REVIEW
`
`doi:10.1111/j.1360-0443.2007.02097.x
`
`Intranasal naloxone for the treatment of suspected
`heroin overdose
`
`Debra Kerr1, Paul Dietze2 & Anne-Maree Kelly3
`Joseph Epstein Centre for Emergency Medicine Research, The University of Melbourne, Australia,1 Burnet Institute, Monash Institute of Health Services Research,
`Australia2 and Joseph Epstein Centre for Emergency Medicine Research, Office of Research, Western Health and The University of Melbourne, Australia3
`
`ABSTRACT
`
`Aims This paper reviews available literature regarding the effectiveness, safety and utility of intranasal (i.n.) nalox-
`one for the treatment of heroin overdose. Methods Scientific literature in the form of published articles during the
`period January 1984 to August 2007 were identified by searching several databases including Medline, Cinahl and
`Embase for the following terms: naloxone, narcan, intranasal, nose. The data extracted included study design, patient
`selection, numbers, outcomes and adverse events. Results Reports of the pharmacological investigation and admin-
`istration of i.n. naloxone for heroin overdose are included in this review. Treatment of heroin overdose by administra-
`tion of
`i.n. naloxone has been introduced as first-line treatment in some jurisdictions in North America, and is
`currently under investigation in Australia. Conclusion Currently there is not enough evidence to support i.n. nalox-
`one as first-line intervention by paramedics for treatment of heroin overdose in the pre-hospital setting. Further
`research is required to confirm its clinical effectiveness, safety and utility. If proved effective, the i.n. route may be useful
`for drug administration in community settings (including peer-based administration), as it reduces risk of needlestick
`injury in a population at higher risk of blood-borne viruses. Problematically, naloxone is not manufactured currently
`in an ideal form for i.n. administration.
`
`Keywords Heroin, intranasal, naloxone, opioid, overdose, paramedic, resuscitation.
`
`Correspondence to: Debra Kerr, The Joseph Epstein Centre for Emergency Medicine Research, Western Health, Sunshine Hospital, 176 Furlong Road,
`St Albans, Vic. 3021, Australia. E-mail: debbie.kerr@wh.org.au
`Submitted 26 July 2007; initial review completed 27 September 2007; final version accepted 7 November 2007
`
`INTRODUCTION
`Administration of naloxone by the intranasal (i.n.) route
`to victims of suspected heroin overdose is a new and
`novel approach. Naloxone reverses the effects of heroin
`and, most importantly, respiratory depression, which is
`the most common cause of death after overdose.
`Traditionally, naloxone has been administered via the
`intramuscular (i.m.) and intravenous (i.v.) routes in
`emergency situations by trained health professionals in
`hospital and community settings. Drug administration by
`these routes is problematic in a population at higher risk
`of blood-borne viruses (BBV).
`the effectiveness and
`Several promising reports of
`utility of intranasal naloxone for the treatment of heroin
`overdose in emergency situations have been published
`recently. This review examines the available scientific
`literature regarding the use and practicality of
`i.n.
`naloxone for the treatment of heroin overdose, and also
`
`explores issues around the wider dissemination of its use
`in community settings by non-health-care providers.
`
`METHODS
`
`The Medline, Cochrane, Embase and Cinahl databases
`were searched using the following terms: ‘naloxone.mp’
`or ‘exp naloxone’,
`‘narcan.mp.’ or ‘exp.Narcan’ and
`‘exp administration,
`intranasal/or intranasal.mp’ or
`‘nose.mp’. Fifteen papers were identified initially by
`Medline, of which seven were relevant [1–7]. Six reported
`findings from case series or clinical studies, and one was a
`brief review [1]. This short review [1] of the available
`literature in this field was performed to establish whether
`intranasal naloxone is effective in suspected opiate
`overdose. While this report outlined study findings, the
`authors did not elaborate on the safety, effectiveness
`and clinical importance of intranasal administration of
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`Response
`Response
`Response
`Response
`Response
`Severityofwithdrawal
`Severityofwithdrawal
`Bioavailability
`
`Comparison:i.v.(104)versusi.n.(50)
`Comparison:i.m.(71)versusi.n.(84)
`Observational:i.n.
`Observational:i.n.
`Observational:i.n.
`Comparison:i.v.versusi.m.(7),i.v.versusi.n.(10)
`Observational
`Comparison:i.v.(3)versusi.n.(3)
`
`Observational,medicalrecordreview
`Randomizedcontrolledtrial
`Caseseries
`Caseseries
`Caseseries
`Randomizedcontrolledtrial
`Controlledtrial
`Controlledtrial
`
`Suspectedheroinoverdose(154)
`Suspectedheroinoverdose(155)
`Suspectedheroinoverdose(95)
`Suspectedheroinoverdose(30)
`Adult(6),heroinoverdose
`Maleadult(17),opiate-dependent
`Maleadult(30),opiate-dependent
`Malerats(6)
`
`Robertsonetal.(2005)[9]
`Kellyetal.(2005)[4]
`Bartonetal.(2005)[2]
`Bartonetal.(2002)[3]
`Kelly&Koutsogiannis(2002)[5]
`Loimeretal.(1994)[7]
`Loimeretal.(1992)[6]
`Hussainetal.(1984)[8]
`
`Outcome
`
`Studytype:(n)
`
`Intervention
`
`Patientgroup(n)
`
`Author(date)
`
`Table1Summaryofinvestigationsforintranasalnaloxone.
`
`i.v.:intravenous;i.n.:intranasal;i.m.:intramuscular
`
`380
`
`Debra Kerr et al.
`
`naloxone. We considered that a more detailed review
`of
`this topic was necessary and proceeded with our
`investigation.
`No further papers were identified after review of the
`other databases; however, two further papers were found
`after assessment of references of identified papers: one a
`study in rats and the other a clinical study reported as an
`abstract at a scientific meeting [8,9].
`Papers were deemed to be relevant if they discussed
`the effectiveness of naloxone by intranasal administra-
`tion for opiate reversal. A total of eight papers were iden-
`tified, as summarized in Table 1.
`
`HEROIN USE AND OVERDOSE
`
`Heroin is an opioid that is absorbed rapidly after all
`methods of administration: within 1 minute for intra-
`venous [10], within 3–5 minutes for i.n. and i.m. [11]
`and within 5–10 minutes for subcutaneous administra-
`tion [12]. Heroin usually produces euphoric effects, but
`in overdose toxic signs include abnormal mental status,
`substantial respiratory depression and miotic pupils
`[13].
`Drug overdose is a leading cause of premature death
`for injecting drug users (IDUs) [14,15], and it has been
`estimated that 38–68% of users have overdosed at least
`once [16–18]. Overdose among IDUs typically involves
`heroin resulting in a mortality rate that is much higher
`than other groups in the community of the same age
`[15,19].
`Death after heroin overdose results from loss of con-
`sciousness and respiratory suppression [20]. Fortunately,
`death rates after heroin overdose have been reported to be
`as low as 3% [21], and a minority of
`fatalities occur
`instantly after drug ingestion [13,22,23]. This delay
`offers a window for intervention.
`Aside from death, other sequelae reported after heroin
`overdose include: neurological damage after prolonged
`hypoxia,
`rhabdomyolysis, pulmonary oedema and
`pulmonary aspiration [24]. Prompt reversal of heroin
`overdose limits the occurrence and/or severity of these
`events, and full recovery is possible if hypoxia is reversed
`before permanent organ damage results.
`
`NALOXONE THERAPY
`
`Naloxone is a pure opioid antagonist that challenges the
`mu, kappa and delta receptors of the central nervous
`system [25]. As such, it is an effective agent for reversing
`the acute effects of opioids such as heroin and exerts little
`or no pharmacological effect when administered to
`patients who have not consumed opioids
`[6,25].
`Naloxone is effective rapidly, with onset of action within
`1–2 minutes after i.v. administration [25]. Duration of
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`effect usually persists in the range of 1–4 hours after
`i.v. administration, with an elimination half-life of
`60–90 minutes [25].
`Serious complications (seizure, pulmonary oedema,
`asystole, cardiac arrest) after naloxone administration
`are reportedly rare (0.3 and 1.6%) [26–28]. Signs of
`opioid withdrawal (confusion, headache, nausea or vom-
`iting, aggressiveness, tachycardia, sweating and tremor)
`are more likely to occur [26–28].
`Historically, the treatment of heroin overdose with
`naloxone occurred in the hospital environment, where
`naloxone was administered parenterally (i.m. and i.v.)
`after ambulance transfer of patients. Today, treatment of
`these patients often occurs in the pre-hospital setting
`with the administration of naloxone undertaken by para-
`medics [4,28,29]. More recently there have been trials of
`peer-administered naloxone for heroin overdose in com-
`munity settings with reported success [30–36].
`
`DIFFICULTIES WITH CURRENT MODE
`OF TREATMENT
`
`While there is evidence of success with the parenteral
`(i.v., i.m.) administration of naloxone for heroin overdose,
`there are several recognized problems including venous
`access, BBV risk and technical competence.
`A large proportion of heroin users inject intrave-
`nously [37–39]. It can be challenging for health profes-
`sionals, including paramedics, to access patent peripheral
`veins in IDUs whose veins may be damaged after excessive
`use for illicit drug administration. Difficult and repeat
`cannulations are time-consuming, which may lead to
`treatment delays.
`A degree of clinical expertise is required in the use of
`needles, syringes, vials and ampoules in order to admin-
`ister naloxone using parenteral routes. Patients are often
`found in less than ideal environments, including alley-
`ways, parks and public toilets [4,26] that can be dark
`and cramped, rendering injection and cannulation more
`difficult. Also, after heroin reversal patients are often
`restless and aggressive upon awakening [4,26]. Risk
`of needlestick injury to the health-care provider is
`increased in these situations. Given the increased preva-
`lence of BBV, such as hepatitis B and C and HIV, in the
`IDU population [40,41] there is a risk of transmission of
`these viruses during needlestick injury. In addition, the
`safe disposal of used syringes and needles is a major
`issue. Regardless of the outcome of a needlestick injury,
`the affected person and kin are usually anxious until
`negative test results are obtained (which can take
`several months) [42]. HIV prophylactic medications
`taken during this time have significant and impeding
`iatrogenic side effects [43].
`
`Intranasal naloxone in heroin overdose
`
`381
`
`It is estimated that 378 000–756 000 needlestick
`injuries occur annually in the United States [44]. One
`response to this issue has been the Needlestick Safety
`and Prevention Act introduced by the Occupational
`Safety and Health Administration in 2001 [45]. Passed
`as a response to the continued prevalence of infectious
`disease transmission via needlestick injury in the health-
`care work-place, this legislation outlined the responsibil-
`ity of employers to identify, evaluate and implement safer
`medical devices with the aim of decreasing needlestick
`and sharps injuries. Strategies introduced in accordance
`with these responsibilities included the elimination of
`needle recapping and the use of safer needle devices, the
`use of sharps collection boxes, gloves and personal pro-
`tective gear, as well as universal precautions. As a result
`of these strategies needlestick injuries have declined in
`the United States from an estimated 1 million exposures
`per year in 1996 to 385 000 per year in 2000 [46]. In
`spite of this apparent success, the incidence of needle-
`stick injury is high.
`
`INTRANASAL MEDICATION
`ADMINISTRATION
`
`The administration of medication via non-parenteral
`routes is another means of reducing occupational hazard
`for health-care workers by reducing risk of needlestick
`injury. Intranasal medication administration has been
`investigated widely for a broad range of pharmacothera-
`pies in emergency medicine, including fentanyl for pain
`relief [47], metoclopramide for nausea [48] and mida-
`zolam for seizure treatment [49]. A full list of medications
`studied for
`i.n. administration has been reported
`previously [2].
`Nasal administration is attractive for several reasons.
`Drug administration is simple and convenient, without
`the requirement for needles. This reduces the risk of
`needlestick injuries to care-givers, and reduces discom-
`fort to patients. Delivery of medication does not require
`sterile or technologically advanced equipment, and nasal
`passages are easily accessible.
`The nose has an extensive absorptive surface with
`considerable blood flow. This allows rapid and thorough
`drug absorption via the bloodstream and cerebral spinal
`fluid [50,51]. Absorption rates and plasma concentra-
`tions are comparable for i.n. and i.v. administration [50].
`Nasal absorption is dependent upon several variables,
`including drug formula, anatomy and physiology and
`medication characteristics that influence drug bioavail-
`ability (molecular size, pH, concentration/volume, for-
`mulation vehicle) [51]. It is recommended that less than
`1 ml be administered into each nares to avoid excess
`volumes escaping the nasal passage [51]. Nasal mucosal
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`Debra Kerr et al.
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`destruction and excess mucous and blood secretions can
`inhibit drug absorption and render the medication less
`effective [51].
`Maximal surface area coverage of the nasal passages
`achieves optimal drug absorption. This is achieved by dis-
`tribution between two nostrils and the use of atomized
`drug delivery systems. Compared with drops and spray
`methods, atomization of the drug for i.n. administration,
`using commercial equipment such as the mucosal atomi-
`zation device (MAD®, Wolfe Tory Medical Inc., Salt Lake
`City, UT, USA), results in superior surface area coverage
`[51,52].
`
`THE EVIDENCE REGARDING
`INTRANASAL NALOXONE
`
`As a strategy to reduce BBV transmission, researchers
`have sought alternative routes for administration of
`naloxone, in particular non-invasive methods. Investiga-
`tion of the oral [53] and conjunctival routes [54] have
`been unsuccessful. Hussain and colleagues were the first
`to report investigation of naloxone for i.n. administration
`[8] in comparison to i.v. administration. They found the
`i.n. route to have similar pharmacokinetics to the i.v.
`route with 100% bioavailability, a half-life duration of
`40–45 minutes and peak plasma concentrations within
`3 minutes [8].
`Detection of opioid dependence has been demon-
`strated in two smaller studies after i.n. naloxone admin-
`istration [6,7]. The first study, by Loimer et al. [6],
`involved 30 patients (22 opiate-dependent and eight con-
`trols). Opiate-dependent participants demonstrated a sig-
`nificant increase in withdrawal distress and pupillary
`dilation after 1 mg naloxone by i.n. administration, and
`the effect peaked at 10 minutes after treatment. No
`response of withdrawal was observed in control subjects.
`In a study of 17 opiate-dependent volunteers [7] the
`efficacy of i.n. naloxone was compared with alternative
`routes (i.m. and i.v.) by examination of the severity of
`withdrawal symptoms and pupillary responses. Subjects
`were divided randomly into two treatment groups: (i) i.v.
`versus i.m., seven subjects; or (ii) i.n. versus i.v., 10 sub-
`jects. Intranasal naloxone was shown to be as effective
`as the i.v. route, with similar responses for severity of
`withdrawal symptoms (peak response at 5 minutes) and
`pupillary reaction in opioid addicts. Response to naloxone
`administered by the i.m. route was delayed in comparison
`to both the i.n. and i.v. routes.
`These two studies [6,7], performed in non-emergency
`settings, provided evidence that naloxone administered
`intranasally precipitated abstinence symptoms in opioid-
`dependent subjects. Naloxone was found to be absorbed
`rapidly from the nasal cavity, and the authors recom-
`mended its use in emergency medicine.
`
`TREATING OPIOID OVERDOSE
`EMERGENCIES USING INTRANASAL
`NALOXONE
`
`There is increasing evidence that the i.n. route may be
`useful for the administration of naloxone in cases of
`opioid overdose. Several case series [2,3,5,9] have
`reported use of i.n. naloxone for suspected opiate over-
`dose in both pre-hospital and hospital settings. Its use was
`reported first by Barton et al. [3] for the management of
`heroin overdose in a pre-hospital setting in Denver, USA
`[3]. Using a formulation of 1 mg/ml/nostril, 30 patients
`were given i.n. naloxone by atomization. Eleven (36.7%)
`patients responded to naloxone therapy (i.v. or i.n.). An
`average response time of 3.4 minutes was observed, and
`the majority (10 of 11 patients) responded to i.n. nalox-
`one alone; i.v. access was not required for seven (64%)
`patients. In that study, patients encountered by paramed-
`ics with altered mental status (AMS), ‘found down’ (FD)
`(e.g. collapsed at the roadside) or with suspected heroin
`overdose (OD) were initially administered 2 mg of nalox-
`one using MAD®. Of these, one patient in the AMS group
`(9%, one of 11), no patient in the FD group (0%, none of
`seven) and 10 patients in the OD group (10 of 12, 83%)
`responded to naloxone.
`A larger case series was reported by Barton et al. in
`2005. That study included 95 patients who received
`naloxone for AMS, being FD or suspected heroin overdose
`in a 6-month period [2]. All patients received 2 mg nalox-
`one i.n., followed by i.v. naloxone. Approximately half the
`study participants (52 of 95 patients) responded to nalox-
`one, of whom 43 (83%) responded to i.n. naloxone alone.
`As described for the earlier study [3], patients with AMS,
`FD or OD were eligible for study inclusion. Consequently,
`naloxone was administered to a large proportion of non-
`opioid overdoses or alternate clinical conditions.
`More recently a before-and-after case study of 154
`patients [104 i.v. (before) and 50 i.n. (after)] was reported
`[9]. More patients in the intranasal group received a
`second dose of naloxone (18% i.v. versus 34% i.n.,
`P = 0.05), and time to adequate clinical response was
`delayed for this group (13 versus 8 minutes, P = 0.02).
`Use of
`i.n. naloxone in a hospital setting has been
`reported for patients who presented to an emergency
`department [5]. This was a small informal study of six
`patients with suspected heroin overdose who were
`administered i.n. naloxone by syringe drops using various
`doses (0.8–2 mg). Heroin reversal was achieved for all
`patients within 2 minutes. There was no comparative
`treatment option for these cases.
`One prospective unblinded randomized study has
`examined the effectiveness and safety of i.n. naloxone in
`comparison to i.m. naloxone for the treatment of patients
`with suspected heroin overdose [4]. One hundred and
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`fifty-five unrousable patients with inadequate respira-
`tions were administered 2 mg naloxone by paramedics
`using either the i.m. (71) or i.n. (84) route [4]. In Austra-
`lia at the time of the study, naloxone was available only in
`a preparation of 0.4 mg/ml, resulting in an i.n. volume of
`5 ml (2 mg dose)—far in excess of expert recommenda-
`tions for nasal administration (less than 1 ml per nostril)
`[51]. Patients who received i.n. naloxone were more
`likely to require a second dose (i.m. 13%, versus i.n.
`26%). Adequate spontaneous ventilation was quicker in
`the i.m. group [5 minutes (95% confidence interval
`4–6 minutes) versus 7 minutes (95% confidence interval
`6–8 minutes), P = 0.006]; however, time to adequate
`conscious state was not significantly different between
`the two groups. Withdrawal symptoms were more
`common for the subjects who received i.m. naloxone
`[21% (i.m.) versus 12% (i.n.)].
`A summary effect size cannot be calculated because
`the outcomes and study designs used in these investiga-
`tions are too diverse.
`
`LIMITATIONS OF EVIDENCE
`
`Research in this field has not been extensive. Several com-
`peting issues challenge robust study designs for research
`conducted in emergency settings. Recently, Clarke et al.
`[55] highlighted the difficulties in conducting random-
`ized controlled clinical trials investigating naloxone for
`opioid poisoning. First, the majority of patients who
`receive naloxone in the pre-hospital setting are uncon-
`scious and are therefore incapable of providing informed
`consent for participation. Research has shown that the
`processes for obtaining exemption of informed consent
`from human research committees are both costly and
`timely [56]. Secondly, the nature of illness demands swift
`administration of
`life-saving health-care measures,
`including respiratory support and drug administration.
`Treatment by different modes in combination, that would
`be required for a blinded study, would not be efficient or
`safe. Thirdly, the majority of reporting required for data
`collection is reliant upon accurate and precise documen-
`tation by paramedics. Data collected in this format may
`be inaccurate and biased. Finally, serious adverse out-
`comes are rare after naloxone therapy [57]. For random-
`ized controlled trials where the outcome of
`interest is
`rare, prohibitively large numbers are required to achieve
`sufficient power.
`Despite this, a recent report [1] has suggested that
`while the evidence regarding i.n. naloxone compared to
`i.v. and i.m. routes is weak and conflicting, it appears that
`it is safe and has significant efficacy in reversing opiate
`overdose. There have been no reports of any serious
`adverse events during i.n. naloxone administration.
`
`Intranasal naloxone in heroin overdose
`
`383
`
`THE CURRENT PLACE OF INTRANASAL
`NALOXONE IN TREATMENT
`
`Treatment of heroin overdose by paramedics has proved
`to be safe and effective [13,29,58,59]. In some regions,
`administration of naloxone using the i.n. route by
`paramedics for suspected heroin overdose has been
`introduced [2,9], but to our knowledge its use is not
`widespread. At this stage, universal introduction in para-
`medic protocols may be limited by the absence of strong
`evidence that i.n. naloxone is superior to or equally effec-
`tive as injectable forms. Further research is needed to
`investigate alternative naloxone preparations (absorp-
`tion, concentration, dosage) that confirm effectiveness,
`adverse event profiling and clinical utility.
`Compounding the lack of confirmatory evidence,
`administration by devices currently available are not
`simple to use. Available solutions are manufactured and
`stored in vials. The medication is extracted using a needle
`and syringe. This level of complexity may be too
`advanced for use by non-health-care trained personnel.
`Also, current formulations of naloxone are not ideal for
`nasal administration. As mentioned previously, volume
`should not exceed 1 ml per nostril [51]. In Australia,
`naloxone is available either as a prefilled Min-I-Jet syringe
`(CSL Ltd., Victoria, Australia) (0.8 mg/2 ml, 2 mg/5 ml)
`or ampoule (400 mg/1 ml). Neither preparation is suit-
`able for nasal administration.
`
`THE POTENTIAL FUTURE PLACE OF
`INTRANASAL NALOXONE
`
`Reversal of heroin overdose could be expedited with
`bystander response in the form of peer-administered
`naloxone. Many heroin users have witnessed overdose by
`others [60,61]. The introduction of programmes for
`peer-administered naloxone, along with appropriate
`first aid training (heroin overdose prevention, recognition
`of signs and symptoms and management strategies),
`has been introduced successfully in some areas
`[31,34,62,63]. There is considerable debate in the
`literature regarding the efficacy and safety of peer-
`administered naloxone. Opponents to such programmes
`have raised concerns, including that heroin users may
`perceive such programmes as support and acceptance
`that drug use is condoned, that drug users may engage in
`more risky behaviour if the antidote is accessible, the
`short half-life of naloxone and concerns of re-sedation,
`shelf life and stability of naloxone, polydrug use, solitary
`heroin use, administration by intoxicated peers and
`undermining of other preventative strategies, including
`calling for an ambulance [33,35,64–68]. There are also
`medico–legal impedients in that the drug is most likely to
`be administered by a third party, compromising the
`patient and prescriber [35,67]. Treatment of acute life-
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`threatening conditions such as reversal of allergic reac-
`tion by adrenaline injection is supported by prescription
`of the drug to patients and their responsible carers. This is
`conducted with the understanding that a person other
`than the patient will most probably be responsible for
`drug administration.
`Several other professional groups come into contact
`with heroin users in overdose situations as part of their
`day-to-day work, including outreach workers, pharma-
`cists and community workers. Family and non-heroin-
`using friends might also prevent harm from overdose
`with emergency intervention,
`including naloxone
`administration.
`Despite recognition of these significant barriers to
`wider dissemination of naloxone, support has been
`shown from prescribers [69,70] and users [36]. Reports
`of
`successful naloxone distribution programmes are
`beginning to emerge, but with only limited investigation
`into areas such as suitable client groups, follow-up after
`naloxone administration, impact on overdose mortality
`rates and training and legal requirements [34,62,63].
`
`CONCLUSIONS
`
`Research investigating i.n. naloxone administration for
`opioid overdose has been limited, with few comparative
`studies evaluating alternative doses, drug formulations
`and delivery devices; i.n. administration is a simple treat-
`ment option that, if found to be safe and effective, could
`be extended to non-health-care settings. Unfortunately,
`current preparations of naloxone are not ideal for i.n.
`administration, as effective doses require drug amounts
`in excess of recommended volumes for adequate nasal
`absorption. Further well-designed research is needed to
`confirm effectiveness, adverse event profile and utility,
`and should ensure that highly relevant end-points such
`as total time from arrival at scene to recovery and the
`proportion of cases where needles are avoided are
`reported.
`
`References
`
`1. Ashton H., Hassan Z. Best evidence topic report. Intranasal
`naloxone in suspected opioid overdose. Emerg Med J 2006;
`23: 221–3.
`2. Barton E. D., Colwell C. B., Wolfe T., Fosnocht D., Gravitz C.,
`Bryan T. et al. Efficacy of intranasal naloxone as a needleless
`alternative for treatment of opioid overdose in the prehos-
`pital setting. J Emerg Med 2005; 29: 265–71.
`3. Barton E. D., Ramos J., Colwell C., Benson J., Baily J., Dunn
`W. Intranasal administration of naloxone by paramedics.
`Prehosp Emerg Care 2002; 6: 54–8.
`4. Kelly A. M., Kerr D., Dietze P., Patrick I., Walker T., Kout-
`sogiannis Z. Randomised trial of
`intranasal versus intra-
`muscular naloxone in prehospital treatment for suspected
`opioid overdose. Med J Aust 2005; 182: 24–7.
`
`5. Kelly A. M., Koutsogiannis Z. Intranasal naloxone for life
`threatening opioid toxicity. Emerg Med J 2002; 19: 375.
`6. Loimer N., Hofmann P., Chaudhry H. R. Nasal administra-
`tion of naloxone for detection of opiate dependence. J Psy-
`chiatr Res 1992; 26: 39–43.
`7. Loimer N., Hofmann P., Chaudhry H. R. Nasal administra-
`tion of naloxone is as effective as the intravenous route in
`opiate addicts. Int J Addict 1994; 29: 819–27.
`8. Hussain A., Kimura R., Huang C. H. Nasal absorption of
`naloxone and buprenorphine in rats. Int J Pharm 1984; 21:
`233–7.
`9. Robertson T., Hendey G., Stroh G., Shalit M. Prehospital
`Intranasal Versus Intravenous Administration of Naloxone for
`Narcotic Overdose. New York: Society for Academic Emer-
`gency Medicine; 2005, p. 166–7.
`10. Inturrisi C. E., Max M. B., Foley K. M., Schultz M., Shin S. U.,
`Houde R. W. The pharmacokinetics of heroin in patients
`with chronic pain. N Engl J Med 1984; 310: 1213–17.
`11. Skopp G., Ganssmann B., Cone E. J., Aderjan R. Plasma
`concentrations of heroin and morphine-related metabolites
`after intranasal and intramuscular administration. J Anal
`Toxicol 1997; 21: 105–11.
`12. Way E. L., Kemp J. W., Young J. M., Grassetti D. R. The
`pharmacologic effects of heroin in relationship to its rate of
`biotransformation. J Pharmacol Exp Ther 1960; 129: 144–
`54.
`13. Sporer K. A. Acute heroin overdose. Ann Intern Med 1999;
`130: 584–90.
`14. Gossop M., Stewart D., Treacy S., Marsden J. A prospective
`study of mortality among drug misusers during a 4-year
`period after seeking treatment. Addiction 2002; 97: 39–47.
`15. Quaglio G., Talamini G., Lechi A., Venturini L., Lugoboni F.,
`Mezzelani P. Study of 2708 heroin-related deaths in north-
`eastern Italy 1985–98 to establish the main causes of
`death. Addiction 2001; 96: 1127–37.
`16. Darke S., Ross J., Hall W. Overdose among heroin users in
`Sydney, Australia. I. Prevalence and correlates of non-fatal
`overdose. Addiction 1996; 91: 405–11.
`17. Ochoa K. C., Hahn J. A., Seal K. H., Moss A. R. Overdosing
`among young injection drug users in San Francisco. Addict
`Behav 2001; 26: 453–60.
`18. Powis B., Strang J., Griffiths P., Taylor C., Williamson S.,
`Fountain J. et al. Self-reported overdose among injecting
`drug users in London: extent and nature of the problem.
`Addiction 1999; 94: 471–8.
`19. Hulse G. K., English D. R., Milne E., Holman C. D. The quan-
`tification of mortality resulting from the regular use of illicit
`opiates. Addiction 1999; 94: 221–9.
`20. White J. M., Irvine R. J. Mechanisms of fatal opioid overdose.
`Addiction 1999; 94: 961–72.
`21. Darke S., Mattick R. P., Degenhardt L. The ratio of non-fatal
`to fatal heroin overdose. Addiction 2003; 98: 1169–71.
`22. Zador D., Sunjic S., Darke S. Heroin-related deaths in New
`South Wales, 1992: toxicological findings and circum-
`stances. Med J Aust 1996; 164: 204–7.
`23. Darke S., Ross J., Zador D., Sunjic S. Heroin-related deaths in
`New South Wales, Australia, 1992–1996. Drug Alcohol
`Depend 2000; 60: 141–50.
`24. Warner-Smith M., Darke S., Lynskey M., Hall W. Heroin
`overdose: causes and consequences. Addiction 2001; 96:
`1113–25.
`25. MIMS (Monthly Index of Medical Specialities Annual
`2007). Naloxone. Melbourne, Australia: MIMS Australia.
`2007.
`
`© 2008 The Authors. Journal compilation © 2008 Society for the Study of Addiction
`
`Addiction, 103, 379–386
`
`Nalox1035
`Nalox-1 Pharmaceuticals, LLC
`Page 6 of 8
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`26. Buajordet I., Naess A. C., Jacobsen D., Brors O. Adverse
`events after naloxone treatment of episodes of suspected
`acute opioid overdose. Eur J Emerg Med 2004; 11: 19–23.
`27. Osterwalder J. J. Naloxone—for intoxications with intrave-
`nous heroin and heroin mixtures—harmless or hazardous?
`A prospective clinical study. J Toxicol Clin Toxicol 1996; 34:
`409–16.
`28. Yealy D. M., Paris P. M., Kaplan R. M., Heller M. B., Marini S.
`E. The safety of prehospital naloxone administration by
`paramedics. Ann Emerg Med 1990; 19: 902–5.
`29. Sporer K. A., Firestone J., Isaacs S. M. Out-of-hospital treat-
`ment of opioid overdoses in an urban setting. Acad Emerg
`Med 1996; 3: 660–7.
`30. Dettmer K., Saunders B., Strang J. Take home naloxone and
`the prevention of deaths from opiate overdose: two pilot
`schemes. BMJ 2001; 322: 895–6.
`31. Bigg D. Data on take home naloxone are unclear but not
`condemnatory. BMJ 2002; 324: 678.
`32. Seal K. H., Downing M., Kral A. H., Singleton-Banks S.,
`Hammond J. P., Lorvick J. et al. Attitudes about prescribing
`take-home naloxone to injection drug users for the manage-
`ment of heroin overdose: a survey of street-recruited injec-
`tors in the San Francisco Bay Area. J Urban Health 2003; 80:
`291–301.
`33. Baca C. T., Grant K. J. Take-home naloxone to reduce heroin
`death. Addiction 2005; 100: 1823–31.
`34. Seal K. H., Thawley R., Gee L., Bamberger J., Kral A. H.,
`Ciccarone D. et al. Naloxone distribution and cardiopulmo-
`nary resuscitation training for injection drug users to
`prevent heroin overdose death: a pilot intervention study.
`J Urban Health 2005; 82: 303–11.
`35. Lenton S. R., Hargreaves K. M. Should we conduct a trial of
`distributing naloxone to heroin users for peer administra-
`tion to prevent fatal overdose? Med J Aust 2000; 173:
`260–3.
`36. Strang J., Powis B., Best D., Vingoe L., Griffiths P., Taylor C.
`et al. Preventing opiate overdose fatalities with take-home
`naloxone: pre-launch study of possible impact and accept-
`ability. Addiction 1999; 94: 199–204.
`37. Strang J., Griffiths P., Powis