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Three Part Question

In a [patient with a suspected opioid overdose] is the [intranasal administration of Naloxone] a safe and effective method of [reversing the effects of the overdose]

Clinical Scenario

A 25 year old male is brought into A&E by ambulance with a history of respiratory arrest following a suspected Opioid overdose. One of the paramedics describes struggling and failing to achieve peripheral venous access, sustaining a needle stick injury in the process. The paramedic describes proceeding to administer a total of 800mcg of Naloxone intramuscularly to which the patient's response has been slow. You wonder whether the administration of Naloxone intranasally, would have been effective in both reversing the effects of the overdose and eliminating the need to use needles in the pre-hospital environment in a patient at high risk of having both limited peripheral venous access and potentially contractible blood-borne viruses.

Search Strategy

Medline 1966-11/2005 using Ovid Interface
Embase 1980 to 2005 Week 53 using Ovid Interface
[(exp ADMINISTRATION, INTRANASAL OR Intranasal$.mp. OR exp NOSE OR exp NASAL MUCOSA OR exp NASAL CAVITY OR Nasal.mp. OR Pernasal$mp. OR Transnasal$.mp. or exp MUCOUS MEMBRANE or Transmucosal$.mp.) AND (Naloxone.mp. OR exp NALOXONE OR Narcan.mp. OR Nalone.mp OR Naloxon.mp OR Narcotic Antagonist$.mp. OR exp NARCOTIC ANTAGONISTS OR Opioid Antagonist$.mp. OR Opioid Receptor Antagonist$ OR Opiate Antagonist$.mp. OR Opiate Receptor Antagonist$.mp.)] LIMIT to English Language.
Plus Google Search for Intranasal Naloxone.

Search Outcome

280 papers were identified on Medline of which 5 and 416 papers were identified on Embase of which an additional 2 were relevant. One further relevant paper / poster presentation was identified on a Google Search.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Robertson et al, 2005, USA	154 patients with suspected narcotic overdose in the pre-hospital setting. 104 given IV and 50 IN Naloxone.	Retrospective Case Note Review (before and after introduction of IN Naloxone into pre-hospital protocols) (poster presentation)	Time from medication administration to Clinical Response (defined as increase in RR or GCS> 6)	Significantly longer in IN group (8.1 vs. 12.9 min, P=0.02)	Small study No mention of ethical approval Patient baseline obs not verified. Dose /Concentration of Naloxone and administrative instrument not verified. GCS of 6 and un-quantified rise in RR not clinically useful endpoints.
			Time from patient contact to Clinical Response	No significant difference in response times (20.3 IV vs. 20.7min IN, P=0.9)
			Patients requiring rescue doses by same route	No statistical difference (18% IV vs 34% IN, P=0.05.) NB. 3 patients in IN group required IM or IV rescue
			Clinical Response (Defined as increase in RR or GCS >6)	IV group 56%, IN Group 66%
Kelly et al, 2005, Australia	155 patients with suspected opiate OD who were un-rousable with RR < 10. Randomised to receive 2mg Naloxone IM (n=71) or IN (0.4mg/ml) via atomizer (n=84) pre-hospital.	Randomised Controlled Trial.	Time to regain RR>10	Faster in IM group (mean 6min vs. 8min, P=0.006)	Unblinded study Adequate sample size not achieved Statistics not based on intention to treat (3 patients excluded because of technical problems with nasal administration) GCS used in non-trauma patients
			Patients with spontaneous resps at 8 min	Greater in IM group (82% vs. 63%, P=0.0163)
			Patients with GCS >11 at 8 min	No statistical difference between groups. (72% IM vs. 57%IN, P=0.0829)
			Patients requiring rescue Naloxone	No statistical difference between groups. (13%IM vs. 26%IN, P=0.0558)
			Patients in IN group requiring additional therapy.	26%
			Adverse events	More agitation/irritation in IM group (13% vs. 2%, P=0.0278)
Barton et al, 2002, USA	30 patients presenting pre-hospital with Altered Mental Status (AMS) n=11, Found Down (FD) n=7 or Suspected Opiate OD) (OD) n=12. Given 2mg (1mg/ml) IN Naloxone via atomizer, followed by IV rescue dose if required.	Case Series	Response to Naloxone by any route	37% (n=11)	Small numbers, Uncontrolled Response not clinically defined Study population appear to be part of the population studied in the 2005 Barton E D. paper
			Response to IN Naloxone	10 patients (91% of total responders) with average response rate of 3.4min
			Need for and response to rescue IV Naloxone (given if no response to IN by the time a secure airway/IV)	One patient responded to IV and not IN (has epistaxis)
			Number of IV attempts that could be avoided	91% of all Naloxone responders did so with IN alone. 64% of all patients did not require IV placement.
Lorimer et al, 1994, Pakistan	17 male opiate dependent patients. Given 1mg IV Naloxone, being recommenced on Opium then given a further 1mg Naloxone IM (n=7) or IN (1mg/400µL) via nasal spray (n=10)	Randomised Controlled Trial	Series of measurements from 0 to 180 mins of; Severity of withdrawal symptoms (Objective Opiate Withdrawal Scale)	Significant changes from baseline seen at 1min IV, 5min IN, 15min IM.	No mention of ethical approval Small, unblinded study Method of randomisation not stated Inadequate basic data reporting
			Vital Signs (Pulse/BP)	Significant increase in size seen at 5min in IV and IN groups. No change seen in IM group
			Pupillary Response	No significant change seen after any route of administration
Lorimer et al, 1992, Pakistan	30 patients, 22 male opiate dependent and 8 male controls. Each receiving 1mg naloxone (1mg/400µL) via nasal spray.	Controlled Clinical Trial	Series of measurements from 0 to 30mins of; Severity of withdrawal symptoms (Modified rating score)	No difference between groups at baseline, significant changes between groups and within group opiate dependent group from 1-30 mins. (P<0.01-<0.05)	No mention of ethical approval Small numbers
			Pulse and BP	No statistically significant changes within or between groups.
			Pupillary Response	No change in control group. Opiate dependent group more constricted at baseline and had dilated significantly by 10mins (P<0.01)
Hussain et al, 1984, USA	Male rats approximately 240g, anaesthetised with Phenobarbital, receiving 30mcg radiolabelled naloxone either IN via micropipette (n=3) or IV (n=3)	Animal study, Controlled Trial	Bioavailability of naloxone based on plasma concentrations from arterial sampling	Both methods show 100% bioavailability.	No mention of ethical approval, could be considered ethically unjustifiable. Results may not be reproducible in humans
			Half life of Naloxone	Half life same IV and IN.
			Time at which peak plasma levels occurred	Peak plasma levels of IN occurred within 3mins
Barton ED et al 2005 USA	95 Patients presenting pre-hospital with Altered Mental Status (AMS) n=40, Found Down (FD) n=20 or Suspected Opiate OD) (OD) n=38. (NB 3 patients listed in 2 categories) Given 2mg (1mg/ml) IN Naloxone via atomizer, followed by IV rescue dose if no response to IN by the time a secure airway/IV established.	Case Series	Response to Naloxone by any route (Response = "a significant improvement in consciousness")	52 patients	Small numbers No baseline Obs Clinical response not well defined 4 of the 9 patients reported to have responded to IV and not IN, received the IN dose < 4 mins after the IN dose, allowing limited time for the IN dose to take effect. Potential conflict of interest declared (one of authors is Vice President and Medical Director of company supplying the atomizer device)
			Response to IN Naloxone	43 patients (83% of all Naloxone responders)
			Need for further Naloxone following initial response to IN (due to recurrent somnolence)	7 Patients
			Time from initial patient contact to response	9.9 (+/- 4.4SD) Median 3.0 with IN, 2.8 (+/-7.6SD) Median 10 with IV
			Time from drug administration to response	4.2 (+/-2.7SD) Median 3.0 with IN, 3.7 (+/-2.3SD) Median 3.0 with IV
			Nasal Abnormalities	5 of the 9 patients reported to have responded to IV and not IN
Kelly et al. 2002 Australia	6 patients with acute heroin OD treated in the Emergency Department with IN Naloxone 0.8 to 2mg	Case Series	Time to return of adequate spontaneous respiration	All patients responded within 2 minutes	No mention of ethical approval Very small numbers Definition of acute heroin OD / baseline obs. not stated Concentration of Naloxone used and administrative instrument not stated Dose of Naloxone not standardised Clinical response not well defined

Comment(s)

The evidence from the above papers is weak and there are conflicting results regarding the efficacy of intranasal compared to iontravenous and intramuscular routes of Naloxone administration. It does seem, however, that intranasal Naloxone is safe and has significant efficacy in reversing the effects of an opioid overdose. The intranasal route of administration may be a potentially useful first line intervention in managing Opioid OD in the community, as it reduces the need for needles to be used in an often hostile prehospital environment, in patients who are often poor candidates for peripheral venous cannulation and at increased risk of carrying blood-borne pathogens. The option of being able to administer rescue intravenous or intramuscular Naloxone, would however need to remain in place. One problem with efficacy was highlighted in patients who didn't respond to intranasal Naloxone due to nasal abnormality (epistaxis/trauma/deformity/mucous). Other nasal pathology and prior use of intranasal drugs such as Cocaine could therefore potentially also lead to treatment failure. At present Naloxone remains unlicenced for IN use and is not available in the UK at a concentration greater than 0.4 mg/ml.

Clinical Bottom Line

It is likely that intranasal Naloxone is a safe and effective first line prehospital intervention in reversing the effects of an Opioid overdose and helping to reduce the risk of needle stick injury. A large, well conducted trial into it's usage is however required.

References

1. Robertson T M, Hendey G W, Stroh G, Shalit M. Versus Intravenous Naloxone for Prehospital Narcotic Overdose. Academic Emergency Medicine 12(5) suppl 1, 166-167, 2005 May.
2. Kelly A M, Kerr D, Dietze P, Patrick I, Walker T, Koutsogiannis Z. Randomised Trial of Intranasal versus Intramuscular Naloxone in Prehospital Treatment For Suspected Opioid Overdose. Medical Journal of Australia. 182(1):24-7, 2005 Jan.
3. Barton E D, Ramos J, Colwell C, Benson J, Baily J, Dunn W. Intranasal Administration of Naloxone by Paramedics. Prehospital Emergency Care 6(1):54-8, 2002 Jan-Mar.
4. Loimer N, Hofmann P, Chaudhry H R. Nasal Administration of Naloxone is as Effective as the Intravenous Route in Opiate Addicts. International Journal of the Addictions. 29(6):819-27,1994 Apr.
5. Loimer N, Hofmann P, Chaudhry H R. Nasal Administration of Naloxone for Detection of Opiate Dependence. Journal of Psychiatric Research. 26(1):39-43, 1992 Jan.
6. Hussain A, Kimura R, Huang C-H, Kashihara T. Nasal Absorption of Naloxone and Buprenorphine in Rats International Journal of Pharmaceutics 21(2):233-237, 1984.
7. Barton E D, Colwell C B, Wolff T, Fosnocht D, Gravitz C, Bryan T, Dunn W, Benson J, Bailey J. Efficacy of Intranasal Naloxone as a Needleless Alternative for Treatment of Opioid Overdose in the Prehospital Setting Journal of Emergency Medicine 29(3);265-271
8. Kelly A M, Koutsogiannis Z Intranasal Naloxone for Life Threatening Opioid Overdose. Emergency Medicine Journal. 2002;19(4);375 2002