12-month randomized, double-blind, placebo-controlled, pharmacological clinical trial to evaluate the effectiveness, cost-utility and neurobiological effects of low-dose Naltrexone in patients with fibromyalgia (INNOVA Project)

INTERVENTION: Product Name: Naltrexone Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: NALTREXONE HYDROCHLORIDE Other descriptive name: NALTREXONE HYDROCHLORIDE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 4.5‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use CONDITION: Fibromyalgia ; MedDRA version: 20.0 Level: PT Classification code 10048439 Term: Fibromyalgia System Organ Class: 10028395 ‐ Musculoskeletal and connective tissue disorders Therapeutic area: Diseases [C] ‐ Musculoskeletal Diseases [C05] PRIMARY OUTCOME: Main Objective: 1.To evaluate the efficacy and safety of pharmacological treatment with LDN for FM added to the usual treatment at 3, 6, and 12 months compared to placebo.; 2. Evaluate the cost‐utility of drug treatment with LDN added to routine treatment from the perspective of the health system and society at 12 months.; 3. Evaluate changes in glutamate and glutamate / glutamine levels in areas related to pain processing and with evidence of alteration in FM associated with LDN treatment at the beginning of the study and after 3 months of treatment. Changes in other brain metabolites in the same areas will also be evaluated. This objective corresponds to the biomarker and neuroimaging substudy.; 4.Compare LDN‐associated changes in pro and anti‐inflammatory cytokine levels with evidence of alteration in FM. This objective corresponds to the biomarker and neuroimaging substudy. Primary end point(s): Pain intensity perception at the current moment (Pain Monitor app); Pain and the rest of the variables can fluctuate over the days depending on the stressors in the environment and, therefore, evaluating retrospectively introduces memory biases. Retrospective evaluation causes an overestimation of symptoms, which can be avoided by frequent evaluations of the Present symptoms, resulting in possible fatigue or saturation of the participants in their respective evaluations. In contrast, prospective and repeated evaluation over time substantially improves the precision, reliability, and quality of research, in addition to adding a traditionally low value such as ecological validity to psychopathological research. Smartphone apps are very easy to use, are easily accepted by chronic pain patients, and compliance rates with the use of mobile technology at all ages are around 75%. We will use the Pain Monitor® app, validated in an empirical study for use on Android smartphones, to evaluate daily (twice a day, one in the morning and one in the afternoon) the intensity of pain, the interference of pain in daily activities , fatigue, anxiety, depression, sleep, activity levels, and adverse effects of medications during the treatment period. Thanks to a collaboration agreement with Dr. Azucena García Palacios of the Jaume I University of Castelló, we will be able to use the app for free and the information collected will be stored on the UJI's servers.; The Pain Monitor® app has been developed by a team of researchers from the UJI, with the collaboration of the non‐profit medical team of the Pain Unit of the Vall d'Hebron University Hospital, for research purposes and is protected, by Therefore, for all purposes, to the provisions of article 37 of the Intellectual Property Law.; It is not currently in commercial use. The content of the app, in addition to having been created by specialists in the management of chronic pain according to the recommendations of the Initiative on Methods, Measurements and Evaluation of Pain in Clinical Trials and following a biopsychosocial approach to pain, has been validated in a study carried out in the pain unit of the Vall d'Hebron University Hospital to guarantee that the results obtained through its use are valid.; The data obtained through the APP is not linked to any personal information of the patient, since the app only uses a random code to identify the answers. Only the PI or the physician responsible for the patient may link the personal or identifying data to the answers stored by each participant in the app and in REDCap, the platform on which the study variables will be recorded. Therefore, a document will be used where they will relate the alphanumeric code assigned in the app with their medical record number. This document will be stored safely following current regulations. For the study, patients will use a version of the Pain Monitor application that requires a code for its use and is called Multicenter Pain Monitor (it contains the same content as Pain Monitor, but allows easier monitoring of patients in studies research by requiring a code for its use).; The answers in the app will be stored under secure conditions by the UJI Labpsitec team, represented in this study by Dr. García Palacios, Dr. Suso Ribera and Dr. Castilla López (dolorcronico@uji.es). The guidelines of the LOPD‐GDD will be followed. The app has several layers of security to avoid unwanted access to the system; These systems are based on the encryption of the channel by means of certificates and the randomization of an access key each time the connection is made. The management of the application is carried out through a web with asp.net technology with the 4.0 framework and SQL server Enterprise database. For the access of the mobile application, several web services have been developed using Microsoft WCF technology.; The research team will receive the responses stored in the app through protected databases. The members of the Labpsitec group, external collaborators in this study, undertake to follow current regulations to guarantee data security. Labpsitec researchers will only have access to the random code to identify the responses of the study participants. In no case may this code be related to the identifying information of the patients, which will only be available to the PI of the project and the personnel hired in charge of the project (if any). Secondary Objective: 5.It will be explored whether the effects of LDN at 12 months on clinical variables (functional status, quality of life, anxiety‐depression, etc.) are mediated by changes from the baseline at 3 months in brain metabolites and inflammatory markers.; 6. Patients with FM will be classified into responders vs. nonresponders to LDN as a function of the level of improvement in pain and which socio‐demographic, clinical, neurobiological and immune variables evaluated at baseline predict the response to LDN will be explored. Timepoint(s) of evaluation of this end point: At 3, 6, and 12 months INCLUSION CRITERIA: 1. Women between 18 and 70 years old. 2. FM diagnosis according to ACR 2016 criteria. 3. Report musculoskeletal pain at least moderate (> 4 out of 10) during the last 6 months. 4. Comprehension of Spanish. 5. Written informed consent of the patient himself. * Additional inclusion criteria for the biomarker substudy 1. Be right‐handed (for neuroimaging tests). Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 100 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 20 SECONDARY OUTCOME: Secondary end point(s): The secondary variables will be evaluated, recorded and stored in the REDCap platform, in order to facilitate the management, security and analysis of the study data. The battery of instruments that will be used to measure these variables is detailed below:; ‐ Revised Fibromyalgia Impact Questionnaire (FIQR). Questionnaire on physical function, global impact and severity of symptoms associated with FM.; ‐ Depression Anxiety Stress Scales‐21 (DASS‐21). Scale designed to evaluate depression, anxiety and stress in clinical and non‐clinical samples.; ‐ Multidimensional Inventory of Subjective Cognitive Impairment (MISCI). Inventory to evaluate fibrofog in FM patients.; ‐ The 12‐item interviewer administered version of the World Health Organization Disability Assessment Schedule 2.0 (12‐item WHODAS 2.0). Scale to evaluate the level of difficulty or limitation that a person has experienced in each activity presented during the last year.; ‐ The Generalized Anxiety Disorder 7‐item scale (GAD‐7). Questionnaire that measures the symptoms of generalized anxiety (pathological concern). This instrument has been used in other studies for FM.; ‐ The Fibromyalgia Survey Diagnostic Criteria (FSDC). Scale that assesses the main symptoms of FM according to the latest revision of the American College of Rheumatology (ACR) criteria. This instrument includes 2; subscales: (1) generalized pain index and (2) symptom severity scale. A total FM score is obtained, with higher values ??indicating greater severity (range: 0 to 31 points); ‐ EuroQoL‐5D (EQ‐5D‐5L). Health‐related quality of life assessment instrument. It is made up of two parts: (1) difficulties in mobility, self‐care, pain / discomfort and anxiety / depression; and (2) current state of health (visual scale from 0 to 100).; ‐ Client Service Receipt Inventory (CSRI). Retrospective collection notebook on the use of health and social services during the last 12 months.; ‐ Patient Global and Specific Impression of Change (PGIC / PSIC). Indicator of perception of clinically relevant changes in specific domains (physical and social functionality, work‐related activities, mood and pain).; ‐ Evaluation of adverse events of the treatments through the Multicenter Pain Monitor application. Safety will be evaluated in each of the face‐to‐face visits and telephone contact made during the study (ie sleep disturbances, headache, nausea, nightmares, insomnia, dry mouth, anxiety, agitation, increased sweating and any other type adverse event). Timepoint(s) of evaluation of this end point: At 3, 6, and 12 months