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Three Part Question

For [adult patients with confirmed or suspected opiate overdose] is [intranasal Naloxone a safe and effective alternative to intravenous Naloxone] in [the prehospital environment]?

Clinical Scenario

The ambulance service is called to a 33-year-old-gentleman who has been found unresponsive. The dwelling is dark and confined with poor hygiene. The patient is confirmed to have self-administered opiates intravenously and is also reported to be HIV positive. On examination the patients peripheral vasculature is delicate and bruised. The intranasal (IN) route, as opposed to intravenous (IV) or intramuscular (IM) routes, of administering Naloxone is considered.

Search Strategy

MEDLINE using the OVID interface, 2006-2019. [(“Naloxone” ti. AND “exp. Prehospital af.)] COMBINE [(“Intranasal” ti.)]. LIMIT to English Language. LIMIT to adaptive clinical trial OR case report OR clinical trial all OR comparative study OR controlled clinical trial OR observational study OR pragmatic clinical trial OR randomised controlled trial OR systematic review.
PUBMED, 2006-2019. [(“Intranasal” ti. AND “Naloxone” af.)]. COMBINE [“Prehospital” af.)]. LIMIT to English Language. LIMIT to adaptive clinical trial OR case report OR clinical trial all OR comparative study OR controlled clinical trial OR observational study OR pragmatic clinical trial OR randomised controlled trial OR systematic review.

Search Outcome

Medline and PubMed yielded 12 and 13 results respectively after combination of search terms and application of limitations. Duplications were found in the results and disregarded accordingly. Results that were published prior to 2006 were also disregarded so as to examine the latest research and exclude papers that have already been critiqued in a previous BestBET submission by Ashton, H. and Ziauddin, H. (2006). Finally some results were not considered academic pieces and as such were excluded, leaving 4 publications.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Merlin, M., Saybolt, M. and Kapitanyan, R. et al. (2008).	344 patients receiving naloxone from paramedics. Of those with confirmed opiate overdose, 55 given IV and 38 given IN.	Retrospective cohort study.	Pre- and Post-intervention respiratory rates compared as a level of effectiveness.	Average change in respiratory rate was +6 for the IV group and +4 for the IN group (P=0.08)	Non-randomised, non-blinded and retrospective. Small numbers as only patient records from one hospital reviewed. Possible bias in data collection and patient inclusion by clinicians.
			Pre- and Post-intervention GCS scores compared as a level of effectiveness	Average change in GCS was +4 for the IV group and +3 for the IN group. (P=0.19)
McDermott, C. and Collins, N. (2012)	18 advanced paramedic trainees randomised to administer either IV or IN naloxone to a mannequin.	Retrospective cohort study. Randomised Controlled Trial	Time taken for medication delivery compared.	Mean time to deliver IV and IN naloxone was 178.2 and 87.1 seconds respectively (mean difference of 91.1secs) (confidence interval 55.2secs to 126.9secs and P<0.0001)	Small sample size and no blinding. Trainees may not have had a suitable length of experience in cannulation. Simulation and not “real life”.
			End-user satisfaction assessed (ease of use and safety).	89% of advanced paramedic trainees reported the IN route to be safer and easier
Fisher, R., O’Donnell, D. and Ray, B. et al (2016).	126 patients treated by police medics for suspected opiate overdose with intranasal naloxone.	Cohort Study	Indications for administration	Most common indication was unconsciousness/unresponsiveness (92.9%), followed by slow breathing (57.1%), appeared blue (50%) and not breathing (32.5%).	Based on retrospective data that has been has been selected for confirmed opiate overdoses and thus liable to bias. 28 of the final casualty reports were not accessible from EMS due to administrative issues, therefore reporting on incomplete data.
			Physiological response to IN Naloxone	65.1% regained consciousness, followed by 56.3% starting to breathe again. Nothing happened in 17.5%.
			Patient disposition	Majority of patients were conveyed to hospital (96.8%) while one report documents patient becoming combative.
Weiner, S., Mitchell, P. and Temin, E. et al (2017).	793 patients administered IN naloxone by BLS providers for suspected opiate overdose.	Retrospective cohort study	Escalation to ALS	ALS intervention was required in 14.6% of patients with an additional 1.4% requiring intubation.	Reporting on one EMS provider whose journey times are relatively short and therefore may skew data. Retrospective study and relied on accuracy of data recording at the time of treatment. No confirmation of opiates on toxicology and therefore cannot rule out other causes of symptoms. No outcome data for patients who left against advice / without being seen.
			IN Naloxone having a positive effect	In Naloxone had a positive effect in 95.2% of patients.
			Requirement for additional naloxone	An additional dose of Naloxone was given to patients in the ED to 8.8% of patients.
			Patient disposition	70% of patients discharged, 14.5% admitted for further care / observation, 15.5% left against advice / without being seen.

Comment(s)

With changes being made to the Human Medicines Regulations (2019) to allow drug services to obtain / administer Naloxone without a prescription (in order to save a life in an emergency), it has become pertinent to re-examine the evidence surrounding intranasal administration of the drug. Whilst JRCALC Clinical Practice Guidelines (2019) currently do not give recommendations on intranasal dosing of Naloxone, numerous studies have been conducted to examine its speed and efficacy when compared to other routes of administration. McDermott, C. and Collins, N. (2012) conducted a randomised control trial in which ambulance trainees were timed in their ability to administer either IN or IV Naloxone to manikins. The time taken to set up and administer an IN dose of Naloxone was significantly quicker (87.1secs vs. 178.2secs). It is worthy of note however, in their BestBETS submission, Ashton. H and Ziauddin, H. (2006) reviewed a retrospective cohort study by Robertson, T., Hendey, G. and Stroh, G. et al. (2009), in which it was shown that whilst IN administration may be quicker, peak of effect of IV Naloxone is achieved more quickly after administration via the IV route. That said, there was no statistical difference in time from patient contact to pharmacological response (p=0.9). McDermott, C. and Collins, N. (2012) commented on trainees satisfaction with the improved safety that IN administration of drugs afforded them, particularly for confined spaces / low levels of light thus reducing the risk of needle stick injury. Weaknesses of this study cannot be ignored however; trainees may not have had a suitable length of experience in cannulation to adequately compare against IN routes of administration. It would also be fair to suggest that manikin-based studies have limited reliability. As part of a cohort study, Fisher, R., O’Donnell, D. and Ray, B. et al (2016) reviewed lay responders reasoning for administering naloxone after a short training session provided by medical staff. Whilst unconsciousness or unresponsiveness was the most common indication for Naloxone delivery, responders were accurately able to identify classic signs of opiate overdose, giving the notion that IN Naloxone is ideal for both registered health professionals as well trained lay persons. The study by Fisher, R., O’Donnell, D. and Ray, B. et al (2016) also considered the level of physiological response to IN Naloxone, albeit in the rather rudimentary method of recording return of consciousness or spontaneous respiration. It was shown that IN Naloxone had a positive outcome in the majority of cases; more intricate data could only have been expected had training interventions been significantly more in depth. Unfortunately, this study was also not without limitations in that some data was incomplete and therefore lacked statistical power. Retrospective data collection was also ‘cherry-picked’ and was therefore liable to bias. To analyse the physiological effects more closely, Merlin, M., Saybolt, M. and Kapitanyan, R. et al. (2008) retrospectively reviewed 344 patient report forms, in which the use of IN / IV naloxone had been documented. Effectiveness of IN Naloxone was measured against IV administration by means of average change in respiratory rate and Glasgow Coma Scale (GCS) scoring. Whilst the results were statistically significant in showing that IN Naloxone provided a positive change in patients respiratory rates and GCS score, it was found however that the IV route yielded better results. The study also acknowledged the fact that data accuracy was reliant on clinicians correctly obtaining and recording respiratory rates (and GCS scores), which experience shows is notoriously miscalculated. In their retrospective cohort study, Weiner, S., Mitchell, P. and Temin, E. et al (2017) also report positive results to IN naloxone administration, with 95.2% of patients having a ‘positive effect’ to IN Naloxone, although the degree in which the Naloxone is successful in reversing the effects of opiates is undocumented. However, Weiner, S., Mitchell, P. and Temin, E. et al (2017) do continue to report that only 14.6% of patients required Advanced Life Support (ALS) interventions and only 8.8% required additional doses of naloxone. It was noted however that this study reported on only one EMS provider whose journey times were relatively short and therefore may affect statistical outcomes. There was also no confirmation of opiates on toxicology and therefore one cannot rule out other causes of patients symptoms. It is of course questionable whether any of these findings have any bearing of UK practice as all of the studies documented analyse the effects of a ‘US standard’ 2mg dose of Naloxone hydrochloride, whereas the UK dosing of the newly licensed “Nyxoid” (Nalxone Dihydrate) is 1.8mg. Similarly, Kelly, A., Kerr, D. and Dietze, P. et al (2005) point out that opioid load “may have an effect on both response rate and time”; this could arguably be extrapolated to requirement of further Naloxone doses. Whilst Fisher, R., O’Donnell, D. and Ray, B. et al (2016) report 96.8% of patients being transported to hospital, Weiner, S., Mitchell, P. and Temin, E. et al (2017) document 70% of patients in their study were discharged without follow-up. A further 15.5% of patients self-discharged (either before or after being seen) but their outcomes are not documented. As a result the data could be viewed as incomplete or even skewed as it is not known if those patients required further treatment.

Clinical Bottom Line

The intranasal route of administering Naloxone is deemed a quick, safe and efficient way of treating patients with confirmed or suspected opiate overdose in the prehospital setting. The method requires very little training and significantly reduces the risk of needle stick injury. Whilst the peak effects of Naloxone are seen more quickly via the intravenous route, this is negated by the reduction in time taken to administer the drug intranasally. Whilst small number of patients receiving naloxone via the IN route are more likely to require a further dose to maintain the effects of the naloxone given thus far, it would be fair to suggest this is case-dependant.

References

1. Merlin, M.A., Saybolt, M., Kapitanyan, R., Alter, S.M., Jeges, J., Liu, J., Calabrese, S., Rynn, K.O., Perritt, R. and Pryor, P.W. (2010). Intranasal naloxone delivery is an alternative to intravenous naloxone for opioid overdoses. The American Journal of Emergency Medicine 28(3), pp.296–303.
2. McDermott, C. and Collins, N.C. (2012) Prehospital Medication Administration: A Randomised Study Comparing Intranasal and Intravenous Routes. Emergency Medicine International 2012, pp.1–5.
3. Fisher, R., O’Donnell, D., Ray, B. and Rusyniak, D. (2016) Police Officers Can Safely and Effectively Administer Intranasal Naloxone. Prehospital Emergency Care pp.675–680.
4. Weiner, S.G., Mitchell, P.M., Temin, E.S., Langlois, B.K. and Dyer, K.S. (2017) Use of Intranasal Naloxone by Basic Life Support Providers Prehospital Emergency Care 21(3), pp.322–326.
5. Ashton, H. and Ziauddin, H. (2019) Intranasal naloxone in suspected opioid overdose BestBETS
6. Association of Ambulance Chief Executives and Joint Royal Colleges Ambulance Liaison Committee (2019) JRCALC Clinical Practice Guidelines 2019 Bridgwater: Class Publishing
7. Legislation.gov.uk. (2019) The Human Medicines (Amendment) Regulations 2019. [online] UK Government
8. Kelly, A., Kerr, D. and Dietze, P. (2005) Randomised trial of intranasal versus intramuscular naloxone in prehospital treatment for suspected opioid overdose. Medical Journal of Australia 182(8), pp.427–429.
9. Robertson, T.M., Hendey, G.W., Stroh, G. and Shalit, M. (2009) Intranasal Naloxone Is a Viable Alternative to Intravenous Naloxone for Prehospital Narcotic Overdose Prehospital Emergency Care 13(4), pp.512–515.