`DOI 10.1007/s13346-012-0092-0
`
`REVIEW ARTICLE
`
`A response to the opioid overdose epidemic:
`naloxone nasal spray
`
`Daniel P. Wermeling
`
`Published online: 1 August 2012
`# Controlled Release Society 2012
`
`Abstract Opioid overdose morbidity and mortality is rec-
`ognized to have epidemic proportions. Medical and public
`health agencies are adopting opioid harm reduction strate-
`gies to reduce the morbidity and mortality associated with
`overdose. One strategy developed by emergency medical
`services and public health agencies is to deliver the opioid
`antidote naloxone injection intranasally to reverse the
`effects of opioids. Paramedics have used this route to quick-
`ly administer naloxone in a needle-free system and avoiding
`needlestick injuries and contracting a blood-born pathogen
`disease such as hepatitis or human immunodeficiency virus.
`Public health officials advocate broader lay person access
`since civilians are likely witnesses or first responders to an
`opioid overdose in a time-acute setting. The barrier to great-
`er use of naloxone is that a suitable and optimized needle-
`free drug delivery system is unavailable. The scientific basis
`for design and study of an intranasal naloxone product is
`described. Lessons from nasal delivery of opioid analgesics
`are applied to the consideration of naloxone nasal spray.
`
`Keywords Intranasal . Naloxone . Opioid . Overdose .
`Antidote
`
`Introduction
`
`In 2008, poisoning surpassed motor vehicle accidents as the
`leading cause of “injury deaths” in the USA [1]. Nearly
`90 % of poisoning deaths are caused by drugs. During the
`past three decades, the number of drug poisoning deaths
`increased sixfold from about 6,100 in 1980 to 36,500 in
`
`D. P. Wermeling (*)
`University of Kentucky College of Pharmacy,
`789 South Limestone Street,
`Lexington, KY 40536-0596, USA
`e-mail: dwermel@uky.edu
`
`2008. Of the 36,500 drug poisoning deaths in 2008, 14,800
`involved prescription opioid analgesics. Approximately
`3,000 deaths also involved heroin overdose. In 2008, the
`overall death rate in the USA was 4.8 per 100,000 for
`nonmedical use of prescription opioids [2, 3].
`The opioid overdose crisis is a worldwide phenomenon
`crossing sovereign, cultural, and socio-economic bound-
`aries. The US Centers for Disease Control considers pre-
`scription drug overdose in epidemic proportions,
`in
`particular, the morbidity and mortality associated with use,
`abuse, and misuse of prescription opioids [4]. Hospitaliza-
`tions from prescription opioid poisoning increased by over
`50 % from 1999 to 2006, paralleling the increased prescrib-
`ing of these medications for the treatment of pain [5, 6].
`Although many deaths are associated with drug abuse, there
`is also a growing trend of therapeutic misadventures for pain
`patients prescribed powerful analgesics, including opioids.
`Chronic cancer and nonmalignant pain pharmacotherapy
`regimens frequently involve combinations of medications
`with additive or synergistic central nervous system depres-
`sion adverse effects.
`Injection drug use, principally heroin, is one of the most
`significant correlates to opiate use mortality. Eurasia, Aus-
`tralia, Canada, Italy, and Great Britain, among others, all
`describe significant injection drug use populations that ex-
`perience drug overdose with similar rates of mortality re-
`gardless of socioeconomic status [7–12].
`Government and nongovernment public health agencies,
`the pharmaceutical industry, and others are adopting preven-
`tion and intervention strategies in an attempt to reduce
`opioid overdose mortality. One “harm-reduction” strategy
`has been to provide education and training on opioid over-
`dose recognition and emergency treatment to addicts and
`their close daily contacts [13]. In addition, the addict and
`their loved ones are trained to rescue breathe, call emergen-
`cy medical services, and to administer the opioid antidote
`naloxone.
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`Naloxone is the drug of choice to reverse respiratory and
`central nervous system depression caused by opioid over-
`dose [14]. Naloxone injection has been marketed in the
`USA for 41 years, initially under the trade name Narcan®.
`Naloxone hydrochloride (HCl), known chemically as 17-
`Allyl-4,5α,-epoxy-3, 14-dihydroxymorphinan-6-one hydro-
`chloride, is a potent mu-receptor antagonist. It has subse-
`quently become a multisource prescription generic drug
`manufactured by International Medication Systems, Limited
`and Hospira, Inc. [15, 16]. Ampoules of naloxone injection
`are also available in many countries. The injection is avail-
`able in two strengths, 0.4 and 1.0 mg/mL. Naloxone is a
`standard drug carried by emergency services personnel in
`ambulances and medication kits for reversal of suspected
`opioid overdose, whether accidental or intentional. Hospital
`emergency departments also use this medication routinely
`for this purpose. The initial adult dose of naloxone in known
`or suspected narcotic overdose is 0.4–2 mg, which may be
`repeated to a total dose of 10 mg. The current formulations
`of naloxone are approved for intravenous (IV), intramuscu-
`lar (IM), and subcutaneous (SC) administration, with IV
`being the recommended route [17, 18]. Naloxone is also
`indicated as a reversal agent when the effects of therapeutic
`use of opioids are no longer medically necessary, such as in
`reversal of opioid effects in general anesthesia [15, 16].
`Lastly, naloxone is coformulated with buprenorphine as an
`oral product providing an abuse-deterrent formulation for
`opioid maintenance in opioid dependent patients.
`In the last several years, the emergency medical systems
`(EMS) community in the USA and elsewhere has developed
`an interest in administering naloxone in a needleless system
`via the intranasal (IN) route. Some EMS programs have now
`moved toward intranasal administration of naloxone since
`many of the patients needing naloxone are injection drug
`users; 80 % of the injection drug user population in large
`metropolitan areas is hepatitis C positive or HIV positive.
`For example, the Denver and San Francisco EMS uses this
`drug administration technique as standard of care to prevent
`needlestick injuries to emergency medical technicians [17,
`19, 20].
`Some EMS programs have developed a system using
`existing technologies of an approved drug and an existing
`medical device to administer this opioid antidote, albeit in a
`non-Food and Drug Administration (FDA)-approved man-
`ner [19, 20]. This has been accomplished by using the
`injectable formulation (1 mg/mL) and administering 1 mL
`per nostril via a marketed nasal atomizer/nebulizer device.
`The system combines an FDA-approved naloxone injection
`product (with a Luer fitted tip, no needles) with a marketed
`[510(k) exempt] medical device called the Mucosal Atom-
`ization Device (MAD™ Nasal, Wolfe Tory Medical, Inc.).
`This initiative is consistent with the US Needlestick Safety
`and Prevention Act (Public Law 106–430) [21–25].
`
`The EMS programs recognize limitations of this system,
`one limitation being that it is not assembled and ready to
`use. Although this administration mode appears to be effec-
`tive in reversing narcosis, the formulation is not concentrat-
`ed for retention in the nasal cavity. The 1 mL delivery
`volume per naris is larger than that generally utilized for
`intranasal drug administration. Therefore, there is loss of
`drug from the nasal cavity, due either to drainage into the
`nasopharynx or externally from the nasal cavity. An im-
`provement would be to design a ready-to-use product spe-
`cifically optimized, concentrated, and formulated for nasal
`delivery.
`The drug abuse treatment and overdose prevention com-
`munities worldwide have also recognized the desire for a
`needle-free system for naloxone delivery [26]. Clients at
`needle-exchange centers provide kits containing naloxone,
`with either needles or nasal spray atomizers, and instruc-
`tions for use. Such programs are well-described in the USA
`and Great Britain, commonly operating in conjunction with
`needle-exchange programs [27–33]. In May 2012, the Brit-
`ish Advisory Council on the Misuse of Drugs published a
`report advocating for greater distribution of naloxone and
`training for administration [34]. The Council reiterates that
`naloxone is safe and effective, that there is evidence that
`take-home naloxone can be effective for reversing heroin
`overdoses. Cost-effectiveness of these programs is still be-
`ing assessed.
`An unmet medical need exists to provide greater access
`to the opioid antidote naloxone. A significant barrier to this
`goal is that naloxone is only available as an injection for IV,
`IM, or SC administration. A needleless system that integra-
`tes a concentrated formulation and a nasal delivery device
`would help satisfy this unmet need.
`
`Nasal physiology, drug, and formulation considerations
`for nasal delivery
`
`Nasal physiology
`
`Intranasal sprays of medication intended for systemic
`drug absorption are generally designed to target
`the
`turbinates on the medial wall of the nasal cavity. The
`turbinates serve as a baffle in which inspired air is
`humidified and filtered. This region of the nasal cavity
`is covered with a thin mucus layer, a monolayer ciliated
`epithelium, with an abundant underlying blood supply.
`These conditions are ideal
`to permit passive diffusion
`(transcellular) of medications with certain chemical
`characteristics across cell membranes and into the
`bloodstream. Some medications also transit to the blood
`stream by passing through the tight-cell
`junctions be-
`tween cells (paracellular) [35].
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`To reach the turbinates, the nasal spray device must be
`inserted fully into the nasal vestibule with the atomizer tip
`placed at the nasal valve, and then aimed laterally toward
`the turbinates. Activation of the device ejects the liquid as
`an atomized spray or plume. The bulk of the spray impacts
`the anterior and inferior portions of the nasal cavity as a
`function of straight-line impact of particles greater than
`10 μm in size [36–38]. The smallest particles, less than
`10 μm in size, may be carried by air currents more superi-
`orly in the nasal cavity and impact on the superior turbinate
`and possibly reach the olfactory region and nerve. There is
`substantial evidence in animals, and some evidence in man,
`that the olfactory nerve can absorb or actively transport
`medications to the central nervous system via the olfactory
`bulb (nose to brain theory). Differences in animal and hu-
`man nasal apparatus anatomy, and certain characteristics of
`the medication, seem to play roles as to whether medication
`is transported to the brain via this mechanism and if a
`pharmacologic effect is observed [39–41].
`Under ideal conditions, most medication is absorbed
`from the nasal cavity and into the bloodstream within 15–
`20 min, thus generally avoiding the gut first-pass metabo-
`lism [35, 36]. Medication remaining in the nasal cavity
`beyond this time is subject to elimination via various en-
`zyme systems present within the nasal mucus and by swal-
`lowing. A second absorption phase (oral) can be observed
`with nasally administered medications having incomplete
`nasal absorption that are not subject to high first pass gut
`metabolism.
`Nasal physiologic changes during pathologic conditions,
`such as polyposis and allergic and vasomotor rhinitis, could
`theoretically alter the biopharmaceutics of intranasal medi-
`cations intended for systemic drug administration [35, 36,
`42, 43]. Physical obstruction of the nasal passage(s) due to
`prior trauma and subsequent deflection of the passageways
`is another possibility. Concurrent use of medications with
`vasoconstriction or vasodilation properties may also affect
`drug absorption. Lastly, increases in mucus production and
`changes in mucociliary clearance rates could affect bioavail-
`ability [35–38].
`regulatory agencies have required
`Pharmaceutical
`studies of the effect of rhinitis on nasal drug delivery
`biopharmaceutics [43, 44]. It has been demonstrated that
`there is a lack of effect of nasal mucosal inflammation
`on the absorption of hydromorphone, butorphanol,
`buserelin, and triamcinolone acetonide—an exception
`was reported for desmopressin. Inconsistent results have
`been reported on the biopharmaceutical disposition of
`these medications when pretreatment with oral or topical
`decongestant was administered [37, 43, 44]. Small but
`statistically measureable changes in rate or extent of
`absorption have been reported when decongestants were
`co-administered.
`
`Drug and formulation considerations
`
`Many intranasal delivery products are designed to serve
`certain purposes or unmet medical needs. Clearly, a nasal
`spray can remove the needle from drug administration, as is
`the case with the conversion of the protein calcitonin from a
`daily injection to a nasal spray. Furthermore, beyond just
`removing the needle from delivery, intranasal products are
`designed for rapid action, such as those products designed to
`treat seizures (benzodiazepines) migraine headache (suma-
`triptan, butorphannol, zolmitriptan, dihydroergotamine) or
`pain in general (fentanyl, hydromorphone) [45–49].
`Successful intranasal products satisfied several design
`fundamentals necessary for intranasal delivery. The proper-
`ties of the drug generally follow these characteristics:
`& Mass of 20 mg or less per dose
`& Molecular weight <1,000 Da
`& Excellent water solubility
`&
`Ionization and pH control of aqueous solutions
`& Osmolality—isotonic to slightly hypertonic
`&
`Stability in processing and storage
`& Compatibility container closure and sprayer components
`& Compatible with excipients (buffers, antioxidants, cosol-
`vents, etc.)
`Physical–chemical properties of the candidates must also
`be considered. Water solubility is important for formulation
`considerations. Log P, derived from the octanol/water parti-
`tion coefficient, is a surrogate for lipophilicity and potential
`for compounds to diffuse across biologic membranes. Suc-
`cessful intranasal medications tend to be water soluble and
`have sufficient lipophilic character to readily cross biologic
`membranes [35, 36].
`The dose must have sufficient solubility to be adminis-
`tered in approximately 100–200 μL (one spray per naris) of
`solution. The nasal cavity can retain 100–150 μL without
`causing immediate runoff out the front of the nose or down
`the nasopharynx [35, 36]. Additional solubilization strate-
`gies may be necessary including the use of organic cosol-
`vents, excipients such as cyclodextrins or other agents to
`from water-soluble inclusion complexes, or preparation of
`emulsions. Permeation enhancers may also be necessary to
`enhance drug penetration through cell membranes [50].
`Design of the formulation must account for other factors
`as well. It is useful to design the formulation to be isotonic
`to slightly hypertonic to optimize absorption and tolerabili-
`ty. Viscosity enhancing agents such as methylcellulose and
`others can promote retention in the nasal cavity by slowing
`the ciliary movement of mucus [35, 36]. Surfactants or
`polymers can be employed to enhance transmembrane per-
`meation [50]. Lastly, the drug and formulation have to be
`stable in the device during processing, i.e., sterilization and
`storage, and thus may require stabilizers.
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`The choice of delivery device for the medication is an-
`other critical consideration. Squeeze bottles are available but
`have no metering device appropriate to administer potent
`systemic medications. Multidose bottles provide a metered
`dose and are available for chronic drug administration. A
`standard syringe with Luer fitting to accept a nasal atomizer
`has been used to draw up and administer injection-based
`drug solutions into the nasal cavity for opiate overdoses,
`acute pain, and to deliver midazolam injection to the nasal
`cavity of a seizing patient. Unit–dose devices similar to
`those used for migraine treatment are also available and
`being used in development of benzodiazepine nasal spray
`products. The choice of device depends upon factors such as
`intended clinical use, setting, stability with the drug and
`formulation, among others [35, 36].
`Ideally, a well-designed formulation must not induce
`localized toxicity with acute or chronic use. For example,
`chronic vasoconstriction, irritation, or inflammation can in-
`duce tissue damage including ulceration, epistaxis, nasal–
`septal defects, and fistulae. Formulations should not cause
`damage to the cilia. Chronic, or daily use, of an irritating
`product could lead to more serious sequallae from nasal
`delivery [36].
`
`Properties of naloxone hydrochloride dihydrate
`
`Naloxone is supplied as naloxone HCl dihydrate. The em-
`pirical formula of naloxone HCl dihydrate is C19H22ClNO4,
`2H2O and its molecular weight is 399.9 g/mol. The struc-
`tural formula for naloxone is described in Fig. 1a [15, 16].
`Naloxone HCl has a physical form of white, or almost
`white, crystalline powder, and is hygroscopic. Its melting
`point is 200–205 °C. Naloxone HCl is freely soluble in
`water and 96 % alcohol, but practically insoluble in toluene.
`It is also slightly soluble in alcohol and practically insoluble
`in ether or chloroform. The dissociation constant pKa of
`naloxone is 7.9 and the log P is 1.92. These physical–
`chemical characteristics suggest a naloxone aqueous solu-
`tion is likely feasible [36].
`Given its high water solubility, naloxone HCl is an ex-
`cellent candidate to consider for intranasal delivery and
`satisfies many criteria necessary for this route. Naloxone is
`a high first-pass metabolism medication; oral bioavailability
`is reported to be ≤5 %. The parenteral dose is 2 mg or less; it
`is highly potent when injected [14–16].
`Nasal sprays of compounds chemically related to nalox-
`one have been described. Medications studied include the
`opioid antagonist naltrexone, and the opioid agonists hydro-
`morphone and butorphanol (Fig. 1b–d). Examination of the
`formulation methods and human biopharmaceutics of other
`chemically related compounds will be instructive for con-
`siderations of a naloxone nasal spray [36, 45, 48, 49].
`
`Translation of intranasal opioid formulations
`to naloxone nasal spray
`
`Naturally occurring and semi-synthetic opioids and antago-
`nists share the core structure of thebaine [51]. The addition
`of functional groups to the core structure imparts different
`physical–chemical and pharmacologic properties. However,
`the molecular weights and pKa values are roughly similar
`and the acid salts tend to be freely soluble in water. Certain
`cogeners have relatively higher log P as compared to others
`and so transmembrane delivery may be more accommoda-
`tive for these molecules [36]. Functional group changes also
`impart pharmacological properties of being a full mu-
`receptor agonist, partial agonist, or antagonist. Similarly,
`these changes may affect the degree of first-pass metabolism
`upon oral administration. Many of these cogeners are also
`quite potent—doses may range from 0.5 to 10 mg.
`A recent manuscript has provided a comprehensive re-
`view on intranasal delivery of opioids [36]. Tables on phys-
`ical–chemical properties and biopharmaceutics of various
`agents are provided. Data for naltrexone, hydromorphone,
`and butorphanol are provided (Table 1). These molecules
`may be of particular interest since the intravenous and
`intranasal dosing appears to be similar and the molecules
`share chemical characteristics to naloxone. Table 2 provides
`a comparison of the biopharmaceutics of nasally adminis-
`tered naltrexone, hydromorphone and butorphanol. Interest-
`ingly, the clinical doses of these drugs (dose normalized for
`naltrexone) are comparable to that of naloxone injection.
`Concentration–time profiles for naltrexone, hydromor-
`phone, and butorphanol are provided in Fig. 2 (dose nor-
`malized). These data may suggest the likely outcome of an
`intranasally delivered concentrated solution of naloxone
`HCl. A 2 mg nasal solution dose will likely have a Cmax
`of 3–5 ng/mL and a tmax of approximately 20 min, similar to
`naltrexone and hydromorphone [48]. The greater absorption
`of butorphanol is likely related to its higher Log P and
`ability to diffuse across biologic membranes.
`
`Biopharmaceutics of intranasal naloxone
`
`The nasal administration of 3H-naloxone to anesthetized
`male rats (n03/group) at a single dose of 30 μg (0.1 mg/
`kg, based on their average weight of 270 g/rat) in 0.1 mL
`was compared to a similar dose in 0.1 mL given by the
`intravenous and intraduodenal routes [52]. Nasally admin-
`istered naloxone was rapidly and completely absorbed
`(Fig. 3). The plasma elimination half-life of radioactivity
`was found to be 40–45 min. The nasal bioavailability for
`naloxone calculated from the ratio of the AUC0- INF (na-
`sal/intravenous 01,517.5/1,498.7 ng·h/mL) was 101 %.
`The intraduodenal bioavailability for naloxone was only
`1.5 % (intraduodenal/intravenous022.0/1,498.7 ng·h/mL).
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`Fig. 1 Chemical structure of
`naloxone (a), naltrexone (b),
`hydromorphone (c) and
`butorphanol (d) (Pub Chem,
`pubchem.ncbi.nlm.nih.gov)
`
`These results established the nasal route for the adminis-
`tration of naloxone in rats was equivalent to the parenteral
`route.
`The pharmacokinetic properties of intranasal naloxone
`in humans are not well described. A literature review
`found there are no papers describing the human phar-
`macokinetics of intranasal naloxone using what might
`be considered a highly concentrated nasal solution for-
`mulation. One paper describes pharmacokinetics of nasal
`administration of commercial injectable naloxone in man
`[53]. The intranasal formulation employed was an injec-
`tion in which 0.8 mg was administered in a volume of
`2 mL (1 mL/naris) even though it is commonly under-
`stood the nasal cavity can retain only 100–200 μL per
`naris. The study compared intravenous and intramuscu-
`lar administration to intranasal administration. The
`reported intranasal bioavailability of 4 % is dependent
`upon this non-optimized delivery volume, as it can be
`
`assumed that much of the medication ran away from the
`site of absorption. Therefore,
`the report may be mis-
`leading regarding predicting nasal naloxone absorption
`in humans using a solution concentrated and designed
`to accommodate the absorptive surface of the naris.
`A recent publication provides a more relevant exam-
`ination of the possible pharmacokinetic profile of a
`formulated naloxone nasal spray. The study provides
`information regarding the nasal absorption of naloxone
`in humans from a powder obtained from crushed Sub-
`oxone® (buprenorphine and naloxone sublingual tablets)
`[54]. After administration of 2 mg (naloxone) nasal
`powder, the absolute bioavailability was 30 %, with a
`tmax of 20 min and a Cmax of 1.6 ng/mL. A powder will
`behave somewhat differently than a solution adminis-
`tered intranasally because dissolution must occur during
`the time that
`the naloxone powder is present
`in the
`nasal cavity and before the ciliated epithelia sweep the
`
`Table 1 Chemical properties of naloxone, naltrexone, hydromor-
`phone, and butorhpanol [36]
`
`Table 2 Biopharmaceutics of intranasal naltrexone, hydromorphone
`and butorphanol [48, 49]
`
`Drug name
`
`Molecular weight
`
`pKa
`
`Log P
`
`Drug and dose
`
`Cmax
`(ng/mL)
`
`Tmax
`(minutes)
`
`Bioavailability (%)
`
`Naloxone
`Naltrexone
`Hydromorphone
`Butorphanol tartrate
`
`327
`341
`285
`327
`
`7.9
`8.1
`8.5
`8.6
`
`2
`1.9
`1.8
`3.77
`
`14.9
`Naltrexone HCl, 10 mg
`Hydromorphone HCl, 2 mg 3.5
`Butorphanol tartrate, 2 mg
`5.5
`
`22
`20
`10
`
`600 (to oral)
`50–60
`60–70
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`Fig. 2 Concentration–time profiles for naltrexone (10 mg intranasal and 50 mg oral; a), hydromorphone (2 mg IV and 1 and 2 mg intranasal; b), and
`butorphanol (1 and 2 mg intranasal; c) [48, 49]
`
`product posterior to be swallowed. A solution of nalox-
`one may have a slightly higher bioavailability and Cmax.
`Figure 4 presents a concentration–time profile for 0.5
`and 2.0 mg of intranasal naloxone powder from a Sub-
`oxone® tablet.
`The nasal delivery of naloxone powder, and subse-
`quent exposure, can be used as a surrogate marker as to
`the potential for naloxone nasal spray to reverse narco-
`sis. The essential question remains as to whether nalox-
`one nasal spray will produce an exposure that
`is
`clinically relevant. The Dowling paper suggests that
`naloxone nasal spray will produce a systemic exposure
`that is clinically relevant if compared to the profiles of
`intravenous and intramuscular administration. Figure 5
`presents the concentration–time profile for 0.8 mg nal-
`oxone, a clinically relevant dose within the naloxone
`prescribing label, for intravenous and intramuscular ad-
`ministration. The intramuscular administration is partic-
`ularly relevant given the absorption phase. A Cmax of
`about 1.5 ng/mL and a tmax 12 min were derived from
`this route of administration [53]. These data are not
`greatly different from the profile demonstrated from
`intranasal naloxone powder administration.
`
`Clinical experience with intranasal naloxone in reversing
`narcosis
`
`Emergency medicine practitioners and drug abuse treatment
`and prevention clinicians have considerable experience with
`administering naloxone injection for treatment of suspected
`opioid overdose. It appears the practice of nasal naloxone
`administration has outpaced the biopharmaceutic and clini-
`cal pharmacologic aspects typical of understanding the
`properties of a medication and delivery system. Regardless,
`the system appears to work and is further described.
`Nasal administration of naloxone was first reported by
`Loimer in 1992 [55]. Naloxone was studied using a 1 mg
`intranasal dose to identify potentially physically dependent
`opioid users. Withdrawal distress, pupillary response, pulse
`rate and blood pressure were recorded. Withdrawal symp-
`toms highly correlated with subject history and the presence
`of opioid metabolites in urine. The authors conclude that
`nasal delivery of naloxone is as effective as intravenous
`injection to identify physically dependent opioid users and
`could be useful in emergency medicine treatment.
`A second study by Loimer was conducted in 17 opioid-
`dependent patients to compare the efficacy of 1 mg of
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`Fig. 3 Mean plasma naloxone levels in rats after a single nasal (open
`circle), intravenous (filled circle), or intraduodenal (empty square) dose
`of 30 μg of 3H-naloxone [52]
`
`intranasal naloxone to intramuscular and intravenous nalox-
`one administration [56]. Withdrawal symptoms and vital
`sign changes were again used as endpoints at 1, 5, 15, 45,
`90, and 180 min after administration. The data demonstrated
`that intranasal administration had a more rapid onset and
`intensity of withdrawal as compared to intramuscular ad-
`ministration, but was not as rapid or as intense as intrave-
`nous administration. All endpoints returned to baseline by
`180 min in all groups.
`Naloxone is approved for use in the USA by IV, IM, or
`SC routes [14–16]. It is suggested that the onset of action of
`
`Fig. 4 Mean±SEM for plasma concentrations of naloxone in volun-
`teers, analyzed for up to 8 h after 0.5 or 2 mg dose of naloxone from
`Suboxone® tablets [54]
`
`Fig. 5 Concentration–time profile for 0.8 mg naloxone give IV and IM
`[53]
`
`the IV will be faster, so is preferred in emergency situations.
`However, obtaining IV access in the prehospital setting,
`especially among injection drug abusers can be time con-
`suming and difficult. Wanger conducted a study to deter-
`mine the actual onset of effect (defined as a respiratory rate
`of ≥10 breaths/minute) calculated from the time of arrival at
`the patient’s side using two approved injection routes [57].
`That is, this approach takes into account the time to set up
`and deliver the drug by the intended route.
`The study utilized naloxone injection, as used in nonhos-
`pital settings for presumed heroin overdoses. Patients were
`enrolled in series, rather than randomized. The first series
`treated patients with naloxone 0.4 mg IV followed by an
`additional 0.4 mg IV in the case of unsatisfactory response
`by 5 min (satisfactory response was ≥10 breaths/min). The
`second phase of the protocol treated patients with 0.8 mg
`naloxone SC. If a satisfactory response was not observed by
`5 min, the IV protocol was followed.
`While the time to effect after IV administration was faster,
`it was offset by the time needed to obtain IV access and
`administer the drug, as compared to SC administration, such
`that there was no difference in time to response. The SC
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`response data may be quite relevant to assessing possible
`doses and response profile of naloxone nasal spray. A sec-
`ond dose was needed in 35 % of the patients treated with IV
`naloxone and a second dose (given IV) was needed in 15 %
`of the patients treated with SC naloxone. Subjectively, the
`ambulance attendants administering the naloxone indicated
`that emergence was more gradual, resulting in less violence
`and aggression at the scene after SC administration as com-
`pared to IV administration. A similar effect may be seen
`after intranasal route of administration (see Table 3).
`Barton was the first to demonstrate intranasal delivery of
`naloxone by paramedics. Thirty patients in Denver, CO,
`USA encountered by paramedics received 2 mg of naloxone
`(injection formulation, 1 mg/mL) administered intranasally
`with the disposable nasal spray atomizer called the Mucosal
`Atomization Device [58]. One milliliter was administered
`into each naris upon initial patient contact. Paramedics then
`assessed/provided airway management and IV line place-
`ment unless the patient initially responded to the naloxone
`and no additional treatment was needed. Nasal abnormali-
`ties were also noted. Eighty-three percent of the patients
`with an opioid overdose responded to intranasal naloxone,
`with an average response time of 3.4 min. One patient
`responded to IV naloxone and not to IN naloxone alone.
`Sixty-four percent of the naloxone responders did not re-
`quire an IV placement. This was the first paper demonstrat-
`ing use of this delivery route in clinical practice.
`Barton published a final report of the aforementioned
`study. In this analysis of 95 patients, response rates to
`treatment remained similar [59]. That is, 83 % of naloxone
`responders responded to intranasal naloxone. Seven (16 %)
`of the intranasal responders required additional doses of IV
`naloxone. None of the “naloxone responders” were reported
`to have severe withdrawal reactions from either IV or IN
`naloxone. Nasal abnormalities (epistaxis, mucus, trauma, or
`septal abnormalities) were noted in five patients (of nine)
`who did not respond to IN naloxone. None of the IN
`naloxone responders had any nasal abnormality noted by
`paramedics.
`The mean time from drug administration to clinical re-
`sponse was slightly longer with intranasal (4.2 min) as
`compared to intravenous administration (3.7 min); the
`medians were not different (3.0 min for each route). How-
`ever, because of the time needed to obtain IV access in these
`
`patients, the time from first patient contact to time of clinical
`response is not different between the routes. The median
`time from arrival to the patient’s side to clinical response
`was 8 min for IN and 10 min for IV (means reported as 9.9
`and 12.8 min, respectively). Thus, the nasal route can be a
`quick first response while additional intervention and mon-
`itoring are conducted by rescue personnel.
`A randomized trial comparing 2 mg intranasal to 2 mg
`intramuscular naloxone was reported by Kelly in 2005 [22].
`One hundred fifty-five patients (71 IM and 84 IN) requiring
`prehospital treatment for suspected overdose received 2 mg/
`5 mL naloxone by one of the routes of administration. Sixty-
`three percent of the IN patients had 10 or more spontaneous
`respirations within 8 min of treatment as compared to 82 %
`of the intramuscular naloxone treated patients. Additional
`rescue naloxone was needed in 13 % of IM patients and
`26 % of IN patients (p0NS). The time to achieve a Glasgow
`Coma Scale (GCS) greater than 11 was not significantly
`different between groups. There were no major adverse
`events in either group, although the intramuscular group
`more commonly experienced withdrawal symptoms, espe-
`cially agitation and/or irritation. The authors conclude that
`IN naloxone wa