Nomast/PeaPure info for MDs: science and prescription info

Palmitoylethanolamide (‘PEA’) is a body-own compound and is in Europe available for the treatment of chronic pain and chronic inflammation under two brandnames: produced in Italy for consumers in Italy and Spain, and PeaPure (Russell Science Ltd), produced in the Netherlands and distributed internationally.

Most clinical data have been gathered and published around its efficacy in various neuropathic painstates, such as in diabetes, carpal tunnel syndrome, sciatic pain, and we outline these indications and the clinical and preclinical data below.

Palmitoylethanolamide has be described as an endogenous fatty acid amide, belonging to the class of endocannabinoids. Since 50 years of research around this molecule, the last decade the number of scientific papers on PEA’s biological and clinical activity has been expanded to nearly 300.

PEA has been demonstrated to bind to a receptor in the cell-nucleus ( a nuclear receptor, PPAR) and exerts a great varity of biological functions related to chronic pain and inflammation. It is considered as a breakthourgh in the treament of chonic pain, and with PEA a new mechanism of action in the world of analgesics has been introduced and validated in a great number of studies. PEA can be seen as a glia modulator and proof of principle (POP) as well as proof of concept (POC) has been generated via PEA studies of glia as an important factor in the genesis of neuropathic pain.

Main target of palmitoylethanolamide: PPAR-alpha receptor

The main biological target of PEA most probably is the peroxisome proliferator-activated receptor alpha (PPAR-α) [1][2] PEA also has affinity to G-coupled receptors, novel cannabinoid receptors, to date still with an unknown function, such as the GPR55 and GPR119. [3] However, its affinity for the classical cannabis receptors CB1 and CB2 is absent, and PEA’s mechanism of action intracellular is only converging with the mechanism of action of real CB 1 and CB2 endocannabinoids, such as anandaminde and 2-arachidonoylglycerol (2-AG), most probably via the nuclear receptor PPAR.

Therefore, PEA, and its structural analogue N-oleoylethanolamide, OEA, can not strictly be considered as classical endocannabinoids. [4] The absence of affinity for the CB1 receptor also explains the absence of psychotropic side effects of this compound in men and animals.

PEA has been shown to have anti-inflammatory, anti-nociceptive [5], neuroprotective [6], and anticonvulsant properties [7]

Palmitoylethanolamide is available for clinical use and is marketed in Italy and Spain under the trade name een PEA-houdend product. Two different formulations have been developed, a ultra-micronized formulation of palmitoylethanolamide for sublingual use, containing 600 mg, and palmitoylethanolamide in a tablet, in 300 and 600 mg.

Palmitoylethanolamide: ALIAmide and glia-modulator

Palmitoylethanolamide protects against injury, reason for the Nobel laureate Levi-Montalcini to create the new term Autocoid Local Anti-injury Aliamide for PEA and related compounds in 1993. Palmitoylethanolamide upregulates the PPAR receptor in times of injury, such as has been shown in a model of spinal cord injury. In this model, due to the injury, the PPAR recptor is down regulated, and, as a result many inflammatory cascades, leaading to tissue desctruction, are activated. PPAR inhibits these cascades. PEA upregulats the PPAR receptor, and accrodingly read outs like TNF- alpha and interleukines decrease, thus supporting PEA”s role as an modulator of inflammation and pain. [8]

PEA is has physico-chemical properties comparable to anandamide and is mostly referred to as belonging to the class of endogenous cannabinoids. Lipid molecules like PEA often act as signaling molecules, activating intracellular and membrane-associated receptors to regulate a variety of physiological functions.

The signaling lipid PEA is known to activate intracellular, nuclear and membrane-associated receptors and regulate many physiological functions related to the inflammatory cascade and chronic pain states. Endocannabinoid lipids like PEA are widely distributed in nature, in a variety of plant, invertebrate, and mammalian tissues. [9]

PEA’s mechanism of action sometimes is described using the acronym ALIA. [10] ALIA stands for Autacoid Local Injury (or inflammation) Antagonism, and PEA under this nomenclature is an ALIAmide.

It was the group of the Nobel price laureate Rita Levi-Montalcini as said, who in 1993 first presented evidence supporting that lipid amides of the N-acylethanolamine type (such as PEA) are potential prototypes of naturally ocurring molecules capable of modulating mast cell activation and her group coined in that paper the acronym ALIA. [11] An autocoid is a regulating molecule, locally produced. Prostaglandines are classical examples of autocoids. An ALIAmide is an autocoid synthesized in response to injury or inflammation, and acting locally to counteract such pathology.

PEA is a classical example of an ALIAmide. The mast cell soon after the breaktrough paper of Levi-Montalcini indeed appeared to be an important target for the anti-inflammatory activity of PEA, and in the period 1993-2011 at least 25 papers were published on the various effects of PEA on the mast cell. Since 2005 we understand that much of the biological effects on cells as the mast cell, most probably can be understood via its affinity of the PPAR receptor. Even rapid analgesic activity is partly described via the PPAR interaction. [12]

Mast cells are often found in proximity to sensory nerve endings and their degradation can enhance the nociceptive signal, the reason why peripheral mast cells are considered to be pro-inflammatory and pro-nociceptive.[13]

Mast cells also can be found in the spinal dura, the thalamus and the dura mater. Meanwhile, due to PEA’S affinity to the PPAR receptor and due to the wide presence of those receptors in the central nervous system, especially also in glia and asterocytes [14], PEA’s activity is currently seen as an important new inroad in the treatment of neuropathic pain. Glia and asterocytes play a key role in the winding up phenomena and central sensitization. [15] [16]

In the following video the Coalition for Chronic Pain presents the mechanism of action of PEA and the pathogenesis of neuropathic pain linked to glia and the asterocytes, were neuropathic pain is basically regarded as gliopathic pain from a pathogenetic point of view.

Palmitoylethanolamide: first clinical studies

In 1968 the first paper on PEA was indexed in Pubmed and since then more than 200 entries can be found, using the keyword ‘palmitoylethanolamide’.[17] In the 90s the relation between anandamide and PEA was described, and the expression on mastcells of receptors sensitive for those two molecules was first demonstrated. [10]

In this period more insight into the function of the endogenous fatty acid derivatives emerged, and compounds such as oleamide, palmitoylethanolamide, 2-lineoylglycerol, 2-palmitoylglycerol, all endocannabinoids, were explored for their capacity to modulate pain sensitivity and inflammation. [19][20]

One demonstrated that PEA could alleviate, in a dose-dependent manner, pain behaviors elicited in mice-pain models and could downregulate hyperactive mast cells. [5] [22]

Palmitoylethanolamide in animal models

In a variety of animal models PEA seems promising, and researchers could demonstrate relevant clinical activity in a variety of disorders, from multiple sclerosis to neuropathic pain. [23] [24]

In the so called mice forced swimming test palmitoylethanolamide was comparable in anti-depressant effects to fluoxetine. [25] Palmitoylethanolamide could reduced the raised intraocular pressure in glaucoma. [26] The compound could also reduce neurological deficit in a spinal trauma model, through the reduction of mast cell infiltration and activation. Palmitoylethanolamide in this model also reduced the activation of microglia and astrocytes. [8]

Its activity as an inhibitor of inflammation could counteracts reactive astrogliosis induced by beta-amyloid peptide, in a model relevant for neurodegeneration, most probably via the PPAR-α mechanism of action. [28] In models of stroke and other traumata of the central nervous system, palmitoylethanolamide exerted neuroprotective properties. [29][6][31][32][33]
Palmitoylethanolamide in animal models of chronic pain and inflammation

Chronic pain and neuropathic pain are indications for which there is high unmet need in the clinic. PEA has been tested In a variety of animal models for chronic and neuropathic pain. As Cannabinoids such as THC have been proven to be effective in neuropathic pain states, it makes sense to further explore the analgesic efficacy of endocannabinoids. [34] The analgesic and antihyperalgesic effects of PEA in two models of acute and persistent pain seemed to be explained at least partly via the de novo neurosteroid synthesis. [35] [36]

In chronic granulomatous pain and inflammation model PEA could prevent nerve formation and sprouting, mechanical allodynia, and PEA inhibited dorsal root ganglia activation, which is a hallmark for winding up in neuropathic pain. [37]The mechanism of action of PEA as an analgesic and anti-inflammatory drug is probably based on different aspects. PEA inhibits the release of both preformed and newly synthesised mast cell mediators, such as histamine and TNF-alpha. [38] PEA, as well as its analogue adelmidrol (di-amide derivative of azelaic acid) both can down-regulate mast cells. [39] PEA reduces the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) and prevents IkB-alpha degradation and p65 NF-kappaB nuclear translocation, the latter related to PEA as a endogenous PPAR-alpha agonist. [40]

In a model of visceral pain (inflammation of the urinary bladder) PEA was able to attenuate the viscero-visceral hyper-reflexia induced by inflammation of the urinary bladder, one of the reasons why PEA is currently explored in the painful bladdersyndrome. [41] In a different model for bladder pain, the turpentine-induced urinary bladder inflammation in the rat, PEA also attenuated a referred hyperalgesia in a dose-dependent way. [42] Chronic pelvic pain in patients indeed seems to respond favourably to a treatment with PEA. [43] [44]
PEA seems to be produced in human as well as in animals as a biological response and a repair mechanism in chronic inflammation and chronic pain.[45]

Palmitoylethanolamide: clinical perspective

PEA has been explored in man in various clinical trials in a variety of pain states, as well as in pet animals, for inflammatory and painsyndromes. [46] [47] [44] [49] [50] [4]

PEA is available for human use as food for medical purposes in Italy and Spain under the brandname and as dietsupplement under the brandname PeaPure. A PEA-related moleule, adelmidrol, is available as a topical preparation for dermatological indications. [52] Dose recommended is 1200 mg daily.

From a clinical perspective the most important and promising indications for palmitoylethanolamide are linked to neuropathic and chronic pain states, such as diabetic neuropathic pain, sciatic pain, pelvic pain and entrapment neuropathic painstates. From the clinical data gathered so far, as well as based on its mechanism of action these are relevant indications to consider the use of palmitloylethanolamide:

General chronical painsyndromes [40] [28] [38] [24] [57][24][59][60][12][42][41] [37][65][66] Herniapijn [67] Diabetische neuropathische pijnen [68] [69] Herpes zosterpijn (gordelroospijn) [49][71]

Neuropathic pains in a variety of indications: CIAP, CIDP, etc [60] CTS [73] [47]

CRPS (Sudeck) [75]

Neuropathic pain and spasms in multiple sclerosis [8] [77] [78] [23] [80][81] [82][83][84][85][86]

Central neuropathic pain after stroke [87][88][6][32][91]

Central neuropathic pain after syrongomyelia and spinal cord injury [8] [93]

Migraine [94] [95] [96][97]

Fibromyalgie [98]

Reumatoid artritis pain [99] [100][101]

Artritis psoriatica [102]

Syndrome of Costen, temporomandibulair painsyndrome [103]

Itching and pain after chemotherapy[104][105]

Interstitial cystitis (painful bladder) [106] [107] [108][109][110][111]

Vaginal pains and vulvodynia [112] Vulvovestibulitis [113][114] [115] [116] [117]

Perineodynia [43]

Endometriosis [44]

One of the targets of PEA is the glia. [120] Modern neurobiological research increasingly points out the relevance of the glia and asterocytes in the pathogenesis of neuropathic pain. One even coined the term gliopathic pain as an alternative for neuropathic pain. [121] Glia and asterocytes therefore are an important new target for the development of new analgesic compounds in the treatment of neuropathic pain. [122]

Treating neuropathic pain prescribing the current anti-neuropathic pain drugs, belonging to the classes of antidepressants and anticonvulsants, is often not satisfactory. [123] New drugs aiming for different non-neuronal targets, in this case the glia, such as palmitoylethanolamide, are needed.[124]

Palmitoylethanolamide’s metabolism

PEA is metabolized by [[fatty acid amide hydrolase]] (FAAH) and [[N-acylethanolamine-hydrolyzing acid amidase]] (NAAA), the latter of which has more specificity toward PEA over other fatty acid amides.[125] Due to this cellular metabolism, it seems that dose adjustment for renal insufficiency will be unnecessary, although formal human studies are not yet available. To date, no drug interactions have been reported in literature, neither any clinical relevant side effect.
Dose recommendations palmitoylethanolamide

In our practice we prescibe Peapure, comtaining pure palmitoylethanolamide only, without excipients, for a great variety of neuropathic painstates, mostly with impressive results. Combination of therapy with opiods, gabapentoids and antidepressants is possible, and no drug-drug interactions have been reported.

Dose recommendations

The dose to begin with is always 12000 mg palmitoylethnalamide/day, as PeaPure capsules for instance 2 times 400 mg in the morning and 1 capsule in the eventing, with or after a meal.

If pain is reduced at least 30-50% at least at week 8, a lower dose for continuation can be selected, 400 mg b.i.d.

In case of partial response, higher doses are possible, even up to twice daily 1200 mg we have used without seing side effects. In clinical trials 1600 mg daily has been evaluated in many hundreds of patients.

Physicians wanting to consult the author of this article can do so by sending an email to info@ores.nl

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