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Participants were assigned to either Group A (control), Group B (intraoral cryotherapy) using ice-gel packs, Group C (intra-canal cryotherapy with saline) with a final flush of cold saline at 2\u20134\u00a0\u00b0C for 10\u00a0min and Group D (intra-canal cryotherapy with hypochlorite) (NaOCl, 2\u20134\u00a0\u00b0C) during chemo-mechanical preparation. (POP) was measured using a visual analogue scale (VAS), and SP levels were assessed from apical fluid samples using enzyme-linked immunosorbent assay (ELISA).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Showed that Group D produced a statistically significant reduction in POP (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001), while Groups B and C showed intermediated POP reductions and the Group A consistently demonstrated the highest POP values. Regarding SP, Group C demonstrated the greatest decrease in SP levels and the largest pre- to post-treatment difference (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Group D achieved intermediate reductions, whereas Group B yielded outcomes comparable to the Group A. A moderate to strong positive correlation was observed between SP levels and VAS scores 6\u00a0h postoperatively. These findings confirm that cryotherapy techniques, particularly cold irrigants, are effective in reducing POP and SP expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Different Cryotherapy techniques effectively reduce (POP) and modulate SP expression. Irrigation with cold hypochlorite throughout chemo mechanical process was most effective for pain reduction while final flush with cold saline achieved the greatest decrease in SP.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical relevance<\/jats:title>\n                    <jats:p>It provides a straightforward approach to alleviating postoperative pain in patients with symptomatic apical periodontitis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Implication<\/jats:title>\n                    <jats:p>Cryotherapy techniques should be more widely incorporated into endodontic clinical practice, as they effectively reduce POP and regulate SP levels. Also, it should be supported as valuable adjunct for improving patients\u2019 outcomes. The trial was registered at ClinicalTrials.gov (NCT07138365, release date 22\/8\/2025).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00784-026-07073-6","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T05:12:51Z","timestamp":1787375571000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical and biochemical effects of cryotherapy protocols on mandibular premolars with symptomatic apical periodontitis: a randomized clinical trial"],"prefix":"10.1007","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7275-6833","authenticated-orcid":false,"given":"Maram Farouk","family":"Obeid","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reem Mohammed Amr","family":"Sharaf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibraheem Mohamed Ibraheem","family":"Hamza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,22]]},"reference":[{"key":"7073_CR1","doi-asserted-by":"publisher","unstructured":"\u00d6zdemir O (2020) Postoperative Pain in Endodontics. 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