Intranasal naloxone and related strategies for opioid overdose intervention by nonmedical personnel: a review

Figures & data

Table 1 Comparative studies of IN and parenteral naloxone formulations in patients

Reference	Study design	n and population	IN dose and formulation	Dose comparator	Summary of key findings
Loimer et al^Citation34	Randomized trial	17 patients (7 IV vs IM; 10 IV vs IN)	1 mg (1 mg/0.4 mL)	1 mg IM	Both IN and IM groups showed significant withdrawal symptoms at 15 and 45 min. Only the IN group exhibited withdrawal symptoms at 5 min, suggesting more rapid onset with IN administration
Loimer et al^Citation35	Controlled, nonrandomized, prospective trial	30 patients (22 opioid dependent, 8 control)	1 mg (1 mg/0.4 mL)	None	After opioid challenge test of IN naloxone administration, opiate-dependent patients showed significantly higher ratings on a withdrawal scale for up to 30 min (in comparison to controls)
Kelly and Koutsogiannis^Citation37	Case report	Six patients	0.8–2 mg	None	For all patients, return of adequate spontaneous respiration occurred with a median of 50 s (range: 30 s–2 min)
Barton et al^Citation38	Case series	30 patients	2 mg (1 mg/mL)	2 mg IV if no response	11 patients responded to naloxone challenge (IN or IV), of whom 10 (91%) responded to IN alone, with an average response time of 3.4 min
Barton et al^Citation39	Case series	95 patients	2 mg (1 mg/mL)	2 mg IV if no response	52 patients responded to naloxone challenge (IN or IV), of whom 43 (83%) responded to IN alone, with an average response time of 4.2 min
Kelly et al^Citation40	Randomized trial	155 patients (71 IM, 84 IN)	2 mg/5 mL	2 mg IM	The IM group had more rapid respiratory response (6 min) than the IN group (8 min), but no significant difference in GCS scores or need for rescue naloxone (13% IM vs 26% IN)
Kerr et al^Citation41	Randomized trial	172 patients (89 IM, 83 IN)	2 mg (2 mg/mL; 0.5 mL/nostril)	2 mg IM	The rates of response within 10 min were similar: IN naloxone (60/83, 72.3%) compared with IM naloxone (69/89, 77.5%). No group difference in mean response time (IN: 8.0, IM: 7.9 min) Significant group difference in need for rescue naloxone: IN 18% vs IM 5%
Doe-Simkinset al^Citation45	Pre–post comparison	385 opioid users	2 mg 2 mg/2 mL)	None	Participants reported 74 successful OD reversals; no deaths
Robertson et al^Citation43	Retrospectivechart review	154 patients (50 IN, 104 IV)	2 mg (1 mg/nostril)	1 mg IV	Although the time from dose administration to clinical response (increase in RR or GCS >6 points) took significantly longer for IN than IV patients (12.9 vs 8.1 min), the overall time from patient contact to response was the same (~20 min). Ninety-four percent of IN patients did not require supplemental naloxone by IV or IM administration
Merlin et al^Citation44	Retrospective chart review	93 (38 IN, 55 IM; subsample of 344 cases)	2 mg (1 mg/nostril)	IV naloxone titrated to effect: 2 mg average	No group difference in RR or GCS pre-naloxone administration. Post-naloxone administration, both the median RR and GCS scores were significantly higher for the IV group than the IN group; nine IN patients (23%) required rescue IV naloxone
Weber et al^Citation11	Retrospective chart review	105 patients	2 mg (2 mg/3 mL)	None	Of all 105 cases, 23 (22%) had complete response, 62 (59%) had partial response, and 20 (19%) showed no response, as indicated by GCS score and RR. Eleven cases (10%) received rescue naloxone (6 IV, 5 IM). No adverse events or deaths occurred
Walley et al^Citation46	Interrupted time-series analysis	2,912 opioid users	2 mg (2 mg/2 mL)	Communities without take- home naloxone	Participants reported 327 successful OD reversals; no deaths OD mortality rates were reduced in 19 communities with THN, compared to those without THN
Walley et al^Citation47	Pre–post comparison	1,553 methadone clients	2 mg (2 mg/2 mL)	None	Methadone clients reported 92 successful OD reversals; no deaths
Sabzghabaee et al^Citation42	Randomized trial	100 patients (50 IN, 50 IV)	0.4 mg (0.4 mg/2 mL; 1 mL/nostril)	0.4 mg IV	Although patients responded about 1 min sooner to IV compared to IN naloxone, the level of consciousness was higher in patients administered IN naloxone (0% obtunded or lower) than those in the IV group (40% obtunded). Post-naloxone agitation occurred in 25% of IV patients and 0% of IN patients

Notes: The table is updated and modified from tables of studies compiled in previous reviews;^16,19,25 summaries of the listed studies differ from those previously provided in several cases, as deemed appropriate based on clinical as well as statistical significance.

Abbreviations: GCS, Glasgow Coma Scale; IM, intramuscular; IN, intranasal; IV, intravenous; OD, overdose; RR, respiratory rate; THN, take-home naloxone.

Table 2 Naloxone kits distributed and used, overdose deaths, and overdose reversals

References	n	THN kits distributed	THN kits used (%)	Deaths	OD reversals (%)
Bennett et al^Citation68	426	426	249 (58)	2	≥96f
Bennet et al^Citation69	525	NR	28 (NR)	1	96
Dettmer et al^Citation70	225	225	34 (15)	0	100
Doe-Simkins et al^Citation45a,b	385	385	74 (19)	0	100
Dwyer et al^Citation71a	415	56	6 (11)	0	100
Enteen et al^Citation72	1942	2962	399 (13)	6	≥89
Galea et al^Citation73	25	25	10 (40)	1c	100
Lankenau et al^Citation74a	30	30	15 (50)	0	≥97
Leece et al^Citation75	209	209	17 (8)	0	100
Lopez-Gaston et al^Citation76	70	70	0 (0)	1c	NA
Markham Piper et al^Citation77	122	122	82 (67)	0	≥83
Maxwell et al^Citation64	1120	3500	319 (9)	1d	99
McAuley et al^Citation78	41	19	2 (11)	1c	100
Rowe et al^Citation79	2500	2500	702 (28)	10	99
Seal et al^Citation80	24	24	15 (63)	0	100
Strang et al^Citation81	239	239	1 (5)	1c	100
Tobin et al^Citation82	250	250	22 (9)	0	100
Tzemis et al^Citation83	692	836	85 (10)	0	100
Wagner et al^Citation84	66	66	28 (42)	4e	NR
Walley et al^Citation46b	2912	2912	327 (11)	0	100
Walley et al^Citation47a,b	1553	1553	92 (6)	0	100
Yokell et al^Citation85	120	120	5 (4)	0	100

Notes: The table is modified from substantially overlapping tables of studies provided in previous reviews.^19,32,60

a Not included in summary measures to avoid (partial) duplication of samples;

b 2 mg naloxone administered IN (2 mg/2 mL); other studies used different (non-nasal) routes of THN;

c naloxone not administered;

d nonopioids present;

e unclear if naloxone administered;

f where applicable, unknown outcomes were counted toward unsuccessful THN administration (as indicated by the ≥ symbol).

Abbreviations: IN, intranasal; NA, not applicable; NR, not reported; OD, overdose; THN, take-home naloxone.

Table 3 Summary of the debate over IN and nonmedical naloxone

Objections to IN naloxone	Responses to objections
The results from ambulance-based studies indicate that not all opioid overdose victims respond to IN naloxone, with some needing a rescue dose of IM or IV naloxone. Emergency care with an IN naloxone kit is limited by the absence of injectable naloxone as a backup^Citation25,Citation31	While IN naloxone may require a second dose more frequently, this alone should not preclude its nonmedical or take-home use.^Citation26 The FDA required Narcan Nasal Spray to be marketed in a two-pack configuration, ensuring that a second dose would be available in the event of an inadequate response to the first dose^Citation50
Clinicians should prescribe take-home naloxone only as one of its formally approved formulations, since the reliability of absorption and effectiveness of the improvised nasal spray remains uncertain^Citation25	Providers may still choose to recommend or provide off-label products even when approved products are available, because of the cost–benefit balance^Citation30 The lack of availability of “any” naloxone is a much greater threat to opioid users than the lack of availability of formally approved products^Citation28
Progress with basic pharmacokinetic study of IN naloxone has been slow, with the only peer-reviewed pharmacokinetic study^Citation55 reporting extremely poor bioavailability (4%) for nasal naloxone^Citation25,Citation31	In addition to the cited study,^Citation55 which some consider is flawed by use of excess intranasal delivery volumes,^Citation24,Citation25 more recent pharmacokinetic studies of formulations exhibiting much higher bioavailability are described in patents,^Citation52,Citation53 FDA reports,^Citation50 and a peer-reviewed paper^Citation51
Unapproved IN naloxone at 1 mg/mL may be inadequate for efficacy, compared to 0.4 mg IM injectable naloxone^Citation25,Citation31	Opioid overdose mortality was reduced by almost 50% in areas where 1 mg/mL naloxone nasal spray was accessible, compared to areas with no access^Citation46
Wherever possible, clinicians should prescribe medications for use by the approved route of proven and highest effectiveness (i.e., IM as opposed to IN naloxone)^Citation25	The broader public is considered to have low acceptance for needles, with nasal spray being much more palatable for nonmedical use^Citation28 Needlestick injuries to rescuers represent a serious risk of blood-borne infections, including HIV and hepatitis,^Citation8 a risk that is eliminated with IN naloxone
Despite the FDA approval of naloxone nasal spray, there are persistent concerns:^Citation3
1. IN naloxone has historical nonresponse rates of between 9% and 26%^Citation31	1. Bioequivalency testing of Narcan IN naloxone demonstrated plasma levels that exceeded 0.4 mg IM plasma levels at all time points, starting at 2.5 min, with a similar time to maximum plasma concentration compared to IM naloxone, with levels exceeding the 0.4 mg IM peak plasma level for over 2 h^Citation50,Citation51 This historical rate estimate is from studies of the off-label improvised nasal spray, inapplicable to the FDA-approved IN formulation. Also, even a lower limit of response rate of 74%–91% is better than the alternative without any naloxone
2. Nonmedical use and reliance on IN naloxone may substitute for or delay use of emergency medical services and availability of naloxone injection	2. Distributors of off-label IN naloxone generally provide training, including instructions to immediately contact EMS after dosing;^Citation46 approved IN naloxone kits provide the same instructions^Citation54
3. There is still uncertainty about dose adequacy and comparability of nasal naloxone to injectable formulations	3. Bioequivalence to injectable naloxone has been demonstrated for FDA-approved IN Narcan^Citation50,Citation51
4. At a practical level, there are uncertainties about the effectiveness of a nasal spray (e.g., the spray device is limited by possible poor functioning in a horizontal position)	4. The ability of IN naloxone sprays to operate in a horizontal position has already been established for both improvised^Citation42 and approved^Citation50,Citation51 IN spray devices
5. IN naloxone effectiveness may be limited by the impact of compromised nasal mucosa, for example, chronic ulceration from nasal drug use snorting	5. Compromise of the normal barrier function of the nasal mucosa would tend to increase drug penetration, with naloxone being more rather than less effective^Citation94
6. Effectiveness may be limited by nasal obstruction from vomit, precluding IN administration	6. Although a theoretical concern, nasal obstruction from vomit has not been reported as a significant problem in the substantial literature of case studies of IN naloxone^Citation60

Abbreviations: FDA, US Food and Drug Administration; IM, intramuscular; IN, intranasal; IV, intravenous.

LoimerNHofmannPChaudhryHRNasal administration of naloxone for detection of opiate dependenceJ Psychiat Res199226139431560408

 PubMed Web of Science ®Google Scholar

LoimerNHofmannPChaudhryHRNasal administration of naloxone is as effective as the intravenous route in opiate addictsInt J Addic1994296819827

 PubMed Web of Science ®Google Scholar

KellyAKoutsogiannisZIntranasal naloxone for life threatening opioid toxicityEmerg Med J2002194375

 Web of Science ®Google Scholar

BartonEDRamosJColwellCBensonJBailyJDunnWIntranasal administration of naloxone by paramedicsPrehosp Emerg Care200261545811789651

 PubMedGoogle Scholar

BartonEDColwellCBWolfeTEfficacy of intranasal naloxone as a needleless alternative for treatment of opioid overdose in the prehospital settingJ Emerg Med200529326527116183444

 PubMed Web of Science ®Google Scholar

KellyAMKerrDDietzePPatrickIWalkerTKoutsogiannisZRandomised trial of intranasal versus intramuscular naloxone in prehospital treatment for suspected opioid overdoseMed J Austral20051821242715651944

 PubMed Web of Science ®Google Scholar

KerrDKellyAMDietzePJolleyDBargerBRandomized controlled trial comparing the effectiveness and safety of intranasal and intramuscular naloxone for the treatment of suspected heroin overdoseAddiction2009104122067207419922572

 PubMed Web of Science ®Google Scholar

Doe-SimkinsMWalleyAYEpsteinAMoyerPSaved by the nose: bystander-administered intranasal naloxone hydrochloride for opioid overdoseAm J Public Health200999578879119363214

 PubMed Web of Science ®Google Scholar

RobertsonTMHendeyGWStrohGShalitMIntranasal naloxone is a viable alternative to intravenous naloxone for prehospital narcotic overdosePrehosp Emerg Care200913451251519731165

 PubMed Web of Science ®Google Scholar

MerlinMASayboltMKapitanyanRIntranasal naloxone delivery is an alternative to intravenous naloxone for opioid overdosesAm J Emerg Med201028329630320223386

 PubMed Web of Science ®Google Scholar

WeberJMTatarisKLHoffmanJDAksSEMycykMBCan nebulized naloxone be used safely and effectively by emergency medical services for suspected opioid overdose?Prehosp Emerg Care201216228929222191727

 PubMed Web of Science ®Google Scholar

WalleyAYXuanZHackmanHHOpioid overdose rates and implementation of overdose education and nasal naloxone distribution in Massachusetts: interrupted time series analysisBrit Med J2013346f17423372174

 PubMed Web of Science ®Google Scholar

WalleyAYDoe-SimkinsMQuinnEPierceCXuanZOzonoffAOpioid overdose prevention with intranasal naloxone among people who take methadoneJ Subst Abuse Treat201344224124722980450

 PubMed Web of Science ®Google Scholar

SabzghabaeeAMEizadi-MoodNYaraghiAZandifarSNaloxone therapy in opioid overdose patients: intranasal or intravenous? A randomized clinical trialArch Med Sci201410230931424904666

 PubMed Web of Science ®Google Scholar

AshtonHHassanZBest evidence topic report. Intranasal naloxone in suspected opioid overdoseEmerg Med J200623322122316498165

 PubMed Web of Science ®Google Scholar

ClarkAKWilderCMWinstanleyELA systematic review of community opioid overdose prevention and naloxone distribution programsJ Addict Med20148315316324874759

 PubMed Web of Science ®Google Scholar

StrangJMcDonaldRTasBDayEClinical provision of improvised nasal naloxone without experimental testing and without regulatory approval: imaginative shortcut or dangerous bypass of essential safety procedures?Addiction2016111457458226840916

 PubMed Web of Science ®Google Scholar

BennettASBellA, TomediL, HulseyEG, KralAH. Characteristics of an overdose prevention, response, and naloxone distribution program in Pittsburgh and Allegheny CountyJ Urban Health20118861020103021773877

 PubMed Web of Science ®Google Scholar

BennettTHollowayKThe impact of take-home naloxone distribution and training on opiate overdose knowledge and response: an evaluation of the THN project in WalesDrugs Educ Prev Policy2012194320328

 Web of Science ®Google Scholar

DettmerKSaundersBStrangJTake home naloxone and the prevention of deaths from opiate overdose: two pilot schemesBMJ2001322729189589611302902

 PubMed Web of Science ®Google Scholar

DwyerKWalleyAYLangloisBKOpioid education and nasal naloxone rescue kits in the emergency departmentWest J Emerg Med201516338138425987910

 PubMed Web of Science ®Google Scholar

EnteenLBauerJMcLeanROverdose prevention and naloxone prescription for opioid users in San FranciscoJ Urban Health201087693194120967505

 PubMed Web of Science ®Google Scholar

GaleaSWorthingtonNPiperTMNandiVVCurtisMRosenthalDMProvision of naloxone to injection drug users as an overdose prevention strategy: early evidence from a pilot study in New York cityAddict Behav200631590791216139434

 PubMed Web of Science ®Google Scholar

LankenauSEWagnerKDSilvaKInjection drug users trained by overdose prevention programs: responses to witnessed overdosesJ Community Health201338113314122847602

 PubMed Web of Science ®Google Scholar

LeecePNHopkinsSMarshallCOrkinAGassanovMAShahinRMDevelopment and implementation of an opioid overdose prevention and response program in Toronto, OntarioCan J Pub Heal20131043e200e204

 PubMed Web of Science ®Google Scholar

Lopez-GastonRBestDManningVDayECan we prevent drug related deaths by training opioid users to recognize and manage overdosesHarm Reduct J2009612619781073

 PubMed Web of Science ®Google Scholar

Markham PiperTMStancliffSRudenstineSEvaluation of a naloxone distribution and administration program in New York CitySubst Use Misuse200843785887018570021

 PubMed Web of Science ®Google Scholar

MaxwellSBiggDStanczykiewiczKCarlberg-RacichSPrescribing naloxone to actively injecting heroin users: a program to reduce heroin overdose deathsJ Addict Dis20062538996

 PubMed Web of Science ®Google Scholar

McAuleyALindsayGWoodsMLouttitDResponsible management and use of a personal take-home naloxone supply: a pilot projectDrugs Educ Prev Policy2010174388399

 Web of Science ®Google Scholar

RoweCSantosG-MVittinghoffEWheelerEDavidsonPCoffinPOPredictors of participant engagement and naloxone utilization in a community-based naloxone distribution programAddiction201511081301131025917125

 PubMed Web of Science ®Google Scholar

SealKHThawleyMRGeeMLNaloxone distribution and cardiopulmonary resuscitation training for injection drug users to prevent heroin overdose death: a pilot intervention studyJ Urban Health200582230331115872192

 PubMed Web of Science ®Google Scholar

StrangJManningVMayetSOverdose training and take-home naloxone for opiate users: prospective cohort study of impact on knowledge and attitudes and subsequent management of overdosesAddiction2008103101648165718821875

 PubMed Web of Science ®Google Scholar

TobinKEShermanSGBeilensonPWelshCLatkinCAEvaluation of the staying alive programme: training injection drug users to properly administer naloxone and save livesInt J Drug Policy200920213113618434126

 PubMed Web of Science ®Google Scholar

TzemisDAl-QutubDAmlaniAKesselringSBuxtonJAA quantitative and qualitative evaluation of the British Columbia take home naloxone programCan Med Assoc J Open201423E153E161

 Google Scholar

WagnerKDValenteTWCasanovaMEvaluation of an overdose prevention and response training programme for injection drug users in the Skid Row area of Los Angeles, CAInt J Drug Policy201021318619319268564

 PubMed Web of Science ®Google Scholar

YokellMAGreenTCBowmanSMcKenzieMRichJDOpioid overdose prevention and naloxone distribution in Rhode IslandMed Health R I201194824024221913619

 PubMedGoogle Scholar

McDonaldRStrangJAre take-home naloxone programmes effective? Systematic review utilizing application of the Bradford Hill criteriaAddiction201611171177118727028542

 PubMed Web of Science ®Google Scholar

US Food and Drug AdministrationJoint Meeting of Anesthetic and Analgesic Drug Products Advisory Committee and Drug Safety and Risk Management Advisory Committee October 5, 2016 Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/UCM522687.pdfAccessed November 24, 2016

 Google Scholar

StrangJMcdonaldRNew approved nasal naloxone welcome, but unlicensed improvised naloxone spray kits remain a concern: proper scientific study must accompany innovationAddiction2016111459059226995172

 PubMed Web of Science ®Google Scholar

WinstanleyELTangled-up and blue: releasing the regulatory choke-hold on take-home naloxoneAddiction2016111458358426995167

 PubMed Web of Science ®Google Scholar

US Food and Drug AdministrationNarcan Nasal Spray Summary Review for Regulatory Action Available from: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentRe-sources/UCM480092.pdfAccessed June 7, 2016

 Google Scholar

BalsterRLWalshSLEnsure global access to naloxone for opioid overdose managementAddiction2016111458959026995171

 PubMed Web of Science ®Google Scholar

LobmaierPPClausenTRadical red tape reduction by government supported nasal naloxone: the Norwegian pilot project is innovative, safe and an important contribution to further development and dissemination of take-home naloxoneAddiction2016111458658726995169

 PubMed Web of Science ®Google Scholar

DowlingJIsbisterGKKirkpatrickCMNaidooDGraudinsAPopulation pharmacokinetics of intravenous, intramuscular, and intranasal naloxone in human volunteersTher Drug Monit200830449049618641540

 PubMed Web of Science ®Google Scholar

WermelingDPReview of naloxone safety for opioid overdose: practical considerations for new technology and expanded public accessTher Advan Drug Saf201561203125642320

 PubMed Web of Science ®Google Scholar

CrystalRWeissMBinventorsLightlake Therapeutics Inc., assigneeNasal drug products and methods of their useUnited States Patent US92112532015

 Google Scholar

WyseJDeHartMPinventorsAntiOp, Inc., assigneeIntranasal naloxone compositions and methods of making and using sameUnited States Patent US9192570B22015

 Google Scholar

KrieterPChiangNGyawSPharmacokinetic properties and human use characteristics of an FDA-approved intranasal naloxone product for the treatment of opioid overdoseJ Clin Pharmacol201656101243125327145977

 PubMed Web of Science ®Google Scholar

RatcliffeJMLydenJTSousaSOrelienJGBoalWLJaggerJBlood exposure among paramedics: incidence rates from the national study to prevent blood exposure in paramedicsAnn Epidemiol200616972072516581265

 PubMed Web of Science ®Google Scholar

DahanAAartsLSmithTWIncidence, reversal, and prevention of opioid induced respiratory depressionAnesthesiology2010112122623820010421

 PubMed Web of Science ®Google Scholar

Adapt Pharma, IncNARCAN^® (naloxone HCl) Nasal Spray 2 mg Approved by U.S. Food and Drug Administration (FDA) Available from: http://adaptpharma.com/adapt_press_release/january-25-2017-narcan-nasal-spray-2mg-approved-by-us-food-and-drug-administration/Accessed June 7, 2016

 Google Scholar

SalamaNNEddingtonNDFasanoATight junction modulation and its relationship to drug deliveryAdv Drug Deliv Rev2006581152816517003

 PubMed Web of Science ®Google Scholar