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Three Part Question

In [patients with opiate overdose] are [nasal and injected naloxone] equally effective at achieving [clinically significant reversal of toxicity]?

Clinical Scenario

A young man is brought into your emergency department by ambulance with a suspected opiate overdose. His respiratory rate was initially adequate but has now dropped to 7/min, and his GCS is 6. His peripheral veins all seem obliterated and, recognising him from previous attendances, you remember him to be HCV positive.
You have heard that naloxone is now given intranasally by a number of ambulance services in the US and wonder whether this might be worth trying.

Search Strategy

MEDLINE 1951 to 16 Aug 2005
EMBASE 1974 to 16 Aug 2005
CINAHL 1982 to 16 Aug 2005
PsycINFO 1806 to 16 Aug 2005
(all via NHS Dialog DataStar web interface)
The Cochrane Library 2005, issue 3, via Wiley InterScience web interface
Google
{[NALOXON$ or NALONE or NARCAN$ or NALOXONE#.W..DE.] and [NASAL or INTRANASAL or NOSE or PERNASAL or TRANSNASAL or ADMINISTRATION-INTRANASAL#.DE. or NASAL-CAVITY#.DE. or NASAL-MUCOSA#.DE. or NOSE#.W..DE.]} not [animals.DE. not (humans.DE. and animals.DE.)]

Search Outcome

MEDLINE: 35 references found, three of which were relevant (one further preliminary
report of an already included study was discarded)
EMBASE: 163 references found but no further relevant papers
CINAHL: 27 references found but no further relevant papers
PsycINFO: 74 references found but no further relevant papers
The Cochrane library: 12 references found but no further relevant papers
Google: One further relevant abstract / poster presentations found (one further preliminary report of an already included study was discarded)

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Barton ED et al. 2005 USA	95 pts - with altered mental state (40), suspected opioid overdose (38) or 'found down' (20) - treated with 2mg IN naloxone by paramedics	Case series Evidence level 4	Proportion of pts with significant improvement in level of consciousness	Of 52 pts responding to naloxone, 43 (83%) pts did so after IN dose	Uncontrolled study Heterogeneous pt group Response poorly defined
			Response time	Median response time 3.0min
Kelly AM et al. 2002 Australia	6 pts with isolated heroin overdose receiving ventilatory support in an emergency department, treated with 0.8 – 2mg IN naloxone	Case series Evidence level 4	Time to spontaneous respiration	All pts responded within 2 min; median 50sec	Tiny, uncontrolled study Intervention not standardised Response poorly defined
Robertson TM et al. 2005 USA	154 pts with suspected narcotic overdose, treated with naloxone IV (104) or IN (50) by paramedics	Retrospective before-and-after (case control) study Evidence level 4	Time from intervention to increase in RR or GCS of >5	Significantly shorter in IV group (mean 8.1min vs. 12.9min)	No power calculation No information about control group matching No information about doses given Usefulness of outcome measures questionable
			Time from pt contact to increase in RR or GCS of >5	No significant difference (mean around 20min)
			Proportion of pts requiring further naloxone	Significantly more pts in IN group needed further doses (34 vs 18%; NNH 6.4, 95% CI 3.2 - 72.8)
Kelly AM et al. 2005 Australia	155 pts with suspected narcotic overdose, treated with 2mg naloxone IM (71) or IN (84) by paramedics	Randomised controlled, unblinded trial Evidence level 2b	Time to RR >10	Significantly shorter in IM group (mean 6 vs 8min)	Naloxone concentration used probably unsuitable (required volume too large) Usefulness of outcome measures questionable Calculated sample size not reached Important outcome – response times from pt contact - not considered
			Time to GCS > 11	No significant difference
			Proportion of pts with RR >10 at 8min	Significantly greater in IM group (82 vs 63%)
			Proportion of pts with GCS >11 at 8min	No significant difference
			Proportion of pts needing further (IM) naloxone	No significant difference (NNH 7.4, 95% CI 3.9 - 123.4)

Comment(s)

Intranasal (IN) administration of naloxone is still experimental, and the few studies looking at its effectiveness have been of mixed quality - a common problem in toxicology. It seems to work, albeit possibly not as well as the injected drug. In practical terms, this means that patients given IN naloxone may have to be ventilated a few minutes longer, and that some of them might need a second dose. In the US, valid concerns about the risks associated with needle stick injuries from this patient group have won the argument over considerations of clinical effectiveness alone. If you are thinking of giving it a go, you might want to a. bear in mind that naloxone is not licensed to be given by the IN route and b. use the 1mg/mL formulation with a mucosal atomiser to ensure better absorption. Instil 1mL into each nostril.

Editor Comment

RB

Clinical Bottom Line

IN naloxone would be a valid treatment option in this clinical scenario, but be prepared for it to be less effective than an IV or IM injection. Local consensus should be sought prior to any use by individual clinicians.

References

1. Barton ED, Colwell CB, Wolfe T et al. Efficacy of intranasal naloxone as a needleless alternative for treatment of opioid overdose in the prehospital setting. J Emerg Med. 29(3):265-71, 2005 Oct
2. Kelly AM, Koutsogiannis Z. Intranasal naloxone for life threatening opioid toxicity EMJ July 2002 page 375
3. Robertson TM, Hendey GW, Stroh G et al. Intranasal versus intravenous naloxone for prehospital narcotic overdose. Acad Emerg Med 12 May 2005 pages 166-167S
4. Kelly AM, Kerr D, Dietze P et al. Randomised trial of intranasal versus intramuscular naloxone in prehospital treatment for suspected opioid overdose MJA 03/01/2005 pages 24-27