{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T14:46:51Z","timestamp":1767797211731,"version":"3.49.0"},"reference-count":47,"publisher":"BMJ","issue":"12","license":[{"start":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T00:00:00Z","timestamp":1767139200000},"content-version":"unspecified","delay-in-days":30,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["32003B_201072"],"award-info":[{"award-number":["32003B_201072"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2025,12,15]]},"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The analgesic and antipyretic paracetamol (acetaminophen) is generally considered safe in therapeutic doses. The most important toxic effect is hepatotoxicity after supratherapeutic doses or in the presence of risk factors (eg, malnutrition, alcoholism). According to the WHO analgesic ladder, a combination of a non-opioid analgesic such as paracetamol with a strong opioid is recommended as step III treatment of patients with chronic pain, despite limited evidence for this approach. The main aim of this study is to test the hypothesis that paracetamol does not provide clinically relevant benefits when added to strong opioids in patients with chronic pain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>Investigator-initiated, randomised, double-blind, placebo-controlled, non-inferiority trial at two Swiss hospitals. A total of 140 patients with chronic pain requiring strong opioids and paracetamol \u22651.5\u2009g\/day for at least 7\u2009days will be enrolled and randomised to either continued combination treatment or strong opioid plus placebo. In the first study phase (days 1\u20137), patients receive identically looking capsules containing either paracetamol at the exact dose previously used or a placebo. During a second study phase (days 7\u201314), all patients stop the blinded study medication (paracetamol and placebo) with follow-up to day 14. Adherence will be assessed by pill count and measurement of paracetamol and opioid serum concentrations. Patients are instructed to use a pain diary daily during the whole study. The primary outcome is the average pain score on day 7 using a 10\u2009cm visual analogue scale (VAS). A difference between groups of \u22648\u2009mm will be considered clinically irrelevant. Secondary outcomes will include VAS pain score on day 14, number of opioid rescue doses used, subjective ratings of overall feeling of well-being, quality of life, nausea\/vomiting, drowsiness and constipation, and other adverse events, and potential effects of study drug concentrations and opioid receptor and cytochrome P450 (CYP) genotypes on the observed differences.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The study was approved by the Ethics Committee (Ethikkommission Bern, reference number 2021-01518) and the Swiss Agency for Therapeutic Products (Swissmedic, reference number 701286). Results will be published in open-access policy peer-reviewed journals. The study is funded by the Swiss National Science Foundation (grant number 32\u2009003B_201072).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05088876\">NCT05088876<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2025-107360","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T12:00:27Z","timestamp":1767182427000},"page":"e107360","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Efficacy of paracetamol added to WHO step III opioids in chronic pain control: study protocol for a randomised, double-blind, placebo-controlled, non-inferiority, 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