{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T15:55:39Z","timestamp":1786982139891,"version":"build-2736575974"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2020,8,26]],"date-time":"2020-08-26T00:00:00Z","timestamp":1598400000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2020,8,26]],"date-time":"2020-08-26T00:00:00Z","timestamp":1598400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Curr Pain Headache Rep"],"published-print":{"date-parts":[[2020,10]]},"DOI":"10.1007\/s11916-020-00898-0","type":"journal-article","created":{"date-parts":[[2020,8,26]],"date-time":"2020-08-26T03:02:42Z","timestamp":1598410962000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Low-Dose Naltrexone for Chronic Pain: Update and Systemic Review"],"prefix":"10.1007","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0249-078X","authenticated-orcid":false,"given":"Phillip S.","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Fishman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,8,26]]},"reference":[{"key":"898_CR1","doi-asserted-by":"publisher","unstructured":"Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Vol 26. Washington, DC: The National Academies Press 2012. https:\/\/doi.org\/10.3109\/15360288.2012.678473","DOI":"10.3109\/15360288.2012.678473"},{"issue":"4","key":"898_CR2","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1007\/s10067-014-2517-2","volume":"33","author":"J Younger","year":"2014","unstructured":"\u2022 Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol. 2014;33(4):451\u20139. https:\/\/doi.org\/10.1007\/s10067-014-2517-2This study is small and follow-up from previous study. A well-done and rigorous study supporting use of low dose naltrexone for fibromyalgia.","journal-title":"Clin Rheumatol"},{"key":"898_CR3","doi-asserted-by":"publisher","unstructured":"Boissevain MD, McCain GA. Toward an integrated understanding of fibromyalgia syndrome. I. Medical and pathophysiological aspects. Pain. 1991. https:\/\/doi.org\/10.1016\/0304-3959(91)90047-2.","DOI":"10.1016\/0304-3959(91)90047-2"},{"issue":"4","key":"898_CR4","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1111\/j.1526-4637.2009.00613.x","volume":"10","author":"J Younger","year":"2009","unstructured":"Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med. 2009;10(4):663\u201372. https:\/\/doi.org\/10.1111\/j.1526-4637.2009.00613.x.","journal-title":"Pain Med"},{"key":"898_CR5","first-page":"1","volume":"3","author":"Y Hang","year":"2019","unstructured":"Hang Y, Kim J, West K. Treating chronic pain with low dose naltrexone and ultralow dose naltrexone: a review paper. History of naltrexone. J Pain Manag Ther. 2019;3:1 http:\/\/www.alliedacademies.org\/pain-management-and-therapy\/.","journal-title":"J Pain Manag Ther"},{"key":"898_CR6","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/0006-8993(89)90059-0","volume":"491","author":"KF Shen","year":"1989","unstructured":"Shen KF, Crain SM. Dual opioid modulation of the action potential duration of mouse dorsal root ganglion neurons in culture. Brain Res. 1989;491:227\u201342. https:\/\/doi.org\/10.1016\/0006-8993(89)90059-0.","journal-title":"Brain Res"},{"key":"898_CR7","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1016\/j.jpain.2008.03.005","volume":"9","author":"TM Largent-Milnes","year":"2008","unstructured":"Largent-Milnes TM, Guo W, Wang HY, Burns LH, Vanderah TW. Oxycodone plus ultra-low-dose naltrexone attenuates neuropathic pain and associated \u03bc-opioid receptor-Gscoupling. J Pain. 2008;9:700\u201313. https:\/\/doi.org\/10.1016\/j.jpain.2008.03.005.","journal-title":"J Pain"},{"issue":"2","key":"898_CR8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0001554","volume":"3","author":"HY Wang","year":"2008","unstructured":"Wang HY, Frankfurt M, Burns LH. High-affinity naloxone binding to filamin a prevents mu opioid receptor-Gs coupling underlying opioid tolerance and dependence. PLoS One. 2008;3(2):1\u201310. https:\/\/doi.org\/10.1371\/journal.pone.0001554.","journal-title":"PLoS One"},{"key":"898_CR9","doi-asserted-by":"publisher","first-page":"857","DOI":"10.4137\/CMT.S4870","volume":"2","author":"LH Burns","year":"2010","unstructured":"\u2022\u2022 Burns LH, Wang HY. Ultra-low-dose naloxone or naltrexone to improve opioid analgesia: the history, the mystery and a novel approach. Clin Med Insights Ther. 2010;2:857\u201368. https:\/\/doi.org\/10.4137\/CMT.S4870Review and update of low dose naltrexone with focus on animal studies and mechanism of analgesia.","journal-title":"Clin Med Insights Ther"},{"key":"898_CR10","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1097\/SPC.0b013e3283005479","volume":"2","author":"S Perrot","year":"2008","unstructured":"Perrot S. Fibromyalgia syndrome: a relevant recent construction of an ancient condition? Curr Opin Support Palliat Care. 2008;2:122\u20137. https:\/\/doi.org\/10.1097\/SPC.0b013e3283005479.","journal-title":"Curr Opin Support Palliat Care"},{"key":"898_CR11","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.tins.2011.02.005","volume":"34","author":"E Okun","year":"2011","unstructured":"Okun E, Griffioen KJ, Mattson MP. Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci. 2011;34:269\u201381. https:\/\/doi.org\/10.1016\/j.tins.2011.02.005.","journal-title":"Trends Neurosci"},{"key":"898_CR12","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1016\/j.ygyno.2011.04.009","volume":"122","author":"RN Donahue","year":"2011","unstructured":"Donahue RN, McLaughlin PJ, Zagon IS. The opioid growth factor (OGF) and low dose naltrexone (LDN) suppress human ovarian cancer progression in mice. Gynecol Oncol. 2011;122:382\u20138. https:\/\/doi.org\/10.1016\/j.ygyno.2011.04.009.","journal-title":"Gynecol Oncol"},{"key":"898_CR13","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/j.conb.2013.02.005","volume":"23","author":"PE Lutz","year":"2013","unstructured":"Lutz PE, Kieffer BL. The multiple facets of opioid receptor function: implications for addiction. Curr Opin Neurobiol. 2013;23:473\u20139. https:\/\/doi.org\/10.1016\/j.conb.2013.02.005.","journal-title":"Curr Opin Neurobiol"},{"key":"898_CR14","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/j.mehy.2008.06.048","volume":"72","author":"N Brown","year":"2009","unstructured":"Brown N, Panksepp J. Low-dose naltrexone for disease prevention and quality of life. Med Hypotheses. 2009;72:333\u20137. https:\/\/doi.org\/10.1016\/j.mehy.2008.06.048.","journal-title":"Med Hypotheses"},{"issue":"October 2016","key":"898_CR15","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.jad.2016.08.029","volume":"208","author":"D Mischoulon","year":"2017","unstructured":"Mischoulon D, Hylek L, Yeung AS, Clain AJ, Baer L, Cusin C, et al. Randomized, proof-of-concept trial of low dose naltrexone for patients with breakthrough symptoms of major depressive disorder on antidepressants. J Affect Disord. 2017;208(October 2016):6\u201314. https:\/\/doi.org\/10.1016\/j.jad.2016.08.029.","journal-title":"J Affect Disord"},{"key":"898_CR16","doi-asserted-by":"publisher","first-page":"5258","DOI":"10.1073\/pnas.011538198","volume":"98","author":"R Lin","year":"2001","unstructured":"Lin R, Karpa K, Kabbani N, Goldman-Rakic P, Levenson R. Dopamine D2 and D3 receptors are linked to the actin cytoskeleton via interaction with filamin A. Proc Natl Acad Sci U S A. 2001;98:5258\u201363. https:\/\/doi.org\/10.1073\/pnas.011538198.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"898_CR17","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1001\/archpsyc.64.3.327","volume":"64","author":"BW Dunlop","year":"2007","unstructured":"Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry. 2007;64:327\u201337. https:\/\/doi.org\/10.1001\/archpsyc.64.3.327.","journal-title":"Arch Gen Psychiatry"},{"key":"898_CR18","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/0024-3205(93)90612-7","volume":"53","author":"GW Lambert","year":"1993","unstructured":"Lambert GW, Eisenhofer G, Jennings GL, Esler MD. Regional homovanillic acid production in humans. Life Sci. 1993;53:63\u201375. https:\/\/doi.org\/10.1016\/0024-3205(93)90612-7.","journal-title":"Life Sci"},{"key":"898_CR19","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1016\/S0006-3223(02)01383-5","volume":"52","author":"V Klimek","year":"2002","unstructured":"Klimek V, Schenck JE, Han H, Stockmeier CA, Ordway GA. Dopaminergic abnormalities in amygdaloid nuclei in major depression: a postmortem study. Biol Psychiatry. 2002;52:740\u20138. https:\/\/doi.org\/10.1016\/S0006-3223(02)01383-5.","journal-title":"Biol Psychiatry"},{"issue":"5","key":"898_CR20","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1188\/08.ONF.802-807","volume":"35","author":"JS Myers","year":"2008","unstructured":"Myers JS. Proinflammatory cytokines and sickness behavior: implications for depression and cancer-related symptoms. Oncol Nurs Forum. 2008;35(5):802\u20137. https:\/\/doi.org\/10.1188\/08.ONF.802-807.","journal-title":"Oncol Nurs Forum"},{"key":"898_CR21","doi-asserted-by":"publisher","first-page":"2919","DOI":"10.1002\/cncr.11382","volume":"97","author":"CS Cleeland","year":"2003","unstructured":"Cleeland CS, Bennett GJ, Dantzer R, Dougherty PM, Dunn AJ, Meyers CA, et al. Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms. Cancer. 2003;97:2919\u201325. https:\/\/doi.org\/10.1002\/cncr.11382.","journal-title":"Cancer"},{"key":"898_CR22","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1159\/000079408","volume":"11","author":"BN Lee","year":"2004","unstructured":"Lee BN, Dantzer R, Langley KE, Bennett GJ, Dougherty PM, Dunn AJ, et al. A cytokine-based neuroimmunologic mechanism of cancer-related symptoms. Neuroimmunomodulation. 2004;11:279\u201392. https:\/\/doi.org\/10.1159\/000079408.","journal-title":"Neuroimmunomodulation"},{"key":"898_CR23","unstructured":"Illman J, Corringham R, Robinson D, et al. Are inflammatory cytokines the common link between cancer-associated cachexia and depression. J Support Oncol. 2005."},{"key":"898_CR24","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/S0885-3924(03)00139-8","volume":"25","author":"RA Cruciani","year":"2003","unstructured":"Cruciani RA, Lussier D, Miller-Saultz D, Arbuck DM. Ultra-low dose oral naltrexone decreases side effects and potentiates the effect of methadone [1]. J Pain Symptom Manag. 2003;25:491\u20134. https:\/\/doi.org\/10.1016\/S0885-3924(03)00139-8.","journal-title":"J Pain Symptom Manag"},{"key":"898_CR25","unstructured":"Hamann S, Sloan P. Oral naltrexone to enhance analgesia in patients receiving continuous intraythecal morphine for chronic pain: a randomized, double-blind, prospective pilot study. J Opioid Manag. 2007."},{"issue":"3","key":"898_CR26","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1007\/s11481-013-9451-y","volume":"8","author":"P Chopra","year":"2013","unstructured":"Chopra P, Cooper MS. Treatment of complex regional pain syndrome (CRPS) using low dose naltrexone (LDN). J NeuroImmune Pharmacol. 2013;8(3):470\u20136. https:\/\/doi.org\/10.1007\/s11481-013-9451-y.","journal-title":"J NeuroImmune Pharmacol"},{"key":"898_CR27","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1213\/XAA.0000000000000292","volume":"6","author":"LB Weinstock","year":"2016","unstructured":"Weinstock LB, Myers TL, Walters AS, Schwartz OA, Younger JW, Chopra PJ, et al. Identification and treatment of new inflammatory triggers for complex regional pain syndrome: small intestinal bacterial overgrowth and obstructive sleep apnea. A A case reports. 2016;6:272\u20136. https:\/\/doi.org\/10.1213\/XAA.0000000000000292.","journal-title":"A A case reports"},{"key":"898_CR28","doi-asserted-by":"publisher","unstructured":"Parkitny L, Younger J. Reduced pro-inflammatory cytokines after eight weeks of low-dose naltrexone for fibromyalgia. Biomedicines. 2017;5. https:\/\/doi.org\/10.3390\/biomedicines5020016.","DOI":"10.3390\/biomedicines5020016"},{"key":"898_CR29","doi-asserted-by":"publisher","first-page":"1076","DOI":"10.1177\/1352458508095828","volume":"14","author":"M Gironi","year":"2008","unstructured":"Gironi M, Martinelli-Boneschi F, Sacerdote P, Solaro C, Zaffaroni M, Cavarretta R, et al. A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. Mult Scler. 2008;14:1076\u201383. https:\/\/doi.org\/10.1177\/1352458508095828.","journal-title":"Mult Scler"},{"key":"898_CR30","doi-asserted-by":"publisher","first-page":"205521731667224","DOI":"10.1177\/2055217316672242","volume":"2","author":"MD Ludwig","year":"2016","unstructured":"Ludwig MD, Turel AP, Zagon IS, McLaughlin PJ. Long-term treatment with low dose naltrexone maintains stable health in patients with multiple sclerosis. Mult Scler J \u2013 Exp Transl Clin. 2016;2:205521731667224. https:\/\/doi.org\/10.1177\/2055217316672242.","journal-title":"Mult Scler J \u2013 Exp Transl Clin"},{"key":"898_CR31","doi-asserted-by":"publisher","unstructured":"\u2022\u2022 Sharafaddinzadeh N, Moghtaderi A, Kashipazha D, Majdinasab N, Shalbafan B. The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial. Mult Scler. 2010. https:\/\/doi.org\/10.1177\/1352458510366857Recent randomized study on low dose naltrexone with multiple sclerosis and implication on quality of life. Should be compared to other randomized study with multiple sclerosis.","DOI":"10.1177\/1352458510366857"},{"key":"898_CR32","doi-asserted-by":"publisher","unstructured":"Cree BAC, Kornyeyeva E, Goodin DS. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol. 2010. https:\/\/doi.org\/10.1002\/ana.22006.","DOI":"10.1002\/ana.22006"},{"key":"898_CR33","doi-asserted-by":"publisher","first-page":"S268","DOI":"10.1016\/s0002-9270(03)01577-6","volume":"98","author":"R Kariv","year":"2003","unstructured":"Kariv R. Low-dose naltrexone for the treatment of irritable bowel syndrome. Am J Gastroenterol. 2003;98:S268. https:\/\/doi.org\/10.1016\/s0002-9270(03)01577-6.","journal-title":"Am J Gastroenterol"},{"key":"898_CR34","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1111\/j.1572-0241.2007.01045.x","volume":"102","author":"JP Smith","year":"2007","unstructured":"Smith JP, Stock H, Bingaman S, Mauger D, Rogosnitzky M, Zagon IS. Low-dose naltrexone therapy improves active Crohn\u2019s disease. Am J Gastroenterol. 2007;102:820\u20138. https:\/\/doi.org\/10.1111\/j.1572-0241.2007.01045.x.","journal-title":"Am J Gastroenterol"},{"key":"898_CR35","doi-asserted-by":"publisher","unstructured":"Parker CE, Nguyen TM, Segal D, Macdonald JK, Chande N. Low dose naltrexone for induction of remission in Crohn\u2019s disease. Cochrane Database Syst Rev. 2018. https:\/\/doi.org\/10.1002\/14651858.CD010410.pub3.","DOI":"10.1002\/14651858.CD010410.pub3"},{"key":"898_CR36","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1097\/MCG.0b013e3182702f2b","volume":"47","author":"JP Smith","year":"2013","unstructured":"Smith JP, Field D, Bingaman SI, Evans R, Mauger DT. Safety and tolerability of low-dose naltrexone therapy in children with moderate to severe Crohn\u2019s disease: a pilot study. J Clin Gastroenterol. 2013;47:339\u201345. https:\/\/doi.org\/10.1097\/MCG.0b013e3182702f2b.","journal-title":"J Clin Gastroenterol"},{"issue":"12","key":"898_CR37","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1016\/j.jpain.2006.05.005","volume":"7","author":"LR Webster","year":"2006","unstructured":"Webster LR, Butera PG, Moran LV, Wu N, Burns LH, Friedmann N. Oxytrex minimizes physical dependence while providing effective analgesia: a randomized controlled trial in low back pain. J Pain. 2006;7(12):937\u201346. https:\/\/doi.org\/10.1016\/j.jpain.2006.05.005.","journal-title":"J Pain"},{"issue":"6","key":"898_CR38","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1016\/j.jpain.2005.01.356","volume":"6","author":"VL Chindalore","year":"2005","unstructured":"Chindalore VL, Craven RA, Yu KP, Butera PG, Burns LH, Friedmann N. Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia: a randomized, controlled trial of oxytrex. J Pain. 2005;6(6):392\u20139. https:\/\/doi.org\/10.1016\/j.jpain.2005.01.356.","journal-title":"J Pain"},{"key":"898_CR39","unstructured":"(CSAT) C for SA. Chapter 4- Oral Naltexone. In: Alcohol Pharmacother. Intro Med. Pract. (Treatment Improv. Protoc. Ser. No.49). Rockville, MD: Substance Abuse and Mental Health Services administration 2009:30."},{"key":"898_CR40","doi-asserted-by":"publisher","first-page":"e25","DOI":"10.1212\/nxi.0000000000000025","volume":"1","author":"\u00d8 Torkildsen","year":"2014","unstructured":"Torkildsen \u00d8, Myhr K-M, Wergeland S. Treatment-resistant immune thrombocytopenic purpura associated with LDN use in a patient with MS. Neurol - Neuroimmunol Neuroinflammation. 2014;1:e25. https:\/\/doi.org\/10.1212\/nxi.0000000000000025.","journal-title":"Neurol - Neuroimmunol Neuroinflammation"},{"issue":"2","key":"898_CR41","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1001\/jama.2019.20288","volume":"323","author":"J Darrow","year":"2020","unstructured":"Darrow J, Avorn J, Kesselheim S. FDA approval and regulation of pharmaceuticals, 1983-2018. Jama. 2020;323(2):164\u201376. https:\/\/doi.org\/10.1001\/jama.2019.20288.","journal-title":"Jama"},{"issue":"7","key":"898_CR42","doi-asserted-by":"publisher","first-page":"2088","DOI":"10.1007\/s10620-011-1653-7","volume":"56","author":"JP Smith","year":"2011","unstructured":"Smith JP, Bingaman SI, Ruggiero F, Mauger DT, Mukherjee A, McGovern CO, et al. Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn\u2019s disease: a randomized placebo-controlled trial. Dig Dis Sci. 2011;56(7):2088\u201397. https:\/\/doi.org\/10.1007\/s10620-011-1653-7.","journal-title":"Dig Dis Sci"}],"container-title":["Current Pain and Headache Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11916-020-00898-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11916-020-00898-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11916-020-00898-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T19:09:39Z","timestamp":1629918579000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11916-020-00898-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,26]]},"references-count":42,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2020,10]]}},"alternative-id":["898"],"URL":"https:\/\/doi.org\/10.1007\/s11916-020-00898-0","relation":{},"ISSN":["1531-3433","1534-3081"],"issn-type":[{"value":"1531-3433","type":"print"},{"value":"1534-3081","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,26]]},"assertion":[{"value":"26 August 2020","order":1,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"64"}}