Palmitoylethanolamide in Ulcerative Colitis

Official title

The Effect of Palmitoylethanolamide on the Clinical Outcomes in Ulcerative Colitis Patients

Overview

Evaluate the effects of PEA supplementation on disease activity, health-related quality of life (HRQoL) and inflammatory biomarkers in patients with active mild-to-moderate UC.

Detailed description

Ulcerative colitis (UC) is a chronic immune-mediated inflammatory bowel disease (IBD) of the large intestine characterized by a continuous pattern of mucosal and submucosal inflammation and ulceration involving the distal, the proximal or even the entire colon. It is reported to commonly affect people aged 15-30 years with a slight male predominance. The global prevalence rate of UC is estimated to be about 120 per 100,000 as of 2025 with a rapidly rising incidence especially in industrialized regions. It follows a relapsing-remitting course and commonly presents with abdominal pain, bloody diarrhea, urgency, and tenesmus. Although its etiology is poorly understood, multiple factors are thought to be implicated in its pathogenesis including genetic susceptibility, environmental factors such as diet, infections, medications…etc. and changes in intestinal microbiome composition which trigger an overreactive immune response damaging the mucosal barrier, and genetic susceptibility.

Multiple modalities are utilized in the pharmacological management of UC targeting the local and systemic chemical mediators of inflammation like 5-aminosalicylates, corticosteroids, immunomodulators and biologics. Molecular targets like: TNF-α, IL-6, IL-12, IL-17, IL-23, leukotrienes and integrins have been extensively studied which led to the development of therapeutic ligands. Interestingly, peroxisome proliferator-activated receptor- α (PPAR-α), a member of nuclear hormone receptor superfamily of ligand-activated transcription factors, is a promising target investigated in animal models for its anti-inflammatory and protective effects. Activation of such receptor is thought to reduce NO production, neutrophil influx, and decrease the expression of proinflammatory proteins, such as inducible NO synthase (iNOS), cyclo-oxygenase-2 (COX-2) and TNF- α.

The currently approved interventions can only calm down the underlying abnormal immune response and the associated inflammation successfully achieving remission. However, they cannot completely eradicate the cause of autoimmunity or restore the regular immune balance. Their use, especially biologics, is associated with loss of efficacy over time due to possible immunogenicity, high risk of infection and allergic reactions. Multisystem side effects are also commonly seen with corticosteroids' use particularly in the long term. Therefore, the focus has shifted in recent years towards complementary and alternative medicine in order to provide safe and reliably effective options.

Palmitoylethanolamide (PEA) is an endocannabinoid-like bioactive lipid mediator which belongs to the family of N-acylethanolamine (NAE) fatty acid amides. It exerts anti-inflammatory, antioxidant, antimicrobial, analgesic, immunomodulatory and neuroprotective actions through acting at different sites like: PPAR-α, G-protein coupled receptor 55 (GPR55), cannabinoid receptors 1 and 2 (CB1 and CB2) and transient receptor potential vanilloid receptor 1 (TRPVR1) channels. PEA is a commercially available supplement mainly used to alleviate chronic neuropathic pain and persistent musculoskeletal pain. PEA has proven to be safe and tolerable across multiple studies with very rare cases reporting mild side effects like: intermittent headache, nausea, constipation, urticaria and fatigue.

PEA has demonstrated broad analgesic and anti-inflammatory effects across multiple conditions. It effectively reduces diabetic peripheral neuropathic pain, chronic pain in knee osteoarthritis, and cutaneous adverse effects related to interferon-β therapy in multiple sclerosis in previous clinical trials, while also lowering circulating pro-inflammatory cytokines. PEA has further shown the ability to attenuate inflammatory, oxidative stress, and serological biomarkers in early COVID-19. In gastrointestinal disorders, particularly irritable bowel syndrome (IBS), PEA -especially when combined with polydatin- significantly alleviates abdominal pain in pediatrics. Experimental evidence from murine colitis models and ex-vivo human and animal colonic tissues suggests a potential therapeutic role for PEA in UC. Its anti-inflammatory action is mainly mediated through selective activation of PPAR-α, leading to suppression of enteroglial S100B release, inhibition of toll-like receptor signaling, and downstream inflammatory pathways. Additionally, PEA may exert anti-angiogenic effects and provide protection against colonic carcinogenesis by reducing VEGF release via modulation of the AKT/mTOR pathway.

Interventions

• Dietary supplement Palmitoylethanolamide (PEA)
  Palmitoylethanolamide (PEA) is an endocannabinoid-like bioactive lipid mediator which belongs to the family of N-acylethanolamine (NAE) fatty acid amides. It exerts anti-inflammatory, antioxidant, antimicrobial, analgesic, immunomodulatory and neuroprotective actions through acting at different sites like: PPAR-α, G-protein coupled receptor 55 (GPR55), cannabinoid receptors 1 and 2 (CB1 and CB2) and transient receptor potential vanilloid receptor 1 (TRPVR1) channels. PEA is a commercially availa
• Other Placebo
  Placebo capsules matching the active treatment

Primary outcome measures

• Clinical response [Time frame: 3 months]

Secondary outcome measures (6)

• Clinical remission [Time frame: 3 months]
• Change in disease activity [Time frame: 3 months]
• Serum C-reactive protein (CRP) [Time frame: 3 months]
• Serum pentraxin-3 (PTX-3) [Time frame: 3 months]
• Fecal calprotectin (FCP) [Time frame: 3 months]
• Health-related quality of life (HRQoL) [Time frame: 3 months]

Eligibility criteria

Inclusion criteria

• Confirmed diagnosis of ulcerative colitis (UC) by established clinical and endoscopic criteria.
• Active mild-to-moderate UC patients defined by a SCCAI score ≥ 5 and < 12 at screening, not responding to 5-aminosalicylates (5-ASA) defined as persistent rectal bleeding beyond 2 weeks or failure to achieve sustained symptom relief after 40 days of appropriate 5-ASA therapy, steroid-dependent defined as unable to reduce steroids below the equivalent of prednisolone 10 mg/day or budesonide below 3 mg/day within 3 months of starting steroids, without recurrent active disease or who have a relapse within 3 months of stopping steroids and they currently take azathioprine.

Exclusion criteria

• Pregnancy or breastfeeding.
• Alcohol or drug abuse.
• Allergy or known hypersensitivity to palmitoylethanolamide.
• Active infection (enteric or systemic).
• Uncontrolled metabolic/ neurologic conditions: uncontrolled hypertension, uncontrolled diabetes, migraine disorders or other uncontrolled neurologic disease.
• Other autoimmune diseases.
• Severe or acute severe colitis requiring hospitalization.
• UC patients requiring colectomy.
• Crohn disease (CD), chronic pancreatitis, cholecystitis or other inflammatory conditions involving the gastrointestinal tract (GIT).
• Patients with renal or liver disease.
• Patients who have never been treated for UC.
• Any patients on biologics.
• Patients using NSAIDs or aspirin (due to interference with fecal calprotectin results).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Egypt · 1 center

• Internal Medicine and Gastroenterology clinic, El-Demerdash Hospital — Cairo

Publications

• Walmsley RS, Ayres RC, Pounder RE, Allan RN. A simple clinical colitis activity index. Gut. 1998 Jul;43(1):29-32. doi: 10.1136/gut.43.1.29. PMID 9771402
• Steels E, Venkatesh R, Steels E, Vitetta G, Vitetta L. A double-blind randomized placebo controlled study assessing safety, tolerability and efficacy of palmitoylethanolamide for symptoms of knee osteoarthritis. Inflammopharmacology. 2019 Jun;27(3):475-485. doi: 10.1007/s10787-019-00582-9. Epub 2019 Mar 29. PMID 30927159
• Shivashankar R, Tremaine WJ, Harmsen WS, Loftus EV Jr. Incidence and Prevalence of Crohn's Disease and Ulcerative Colitis in Olmsted County, Minnesota From 1970 Through 2010. Clin Gastroenterol Hepatol. 2017 Jun;15(6):857-863. doi: 10.1016/j.cgh.2016.10.039. Epub 2016 Nov 14. PMID 27856364
• Shahrokh S, Qobadighadikolaei R, Abbasinazari M, Haghazali M, Asadzadeh Aghdaei H, Abdi S, Balaii H, Khanzadeh-Moghaddam N, Zali MR. Efficacy and Safety of Melatonin as an Adjunctive Therapy on Clinical, Biochemical, and Quality of Life in Patients with Ulcerative Colitis. Iran J Pharm Res. 2021 Spring;20(2):197-205. doi: 10.22037/ijpr.2020.113822.14508. PMID 34567156
• Sarnelli G, D'Alessandro A, Iuvone T, Capoccia E, Gigli S, Pesce M, Seguella L, Nobile N, Aprea G, Maione F, de Palma GD, Cuomo R, Steardo L, Esposito G. Palmitoylethanolamide Modulates Inflammation-Associated Vascular Endothelial Growth Factor (VEGF) Signaling via the Akt/mTOR Pathway in a Selective Peroxisome Proliferator-Activated Receptor Alpha (PPAR-alpha)-Dependent Manner. PLoS One. 2016 May PMID 27219328
• Pickering E, Steels EL, Steadman KJ, Rao A, Vitetta L. A randomized controlled trial assessing the safety and efficacy of palmitoylethanolamide for treating diabetic-related peripheral neuropathic pain. Inflammopharmacology. 2022 Dec;30(6):2063-2077. doi: 10.1007/s10787-022-01033-8. Epub 2022 Sep 4. PMID 36057884
• Orefice NS, Alhouayek M, Carotenuto A, Montella S, Barbato F, Comelli A, Calignano A, Muccioli GG, Orefice G. Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-beta1a and Circulating Proinflammatory Cytokines in Relapsing-Remitting Multiple Sclerosis. Neurotherapeutics. 2016 Apr;13(2):428-38. doi: 10.1007/s13311-016-0420-z. PMID 26857391
• Moradi S, Bagheri R, Amirian P, Zarpoosh M, Cheraghloo N, Wong A, Zobeiri M, Entezari MH. Effects of Spirulina supplementation in patients with ulcerative colitis: a double-blind, placebo-controlled randomized trial. BMC Complement Med Ther. 2024 Feb 29;24(1):109. doi: 10.1186/s12906-024-04400-w. PMID 38424572

Identifiers

NCT: NCT07609810 · PEA in Ulcerative colitis

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗