C L I N I C A L
`
`Intranasal Drug Delivery:
`
`An Alternative to Intravenous Administration
`
`in Selected Emergency Cases
`
`Authors: Timothy R. Wolfe, MD , and Tony Bernstone, RN, Salt
`Lake City, Utah
`
`Timothy R. Wolfe is Associate Professor, Division of Emergency
`Medicine, University of Utah School of Medicine, and Vice President
`and Medical Director, Wolfe Tory Medical, Inc, Salt Lake City, Utah.
`He is the inventor of the MAD 100 and MADomizer that are discussed
`in this article. Tony Bernstone is Clinical Nurse Coordinator,
`Surgical Intensive Care Unit, and Emergency Nurse, University of
`Utah School of Medicine, Salt Lake City, Utah.
`For reprints, write: Timothy R. Wolfe, MD, 1119 East Alpine Place,
`Salt Lake City, UT 84105; E-mail: wolfeman@csolutions.net.
`J Emerg Nurs 2004;30:141-7.
`0099-1767/$30.00
`Copyright n 2004 by the Emergency Nurses Association.
`doi: 10.1016/j.jen.2004.01.006
`
`N asal transmucosal medication delivery is an
`
`active area of research, both in new drug
`development by the pharmaceutical
`industry
`and by clinicians using already available intravenous
`medications. The nasal mucosa is an attractive area in
`which to deliver medications because the procedure is
`painless and needleless, which eliminates the risk of
`needle-stick injuries and reduces patient discomfort. The
`delivery system does not require sterile technique or
`intravenous catheters, and the route is immediately availa-
`ble in all patients. In addition, the nasal mucosa offers a
`large absorptive surface that has considerable blood flow,
`allowing rapid drug absorption into the bloodstream and
`cerebral spinal fluid.1,2 In addition, because intranasal
`drug delivery results in direct medication absorption,
`gastrointestinal destruction and hepatic first-pass metabo-
`lism (ie, destruction of drugs by the liver enzymes) are
`avoided, allowing more drug to be available more rapidly
`than if it were administered orally.1 The result is that
`many medications delivered intranasally achieve absorp-
`tion rates and plasma concentrations comparable with that
`obtained by intravenous administration.1
`
`Factors affecting nasal drug absorption
`
`The percentage of medication that ends up in the blood-
`stream after administration is termed ‘‘bioavailability.’’
`Intravenous medication is 100% bioavailable after admin-
`istration. Oral medications are about 5% to 10% bioavaila-
`ble because of gastrointestinal and hepatic destruction.
`Intranasal medication bioavailability varies from negligible
`to almost 100%.
`
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`TABLE 1
`Nasal medication delivery device options
`
`Device type
`
`Cotton swabs
`Syringe droppers
`
`Single use
`syringe-driven
`devices
`MAD Nasal
`(Figure 1)
`
`Positive
`displacement
`pump atomizers
`MADomizer*
`(Figure 2)
`Go Medicaly Nasal
`Inhaler (Figure 3)
`
`Advantages
`
`Disadvantages
`
`Per patient cost
`
`Inexpensive
`Measured dose (syringe)
`
`Improved bioavailability:
`atomized drug delivery
`Measured dose
`
`Improved bioavailability:
`atomized drug delivery
`Measured dose
`Inexpensive
`(MADomizer)
`
`Unmeasured dose (swab)
`No atomization
`Uncomfortable (swab)
`Bioavailability problem:
`limited area of mucosal
`contact
`
`More expensive than
`dripping in with a
`syringe or using a
`cotton swab
`
`More expensive than
`dripping in with a
`syringe or using a
`cotton swab
`
`Pennies
`
`$2.45*
`
`MADomizer tip: $0.84
`Go Medical Nasal Inhaler
`costs approximately
`$10 US; entire pump
`is disposable y
`
`Venturi Atomizer
`De Vilbissz
`
`Improved bioavailability:
`atomized drug delivery
`
`Expensive, unmeasured
`dose; potentially
`substantial medication
`wasting; resterilization
`prior to reuse§
`
`Cleaning, sterilization,
`replacement parts and
`reassembly costs§; capital
`expenditure§
`
`* Manufacturer: Wolfe Tory Medical, Inc, Salt Lake City, Utah.
`y Manufacturer: Go Medical, Subiaco, Western Australia.
`z Manufacturer: De Vilbiss Atomizers, Sunrise Medical, Carlsbad, Calif.
`§ Venturi devices pose infectious risk unless cleaned between each patient. Therefore, per patient costs include labor involved in disassembly, cleaning/sterilization, and
`reassembly. Capital expenditure may include autoclave, air compressor, and atomizer cart purchase and upkeep, compressed air hosing routed to every location, and
`device purchase.
`
`If a drug molecule can cross the nasal mucosa, the
`primary factors influencing bioavailability are medication
`concentration and volume, delivery method, and nasal
`mucosal health.1 The most concentrated form of the medi-
`cation available should be used, because large volumes
`(more than .5 to 1 mL per nostril) will run out of the
`nose, reducing total absorption. If volumes greater than 1
`mL are required, they should be applied as divided doses,
`allowing a few minutes for the first dose to absorb. On
`the other hand, if small volume doses are used, be aware
`that delivery devices have a ‘‘dead space’’ in the applicator
`tip where some medication will remain. This should be
`kept in mind when calculating the volume of medication
`to be administered.
`
`To optimize drug absorption, the delivery system
`must allow maximal surface area coverage with a thin layer
`of drug.1 The easiest method is to deliver half the dose into
`each nostril, doubling the absorptive surface area. Atom-
`ized drug delivery systems result in superior surface area
`coverage compared with drops or spray methods and will
`improve medication bioavailability3 (Table 1; Figures 1-3).
`Nasal mucosal destruction and copious mucous or blood
`secretions inhibit medication absorption. With a quick
`look into the nostril, the nurse can notice mucosal
`abnormalities and predict in advance whether nasal drug
`absorption will be less effective.
`
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`FIGURE 1
`The MAD 100 single-use, syringe-driven atomizer allows the
`administration of a measured dose of intranasal medication.
`(Photo courtesy of Wolfe Tory Medical, Inc.)
`
`Intranasal medication delivery in the
`emergency department
`
`A number of commonly used ED medications are
`effective when delivered intranasally. These medications
`include the synthetic opiates fentanyl and sufentanil for
`the treatment of acute pain; midazolam, for procedural
`sedation and for the treatment of seizures; naloxone, for
`opiate overdose; and topical anesthetics/vasoconstrictors
`for use prior to nasal
`intubation or nasogastric tube
`(NGT) placement or
`for
`the treatment of epistaxis
`(Table 2).
`
`Pain control: intranasal opiates
`
`Many patients who visit the emergency department fail
`to obtain adequate pain relief.4 One reason is the lack
`of a rapid, effective, painless method for pain control.
`Nasal opiates offer an effective,
`inexpensive solution.
`The synthetic opiates fentanyl and sufentanil are unique-
`ly suited for transmucosal delivery because of their high
`lipid solubility and their high potency (100 to 1000
`than morphine).2,5-7 Sufentanil
`times more potent
`is
`
`FIGURE 2
`A positive displacement pump atomizer, the MADomizer, is
`an inexpensive system for administering medications across the
`nasal mucosa. (Photo courtesy of Wolfe Tory Medical, Inc.)
`
`probably the best opiate medication currently available
`for intranasal drug delivery because of its high concen-
`tration, rapid mucosal absorption, and large therapeutic
`index.2 Dipping a cotton swab tip into sufentanil and
`applying it
`to the nasal mucosa produces an effect
`within seconds.2 In addition, it produces longer lasting
`analgesia with less persistent respiratory depression than
`does fentanyl.2 Situations in which intranasal opiates
`may be particularly useful are for minor fractures and
`contusions, wound dressing changes, and in children
`with acutely painful conditions.6,7 Most of these patients
`never get an intravenous line, and intramuscular injec-
`tions or oral medications are too painful or too slow to
`allow timely interventions. Spraying atomized fentanyl
`or sufentanil intranasally will result in rapid pain control
`and allow the nurse to proceed with care.
`
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`this reason, a combination of medications and the ability
`to titrate their effect
`is attractive. Third, respiratory
`depression is still a risk, especially when potent opiates
`are used. Therefore, staff must monitor the patient
`closely. Finally, adverse effects, such as nasal burning,
`are common with nasal midazolam.8 Nevertheless, in the
`pediatric setting, where mild sedation is often enough to
`relieve the anxiety of the parents as well as the child,
`intranasal medications are effective sedatives.
`
`Many medications delivered
`intranasally achieve absorption rates
`and plasma concentrations comparable
`with that obtained by
`intravenous administration.
`
`Seizure control: intranasal benzodiazepines
`
`In situations where an intravenous line is not available,
`intranasally administered benzodiazepines offer a rapid,
`effective method to treat an acutely seizing patient. Fisgin
`et al9 found that intranasally administered midazolam was
`effective in 87% of patients with prolonged seizures,
`whereas rectally administered diazepam was only effective
`60% of the time (P < 0.05). The authors concluded that
`intranasal midazolam is more effective, socially acceptable,
`and convenient than rectally administered diazepam. A
`similar study compared intranasal midazolam to intrave-
`nous diazepam.10 These authors found that nasally ad-
`ministered midazolam stopped 88% of seizures, whereas
`92% were controlled with intravenously administered
`diazepam (P = NS). Although similarly effective, intrana-
`sally administered midazolam worked more rapidly: The
`mean time to seizure cessation was 6.1 minutes with
`midazolam and 8.0 minutes with diazepam. The single
`study that has investigated intranasal lorazepam absorption
`suggests that it should be effective for seizure control.11
`However,
`its use remains investigative. Based on these
`studies, many EMS agencies have adopted intranasal
`midazolam as the first-line therapy for treating seizures
`in the field.12
`
`FIGURE 3
`The Go Medical Nasal Inhaler is a disposable pump atomizer
`for delivering intranasal medications. It costs approximately
`US $10. (Photo courtesy of Go Medical.)
`
`[Intranasal medication administration]
`is painless and needleless, which
`eliminates the risk of
`needle-stick injuries and reduces
`patient discomfort.
`
`Procedural sedation: intranasal opiates, benzodiazepines,
`and ketamine
`
`Procedural sedation also can be achieved using intranasal
`medications.5,7,8 Midazolam is the most commonly stud-
`ied medication for this indication, although data on
`fentanyl, ketamine, sufentanil, and combinations of these
`drugs are available.5 The data allow a few generalizations.
`First,
`intranasal medications are effective for mild to
`moderate sedation but not for deep sedation. Second,
`benzodiazepines and opiates produce varying levels of
`patient sedation, regardless of the route of delivery. For
`
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`TABLE 2
`Intranasal medications and doses for treatment of emergency conditions
`
`Clinical scenario
`
`Pain control
`
`Intranasal medication and dose
`Sufentanil 0.2 to 1.0 Ag/kg
`Fentanyl 1.5 to 3.0 Ag/kg
`
`Sedation
`
`Seizures
`
`Midazolam 0.5 mg/kg
`Sufentanil 0.2 to 1.0 Ag/kg
`Fentanyl 1.5 to 3.0 Ag/kg
`Ketamine 6-8 mg/kg
`Midazolam 0.2 to 0.3 mg/kg
`(Use 10 mg in teenagers and adults)
`
`Opiate overdose
`
`Naloxone 2 mg (2 mL)
`
`Epistaxis
`
`Oxymetazoline 0.5-1.0 mL
`to affected nostril (2 squeezes
`of bottle or measure it and
`deliver with atomizer)
`Add 1.5 mL lidocaine 4% if
`cautery will be performed
`
`Lidocaine 4% (plus
`oxymetazoline 0.5 mL)
`
`Nasal procedures
`(nasogastric tube,
`fiberoptics,
`nasopharyngeal
`airway, nasal
`intubation)
`
`Important reminders
`
`Always monitor for respiratory depression
`Only use a device that can deliver an exact
`dose of medication
`Titration is possible
`Always monitor for respiratory depression
`Combination therapy probably more
`effective than single drug therapy
`Titration is possible
`ALWAYS use the concentrated form of
`midazolam: 5 mg/mL
`Deliver immediately to allow absorption to
`occur while you support the airway
`ALWAYS use the concentrated form of
`naloxone: 1 mg/mL
`Deliver immediately to allow absorption to
`occur while you support the airway
`Have patient blow nose to remove all clots
`from nostril prior to delivery of the
`medication
`Spray 0.5-1.0 mL of medication up affected
`nostril(s)
`Soak a cotton swab with additional
`oxymetazoline and insert into nose
`Pinch nose for 5-10 minutes then re-examine
`and cauterize, if necessary
`Have patient purchase oxymetazoline over
`the counter and use at home
`Spray both the nose (1.5 mL lidocaine) and
`the throat (3 mL lidocaine)
`Wait 3 minutes for full anesthetic effect
`before doing the procedure; repeat half the
`dose, if necessary
`
`Nasopharyngeal procedures: nasal and oral 4% lidocaine
`
`Nasogastric tube placement is a very painful procedure.
`Nevertheless, it is routinely performed with little or no
`analgesia.13 A number of prospective studies demonstrate
`that topical 4% lidocaine applied to both the nose and the
`throat results in dramatic reduction in pain compared
`with lidocaine jelly alone.13,14 The addition of a topical
`vasoconstrictor also appears beneficial because of nasal
`mucosal shrinkage and the prevention of epistaxis. These
`data strongly suggest that topical nasal and oral anesthetics/
`
`vasoconstrictors should be considered for all conscious
`patients before NGT placement. Be aware that vasocon-
`strictors can be absorbed and cause hypertension prob-
`lems, especially in patients taking h-blockers who receive
`phenylephrine (Neosynephrine).15 Although oxymetazo-
`line (Afrin) has milder cardiovascular effects than does
`phenylephrine, care should be taken when administering
`vasoconstrictors to patients with significant cardiovascular
`disease or hypertension.
`
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`Epistaxis: nasal oxymetazoline and 4% lidocaine
`
`Epistaxis is a common and messy problem, and its
`treatment can require substantial time and resources.
`Interestingly, otolaryngologists note that most epistaxis is
`easily controlled with intranasal oxymetazoline.16,17 This
`method eliminates suction, cautery, and nasal packing, and
`the patient can continue topical oxymetazoline treatment
`at home. Triage nurses can start the treatment (in patients
`without significant cardiovascular disease), often resulting
`in bleeding cessation before the physician sees the patient.
`Pretreatment with intranasal 4% lidocaine and oxymetazo-
`line also is useful in preventing pain and epistaxis before
`nasal procedures such as intubation, nasopharyngeal air-
`way placement, and NGT placement.18
`
`The most concentrated form of the
`medication available should be used,
`because large volumes (more than .5 to
`1 mL per nostril) will run out of the
`nose, reducing total absorption.
`
`Opiate overdose treatment: intranasal naloxone
`
`Intravenous drug abusers requiring injectable naloxone
`place the emergency nurse at an especially high risk for
`bloodborne pathogen exposure.19 Because these patients
`rarely need an intravenous line for any reason beyond
`the administration of naloxone, it would be helpful to
`have a needleless method for administering the medica-
`tion.20 Fortunately, naloxone is a small molecule that
`easily crosses the nasal mucosal membranes. Intranasal
`naloxone exhibits opiate antagonist effects almost as
`rapidly as does intravenous naloxone, with bioavailability
`approaching 100%.21 The Denver Health Paramedic
`system investigated the use of
`intranasal naloxone in
`heroin overdose patients and found it
`to be 83%
`effective at awakening patients.22 Awakening times were
`comparable with those in previous studies investigating
`intravenously administered naloxone and faster than
`when naloxone was administered subcutaneously.23
`Treatment
`‘‘failures’’ occurred in 2 situations: either
`intravenous naloxone was given so rapidly that
`the
`intranasal naloxone did not have time to be effective,
`or the treated patient had significant bloody or mucosal
`
`146
`
`nasal discharge, making absorption inadequate. The
`authors concluded that intranasal naloxone can be effec-
`tive in the field, acts rapidly, and reduces the risk of
`needle-stick injury.
`
`Atomized drug delivery systems result in
`superior surface area coverage compared
`to drops or spray methods and will
`improve medication bioavailability.
`
`Conclusion
`
`Although the intranasal route is a rapid and convenient
`way to deliver medications in the emergency department,
`it will not replace the need for injections. However,
`awareness of its limitations combined with the correct
`equipment and medication concentrations will allow
`emergency nurses to bypass the need for intravenous lines
`in certain cases. This improves the safety of the work
`environment and eliminates the professional, personal, and
`family turmoil that may occur when a medical worker
`incurs a needle-stick injury.
`
`R EFER ENCES
`1. Chien YW, Su KSE, Chang SF. Nasal systemic drug delivery.
`In: Anatomy and physiology of the nose. Dekker: New York;
`1989. p. 1-26.
`2. Stanley TH. Anesthesia for the 21st century. BUMC Proceed-
`ings 2000;13:7-10.
`3. Henry RJ, Ruano N, Casto D, Wolf RH. A pharmacokinetic
`study of midazolam in dogs: nasal drop vs. atomizer adminis-
`tration. Pediatr Dent 1998;20:321-6.
`4. Brown JC, Klein EJ, Lewis CW, Johnston BD, Cummings P.
`Emergency department analgesia for fracture pain. Ann Emerg
`Med 2003;42:197-205.
`5. Abrams R, Morrison JE, Villasenor A, Hencmann D, Da Fon-
`seca M, Mueller W. Safety and effectiveness of intranasal admin-
`istration of sedative medications (ketamine, midazolam, or
`sufentanil) for urgent brief pediatric dental procedures. Anesth
`Prog 1993;40:63-6.
`6. Borland ML, Jacobs I, Geelhoed G. Intranasal fentanyl reduces
`acute pain in children in the emergency department: a safety and
`efficacy study. Emerg Med (Fremantle) 2002;14:275-80.
`7. Bates BA, Schutzman SA, Fleisher GR. A comparison of intra-
`nasal sufentanil and midazolam to intramuscular meperidine,
`promethazine, and chlorpromazine for conscious sedation in
`children. Ann Emerg Med 1994;24:646-51.
`8. Yealy DM, Ellis JH, Hobbs GD, Moscati RM. Intranasal mid-
`azolam as a sedative for children during laceration repair. Am J
`Emerg Med 1992;10:584-7.
`9. Fisgin T, Gurer Y, Tezic T, Senbil N, Zorlu P, Okuyaz C, et al.
`
`AQUESTIVE EXHIBIT 1145 Page 0006
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`
`Effects of intranasal midazolam and rectal diazepam on acute
`convulsions in children: prospective randomized study. J Child
`Neurol 2002;17:123-6.
`10. Lahat E, Goldman M, Barr J, Bistritzer T, Berkovitch M. Com-
`parison of intranasal midazolam with intravenous diazepam for
`treating febrile seizures in children: prospective randomised
`study. BMJ 2000;321:83-6.
`11. Wermeling DP, Miller JL, Archer SM, Manaligod JM, Rudy
`AC. Bioavailability and pharmacokinetics of lorazepam after
`intranasal, intravenous, and intramuscular administration. J
`Clin Pharmacol 2001;41:1225-31.
`12. Wolfe TR, Barton ED. Reducing needlestick risk: nasal drug
`delivery in EMS. J Emerg Med Serv JEMS 2003;28:53-63.
`13. Singer AJ, Konia N. Comparison of topical anesthetics and
`vasoconstrictors vs lubricants prior to nasogastric intubation: a
`randomized, controlled trial. Acad Emerg Med 1999;6:184-90.
`14. Wolfe TR, Fosnocht DE, Linscott MS. Atomized lidocaine as
`topical anesthesia for nasogastric tube placement: A randomized,
`double-blind, placebo-controlled trial. Ann Emerg Med 2000;
`35:421-5.
`15. Groudine SB, Hollinger I, Jones J, DeBouno BA. New York
`State guidelines on the topical use of phenylephrine in the op-
`erating room. The Phenylephrine Advisory Committee. Anes-
`thesiology 2000;92:859-64.
`16. Krempl GA, Noorily AD. Use of oxymetazoline in the manage-
`ment of epistaxis. Ann Otol Rhinol Laryngol 1995;104:704-6.
`17. Doo G, Johnson DS. Oxymetazoline in the treatment of pos-
`terior epistaxis. Hawaii Med J 1999;58:210-2.
`18. Katz RI, Hovagim AR, Finkelstein HS, Grinberg Y, Boccio RV,
`Poppers PJ. A comparison of cocaine, lidocaine with epineph-
`rine, and oxymetazoline for prevention of epistaxis on nasotra-
`cheal intubation. J Clin Anesth 1990;2:16-20.
`19. Kelen GD, Green GB, Purcell RH, Chan DW, Qaqish BF,
`Sivertson KT, et al. Hepatitis B and hepatitis C in emergency
`department patients. N Engl J Med 1992;326:1399-404.
`20. Vilke GM, Buchanan J, Dunford JV, Chan TC. Are heroin
`overdose deaths related to patient release after prehospital treat-
`ment with naloxone? Prehosp Emerg Care 1999;3:183-6.
`21. Hussain A, Kimura R, Huang CH. Nasal absorption of nalox-
`one and buprenorphine in rats. Int J Pharm 1984;21:233-7.
`22. Barton ED, Ramos J, Colwell C, Benson J, Baily J, Dunn W.
`Intranasal administration of naloxone by paramedics. Prehosp
`Emerg Care 2002;6:54-8.
`23. Wanger K, Brough L, Macmillan I, Goulding J, MacPhail I,
`Christenson JM. Intravenous vs subcutaneous naloxone for out-
`of-hospital management of presumed opioid overdose. Acad
`Emerg Med 1998;5:293-9.
`
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