Opioid overdose: evidence-based management guidelines and new antidote development
Main Article Content
Abstract
Importance: Opioid overdose is the commonest cause of drug-related deaths worldwide. Naloxone is an effective treatment when instituted early. The emergence of highly potent novel synthetic opioids such as nitazenes and fentanyl analogues has led to a systematic reappraisal of the evidence on management of opioid toxicity with naloxone and development of evidence-based clinical guidelines to reduce opioid-related deaths.
Observations: Guidelines on management of opioid-associated out-of-hospital cardiac arrest recommend standard resuscitation alone in pulseless patients and administration of naloxone if there is uncertainty about the presence of a pulse. For pre-hospital and in-hospital reversal of respiratory depression, intravenous or intranasal naloxone is recommended. Current guidelines recommend a titrated dosing strategy in hospital to reduce the risk of opioid withdrawal. New formulations of intranasal naloxone have been approved to facilitate take-home naloxone and community-based naloxone distribution programmes to reduce opioid-related deaths. Nalmefene and buprenorphine are existing licensed drugs which are being considered as alternatives to naloxone for toxicity from long-acting opioids. Several new experimental antidotes are currently in development to counter the threat from novel synthetic opioids.
Conclusions: Naloxone remains the gold standard antidote for opioid toxicity, both for pre-hospital and hospital use. Further research is required to determine the optimal dose and route of administration. New antidotes are in development but require randomised clinical trials to test their safety and efficacy before they can be implemented in clinical practice.
Keywords:
opioid, naloxone, nitazenes, fentanyl, antidotes, drug-related death
Article Details
How to Cite
KING, Aidan; THANACOODY, Ruben HK.
Opioid overdose: evidence-based management guidelines and new antidote development.
Medical Research Archives, [S.l.], v. 13, n. 10, oct. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6949>. Date accessed: 06 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i10.6949.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Thanacoody R. Opioid overdose. BMJBestPractice 2025. https://bestpractice.bmj.com/topics/en-us/339
2. Balter DR, Howell BA. Take-Home Naloxone, Release From Jail, and Opioid Overdose—A Piece of the Puzzle. JAMA Netw Open. 2024; 7(12):e244 8667. doi:10.1001/jamanetworkopen.2024.48667
3. Rambaran KA, Fleming SW, An J, Burkhart S, et al. U-47700: A Clinical Review of the Literature. J Emerg Med. 2017; 53(4):509-519. doi: 10.1016/j. jemermed.2017.05.034.
4. Hikin L, Smith PR, Ringland E, Hudson S, Morley SR. Multiple fatalities in the North of England associated with synthetic fentanyl analogue exposure: Detection and quantitation a case series from early 2017. Forensic Sci Int. 2018; 282:179-183. doi: 10.1016/j.forsciint.2017.11.036
5. Shafi A, Berry AJ, Sumnall H, Wood DM, Tracy DK. Synthetic opioids: a review and clinical update. Ther Adv Psychopharmacol. 2022; 10;12: 2045125 3221139616. doi: 10.1177/20451253221139616
6. Pergolizzi J Jr, Raffa R, LeQuang JAK, Breve F, Varrassi G. Old Drugs and New Challenges: A Narrative Review of Nitazenes. Cureus. 2023; 21; 15(6):e40736. doi: 10.7759/cureus.40736
7. Tsai MM, Chen L, Baumann MH, Canals M, Javitch JA, Lane JR, Shi L. The in vitro functional profiles of fentanyl and nitazene analogs at the μ-opioid receptor - high efficacy is dangerous regardless of signalling bias. bioRxiv 2023; 2023.11 .10.566672. doi: 10.1101/2023.11.10.566672
8. Alhosan N, Cavallo D, Santiago M, Kelly E, Henderson G. Slow dissociation kinetics of fentanyls and nitazenes correlates with reduced sensitivity to naloxone reversal at the μ-opioid receptor. Br J Pharmacol 2025; 182(4): 969–987. https://doi.org/10.1111/bph.17376
9. Vandeputte MM, Bilel S, Tirri M, et al. Elucidating the harm potential of brorphine analogues as new synthetic opioids: Synthesis, in vitro, and in vivo characterization, Neuropharmacol 2024;260:110113 https://doi.org/10.1016/j.neuropharm.2024.110113
10. van Kempen E, Brand H. Effects of krokodil (desomorphine) use on oral health - a systematic review. Br Dent J 2019; 227: 806–812 https://doi.org/10.1038/s41415-019-0854-x
11. Hasegawa K, Minakata K, Suzuki M, Suzuki O. Non-fentanyl-derived synthetic opioids emerging during recent years. Forensic Toxicol. 2022; 40(2):234-243. doi: 10.1007/s11419-022-00624-y.
12. UNODC. World Drug Report 2024. Key Findings and conclusions https://www.unodc.org/documents/data-and-analysis/WDR_2024/WDR24_Key_findings_and_conclusions.pdf
13. The Lancet Regional Health-Americas. Opioid crisis: addiction, overprescription, and insufficient primary prevention. Lancet Reg Health Am. 2023 :12; 23:100557. doi: 10.1016/j.lana.2023.100557
14. Office for National Statistics Deaths related to drug poisoning by selected substances, England and Wales 2024. https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/datasets/deathsrelatedtodrugpoisoningbyselectedsubstances
15. Centers for Disease Control and Prevention. National center for health statistics: U.S. overdose deaths decrease almost 27% in 2024. May 2025 [internet publication]. Full text (https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2025/20250514.htm )
16. European Drug Report 2025. https://www.euda.europa.eu/publications/european-drug-report/2025/drug-induced-deaths_en#0-level-8
17. Office for Health Improvement and Disparities. Deaths Linked to potent Synthetic Opioids 2024. https://www.gov.uk/government/publications/deaths-linked-to-potent-synthetic-opioids/deaths-linked-to-potent-synthetic-opioids
18. Centers for Disease Control and Prevention. Morbidity and mortality weekly report (MMWR): detection of illegally manufactured fentanyls and carfentanil in drug overdose deaths - United States, 2021-2024. Dec 2024 [internet publication]. Full text (https://www.cdc.gov/mmwr/volumes/73/wr/mm7348a2.htm )
19. Wise J. Nitazenes: toxicologists warn of rise in overdoses linked to class of synthetic opioids. BMJ. 2024; 387:q2465.
20. Saari TI, Strang J, Dale O. Clinical Pharmacokinetics and Pharmacodynamics of Naloxone. Clin Pharmacokinet 2024; 63: 397–422. https://doi.org/10.1007/s40262-024-01355-6
21. Dahan A, Franko TS, Carroll JW, et al. Fact vs. fiction: naloxone in the treatment of opioid-induced respiratory depression in the current era of synthetic opioids. Front Public Health. 2024;12:134 6109. doi: 10.3389/fpubh.2024.1346109
22. Moss RB, Carleton F, Lollo CP, Carlo DJ. An Open-Label, Randomized, Single-Dose, Two-Period, Two-Treatment Crossover Bioavailability Study Comparing 5 mg/0.5 ML of Intramuscular Naloxone Hydrochloride to 2 mg/0.4 ML Intramuscular Naloxone Hydrochloride Autoinjector in Healthy Subjects. J Opioid Manag. 2020; 16(3): 209-14, doi:10.5055/jom.2020.0569
23. Joseph M, Amin K, Siddens C, Jaime G, Seeger CM, Mercer K, Chau T. Pulmonary edema after naloxone administration for opioid reversal: a systematic review of case reports and causality assessment using the Naranjo scale. Clin Toxicol (Phila). 2024; 62(5):334-342. doi: 10.1080/1556365 0.2024.2348108.
24. Dezfulian C, Orkin AM, Maron BA, et al. Opioid-associated out-of-hospital cardiac arrest: distinctive clinical features and implications for health care and public responses: a scientific statement from the American Heart Association. Circulation. 2021;143(16):e836-70
25. Grunau B, O'Neil BJ, Giustini D, Drennan IR, Lavonas EJ; Advanced Life Support Task Force of the International Liaison Committee on Resuscitation. Opioid-associated cardiac arrest: A systematic review of intra-arrest naloxone and other opioid-specific advanced life-support therapies. Resusc Plus. 2025;14; 22:100906. doi: 10.1016/j.resplu. 2025.100906
26. Dillon DG, Montoy JCC, Nishijima DK, et al. Naloxone and patient outcomes in out-of-hospital cardiac arrests in California. J Am Med Assoc Netw Open 2024: e2429154. https://doi.org/10.1001/jamanetworkopen.2024.29154.
27. Quinn E, Murphy E, Du Pont D, et al. Outcomes of out-of-hospital cardiac arrest patients who received naloxone in an emergency medical services system with a high prevalence of opioid overdose. J Emerg Med 2024; 67(3):e249–58. https://doi.org/10.1016/j.jemermed.2024.03.038
28. Strong N, Daya M, Neth M, Noble M, Jui J, Lupton J. The Association between naloxone administration and outcomes for out-of-hospital cardiac arrest due to suspected overdose. Circulation 2023;148 (Suppl 1)
29. Strong NH, Daya MR, Neth MR, et al. The association of early naloxone use with outcomes in non-shockable out-of-hospital cardiac arrest. Resuscitation 2024;201. https://doi.org/10.1016/j.resuscitation.2024.110263
30. Chou R, Korthuis PT, McCarty D, et al. Management of Suspected Opioid Overdose With Naloxone in Out-of-Hospital Settings: A Systematic Review. Ann Intern Med. 2017 Dec 19;167(12):867-875. doi: 10.7326/M17-2224.
31. Aziz R, Nguyen L, Ruhani W, Nguyen A, Zachariah B. The Optimal Initial Dose and Route of Naloxone Administration for Successful Opioid Reversal: A Systematic Literature Review. Cureus. 2024:16(1):e52671. doi: 10.7759/cureus.52671.
32. Yousefifard M, Vazirizadeh-Mahabadi MH, Neishaboori AM, Alavi SNR, Amiri M, Baratloo A, Saberian P. Intranasal versus Intramuscular/ Intravenous Naloxone for Pre-hospital Opioid Overdose: A Systematic Review and Meta-analysis. Adv J Emerg Med. 2019; 4(2):e27. doi: 10.2211 4/ajem.v0i0.279.
33. Williams K, Lang ES, Panchal AR, et al. Evidence-Based Guidelines for EMS Administration of Naloxone, Prehospital Emergency Care 2019; 23: 749-763,DOI: 10.1080/10903127.2019.1597955
34. Edwards ET, Edwards ES, Davis E, Mulcare M, Wiklund M, Kelley G. Comparative Usability Study of a Novel Auto-Injector and an Intranasal System for Naloxone Delivery. Pain Ther. 2015; 4(1):89-105. doi: 10.1007/s40122-015-0035-9
35. Klebacher R, Harris MI, Ariyaprakai N, et al. Incidence of naloxone redosing in the age of the new opioid epidemic. Prehosp Emerg Care. 2017; 21: 682–687. doi: 10.1080/10903127.2017.1335818.
36. Thompson J, Salter J, Bui P, Herbert L, Mills D, Wagner D, Brent C. Safety, efficacy, and cost of 0.4-mg versus 2-mg intranasal naloxone for treatment of prehospital opioid overdose. Ann Pharmacother. 2022; 56: 285–289. doi: 10.1177/ 10600280211030918
37. Rando J, Broering D, Olson JE, Marco C, Evans SB. Intranasal naloxone administration by police first responders is associated with decreased opioid overdose deaths. Am J Emerg Med. 2015; 33:1201–1204. doi: 10.1016/j.ajem.2015.05.022.
38. Kelly AM, Kerr D, Dietze P, et al. Randomized trial of intranasal versus intramuscular naloxone in prehospital treatment for suspected opioid overdose. Med J Aust. 2005; 182(1):24–7.
39. Kerr D, Kelly AM, Dietze P, et al. Randomized controlled trial comparing the effectiveness and safety of intranasal and intramuscular naloxone for the treatment of suspected heroin overdose. Addiction. 2009; 104(12):2067–74. doi: 10.1111/j.1 3600443.2009.02724.x.
40. Dietze P, Jauncey M, Salmon A, et al. Effect of Intranasal vs Intramuscular Naloxone on Opioid Overdose: A Randomized Clinical Trial. JAMA Netw Open. 2019; 2(11):e1914977. doi: 10.1001/ jamanetworkopen.2019.14977
41. Skulberg AK, Tylleskär I, Valberg M, et al. Comparison of intranasal and intramuscular naloxone in opioid overdoses managed by ambulance staff: a double-dummy, randomised, controlled trial. Addiction. 2022;117(6):1658-1667. doi: 10.1111/add.15806
42. Merlin MA, Saybolt M, Kapitanyan R, et al. Intranasal naloxone delivery is an alternative to intravenous naloxone for opioid overdoses. Am J Emerg Med. 2010; 28(3):296–303. doi: 10.1016/ j.ajem.2008.12.009.
43. Robertson TM, Hendey GW, Stroh G, et al. Intranasal naloxone is a viable alternative to intravenous naloxone for prehospital narcotic overdose. Prehosp Emerg Care. 2009; 13(4):512–5. doi:10.1080/10903120903144866.
44. Sporer KA, Firestone J, Isaacs SM. Out-of hospital treatment of opioid overdoses in an urban setting. Acad Emerg Med. 1996; 3(7):660–7.
45. Wanger K, Brough L, Macmillan I, et al. Intravenous vs subcutaneous naloxone for out-of-hospital management of presumed opioid overdose. Acad Emerg Med. 1998; 5(4):293–9
46. Blundell M, Gill R, Thanacoody R, Humphries C, Wood DM, Dargan PI. Joint RCEM and NPIS best practice guideline: assessment and management of acute opioid toxicity in adults in the emergency department. Emerg Med J. 2024; 41(7):440-445. doi: 10.1136/emermed-2024-214163.
47. Carpenter J, Murray BP, Atti S, Moran TP, Yancey A, Morgan B. Naloxone dosing after opioid overdose in the era of illicitly manufactured fentanyl. J Med Toxicol. 2020;16:41–48. doi: 10.10 07/s13181-019-00735-w.
48. Wong F, Edwards CJ, Jarrell DH, Patanwala AE. Comparison of lower-dose versus higher-dose intravenous naloxone on time to recurrence of opioid toxicity in the emergency department. Clin Toxicol (Phila) 2019; 57:19–24. doi: 10.1080/155 63650.2018.1490420
49. Sabzghabaee AM, Eizadi-Mood N, Yaraghi A, et al. Naloxone therapy in opioid overdose patients: intranasal or intravenous? a randomized clinical trial. Arch Med Sci. 2014;10(2):309–14. doi: 10.5114/aoms.2014.42584
50. Isoardi KZ, Harris K, Currey E, Buckley NA, Isbister GK. Effectiveness of intramuscular naloxone 1,600 μg in addition to titrated intravenous naloxone 100 μg for opioid poisoning: a randomised controlled trial. Clin Toxicol 2024; 62(10), 643–650. https://doi.org/10.1080/15563650.2024.2396447
51. Stangeland M, Dale O, Skulberg AK. Nitazenes: review of comparative pharmacology and antagonist action. Clin Toxicol (Phila). 2025; 63(6):393-406. doi: 10.1080/15563650.2025.2504133.
52. Strang J. Take-Home Naloxone and the Prevention of Deaths from Heroin Overdose: Pursuing Strong Science, Fuller Understanding, Greater Impact. Eur Addict Res. 2022;28(3):161-175. doi: 10.1159/000519939
53. Fischer LS, Asher A, Stein R, Becasen J, Doreson A, Mermin J, Meltzer MI, Edlin BR. Effectiveness of naloxone distribution in community settings to reduce opioid overdose deaths among people who use drugs: a systematic review and meta-analysis. BMC Public Health. 2025; 25(1):1135. doi: 10.1186/s12889-025-22210-8.
54. Ellison M, Hutton E, Webster L, Skolnick P. Reversal of Opioid-Induced Respiratory Depression in Healthy Volunteers: Comparison of Intranasal Nalmefene and Intranasal Naloxone. J Clin Pharmacol. 2024; 64(7):828-839. doi: 10.1002/jcph.2421
55. Cipriano A, Apseloff G, Kapil RP, He E, Shet M, Harris SC. Time Course of Reversal of Fentanyl-Induced Respiratory Depression in Healthy Subjects by Intramuscular Nalmefene and Intramuscular and Intranasal Naloxone. J Clin Pharm 2025; 65: 206-216. https://doi.org/10.1002/jcph.6132
56. Nallani SC, Li Z, Florian J, Xu Y, et al. FDA Approval Summary: Nalmefene Nasal Spray for the Emergency Treatment of Known or Suspected Opioid Overdose. Clin Pharmacol Ther. 2025; 117(3):620-626. doi: 10.1002/cpt
57. Zamani N, Buckley NA, Hassanian-Moghaddam H. Buprenorphine to reverse respiratory depression from methadone overdose in opioid-dependent patients: a prospective randomized trial. Crit Care 2020; 24: 44 https://doi.org/10.1186/s13054-020-2740-y
58. Bremer PT, Burke EL, Barrett AC, et al. Investigation of monoclonal antibody CSX-1004 for fentanyl overdose. Nat Commun 2023;14: 7700. https://doi.org/10.1038/s41467-023-43126-0
59. Jordan CG, Kennalley AL, Roberts AL, Nemes KM, Dolma T, Piper BJ. The Potential of Methocinnamox as a Future Treatment for Opioid Use Disorder: A Narrative Review. Pharmacy (Basel). 2022; 19;10(3):48. doi: 10.3390/pharmacy10030048.
60. O’Brien ES, Rangari VA, El Daibani A, et al. A µ-opioid receptor modulator that works cooperatively with naloxone. Nature 2024; 631: 686–693 https://doi.org/10.1038/s41586-024-07587-7
61. Royal College of Emergency Medicine. Best practice guidelines: management of suspected internal drug trafficker (SIDT). Dec 2020 [internet publication]. Full text (https://rcem.ac.uk/wp-content/uploads/2021/10/Management_of_Suspected_Internal_Drug_Trafficker_December_2020.pdf)
62. Stolbach AI, Mazer-Amirshahi ME, Nelson LS, et al. American College of Medical Toxicology and the American Academy of Clinical Toxicology position statement: nalmefene should not replace naloxone as the primary opioid antidote at this time. Clin Toxicol (Phila). 2023; 61(11):952-5.
63. Infante AF, Elmes AT, Gimbar RP, et al. Stronger, longer, better opioid antagonists? Nalmefene is NOT a naloxone replacement. Int J Drug Policy. 2024;124:104323.
2. Balter DR, Howell BA. Take-Home Naloxone, Release From Jail, and Opioid Overdose—A Piece of the Puzzle. JAMA Netw Open. 2024; 7(12):e244 8667. doi:10.1001/jamanetworkopen.2024.48667
3. Rambaran KA, Fleming SW, An J, Burkhart S, et al. U-47700: A Clinical Review of the Literature. J Emerg Med. 2017; 53(4):509-519. doi: 10.1016/j. jemermed.2017.05.034.
4. Hikin L, Smith PR, Ringland E, Hudson S, Morley SR. Multiple fatalities in the North of England associated with synthetic fentanyl analogue exposure: Detection and quantitation a case series from early 2017. Forensic Sci Int. 2018; 282:179-183. doi: 10.1016/j.forsciint.2017.11.036
5. Shafi A, Berry AJ, Sumnall H, Wood DM, Tracy DK. Synthetic opioids: a review and clinical update. Ther Adv Psychopharmacol. 2022; 10;12: 2045125 3221139616. doi: 10.1177/20451253221139616
6. Pergolizzi J Jr, Raffa R, LeQuang JAK, Breve F, Varrassi G. Old Drugs and New Challenges: A Narrative Review of Nitazenes. Cureus. 2023; 21; 15(6):e40736. doi: 10.7759/cureus.40736
7. Tsai MM, Chen L, Baumann MH, Canals M, Javitch JA, Lane JR, Shi L. The in vitro functional profiles of fentanyl and nitazene analogs at the μ-opioid receptor - high efficacy is dangerous regardless of signalling bias. bioRxiv 2023; 2023.11 .10.566672. doi: 10.1101/2023.11.10.566672
8. Alhosan N, Cavallo D, Santiago M, Kelly E, Henderson G. Slow dissociation kinetics of fentanyls and nitazenes correlates with reduced sensitivity to naloxone reversal at the μ-opioid receptor. Br J Pharmacol 2025; 182(4): 969–987. https://doi.org/10.1111/bph.17376
9. Vandeputte MM, Bilel S, Tirri M, et al. Elucidating the harm potential of brorphine analogues as new synthetic opioids: Synthesis, in vitro, and in vivo characterization, Neuropharmacol 2024;260:110113 https://doi.org/10.1016/j.neuropharm.2024.110113
10. van Kempen E, Brand H. Effects of krokodil (desomorphine) use on oral health - a systematic review. Br Dent J 2019; 227: 806–812 https://doi.org/10.1038/s41415-019-0854-x
11. Hasegawa K, Minakata K, Suzuki M, Suzuki O. Non-fentanyl-derived synthetic opioids emerging during recent years. Forensic Toxicol. 2022; 40(2):234-243. doi: 10.1007/s11419-022-00624-y.
12. UNODC. World Drug Report 2024. Key Findings and conclusions https://www.unodc.org/documents/data-and-analysis/WDR_2024/WDR24_Key_findings_and_conclusions.pdf
13. The Lancet Regional Health-Americas. Opioid crisis: addiction, overprescription, and insufficient primary prevention. Lancet Reg Health Am. 2023 :12; 23:100557. doi: 10.1016/j.lana.2023.100557
14. Office for National Statistics Deaths related to drug poisoning by selected substances, England and Wales 2024. https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/datasets/deathsrelatedtodrugpoisoningbyselectedsubstances
15. Centers for Disease Control and Prevention. National center for health statistics: U.S. overdose deaths decrease almost 27% in 2024. May 2025 [internet publication]. Full text (https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2025/20250514.htm )
16. European Drug Report 2025. https://www.euda.europa.eu/publications/european-drug-report/2025/drug-induced-deaths_en#0-level-8
17. Office for Health Improvement and Disparities. Deaths Linked to potent Synthetic Opioids 2024. https://www.gov.uk/government/publications/deaths-linked-to-potent-synthetic-opioids/deaths-linked-to-potent-synthetic-opioids
18. Centers for Disease Control and Prevention. Morbidity and mortality weekly report (MMWR): detection of illegally manufactured fentanyls and carfentanil in drug overdose deaths - United States, 2021-2024. Dec 2024 [internet publication]. Full text (https://www.cdc.gov/mmwr/volumes/73/wr/mm7348a2.htm )
19. Wise J. Nitazenes: toxicologists warn of rise in overdoses linked to class of synthetic opioids. BMJ. 2024; 387:q2465.
20. Saari TI, Strang J, Dale O. Clinical Pharmacokinetics and Pharmacodynamics of Naloxone. Clin Pharmacokinet 2024; 63: 397–422. https://doi.org/10.1007/s40262-024-01355-6
21. Dahan A, Franko TS, Carroll JW, et al. Fact vs. fiction: naloxone in the treatment of opioid-induced respiratory depression in the current era of synthetic opioids. Front Public Health. 2024;12:134 6109. doi: 10.3389/fpubh.2024.1346109
22. Moss RB, Carleton F, Lollo CP, Carlo DJ. An Open-Label, Randomized, Single-Dose, Two-Period, Two-Treatment Crossover Bioavailability Study Comparing 5 mg/0.5 ML of Intramuscular Naloxone Hydrochloride to 2 mg/0.4 ML Intramuscular Naloxone Hydrochloride Autoinjector in Healthy Subjects. J Opioid Manag. 2020; 16(3): 209-14, doi:10.5055/jom.2020.0569
23. Joseph M, Amin K, Siddens C, Jaime G, Seeger CM, Mercer K, Chau T. Pulmonary edema after naloxone administration for opioid reversal: a systematic review of case reports and causality assessment using the Naranjo scale. Clin Toxicol (Phila). 2024; 62(5):334-342. doi: 10.1080/1556365 0.2024.2348108.
24. Dezfulian C, Orkin AM, Maron BA, et al. Opioid-associated out-of-hospital cardiac arrest: distinctive clinical features and implications for health care and public responses: a scientific statement from the American Heart Association. Circulation. 2021;143(16):e836-70
25. Grunau B, O'Neil BJ, Giustini D, Drennan IR, Lavonas EJ; Advanced Life Support Task Force of the International Liaison Committee on Resuscitation. Opioid-associated cardiac arrest: A systematic review of intra-arrest naloxone and other opioid-specific advanced life-support therapies. Resusc Plus. 2025;14; 22:100906. doi: 10.1016/j.resplu. 2025.100906
26. Dillon DG, Montoy JCC, Nishijima DK, et al. Naloxone and patient outcomes in out-of-hospital cardiac arrests in California. J Am Med Assoc Netw Open 2024: e2429154. https://doi.org/10.1001/jamanetworkopen.2024.29154.
27. Quinn E, Murphy E, Du Pont D, et al. Outcomes of out-of-hospital cardiac arrest patients who received naloxone in an emergency medical services system with a high prevalence of opioid overdose. J Emerg Med 2024; 67(3):e249–58. https://doi.org/10.1016/j.jemermed.2024.03.038
28. Strong N, Daya M, Neth M, Noble M, Jui J, Lupton J. The Association between naloxone administration and outcomes for out-of-hospital cardiac arrest due to suspected overdose. Circulation 2023;148 (Suppl 1)
29. Strong NH, Daya MR, Neth MR, et al. The association of early naloxone use with outcomes in non-shockable out-of-hospital cardiac arrest. Resuscitation 2024;201. https://doi.org/10.1016/j.resuscitation.2024.110263
30. Chou R, Korthuis PT, McCarty D, et al. Management of Suspected Opioid Overdose With Naloxone in Out-of-Hospital Settings: A Systematic Review. Ann Intern Med. 2017 Dec 19;167(12):867-875. doi: 10.7326/M17-2224.
31. Aziz R, Nguyen L, Ruhani W, Nguyen A, Zachariah B. The Optimal Initial Dose and Route of Naloxone Administration for Successful Opioid Reversal: A Systematic Literature Review. Cureus. 2024:16(1):e52671. doi: 10.7759/cureus.52671.
32. Yousefifard M, Vazirizadeh-Mahabadi MH, Neishaboori AM, Alavi SNR, Amiri M, Baratloo A, Saberian P. Intranasal versus Intramuscular/ Intravenous Naloxone for Pre-hospital Opioid Overdose: A Systematic Review and Meta-analysis. Adv J Emerg Med. 2019; 4(2):e27. doi: 10.2211 4/ajem.v0i0.279.
33. Williams K, Lang ES, Panchal AR, et al. Evidence-Based Guidelines for EMS Administration of Naloxone, Prehospital Emergency Care 2019; 23: 749-763,DOI: 10.1080/10903127.2019.1597955
34. Edwards ET, Edwards ES, Davis E, Mulcare M, Wiklund M, Kelley G. Comparative Usability Study of a Novel Auto-Injector and an Intranasal System for Naloxone Delivery. Pain Ther. 2015; 4(1):89-105. doi: 10.1007/s40122-015-0035-9
35. Klebacher R, Harris MI, Ariyaprakai N, et al. Incidence of naloxone redosing in the age of the new opioid epidemic. Prehosp Emerg Care. 2017; 21: 682–687. doi: 10.1080/10903127.2017.1335818.
36. Thompson J, Salter J, Bui P, Herbert L, Mills D, Wagner D, Brent C. Safety, efficacy, and cost of 0.4-mg versus 2-mg intranasal naloxone for treatment of prehospital opioid overdose. Ann Pharmacother. 2022; 56: 285–289. doi: 10.1177/ 10600280211030918
37. Rando J, Broering D, Olson JE, Marco C, Evans SB. Intranasal naloxone administration by police first responders is associated with decreased opioid overdose deaths. Am J Emerg Med. 2015; 33:1201–1204. doi: 10.1016/j.ajem.2015.05.022.
38. Kelly AM, Kerr D, Dietze P, et al. Randomized trial of intranasal versus intramuscular naloxone in prehospital treatment for suspected opioid overdose. Med J Aust. 2005; 182(1):24–7.
39. Kerr D, Kelly AM, Dietze P, et al. Randomized controlled trial comparing the effectiveness and safety of intranasal and intramuscular naloxone for the treatment of suspected heroin overdose. Addiction. 2009; 104(12):2067–74. doi: 10.1111/j.1 3600443.2009.02724.x.
40. Dietze P, Jauncey M, Salmon A, et al. Effect of Intranasal vs Intramuscular Naloxone on Opioid Overdose: A Randomized Clinical Trial. JAMA Netw Open. 2019; 2(11):e1914977. doi: 10.1001/ jamanetworkopen.2019.14977
41. Skulberg AK, Tylleskär I, Valberg M, et al. Comparison of intranasal and intramuscular naloxone in opioid overdoses managed by ambulance staff: a double-dummy, randomised, controlled trial. Addiction. 2022;117(6):1658-1667. doi: 10.1111/add.15806
42. Merlin MA, Saybolt M, Kapitanyan R, et al. Intranasal naloxone delivery is an alternative to intravenous naloxone for opioid overdoses. Am J Emerg Med. 2010; 28(3):296–303. doi: 10.1016/ j.ajem.2008.12.009.
43. Robertson TM, Hendey GW, Stroh G, et al. Intranasal naloxone is a viable alternative to intravenous naloxone for prehospital narcotic overdose. Prehosp Emerg Care. 2009; 13(4):512–5. doi:10.1080/10903120903144866.
44. Sporer KA, Firestone J, Isaacs SM. Out-of hospital treatment of opioid overdoses in an urban setting. Acad Emerg Med. 1996; 3(7):660–7.
45. Wanger K, Brough L, Macmillan I, et al. Intravenous vs subcutaneous naloxone for out-of-hospital management of presumed opioid overdose. Acad Emerg Med. 1998; 5(4):293–9
46. Blundell M, Gill R, Thanacoody R, Humphries C, Wood DM, Dargan PI. Joint RCEM and NPIS best practice guideline: assessment and management of acute opioid toxicity in adults in the emergency department. Emerg Med J. 2024; 41(7):440-445. doi: 10.1136/emermed-2024-214163.
47. Carpenter J, Murray BP, Atti S, Moran TP, Yancey A, Morgan B. Naloxone dosing after opioid overdose in the era of illicitly manufactured fentanyl. J Med Toxicol. 2020;16:41–48. doi: 10.10 07/s13181-019-00735-w.
48. Wong F, Edwards CJ, Jarrell DH, Patanwala AE. Comparison of lower-dose versus higher-dose intravenous naloxone on time to recurrence of opioid toxicity in the emergency department. Clin Toxicol (Phila) 2019; 57:19–24. doi: 10.1080/155 63650.2018.1490420
49. Sabzghabaee AM, Eizadi-Mood N, Yaraghi A, et al. Naloxone therapy in opioid overdose patients: intranasal or intravenous? a randomized clinical trial. Arch Med Sci. 2014;10(2):309–14. doi: 10.5114/aoms.2014.42584
50. Isoardi KZ, Harris K, Currey E, Buckley NA, Isbister GK. Effectiveness of intramuscular naloxone 1,600 μg in addition to titrated intravenous naloxone 100 μg for opioid poisoning: a randomised controlled trial. Clin Toxicol 2024; 62(10), 643–650. https://doi.org/10.1080/15563650.2024.2396447
51. Stangeland M, Dale O, Skulberg AK. Nitazenes: review of comparative pharmacology and antagonist action. Clin Toxicol (Phila). 2025; 63(6):393-406. doi: 10.1080/15563650.2025.2504133.
52. Strang J. Take-Home Naloxone and the Prevention of Deaths from Heroin Overdose: Pursuing Strong Science, Fuller Understanding, Greater Impact. Eur Addict Res. 2022;28(3):161-175. doi: 10.1159/000519939
53. Fischer LS, Asher A, Stein R, Becasen J, Doreson A, Mermin J, Meltzer MI, Edlin BR. Effectiveness of naloxone distribution in community settings to reduce opioid overdose deaths among people who use drugs: a systematic review and meta-analysis. BMC Public Health. 2025; 25(1):1135. doi: 10.1186/s12889-025-22210-8.
54. Ellison M, Hutton E, Webster L, Skolnick P. Reversal of Opioid-Induced Respiratory Depression in Healthy Volunteers: Comparison of Intranasal Nalmefene and Intranasal Naloxone. J Clin Pharmacol. 2024; 64(7):828-839. doi: 10.1002/jcph.2421
55. Cipriano A, Apseloff G, Kapil RP, He E, Shet M, Harris SC. Time Course of Reversal of Fentanyl-Induced Respiratory Depression in Healthy Subjects by Intramuscular Nalmefene and Intramuscular and Intranasal Naloxone. J Clin Pharm 2025; 65: 206-216. https://doi.org/10.1002/jcph.6132
56. Nallani SC, Li Z, Florian J, Xu Y, et al. FDA Approval Summary: Nalmefene Nasal Spray for the Emergency Treatment of Known or Suspected Opioid Overdose. Clin Pharmacol Ther. 2025; 117(3):620-626. doi: 10.1002/cpt
57. Zamani N, Buckley NA, Hassanian-Moghaddam H. Buprenorphine to reverse respiratory depression from methadone overdose in opioid-dependent patients: a prospective randomized trial. Crit Care 2020; 24: 44 https://doi.org/10.1186/s13054-020-2740-y
58. Bremer PT, Burke EL, Barrett AC, et al. Investigation of monoclonal antibody CSX-1004 for fentanyl overdose. Nat Commun 2023;14: 7700. https://doi.org/10.1038/s41467-023-43126-0
59. Jordan CG, Kennalley AL, Roberts AL, Nemes KM, Dolma T, Piper BJ. The Potential of Methocinnamox as a Future Treatment for Opioid Use Disorder: A Narrative Review. Pharmacy (Basel). 2022; 19;10(3):48. doi: 10.3390/pharmacy10030048.
60. O’Brien ES, Rangari VA, El Daibani A, et al. A µ-opioid receptor modulator that works cooperatively with naloxone. Nature 2024; 631: 686–693 https://doi.org/10.1038/s41586-024-07587-7
61. Royal College of Emergency Medicine. Best practice guidelines: management of suspected internal drug trafficker (SIDT). Dec 2020 [internet publication]. Full text (https://rcem.ac.uk/wp-content/uploads/2021/10/Management_of_Suspected_Internal_Drug_Trafficker_December_2020.pdf)
62. Stolbach AI, Mazer-Amirshahi ME, Nelson LS, et al. American College of Medical Toxicology and the American Academy of Clinical Toxicology position statement: nalmefene should not replace naloxone as the primary opioid antidote at this time. Clin Toxicol (Phila). 2023; 61(11):952-5.
63. Infante AF, Elmes AT, Gimbar RP, et al. Stronger, longer, better opioid antagonists? Nalmefene is NOT a naloxone replacement. Int J Drug Policy. 2024;124:104323.