{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T14:07:05Z","timestamp":1791209225157,"version":"4.1.0"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Intravenous (IV) lidocaine has emerged as a non-opioid alternative for chronic pain management. However, the safety profile of repeated, long-term administration, particularly regarding cumulative exposure and cardiovascular comorbidities, remains poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To identify risk factors for serious adverse outcomes (SAOs) following IV lidocaine infusion in chronic pain patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A retrospective cohort study examined 1093 patients treated with IV lidocaine at a hospital-based pain clinic in Israel (2014-2022), totaling 15\u00a0820 infusions. SAOs were defined as emergency department visits within 14\u2009days of infusion. Multivariable logistic regression and Generalized Estimating Equations (GEE) were used to assess predictors, including cardiovascular disease, cerebrovascular accident (CVA) history, diabetes mellitus, and cumulative infusion count, to distinguish between true dose-frequency effects and artifacts of cumulative exposure time. A secondary analysis retained only events plausibly attributable to lidocaine based on its pharmacological profile.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Fifty-five patients (5.0%) experienced SAOs. Cumulative exposure exceeding 50 infusions was the strongest predictor of adverse outcomes (OR\u2009=\u200912.58, P &amp;lt; .001). A GEE model accounting for repeated measures revealed that the risk per individual infusion remained stable and did not increase with the infusion sequence number (OR\u2009=\u20091.00, P = .854). CVA history was initially significant but lost significance in the secondary analysis when restricted to plausibly lidocaine-related events (n\u2009=\u200930), suggesting the association reflected disease progression rather than treatment effect. Conversely, pre-existing cardiovascular disease emerged as a significant predictor only in the refined analysis (OR\u2009=\u20093.88, P = .008), consistent with lidocaine\u2019s known cardiac electrophysiological effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>IV lidocaine demonstrates a favorable safety profile with low SAO incidence. While the statistical probability of an event increases with total exposure time, the per-infusion risk remains stable across the treatment course suggesting an absence of cumulative physiological toxicity. Pre-existing cardiovascular disease, specifically ischemic heart disease and arrhythmias, remains a primary risk factor. These findings support the use of enhanced cardiac monitoring for patients with these specific cardiovascular comorbidities and periodic risk-benefit reassessments for high-utilization patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/pm\/pnag066","type":"journal-article","created":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T11:31:59Z","timestamp":1779017519000},"page":"1123-1128","source":"Crossref","is-referenced-by-count":0,"title":["Cumulative exposure and cardiovascular risk: predictors of serious adverse outcomes following long-term intravenous lidocaine therapy for chronic pain"],"prefix":"10.1093","volume":"27","author":[{"given":"Natalie","family":"Shalit","sequence":"first","affiliation":[{"name":"Sheba Medical Center Pain Medicine Institute, , Ramat Gan,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy","family":"Shalit","sequence":"additional","affiliation":[{"name":"Sheba Medical Center The Dalia and David Arabov Endocrinology and Diabetes Research Center, , Ramat Gan,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1819-9885","authenticated-orcid":false,"given":"Michelle","family":"Levitan","sequence":"additional","affiliation":[{"name":"Sheba Medical Center Pain Medicine Institute, , Ramat Gan,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadas","family":"Afgin","sequence":"additional","affiliation":[{"name":"Sheba Medical Center Endocrinology, Pain Medicine Institute, , Ramat Gan,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ofir","family":"Morag","sequence":"additional","affiliation":[{"name":"Sheba Medical Center Cancer Unit, , Ramat Gan,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itay","family":"Goor-Aryeh","sequence":"additional","affiliation":[{"name":"Sheba Medical Center Pain Medicine Institute, , Ramat Gan,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"2026100509370376000_pnag066-B1","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1001\/jama.2011.1158","article-title":"cultural transformation needed to solve public health problem of chronic pain","volume":"306","author":"Slomski","year":"2011","journal-title":"JAMA"},{"key":"2026100509370376000_pnag066-B2","doi-asserted-by":"publisher","DOI":"10.17226\/24781","volume-title":"Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use","author":"National Academies of Sciences, Engineering, and Medicine","year":"2017"},{"key":"2026100509370376000_pnag066-B3","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1037\/0022-006x.70.3.678","article-title":"Psychological factors in chronic pain: evolution and revolution","volume":"70","author":"Turk","year":"2002","journal-title":"J Consult Clin Psychol"},{"key":"2026100509370376000_pnag066-B4","doi-asserted-by":"publisher","first-page":"457","DOI":"10.2147\/JPR.S105892","article-title":"A review of chronic pain impact on patients, their social environment and the health care system","volume":"9","author":"Due\u00f1as","year":"2016","journal-title":"J Pain Res"},{"key":"2026100509370376000_pnag066-B5","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.pnpbp.2017.06.032","article-title":"Substance-related disorders: a review of prevalence and correlates among patients with chronic pain","volume":"87","author":"Martel","year":"2018","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"2026100509370376000_pnag066-B6","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1007\/s00540-017-2339-x","article-title":"Prevention of chronic post-surgical pain: the importance of early identification of risk factors","volume":"31","author":"Tawfic","year":"2017","journal-title":"J Anesth"},{"key":"2026100509370376000_pnag066-B7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.15585\/mmwr.rr7103a1","article-title":"CDC clinical practice guideline for prescribing opioids for pain\u2013United States, 2022","volume":"71","author":"Dowell","year":"2022","journal-title":"MMWR Recomm Rep"},{"key":"2026100509370376000_pnag066-B8","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.explore.2018.02.001","article-title":"Evidence-based nonpharmacologic strategies for comprehensive pain care: the Consortium Pain Task Force white paper","volume":"14","author":"Tick","year":"2018","journal-title":"Explore (NY)"},{"key":"2026100509370376000_pnag066-B9","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/S0304-3959(00)00229-3","article-title":"Systemic lidocaine for neuropathic pain relief","volume":"87","author":"Mao","year":"2000","journal-title":"Pain"},{"key":"2026100509370376000_pnag066-B10","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.hlc.2017.07.004","article-title":"Antiarrhythmics in cardiac arrest: a systematic review and meta-analysis","volume":"27","author":"Chowdhury","year":"2018","journal-title":"Heart Lung Circ"},{"key":"2026100509370376000_pnag066-B11","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1111\/anae.15270","article-title":"The use of intravenous lidocaine for postoperative pain and recovery: International Consensus Statement on Efficacy and Safety","volume":"76","author":"Foo","year":"2021","journal-title":"Anaesthesia"},{"key":"2026100509370376000_pnag066-B12","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1136\/rapm-2023-105174","article-title":"ASRA Pain Medicine practice advisory on intravenous lidocaine","volume":"49","author":"Schwenk","year":"2024","journal-title":"Reg Anesth Pain Med"},{"key":"2026100509370376000_pnag066-B13","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/j.pmn.2019.06.008","article-title":"Intravenous lidocaine for chronic neuropathic pain: a systematic review addressing nursing care","volume":"21","author":"Lancaster","year":"2020","journal-title":"Pain Manag Nurs"},{"issue":"Suppl. 3","key":"2026100509370376000_pnag066-B14","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1016\/j.jpain.2006.01.444","article-title":"The role of sodium channels in chronic inflammatory and neuropathic pain","volume":"7","author":"Gold","year":"2006","journal-title":"J Pain"},{"key":"2026100509370376000_pnag066-B15","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1002\/neu.20094","article-title":"Voltage-gated sodium channels and pain pathways","volume":"61","author":"Wood","year":"2004","journal-title":"J Neurobiol"},{"key":"2026100509370376000_pnag066-B16","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1093\/bja\/54.5.501","article-title":"Analgesic responses to i.v. lignocaine","volume":"54","author":"Boas","year":"1982","journal-title":"Br J Anaesth"},{"key":"2026100509370376000_pnag066-B17","doi-asserted-by":"crossref","first-page":"73","DOI":"10.64719\/pb.4495","article-title":"Intravenous lidocaine for the management of chronic pain: a narrative review of randomized clinical trials","volume":"54","author":"Onyeaka","year":"2024","journal-title":"Psychopharmacol Bull"},{"key":"2026100509370376000_pnag066-B18","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1097\/AAP.0b013e3181d2310b","article-title":"Clinical presentation of local anesthetic systemic toxicity: a review of published cases, 1979 to 2009","volume":"35","author":"Di Gregorio","year":"2010","journal-title":"Reg Anesth Pain Med"},{"key":"2026100509370376000_pnag066-B19","doi-asserted-by":"publisher","first-page":"3459","DOI":"10.2147\/JPR.S379208","article-title":"Intravenous lidocaine for treatment of chronic pain: a retrospective cohort study","volume":"15","author":"Horvat","year":"2022","journal-title":"J Pain Res"},{"key":"2026100509370376000_pnag066-B20","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1177\/20494637211054198","article-title":"Lidocaine infusions in chronic pain management: a prospective case series analysis","volume":"16","author":"Vacher","year":"2022","journal-title":"Br J Pain"},{"key":"2026100509370376000_pnag066-B21","doi-asserted-by":"publisher","first-page":"e38253","DOI":"10.1097\/MD.0000000000038253","article-title":"Long-term pain outcomes after serial lidocaine infusion in participants with recent onset of peripheral neuropathic pain: a pilot double-blind, randomized, placebo-controlled trial","volume":"103","author":"Wangnamthip","year":"2024","journal-title":"Medicine (Baltimore)"},{"key":"2026100509370376000_pnag066-B22","first-page":"1","article-title":"The R Package geepack for generalized estimating equations","volume":"15","author":"H\u00f8jsgaard","year":"2006","journal-title":"J Stat Softw"},{"key":"2026100509370376000_pnag066-B23","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1093\/pm\/pnx167","article-title":"Tertiary care clinical experience with intravenous lidocaine infusions for the treatment of chronic pain","volume":"19","author":"Iacob","year":"2018","journal-title":"Pain Med"},{"key":"2026100509370376000_pnag066-B24","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1111\/pme.12642","article-title":"Intravenous lidocaine for neuropathic pain: a retrospective analysis of tolerability and efficacy","volume":"16","author":"Hutson","year":"2015","journal-title":"Pain Med"},{"key":"2026100509370376000_pnag066-B25","doi-asserted-by":"publisher","first-page":"1738","DOI":"10.1213\/01.ANE.0000186348.86792.38","article-title":"Systemic administration of local anesthetics to relieve neuropathic pain: a systematic review and meta-analysis","volume":"101","author":"Tremont-Lukats","year":"2005","journal-title":"Anesth Analg"},{"key":"2026100509370376000_pnag066-B26","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1097\/ALN.0b013e3181c43103","article-title":"Practice guidelines for chronic pain management: an updated report by the American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine","volume":"112","author":"American Society of Anesthesiologists Task Force on Chronic Pain Management","year":"2010","journal-title":"Anesthesiology"},{"key":"2026100509370376000_pnag066-B27","doi-asserted-by":"publisher","first-page":"CD003345","DOI":"10.1002\/14651858.CD003345.pub2","article-title":"Systemic administration of local anesthetic agents to relieve neuropathic pain","volume":"2005","author":"Tremont-Lukats","year":"2005","journal-title":"Cochrane Database Syst Rev"}],"container-title":["Pain Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/painmedicine\/advance-article-pdf\/doi\/10.1093\/pm\/pnag066\/68363914\/pnag066.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/painmedicine\/article-pdf\/27\/10\/1123\/68363914\/pnag066.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/painmedicine\/article-pdf\/27\/10\/1123\/68363914\/pnag066.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:37:09Z","timestamp":1791207429000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/painmedicine\/article\/27\/10\/1123\/8690192"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,21]]},"references-count":27,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5,21]]},"published-print":{"date-parts":[[2026,10,1]]}},"URL":"https:\/\/doi.org\/10.1093\/pm\/pnag066","relation":{},"ISSN":["1526-2375","1526-4637"],"issn-type":[{"value":"1526-2375","type":"print"},{"value":"1526-4637","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,10]]},"published":{"date-parts":[[2026,5,21]]}}}