{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:29:54Z","timestamp":1792794594461,"version":"4.5.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Tonix Pharmaceuticals","id":[{"id":"https:\/\/ror.org\/045sr2y25","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Fibromyalgia is the prototypic nociplastic chronic pain syndrome, characterized by widespread pain, nonrestorative sleep, and fatigue. We evaluated efficacy and safety of bedtime TNX-102 SL (sublingual cyclobenzaprine) 5.6\u2009mg for treatment of fibromyalgia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This phase 3, double-blind, multicenter, placebo-controlled trial randomized patients 1:1 to once-nightly TNX-102 SL 2.8\u2009mg for 2\u2009weeks, followed by 5.6\u2009mg for 12\u2009weeks, or to matching placebo (NCT05273749). The primary endpoint was change from baseline at week 14 in weekly average of daily diary pain intensity scores. Secondary endpoints included Patient Global Impression of Change, Fibromyalgia Impact Questionnaire (Revised) Symptoms and Function domains, Patient-Reported Outcomes Measurement Information System instruments for Sleep Disturbance and Fatigue, and daily diary sleep quality scores.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Overall, 81.0% (n\u2009=\u2009187\/231) and 79.6% (n\u2009=\u2009179\/225) of patients receiving TNX-102 SL and placebo completed the trial, respectively. Treatment with TNX-102 SL vs placebo was associated with significantly greater reductions in the primary pain endpoint (P\u2009&amp;lt;\u2009.001; mean [SE], \u22121.8 [0.12] vs \u22121.2 [0.12]) and in each of the 6 secondary endpoints (P\u2009\u2264\u2009.001; all). The most common systemic treatment-emergent adverse events (TEAEs) with TNX-102 SL and placebo were COVID-19 (4.3% vs 3.1%, respectively), headache (3.0% vs 1.8%), and somnolence (3.0% vs 1.3%); the most common TEAEs overall were local administration-site reactions including oral hypoesthesia (23.4% vs 0.4%), product taste abnormal (11.3% vs 0.9%), and oral paresthesia (6.9% vs 0.9%), which were transient and self-limited.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Bedtime TNX-102 SL treatment was associated with significant improvements in fibromyalgia symptoms and function and was well tolerated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical trial registration<\/jats:title>\n                    <jats:p>ClinicalTrials.gov\/study\/NCT05273749, first patient screened March 21, 2022.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/pm\/pnaf089","type":"journal-article","created":{"date-parts":[[2025,7,6]],"date-time":"2025-07-06T07:30:52Z","timestamp":1751787052000},"page":"86-94","source":"Crossref","is-referenced-by-count":16,"title":["Pain relief by targeting nonrestorative sleep in fibromyalgia: a phase 3 randomized trial of bedtime sublingual cyclobenzaprine"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2781-1455","authenticated-orcid":false,"given":"Seth","family":"Lederman","sequence":"first","affiliation":[{"name":"Tonix Pharmaceuticals, Inc ., Chatham, NJ 07928,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0393-9948","authenticated-orcid":false,"given":"Lesley M","family":"Arnold","sequence":"additional","affiliation":[{"name":"University of Cincinnati College of Medicine , Cincinnati, OH 45267,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1759-1682","authenticated-orcid":false,"given":"Ben","family":"Vaughn","sequence":"additional","affiliation":[{"name":"Rho Inc. , Chapel Hill, NC 27713,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0098-5133","authenticated-orcid":false,"given":"Jean M","family":"Engels","sequence":"additional","affiliation":[{"name":"Tonix Pharmaceuticals, Inc ., Chatham, NJ 07928,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1309-1780","authenticated-orcid":false,"given":"Mary","family":"Kelley","sequence":"additional","affiliation":[{"name":"Tonix Pharmaceuticals, Inc ., Chatham, NJ 07928,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1707-4490","authenticated-orcid":false,"given":"Gregory M","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Tonix Pharmaceuticals, Inc ., Chatham, NJ 07928,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,7,8]]},"reference":[{"issue":"3","key":"2026012109021110800_pnaf089-B1","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.semarthrit.2016.08.012","article-title":"2016 Revisions to the 2010\/2011 fibromyalgia diagnostic criteria","volume":"46","author":"Wolfe","year":"2016","journal-title":"Semin Arthritis Rheum"},{"issue":"5","key":"2026012109021110800_pnaf089-B2","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1002\/acr.21896","article-title":"Prevalence of fibromyalgia: a population-based study in Olmsted County, Minnesota, utilizing the Rochester Epidemiology Project","volume":"65","author":"Vincent","year":"2013","journal-title":"Arthritis Care Res (Hoboken)"},{"issue":"4","key":"2026012109021110800_pnaf089-B3","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1097\/00006842-197507000-00008","article-title":"Musculosketal symptoms and non-REM sleep disturbance in patients with \u201cfibrositis syndrome\u201d and healthy subjects","volume":"37","author":"Moldofsky","year":"1975","journal-title":"Psychosom Med"},{"issue":"1","key":"2026012109021110800_pnaf089-B4","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1097\/00006842-197601000-00006","article-title":"Induction of neurasthenic musculoskeletal pain syndrome by selective sleep stage deprivation","volume":"38","author":"Moldofsky","year":"1976","journal-title":"Psychosom Med"},{"issue":"12","key":"2026012109021110800_pnaf089-B5","doi-asserted-by":"publisher","first-page":"4000","DOI":"10.3390\/jcm9124000","article-title":"Poor sleep quality experience and self-management strategies in fibromyalgia: a qualitative metasynthesis","volume":"9","author":"Climent-Sanz","year":"2020","journal-title":"JCM"},{"issue":"2","key":"2026012109021110800_pnaf089-B6","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1016\/s0304-3959(96)03226-5","article-title":"Sequential daily relations of sleep, pain intensity, and attention to pain among women with fibromyalgia","volume":"68","author":"Affleck","year":"1996","journal-title":"Pain"},{"issue":"9","key":"2026012109021110800_pnaf089-B7","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1177\/1359105317751615","article-title":"The relationship between sleep quality and fibromyalgia symptoms","volume":"25","author":"Andrade","year":"2020","journal-title":"J Health Psychol"},{"issue":"2","key":"2026012109021110800_pnaf089-B8","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.rdc.2009.05.008","article-title":"The significance of dysfunctions of the sleeping\/waking brain to the pathogenesis and treatment of fibromyalgia syndrome","volume":"35","author":"Moldofsky","year":"2009","journal-title":"Rheum Dis Clin North Am"},{"issue":"12","key":"2026012109021110800_pnaf089-B9","doi-asserted-by":"publisher","first-page":"2653","DOI":"10.3899\/jrheum.110194","article-title":"Effects of bedtime very low dose cyclobenzaprine on symptoms and sleep physiology in patients with fibromyalgia syndrome: a double-blind randomized placebo-controlled study","volume":"38","author":"Moldofsky","year":"2011","journal-title":"J Rheumatol"},{"issue":"10","key":"2026012109021110800_pnaf089-B10","doi-asserted-by":"publisher","first-page":"2156","DOI":"10.3899\/jrheum.091041","article-title":"Effects of sodium oxybate on sleep physiology and sleep\/wake-related symptoms in patients with fibromyalgia syndrome: a double-blind, randomized, placebo-controlled study","volume":"37","author":"Moldofsky","year":"2010","journal-title":"J Rheumatol"},{"issue":"3","key":"2026012109021110800_pnaf089-B11","first-page":"529","article-title":"The effect of zolpidem in patients with fibromyalgia: a dose ranging, double blind, placebo controlled, modified crossover study","volume":"23","author":"Moldofsky","year":"1996","journal-title":"J Rheumatol"},{"issue":"2","key":"2026012109021110800_pnaf089-B12","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1007\/bf02231524","article-title":"Effect of zopiclone on sleep quality, morning stiffness, widespread tenderness and pain and general discomfort in primary fibromyalgia patients. A double-blind randomized trial","volume":"12","author":"Gr\u00f6nblad","year":"1993","journal-title":"Clin Rheumatol"},{"issue":"10289","key":"2026012109021110800_pnaf089-B13","doi-asserted-by":"publisher","first-page":"2098","DOI":"10.1016\/s0140-6736(21)00392-5","article-title":"Nociplastic pain: towards an understanding of prevalent pain conditions","volume":"397","author":"Fitzcharles","year":"2021","journal-title":"Lancet"},{"issue":"5","key":"2026012109021110800_pnaf089-B14","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1097\/j.pain.0000000000003129","article-title":"A step towards better understanding chronic overlapping pain conditions","volume":"165","author":"Fitzcharles","year":"2024","journal-title":"Pain"},{"issue":"2","key":"2026012109021110800_pnaf089-B15","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1001\/archinte.160.2.221","article-title":"Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder","volume":"160","author":"Aaron","year":"2000","journal-title":"Arch Intern Med"},{"issue":"9","key":"2026012109021110800_pnaf089-B16","doi-asserted-by":"publisher","first-page":"T93","DOI":"10.1016\/j.jpain.2016.06.002","article-title":"Overlapping chronic pain conditions: implications for diagnosis and classification","volume":"17","author":"Maixner","year":"2016","journal-title":"J Pain"},{"issue":"5","key":"2026012109021110800_pnaf089-B17","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1038\/s41591-022-01810-6","article-title":"Unexplained post-acute infection syndromes","volume":"28","author":"Choutka","year":"2022","journal-title":"Nat Med"},{"issue":"6685","key":"2026012109021110800_pnaf089-B18","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1126\/science.adl0867","article-title":"Solving the puzzle of long Covid","volume":"383","author":"Al-Aly","year":"2024","journal-title":"Science"},{"issue":"9","key":"2026012109021110800_pnaf089-B19","doi-asserted-by":"publisher","first-page":"1400","DOI":"10.1111\/pme.12168","article-title":"Longitudinal observation of treatment patterns and outcomes for patients with fibromyalgia: 12-month findings from the reflections study","volume":"14","author":"Robinson","year":"2013","journal-title":"Pain Med"},{"issue":"6","key":"2026012109021110800_pnaf089-B20","doi-asserted-by":"publisher","first-page":"469","DOI":"10.5055\/jom.2019.0537","article-title":"Opioid prescription patterns among patients with fibromyalgia","volume":"15","author":"Sarmento","year":"2019","journal-title":"J Opioid Manag"},{"issue":"1","key":"2026012109021110800_pnaf089-B21","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1186\/1472-6963-10-102","article-title":"A patient survey of the impact of fibromyalgia and the journey to diagnosis","volume":"10","author":"Choy","year":"2010","journal-title":"BMC Health Serv Res"},{"issue":"6","key":"2026012109021110800_pnaf089-B22","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1136\/annrheumdis-2011-201249","article-title":"Comparative efficacy of pharmacological and non-pharmacological interventions in fibromyalgia syndrome: network meta-analysis","volume":"72","author":"N\u00fcesch","year":"2013","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"2026012109021110800_pnaf089-B23","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1002\/art.20076","article-title":"Treatment of fibromyalgia with cyclobenzaprine: a meta-analysis","volume":"51","author":"Tofferi","year":"2004","journal-title":"Arthritis & Rheum"},{"issue":"2","key":"2026012109021110800_pnaf089-B24","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1176\/appi.psy.41.2.104","article-title":"Antidepressant treatment of fibromyalgia. A meta-analysis and review","volume":"41","author":"Arnold","year":"2000","journal-title":"Psychosomatics"},{"issue":"12","key":"2026012109021110800_pnaf089-B25","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1002\/art.1780311210","article-title":"A comparison of cyclobenzaprine and placebo in the management of fibrositis. A double-blind controlled study","volume":"31","author":"Bennett","year":"1988","journal-title":"Arthritis Rheum"},{"issue":"1","key":"2026012109021110800_pnaf089-B26","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1002\/art.1780370106","article-title":"Comparison of amitriptyline, cyclobenzaprine, and placebo in the treatment of fibromyalgia. A randomized, double-blind clinical trial","volume":"37","author":"Carette","year":"1994","journal-title":"Arthritis Rheum"},{"issue":"2","key":"2026012109021110800_pnaf089-B27","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1136\/annrheumdis-2016-209724","article-title":"EULAR revised recommendations for the management of fibromyalgia","volume":"76","author":"Macfarlane","year":"2017","journal-title":"Ann Rheum Dis"},{"key":"2026012109021110800_pnaf089-B28","volume-title":"Presented at: American Society of Clinical Pharmacology","author":"Sullivan","year":"2019"},{"issue":"11","key":"2026012109021110800_pnaf089-B29","doi-asserted-by":"publisher","first-page":"2359","DOI":"10.1002\/acr.25142","article-title":"Efficacy and safety of sublingual cyclobenzaprine for the treatment of fibromyalgia: results from a randomized, double-blind, placebo-controlled trial","volume":"75","author":"Lederman","year":"2023","journal-title":"Arthritis Care Res (Hoboken)"},{"issue":"2","key":"2026012109021110800_pnaf089-B30","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/S0304-3959(01)00349-9","article-title":"Clinical importance of changes in chronic pain intensity measured on a n 11-point numerical pain rating scale","volume":"94","author":"Farrar","year":"2001","journal-title":"Pain"},{"issue":"2","key":"2026012109021110800_pnaf089-B31","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.jbspin.2010.01.005","article-title":"Linguistic validation of six patient-reported outcomes instruments into 12 languages for patients with fibromyalgia","volume":"77","author":"Le Gal","year":"2010","journal-title":"Joint Bone Spine"},{"issue":"4","key":"2026012109021110800_pnaf089-B32","doi-asserted-by":"publisher","first-page":"R120","DOI":"10.1186\/ar2783","article-title":"The Revised Fibromyalgia Impact Questionnaire (FIQR): validation and psychometric properties","volume":"11","author":"Bennett","year":"2009","journal-title":"Arthritis Res Ther"},{"issue":"8","key":"2026012109021110800_pnaf089-B33","doi-asserted-by":"publisher","first-page":"1485","DOI":"10.1093\/pm\/pnw187","article-title":"Reliability and construct validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) instruments in women with fibromyalgia","volume":"18","author":"Merriwether","year":"2017","journal-title":"Pain Med"},{"key":"2026012109021110800_pnaf089-B34","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.1097\/j.pain.0000000000001849","article-title":"John D. Loeser Award Lecture: size does matter, but it isn\u2019t everything: the challenge of modest treatment effects in chronic pain clinical trials","volume":"161(Supplement 1)","author":"Smith","year":"2020","journal-title":"Pain"},{"issue":"8","key":"2026012109021110800_pnaf089-B35","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1002\/ejp.564","article-title":"More ubiquitous effects from non-pharmacologic than from pharmacologic treatments for fibromyalgia syndrome: a meta-analysis examining six core symptoms","volume":"18","author":"Perrot","year":"2014","journal-title":"Eur J Pain"},{"issue":"6","key":"2026012109021110800_pnaf089-B36","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/j.jpain.2010.01.002","article-title":"Comparative efficacy and harms of duloxetine, milnacipran, and pregabalin in fibromyalgia syndrome","volume":"11","author":"Hauser","year":"2010","journal-title":"J Pain"},{"issue":"5","key":"2026012109021110800_pnaf089-B37","doi-asserted-by":"publisher","first-page":"e2212939","DOI":"10.1001\/jamanetworkopen.2022.12939","article-title":"Comparison of amitriptyline and US Food and Drug Administration-approved treatments for fibromyalgia: a systematic review and network meta-analysis","volume":"5","author":"Farag","year":"2022","journal-title":"JAMA Netw Open"},{"issue":"7","key":"2026012109021110800_pnaf089-B38","doi-asserted-by":"publisher","first-page":"CD010292","DOI":"10.1002\/14651858.CD010292.pub2","article-title":"Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia","volume":"2020","author":"Welsch","year":"2018","journal-title":"Cochrane Database Syst Rev"},{"issue":"1","key":"2026012109021110800_pnaf089-B39","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1186\/1477-7525-7-64","article-title":"Evaluation of the impact of fibromyalgia on patients\u2019 sleep and the content validity of two sleep scales","volume":"7","author":"Martin","year":"2009","journal-title":"Health Qual Life Outcomes"},{"key":"2026012109021110800_pnaf089-B40","volume-title":"Presented at: ACR\/ARHP Annual Meeting","author":"Daugherty","year":"2012"},{"key":"2026012109021110800_pnaf089-B41","volume-title":"Presented at: Society of Biological Psychiatry 70th Annual Scientific Convention","author":"Daugherty","year":"2015"},{"key":"2026012109021110800_pnaf089-B42","volume-title":"StatPearls","author":"Khan","year":"2024"},{"key":"2026012109021110800_pnaf089-B43","author":"Pfizer","year":"2004"},{"key":"2026012109021110800_pnaf089-B44","author":"Eli Lilly and Company","year":"2023"},{"key":"2026012109021110800_pnaf089-B45","author":"Allergan","year":"2016"},{"issue":"12","key":"2026012109021110800_pnaf089-B46","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1093\/rheumatology\/ken389","article-title":"Restorative sleep predicts the resolution of chronic widespread pain: results from the EPIFUND study","volume":"47","author":"Davies","year":"2008","journal-title":"Rheumatology (Oxford)"}],"container-title":["Pain Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/painmedicine\/advance-article-pdf\/doi\/10.1093\/pm\/pnaf089\/63704101\/pnaf089.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/painmedicine\/article-pdf\/27\/1\/86\/63704101\/pnaf089.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/painmedicine\/article-pdf\/27\/1\/86\/63704101\/pnaf089.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T14:02:24Z","timestamp":1769004144000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/painmedicine\/article\/27\/1\/86\/8193722"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,8]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,7,8]]},"published-print":{"date-parts":[[2026,1,1]]}},"URL":"https:\/\/doi.org\/10.1093\/pm\/pnaf089","relation":{},"ISSN":["1526-2375","1526-4637"],"issn-type":[{"value":"1526-2375","type":"print"},{"value":"1526-4637","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,1]]},"published":{"date-parts":[[2025,7,8]]}}}