New Targets in Pain, Non-Neuronal Cells, and the Role of Palmitoylethanolamide

Abstract

Persistent pain in neuropathic conditions is often quite refractory to conventional analgesic therapy, with most patients obtaining, at best, only partial relief of symptoms. The tendency still exists to treat these complex pains with one or a combination of two analgesics at the most. Given the complex nature of the underlying pathogenesis, this approach more often than not fails to produce a meaningful improvement. New targets are therefore badly needed. In this regard non-neuronal cells -glia and mast cells in particular -are emerging as new targets for the treatment of neuropathic pain. An extensive preclinical database exists showing that the naturally occurring fatty acid amide palmitoylethanolamide is endowed with anti-inflammatory activity, and clinical trials assessing the efficacy and safety of palmitoylethanolamide in neuropathic pain have been successful in generating proof-of-concept for treatment in man. Here I will review salient preclinical and clinical evidence supporting non-neuronal cells as viable targets in the treatment of neuropathic pain. This will be followed by a discussion of recent proof-of-concept clinical trials demonstrating the efficacy and safety of palmitoylethanolamide in the treatment of various neuropathic pain states.

Mast cell–glia axis in neuroinflammation and therapeutic potential of the anandamide congener palmitoylethanolamide

“…In addition, nearly 40 clinical trials have been conducted to date, with a total of more than 2000 patients having been entered in these trials. All these clinical trials have been reviewed recently [192].…”

Evolution in pharmacologic thinking around the natural analgesic palmitoylethanolamide: from nonspecific resistance to PPAR-α agonist and effective nutraceutical

“…At least 6,000 patients with chronic pain and inflammation have been entered into clinical trials since the first clinical studies in the 1970s, and PEA is becoming recognized as an important therapeutic principle with an impressively positive risk/benefit balance 54. Further, recent data support the hypothesis of deficient synthesis of PEA in pathologic states, such as fibromyalgia.…”

“…Nutraceuticals are in general not patent-protected, so are not a focus for the pharmaceutical industry and therefore less studied, publicized, and recognized. However, a great body of evidence exists for PEA, comprising at least 40 clinical trials in around 6,000 subjects 54,60. This body of evidence shows a positive risk/benefit ratio for PEA, warranting much wider use of this compound by the medical community.…”

Chronic idiopathic axonal neuropathy and pain, treated with the endogenous lipid mediator palmitoylethanolamide: a case collection

“…Since 2010, we have explored the therapeutic profile of PEA, an endogenous fatty acid amide, a novel agent in the treatment of chronic neuropathic pain 13,14. PEA is available as a food supplement in capsules containing 400 mg micronized PEA (PeaPure, JP Russell Science Ltd., Nicosia, Cyprus), and as food for medical purposes in Italy and Spain, in tablets of 200, 300, 400, and 600 mg (Pelvilen, Normast; Epitech Srl., Milano, Italy).…”

“…Amide lipids such as PEA are widely present in nature, in a variety of plant, invertebrate, and mammalian tissues. PEA is also present in many food products, such as peanuts, egg yolk, and soy beans and has been explored since the 1970s in a great number of clinical trials, as summarized by Keppel Hesselink 13,14…”