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Palmitoylethanolamide protects against side-effects anticancer drugs

Kahler's disease is cancer of certain white blood cells, the plasma cells, and leads to death, mostly within 3-4 years. It is the second most frequent occuring forms of blood cancer, after non-Hodgkin's disease. Initially patients can respond to chemotherapy, but treatment resistance often occurs. Furthermore, side effects such as nerve pain and nerve disfunctions (painful neuropathy) are dose limiting and thus optimal treatment of patients is not possible, as the chemotherapy needs to be stopped or reduced. Therfore patients cannot finish the course of chemotherapy and run a higher risk of relapse or recurrence of their cancer. Since years science searches for compounds to protect the nerve function, in order to enable patients suffering from MM to proceed being treated with chemotherapy.

Therefore it is highly important to point out that recently a natural occuring compound palmitoylethanolamide (PEA) has been identified in a clinical trial in MM patients, which indeed counteracts the side-effects of chemotherapy in blood cancer and restores nerve functions.

Italian neurologists from the neurological department of professor Cruccu, of the university of Rome, assessed the effect of PEA on pain and nerve function in patients with chemotherapy-induced painful neuropathy. 

Twenty patients undergoing thalidomide and bortezomib treatment for Kahler’s disease (multiple myeloma, MM) were treated during the development of neurotoxicity (neuropathic pain and nerve function decline) caused by the chemotherapeutic agents with 300 mg PEA twice daily. Thalidomide belongs to one of the most active drugs for the treatment of multiple myeloma and treatment leads to decrease of monoclonal protein of at least 50 % in 30 % of patients with relapsed or refractory multiple myeloma. Neuropathic pains, paresthesias and lead to withdrawal of this effective drug and after withdrawal neurological symptoms resolved in around 12 months. Bortezomib is a chemotherapeutic agent also with high efficacy in MM.

Reduction of pain and improvement of nerve functions in bortezomib-thalidomide patients treated concomitantly with palmitoylethanolamide

Twenty patients suffering from MM treated with a combination of thalidomide and bortezomib treatment. All patients were evaluated before and after a two-month of treatment with the endogenous analgesic and anti-inflammatory compound PEA 300 mg BID. Parameters measured by therapy blinded assessors were:

  1. pain and warmth thresholds;
  2. motor and sensory nerve fibre function and
  3. laser-evoked potentials.

 Pain and all neurophysiological measures-assessing Aα, Aβ, and Aδ fibres functionality  significantly improved compared to baseline, while patient continued their bortezomib/thalidomide therapy (P < 0.05). None of the variables however returned to normal values,

Warmth thresholds, assessing unmyelinated afferents, remained unchanged.

Although a placebo effect might play a role in the reduction of pain-intensity, the changes in neurophysiological measures indicate that PEA exerted a pneuroprotective effect on myelinated nervefibres.

The authors concluded:

In a severe condition such as painful neuropathy associated with multiple myeloma and chemotherapy, a safe substance such as PEA provides significant restoration of nerve function. [1]

Nerve protection and/or regeneration by palmitoylethanolamide

Earlier it has been suggested that PEA has nerve regenerative properties. [ref=21199307] From various animal studies it has become clear that PEA in any case has anti-inflammatory activities. Thalidomide itself also has anti-inflammatory activity and there are suggestions that combining bortezomib and thalidomide might even reduce the polyneuropathic side effects. 

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. [2]

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. [3] PEA also down-regulate immune competent cells such as the mast cells. [4] 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. [5] 

Referentie

[1] Truini A, Biasiotta A, Di Stefano G, Cesa SL, Leone C, Cartoni C, Federico V, Petrucci MT, Cruccu G. | Palmitoylethanolamide Restores Myelinated-Fibre Function in Patients with Chemotherapy-Induced Painful Neuropathy. | CNS Neurol Disord Drug Targets. | 2012 Jan 10. [Epub ahead of print]

[2] De Filippis D, Luongo L, Cipriano M, Palazzo E, Cinelli MP, de Novellis V, Maione S, Iuvone T. | Palmitoylethanolamide reduces granuloma-induced hyperalgesia by modulation of mast cell activation in rats. | Mol Pain. | 2011 Jan 10;7:3.

[3] Cerrato S, Brazis P, della Valle MF, Miolo A, Puigdemont A. | Effects of palmitoylethanolamide on immunologically induced histamine, PGD2 and TNFalpha release from canine skin mast cells. | Vet Immunol Immunopathol. | 2010 Jan 15;133(1):9-15. Epub 2009 Jun 27.

[4] De Filippis D, D'Amico A, Cinelli MP, Esposito G, Di Marzo V, Iuvone T. | Adelmidrol, a palmitoylethanolamide analogue, reduces chronic inflammation in a carrageenin-granuloma model in rats. | J Cell Mol Med. | 2009 Jun;13(6):1086-95. Epub 2008 Apr 18.

[5] D'Agostino G, La Rana G, Russo R, Sasso O, Iacono A, Esposito E, Mattace Raso G, Cuzzocrea S, Loverme J, Piomelli D, Meli R, Calignano A. | Central administration of palmitoylethanolamide reduces hyperalgesia in mice via inhibition of NF-kappaB nuclear signalling in dorsal root ganglia. | Eur J Pharmacol. | 2009 Jun 24;613(1-3):54-9. Epub 2009 Apr 20.