylethanolamide (OEA), and stearoylethanolamide (SEA). Similar to PEA, these compounds perform ancillary functions with respect to endocannabinoid mediators, i.e., anandamide (arachidonoylethanolamide, AEA) (Devane et al., 1992) and 2-arachidonoylglycerol (2-AG) (Mechoulam et al., 1995; Sugiura et al., 1995), that were discovered about 30 years ago by the seminal work of Mechoulam's and Sugiura's independent groups. In contrast to endocannabinoids, the endocannabinoid-like lipids do not bind directly to the canonical cannabinoid receptors type 1 (CB1) and type 2 (CB2) (Fezza et al., 2014; Kleberg, Hassing, & Hansen, 2014).

Variable concentrations of PEA have been detected in several tissues including brain, liver, heart, intestine and adipose tissue (Balvers, Verhoeckx, Meijerink, Wortelboer, & Witkamp, 2013). Since 1950′, several physiological properties (e.g., anti-inflammatory, neuroprotective, immunomodulating, anti-hyperalgesic functions) have been recognized to PEA and the Nobel Laureate Rita Levi Montalcini importantly contributed to research advancement in the ALIAmide field (Levi-Montalcini, Skaper, Dal Toso, Petrelli, & Leon, 1996). Based on its protective properties, the use of PEA as a nutritional intervention for human and animal health has been explored, with this being greatly encouraged by the natural occurrence of this lipid amide not only in the animal and human body, but also in several food sources, as recently reviewed by Petrosino and colleagues (Petrosino & Schiano Moriello, 2020).

In order to overcome the bioavailability problems due to the lipid nature and the large particle size of PEA powder, micron-size formulations (i.e., micronized, ultramicronized and co(ultra)-micronized) have been developed and shown to have superior oral efficacy compared to unprocessed naïve PEA in several preclinical models (Impellizzeri et al., 2014; Petrosino et al., 2018), as further discussed in the next paragraphs.

In addition to preclinical studies - in which the analgesic properties of PEA and its complex mechanism(s) of action have been characterized - a relevant number of clinical trials have been performed on the efficacy and tolerability of ultramicronized PEA in humans, as reviewed in recent meta-analyses (Lang-Illievich et al., 2023; Paladini et al., 2016; Scuteri et al., 2022).

Through the years, several groups, including ours, have widely investigated the contribution of PEA in the control of pain with particular reference to its ability in co-adjuvating the action of other analgesics. This narrative review is aimed at discussing current knowledge on the pain-relieving properties of PEA with a focus on ultramicronized PEA as an add-on to the standard analgesic therapy.