Effect of Intranasal vs Intramuscular Naloxone on Opioid Overdose: A Randomized Clinical Trial.

Importance
Previous unblinded clinical trials suggested that the intranasal route of naloxone hydrochloride was inferior to the widely used intramuscular route for the reversal of opioid overdose.


Objective
To test whether a dose of naloxone administered intranasally is as effective as the same dose of intramuscularly administered naloxone in reversing opioid overdose.


Design, Setting, and Participants
A double-blind, double-dummy randomized clinical trial was conducted at the Uniting Medically Supervised Injecting Centre in Sydney, Australia. Clients of the center were recruited to participate from February 1, 2012, to January 3, 2017. Eligible clients were aged 18 years or older with a history of injecting drug use (n = 197). Intention-to-treat analysis was performed for all participants who received both intranasal and intramuscular modes of treatment (active or placebo).


Interventions
Clients were randomized to receive 1 of 2 treatments: (1) intranasal administration of naloxone hydrochloride 800 μg per 1 mL and intramuscular administration of placebo 1 mL or (2) intramuscular administration of naloxone hydrochloride 800 μg per 1 mL and intranasal administration of placebo 1 mL.


Main Outcomes and Measures
The primary outcome measure was the need for a rescue dose of intramuscular naloxone hydrochloride (800 μg) 10 minutes after the initial treatment. Secondary outcome measures included time to adequate respiratory rate greater than or equal to 10 breaths per minute and time to Glasgow Coma Scale score greater than or equal to 13.


Results
A total of 197 clients (173 [87.8%] male; mean [SD] age, 34.0 [7.82] years) completed the trial, of whom 93 (47.2%) were randomized to intramuscular naloxone dose and 104 (52.8%) to intranasal naloxone dose. Clients randomized to intramuscular naloxone administration were less likely to require a rescue dose of naloxone compared with clients randomized to intranasal naloxone administration (8 [8.6%] vs 24 [23.1%]; odds ratio, 0.35; 95% CI, 0.15-0.66; P = .002). A 65% increase in hazard (hazard ratio, 1.65; 95% CI, 1.21-2.25; P = .002) for time to respiratory rate of at least 10 and an 81% increase in hazard (hazard ratio, 1.81; 95% CI, 1.28-2.56; P = .001) for time to Glasgow Coma Scale score of at least 13 were observed for the group receiving intranasal naloxone compared with the group receiving intramuscular naloxone. No major adverse events were reported for either group.


Conclusions and Relevance
This trial showed that intranasally administered naloxone in a supervised injecting facility can reverse opioid overdose but not as efficiently as intramuscularly administered naloxone can, findings that largely replicate those of previous unblinded clinical trials. These results suggest that determining the optimal dose and concentration of intranasal naloxone to respond to opioid overdose in real-world conditions is an international priority.


Trial Registration
anzctr.org.au Identifier: ACTRN12611000852954.


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These state that a client will receive airway management and oxygenation either via Hudson 108 mask or artificial ventilation (bagging) for five minutes before being considered in need of 109 Naloxone. Where a client's response after five minutes is inadequate, Naloxone will be 110 administered by a registered nurse in accordance with existing standing orders from the 111 Medical Director.

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Inadequate response will be defined as: 126 confidence) to detect a difference of 14% in requirement for secondary Naloxone.

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The project aims to recruit approximately 200 participants, and all costing is based 129 on this. At current rates of opioid overdose and Naloxone administration (based on 130 the most recent quarter) it is anticipated that 180 cases will be enrolled within 12-18 131 months. After six months rate of recruitment will be reviewed to assess expected

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Flyers will be placed around MSIC notifying clients of the study.

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-Screening: All clients with symptoms/signs of an opioid overdose requiring 346 Naloxone administration will be eligible for the study. This is based on existing 347 and approved MSIC protocols and clinical criteria for overdose:

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Research to guide us in a method of obtaining oral consent:

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Informed consent will be obtained from the participants in the following way: -By ensuring that the trial is comprehensively advertised at MSIC;

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-Any newly registering clients will be provided details of the trial;

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-By asking the clients once if they consent to participate and offer any further 363 information requested;

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-When a client declines to participate this will be flagged on the database. This 365 list of clients will be regularly reviewed at clinical case reviews so that all staff are 366 familiar with the clients who do not want to participate;

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-If a consenting client is enrolled, they will be informed of their participation after 368 the intervention. At a point that is suitable bearing in mind the process of the 369 client's recovery, they will be asked if they wish to withdraw that event's data from 370 the study.

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The participant will be enrolled into the study after the informed consent process

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Study participants will receive a random allocation of Naloxone in one of 2 forms: 388 a. Active intranasal Naloxone and intramuscular placebo, or 389 b. Intranasal placebo and active intramuscular Naloxone

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Study packs will be pre-prepared and contain two clearly labelled vials -1)

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Intranasal -Naloxone 800mcg/1mL or placebo (1mL) for IN administration and 2) 392 Intramuscular -800mcg/1ml or placebo for IM administration. The vials will be 393 labelled as intranasal and intramuscular, therefore the person administering the 394 drugs will be blinded to the treatment arms. As per MSIC protocol, two staff 395 members will attend the patient during treatment of opioid overdose. A third 396 attending staff member will record the participants' vital signs on a chart. The 397 chart is currently in use for overdoses.

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The intranasal administration will always precede the intramuscular 400 administration. Contents of the vial for IN administration will be drawn into one 401 syringe. Staff will attach the syringe to a MAD, and administer 0.5mL (400mcg) 402 into each nostril, depressing the syringe rapidly to achieve adequate atomisation.

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In this way, each study participants will receive 0.5mL of fluid in each nostril.

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Supportive care/oxygenation will be administered simultaneously, in accordance

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Any client who fails to respond adequately after ten minutes will be eligible for a 410 second dose. This dose will be a known dose of 800mcg of Naloxone

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Post analysis, the treatment allocations will be de-coded.

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The preparation of Naloxone and placebo will be manufactured by a registered 420 pharmaceutical company, Sypharma Pty Ltd, and will comply with national 421 medication quality and safety standards.

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The DSMB will receive a fortnightly update of study enrollments that will include a 445 comparison of requirement for rescue Naloxone for the two groups (intranasal and 446 intramuscular) and any adverse events. All major adverse events (cardiac arrest, 447 acute pulmonary oedema, cardiac arrhythmias, epileptic seizure) will be reported

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The DSMB may advise the trial be prematurely discontinued if concern arises about 452 differences in adverse event or response rates between the two study arms 453 (intranasal and intramuscular).

455 7. BLINDING AND UNBLINDING 456
Blinding will occur in the following way: study packs will be prepared by 457 Pharmpackpro Pty Ltd. Two vials will be in the study packs, one containing the 458 active Naloxone and one containing placebo. Vials will be individually and clearly 459 labeled either 'intramuscular' or 'intranasal'. During the course of the trial only 460 Pharmpackpro Pty Ltd. will know which packs contain either active Naloxone or 461 placebo, intramuscular or intranasal. Pharmpackpro Pty Ltd. will provide the 462 research co-ordinator, Ian Flaherty, with a code assigned to each treatment arm but that does not reveal whether the arm contains the active Naloxone or placebo. In 464 this way, the two treatment arms will be distinguishable for fortnightly analysis, but 465 the researchers will remain blinded. The packs will be sequentially numbered, and 466 coded according to treatment arm, and the pack number and code used during the 467 trial will be recorded, along with the other clinical observations, by the MSIC staff on 468 the data-form. In this way, the participants, the nurses administering the Naloxone 469 and the researchers will be blinded to the two treatment arms.

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Unblinding will occur in the following way: once all participants have been recruited,     Data-forms will be secured in a locked filing cupboard in a locked office at the MSIC.

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Only the research team will have access to this filing cabinet.

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Data will be entered into an electronic database that will be password protected.

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Only study investigators will have access to the database.

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Data will be kept for a period of 15 years after publication of study findings in a peer-505 reviewed medical journal. At that time, paper files will be destroyed by paper 506 shredder and electronic files will be deleted from computers.      674  Participants will be consecutively enrolled during this period. We estimate at current rates of 675 overdose requiring Naloxone, eighteen months to two years will be required to achieve a   The research design specifically excludes pregnant women, the human foetus and 691 individuals under the age of eighteen. Sydney MSIC specifically excludes these 692 individuals from utilising the MSIC by the following procedure: 693  If it is suspected by MSIC staff that a client may be pregnant, they are referred to a local drug 694 and alcohol programme where they undergo a pregnancy test. The results are then returned 695 to MSIC.

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 If it is suspected a potential client may be under eighteen years old, formal ID is requested of 697 the potential client by MSIC staff. If the person is over eighteen, a copy of the ID is kept on 698 file. If the person is under eighteen, they are referred to a local drug and alcohol service.

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 Anyone who presents as already intoxicated from alcohol or other drugs, anyone 700 accompanied by a child and anyone who has not previously injected drugs are already 701 excluded from using the MSIC according to the internal management protocols required by 702 legislation.

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 Probable incidental recruitment may include people whose primary language is other than    We have used Section 2.2.5 of the National Statement on Ethical Conduct in Human 763 Research to guide us in a method of obtaining oral consent. Informed consent will be 764 obtained from the participants in the following way: 765  By ensuring that the trial is comprehensively advertised at MSIC; 766  Any newly registering clients will be provided details of the trial; 767  By asking the clients once if they consent to participate and offer any further information 768 requested;

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 When a client declines to participate this will be flagged on the database. This list of clients 770 will be regularly reviewed at clinical case reviews so that all staff are familiar with the clients 771 who do not want to participate;

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 If a consenting client is enrolled, they will be informed of their participation after the 773 intervention. At a point that is suitable, bearing in mind the process of the client's recovery, 774 they will be asked if they wish to withdraw that event's data from the study. The participant will be enrolled into the study after the informed consent process has 778 been completed and the participant has met all inclusion criteria and none of the 779 exclusion criteria. Participants will then be consecutively enrolled during all 780 operating hours of the service. All clients of the MSIC will be informed of the study 781 at registration. The participant will be informed of their enrollment once they have 782 fully regained consciousness. If they decline to participate, the data will be 783 eliminated from the database. 784 785 5.7 RANDOMISATION PROCEDURE 786 MSIC staff will manage drug overdoses using existing clinical protocols. These state 787 that a client will receive airway management and oxygenation either via a Hudson 788 mask or artificial ventilation (bagging) for five minutes before being assessed as to 789 the need for Naloxone. Where a client's response after five minutes is inadequate, 790 Naloxone will be administered by a registered nurse in accordance with existing 791 standing orders from the Medical Director. 792 Study participants will receive a random allocation of Naloxone in one of 2 forms: 793  Active intranasal Naloxone and intramuscular placebo, or 794  Intranasal placebo and active intramuscular Naloxone.

795
Study packs will be pre-prepared and contain two clearly labelled vials -1) 796 Intranasal -Naloxone 800mcg/1mL or placebo (1mL) for IN administration and 2) 797 Intramuscular -800mcg/1ml or placebo for IM administration. The vials will be 798 labelled as intranasal and intramuscular, therefore the person administering the drugs 799 will be blinded to the treatment arms. As per MSIC protocol, two staff members will 800 attend the patient during treatment of opioid overdose. A third attending staff 801 member will record the participants' vital signs on a chart. The chart is currently in 802 use for overdoses. 803 To minimise potential bias, the order in which the drug will be administered will be 804 rotated approximately midway through the study. Initially the intranasal drug 805 preparation will be administered first, followed by the intramuscular drug 806 preparation. Approximately midway through recruitment (e.g., after 100 807 enrolments), the intramuscular drug preparation will be administered first, followed 808 by the intranasal drug preparation. 809 Contents of the vial for IN administration will be drawn into one syringe. Staff will 810 attach the syringe to a MAD, and administer 0.5mL (400mcg) into each nostril, 811 depressing the syringe rapidly to achieve adequate atomisation. In this way, each 812 study participants will receive 0.5mL of fluid in each nostril. Supportive 813 care/oxygenation will be administered simultaneously, in accordance with existing 814 MSIC clinical protocols 815 Administration of the IM injection will be by standard practice of drawing the full 816 1ml into a single 5ml syringe and administering to the deltoid muscle via a 23g 817 needle. 818 Any client who fails to respond adequately after ten minutes will be eligible for a 819 second dose. This dose will be a known dose of 800mcg of Naloxone administered 820 intramuscularly and not subject to randomisation. In this manner, all overdoses will 821 receive the same clinical care they would have otherwise, under existing approved 822 clinical protocols, with Naloxone administered at the same time point, in response to 823 the same clinical criteria. The only exception will be that the need for any additional 824 dose of Naloxone will be assessed at ten minutes post-first dose as opposed to five 825 minutes. Importantly, all clients will be adequately oxygenated and fully monitored 826 during this time. 827 Post analysis, the treatment allocations will be de-coded. 828 The preparation of Naloxone and placebo will be manufactured by a registered 829 pharmaceutical company, Sypharma Pty Ltd, and will comply with national 830 medication quality and safety standards. A data safety and monitoring board (DSMB) will comprise two independent and 851 registered emergency medicine clinicians, employed within a major hospital health 852 service in Melbourne, Victoria. Both are emergency medicine consultants. 853 The DSMB will receive a fortnightly update of study enrollments that will include 854 any adverse events. All major adverse events (cardiac arrest, acute pulmonary 855 oedema, cardiac arrhythmias, epileptic seizure) will be reported within 24 hours to 856 the DSMB. (Please see note in "Blinding and Unblinding" regarding coding of the 857 treatment arms). 858 859 6.4 EARLY TERMINATION 860 The DSMB may advise the trial be prematurely discontinued if concern arises about 861 adverse event rates or delayed response rates. 862 863 7. BLINDING AND UNBLINDING 864 Blinding will occur in the following way: study packs will be prepared by 865 Pharmpackpro Pty Ltd. Two vials will be in the study packs, one containing the 866 active Naloxone and one containing placebo. Vials will be individually and clearly 867 labeled either 'intramuscular' or 'intranasal'. During the course of the trial only 868 Pharmpackpro Pty Ltd will know which packs contain either active Naloxone 869 preparation or placebo, or intramuscular preparation or placebo. 870 Pharmpackpro Pty Ltd will provide the research co-ordinator with a code assigned to 871 each treatment arm but that does not reveal whether the arm contains the active 872 Naloxone or placebo. In this way, the two treatment arms will be distinguishable for 873 fortnightly analysis, but the researchers will remain blinded. The packs will be 874 sequentially numbered, and coded according to treatment arm, and the pack number 875 and code used during the trial will be recorded, along with the other clinical 876 observations by the MSIC staff on the data-form. In this way, the participants, the 877 nurses administering the Naloxone and the researchers will be blinded to the two 878 treatment arms. 879 Unblinding will occur in the following way: once all participants have been 880 recruited, and the active phase of the trial has concluded, clinically-significant 881 differences in the responses of the participants will be analysed. After this analysis, 882 treatment allocations will be de-coded by obtaining from Pharmpackpro Pty Ltd. the 883 numbers of the packs and codes that correspond to the two treatment arms, thereby 884 revealing to which treatment arm each of the participants belongs. 885 886 8 STATISTICAL CONSIDERATIONS 887 Recently, the study findings of a RCT comparing IN and IM Naloxone have been 888 reported. 13 In that study, requirement for a secondary dose of Naloxone was reported 889 as IN:18% vs IM:4%. We estimate (using JavaStat) that we would need a sample 890 size of 99 per group to achieve adequate power (power=0.8, with 95% confidence) 891 to detect a difference of 14% in requirement for secondary Naloxone. 892 Descriptive analyses (proportion, median, effect size difference with 95% 893 confidence intervals) will be conducted to compare demographic characteristics and 894 over-dose related variables for the two groups by allocation (IN and IM) (e.g., age, 895 gender demographic data, prior drug use, previous alcohol use, etc). 896 Primary outcomes will be compared by univariate analysis including odds ratio with 897 95% CI, hazard ratio (HR) and chi-square analysis. Response time will be compared 898 using a Kaplan-Meier survival curve. A clinically significant difference in response 899 time will be defined as two minutes. 900 For cases in which response times are not recorded on patient recovery, and 901 subsequent discharge from the treatment room, a default figure of 10 minutes will be 902 recorded. 903 904 9 STORAGE AND ARCHIVING OF STUDY DOCUMENTS 905 Study documents, both hard and soft copies, will be stored in accordance with the 906 Australian Code for the Responsible Conduct of Research. Data-forms will be 907 secured in a locked filing cupboard in a locked office at the MSIC. Only the research 908 team will have access to this filing cabinet. 909 Data will be entered into an electronic database that will be password protected. 910 Only study investigators will have access to the database. 911 Data will be kept for a period of 15 years after publication of study findings in a 912 peer-reviewed medical journal. At that time, paper files will be destroyed by paper 913 shredder and electronic files will be deleted from computers.