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Naloxone dosing in the era of ultra-potent opioid overdoses: a systematic review

  • Jessica Moe (a1) (a2) (a3), Jesse Godwin (a1) (a2), Roy Purssell (a1) (a2) (a3), Fiona O'Sullivan (a1), Jeffrey P. Hau (a1), Elizabeth Purssell (a1), Jason Curran (a4), Mary M. Doyle-Waters (a5), Penelope M.A. Brasher (a5), Jane A. Buxton (a3) (a6) and Corinne M. Hohl (a1) (a2) (a5)...

Abstract

Objectives

Evaluate the relationship between naloxone dose (initial and cumulative) and opioid toxicity reversal and adverse events in undifferentiated and presumed fentanyl/ultra-potent opioid overdoses.

Methods

We searched Embase, MEDLINE, Cochrane Central Register of Controlled Trials, DARE, CINAHL, Science Citation Index, reference lists, toxicology websites, and conference proceedings (1972 to 2018). We included interventional, observational, and case studies/series reporting on naloxone dose and opioid toxicity reversal or adverse events in people >12 years old.

Results

A total of 174 studies (110 case reports/series, 57 observational, 7 interventional) with 26,660 subjects (median age 35 years; 74% male). Heterogeneity precluded meta-analysis. Where reported, we abstracted naloxone dose and proportion of patients with toxicity reversal. Among patients with presumed exposure to fentanyl/ultra-potent opioids, 56.9% (617/1,085) responded to an initial naloxone dose ≤0.4 mg compared with 80.2% (170/212) of heroin users, and 30.4% (7/23) responded to an initial naloxone dose >0.4 mg compared with 59.1% (1,434/2,428) of heroin users. Among patients who responded, median cumulative naloxone doses were higher for presumed fentanyl/ultra-potent opioids than heroin overdoses in North America, both before 2015 (fentanyl/ultra-potent opioids: 1.8 mg [interquartile interval {IQI}, 1.0, 4.0]; heroin: 0.8 mg [IQI, 0.4, 0.8]) and after 2015 (fentanyl/ultra-potent opioids: 3.4 mg [IQI, 3.0, 4.1]); heroin: 2 mg [IQI, 1.4, 2.0]). Where adverse events were reported, 11% (490/4,414) of subjects experienced withdrawal. Variable reporting, heterogeneity and poor-quality studies limit conclusions.

Conclusions

Practitioners have used higher initial doses, and in some cases higher cumulative naloxone doses to reverse toxicity due to presumed fentanyl/ultra-potent opioid exposure compared with other opioids. High-quality comparative naloxone dosing studies assessing effectiveness and safety are needed.

RésuméObjectif

L’étude visait à évaluer la relation entre les doses de naloxone (initiales et cumulatives) et la neutralisation de la toxicité des opioïdes et les événements indésirables survenus dans les cas tous confondus et dans les cas présumés de surdoses de fentanyl ou d'opioïdes extrêmement puissants.

Méthode

Une recherche documentaire a été entreprise dans les bases de données Embase, MEDLINE, Cochrane Central Register of Controlled Trials, DARE, CINAHL et Science Citation Index ainsi que dans les listes de références bibliographiques, les sites web sur la toxicologie et les actes de congrès (1972 à 2018). Ont été retenues des études d'intervention, des études d'observation et des études ou des séries de cas faisant état de doses de naloxone, de la neutralisation de la toxicité des opioïdes ou d’événements indésirables chez des personnes âgées de plus de 12 ans.

Résultats

Ont été retenues 174 études (110 études ou séries de cas, 57 études d'observation et 7 études d'intervention), totalisant 26 660 sujets (âge médian : 35; hommes : 74%). Il n'a pas été possible de procéder à une méta-analyse en raison de l'hétérogénéité des études. Lorsque les données étaient fournies, les chercheurs ont préparé un résumé des doses de naloxone et de la proportion de patients chez qui il y a eu neutralisation de la toxicité. Dans les cas présumés d'exposition au fentanyl ou à des opioïdes extrêmement puissants, 56,9%(617/1085) des sujets ont réagi à une dose initiale de naloxone ≤ 0,4 mg comparativement à 80,2%(170/212) des utilisateurs d'héroïne, et 30,4% (7/23) ont réagi à une dose initiale de naloxone > 0,4 mg comparativement à 59,1% (1434/2428) des utilisateurs d'héroïne. Parmi les patients qui ont réagi à la naloxone, les doses médianes cumulatives de naloxone étaient plus élevées dans les cas présumés de consommation de fentanyl ou d'opioïdes extrêmement puissants que dans les cas de surdose d'héroïne en Amérique du Nord, tant avant 2015 (fentanyl/opioïdes extrêmement puissants : 1,8 mg [intervalle interquartile {IIQ} : 1,0-4,0]; héroïne : 0,8 mg [IIQ : 0,4-0,8]) qu'après 2015 (fentanyl/ opioïdes extrêmement puissants : 3,4 mg [IIQ : 3,0-4,1]; héroïne : 2 mg [IIQ : 1,4-2,0]). Dans les études où était indiquée la survenue d’événements indésirables, 11% (490/4414) des sujets ont éprouvé des signes de manque.

La présentation des variables, l'hétérogénéité des études ainsi que leur piètre qualité limitent la portée de la conclusion.

Conclusion

Les praticiens ont utilisé des doses initiales supérieures et, dans certains cas, des doses cumulatives supérieures de naloxone pour neutraliser la toxicité d'une exposition présumée au fentanyl ou à des opioïdes extrêmement puissants comparativement à d'autres opioïdes. Aussi faudrait-il mener des études comparatives de qualité sur les doses de naloxone afin d'en évaluer l'efficacité et l'innocuité.

Copyright

Corresponding author

Correspondence to: Dr. Jessica Moe, Department of Emergency Medicine, Vancouver General Hospital, 920 West 10th Avenue, Vancouver, British Columbia, Canada, V5Z 1M9; Email: jessica.moe@ubc.ca

References

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Naloxone dosing in the era of ultra-potent opioid overdoses: a systematic review

  • Jessica Moe (a1) (a2) (a3), Jesse Godwin (a1) (a2), Roy Purssell (a1) (a2) (a3), Fiona O'Sullivan (a1), Jeffrey P. Hau (a1), Elizabeth Purssell (a1), Jason Curran (a4), Mary M. Doyle-Waters (a5), Penelope M.A. Brasher (a5), Jane A. Buxton (a3) (a6) and Corinne M. Hohl (a1) (a2) (a5)...

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