Intranasal naloxone in suspected opioid overdose
Date First Published:
August 21, 2005
Last Updated:
January 5, 2006
Report by:
Dr Helen Ashton, Specialist Registrar in Emergency Medicine (Blackburn Royal Infirmary)
Search checked by:
Dr Ziauddin Hassan, Blackburn Royal Infirmary
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
Embase 1980 to 2005 Week 53 using Ovid Interface
Search Details:
[(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.
Plus Google Search for Intranasal Naloxone.
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):
| Study Title | Patient Group | Study type (level of evidence) | Outcomes | Key results | Study Weaknesses |
|---|---|---|---|---|---|
| Versus Intravenous Naloxone for Prehospital Narcotic Overdose. Robertson T M, Hendey G W, Stroh G, Shalit M. 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% | ||||
| Randomised Trial of Intranasal versus Intramuscular Naloxone in Prehospital Treatment For Suspected Opioid Overdose. Kelly A M, Kerr D, Dietze P, Patrick I, Walker T, Koutsogiannis Z. 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) | ||||
| Intranasal Administration of Naloxone by Paramedics. Barton E D, Ramos J, Colwell C, Benson J, Baily J, Dunn W. 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. | ||||
| Nasal Administration of Naloxone is as Effective as the Intravenous Route in Opiate Addicts. Loimer N, Hofmann P, Chaudhry H R. 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;<br><br>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 | ||||
| Nasal Administration of Naloxone for Detection of Opiate Dependence. Loimer N, Hofmann P, Chaudhry H R. 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;<br><br>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) | ||||
| Nasal Absorption of Naloxone and Buprenorphine in Rats Hussain A, Kimura R, Huang C-H, Kashihara T. 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 | ||||
| Efficacy of Intranasal Naloxone as a Needleless Alternative for Treatment of Opioid Overdose in the Prehospital Setting Barton E D, Colwell C B, Wolff T, Fosnocht D, Gravitz C, Bryan T, Dunn W, Benson J, Bailey J. 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 | ||||
| Intranasal Naloxone for Life Threatening Opioid Overdose. Kelly A M, Koutsogiannis Z 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 |
Author Commentary:
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.
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.
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:
- Robertson T M, Hendey G W, Stroh G, Shalit M.. Versus Intravenous Naloxone for Prehospital Narcotic Overdose.
- 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.
- Barton E D, Ramos J, Colwell C, Benson J, Baily J, Dunn W.. Intranasal Administration of Naloxone by Paramedics.
- Loimer N, Hofmann P, Chaudhry H R.. Nasal Administration of Naloxone is as Effective as the Intravenous Route in Opiate Addicts.
- Loimer N, Hofmann P, Chaudhry H R.. Nasal Administration of Naloxone for Detection of Opiate Dependence.
- Hussain A, Kimura R, Huang C-H, Kashihara T.. Nasal Absorption of Naloxone and Buprenorphine in Rats
- 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
- Kelly A M, Koutsogiannis Z. Intranasal Naloxone for Life Threatening Opioid Overdose.