{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T16:07:47Z","timestamp":1788883667334,"version":"build-2803163510"},"reference-count":30,"publisher":"BMJ","issue":"9","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Reg Anesth Pain Med"],"accepted":{"date-parts":[[2026,4,1]]},"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Intrathecal analgesia is recommended for the management of refractory cancer pain. Bupivacaine is the most commonly used local anesthetic in combination intrathecal therapies and is often administered at high doses. However, data on its systemic toxicity in this context remain limited. While the pharmacokinetics of bupivacaine have been described in epidural and spinal anesthesia, those studies involved substantially lower doses and minimal systemic absorption. A maximum serum concentration of 2 \u00b5g\/mL (2000 \u00b5g\/L) is generally considered the upper safety limit to prevent systemic toxicity, yet systemic exposure during chronic intrathecal infusion via an intrathecal drug delivery system has not been well characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This single-center retrospective study aimed to quantify serum bupivacaine concentrations during intrathecal infusion and evaluate factors associated with systemic absorption. Serial bupivacaine plasma concentrations were measured with an in-house analytical assay on blood samples collected before each pump refill.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Thirty-one patients were included, with a total of 162 blood samples analyzed. The mean daily intrathecal bupivacaine dose was 39.5 mg\/day (SD 31.4 mg\/day), resulting in a mean serum concentration of 167.7 \u00b5g\/L (SD 266.2 \u00b5g\/L). Serum bupivacaine levels were positively correlated with the daily dose and were also influenced by body mass index. After adjustment for daily dose, higher infusion flow rates remained independently associated with increased serum concentrations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Chronic intrathecal infusion of bupivacaine for cancer pain management results in systemic exposure well below the established toxicity threshold.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/rapm-2025-107216","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T15:23:17Z","timestamp":1788880997000},"page":"1034-1040","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Bupivacaine serum concentrations during chronic intrathecal infusion for pain management: an observational single-center study"],"prefix":"10.1136","volume":"51","author":[{"given":"Florent","family":"Bienfait","sequence":"first","affiliation":[{"name":"Anesthesiology and Pain Medicine Department, Institut de Canc\u00e9rologie de l\u2019Ouest, Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adele","family":"Huchon-Petriolle","sequence":"additional","affiliation":[{"name":"Anesthesiology and Pain Medicine Department, Institut de Canc\u00e9rologie de l\u2019Ouest, Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Passot","sequence":"additional","affiliation":[{"name":"Research Biology, Institut de Canc\u00e9rologie de l\u2019Ouest, Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Jubier-Hamon","sequence":"additional","affiliation":[{"name":"Anesthesiology and Pain Medicine Department, Institut de Canc\u00e9rologie de l\u2019Ouest, Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Luz","family":"Padilla Del Rey","sequence":"additional","affiliation":[{"name":"Pain Medicine, La Tour H\u00f4pital Priv\u00e9 SA, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Robert","sequence":"additional","affiliation":[{"name":"Pharmacy Department, Institut de Canc\u00e9rologie de l\u2019Ouest, Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Julienne","sequence":"additional","affiliation":[{"name":"Anesthesiology and Pain Medicine Department, Institut de Canc\u00e9rologie de l\u2019Ouest, Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Lebrec","sequence":"additional","affiliation":[{"name":"Anesthesiology and Pain Medicine Department, Institut de Canc\u00e9rologie de l\u2019Ouest, Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1777-2130","authenticated-orcid":false,"given":"Denis","family":"Dupoiron","sequence":"additional","affiliation":[{"name":"Anesthesiology and Pain Medicine Department, Institut de Canc\u00e9rologie de l\u2019Ouest, Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"2026090808101525000_51.9.1034.1","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1016\/j.neurom.2024.08.006","article-title":"The Polyanalgesic Consensus Conference (PACC)\u00ae: Updates on Clinical Pharmacology and Comorbidity Management in Intrathecal Drug Delivery for Cancer Pain","volume":"28","author":"Deer","year":"2025","journal-title":"Neuromodulation"},{"key":"2026090808101525000_51.9.1034.2","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1111\/ner.12538","article-title":"The Polyanalgesic Consensus Conference (PACC): Recommendations on Intrathecal Drug Infusion Systems Best Practices and Guidelines","volume":"20","author":"Deer","year":"2017","journal-title":"Neuromodulation"},{"key":"2026090808101525000_51.9.1034.3","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1097\/SPC.0000000000000427","article-title":"Intrathecal therapy for pain in cancer patients","volume":"13","author":"Dupoiron","year":"2019","journal-title":"Curr Opin Support Palliat Care"},{"key":"2026090808101525000_51.9.1034.4","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy152"},{"key":"2026090808101525000_51.9.1034.5","doi-asserted-by":"publisher","DOI":"10.1097\/00002508-199909000-00002"},{"key":"2026090808101525000_51.9.1034.6","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3959(93)90191-Q"},{"key":"2026090808101525000_51.9.1034.7","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1111\/j.1526-4637.2011.01232.x","article-title":"Combination of intrathecal opioids with bupivacaine attenuates opioid dose escalation in chronic noncancer pain patients","volume":"12","author":"Veizi","year":"2011","journal-title":"Pain Med"},{"key":"2026090808101525000_51.9.1034.8","unstructured":"Bupivacaine synthetic compassionate use program. n.d. Available: https:\/\/ansm.sante.fr\/tableau-acces-derogatoire\/bupivacaine-synthetica#"},{"key":"2026090808101525000_51.9.1034.9","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1111\/ner.13469","article-title":"First Evaluation Switching From Ropivacaine to Highly Concentrated Bupivacaine in Intrathecal Mixtures for Cancer Pain","volume":"24","author":"Bienfait","year":"2021","journal-title":"Neuromodulation"},{"key":"2026090808101525000_51.9.1034.10","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1111\/j.1600-0773.1997.tb00037.x","article-title":"Toxicity of Bupivacaine and Ropivacaine in Relation to Free Plasma Concentrations in Pregnant Rats: A Comparative Study","volume":"81","author":"Danielsson","year":"1997","journal-title":"Pharmacol Toxicol"},{"key":"2026090808101525000_51.9.1034.11","first-page":"333","article-title":"Cardiotoxicity with modern local anaesthetics: is there a safer choice?","volume":"61","author":"Mather","year":"2001","journal-title":"Drugs (Abingdon Engl)"},{"key":"2026090808101525000_51.9.1034.12","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1111\/j.1399-6576.1968.tb00420.x","article-title":"The effect of local anaesthetics on the central circulation and respiration in man and dog","volume":"12","author":"Jorfeldt","year":"1968","journal-title":"Acta Anaesthesiol Scand"},{"key":"2026090808101525000_51.9.1034.13","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/56.5.485"},{"key":"2026090808101525000_51.9.1034.14","doi-asserted-by":"crossref","first-page":"283","DOI":"10.2165\/00003088-198916050-00002","article-title":"Clinical pharmacokinetics of epidural and spinal anaesthesia","volume":"16","author":"Burm","year":"1989","journal-title":"Clin Pharmacokinet"},{"key":"2026090808101525000_51.9.1034.15","doi-asserted-by":"crossref","first-page":"191","DOI":"10.2165\/00003088-198713030-00004","article-title":"Pharmacokinetics of Lidocaine and Bupivacaine in Surgical Patients Following Epidural Administration","volume":"13","author":"Burm","year":"1987","journal-title":"Clin Pharmacokinet"},{"key":"2026090808101525000_51.9.1034.16","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/S0750-7658(05)80621-5","article-title":"Pharmacocin\u00e9tique de la bupivaca\u00efne administr\u00e9e par voie p\u00e9ridurale ou sous-arachno\u00efdienne pour c\u00e9sarienne r\u00e9gl\u00e9e","volume":"12","author":"Ledan","year":"1993","journal-title":"Annales Fran\u00e7aises d\u2019Anesth\u00e9sie et de R\u00e9animation"},{"key":"2026090808101525000_51.9.1034.17","first-page":"72","article-title":"Blood and cerebrospinal fluid levels of bupivacaine in spinal anesthesia","volume":"6","author":"Dennhardt","year":"1983","journal-title":"Reg Anaesth"},{"key":"2026090808101525000_51.9.1034.18","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-197607000-00008"},{"key":"2026090808101525000_51.9.1034.19","doi-asserted-by":"publisher","DOI":"10.1016\/S1529-9430(02)00199-7"},{"key":"2026090808101525000_51.9.1034.20","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1111\/ner.12956","article-title":"Effect of Long-Term Intrathecal Bupivacaine Infusion on Blood Pressure","volume":"22","author":"Hayek","year":"2019","journal-title":"Neuromodulation"},{"key":"2026090808101525000_51.9.1034.21","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1093\/pm\/pnv021","article-title":"Intrathecal Hydromorphone and Bupivacaine Combination Therapy for Post-Laminectomy Syndrome Optimized with Patient-Activated Bolus Device","volume":"17","author":"Hayek","year":"2016","journal-title":"Pain Med"},{"key":"2026090808101525000_51.9.1034.22","doi-asserted-by":"publisher","DOI":"10.1046\/j.1525-1403.2002.02030.x"},{"key":"2026090808101525000_51.9.1034.23","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/58.7.717"},{"key":"2026090808101525000_51.9.1034.24","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-197904040-00001"},{"key":"2026090808101525000_51.9.1034.25","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1213\/00000539-198504000-00003","article-title":"Cardiac electrophysiologic and hemodynamic effects related to plasma levels of bupivacaine in the dog","volume":"64","author":"Hotvedt","year":"1985","journal-title":"Anesth Analg"},{"key":"2026090808101525000_51.9.1034.26","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0000000000002011"},{"key":"2026090808101525000_51.9.1034.27","doi-asserted-by":"crossref","unstructured":"Borman P , Elder D . Q2(R1) validation of analytical procedures. ICH Quality Guidelines, 2017.","DOI":"10.1002\/9781118971147.ch5"},{"key":"2026090808101525000_51.9.1034.28","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1213\/00000539-198666020-00005","article-title":"Body mass and spread of spinal anesthesia with bupivacaine","volume":"66","author":"Pitk\u00e4nen","year":"1987","journal-title":"Anesth Analg"},{"key":"2026090808101525000_51.9.1034.29","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0124264","article-title":"Obesity Is Independently Associated with Spinal Anesthesia Outcomes: A Prospective Observational Study","volume":"10","author":"Kim","year":"2015","journal-title":"PLoS ONE"},{"key":"2026090808101525000_51.9.1034.30","doi-asserted-by":"crossref","first-page":"6144","DOI":"10.12659\/MSM.909476","article-title":"Relationship Between Body Mass Index and Spread of Spinal Anesthsia in Pregnant Women: A Randomized Controlled Trial","volume":"24","author":"Wang","year":"2018","journal-title":"Med Sci Monit"}],"container-title":["Regional Anesthesia &amp; Pain Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/rapm-2025-107216","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T15:25:15Z","timestamp":1788881115000},"score":1,"resource":{"primary":{"URL":"https:\/\/rapm.bmj.com\/lookup\/doi\/10.1136\/rapm-2025-107216"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9]]},"references-count":30,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9,8]]},"published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1136\/rapm-2025-107216"],"URL":"https:\/\/doi.org\/10.1136\/rapm-2025-107216","relation":{},"ISSN":["1098-7339","1532-8651"],"issn-type":[{"value":"1098-7339","type":"print"},{"value":"1532-8651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9]]}}}