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However, their pharmacological properties in the body are still unclear, resulting in a lack of targeted control measures for the prevention of abuse and emergency treatment of acute poisoning. This study comprehensively assessed their therapeutic indices and addiction potential using acute toxicity, hot\u2010plate, conditioned place preference (CPP), and naloxone\u2010precipitated withdrawal tests. Results showed that the subcutaneous median lethal dose (95% confidence interval; LD\u2085\u2080 [95% CI]) values of o\u2010fluorofentanyl were 101 (76.26\u2013135) mg\/kg (female) and 133 (108\u2013264) mg\/kg (male), while the LD\u2085\u2080 (95% CI) values of p\u2010fluorofentanyl were 76 (54.2\u2013118) mg\/kg (female) and 58 (49.2\u201381.8) mg\/kg (male). The acute toxicity of o\u2010fluorofentanyl and p\u2010fluorofentanyl was greatest when administered intravenously, followed by intraperitoneal, subcutaneous, and intragastric gavage. In the hot\u2010plate test, the median effective dose (ED\n                    <jats:sub>50<\/jats:sub>\n                    ) values were 0.076\u2009mg\/kg (95% CI: 0.061\u20130.093\u2009mg\/kg) for fentanyl, 0.014\u2009mg\/kg (95% CI: 0.013\u20130.017\u2009mg\/kg) for o\u2010fluorofentanyl, and 0.088\u2009mg\/kg (95% CI: 0.076\u20130.095\u2009mg\/kg) for p\u2010fluorofentanyl. The therapeutic index (LD\u2085\u2080\/ED\u2085\u2080) of o\u2010fluorofentanyl reached 7214 (95% CI: 5866\u20137941), surpassing the therapeutic index of fentanyl (1000 [95% CI: 693\u20131786]) and the therapeutic index of p\u2010fluorofentanyl (863 [95% CI: 713\u20131242]). In CPP tests, both compounds induced significant effects at 0.1\u2009mg\/kg, compared with the effect of fentanyl at 0.3\u2009mg\/kg. In naloxone\u2010precipitated withdrawal tests, both compounds triggered pronounced jumping and weight loss, indicating that both substances can produce physical dependence similar to that of fentanyl. In conclusion, compared with fentanyl, o\u2010fluorofentanyl exhibits higher analgesic potency (ED\u2085\u2080\u2009=\u20090.014\u2009mg\/kg) and a superior therapeutic index (7214). However, its strong rewarding effects and physical dependence suggest that its addictive potential is significantly higher. The therapeutic index of p\u2010fluorofentanyl (863) is comparable to that of fentanyl, but it also exhibits significant dependence and reward effects. The benzene ring's fluorine position can thus regulate drug effects and dependence risks, offering crucial insights for opioid drug design and regulation.\n                  <\/jats:p>","DOI":"10.1002\/jat.70103","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T00:11:04Z","timestamp":1770941464000},"page":"3066-3074","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Comparative Study of Analgesic Therapeutic Index and Addiction Potential of o\u2010 and p\u2010Fluorofentanyl"],"prefix":"10.1002","volume":"46","author":[{"given":"Deli","family":"Xu","sequence":"first","affiliation":[{"name":"School of Pharmacy China Pharmaceutical University  Nanjing China"},{"name":"Office of China National Narcotics Control Commission, Joint Laboratory on Key Technologies of Narcotics Control China Pharmaceutical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianbin","family":"Zeng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Drug Monitoring and Control, Drug Intelligence and Forensic Center Ministry of Public Security  Beijing China"},{"name":"Beijing Regional Center of National Narcotics Laboratory  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuesong","family":"Shi","sequence":"additional","affiliation":[{"name":"School of Pharmacy China Pharmaceutical University  Nanjing China"},{"name":"Office of China National Narcotics Control Commission, Joint Laboratory on Key Technologies of Narcotics Control China Pharmaceutical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmacy China Pharmaceutical University  Nanjing China"},{"name":"Office of China National Narcotics Control Commission, Joint Laboratory on Key Technologies of Narcotics Control China Pharmaceutical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Wang","sequence":"additional","affiliation":[{"name":"Office of China National Narcotics Control Commission, Joint Laboratory on Key Technologies of Narcotics Control China Pharmaceutical University  Beijing China"},{"name":"Key Laboratory of Drug Monitoring and Control, Drug Intelligence and Forensic Center Ministry of Public Security  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Yan","sequence":"additional","affiliation":[{"name":"School of Pharmacy China Pharmaceutical University  Nanjing China"},{"name":"Office of China National Narcotics Control Commission, Joint Laboratory on Key Technologies of Narcotics Control China Pharmaceutical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Xu","sequence":"additional","affiliation":[{"name":"Office of China National Narcotics Control Commission, Joint Laboratory on Key Technologies of Narcotics Control China Pharmaceutical University  Beijing China"},{"name":"Key Laboratory of Drug Monitoring and Control, Drug Intelligence and Forensic Center Ministry of Public Security  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"e_1_2_11_2_1","unstructured":"CDC.2025.SUDORS Dashboard: Fatal Drug Overdose Data [WWW Document]. 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