{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T16:14:23Z","timestamp":1791648863273,"version":"4.3.4"},"reference-count":45,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Pain"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Low\u2010dose naltrexone (LDN) has been used off\u2010label for fibromyalgia syndrome (FMS) for over a decade, supported by small crossover trials. The INNOVA study evaluated the safety and efficacy of LDN 4.5\u2009mg versus placebo on pain intensity over 12\u2009months in women with FMS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In total, 98 women with FMS were randomised to LDN 4.5\u2009mg\/day (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200948) or placebo (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200950). The primary outcome was change in pain intensity (NRS 0\u201310) from baseline to 3\u2009months in the intention\u2010to\u2010treat population. Secondary outcomes included functional impairment (FIQR), anxiety\u2010depressive symptoms (DASS\u201021), cognitive impairment (MISCI), disability (WHODAS 2.0), pathological worry (GAD\u20107) and impression of change (PGIC\/PSIC), assessed at baseline and at 3, 6 and 12\u2009months. Perceived treatment allocation and safety were also assessed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      At 3\u2009months, mean change in pain intensity was \u22120.33 points with LDN and \u22120.64 with placebo, with an adjusted between\u2010group difference of 0.49 (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.236,\n                      <jats:italic>d<\/jats:italic>\n                      \u2009=\u20090.19). Secondary outcomes showed minor and inconsistent changes, with low and similar responder rates (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.219\u20130.954). Exploratory analyses suggested some improvement among participants who believed they had received LDN, although effects were inconsistent. Adverse events, predominantly mild and transient, were reported by 33 (68.8%) participants in LDN and 36 (72%) in placebo, and no treatment\u2010related serious events occurred.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>LDN was well tolerated but did not demonstrate a clinically meaningful benefit over placebo for pain\u2010related outcomes, underscoring the need for more effective pharmacological treatments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>This RCT provides the first long\u2010term evidence on the efficacy and safety of LDN in FMS. LDN (4.5\u2009mg), administered as an add\u2010on treatment, has a favourable safety profile, but the findings indicate that it does not produce clinically meaningful improvements in FMS symptoms compared to placebo at short\u2010 or long\u2010term follow\u2010up. These findings contribute to the growing body of evidence questioning its clinical utility.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejp.70321","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T20:32:57Z","timestamp":1782937977000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Efficacy of Low\u2010Dose Naltrexone in Women With Fibromyalgia Syndrome: A 12\u2010Month Randomised, Double\u2010Blind, Placebo\u2010Controlled Single\u2010Centre Clinical Trial (\n                    <scp>INNOVA<\/scp>\n                    Study)"],"prefix":"10.1002","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6728-5778","authenticated-orcid":false,"given":"Carla","family":"Rodr\u00edguez\u2010Freire","sequence":"first","affiliation":[{"name":"Teaching, Research &amp; Innovation Unit Parc Sanitari Sant Joan de D\u00e9u  Sant Boi de Llobregat Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9482-4822","authenticated-orcid":false,"given":"Jaime","family":"Navarrete","sequence":"additional","affiliation":[{"name":"Teaching, Research &amp; Innovation Unit Parc Sanitari Sant Joan de D\u00e9u  Sant Boi de Llobregat Spain"},{"name":"Centre for Biomedical Research in Epidemiology and Public Health (CIBERESP)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7555-189X","authenticated-orcid":false,"given":"Antoni","family":"Rozadilla\u2010Sacanell","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Parc Sanitari Sant Joan de D\u00e9u  Sant Boi de Llobregat Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1688-435X","authenticated-orcid":false,"given":"Juan P.","family":"Sanabria\u2010Mazo","sequence":"additional","affiliation":[{"name":"Unit for the Study and Treatment of Pain\u2014ALGOS, Department of Psychology, Research Center for Behavior Assessment (CRAMC) Universitat Rovira i Virgili  Tarragona Spain"},{"name":"Institut d'Investigaci\u00f3 Sanit\u00e0ria Pere Virgili, Universitat Rovira i Virgili  Tarragona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"del Pino\u2010Gaya","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Parc Sanitari Sant Joan de D\u00e9u  Sant Boi de Llobregat Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3972-1385","authenticated-orcid":false,"given":"Xavier","family":"Borr\u00e0s","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research in Epidemiology and Public Health (CIBERESP)  Madrid Spain"},{"name":"Department of Basic, Developmental and Educational Psychology, Faculty of Psychology Autonomous University of Barcelona  Bellaterra Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2810-7670","authenticated-orcid":false,"given":"Albert","family":"Feliu\u2010Soler","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research in Epidemiology and Public Health (CIBERESP)  Madrid Spain"},{"name":"Department of Clinical and Health Psychology, Faculty of Psychology Autonomous University of Barcelona  Bellaterra Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0750-1599","authenticated-orcid":false,"given":"Juan V.","family":"Luciano","sequence":"additional","affiliation":[{"name":"Teaching, Research &amp; Innovation Unit Parc Sanitari Sant Joan de D\u00e9u  Sant Boi de Llobregat Spain"},{"name":"Centre for Biomedical Research in Epidemiology and Public Health (CIBERESP)  Madrid Spain"},{"name":"Department of Clinical and Health Psychology, Faculty of Psychology Autonomous University of Barcelona  Bellaterra Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"issue":"4","key":"e_1_2_11_2_1","first-page":"679","article-title":"Psychometric Properties of the Spanish Version of Depression, Anxiety and Stress Scales (DASS)","volume":"17","author":"Bados A.","year":"2005","journal-title":"Psicothema"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.7326\/AITC202003030"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar2783"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/PR9.0000000000001080"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40263\u2010025\u201001183\u20107"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/pm\/pnaa001"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.4324\/9780203771587"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen\u20102021\u2010055351"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bjane.2022.08.003"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2022.152060"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2665\u20109913(23)00278\u20103"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2007.09.005"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/jabr.12134"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9041219"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11916\u2010024\u201001277\u20109"},{"issue":"2","key":"e_1_2_11_17_1","first-page":"93","article-title":"Topical Review: Placebo Responses and Therapeutic Responses. How Are They Related?","volume":"23","author":"Greene C. S.","year":"2009","journal-title":"Journal of Orofacial Pain"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.adaj.2020.08.019"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11916\u2010025\u201001411\u20101"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj\u20102024\u2010081124"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.MR000006.pub3"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.55563\/clinexprheumatol\/buhd2z"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11916\u2010020\u201000898\u20100"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2015.02.008"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005\u20107967(94)00075\u2010U"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.22034"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.2147\/JPR.S389957"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.2174\/1573397113666170321120329"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/bmb\/ldab015"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis\u20102011\u2010201249"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1080\/15360288.2025.2496526"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines5020016"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/phar.2086"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1097\/PR9.0000000000001222"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2023.105235"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/pme.12168"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/pm\/pnad074"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584\u2010020\u201000506\u2010w"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2015.02.007"},{"issue":"3","key":"e_1_2_11_40_1","first-page":"28","article-title":"Psychometric Validation of the World Health Organization Disability Assessment Schedule 2.0\u201412\u2010Item Version in Persons With Fibromyalgia Syndrome","volume":"82","author":"Smedema S. M.","year":"2016","journal-title":"Journal of Rehabilitation"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/1756\u2010185X.15428"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.166.10.1092"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001384"},{"issue":"2","key":"e_1_2_11_44_1","first-page":"77","article-title":"Spanish Version of the New World Health Organization Disability Assessment Schedule II (WHO\u2010DAS\u2010II): Initial Phase of Development and Pilot Study. Cantabria Disability Work Group","volume":"28","author":"V\u00e1zquez\u2010Barquero J. L.","year":"2000","journal-title":"Actas Espa\u00f1olas de Psiquiatr\u00eda"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1526\u20104637.2009.00613.x"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.37734"}],"container-title":["European Journal of Pain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ejp.70321","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ejp.70321","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ejp.70321","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T15:00:33Z","timestamp":1788447633000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ejp.70321"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7]]},"references-count":45,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1002\/ejp.70321"],"URL":"https:\/\/doi.org\/10.1002\/ejp.70321","archive":["Portico"],"relation":{},"ISSN":["1090-3801","1532-2149"],"issn-type":[{"value":"1090-3801","type":"print"},{"value":"1532-2149","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7]]},"assertion":[{"value":"2026-03-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70321"}}