Chronic Pain in Dogs and Cats: Is There Place for Dietary Intervention with Micro-Palmitoylethanolamide?

Article type: Review Article

Keywords: N-acylethanolamines, palmitoylethanolamide, chronic pain, small animals, micronization, endocannabinoids, microglia, mast cells

Authors: Giorgia della Rocca, Davide Gamba ⚬

Affiliations: Department of Veterinary Medicine, Centro di Ricerca sul Dolore Animale (CeRiDA), Università degli Studi di Perugia, 06123 Perugia, Italy; Operational Unit of Anesthesia, Centro Veterinario Gregorio VII, 00165 Roma, Italy; davidegamba@mac.com; Freelance, DG Vet Pain Therapy, 24124 Bergamo, Italy

License: © 2021 by the authors. CC BY 4.0 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Article links: DOI: 10.3390/ani11040952  |  PubMed: 33805489  |  PMC: PMC8065429

Relevance: Moderate: mentioned 3+ times in text

Full text: PDF (2.5 MB)

1. Introduction

The revised definition of pain endorsed and approved by the International Association for the Study of Pain (IASP) defines pain as “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” [ref. 1]. An important change with respect to the previous definition (1979) consists in the recognition that verbally expressing pain is no more a prerequisite to experiencing pain. The IASP further explains that “Verbal description is only one of several behaviors to express pain; inability to communicate does not negate the possibility that a human or a nonhuman animal experiences pain” [ref. 1].

From a veterinary perspective, this represents a definitive recognition of animal pain and poses veterinary practitioners in an “algological position”, i.e., to play a proactive role in recognizing, assessing and managing animal pain. Indeed, many efforts have been made in this direction during the last decades and several European and US groups are moving toward the development of better protocols to detect [ref. 2,ref. 3,ref. 4,ref. 5,ref. 6,ref. 7], measure [ref. 8,ref. 9,ref. 10,ref. 11,ref. 12,ref. 13,ref. 14] and treat [ref. 7,ref. 15,ref. 16,ref. 17,ref. 18] animal pain accordingly. The ever-increasing availability of well-designed pain scales for acute and chronic pain in dogs and cats [ref. 19,ref. 20,ref. 21,ref. 22,ref. 23,ref. 24,ref. 25,ref. 26] and the Pain Management Guidelines [ref. 27,ref. 28] are good examples.

On the treatment side, one of the most up-to-date and clinically relevant issues consists in the multimodal approach to pain management, i.e., a combination of different therapeutic weapons, like analgesic drugs, acupuncture and physiotherapy techniques, as well as dietary interventions [ref. 29,ref. 30,ref. 31,ref. 32,ref. 33]. With regard to the last measure, calorie restriction and omega-3 fatty acids are the most investigated approaches to chronic pain in pets, particularly osteoarthritis pain [ref. 34,ref. 35].

Increasing evidence is accumulating on the beneficial effects of N-acylethanolamines (NAEs) in chronic pain. NAEs have been detected in several food sources of vegetable [ref. 36,ref. 37,ref. 38] and animal origin [ref. 39]. Moreover, chronic or subchronic high-fat diet, as well as deficient intake of essential fatty acids have been shown to profoundly affect NAE levels in animal body [ref. 40,ref. 41,ref. 42,ref. 43,ref. 44,ref. 45]. One of the most studied NAEs is the endocannabinoid-like mediator palmitoylethanolamide (PEA). Its levels in food sources and its pro-homeostatic role have been recently reviewed [ref. 46].

Interestingly, the autoprotective function of PEA was first suggested in dogs, when it was found that the canine myocardium produced PEA in response to ischemic injury [ref. 47] and canine brain possessed the biosynthetic and degradative machinery for PEA [ref. 48,ref. 49]. Since then, an increasing body of literature has emerged highlighting the importance of dietary intervention with micro-PEA—i.e., the bioavailable form of PEA—for pain relief [ref. 50,ref. 51,ref. 52,ref. 53].

The present paper outlines current information on the involvement of immune cells in chronic pain and reviews the role of endogenous PEA in pain control, as well as the experimental and clinical data on pain relieving effects provided by different PEA formulations.

Given that some micro-PEA-containing dietary supplements for dogs and cats are currently being available on the European market, this review wishes to provide scientific evidence to make informed decisions about the management of chronic pain in cats and dogs.

2. Pain Classification

Pain includes at least two dimensions, i.e., physical and emotional components. From a physical perspective, although pain is often conceived as a homogeneous sensory entity, several distinct types exist: transient, inflammatory, neuropathic and functional pain (Figure 1) [ref. 54].

Transient pain develops when a potentially harmful insult is applied to a superficial or deep tissue (cutaneous/mucous or musculoskeletal/visceral, respectively) for such a short time that it does not cause tissue damage (potential damage). It develops rapidly and has a transient nature, disappearing with the end of the harmful stimulus or shortly thereafter. Transient pain acts like an alarm signal, capable of activating a sudden withdrawal reflex that protects the tissues from the noxious stimulus (adaptive pain). It develops thanks to the activation of the nociceptive system and the transduction, transmission, modulation and integration events that follow (nociceptive pain).

Inflammatory pain derives from damage-induced inflammation to somatic or visceral tissues (actual damage). It can be acute or chronic, depending on the nature of the underlying disease. While the former still has a protective purpose, as it limits movements and further damage until the repair is completed (adaptive pain), the latter lacks any biological purpose (maladaptive pain). Inflammatory pain is the result of nociceptor activation by inflammatory soup mediators released from immune cells, mainly mast cells. This leads to the development of neurogenic inflammation and brings about subsequent neurochemical changes, like wind-up and long-term potentiation, as well as translational and transcriptional modifications (e.g., lower activation threshold of nociceptors and increased expression of functional proteins involved in pain processing). The increased firing rate of the first and projection neuron (i.e., peripheral and central sensitization, respectively) is the main feature of inflammatory pain and leads to primary or secondary hyperalgesia (i.e., increased response to painful stimuli at the site of, or distant to the stimulus) and allodynia (i.e., painful response to harmless stimuli).

Neuropathic pain is defined by IASP as “pain that arises as a direct consequence of a lesion or disease affecting the somatosensitive system”. It results from an abnormal activation of the pain pathways, due to a dysfunction or damage to peripheral nerves and/or dorsal nerve roots (peripheral neuropathic pain) as well as spinal cord and/or brain (central neuropathic pain). Accordingly, it is considered disnociceptive, acquires a pathological, maladaptive nature and can be viewed as a disease itself rather than a symptom. Neuropathic pain can last for months to years or possibly even a lifetime, being thus considered a type of chronic pain. Possible mechanisms of peripheral neuropathic pain are (i) persistent hyperexcitability of nociceptors (even after damage repair), (ii) increased excitability of nociceptive fibers following nerve damage (e.g., after dysmyelinosis or neuroma formation), and (iii) structural/functional changes of spinal synapses following nerve degeneration. The resulting burst stimulation of afferent fibers may lead to central sensitization, a hallmark of several painful disorders like feline osteoarthritis [ref. 55]. Central neuropathic pain involves spinal cord and supramedullary neuronal structures and results from lesions affecting the central nervous system or increased activity of thalamic and cortical neurons due to neurochemical changes (e.g., imbalance of glutamatergic/GABAergic transmission).

Functional pain occurs spontaneously, in the total absence of tissue damage or evident dysfunction or damage to the nociceptive nervous system. It is probably supported by persistent plastic modifications of the central neuronal circuits induced by nociceptive or dysnociceptive algogenic lesions. As a consequence, originally activated central neuronal circuits remain active even when the lesion has resolved. A possible hypothesis is that mechanisms underlying the spontaneous processing of pain are similar to those that underlie memory: modifications of central neuronal circuits, initially induced by tissue or nerve damage, would remain in the CNS as traces of memory and can be “remembered” even after the lesion has resolved. Functional pain is therefore non-nociceptive, it can last months, years or forever, establishing its chronic nature. It has no biological function and is rather pathological (maladaptive). Like neuropathic pain, functional pain can thus be viewed as a disease itself [ref. 29,ref. 54,ref. 56].

3. Role of Non-Neuronal Cells in the Development and Resolution of Chronic Pain

As introduced above, chronic pain is an unpleasant experience outlasting the time of healing. Particular cells of the immune system intimately associated with or located within the nervous system, i.e., “non-neuronal cells”, are increasingly acknowledged as major contributors to the development and maintenance of chronic pain [ref. 51]. In particular, mast cells (within the nervous system and in the periphery) and microglia (at spinal and supraspinal level) interact with neurons under physiological and pathological conditions (Table 1).

While in the first situation non-neuronal cells support the well-function of neurons (e.g., through releasing neurotrophic factors), in the latter they may become hyper-activated and may cause pain to continue after the original injury has healed [ref. 94,ref. 95]. In fact, prolonged activation of non-neuronal cells leads to uncontrolled release of pro-inflammatory mediators resulting in long-lasting plastic changes of synaptic connectivity, with enhanced transmission of nociceptive information, alterations of pain signaling pathways and chronic pain development [ref. 96,ref. 97].

It should also be considered that a bidirectional crosstalk between mast cells and microglia exists [ref. 98] and is currently acknowledged as a critical event in pain hypersensitivity [ref. 64,ref. 99]. Accordingly, non-neuronal cell hyper-activation—and the resulting neuroinflammation—is a key player of pain states (Figure 2) [ref. 100,ref. 101,ref. 102].

Interestingly, non-neuronal cells are also endowed with crucial protective functions in resolution of neuroinflammation and pain [ref. 59]. Indeed, mast cells and microglia are able to reduce sensitization by producing pro-resolution mediators, the so-called specialized pro-resolving lipid mediators [ref. 103,ref. 104,ref. 105].

In this framework, particular attention is currently devoted to endocannabinoids and related lipid compounds, such as NAEs and more particularly PEA [ref. 106,ref. 107,ref. 108,ref. 109]. As detailed below, PEA and similar endocannabinoids are locally released on demand during injury to counterbalance the effects of pro-algesic mediators [ref. 110,ref. 111].

4. Endogenous PEA and Pain Modulation

As briefly introduced above, non-neuronal cells not only dangerously boost pain signaling, but also exert crucial functions in resolution of neuroinflammation and pain, through pro-resolution mediators. Among them, endocannabinoids and related NAEs are increasingly being acknowledged to play key roles in pain modulation, with PEA being one of the most studied [ref. 112]. It has been repeatedly found in dozens of vegetable and animal food sources (in nanogram per gram level), from soy to carrots and from eggs to beef [ref. 39,ref. 46]. Moreover, PEA levels have also been detected in virtually any tissue and body fluid [ref. 46,ref. 51], where it is enzymatically produced “on demand” in response to actual or potential damage and enzymatically cleaved when it has served its purpose [ref. 51,ref. 52,ref. 113,ref. 114,ref. 115].

The late Nobel prize winner Rita Levi Montalcini first proposed that PEA acts as an Autacoid Local Injury Antagonist (ALIA), through down-modulating mast cell degranulation [ref. 116,ref. 117]. It was then found that PEA is synthesized by mast cells and microglia [ref. 118,ref. 119] and is able to keep cell reactivity within physiological boundaries [ref. 51], thereby controlling neuroinflammation and chronic pain [ref. 120,ref. 121,ref. 122].

It has also been demonstrated that PEA not only acts through non-neuronal cells, but may also directly influence neurons. Indeed, PEA was shown to (i) exert protective effects on cultured cortical and cerebellar neurons [ref. 123,ref. 124], (ii) control spontaneous GABAergic synaptic activity in striatal neurons [ref. 125], (iii) dose-dependently increase intracellular calcium concentration in sensory neurons thereby desensitizing pain receptors [ref. 126]; (iv) modulate the activity of dorsal root ganglion neurons [ref. 127].

On the molecular side, PEA controls neuronal and non-neuronal cells through direct or indirect receptor targets, ranging from canonical to putative cannabinoid receptors, i.e., cannabinoid receptor type 1 and 2 (CB1 and CB2), peroxisome proliferator-activated receptor α (PPARα), transient receptor potential vanilloid 1 (TRPV1) and G protein-coupled receptors 55 and 119 (GPR55, GPR119) [ref. 65,ref. 126,ref. 127,ref. 128,ref. 129,ref. 130]. The indirect receptor agonism—i.e., a particular kind of entourage effect—depends on PEA ability to increase the local levels of the endocannabinoids anandamide (AEA) and/or 2-arachydonoylglycerol (2-AG) [ref. 52,ref. 125,ref. 131,ref. 132]. Different types of cannabinoid receptors have been recently localized in canine and feline central and peripheral organs. In particular, the target receptors of PEA have been found in canine and feline skin [ref. 133,ref. 134,ref. 135], along the gastrointestinal tract [ref. 136,ref. 137,ref. 138], in different brain areas [ref. 139,ref. 140,ref. 141,ref. 142], spinal cord and dorsal root ganglia [ref. 141,ref. 143]. The distribution of cannabinoid receptors in dogs and cats has been recently addressed by Gugliandolo et al. [ref. 46], to whose paper the reader is referred for more detailed information.

The multiple receptor mechanism(s) of PEA is responsible for innate pain control (Figure 3) [ref. 46,ref. 52] and provides PEA with a natural analgesic function, originally proposed in the late 1990s by Calignano and colleagues [ref. 144] and later even better designed by Piomelli and Sasso [ref. 145].

Currently, the role of body-own PEA in pain control is unquestionably proven by the recent case of a pain-insensitive woman who lacks the NAE degradative enzyme [ref. 146]. She feels almost no pain and has much higher levels of NAEs, with PEA levels being around 4-fold higher than normal.

In summary, PEA is an endogenous compound endowed with pain-relieving functions. It is locally produced on demand by non-neuronal cells and other cell types in response to an actual or potential damage, and acts as an endocannabinoid direct or indirect agonist to keep non-neuronal cell response within homeostatic boundaries.

5. Causes and Prevalence of Maladaptive Pain in Dogs and Cats

In the last decades, pets are becoming an increasingly important part of family life, being often considered real family members. Owners are more and more often seeking veterinary attention for various diseases affecting their pets, including pain. However, while most information on pain control in dogs and cats exists regarding peri-operative analgesic use, chronic pain conditions are still being undiagnosed and under-treated, especially in the feline species [ref. 147].

Indeed, many conditions may cause maladaptive pain in dogs and cats, as summarized in Table 2.

The incidence of pain in dogs and cats has not received much attention so far. A cross-sectional study on 317 dogs and 112 cats admitted to an emergency service reported that 56% and 54% of dogs and cats respectively were painful, with most dogs suffering from deep somatic pain and most cats from visceral pain [ref. 149]. The percentage was lower in outpatients (1153 dogs and 652 cats), with 20% of dogs and 14% of cats showing evidence of pain [ref. 150]. Neuropathic pain was diagnosed in 7–8% of both species [ref. 150,ref. 151].

Among the causes listed in Table 2, one of the most frequent painful conditions in dogs and cats is osteoarthritis (OA), otherwise referred to as osteoarthrosis or degenerative joint disease. The prevalence of canine OA published so far varies widely. In the UK, estimates range from 6.6% in primary-care services [ref. 152,ref. 153] to 20% based on referral data [ref. 154]. Estimates from North America made on radiographic and clinical data from referral settings show the age-specific prevalence of canine OA, with values ranging from 20% in dogs older than one year to 80% in dogs over eight years [ref. 155]. A cross-sectional study on radiographic signs of feline OA showed an overall prevalence of 92% in randomly selected domestic cats (mean age of 9.9 years) [ref. 156,ref. 157].

Finally, it should be mentioned that recognizing and measuring pain in animals is anything but easy. Further complicating the issue is the discovery that people rate pain sensitivity differently based on breed-specific stereotypes or phenotypic traits and dog breed archetypes [ref. 158]. Many excellent review papers are available on pain assessment in companion animals, which the reader is referred to [ref. 22,ref. 23,ref. 24,ref. 159,ref. 160].

6. Management of Pain in Dogs and Cats

As previously discussed, chronic pain—regardless of the underlying cause—may become maladaptive, i.e., without any beneficial role. Neuropathic pain, functional pain and chronic inflammatory pain are all types of maladaptive pain. Any type of maladaptive pain is thus considered pathological and must be treated accordingly.

A full discussion on pain management in pets is behind the scope of this article. Briefly, non-steroidal anti-inflammatory drugs (NSAIDs), opioids and steroids alone or associated with adjuvant drugs such as gabapentinoids (gabapentin, pregabalin), NMDA-antagonists (amantadine, memantine), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) or tricyclic antidepressants (TCA, e.g., amitriptyline), among others, represent the mainstream pharmacologic treatment of pain [ref. 27,ref. 161,ref. 162]. However, when used alone or even in combination, these drugs may still fail to provide complete pain relief [ref. 149]. Moreover, they can lead to the occurrence of adverse effects, especially in the chronic use [ref. 163,ref. 164]. Chronic pain in pets thus still represents an unmet medical need.

The idea that multimodal analgesia tailored to the patient will have most chances of being effective is increasingly being acknowledged in veterinary practice [ref. 165,ref. 166,ref. 167]. In this view, dietary intervention with pro-resolving lipid compounds may represent an ideal adjunctive approach. PEA is currently one of the most promising options in this regard.

7. PEA and Formulation Challenges: A Size Issue

Before dealing with the effectiveness of PEA in chronic pain, a key formulation question must be addressed. PEA is a highly lipophilic compound and tends to aggregate in large particles (up to 2000 microns)—a big pharmaceutical issue since absorption rate is inversely related to particle size [ref. 46,ref. 108,ref. 168].

Particle size reduction through micronization techniques (down to 0.8 microns) importantly improves the dissolution and thus bioavailability (Figure 4A) [ref. 169]. This results in superior efficacy of orally administered PEA (Figure 4B) [ref. 170,ref. 171,ref. 172], while ensuring its safety [ref. 171]. Mainly for this reason, in clinical practice (in which oral route is preferred because of ease of administration) the micronized (PEA-m) and ultra-micronized (PEA-um) forms (collectively known as micro-PEA [ref. 158]) are privileged and are indeed the most investigated.

On the contrary, in laboratory animals, the intraperitoneal delivery is generally the easiest and most used administration route. Moreover, it results in faster and more complete absorption compared to oral route [ref. 173]. This is especially true if suspension in carboxymethyl cellulose is used [ref. 173], as it is usually the case with intraperitoneally administered PEA. Indeed, no difference was observed between PEA-um and naïve PEA in pain control, in the event of intraperitoneal delivery (Figure 4C), which is absolutely not the case if oral administration is used [ref. 172].

8. Preclinical Evidence for PEA in Pain Relief

The rationale to administer PEA for pain relief and wellbeing was brilliantly foreseen in the late nineties by the Nobel Prize Winner Rita Levi Montalcini, who stated that “the observed effects of Palmitoylethanolamide appear to reflect the consequences of supplying the tissue with a sufficient quantity of its physiological regulator of cellular homeostasis” [ref. 117].

Since then, several studies in preclinical pain models have been performed, with PEA being given mainly via intraperitoneal route, although intraplantar injection [ref. 144,ref. 174] and oral administration of micronised formulations [ref. 175] were also used. Interestingly, the concurrent administration of micro-PEA and morphine for 11 days attenuated the development of opioid tolerance [ref. 176], since micro-PEA strengthens morphine analgesia and allows prolonged and effective pain relief with low doses [ref. 177].

Moreover, a descending analgesic mechanism mediated by the serotonergic system has been suggested [ref. 178].

Table 3 and Table 4 summarize the main preclinical investigations. As shown, PEA exerts a clear anti-nociceptive effect in chronic pain models of either inflammatory [ref. 132,ref. 144,ref. 174,ref. 175,ref. 176,ref. 179,ref. 180,ref. 181,ref. 182,ref. 183,ref. 184,ref. 185,ref. 186,ref. 187,ref. 188,ref. 189,ref. 190,ref. 191], neuropathic [ref. 192,ref. 193,ref. 194,ref. 195,ref. 196,ref. 197,ref. 198] or mixed nature [ref. 199,ref. 200]. In particular, it has been found that the anti-nociceptive effect of PEA is comparable to synthetic or plant-derived cannabinoids used for chronic pain, like nabilone [ref. 181] and delta-9-tetrahydrocannabinol (Δ9-THC) (Figure 5) [ref. 190].

Interestingly, an in-press study by Tagne and collaborators has just shown that hemp oil extract with 9.3% cannabidiol by weight has little or no effect when administered alone but synergizes with PEA to produce a greater-than-additive alleviation of neuropathic pain, upon single-dose administration (Figure 6) [ref. 201]. According to the authors, a possible explanation for the observed synergistic interaction lies in the ability of hemp oil extract to improve pharmacokinetic profile of PEA [ref. 201].

Two particularly interesting issues arise from the above findings. First, PEA is not analgesic sensu stricto since it does not modify the physiological pain threshold of control animals and rather electively normalizes conditions of hypersensitivity [ref. 176,ref. 185]. Second, PEA not only relieves pain itself but also improves pain-induced cognitive impairments [ref. 198].

As far as mechanism of action are concerned, reduced mast cell hyperplasia—even in endoneural sites—and decreased spinal microglia activation were the main observed events [ref. 120,ref. 185]. At the molecular level, the reduction of markers of pain pathway activation (e.g., Fos) and inflammatory mediators (e.g., cytokines, nerve growth factor) as well as modulation of extracellular signal-regulated kinase (ERK) and nuclear pro-inflammatory factors (e.g., NF-kB) were detected in the spinal cord [ref. 120,ref. 132,ref. 182,ref. 193,ref. 195,ref. 197]. Restoration of the glutamatergic synapses homeostasis in the prefrontal cortex and the involvement of de novo neurosteroid synthesis (i.e., allopregnanolone) in the spinal cord were also suggested to mediate PEA-induced analgesia [ref. 198,ref. 202]. Moreover, electrophysiological signs of decreased neuronal hyper-excitability were reported at the spinal cord level of PEA-um treated neuropathic animals [ref. 176,ref. 185,ref. 200]. Finally, the involvement of cannabinoid receptor(s) (e.g., CB2, CB1, PPARα) in the pain-relieving effect of PEA was repeatedly confirmed [ref. 186,ref. 192,ref. 194,ref. 199,ref. 202,ref. 203]. The up-regulation of CB2 expression by microglia through PPARα activation has also been suggested as a possible mechanism underlying the pain-relieving effect of PEA [ref. 204].

According to an impressive meta-analysis by IASP Presidential Taskforce on Cannabis and Cannabinoid Analgesia, PPARα agonists and, more specifically, PEA, are effective in attenuating pain-associated behaviors in a broad range of inflammatory or neuropathic pain models [ref. 205].

9. Clinical Evidence for Micro-PEA Dietary Supplementation in Pain Relief

On the clinical side, micro-PEA (i.e., micronized, ultramicronized or co-micronized PEA) has been orally administered as a dietary food for special medical purposes to human patients, either singly [ref. 206,ref. 207,ref. 208,ref. 209,ref. 210,ref. 211,ref. 212,ref. 213,ref. 214,ref. 215,ref. 216,ref. 217,ref. 218,ref. 219,ref. 220,ref. 221,ref. 222,ref. 223,ref. 224,ref. 225] or in combination with (i.e., add-on dietary intervention to) opioids, gabapentenoids or NSAIDs [ref. 226,ref. 227,ref. 228,ref. 229,ref. 230,ref. 231,ref. 232,ref. 233,ref. 234,ref. 235,ref. 236,ref. 237,ref. 238,ref. 239,ref. 240,ref. 241,ref. 242,ref. 243,ref. 244,ref. 245,ref. 246,ref. 247,ref. 248], as well as antioxidant compounds (e.g., luteolin, quercetin, polydatin) [ref. 249,ref. 250,ref. 251,ref. 252,ref. 253,ref. 254,ref. 255,ref. 256,ref. 257,ref. 258,ref. 259,ref. 260,ref. 261] in several painful conditions [ref. 53,ref. 262].

Altogether, nearly 5000 patients have been clinically investigated so far in dozens of published trials, showing an important overall effect in chronic pain, either neuropathic (Table 5), mixed (Table 6) or pelvic pain (Table 7).

One of the most interesting findings comes from the neurophysiological assessment of 20 patients with chemotherapy-induced painful neuropathy, with daily administered micro-PEA 300 mg/bid for two months. Besides significant pain reduction, increased conduction velocity of myelinated fibers was recorded, with sensory nerve action potentials from sural and ulnar nerves, compound motor action potentials from peroneal and ulnar nerves and laser-evoked potentials for Aδ fibers being significantly improved [ref. 212].

A further striking finding comes from the so-called “number needed to treat” (NNT), i.e., a measure depicting the effectiveness of an intervention (the lower the NNT, the more effective the intervention). The calculation was elegantly made by researchers from the Department of Human Neurosciences, “Sapienza” University of Rome [ref. 216]. In particular, the percentage of patients who manifested at least 50% pain relief in response to a daily supplementation of micro-PEA 600 mg/die was calculated based on data from a multicenter, double-blind, placebo-controlled, randomized study on 636 patients with low back pain. NNT was found to be 1.7 [ref. 216]. It must be pointed out that it is a remarkable NNT value within the broad panorama of treatments for low back pain in human patients. A systematic review on first-line treatments for neuropathic pain has indeed shown that NNT for 50% pain relief ranges from around 4 to 10 across most positive trials (Table 8) [ref. 263]. The much lower NNT for micro-PEA (i.e., 1.7) emphasizes the good outcome for neuropathic pain relief. The relevance of the data is further strengthened by the non-significant (and indeed infinite) number needed to harm [ref. 216], that is, how many patients must receive a particular treatment for one additional patient to experience a particular adverse outcome.

Overall, micro-PEA has shown a very favorable treatment profile in the management of chronic pain in human patients.

As far as privately owned animals are concerned, two trials have recently dealt with micro-PEA dietary administration for pain relief. The first is a case series in four jumping horses orally supplemented with PEA-um for non-responsive lameness and significant impairment of athletic performance [ref. 264]. In particular, the diagnoses were the following: navicular syndrome of the left forelimb (1 case), complicated case of chronic navicular syndrome and OA of the distal interphalangeal joint of the right forelimb (1 case), and OA of the distal intertarsal joint of the right hindlimb (2 cases). Horses were fed daily with PEA-um (2.5 g) mixed with a regular mixture of cereals for four months. At the end of the first month of supplementation, lameness on the AAEP scale (American Association of Equine Practitioners 0–5 scale, with zero indicating no perceptible lameness, and five being most extreme) showed improvement in all horses. Three months later, lameness was graded zero, allowing successful return to showjumping without disease recurrence [ref. 264].

The second study is an open-field trial performed in 13 medium-to-large-breed client-owned adult dogs, with chronic OA and persistent lameness longer than one month. All dogs were supplemented for 4 weeks with a complementary feed containing PEA co-ultramicronized with the natural antioxidant quercetin (i.e., PEA-q, 24 mg/kg body weight). The Canine Brief Pain Inventory (CBPI) questionnaire was used to assess the severity of chronic pain (PSS, Pain Severity Score) and how it interfered with the dog’s normal functioning (PIS, Pain Interference Score). With success defined as a reduction of ≥1 in PSS and PIS, treatment was classified as successful in 54.5% dogs as early as week 2 and CBPI scores significantly decreased throughout the study (Figure 7). Moreover, lameness (either scored by the veterinarian on a 0–4 clinical scale or objectively assessed through a dynamic gait analysis) was found to significantly improve during the treatment period [ref. 265].

The findings of the trials summarized above provide clinical evidence on PEA-um (eventually co-micronized with quercetin) as a promising treatment option for chronic pain and related functional disability in horses, as well as dogs.

10. Conclusions

The management of chronic pain is the burden of veterinary practitioners. Multiple pharmacological agents have been employed to treat diverse pathological pain states, including opiates, NSAIDs, anticonvulsants, antidepressants, and others [ref. 29]. However, adverse effects could limit dosing and therapeutic efficacy [ref. 163,ref. 164].

The recent understanding of the role of non-neuronal cells in pain processing is uncovering potential new targets for managing chronic pain [ref. 104]. Furthermore, it is becoming increasingly clear that enhancing endocannabinoid signalling may prevent patients from developing persistent or chronic pain states mainly through non-neuronal cell modulation [ref. 266,ref. 267,ref. 268,ref. 269]. One such strategy is the dietetic use of the endocannabinoid-like PEA in bioavailable formulations (i.e., micro-PEA). As reviewed here, there is now strong evidence supporting the dietary supplementation with micro-PEA (either as alternative or add-on to conventional treatment) in the management of chronic pain. Such a critical mass of data is being generated that PEA is currently listed among the novel nonopioid interventions to chronic pain [ref. 270].

Although clinical studies in veterinary patients are warranted, the reviewed findings lay the foundations for a scientific and rational use of micro-PEA in the dietary management of chronic pain in dogs and cats.

References

1. S.N. Raja, D.B. Carr, M. Cohen, N.B. Finnerup, H. Flor, S. Gibson, F.J. Keefe, J.S. Mogil, M. Ringkamp, K.A. Sluka. The Revised International Association for the Study of Pain Definition of Pain: Concepts, Challenges, and Compromises. Pain, 2020. [DOI | PubMed]
2. M.L. Wiseman-Orr, E.M. Scott, J. Reid, A.M. Nolan. Validation of a Structured Questionnaire as an Instrument to Measure Chronic Pain in Dogs on the Basis of Effects on Health-Related Quality of Life. Am. J. Vet. Res., 2006. [DOI | PubMed]
3. A. Tomas, D.J. Marcellin-Little, S.C. Roe, A. Motsinger-Reif, B.D.X. Lascelles. Relationship between Mechanical Thresholds and Limb Use in Dogs with Coxofemoral Joint Oa-Associated Pain and the Modulating Effects of Pain Alleviation from Total Hip Replacement on Mechanical Thresholds. Vet. Surg. VS, 2014. [DOI | PubMed]
4. P.V. Steagall, B.P. Monteiro, H.L.M. Ruel, G. Beauchamp, G. Luca, J. Berry, S. Little, E. Stiles, S. Hamilton, D. Pang. Perceptions and Opinions of Canadian Pet Owners about Anaesthesia, Pain and Surgery in Small Animals. J. Small Anim. Pract., 2017. [DOI | PubMed]
5. K.N. Davis, P.W. Hellyer, E.C.J. Carr, J.E. Wallace, L.R. Kogan. Qualitative Study of Owner Perceptions of Chronic Pain in Their Dogs. J. Am. Vet. Med. Assoc., 2019. [DOI | PubMed]
6. D.S. Mills, I. Demontigny-Bédard, M. Gruen, M.P. Klinck, K.J. McPeake, A.M. Barcelos, L. Hewison, H. Van Haevermaet, S. Denenberg, H. Hauser. Pain and Problem Behavior in Cats and Dogs. Amimals, 2020. [DOI]
7. S.M. Fox. Chronic Pain in Small Animal Medicine, 2018
8. C.M. Morton, J. Reid, E.M. Scott, L.L. Holton, A.M. Nolan. Application of a Scaling Model to Establish and Validate an Interval Level Pain Scale for Assessment of Acute Pain in Dogs. Am. J. Vet. Res., 2005. [DOI | PubMed]
9. M.B. Walton, E. Cowderoy, D. Lascelles, J.F. Innes. Evaluation of Construct and Criterion Validity for the “Liverpool Osteoarthritis in Dogs” (LOAD) Clinical Metrology Instrument and Comparison to Two Other Instruments. PLoS ONE, 2013. [DOI | PubMed]
10. M. Freire, D. Knazovicky, B. Case, A. Thomson, B.D.X. Lascelles. Comparison of Thermal and Mechanical Quantitative Sensory Testing in Client-Owned Dogs with Chronic Naturally Occurring Pain and Normal Dogs. Vet. J. Lond. Engl. 1997, 2016. [DOI]
11. L.K. Harris, H.R. Whay, J.C. Murrell. An Investigation of Mechanical Nociceptive Thresholds in Dogs with Hind Limb Joint Pain Compared to Healthy Control Dogs. Vet. J. Lond. Engl. 1997, 2018. [DOI]
12. E.H. Hofmeister, M. Barletta, M. Shepard, B.M. Brainard, C.M. Trim, J. Quandt. Agreement among Anesthesiologists Regarding Postoperative Pain Assessment in Dogs. Vet. Anaesth. Analg., 2018. [DOI | PubMed]
13. J. Hunt, D. Knazovicky, B.D.X. Lascelles, J. Murrell. Quantitative Sensory Testing in Dogs with Painful Disease: A Window to Pain Mechanisms?. Vet. J. Lond. Engl. 1997, 2019. [DOI | PubMed]
14. B.D.X. Lascelles, D.C. Brown, M. Conzemius, M. Gill, M.L. Oshinsky, M. Sharkey. Measurement of Chronic Pain in Companion Animals: Priorities for Future Research and Development Based on Discussions from the Pain in Animals Workshop (PAW) 2017. Vet. J. Lond. Engl. 1997, 2019. [DOI | PubMed]
15. G. Della Rocca, E. Olivieri, A. Di Salvo, J. Malvisi, M. Gogny. Attitude and Concern of Italian Veterinary Practitioners toward Management of Pain in Dogs and Cats. J. Vet. Pharmacol. Ther., 2009
16. A. Catanzaro, A. Di Salvo, P.V. Steagall, D. Zampini, A. Polisca, G. Della Rocca. Preliminary Study on Attitudes, Opinions and Knowledge of Italian Veterinarians with Regard to Abdominal Visceral Pain in Dogs. Vet. Anaesth. Analg., 2016. [DOI | PubMed]
17. C. Bradbrook, L. Clark. State of the Art Analgesia-Recent Developments Pharmacological Approaches to Acute Pain Management in Dogs and Cats: Part 2. Vet. J. Lond. Engl. 1997, 2018. [DOI]
18. A. Baker-Meuten, T. Wendland, S.K. Shamir, A.M. Hess, F.M. Duerr. Evaluation of Acupuncture for the Treatment of Pain Associated with Naturally-Occurring Osteoarthritis in Dogs: A Prospective, Randomized, Placebo-Controlled, Blinded Clinical Trial. BMC Vet. Res., 2020. [DOI | PubMed]
19. D.C. Brown, R.C. Boston, J.T. Farrar. Comparison of Force Plate Gait Analysis and Owner Assessment of Pain Using the Canine Brief Pain Inventory in Dogs with Osteoarthritis. J. Vet. Intern. Med., 2013. [DOI | PubMed]
20. D.C. Brown, R.C. Boston, J.C. Coyne, J.T. Farrar. Ability of the Canine Brief Pain Inventory to Detect Response to Treatment in Dogs with Osteoarthritis. J. Am. Vet. Med. Assoc., 2008. [DOI | PubMed]
21. A.K. Hielm-Björkman, H. Rita, R.-M. Tulamo. Psychometric Testing of the Helsinki Chronic Pain Index by Completion of a Questionnaire in Finnish by Owners of Dogs with Chronic Signs of Pain Caused by Osteoarthritis. Am. J. Vet. Res., 2009. [DOI | PubMed]
22. J. Reid, A.M. Nolan, E.M. Scott. Measuring Pain in Dogs and Cats Using Structured Behavioural Observation. Vet. J. Lond. Engl. 1997, 2018. [DOI]
23. Z. Belshaw, J. Yeates. Assessment of Quality of Life and Chronic Pain in Dogs. Vet. J. Lond. Engl. 1997, 2018. [DOI]
24. I. Hernandez-Avalos, D. Mota-Rojas, P. Mora-Medina, J. Martínez-Burnes, A. Casas Alvarado, A. Verduzco-Mendoza, K. Lezama-García, A. Olmos-Hernandez. Review of Different Methods Used for Clinical Recognition and Assessment of Pain in Dogs and Cats. Int. J. Vet. Sci. Med., 2019. [DOI | PubMed]
25. M. Enomoto, B.D.X. Lascelles, M.E. Gruen. Development of a Checklist for the Detection of Degenerative Joint Disease-Associated Pain in Cats. J. Feline Med. Surg., 2020. [DOI | PubMed]
26. M.C. Evangelista, R. Watanabe, V.S.Y. Leung, B.P. Monteiro, E. O’Toole, D.S.J. Pang, P.V. Steagall. Facial Expressions of Pain in Cats: The Development and Validation of a Feline Grimace Scale. Sci. Rep., 2019. [DOI | PubMed]
27. M. Epstein, I. Rodan, G. Griffenhagen, J. Kadrlik, M. Petty, S. Robertson, W. Simpson. 2015 AAHA/AAFP Pain Management Guidelines for Dogs and Cats. J. Am. Anim. Hosp. Assoc., 2015. [DOI | PubMed]
28. K. Mathews, P.W. Kronen, D. Lascelles, A. Nolan, S. Robertson, P.V. Steagall, B. Wright, K. Yamashita. Guidelines for Recognition, Assessment and Treatment of Pain: WSAVA Global Pain Council Members and Co-Authors of This Document. J. Small Anim. Pract., 2014. [DOI | PubMed]
29. G. Della Rocca, A. Bufalari. Terapia del Dolore Negli Animali da Compagnia, 2016
30. D. Gamba. Il Dolore nel Cane. Valutazione, Diagnosi e Trattamento, 2020
31. S.M. Fox. Multimodal Management of Canine Osteoarthritis, 2017
32. L.M. Fry, S.M. Neary, J. Sharrock, J.K. Rychel. Acupuncture for Analgesia in Veterinary Medicine. Top. Companion Anim. Med., 2014. [DOI | PubMed]
33. D.M. Lane, S.A. Hill. Effectiveness of Combined Acupuncture and Manual Therapy Relative to No Treatment for Canine Musculoskeletal Pain. Can. Vet. J., 2016. [PubMed]
34. R. Gupta, A. Srivastava, R. Lall. Nutraceuticals in Veterinary Medicine, 2019
35. J.-M. Vandeweerd, C. Coisnon, P. Clegg, C. Cambier, A. Pierson, F. Hontoir, C. Saegerman, P. Gustin, S. Buczinski. Systematic Review of Efficacy of Nutraceuticals to Alleviate Clinical Signs of Osteoarthritis. J. Vet. Intern. Med., 2012. [DOI | PubMed]
36. A. Kilaru, E.B. Blancaflor, B.J. Venables, S. Tripathy, K.S. Mysore, K.D. Chapman. The N-Acylethanolamine-Mediated Regulatory Pathway in Plants. Chem. Biodivers., 2007. [DOI | PubMed]
37. B.J. Venables, C.A. Waggoner, K.D. Chapman. N-Acylethanolamines in Seeds of Selected Legumes. Phytochemistry, 2005. [DOI | PubMed]
38. K.D. Chapman. Occurrence, Metabolism, and Prospective Functions of N-Acylethanolamines in Plants. Prog. Lipid Res., 2004. [DOI | PubMed]
39. L. De Luca, R. Ferracane, P. Vitaglione. Food Database of N-Acyl-Phosphatidylethanolamines, N-Acylethanolamines and Endocannabinoids and Daily Intake from a Western, a Mediterranean and a Vegetarian Diet. Food Chem., 2019. [DOI | PubMed]
40. T.A. Diep, A.N. Madsen, B. Holst, M.M. Kristiansen, N. Wellner, S.H. Hansen, H.S. Hansen. Dietary Fat Decreases Intestinal Levels of the Anorectic Lipids through a Fat Sensor. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol., 2011. [DOI | PubMed]
41. S. Lacroix, F. Pechereau, N. Leblanc, B. Boubertakh, A. Houde, C. Martin, N. Flamand, C. Silvestri, F. Raymond, V. Di Marzo. Rapid and Concomitant Gut Microbiota and Endocannabinoidome Response to Diet-Induced Obesity in Mice. mSystems, 2019. [DOI]
42. L. Lin, T. Rideout, N. Yurkova, H. Yang, P. Eck, P.J.H. Jones. Fatty Acid Ethanolamides Modulate CD36-MRNA through Dietary Fatty Acid Manipulation in Syrian Golden Hamsters. Appl. Physiol. Nutr. Metab. Physiol. Appl. Nutr. Metab., 2013. [DOI]
43. K. Kleberg, H.A. Hassing, H.S. Hansen. Classical Endocannabinoid-like Compounds and Their Regulation by Nutrients. BioFactors Oxf. Engl., 2014. [DOI | PubMed]
44. G. Carta, E. Murru, R. Vargiu, M. Collu, M. Carta, S. Banni, R. Stancampiano. Essential Fatty Acids Deficient Diet Modulates N-Acylethanolamide Profile in Rat’s Tissues. Prostaglandins Leukot. Essent. Fatty Acids, 2020. [DOI | PubMed]
45. A. Artmann, G. Petersen, L.I. Hellgren, J. Boberg, C. Skonberg, C. Nellemann, S.H. Hansen, H.S. Hansen. Influence of Dietary Fatty Acids on Endocannabinoid and N-Acylethanolamine Levels in Rat Brain, Liver and Small Intestine. Biochim. Biophys. Acta, 2008. [DOI | PubMed]
46. E. Gugliandolo, A.F. Peritore, C. Piras, S. Cuzzocrea, R. Crupi. Palmitoylethanolamide and Related ALIAmides: Prohomeostatic Lipid Compounds for Animal Health and Wellbeing. Vet. Sci., 2020. [DOI]
47. D.E. Epps, P.C. Schmid, V. Natarajan, H.H. Schmid. N-Acylethanolamine Accumulation in Infarcted Myocardium. Biochem. Biophys. Res. Commun., 1979. [DOI | PubMed]
48. V. Natarajan, P.C. Schmid, P.V. Reddy, M.L. Zuzarte-Augustin, H.H. Schmid. Biosynthesis of N-Acylethanolamine Phospholipids by Dog Brain Preparations. J. Neurochem., 1983. [DOI | PubMed]
49. V. Natarajan, P.C. Schmid, P.V. Reddy, H.H. Schmid. Catabolism of N-Acylethanolamine Phospholipids by Dog Brain Preparations. J. Neurochem., 1984. [DOI | PubMed]
50. G. Re, R. Barbero, A. Miolo, V. Di Marzo. Palmitoylethanolamide, Endocannabinoids and Related Cannabimimetic Compounds in Protection against Tissue Inflammation and Pain: Potential Use in Companion Animals. Vet. J. Lond. Engl. 1997, 2007. [DOI | PubMed]
51. S. Petrosino, A. Schiano Moriello. Palmitoylethanolamide: A Nutritional Approach to Keep Neuroinflammation within Physiological Boundaries-A Systematic Review. Int. J. Mol. Sci., 2020. [DOI | PubMed]
52. S. Petrosino, V. Di Marzo. The Pharmacology of Palmitoylethanolamide and First Data on the Therapeutic Efficacy of Some of Its New Formulations. Br. J. Pharmacol., 2017. [DOI | PubMed]
53. A.F. Peritore, R. Siracusa, R. Crupi, S. Cuzzocrea. Therapeutic Efficacy of Palmitoylethanolamide and Its New Formulations in Synergy with Different Antioxidant Molecules Present in Diets. Nutrients, 2019. [DOI]
54. C.J. Woolf. American College of Physicians; American Physiological Society. Pain: Moving from Symptom Control toward Mechanism-Specific Pharmacologic Management. Ann. Intern. Med., 2004. [DOI | PubMed]
55. B.P. Monteiro, C. Otis, J.R.E. Del Castillo, R. Nitulescu, K. Brown, L. Arendt-Nielsen, E. Troncy. Quantitative Sensory Testing in Feline Osteoarthritic Pain—A Systematic Review and Meta-Analysis. Osteoarthr. Cartil., 2020. [DOI]
56. G. Orlandini. Orlandini, La Semeiotica Del Dolore, 2016
57. D. Elieh Ali Komi, S. Wöhrl, L. Bielory. Mast Cell Biology at Molecular Level: A Comprehensive Review. Clin. Rev. Allergy Immunol., 2020. [DOI | PubMed]
58. S.J. Galli, N. Gaudenzio, M. Tsai. Mast Cells in Inflammation and Disease: Recent Progress and Ongoing Concerns. Annu. Rev. Immunol., 2020. [DOI | PubMed]
59. G. Chen, Y.-Q. Zhang, Y.J. Qadri, C.N. Serhan, R.-R. Ji. Microglia in Pain: Detrimental and Protective Roles in Pathogenesis and Resolution of Pain. Neuron, 2018. [DOI | PubMed]
60. R.-D. Gosselin, M.R. Suter, R.-R. Ji, I. Decosterd. Glial Cells and Chronic Pain. Neurosci. Rev. J. Bringing Neurobiol. Neurol. Psychiatry, 2010. [DOI | PubMed]
61. J. Bienenstock, G. MacQueen, P. Sestini, J.S. Marshall, R.H. Stead, M.H. Perdue. Mast Cell/Nerve Interactions in Vitro and in Vivo. Am. Rev. Respir. Dis., 1991. [DOI | PubMed]
62. Y. Zuo, N.M. Perkins, D.J. Tracey, C.L. Geczy. Inflammation and Hyperalgesia Induced by Nerve Injury in the Rat: A Key Role of Mast Cells. Pain, 2003. [DOI | PubMed]
63. H. Xu, X. Shi, X. Li, J. Zou, C. Zhou, W. Liu, H. Shao, H. Chen, L. Shi. Neurotransmitter and Neuropeptide Regulation of Mast Cell Function: A Systematic Review. J. Neuroinflamm., 2020. [DOI]
64. S.D. Skaper, L. Facci, M. Zusso, P. Giusti. An Inflammation-Centric View of Neurological Disease: Beyond the Neuron. Front. Cell. Neurosci., 2018. [DOI | PubMed]
65. S. Marinelli, B. Basilico, M.C. Marrone, D. Ragozzino. Microglia-Neuron Crosstalk: Signaling Mechanism and Control of Synaptic Transmission. Semin. Cell Dev. Biol., 2019. [DOI | PubMed]
66. I. Matsumoto, Y. Inoue, T. Shimada, T. Aikawa. Brain Mast Cells Act as an Immune Gate to the Hypothalamic-Pituitary-Adrenal Axis in Dogs. J. Exp. Med., 2001. [DOI | PubMed]
67. T.L. Yaksh, J.W. Allen, S.L. Veesart, K.A. Horais, S.A. Malkmus, M. Scadeng, J.J. Steinauer, S.S. Rossi. Role of Meningeal Mast Cells in Intrathecal Morphine-Evoked Granuloma Formation. Anesthesiology, 2013. [DOI | PubMed]
68. J.K. Sandhu, M. Kulka. Decoding Mast Cell-Microglia Communication in Neurodegenerative Diseases. Int. J. Mol. Sci., 2021. [DOI | PubMed]
69. D.P. Green, N. Limjunyawong, N. Gour, P. Pundir, X. Dong. A Mast-Cell-Specific Receptor Mediates Neurogenic Inflammation and Pain. Neuron, 2019. [DOI | PubMed]
70. J. Kalesnikoff, S.J. Galli. New Developments in Mast Cell Biology. Nat. Immunol., 2008. [DOI | PubMed]
71. R. Silver, J.P. Curley. Mast Cells on the Mind: New Insights and Opportunities. Trends Neurosci., 2013. [DOI | PubMed]
72. J. Pastwińska, P. Żelechowska, A. Walczak-Drzewiecka, E. Brzezińska-Błaszczyk, J. Dastych. The Art of Mast Cell Adhesion. Cells, 2020. [DOI]
73. V. Coraggio, F. Guida, S. Boccella, M. Scafuro, S. Paino, D. Romano, S. Maione, L. Luongo. Neuroimmune-Driven Neuropathic Pain Establishment: A Focus on Gender Differences. Int. J. Mol. Sci., 2018. [DOI]
74. H. Zhao, A. Alam, Q. Chen, M.A. Eusman, A. Pal, S. Eguchi, L. Wu, D. Ma. The Role of Microglia in the Pathobiology of Neuropathic Pain Development: What Do We Know?. Br. J. Anaesth., 2017. [DOI | PubMed]
75. A. Héron, D. Dubayle. A Focus on Mast Cells and Pain. J. Neuroimmunol., 2013. [DOI | PubMed]
76. T. Iuvone, G. Affaitati, D. De Filippis, M. Lopopolo, G. Grassia, D. Lapenna, L. Negro, R. Costantini, M. Vaia, F. Cipollone. Ultramicronized Palmitoylethanolamide Reduces Viscerovisceral Hyperalgesia in a Rat Model of Endometriosis plus Ureteral Calculosis: Role of Mast Cells. Pain, 2016. [DOI | PubMed]
77. F. Giancola, U. Volta, R. Repossi, R. Latorre, D. Beeckmans, F. Carbone, K. Van den Houte, F. Bianco, E. Bonora, A. Gori. Mast Cell-Nerve Interactions Correlate with Bloating and Abdominal Pain Severity in Patients with Non-Celiac Gluten/Wheat Sensitivity. Neurogastroenterol. Motil. Off. J. Eur. Gastrointest. Motil. Soc., 2020. [DOI | PubMed]
78. B. Frossi, M. De Carli, A. Calabrò. Coeliac Disease and Mast Cells. Int. J. Mol. Sci., 2019. [DOI | PubMed]
79. R.J. Miller, A.-M. Malfait, R.E. Miller. The Innate Immune Response as a Mediator of Osteoarthritis Pain. Osteoarthr. Cartil., 2020. [DOI | PubMed]
80. J. Richards, S. Tang, G. Gunsch, P. Sul, M. Wiet, D.C. Flanigan, S.N. Khan, S. Moore, B. Walter, D. Purmessur. Mast Cell/Proteinase Activated Receptor 2 (PAR2) Mediated Interactions in the Pathogenesis of Discogenic Back Pain. Front. Cell. Neurosci., 2019. [DOI | PubMed]
81. D. Kempuraj, S. Mentor, R. Thangavel, M.E. Ahmed, G.P. Selvakumar, S.P. Raikwar, I. Dubova, S. Zaheer, S.S. Iyer, A. Zaheer. Mast Cells in Stress, Pain, Blood-Brain Barrier, Neuroinflammation and Alzheimer’s Disease. Front. Cell. Neurosci., 2019. [DOI | PubMed]
82. P. Forsythe. Mast Cells in Neuroimmune Interactions. Trends Neurosci., 2019. [DOI | PubMed]
83. L. Zhang, J. Song, T. Bai, R. Wang, X. Hou. Sustained Pain Hypersensitivity in the Stressed Colon: Role of Mast Cell-Derived Nerve Growth Factor-Mediated Enteric Synaptic Plasticity. Neurogastroenterol. Motil. Off. J. Eur. Gastrointest. Motil. Soc., 2018. [DOI]
84. K. Gupta, I.T. Harvima. Mast Cell-Neural Interactions Contribute to Pain and Itch. Immunol. Rev., 2018. [DOI | PubMed]
85. A. Ioan-Facsinay. Initiating Pain in Osteoarthritis (OA): Is It the Mast Cell?. Osteoarthr. Cartil., 2018. [DOI]
86. M.G. Wiet, A. Piscioneri, S.N. Khan, M.N. Ballinger, J.A. Hoyland, D. Purmessur. Mast Cell-Intervertebral Disc Cell Interactions Regulate Inflammation, Catabolism and Angiogenesis in Discogenic Back Pain. Sci. Rep., 2017. [DOI | PubMed]
87. G. Kaur, N. Singh, A.S. Jaggi. Mast Cells in Neuropathic Pain: An Increasing Spectrum of Their Involvement in Pathophysiology. Rev. Neurosci., 2017. [DOI | PubMed]
88. M. Fusco, S.D. Skaper, S. Coaccioli, G. Varrassi, A. Paladini. Degenerative Joint Diseases and Neuroinflammation. Pain Pract. Off. J. World Inst. Pain, 2017. [DOI | PubMed]
89. S.A. Moore. Managing Neuropathic Pain in Dogs. Front. Vet. Sci., 2016. [DOI | PubMed]
90. L. Cao, C.D. Palmer, J.T. Malon, J.A. De Leo. Critical Role of Microglial CD40 in the Maintenance of Mechanical Hypersensitivity in a Murine Model of Neuropathic Pain. Eur. J. Immunol., 2009. [DOI | PubMed]
91. M. Costigan, J. Scholz, C.J. Woolf. Neuropathic Pain: A Maladaptive Response of the Nervous System to Damage. Annu. Rev. Neurosci., 2009. [DOI | PubMed]
92. I. Spitzbarth, P. Bock, V. Haist, V.M. Stein, A. Tipold, K. Wewetzer, W. Baumgärtner, A. Beineke. Prominent Microglial Activation in the Early Proinflammatory Immune Response in Naturally Occurring Canine Spinal Cord Injury. J. Neuropathol. Exp. Neurol., 2011. [DOI | PubMed]
93. R. Yamasaki, T. Fujii, B. Wang, K. Masaki, M.A. Kido, M. Yoshida, T. Matsushita, J.-I. Kira. Allergic Inflammation Leads to Neuropathic Pain via Glial Cell Activation. J. Neurosci. Off. J. Soc. Neurosci., 2016. [DOI]
94. R.D. Fields. New Culprits in Chronic Pain. Sci. Am., 2009. [DOI | PubMed]
95. S.D. Skaper, L. Facci, P. Giusti. Mast Cells, Glia and Neuroinflammation: Partners in Crime?. Immunology, 2014. [DOI | PubMed]
96. F. Marchand, M. Perretti, S.B. McMahon. Role of the Immune System in Chronic Pain. Nat. Rev. Neurosci., 2005. [DOI | PubMed]
97. R. Ferreira, L. Bernardino. Dual Role of Microglia in Health and Disease: Pushing the Balance toward Repair. Front. Cell. Neurosci., 2015. [DOI | PubMed]
98. H. Yuan, X. Zhu, S. Zhou, Q. Chen, X. Zhu, X. Ma, X. He, M. Tian, X. Shi. Role of Mast Cell Activation in Inducing Microglial Cells to Release Neurotrophin. J. Neurosci. Res., 2010. [DOI | PubMed]
99. T.C. Theoharides, I. Tsilioni, M. Bawazeer. Mast Cells, Neuroinflammation and Pain in Fibromyalgia Syndrome. Front. Cell. Neurosci., 2019. [DOI | PubMed]
100. A. Ellis, D.L.H. Bennett. Neuroinflammation and the Generation of Neuropathic Pain. Br. J. Anaesth., 2013. [DOI | PubMed]
101. R.-R. Ji, Z.-Z. Xu, Y.-J. Gao. Emerging Targets in Neuroinflammation-Driven Chronic Pain. Nat. Rev. Drug Discov., 2014. [DOI | PubMed]
102. M. Matsuda, Y. Huh, R.-R. Ji. Roles of Inflammation, Neurogenic Inflammation, and Neuroinflammation in Pain. J. Anesth., 2019. [DOI | PubMed]
103. V. Chiurchiù, A. Leuti, M. Maccarrone. Bioactive Lipids and Chronic Inflammation: Managing the Fire Within. Front. Immunol., 2018. [DOI | PubMed]
104. K. Ren, R. Dubner. Interactions between the Immune and Nervous Systems in Pain. Nat. Med., 2010. [DOI | PubMed]
105. S.D. Skaper, L. Facci, M. Barbierato, M. Zusso, G. Bruschetta, D. Impellizzeri, S. Cuzzocrea, P. Giusti. N-Palmitoylethanolamine and Neuroinflammation: A Novel Therapeutic Strategy of Resolution. Mol. Neurobiol., 2015. [DOI | PubMed]
106. R. Lerner, D. Pascual Cuadrado, J.M. Post, B. Lutz, L. Bindila. Broad Lipidomic and Transcriptional Changes of Prophylactic PEA Administration in Adult Mice. Front. Neurosci., 2019. [DOI | PubMed]
107. A. Paladini, M. Fusco, T. Cenacchi, C. Schievano, A. Piroli, G. Varrassi. Palmitoylethanolamide, a Special Food for Medical Purposes, in the Treatment of Chronic Pain: A Pooled Data Meta-Analysis. Pain Physician, 2016. [PubMed]
108. S.D. Skaper, L. Facci, M. Fusco, M.F. Della Valle, M. Zusso, B. Costa, P. Giusti. Palmitoylethanolamide, a Naturally Occurring Disease-Modifying Agent in Neuropathic Pain. Inflammopharmacology, 2014. [DOI | PubMed]
109. D. Piomelli, L. Scalvini, Y. Fotio, A. Lodola, G. Spadoni, G. Tarzia, M. Mor. N-Acylethanolamine Acid Amidase (NAAA): Structure, Function, and Inhibition. J. Med. Chem., 2020. [DOI | PubMed]
110. D. Piomelli. A Thickening Network of Lipids. Pain, 2012. [DOI | PubMed]
111. D. Piomelli, A.G. Hohmann, V. Seybold, B.D. Hammock. A Lipid Gate for the Peripheral Control of Pain. J. Neurosci. Off. J. Soc. Neurosci., 2014. [DOI | PubMed]
112. R. D’Amico, D. Impellizzeri, S. Cuzzocrea, R. Di Paola. ALIAmides Update: Palmitoylethanolamide and Its Formulations on Management of Peripheral Neuropathic Pain. Int. J. Mol. Sci., 2020. [DOI | PubMed]
113. F. Piscitelli. Chapter 9—Endocannabinoidomics: “Omics” Approaches Applied to Endocannabinoids and Endocannabinoid-Like Mediators. The Endocannabinoidome, 2015. [DOI]
114. S. Petrosino, V.D. Marzo. Anandamide and Other Acylethanolamides. Handbook of Neurochemistry and Molecular Neurobiology: Neural Lipids, 2009. [DOI]
115. S. Kallendrusch, C. Hobusch, A. Ehrlich, S. Ziebell, N. Ueda, G. Geisslinger, M. Koch, F. Dehghani. Site-Specific and Time-Dependent Activation of the Endocannabinoid System after Transection of Long-Range Projections. PLoS ONE, 2012. [DOI | PubMed]
116. L. Aloe, A. Leon, R. Levi-Montalcini. A Proposed Autacoid Mechanism Controlling Mastocyte Behaviour. Agents Actions, 1993. [DOI | PubMed]
117. R. Levi-Montalcini, S.D. Skaper, R. Dal Toso, L. Petrelli, A. Leon. Nerve Growth Factor: From Neurotrophin to Neurokine. Trends Neurosci., 1996. [DOI | PubMed]
118. T. Bisogno, S. Maurelli, D. Melck, L. De Petrocellis, V. Di Marzo. Biosynthesis, Uptake, and Degradation of Anandamide and Palmitoylethanolamide in Leukocytes. J. Biol. Chem., 1997. [DOI | PubMed]
119. G.G. Muccioli, N. Stella. Microglia Produce and Hydrolyze Palmitoylethanolamide. Neuropharmacology, 2008. [DOI | PubMed]
120. I. Bettoni, F. Comelli, A. Colombo, P. Bonfanti, B. Costa. Non-Neuronal Cell Modulation Relieves Neuropathic Pain: Efficacy of the Endogenous Lipid Palmitoylethanolamide. CNS Neurol. Disord. Drug Targets, 2013. [DOI | PubMed]
121. S.D. Skaper, L. Facci, P. Giusti. Glia and Mast Cells as Targets for Palmitoylethanolamide, an Anti-Inflammatory and Neuroprotective Lipid Mediator. Mol. Neurobiol., 2013. [DOI | PubMed]
122. A. Sayd, M. Antón, F. Alén, J.R. Caso, J. Pavón, J.C. Leza, F. Rodríguez de Fonseca, B. García-Bueno, L. Orio. Systemic Administration of Oleoylethanolamide Protects from Neuroinflammation and Anhedonia Induced by LPS in Rats. Int. J. Neuropsychopharmacol., 2014. [DOI | PubMed]
123. S.D. Skaper, A. Buriani, R. Dal Toso, L. Petrelli, S. Romanello, L. Facci, A. Leon. The ALIAmide Palmitoylethanolamide and Cannabinoids, but Not Anandamide, Are Protective in a Delayed Postglutamate Paradigm of Excitotoxic Death in Cerebellar Granule Neurons. Proc. Natl. Acad. Sci. USA, 1996. [DOI | PubMed]
124. M. Portavella, N. Rodriguez-Espinosa, P. Galeano, E. Blanco, J.I. Romero, M.I. Holubiec, F. Rodriguez de Fonseca, E. Fernández-Espejo. Oleoylethanolamide and Palmitoylethanolamide Protect Cultured Cortical Neurons Against Hypoxia. Cannabis Cannabinoid Res., 2018. [DOI | PubMed]
125. A. Musella, D. Fresegna, F.R. Rizzo, A. Gentile, S. Bullitta, F. De Vito, L. Guadalupi, D. Centonze, G. Mandolesi. A Novel Crosstalk within the Endocannabinoid System Controls GABA Transmission in the Striatum. Sci. Rep., 2017. [DOI | PubMed]
126. P. Ambrosino, M.V. Soldovieri, C. Russo, M. Taglialatela. Activation and Desensitization of TRPV1 Channels in Sensory Neurons by the PPARα Agonist Palmitoylethanolamide. Br. J. Pharmacol., 2013. [DOI | PubMed]
127. I.A. Khasabova, Y. Xiong, L.G. Coicou, D. Piomelli, V. Seybold. Peroxisome Proliferator-Activated Receptor α Mediates Acute Effects of Palmitoylethanolamide on Sensory Neurons. J. Neurosci. Off. J. Soc. Neurosci., 2012. [DOI]
128. M. Koch, S. Kreutz, C. Böttger, A. Benz, E. Maronde, C. Ghadban, H.-W. Korf, F. Dehghani. Palmitoylethanolamide Protects Dentate Gyrus Granule Cells via Peroxisome Proliferator-Activated Receptor-α. Neurotox. Res., 2011. [DOI | PubMed]
129. J. LoVerme, R. Russo, G. La Rana, J. Fu, J. Farthing, G. Mattace-Raso, R. Meli, A. Hohmann, A. Calignano, D. Piomelli. Rapid Broad-Spectrum Analgesia through Activation of Peroxisome Proliferator-Activated Receptor-Alpha. J. Pharmacol. Exp. Ther., 2006. [DOI | PubMed]
130. D.-S. Im. GPR119 and GPR55 as Receptors for Fatty Acid Ethanolamides, Oleoylethanolamide and Palmitoylethanolamide. Int. J. Mol. Sci., 2021. [DOI | PubMed]
131. M.I. Herrera, R. Kölliker-Frers, G. Barreto, E. Blanco, F. Capani. Glial Modulation by N-Acylethanolamides in Brain Injury and Neurodegeneration. Front. Aging Neurosci., 2016. [DOI]
132. B.N. Okine, M.K. Madasu, F. McGowan, C. Prendergast, J.C. Gaspar, B. Harhen, M. Roche, D.P. Finn. N-Palmitoylethanolamide in the Anterior Cingulate Cortex Attenuates Inflammatory Pain Behaviour Indirectly via a CB1 Receptor-Mediated Mechanism. Pain, 2016. [DOI | PubMed]
133. L. Campora, V. Miragliotta, E. Ricci, L. Cristino, V. Di Marzo, F. Albanese, M. Federica Della Valle, F. Abramo. Cannabinoid Receptor Type 1 and 2 Expression in the Skin of Healthy Dogs and Dogs with Atopic Dermatitis. Am. J. Vet. Res., 2012. [DOI | PubMed]
134. V. Miragliotta, P.L. Ricci, F. Albanese, A. Pirone, D. Tognotti, F. Abramo. Cannabinoid Receptor Types 1 and 2 and Peroxisome Proliferator-Activated Receptor-α: Distribution in the Skin of Clinically Healthy Cats and Cats with Hypersensitivity Dermatitis. Vet. Dermatol., 2018. [DOI | PubMed]
135. F. Mercati, C. Dall’Aglio, L. Pascucci, C. Boiti, P. Ceccarelli. Identification of Cannabinoid Type 1 Receptor in Dog Hair Follicles. Acta Histochem., 2012. [DOI | PubMed]
136. G. Polidoro, G. Galiazzo, F. Giancola, S. Papadimitriou, M. Kouki, S. Sabattini, A. Rigillo, R. Chiocchetti. Expression of Cannabinoid and Cannabinoid-Related Receptors in the Oral Mucosa of Healthy Cats and Cats with Chronic Gingivostomatitis. J. Feline Med. Surg., 2020. [DOI | PubMed]
137. A. Stanzani, G. Galiazzo, F. Giancola, C. Tagliavia, M. De Silva, M. Pietra, F. Fracassi, R. Chiocchetti. Localization of Cannabinoid and Cannabinoid Related Receptors in the Cat Gastrointestinal Tract. Histochem. Cell Biol., 2020. [DOI | PubMed]
138. G. Rossi, G. Gioacchini, G. Pengo, J.S. Suchodolski, A.E. Jergens, K. Allenspach, A. Gavazza, S. Scarpona, S. Berardi, L. Galosi. Enterocolic Increase of Cannabinoid Receptor Type 1 and Type 2 and Clinical Improvement after Probiotic Administration in Dogs with Chronic Signs of Colonic Dysmotility without Mucosal Inflammatory Changes. Neurogastroenterol. Motil. Off. J. Eur. Gastrointest. Motil. Soc., 2020. [DOI]
139. A. Pirone, C. Cantile, V. Miragliotta, C. Lenzi, E. Giannessi, B. Cozzi. Immunohistochemical Distribution of the Cannabinoid Receptor 1 and Fatty Acid Amide Hydrolase in the Dog Claustrum. J. Chem. Neuroanat., 2016. [DOI | PubMed]
140. J. Freundt-Revilla, F. Heinrich, A. Zoerner, F. Gesell, M. Beyerbach, M. Shamir, A. Oevermann, W. Baumgärtner, A. Tipold. The Endocannabinoid System in Canine Steroid-Responsive Meningitis-Arteritis and Intraspinal Spirocercosis. PLoS ONE, 2018. [DOI | PubMed]
141. J. Freundt-Revilla, K. Kegler, W. Baumgärtner, A. Tipold. Spatial Distribution of Cannabinoid Receptor Type 1 (CB1) in Normal Canine Central and Peripheral Nervous System. PLoS ONE, 2017. [DOI | PubMed]
142. M. Fernández-Trapero, F. Espejo-Porras, C. Rodríguez-Cueto, J.R. Coates, C. Pérez-Díaz, E. de Lago, J. Fernández-Ruiz. Upregulation of CB2 Receptors in Reactive Astrocytes in Canine Degenerative Myelopathy, a Disease Model of Amyotrophic Lateral Sclerosis. Dis. Model. Mech., 2017. [DOI | PubMed]
143. R. Chiocchetti, G. Galiazzo, C. Tagliavia, A. Stanzani, F. Giancola, M. Menchetti, G. Militerno, C. Bernardini, M. Forni, L. Mandrioli. Cellular Distribution of Canonical and Putative Cannabinoid Receptors in Canine Cervical Dorsal Root Ganglia. Front. Vet. Sci., 2019. [DOI | PubMed]
144. A. Calignano, G. La Rana, A. Giuffrida, D. Piomelli. Control of Pain Initiation by Endogenous Cannabinoids. Nature, 1998. [DOI | PubMed]
145. D. Piomelli, O. Sasso. Peripheral Gating of Pain Signals by Endogenous Lipid Mediators. Nat. Neurosci., 2014. [DOI | PubMed]
146. A.M. Habib, A.L. Okorokov, M.N. Hill, J.T. Bras, M.-C. Lee, S. Li, S.J. Gossage, M. van Drimmelen, M. Morena, H. Houlden. Microdeletion in a FAAH Pseudogene Identified in a Patient with High Anandamide Concentrations and Pain Insensitivity. Br. J. Anaesth., 2019. [DOI | PubMed]
147. D. Adrian, M. Papich, R. Baynes, J. Murrell, B.D.X. Lascelles. Chronic Maladaptive Pain in Cats: A Review of Current and Future Drug Treatment Options. Vet. J., 2017. [DOI | PubMed]
148. G. Della Rocca, M.B. Conti. Terapie Palliative E Cure Di Fine Vita In Medicina Veterinaria, 2018
149. A.J. Wiese, W.W. Muir, T.E. Wittum. Characteristics of Pain and Response to Analgesic Treatment in Dogs and Cats Examined at a Veterinary Teaching Hospital Emergency Service. J. Am. Vet. Med. Assoc., 2005. [DOI | PubMed]
150. W.W. Muir, A.J. Wiese, T.E. Wittum. Prevalence and Characteristics of Pain in Dogs and Cats Examined as Outpatients at a Veterinary Teaching Hospital. J. Am. Vet. Med. Assoc., 2004. [DOI | PubMed]
151. M.E. Epstein. Feline Neuropathic Pain. Vet. Clin. N. Am. Small Anim. Pract., 2020. [DOI | PubMed]
152. D.G. O’Neill, D.B. Church, P.D. McGreevy, P.C. Thomson, D.C. Brodbelt. Prevalence of Disorders Recorded in Dogs Attending Primary-Care Veterinary Practices in England. PLoS ONE, 2014. [DOI | PubMed]
153. K.L. Anderson, D.G. O’Neill, D.C. Brodbelt, D.B. Church, R.L. Meeson, D. Sargan, J.F. Summers, H. Zulch, L.M. Collins. Prevalence, Duration and Risk Factors for Appendicular Osteoarthritis in a UK Dog Population under Primary Veterinary Care. Sci. Rep., 2018. [DOI | PubMed]
154. R.A. Pettitt, A.J. German. Investigation and Management of Canine Osteoarthritis. Practice, 2015. [DOI]
155. S.A. Johnston. Osteoarthritis: Joint Anatomy, Physiology, and Pathobiology. Vet. Clin. N. Am. Small Anim. Pract., 1997. [DOI]
156. B.D.X. Lascelles, Y.-H. Dong, D.J. Marcellin-Little, A. Thomson, S. Wheeler, M. Correa. Relationship of Orthopedic Examination, Goniometric Measurements, and Radiographic Signs of Degenerative Joint Disease in Cats. BMC Vet. Res., 2012. [DOI | PubMed]
157. B.D.X. Lascelles, J.B. Henry, J. Brown, I. Robertson, A.T. Sumrell, W. Simpson, S. Wheeler, B.D. Hansen, H. Zamprogno, M. Freire. Cross-Sectional Study of the Prevalence of Radiographic Degenerative Joint Disease in Domesticated Cats. Vet. Surg. VS, 2010. [DOI | PubMed]
158. M.E. Gruen, P. White, B. Hare. Do Dog Breeds Differ in Pain Sensitivity? Veterinarians and the Public Believe They Do. PLoS ONE, 2020. [DOI | PubMed]
159. G. Della Rocca, A. Catanzaro, A.D. Salvo, M.E. Goldberg. Diagnosis of Pain in Small Companion Animals. Am. J. Anim. Vet. Sci., 2015. [DOI]
160. B.P. Monteiro, P.V. Steagall. Chronic Pain in Cats: Recent Advances in Clinical Assessment. J. Feline Med. Surg., 2019. [DOI | PubMed]
161. P.D. MacFarlane, A.S. Tute, B. Alderson. Therapeutic Options for the Treatment of Chronic Pain in Dogs. J. Small Anim. Pract., 2014. [DOI | PubMed]
162. T. Grubb. Where Do We Go from Here? Future Treatment Strategies for Chronic Pain. Top. Companion Anim. Med., 2010. [DOI | PubMed]
163. B.P. Monteiro-Steagall, P.V.M. Steagall, B.D.X. Lascelles. Systematic Review of Nonsteroidal Anti-Inflammatory Drug-Induced Adverse Effects in Dogs. J. Vet. Intern. Med., 2013. [DOI | PubMed]
164. B. KuKanich. Outpatient Oral Analgesics in Dogs and Cats beyond Nonsteroidal Antiinflammatory Drugs: An Evidence-Based Approach. Vet. Clin. N. Am. Small Anim. Pract., 2013. [DOI | PubMed]
165. T. Grubb, H. Lobprise. Local and Regional Anaesthesia in Dogs and Cats: Overview of Concepts and Drugs (Part 1). Vet. Med. Sci., 2020. [DOI | PubMed]
166. M. Goich, A. Bascuñán, P. Faúndez, A. Valdés. Multimodal Analgesia for Treatment of Allodynia and Hyperalgesia after Major Trauma in a Cat. JFMS Open Rep., 2019. [DOI | PubMed]
167. T.M. Fan. Pain Management in Veterinary Patients with Cancer. Vet. Clin. N. Am. Small Anim. Pract., 2014. [DOI | PubMed]
168. S. Petrosino, M. Cordaro, R. Verde, A. Schiano Moriello, G. Marcolongo, C. Schievano, R. Siracusa, F. Piscitelli, A.F. Peritore, R. Crupi. Oral Ultramicronized Palmitoylethanolamide: Plasma and Tissue Levels and Spinal Anti-Hyperalgesic Effect. Front. Pharmacol., 2018. [DOI | PubMed]
169. S. Sareen, G. Mathew, L. Joseph. Improvement in Solubility of Poor Water-Soluble Drugs by Solid Dispersion. Int. J. Pharm. Investig., 2012. [DOI]
170. D. Impellizzeri, M. Campolo, R. Di Paola, G. Bruschetta, D. de Stefano, E. Esposito, S. Cuzzocrea. Ultramicronized Palmitoylethanolamide Reduces Inflammation an a Th1-Mediated Model of Colitis. Eur. J. Inflamm., 2015. [DOI]
171. E.R. Nestmann. Safety of Micronized Palmitoylethanolamide (MicroPEA): Lack of Toxicity and Genotoxic Potential. Food Sci. Nutr., 2017. [DOI | PubMed]
172. D. Impellizzeri, G. Bruschetta, M. Cordaro, R. Crupi, R. Siracusa, E. Esposito, S. Cuzzocrea. Micronized/Ultramicronized Palmitoylethanolamide Displays Superior Oral Efficacy Compared to Nonmicronized Palmitoylethanolamide in a Rat Model of Inflammatory Pain. J. Neuroinflamm., 2014. [DOI]
173. A. Al Shoyaib, S.R. Archie, V.T. Karamyan. Intraperitoneal Route of Drug Administration: Should It Be Used in Experimental Animal Studies?. Pharm. Res., 2019. [DOI | PubMed]
174. A. Calignano, G. La Rana, D. Piomelli. Antinociceptive Activity of the Endogenous Fatty Acid Amide, Palmitylethanolamide. Eur. J. Pharmacol., 2001. [DOI | PubMed]
175. M.L. Bartolucci, I. Marini, F. Bortolotti, D. Impellizzeri, R. Di Paola, G. Bruschetta, R. Crupi, M. Portelli, A. Militi, G. Oteri. Micronized Palmitoylethanolamide Reduces Joint Pain and Glial Cell Activation. Inflamm. Res. Off. J. Eur. Histamine Res. Soc. Al, 2018. [DOI]
176. L. Di Cesare Mannelli, F. Corti, L. Micheli, M. Zanardelli, C. Ghelardini. Delay of Morphine Tolerance by Palmitoylethanolamide. BioMed Res. Int., 2015. [DOI | PubMed]
177. L. Di Cesare Mannelli, L. Micheli, E. Lucarini, C. Ghelardini. Ultramicronized N-Palmitoylethanolamine Supplementation for Long-Lasting, Low-Dosed Morphine Antinociception. Front. Pharmacol., 2018. [DOI | PubMed]
178. A. González-Hernández, G. Martínez-Lorenzana, J. Rodríguez-Jiménez, G. Rojas-Piloni, M. Condés-Lara. Intracisternal Injection of Palmitoylethanolamide Inhibits the Peripheral Nociceptive Evoked Responses of Dorsal Horn Wide Dynamic Range Neurons. J. Neural Transm. Vienna Austria 1996, 2015. [DOI | PubMed]
179. S. Mazzari, R. Canella, L. Petrelli, G. Marcolongo, A. Leon. N-(2-Hydroxyethyl)Hexadecanamide Is Orally Active in Reducing Edema Formation and Inflammatory Hyperalgesia by down-Modulating Mast Cell Activation. Eur. J. Pharmacol., 1996. [DOI | PubMed]
180. S.I. Jaggar, F.S. Hasnie, S. Sellaturay, A.S. Rice. The Anti-Hyperalgesic Actions of the Cannabinoid Anandamide and the Putative CB2 Receptor Agonist Palmitoylethanolamide in Visceral and Somatic Inflammatory Pain. Pain, 1998. [DOI | PubMed]
181. S. Conti, B. Costa, M. Colleoni, D. Parolaro, G. Giagnoni. Antiinflammatory Action of Endocannabinoid Palmitoylethanolamide and the Synthetic Cannabinoid Nabilone in a Model of Acute Inflammation in the Rat. Br. J. Pharmacol., 2002. [DOI | PubMed]
182. W.P. Farquhar-Smith, S.I. Jaggar, A.S.C. Rice. Attenuation of Nerve Growth Factor-Induced Visceral Hyperalgesia via Cannabinoid CB(1) and CB(2)-like Receptors. Pain, 2002. [DOI | PubMed]
183. G. D’Agostino, G. La Rana, R. Russo, O. Sasso, A. Iacono, E. Esposito, G. Mattace Raso, S. Cuzzocrea, J. Loverme, D. Piomelli. Central Administration of Palmitoylethanolamide Reduces Hyperalgesia in Mice via Inhibition of NF-KappaB Nuclear Signalling in Dorsal Root Ganglia. Eur. J. Pharmacol., 2009. [DOI | PubMed]
184. D. De Filippis, L. Luongo, M. Cipriano, E. Palazzo, M.P. Cinelli, V. de Novellis, S. Maione, T. Iuvone. Palmitoylethanolamide Reduces Granuloma-Induced Hyperalgesia by Modulation of Mast Cell Activation in Rats. Mol. Pain, 2011. [DOI | PubMed]
185. L. Luongo, F. Guida, S. Boccella, G. Bellini, L. Gatta, F. Rossi, V. de Novellis, S. Maione. Palmitoylethanolamide Reduces Formalin-Induced Neuropathic-like Behaviour through Spinal Glial/Microglial Phenotypical Changes in Mice. CNS Neurol. Disord. Drug Targets, 2013. [DOI | PubMed]
186. G. Donvito, I. Bettoni, F. Comelli, A. Colombo, B. Costa. Palmitoylethanolamide Relieves Pain and Preserves Pancreatic Islet Cells in a Murine Model of Diabetes. CNS Neurol. Disord. Drug Targets, 2015. [DOI | PubMed]
187. D. Britti, R. Crupi, D. Impellizzeri, E. Gugliandolo, R. Fusco, C. Schievano, V.M. Morittu, M. Evangelista, R. Di Paola, S. Cuzzocrea. A Novel Composite Formulation of Palmitoylethanolamide and Quercetin Decreases Inflammation and Relieves Pain in Inflammatory and Osteoarthritic Pain Models. BMC Vet. Res., 2017. [DOI | PubMed]
188. W.P. Farquhar-Smith, A.S. Rice. Administration of Endocannabinoids Prevents a Referred Hyperalgesia Associated with Inflammation of the Urinary Bladder. Anesthesiology, 2001. [DOI | PubMed]
189. W.P. Farquhar-Smith, A.S.C. Rice. A Novel Neuroimmune Mechanism in Cannabinoid-Mediated Attenuation of Nerve Growth Factor-Induced Hyperalgesia. Anesthesiology, 2003. [DOI | PubMed]
190. V.L. Haller, D.L. Cichewicz, S.P. Welch. Non-Cannabinoid CB1, Non-Cannabinoid CB2 Antinociceptive Effects of Several Novel Compounds in the PPQ Stretch Test in Mice. Eur. J. Pharmacol., 2006. [DOI | PubMed]
191. F. Pessina, R. Capasso, F. Borrelli, T. Aveta, L. Buono, G. Valacchi, P. Fiorenzani, V. Di Marzo, P. Orlando, A.A. Izzo. Protective Effect of Palmitoylethanolamide in a Rat Model of Cystitis. J. Urol., 2015. [DOI | PubMed]
192. Z. Helyes, J. Németh, M. Thán, K. Bölcskei, E. Pintér, J. Szolcsányi. Inhibitory Effect of Anandamide on Resiniferatoxin-Induced Sensory Neuropeptide Release in Vivo and Neuropathic Hyperalgesia in the Rat. Life Sci., 2003. [DOI | PubMed]
193. T. Genovese, E. Esposito, E. Mazzon, R. Di Paola, R. Meli, P. Bramanti, D. Piomelli, A. Calignano, S. Cuzzocrea. Effects of Palmitoylethanolamide on Signaling Pathways Implicated in the Development of Spinal Cord Injury. J. Pharmacol. Exp. Ther., 2008. [DOI | PubMed]
194. B. Costa, F. Comelli, I. Bettoni, M. Colleoni, G. Giagnoni. The Endogenous Fatty Acid Amide, Palmitoylethanolamide, Has Anti-Allodynic and Anti-Hyperalgesic Effects in a Murine Model of Neuropathic Pain: Involvement of CB(1), TRPV1 and PPARgamma Receptors and Neurotrophic Factors. Pain, 2008. [DOI | PubMed]
195. F. Guida, L. Luongo, F. Marmo, R. Romano, M. Iannotta, F. Napolitano, C. Belardo, I. Marabese, A. D’Aniello, D. De Gregorio. Palmitoylethanolamide Reduces Pain-Related Behaviors and Restores Glutamatergic Synapses Homeostasis in the Medial Prefrontal Cortex of Neuropathic Mice. Mol. Brain, 2015. [DOI | PubMed]
196. D. Impellizzeri, A.F. Peritore, M. Cordaro, E. Gugliandolo, R. Siracusa, R. Crupi, R. D’Amico, R. Fusco, M. Evangelista, S. Cuzzocrea. The Neuroprotective Effects of Micronized PEA (PEA-m) Formulation on Diabetic Peripheral Neuropathy in Mice. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol., 2019. [DOI | PubMed]
197. A.F. Peritore, R. Siracusa, R. Fusco, E. Gugliandolo, R. D’Amico, M. Cordaro, R. Crupi, T. Genovese, D. Impellizzeri, S. Cuzzocrea. Ultramicronized Palmitoylethanolamide and Paracetamol, a New Association to Relieve Hyperalgesia and Pain in a Sciatic Nerve Injury Model in Rat. Int. J. Mol. Sci., 2020. [DOI | PubMed]
198. S. Boccella, I. Marabese, M. Iannotta, C. Belardo, V. Neugebauer, M. Mazzitelli, G. Pieretti, S. Maione, E. Palazzo. Metabotropic Glutamate Receptor 5 and 8 Modulate the Ameliorative Effect of Ultramicronized Palmitoylethanolamide on Cognitive Decline Associated with Neuropathic Pain. Int. J. Mol. Sci., 2019. [DOI | PubMed]
199. M. Alsalem, M. Haddad, S.A. Aldossary, H. Kalbouneh, A. Altarifi, S.M. Jaffal, M.A. Abbas, N. Aldaoud, K. El-Salem. Role of Cannabinoid Receptor 1 and the Peroxisome Proliferator-Activated Receptor α in Mediating Anti-Nociceptive Effects of Synthetic Cannabinoids and a Cannabinoid-like Compound. Inflammopharmacology, 2019. [DOI | PubMed]
200. F. Guida, S. Boccella, C. Belardo, M. Iannotta, F. Piscitelli, F. De Filippis, S. Paino, F. Ricciardi, D. Siniscalco, I. Marabese. Altered Gut Microbiota and Endocannabinoid System Tone in Vitamin D Deficiency-Mediated Chronic Pain. Brain. Behav. Immun., 2020. [DOI | PubMed]
201. A.M. Tagne, Y. Fotio, L. Lin, E. Squire, F. Ahmed, T.I. Rashid, E.K. Azari, D. Piomelli. Palmitoylethanolamide and Hemp Oil Extract Exert Synergistic Anti-Nociceptive Effects in Mouse Models of Acute and Chronic Pain. Pharmacol. Res., 2021. [DOI | PubMed]
202. O. Sasso, R. Russo, S. Vitiello, G.M. Raso, G. D’Agostino, A. Iacono, G. La Rana, M. Vallée, S. Cuzzocrea, P.V. Piazza. Implication of Allopregnanolone in the Antinociceptive Effect of N-Palmitoylethanolamide in Acute or Persistent Pain. Pain, 2012. [DOI | PubMed]
203. L. Di Cesare Mannelli, G. D’Agostino, A. Pacini, R. Russo, M. Zanardelli, C. Ghelardini, A. Calignano. Palmitoylethanolamide Is a Disease-Modifying Agent in Peripheral Neuropathy: Pain Relief and Neuroprotection Share a PPAR-Alpha-Mediated Mechanism. Mediat. Inflamm., 2013. [DOI]
204. F. Guida, S. Boccella, M. Iannotta, D. De Gregorio, C. Giordano, C. Belardo, R. Romano, E. Palazzo, M.A. Scafuro, N. Serra. Palmitoylethanolamide Reduces Neuropsychiatric Behaviors by Restoring Cortical Electrophysiological Activity in a Mouse Model of Mild Traumatic Brain Injury. Front. Pharmacol., 2017. [DOI | PubMed]
205. N. Soliman, S. Haroutounian, A.G. Hohmann, E. Krane, J. Liao, M. Macleod, D. Segelcke, C. Sena, J. Thomas, J. Vollert. A Systematic Review and Meta-Analysis of Cannabis-Based Medicines, Cannabinoids and Endocannabinoid System Modulators Tested for Antinociceptive Effects in Animal Models of Injury-Related or Pathological Persistent Pain. Pain, 2021. [DOI | PubMed]
206. G. Guida, M. de Martino, A. de Fabiani, L. Canteri, A. Alexandre, G. Vassallo, M. Rogai, F. Lanaia, S. Petrosino. La Palmitoiletanolamida (Normast®) En El Dolor Neuropático Crónico Por Lumbociatalgia de Tipo Compresivo: Estudio Clínico Multicéntrico. Dolor, 2010
207. A. Assini, D. Laricchia, R. Pizzo, L. Pandolfini, M. Belletti, M. Colucci, S. Ratto. The Carpal Tunnel Syndrome in Diabetes: Clinical and Electrophysiological Improvement after Treatment with Palmitoylethanolamide. Eur. J. Neurol., 2010. [DOI | PubMed]
208. A. Biasiotta, S.L. Cesa, C. Leone, G.D. Stefano, A. Truini, G. Cruccu. 265 Efficacy of Palmitoylethanolamide in Patients with Painful Neuropathy. A Clinical and Neurophysiological Open Study. Preliminary Results. Eur. J. Pain Suppl., 2010. [DOI]
209. C. Schifilliti, L. Cucinotta, V. Fedele, C. Ingegnosi, G. Savoca, C. Leotta. Palmitoylethanolamide Reduces the Symptoms of Neuropathic Pain in Diabetic Patients. Shock, 2011. [PubMed]
210. A. Assini, D. Laricchia, R. Pizzo. Tunnel Carpale Nel Paziente Diabetico Migliloramento Clinico Ed Elettrofisiologico Dopo Trattamento Con Palmitoiletanolamide. Carpal Tunnel Syndrome in the Diabetic Patient. Clinical and Electrophysiologic Improvement after Treatment with Palmitoylethanolamide. Proceedings of the 34th National Congress AISD—New Frontiers in Pain Medicine
211. R. Conigliaro, V. Drago, P.S. Foster, C. Schievano, V. Di Marzo. Use of Palmitoylethanolamide in the Entrapment Neuropathy of the Median in the Wrist. Minerva Med., 2011. [PubMed]
212. A. Truini, A. Biasiotta, G. Di Stefano, S. La Cesa, C. Leone, C. Cartoni, V. Federico, M.T. Petrucci, G. Cruccu. Palmitoylethanolamide Restores Myelinated-Fibre Function in Patients with Chemotherapy-Induced Painful Neuropathy. CNS Neurol. Disord. Drug Targets, 2011. [DOI | PubMed]
213. C. Schifilliti, L. Cucinotta, V. Fedele, C. Ingegnosi, S. Luca, C. Leotta. Micronized Palmitoylethanolamide Reduces the Symptoms of Neuropathic Pain in Diabetic Patients. Pain Res. Treat., 2014. [DOI | PubMed]
214. Z. Alshelh, E.P. Mills, D. Kosanovic, F. Di Pietro, P.M. Macey, E.R. Vickers, L.A. Henderson. Effects of the Glial Modulator Palmitoylethanolamide on Chronic Pain Intensity and Brain Function. J. Pain Res., 2019. [DOI | PubMed]
215. G. Ottaviani, K. Rupel, M. Gobbo, A. Poropat, V. Zoi, M. Faraon, R. Di Lenarda, M. Biasotto. Efficacy of Ultramicronized Palmitoylethanolamide in Burning Mouth Syndrome-Affected Patients: A Preliminary Randomized Double-Blind Controlled Trial. Clin. Oral Investig., 2019. [DOI]
216. G. Cruccu, G.D. Stefano, P. Marchettini, A. Truini. Micronized Palmitoylethanolamide: A Post Hoc Analysis of a Controlled Study in Patients with Low Back Pain—Sciatica. CNS Neurol. Disord. Drug Targets, 2019. [DOI | PubMed]
217. G. Mancardi, M. Infante, E. Capello, M. Sormani, A. Uccelli. La Palmitoiletanolamide Allevia Il Dolore Neuropatico Associato Alla Sclerosi Multipla. Palmitoylethanolamide Relieves Neuropathic Pain Associated with Multiple Sclerosis. Proceedings of the XL Congress of the Italian Society of Neurology
218. G. Dalla Volta, P. Zavarize, G.F. Ngonga, D. Carli. Ultramicronized Palmitoylethanolamide Reduces Frequency and Pain Intensity in Migraine. A Pilot Study. Int. J. Neurol. Brain Disord., 2016. [DOI]
219. D. Chirchiglia, A. Della Torre, F. Signorelli, G. Volpentesta, G. Guzzi, C.A. Stroscio, F. Deodato, D. Gabriele, A. Lavano. Administration of Palmitoylethanolamide in Combination with Topiramate in the Preventive Treatment of Nummular Headache. Int. Med. Case Rep. J., 2016. [DOI | PubMed]
220. R.S. Calabrò, P. Bramanti. Occipital Neuralgia Responding to Palmitoylethanolamide. Headache, 2017. [DOI | PubMed]
221. D. Chirchiglia, E. Cione, M.C. Caroleo, M. Wang, G. Di Mizio, N. Faedda, T. Giacolini, S. Siviglia, V. Guidetti, L. Gallelli. Effects of Add-On Ultramicronized N-Palmitol Ethanol Amide in Patients Suffering of Migraine With Aura: A Pilot Study. Front. Neurol., 2018. [DOI | PubMed]
222. L. Papetti, G. Sforza, G. Tullo, P. Alaimo di Loro, R. Moavero, F. Ursitti, M.A.N. Ferilli, S. Tarantino, F. Vigevano, M. Valeriani. Tolerability of Palmitoylethanolamide in a Pediatric Population Suffering from Migraine: A Pilot Study. Pain Res. Manag., 2020. [DOI | PubMed]
223. I. Marini, M.L. Bartolucci, F. Bortolotti, M.R. Gatto, G.A. Bonetti. Palmitoylethanolamide versus a Nonsteroidal Anti-Inflammatory Drug in the Treatment of Temporomandibular Joint Inflammatory Pain. J. Orofac. Pain, 2012. [PubMed]
224. E. Steels, R. Venkatesh, E. Steels, G. Vitetta, L. Vitetta. A Double-Blind Randomized Placebo Controlled Study Assessing Safety, Tolerability and Efficacy of Palmitoylethanolamide for Symptoms of Knee Osteoarthritis. Inflammopharmacology, 2019. [DOI | PubMed]
225. I. Sani, Y. Hamza. A Systematic Review on the Effectiveness of Palmitoylethanolamide for the Treatment of Pain in Arthrogenic Temporomandibular Joint Dysfunction and Related Disorders. J. Dent. Maxillofac. Res., 2019. [DOI]
226. L. Canteri, S. Petrosino, G. Guida. Reducción Del Consumo de Antiinflamatorios y Analgésicos En El Tratamiento Del Dolor Neuropático Crónico En Pacientes Afectados Por Lumbociatalgia de Tipo Compresivo y En Tratamiento Con Normast® 300 Mg. Dolor, 2010
227. P. Desio. Associazione tra pregabalin e palmitoiletanolamide (PEA) per il trattamento del dolore neuropatico. Pathos, 2010
228. R.A. Palomba, S. Adiletta, A. Candiello, M. Penimpede, P. Bonaccia, C.J. De Martino. Analgesia multimodale per il dolore cronico: Direttive future e razionale. Multimodal analgesia for chronic pain: Rationale and future directions. Proceedings of the 33rd National Congress of the Italian Association for the Study of Pain (AISD)
229. C.M. Dominguez, A.A. Diaz Martin, F.G. Ferrer. Palmitoiletanolamida (PEA) En Lumbociatica En Asociacion al Tratamiento Habitual. Palmitoylethanolamide in Lumbosciatic Pain in Association with Standard Therapy. Proceedings of the 8th National Congress of the Sociedad Española Del Dolor
230. P. Desio. Associazione Dell’ossicodone a Lenta Titolazione Con Palmitoiletanolamide per Il Trattamento Del Low Back Pain. Anest. E Med. Crit. AMC, 2011
231. A. Di Paolo, V. Gianfelice, C. Silvestri. La Palmitoiletanolamide Nel Trattamento Del Dolore Attivato Dal Sistema Gliale: Nostra Esperienza. Palmitoylethanolamide in the Management of Glia-Activated Pain. Our Experience. Proceedings of the 34th National Congress of the Italian Association for the Study of Pain (AISD)
232. S. Adiletta, A. Candiello, D. Arminio, S. Porcaro, M.M. Saporito, R. Palomba. Sinergismo Tra Pregabalin e Palmitoiletanolamide (PEA) Nel Trattamento Della Neuropatia Diabetica. Proceedings of the 34th National Congress of the Italian Association for the Study of Pain (AISD)
233. C.M. Domínguez, A.D. Martín, F.G. Ferrer, M.I. Puertas, A.L. Muro, J.M. González, J.P. Prieto, I.R. Taberna. N-Palmitoylethanolamide in the Treatment of Neuropathic Pain Associated with Lumbosciatica. Pain Manag., 2012. [DOI | PubMed]
234. A. Gatti, M. Lazzari, V. Gianfelice, A. Di Paolo, E. Sabato, A.F. Sabato. Palmitoylethanolamide in the Treatment of Chronic Pain Caused by Different Etiopathogenesis. Pain Med. Malden Mass, 2012. [DOI]
235. D. Cocito, E. Peci, P. Ciaramitaro, A. Merola, L. Lopiano. Short-Term Efficacy of Ultramicronized Palmitoylethanolamide in Peripheral Neuropathic Pain. Pain Res. Treat., 2014. [DOI | PubMed]
236. R. Del Giorno, S. Skaper, A. Paladini, G. Varrassi, S. Coaccioli. Palmitoylethanolamide in Fibromyalgia: Results from Prospective and Retrospective Observational Studies. Pain Ther., 2015. [DOI | PubMed]
237. P. Desio. Aliamidi e duloxetina nel trattamento del low back pain Aliamides and duloxetina in the treatment of low back pain. Pathos, 2016
238. A. Paladini, G. Varrassi, G. Bentivegna, S. Carletti, A. Piroli, S. Coaccioli. Palmitoylethanolamide in the Treatment of Failed Back Surgery Syndrome. Pain Res. Treat., 2017. [DOI | PubMed]
239. F. Germini, A. Coerezza, L. Andreinetti, A. Nobili, P.D. Rossi, D. Mari, G. Guyatt, M. Marcucci. N-of-1 Randomized Trials of Ultra-Micronized Palmitoylethanolamide in Older Patients with Chronic Pain. Drugs Aging, 2017. [DOI | PubMed]
240. M.B. Passavanti, M. Fiore, P. Sansone, C. Aurilio, V. Pota, M. Barbarisi, D. Fierro, M.C. Pace. The Beneficial Use of Ultramicronized Palmitoylethanolamide as Add-on Therapy to Tapentadol in the Treatment of Low Back Pain: A Pilot Study Comparing Prospective and Retrospective Observational Arms. BMC Anesthesiol., 2017. [DOI | PubMed]
241. D. Chirchiglia, P. Chirchiglia, F. Signorelli. Nonsurgical Lumbar Radiculopathies Treated with Ultramicronized Palmitoylethanolamide (UmPEA): A Series of 100 Cases. Neurol. Neurochir. Pol., 2018. [DOI | PubMed]
242. D. Chirchiglia, S. Paventi, P. Seminara, E. Cione, L. Gallelli. N-Palmitoyl Ethanol Amide Pharmacological Treatment in Patients With Nonsurgical Lumbar Radiculopathy. J. Clin. Pharmacol., 2018. [DOI | PubMed]
243. M. Evangelista, V. Cilli, R. De Vitis, A. Militerno, F. Fanfani. Ultra-Micronized Palmitoylethanolamide Effects on Sleep-Wake Rhythm and Neuropathic Pain Phenotypes in Patients with Carpal Tunnel Syndrome: An Open-Label, Randomized Controlled Study. CNS Neurol. Disord. Drug Targets, 2018. [DOI | PubMed]
244. D. Chirchiglia, P. Chirchiglia, R. Marotta, L. Gallelli. Add-on Administration of Ultramicronized Palmitoylethanolamide in the Treatment of New-Onset Burning Mouth Syndrome. Int. Med. Case Rep. J., 2019. [DOI | PubMed]
245. D. Scaturro, C. Asaro, L. Lauricella, S. Tomasello, G. Varrassi, G. Letizia Mauro. Combination of Rehabilitative Therapy with Ultramicronized Palmitoylethanolamide for Chronic Low Back Pain: An Observational Study. Pain Ther., 2020. [DOI | PubMed]
246. V. Schweiger, A. Martini, P. Bellamoli, K. Donadello, C. Schievano, G.D. Balzo, P. Sarzi-Puttini, M. Parolini, E. Polati. Ultramicronized Palmitoylethanolamide (Um-PEA) as Add-on Treatment in Fibromyalgia Syndrome (FMS): Retrospective Observational Study on 407 Patients. CNS Neurol. Disord. Drug Targets, 2019. [DOI | PubMed]
247. M. Parabita, R.M.D. Amore, F. Marinosci, M.G. Matera, A. Izzo, G.A. Russo. Reduction of Post Stroke Spasticity with Palmitoylethanolamide Treatment. Shock, 2011
248. I. Marini, M. Cavallaro, M. Bartolucci, A. Alessandri-Bonetti, M. Gatto, M. Cordaro, L. Checchi. Can Celecoxib Enhance Palmitoylethanolamide’s Effect in the Treatment of Temporo-Mandibular Arthralgia in Osteoarthritis Patients?. J. Transl. Sci., 2018. [DOI]
249. C. Caltagirone, C. Cisari, C. Schievano, R. Di Paola, M. Cordaro, G. Bruschetta, E. Esposito, S. Cuzzocrea. Co-Ultramicronized Palmitoylethanolamide/Luteolin in the Treatment of Cerebral Ischemia: From Rodent to Man. Transl. Stroke Res., 2016. [DOI | PubMed]
250. R. Palomba, M. De Simone, A. Giovannini, P. Bonaccia, D. Pinto. Use of Palmitoylethanolamide (PEA) + Polydatin in the Chronic Pelvic Pain. Proceedings of the 64th National Congress of the Italian Society of Anesthesia, Analgesia and Intensive Care (SIAARTI)
251. A. Fulghesu, R. Magnini, S. Mazzella, A. Cappai, A. Orrù, M. Pisu. Treatment of Adolescent Dysmenorrhea by a New Inhibitor of Mast Cells-Induced Infiammation (Palmitoylethanolamide + Trans Polidatin). Proceedings of the 16th World Congress of Pediatric and Adolescent Gynecology
252. U. Indraccolo, F. Barbieri. Effect of Palmitoylethanolamide-Polydatin Combination on Chronic Pelvic Pain Associated with Endometriosis: Preliminary Observations. Eur. J. Obstet. Gynecol. Reprod. Biol., 2010. [DOI | PubMed]
253. R.S. Calabrò, G. Gervasi, S. Marino, P.N. Mondo, P. Bramanti. Misdiagnosed Chronic Pelvic Pain: Pudendal Neuralgia Responding to a Novel Use of Palmitoylethanolamide. Pain Med. Malden Mass, 2010. [DOI | PubMed]
254. L. Cobellis, M.A. Castaldi, V. Giordano, E. Trabucco, P. De Franciscis, M. Torella, N. Colacurci. Effectiveness of the Association Micronized N-Palmitoylethanolamine (PEA)-Transpolydatin in the Treatment of Chronic Pelvic Pain Related to Endometriosis after Laparoscopic Assessment: A Pilot Study. Eur. J. Obstet. Gynecol. Reprod. Biol., 2011. [DOI | PubMed]
255. G. Lo Monte, I. Soave, R. Marci. Administration of micronized palmitoylethanolamide (PEA)-transpolydatin in the treatment of chronic pelvic pain in women affected by endometriosis: Preliminary results. Minerva Ginecol., 2013. [PubMed]
256. E. Giugliano, E. Cagnazzo, I. Soave, G. Lo Monte, J.M. Wenger, R. Marci. The Adjuvant Use of N-Palmitoylethanolamine and Transpolydatin in the Treatment of Endometriotic Pain. Eur. J. Obstet. Gynecol. Reprod. Biol., 2013. [DOI | PubMed]
257. F. Murina, A. Graziottin, R. Felice, G. Radici, C. Tognocchi. Vestibulodynia: Synergy between Palmitoylethanolamide + Transpolydatin and Transcutaneous Electrical Nerve Stimulation. J. Low. Genit. Tract Dis., 2013. [DOI | PubMed]
258. E. Tartaglia, M. Armentano, B. Giugliano, T. Sena, P. Giuliano, C. Loffredo, P. Mastrantonio. Effectiveness of the Association N-Palmitoylethanolamine and Transpolydatin in the Treatment of Primary Dysmenorrhea. J. Pediatr. Adolesc. Gynecol., 2015. [DOI | PubMed]
259. C. Cremon, V. Stanghellini, M.R. Barbaro, R.F. Cogliandro, L. Bellacosa, J. Santos, M. Vicario, M. Pigrau, C. Alonso Cotoner, B. Lobo. Randomised Clinical Trial: The Analgesic Properties of Dietary Supplementation with Palmitoylethanolamide and Polydatin in Irritable Bowel Syndrome. Aliment. Pharmacol. Ther., 2017. [DOI | PubMed]
260. E. Stochino Loi, A. Pontis, V. Cofelice, S. Pirarba, M.F. Fais, A. Daniilidis, I. Melis, A.M. Paoletti, S. Angioni. Effect of Ultramicronized-Palmitoylethanolamide and Co-Micronized Palmitoylethanolamide/Polydatin on Chronic Pelvic Pain and Quality of Life in Endometriosis Patients: An Open-Label Pilot Study. Int. J. Womens Health, 2019. [DOI | PubMed]
261. M. Cervigni, L. Nasta, C. Schievano, N. Lampropoulou, E. Ostardo. Micronized Palmitoylethanolamide-Polydatin Reduces the Painful Symptomatology in Patients with Interstitial Cystitis/Bladder Pain Syndrome. BioMed Res. Int., 2019. [DOI | PubMed]
262. B.B. Artukoglu, C. Beyer, A. Zuloff-Shani, E. Brener, M.H. Bloch. Efficacy of Palmitoylethanolamide for Pain: A Meta-Analysis. Pain Physician, 2017. [PubMed]
263. N.B. Finnerup, N. Attal, S. Haroutounian, E. McNicol, R. Baron, R.H. Dworkin, I. Gilron, M. Haanpää, P. Hansson, T.S. Jensen. Pharmacotherapy for Neuropathic Pain in Adults: A Systematic Review and Meta-Analysis. Lancet Neurol., 2015. [DOI | PubMed]
264. E. Gugliandolo, A. Barbagallo, A.F. Peritore, S. Cuzzocrea, R. Crupi. Oral Supplementation with Ultramicronized Palmitoylethanolamide for Joint Disease and Lameness Management in Four Jumping Horses: A Case Report. Amimals, 2020. [DOI]
265. A. Vezzoni, F. Crupi, S. Boiocchi, S. Boano. Effect of Palmitoylethanolamide Co-Ultra Micronized with Quercetin in Dogs with Osteoarthritis by Means of Dynamic Gate Analysis and Canine Brief Pain Inventory Questionnaire. Proceedings of the 5th World Veterinary Orthopaedic Congress ESVOT-VOS
266. M.S. Alkaitis, C. Solorzano, R.P. Landry, D. Piomelli, J.A. DeLeo, E.A. Romero-Sandoval. Evidence for a Role of Endocannabinoids, Astrocytes and P38 Phosphorylation in the Resolution of Postoperative Pain. PLoS ONE, 2010. [DOI | PubMed]
267. R. Guerrero-Alba, P. Barragán-Iglesias, A. González-Hernández, E.E. Valdez-Moráles, V. Granados-Soto, M. Condés-Lara, M.G. Rodríguez, B.A. Marichal-Cancino. Some Prospective Alternatives for Treating Pain: The Endocannabinoid System and Its Putative Receptors GPR18 and GPR55. Front. Pharmacol., 2018. [DOI | PubMed]
268. L. Luongo, S. Maione, V. Di Marzo. Endocannabinoids and Neuropathic Pain: Focus on Neuron-Glia and Endocannabinoid-Neurotrophin Interactions. Eur. J. Neurosci., 2014. [DOI | PubMed]
269. S. Maione, B. Costa, V. Di Marzo. Endocannabinoids: A Unique Opportunity to Develop Multitarget Analgesics. Pain, 2013. [DOI | PubMed]
270. A.D. Kaye, E.M. Cornett, B. Hart, S. Patil, A. Pham, M. Spalitta, K.F. Mancuso. Novel Pharmacological Nonopioid Therapies in Chronic Pain. Curr. Pain Headache Rep., 2018. [DOI | PubMed]