Generic placeholder image

CNS & Neurological Disorders - Drug Targets


ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Clinical Trial

Ultramicronized Palmitoylethanolamide (um-PEA) as Add-on Treatment in Fibromyalgia Syndrome (FMS): Retrospective Observational Study on 407 Patients

Author(s): Vittorio Schweiger*, Alvise Martini, Paola Bellamoli, Katia Donadello, Carlo Schievano, Giovanna D. Balzo, Piercarlo Sarzi-Puttini, Massimo Parolini and Enrico Polati

Volume 18, Issue 4, 2019

Page: [326 - 333] Pages: 8

DOI: 10.2174/1871527318666190227205359

Price: $65


Background: Fibromyalgia syndrome is a chronic multifaceted disease characterized by widespread pain, muscle stiffness, fatigue, unrefreshing sleep and cognitive disorders. To date, no medication has been shown to significantly improve pain, associated symptoms and Quality of Life in fibromyalgic patients.

Methods: In this retrospective observational study, we analyzed data regarding 407 patients with diagnosis of fibromyalgia syndrome who between 2013 and 2016 have been prescribed orally ultramicronized palmitoylethanolamide tablets (Normast® Epitech Group SpA, Saccolongo, Italy) regardless of the concomitant pharmacological therapy (add-on treatment).

Results: Regarding efficacy, in the 359 analyzed patients, the change over time in Visual Analogue Scale pain score was statistically significant, ranging from 75.84 (±15.15) to 52.49 (±16.73) (p<0.001). Regarding quality of life, the change over time in Fibromyalgia Impact Questionnaire score was statistically significant, ranging from 68.4 (±14.1) to 49.1 (±19.6) (p<0.001). In the treated population, only 36 patients (13,7%) reported Adverse Events predominantly of gastrointestinal type (diarrhea, dyspepsia, bloating, constipation, vomiting). Globally, 151 patients (57,63%) left the treatment due to inefficacy.

Conclusion: The results of ultramicronized palmitoylethanolamide treatment in this retrospective analysis represent an important step for the development of a new and well-tolerated therapy for fibromyalgia syndrome, mostly suitable for these patients who need long-term treatments. Further methodologically stronger studies will be necessary to validate our observation.

Keywords: Fibromyalgia syndrome (FMS), ultramicronized Palmitoylethanolamide (um-PEA), Widespread Pain Index (WPI), Symptoms Severity Score (SS), Visual Analogue Scale (VAS), Fibromyalgia Impact Questionnaire (FIQ), Adverse Events (AEs), Mast-cells (MC).

Graphical Abstract
Schmidt-Wilcke T, Clauw DJ. Fibromyalgia: From pathophysiology to therapy. Nat Rev Rheumatol 2011; 7: 518-27.
Clauw DJ. Fibromyalgia a clinical review. JAMA 2014; 311(15): 1547-55.
Thieme K, Mathys M, Turk DC. Evidenced-based guidelines on the treatment of fibromyalgia patients: Are they consistent and if not, why not? Have effective psychological treatments been overlooked? J Pain 2017; 18(7): 747-56.
Calandre EP, Rico-Villademoros F, Slim M. An update on pharmacotherapy for the treatment of fibromyalgia. Expert Opin Pharmacother 2015; 16(9): 1347-6.
Nightingale S. The neuropathic pain market. Nat Rev Drug Discov 2012; 11: 101-2.
O’Connor AB Neuropathic pain: A review of the quality of life impact, costs, and cost-effectiveness of therapy. Pharmacoeconomics 2009; 27: 95-112.
Langley PC, Van Litsenburg C, Cappelleri JC, Carroll D. The burden associated with neuropathic pain in Western Europe. J Med Econ 2013; 16: 85-95.
Varrassi G, Collett B, Morlion B, et al. Proceedings of the CHANGE PAIN Expert Summit in Rome, 2010. Curr Med Res Opin 2011; 27: 2061-2.
Dworkin RH, O’Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: An overview and literature update. Mayo Clin Proc 2010; 85(3)(Suppl.): S3-S14.
Dworkin RH. Mechanism-based treatment of pain. Pain 2012; 153: 2300.
Ren K, Dubner R. Interactions between the immune and nervous systems in pain. Nat Med 2010; 16: 1267-76.
Calvo M, Dawes JM, Bennett DL. The role of the immune system in the generation of neuropathic pain. Lancet Neurol 2012; 11: 629-42.
Sacerdote P, Franchi S, Moretti S, et al. Cytokine modulation is necessary for efficacious treatment of experimental neuropathic pain. J Neuroimmune Pharmacol 2013; 8: 202-11.
Skaper SD, Facci L. Mast cell-glia axis in neuroinflammatio and therapeutic potential of the anandamide congener palmitoylethanolamide. Philos Trans Soc Lond B Biol Sci 2012; 367: 3312-25.
Tabas I, Glass CK. Anti-inflammatory therapy in chronic disease: Challenges and opportunities. Science 2013; 339: 166-72.
Nijs J, Loggia ML, Polli A, et al. Sleep disturbances and severe stress as glial activators: Key targets for treating central sensitization in chronic pain patients? Expert Opin Ther Targets 2017; 21(8): 817-26.
Facci L, Dal Toso R, Romanello S, Buriani A, Skaper SD, Leon A. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci USA 1995; 92: 3376-80.
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; 133(1): 9-15.
Franklin A, Parmentier-Batteur S, Walter L, Greenberg DA, Stella N. Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility. J Neurosci 2003; 23: 7767-75.
Loría F, Petrosino S, Mestre L, et al. Spagnolo tudy of the regulation of the endocannabinoid system in a virus model of multiple sclerosis reveals a therapeutic effect of palmitoylethanolamide. Eur J Neurosci 2008; 28: 633-41.
Luongo L, Guida F, Boccella S, et al. Palmitoylethanolamide reduces formalin-induced neuropathic-like behavior through spinal glial/microglial phenotypical changes in mice. CNS Neurol Disord Drug Targets 2013; 12: 45-54.
Esposito E, Cuzzocrea S. Palmitoylethanolamide is a new possible pharmacological treatment for the inflammation associated with trauma. Mini Rev Med Chem 2013; 13: 237-55.
Mazzari S, Canella R, Petrelli L, Marcolongo G, Leon AN. -(2-hydroxyethyl) hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation. Eur J Pharmacol 1996; 300: 227-36.
De Filippis D, Luongo L, Cipriano M. Palmitoylethanolamide reduces granuloma-induced hyperalgesia by modulation of mast cell activation in rats. Mol Pain 2011; 10: 3.
Bettoni I, Comelli F, Colombo A, Bonfanti P, Costa B. Non-neuronal cell modulation relieves neuropathic pain: Efficacy of the endogenous lipid palmitoylethanolamide. CNS Neurol Disord Drug Targets 2013; 12: 34-44.
Di Cesare ML, D’Agostino G, Pacini A, et al. Palmitoylethanolamide is a disease-modifying agent in peripheral neuropathy: Pain relief and neuroprotection share a PPAR-alpha mediated mechanism. Mediators Inflamm 2013; 2013328797
Gatti A, Lazzari M, Gianfelice V, Di Paolo A, Sabato E, Sabato AF. Palmitoylethanolamide in the treatment of chronic pain caused by different etiopathogeneses. Pain Med 2012; 13: 1121-30.
Cocito D, Peci E, Ciaramitaro P, Cocito C, Merola A, Lopiano L. Short-term efficacy of ultramicronized palmitoylethanolamide in peripheral neuropathic pain. Pain Res Treat 2014; 2014854560
Montella S, Carotenuto A, Orefice NS, Orefice G. A double-blind, randomized,versus-placebo study of ultramicronized palmitoylethanolamide in subjects with relapsing-remitting multiple sclerosis: Preliminary results. 2014 EFNS-ENS. Eur J Neurol 2014; 21: 676.
Passavanti MB, Fiore M, Sansone P, et al. 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; 17: 171.
Putzu GA. Efficacy of ultramicronized palmitoylethanolamide on the clinical symptoms of charcot-marie-tooth neuropathy. Archiv Neurol Neurosurgery 2016; 1: 103.
Brotini S, Schievano C, Guidi L. Ultra-micronized palmitoylethanolamide: An efficacious adjuvant therapy for Parkinson’s disease. CNS Neurol Disord Drug Targets 2017; 16(6): 705-13.
Del Giorno R, Skaper S, Paladini A, Varrassi G, Coaccioli S. Palmitoylethanolamide in Fibromyalgia: Results from prospective and retrospective observational studies. Pain Ther 2015; 4(2): 169-78.
Schifilliti C, Cucinotta L, Fedele V, Ingegnosi C, Luca S, Leotta C. Micronized palmitoylethanolamide reduces the symptoms of neuropathic pain in diabetic patients. Pain Res Treat 2014; 2014849623
Paladini A, Varrassi G, Bentivegna G, Carletti S, Piroli A, Coaccioli S. Palmitoylethanolamide in the treatment of failed back surgery syndrome. Pain Res Treat 2017; 20171486010
Wolfe F, Clauw DJ, Fitzcharles MA, et al. Fibromyalgia criteria and severity scales for clinical and epidemiological studies: A modification of the ACR preliminary diagnostic criteria for fibromyalgia. J Rheumatol 2011; 38(6): 1113-22.
Sarzi-Puttini P, Atzeni F, Fiorini T, et al. Validation of an Italian version of the fibromyalgia impact questionnaire (FIQ-I). Clin Exp Rheumatol 2003; 21: 459-64.
Welsch P, Üçeyler N, Klose P, Walitt B, Häuser W. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia. Cochrane Database Syst Rev 2018; 2CD010292
Derry S, Cording M, Wiffen PJ, Law S, Phillips T, Moore RA. Pregabalin for pain in fibromyalgia in adults Cochrane Database Syst Rev 2016; 29; 9: CD011790.
Sewitch MJ, Dobkin PL, Bernatsky S, et al. Medication non-adherence in women with fibromyalgia. Rheumatology 2004; 43(5): 648-54.
Albrecht DS, Forsberg A, Sandstrom A, et al. Brain glial activation in fibromyalgia. A multi-site positron emission tomography investigation. Brain Behav Immun 2018.
Littlejohn G. Neurogenic neuroinflammation in fibromyalgia and complex regional pain syndrome. Nat Rev Rheumatol 2015; 11: 639-48.
Rahman A. Fibromyalgia BMJ 2014; 348-60.
Aich A, Afrin LB, Gupta K. Mast cell-mediated mechanisms of nociception. Int J Mol Sci 2015; 16: 29069-92.
Battista N, Di Tommaso M, Bari M, Maccarrone M. The endocannabinoid system: An overview. Front Behav Neurosci 2012; 6(9): 1-7.
Piomelli D, Sasso O. Peripheral gating of pain signals by endogenous lipid mediators. Nat Neurosci 2014; 17(2): 165-75.
Freitag CM, Miller RJ. Peroxisome proliferator activated receptor agonists modulate neuropathic pain: A link to chemokines? Front Cell Neurosci 2014; 8: 238.
Paladini A, Fusco M, Cenacchi T, Schievano C, Piroli A, Varrassi G. Palmitoylethanolamide, a special food for medical purposes, in the treatment of chronic pain: A pooled data meta-analysis. Pain Physician 2016; 19(2): 11-24.
Hayashida S, Arimoto A, Kuramoto Y, et al. Fasting promotes the expression of SIRT1, an NAD+ -dependent protein deacetylase, via activation of PPARalpha in mice. Mol Cell Biochem 2010; 339(1-2): 285-92.
Oka S, Zhai P, Yamamoto T, et al. Peroxisome proliferator activated receptor-α association with silent information regulator 1 suppresses cardiac fatty acid metabolism in the failing heart. Circ Heart Fail 2015; 8(6): 1123-32.
Zhou CH, Zhang MX, et al. SIRT1 attenuates neuropathic pain by epigenetic regulation of mGluR1/5 expressions in type 2 diabetic rats. Pain 2017; 158(1): 130-9.
Gabrielsson L, Mattsson S, Fowler CJ. Palmitoylethanolamide for the treatment of pain: Pharmacokinetics, safety and efficacy. Br J Clin Pharmacol 2016; 82: 932-42.
Petrosino S, Di Marzo V. The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations. Br J Pharmacol 2017; 174(11): 1349-65.
Petrosino S, Cordaro M, Verde R, et al. Oral ultramicronized palmitoylethanolamide: Plasma and tissue levels and spinal anti-hyperalgesic effect. Front Pharmacol 2018; 9(249): 1-17.
Bennett RM, Bushmakin AG, Cappelleri JC, Zlateva G, Sadosky AB. Minimal clinically important difference in the fibromyalgia impact questionnaire. J Rheumatol 2009; 36(6): 1304-11.
Robinson RL, Kroenke K, Williams DA, et al. Longitudinal observation of treatment patterns and outcomes for patients with fibromyalgia: 12-month findings from the reflections study. Pain Med 2013; 14(9): 1400-15.
Ben-Ami Shor D, Weitzman D, Dahan S, et al. Adherence and persistence with drug therapy among fibromyalgia patients: Data from a large health maintenance organization. J Rheumatol 2017; 44(10): 1499-506.
Liu Y, Qian C, Yang M. Treatment patterns associated with ACR-recommended medications in the management of fibromyalgia in the United States. J Manag Care Spec Pharm 2016; 22(3): 263-71.

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy