What is the comparative efficacy and pharmacokinetics of naloxone IV vs IM vs nasal?

Comment by InpharmD Researcher

Comparative efficacy of naloxone formulations appears to vary amongst studies, some of which compared differing doses between formulations. While no recent data were identified comparing intravenous versus intramuscular naloxone, studies have compared either intravenous or intramuscular versus intranasal formulations. A 2019 meta-analysis concluded no difference between injectable formulations when compared to intranasal for most outcomes, including therapeutic success for management of opioid overdose, however, these studies were based on higher-than-normal naloxone doses. Other recent studies comparing intranasal versus intramuscular naloxone have found the latter to be more successful. A pharmacokinetic analysis of each formulation can be found in Table 3.

Background

A 2019 systematic review and meta-analysis compiled data from 6 studies (N= 965 patients) to compare the efficacy of intranasal versus intramuscular/intravenous (i.e., injectable) naloxone administration for prehospital management of opioid overdose, defined as recovery of patients’ consciousness and spontaneous respiration. The most commonly utilized dose of naloxone was 2 mg for all formulations, but one study utilized lower doses of both intravenous and intranasal formulations (0.4 mg each). Based on all 6 studies, no significant differences were observed between injectable naloxone formulations compared to intranasal for therapeutic success in management of opioid overdose (80.39% vs. 82.54%; odds ratio [OR] 1.01; 95% CI 0.42 to 2.42; p= 0.98). Pooled data from 5 studies indicated time to response with intranasal naloxone is longer than injectable naloxone (standardized mean difference [SMD] 0.63; 95% CI 0.07 to 1.19; p= 0.03); although this difference was considered statistically significant, this difference may not be clinically impactful. The efficacy of naloxone in respiratory depression recovery after opioid overdose was evaluated in 3 studies, finding slightly improved efficacy with injectable formulations compared to intranasal (96.3% vs. 93.63%; OR 0.42; 95% CI 0.21 to 0.85; p= 0.016). Comparisons were also conducted between injectable and intranasal formulations for efficacy in recovery of consciousness following opioid overdose and incidence of naloxone adverse effects, finding no significant difference between groups (OR 1.33; 95% CI 0.02 to 87.55; p= 0.894 and OR 0.64; 95% CI 0.17 to 2.34; p= 0.497, respectively). Major complications were not reported, and most side-effects across all the included studies were considered to be minor. Need for rescue dose of naloxone was assessed in 5 studies, finding that a rescue dose was required in 33.26% of intranasal naloxone cases compared to 17.74% of injectable cases (OR 2.17; 95% CI 1.53 to 3.09; p<0.0001). Overall, the data demonstrate comparable success rates of injectable vs. intranasal naloxone formulations, suggesting intranasal naloxone may be a viable alternative in prehospital settings. Unfortunately, data were not stratified between intramuscular and intravenous formulations. [1]

References: [1] Yousefifard M, Vazirizadeh-Mahabadi MH, Neishaboori AM, et al. Intranasal versus Intramuscular/Intravenous Naloxone for Pre-hospital Opioid Overdose: A Systematic Review and Meta-analysis. Adv J Emerg Med. 2019;4(2):e27. Published 2019 Nov 16. doi:10.22114/ajem.v0i0.279
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the comparative efficacy and pharmacokinetics of naloxone IV vs IM vs nasal?

Please see Tables 1-3 for your response.

 

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

Design

Randomized, double-blind, double-dummy, single-center, controlled trial

N= 197

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

Study Groups

Intramuscular (n= 93)

Intranasal (n= 104)

Inclusion Criteria

 Adults aged ≥ 18 years; history of injectable drug use; observed signs of overdose at the designated clinic

Exclusion Criteria

Persons already intoxicated from other drugs (including alcohol); persons accompanied by a child; received naloxone outside of the designated time window; received a dose of naloxone prior to entry; did not receive the designated treatment

Methods

This was a single-center, randomized study at a medically supervised injecting center in Australia, where persons can safely administer their own IV drugs under supervision of clinically trained staff. Eligible patients entered the clinic of their own volition and were randomized to either naloxone 800 mcg/mL intranasally or intramuscular if an overdose occurred. All participants also received a placebo of the other route (saline injection or water spray). 

For the intranasal group, each nostril received 400 mcg of naloxone per spray.

Duration

 February 1, 2012 to January 3, 2017

Outcome Measures

Primary: requirement for a secondary dose of naloxone at 10 minutes

Secondary: effective and spontaneous respirations at a rate ≥10/min; time to Glasgow coma score (GCS) ≥13

Baseline Characteristics

  

Intramuscular (n= 93)

Intranasal (n= 104)

  

Age, years

 33.6 ± 7.5 34.4 ± 8.1  

Male

 87.1% 88.5%  
Starting age of IV drug use, years 19.6 ± 6.7 19.6 ± 7.8  

Reported drug injection

Heroin

Morphine or oxycodone

Fentanyl

Methadone

 

60.2%

22.6%

11.8%

5.4%

 

62.5%

19.2%

13.5%

4.8%

  
Current buprenorphine or methadone use 3.2% 4.8%  

Results

Endpoint

Intramuscular (n= 93)

Intranasal (n= 104)

OR/HR (95% CI)

Need for second naloxone dose

 8.6% 23.1% 0.35 (0.15 to 0.66)
Time to GCS ≥13, minutes (IQR) 8.0 (6.8-9.2) 15.0 (13.9-16.1) 1.65 (1.21-2.25)
Time to respiratory rate ≥10/min, minutes (IQR) 8.0 (6.1-9.9) 17.0 (14.1-19.9) 1.81 (1.28-2.56)

Adverse Events

 Not studied

Study Author Conclusions

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.

InpharmD Researcher Critique

 This trial used a higher-than-standard dose of IM naloxone (800 mcg/mL); however, this dose was matched in the comparator group. Other limitations of this trial include the single-center approach outside of the United States and willing population.



References:
[1] Dietze P, Jauncey M, Salmon A, et al. Effect of Intranasal vs Intramuscular Naloxone on Opioid Overdose: A Randomized Clinical Trial [published correction appears in JAMA Netw Open. 2020 Apr 1;3(4):e206593]. JAMA Netw Open. 2019;2(11):e1914977. Published 2019 Nov 1. doi:10.1001/jamanetworkopen.2019.14977

 

Comparison of intranasal and intramuscular naloxone in opioid overdoses managed by ambulance staff: a double‐dummy, randomised, controlled trial

Design

Randomized, controlled, double‐dummy, blinded, non‐inferiority trial

N= 201

Objective

To measure and evaluate clinical response to nasal naloxone in opioid overdoses in the pre‐hospital environment

Study Groups

Intramuscular (n= 108)

Intranasal (n= 93)

Inclusion Criteria

 Participants treated by ambulance services for suspected opioid overdose; recognized by reduced or absent spontaneous respiration (≤8 breaths/min); Glasgow Coma Score <12; presented with miosis

Exclusion Criteria

 Cardiac arrest, suspected pregnancy, age below 18 years, or had received naloxone before the arrival of ambulance staff

Methods

 This was a randomized trial conducted in metro Oslo, Norway. Eligible participants were randomized to receive either 1.4 mg/0.1 mL naloxone nasal spray or 0.4 mg/mL intramuscular injection. All patients also received a placebo of the other route. 

Duration

 Follow-up: up to 12 hours

Outcome Measures

Primary: return of spontaneous respiration (≥10 breaths/min) within 10 minutes of administration

Secondary: time from administration of naloxone to respiration of ≥10 breaths/min, receiving additional naloxone, and recurrence of opioid overdose within 12 hours of inclusion

Baseline Characteristics

  

Intramuscular (n= 108)

Intranasal (n= 93)

Age, years

 37.3 ± 10.2 38.5 ± 10.8
Male 81.5% 80.6%

Respiratory rate, breaths/min

0

1-4

5-9

 

27.8%

42.6%

29.6%

 

28%

38.7%

33.3%

Glasgow coma score

3

4-11

 

79.6%

20.4%

 

76.3%

23.7%

Primary suspected drug use

Heroin

Methadone

Other opioids

 

98.1%

0

1.9%

 

96.8%

1.1%

2.2%

Concomitant CNS depressant suspected

17.6%

17.2%

Results

Endpoint

Intramuscular (n= 108)

Intranasal (n= 93)
Spontaneous breathing within 10 mins 97.2%

79.6%

Additional naloxone

 9.3% 29%

Overdose events

 3.7% 4.3%

Adverse Events

 Bradycardia (0 vs 0.9%); nausea (3.9% vs 6.4%); withdrawal symptoms (11.6% vs 4.6%)

Study Author Conclusions

Intranasal naloxone (1.4 mg/0.1 mL) was less efficient than 0.8 mg intramuscular naloxone for return to spontaneous breathing within 10 minutes in overdose patients in the pre‐hospital environment when compared head‐to‐head. Intranasal naloxone at 1.4 mg/0.1 mL restored breathing in 80% of participants after one dose and had few mild adverse reactions.

InpharmD Researcher Critique

 This study is limited by the small sample size and population outside of the United States. Single doses were measured instead of steady naloxone titration. This study also only included patients with more severe overdose presentations, and the time since drug administration/overdose onset was not known.



References:
[1] 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

 

Pharmacokinetic Data Comparison Summary

Design

Intranasal1 200μg (100μg/nostril)

Intranasal1 400μg (200μg/nostril)

Intranasal3 0.8 mg

Intranasal4 1 mg (1 mg/0.1 ml in one nostril)

Intranasal4 2 mg (2 mg/0.1 ml in one nostril) 

Intranasal4 4 mg (2 mg/0.1 ml in each nostril)

Intranasal2 8mg/0.4mL from 20mg/mL

Intranasal2 16mg/0.4mL from 40mg/mL

 Intravenous4 0.4 mg Intravenous1 0.8 mg Intravenous2 1 mg Intramuscular4 0.4 mg Intramuscular1;3 0.8 mg

Time to onset, minutes

-

 - - - - - - -  - - -  - -

Tmax, minutes, median (range)

 12.5 (5-15*) 5 (5-15*) 28.0 (22.0-34.0**)  15 (10-60)  30 (8-60)  15 (10-60) 0.33 (0.07-0.50) hours 0.33 (0.07-0.67) hours 2 (1-15) - 0.07 (0.03-4.00) hours  10 (4-90)

22.5 (10-60*)1;

7.75 (5.01-10.5**)3

Absorption time, minutes

 6.7 ± 4.9 31 ± 22 - - - - - -  - - -  - 74 ± 8.81

Cmax, ng/mL

 5.7 (3.3-10.0*) 3.0 (1.7-5.3*) - 1.51 geometric mean (50.2 coefficient of variation %) 2.87 geometric mean (49.6 coefficient of variation %) 6.02 geometric mean (54.5 coefficient of variation %) 12.83 ±4.47 18.25 ±7.50 5.94 geometric mean (92.9 coefficient of variation%) - 9.64 ±12.66 1.27 geometric mean (55.8 coefficient of variation %) 3.1 (2.3-4.2*)1

AUClast, min/ng/mL

 266 (190-373*) 147 (112-194*) 160 (125-195) 2.56 geometric mean (43.2 coefficient of variation%) hour/ng/mL 4.86 geometric mean (39.4 coefficient of variation%) hour/ng/mL 10.01 geometric mean (35.8 coefficient of variation%) hour/ng/mL 20.07 ±4.93 hours/ng/mL 32.81 ±10.22 hours/ng/mL 2.01 geometric mean (22.5 coefficient of variation%) hours/ng/mL 650 (535-789*) 8.83 ±4.90 hours/ng/mL 2.01 geometric mean (17.7 coefficient of variation%) hour/ng/mL

347 (310-390*)1;

244 (197-292**)3

AUCinfinity, min/ng/mL

282 (200-399*)

 168 (117-240*) - 2.69 geometric mean (40.5 coefficient of variation%) hour/ng/mL 4.97 geometric mean (38.5 coefficient of variation%) hour/ng/mL 10.07 geometric mean (35.8 coefficient of variation%) hour/ng/mL - - 2.10 geometric mean (21.1 coefficient of variation%) hours/ng/mL 748 (586-954*) - 2.12 geometric mean (16.6 coefficient of variation%) hour/ng/mL

434 (386-487*)1;

-3

Absolute bioavailability %, median (range)

 41 (27-62*) 24 (15-33*) 54 - - - 27.7% 24.6%  - - - - 55 (43-70*)1

Bioavailability relative to intramuscular injection

 75 (59-96*) 44 (35-49*) 75 - - - - -  - N/A - - N/A

Volume of distribution, L

 - - 317 (245-390**) - - - - -  - - - -

-1; 

325 (232-419**)3

Clearance, ml/min

 - - 3420 (2745-4095**)  -  -  - - -  - - - -

-1;

3150 (2600-3719**)3

T1/2, minutes

 61 (53-72*) 80 (56-113*) 63.7 (59.2-68.2**)  80 ±23  84 ±30  102 ±28 0.12 ±0.06 hours 0.13 ±0.07 hours  75 ±13 91 (64-130*) 0.06 ±0.05 hours  81 ±16

100 (89-111*)1;

69.7 (59.5–79.8**)3

Abbreviations:

*: 90% Confidence Interval

**: 95% Confidence Interval

 

References:
[1] [1] Gufford BT, Ainslie GR, White JR Jr, et al. Comparison of a New Intranasal Naloxone Formulation to Intramuscular Naloxone: Results from Hypothesis-generating Small Clinical Studies. Clin Transl Sci. 2017;10(5):380-386. doi:10.1111/cts.12473
[2] [2] Mundin G, McDonald R, Smith K, Harris S, Strang J. Pharmacokinetics of concentrated naloxone nasal spray over first 30 minutes post-dosing: analysis of suitability for opioid overdose reversal. Addiction. 2017;112(9):1647-1652. doi:10.1111/add.13849
[3] [3] Skulberg AK, Tylleskar I, Nilsen T, et al. Pharmacokinetics and -dynamics of intramuscular and intranasal naloxone: an explorative study in healthy volunteers. Eur J Clin Pharmacol. 2018;74(7):873-883. doi:10.1007/s00228-018-2443-3
[4] [4] McDonald R, Lorch U, Woodward J, et al. Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: Phase I healthy volunteer study. Addiction. 2018;113(3):484-493. doi:10.1111/add.14033