title: Efficacy of ultra-micronized palmitoylethanolamide (um-PEA) in geriatric patients with chronic pain: study protocol for a series of N-of-1 randomized trials.
abstract: Chronic pain in older people is highly prevalent, often underestimated, and associated with adverse outcomes. Most available analgesic drugs are often either ineffective or not tolerated, with many side effects. Palmitoylethanolamide (PEA) is an endogenous widely distributed N-acylethanolamina involved in neuroinflammation and pain-generating processes. Formulations containing ultra-micronized palmitoylethanolamide (um-PEA) are available but their effectiveness on chronic pain in highly heterogeneous geriatric patients is not clear and probably not generalizable. We planned to adopt the N-of-1 trial approach to test the effectiveness of um-PEA objectively at the individual level in our older outpatients.
  
  
  
  Persons 65 years or older referring to the Geriatric Unit of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico of Milan complaining of noncancer chronic pain of any origin will be eligible. Each trial will be a placebo-controlled randomized crossover trial including two um-PEA (600 mg twice a day) and placebo treatment pairs. The um-PEA or placebo 3-week periods will be separated by 2-week washout intervals to overcome possible carryover effects. Pain intensity, need of on-demand analgesic medications, and impact on daily activities will be evaluated. Cognitively impaired patients will be eligible as long as an expression of pain can be recognized and its frequency assessed by a caregiver. Trial results will be discussed with the patient or caregiver and the treating physician to decide whether to continue the treatment. The impact of the N-of-1 approach on the physician's management plan and confidence will be assessed. We will secondarily meta-analyze the performed N-of-1 trials to obtain an estimate of the average effect of um-PEA compared with placebo using a frequentist and Bayesian approach.
  
  
  
  While pursuing an ultimate clinical objective, i.e. to empirically and objectively decide the best treatment choice for an individual older patient with chronic pain, these series of geriatric N-of-1 trials on PEA will bring the principles of evidence-based medicine into the care of patients not usually represented in conventional randomized controlled trials, and realize a patient-centered outcome approach necessary to improve appropriate prescribing in elderly patients with multimorbidity and polypharmacy.
  
  
  
  ClinicalTrials.gov NCT02699281 . Registered on 3 March 2016.
authors.affiliation: Geriatric Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Via Pace 9, 20122, Milan, Italy. marcucci.maura@gmail.com.|Department of Clinical Sciences and Community Health, Università degli Studi di Milano, via Francesco Sforza 35, 20122, Milan, Italy. marcucci.maura@gmail.com.
authors.forename: Maura
authors.initials: M
authors.lastname: Marcucci
authors.affiliation: Geriatric Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Via Pace 9, 20122, Milan, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Germini
authors.affiliation: Geriatric Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Via Pace 9, 20122, Milan, Italy.|Department of Clinical Sciences and Community Health, Università degli Studi di Milano, via Francesco Sforza 35, 20122, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Coerezza
authors.affiliation: Department of Clinical Sciences and Community Health, Università degli Studi di Milano, via Francesco Sforza 35, 20122, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Andreinetti
authors.affiliation: Geriatric Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Via Pace 9, 20122, Milan, Italy.|Department of Clinical Sciences and Community Health, Università degli Studi di Milano, via Francesco Sforza 35, 20122, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Bellintani
authors.affiliation: Laboratory for Quality Assessment of Geriatric Therapies and Services, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", via Giuseppe La Masa 19, 20156, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Nobili
authors.affiliation: Geriatric Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Via Pace 9, 20122, Milan, Italy.
authors.forename: Paolo Dionigi
authors.initials: PD
authors.lastname: Rossi
authors.affiliation: Geriatric Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Via Pace 9, 20122, Milan, Italy.|Department of Clinical Sciences and Community Health, Università degli Studi di Milano, via Francesco Sforza 35, 20122, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Mari
mesh_terms: D000368:Aged; D000577:Amides; D000700:Analgesics / Q000008:administration & dosage*; D001499:Bayes Theorem; D059350:Chronic Pain / Q000188:drug therapy*; D002985:Clinical Protocols; D018592:Cross-Over Studies; D004983:Ethanolamines / Q000008:administration & dosage*; D006801:Humans; D010169:Palmitic Acids / Q000008:administration & dosage*; D018401:Sample Size
chemical_list: D000577:Amides; D000700:Analgesics; D004983:Ethanolamines; D010169:Palmitic Acids; C005958:palmidrol
keywords: Aged; Analgesics; Chronic pain; Clinical trial; Elderly; Geriatric; N-of-1 trial; Normast; Palmitoylethanolamide