Intranasal Drug Delivery – Clinical
Implications for Emergency Medicine
and EMS
Lecture outline
 Why use intranasal medications?
 Intranasal drug delivery: General concepts
 Intranasal drugs indications with clinical cases
and personal insights:
• Pain Control
• Sedation
• Seizures
 Drug doses
 Resources
• Opiate overdose
• Epistaxis
• Nasopharyngeal procedures
Advantages of Nasal drugs
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Ease of use and convenience
Saves time / reduces resource utilization
Rapidly effective - onset within 2-10 minutes
Safe – No high peak serum levels yet rapidly therapeutic
No special training is required to deliver the medication
No shots are needed
Painless
No needle stick risk
Extensive literature support
Patients (& Parents & clinicians) really like this approach
Faster care and discharge
Understanding IN delivery:
General principles
First pass metabolism
Nose brain pathway
Bioavailability
Safety vs IV drugs
First pass metabolism
Nasal Mucosa:
No first pass
metabolism
Gut
mucosa:
Subject to
first pass
metabolism
Nose brain pathway
 The olfactory mucosa
(smelling area in nose) is in
direct contact with the brain
and CSF.
 Medications absorbed across
the olfactory mucosa directly
enter the CSF.
 This area is termed the nose
brain pathway and offers a
rapid, direct route for drug
delivery to the brain.
Olfactory mucosa, nerve
Brain
CSF
Highly vascular nasal mucosa
Nose brain pathway
Bioavailability
How much of the administered medication actually
ends up in the blood stream.
Examples:
 IV medications are 100% bioavailable by definition.
 Most oral medications are about 5%-10% bioavailable
due to destruction in the gut and liver.
 Nasal medications vary depending on molecule, pH, etc
 Midazolam 75+%
 Fentanyl and Sufentanil 80+%
 Naloxone 90+%
 Lorazepam, ketamine, Romazicon, etc
Optimizing Bioavailability of IN
drugs
Critical
 Minimize volume - Maximize concentrationConcept
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0.2 to 0.3 ml per nostril ideal, 1 ml is maximum
Most potent (highly concentrated) drug should be used
 Maximize total absorptive mucosal surface area
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Use BOTH nostrils (doubles your absorptive surface area)
 Use a delivery system that maximizes mucosal
coverage and minimizes run-off.
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Atomized particles across broad surface area
Dropper vs Atomizer
Absorption
 Drops = runs down to
pharynx and swallowed
 Atomizer = sticks to broad
mucosal surface and absorbs
Usability / acceptance
 Drops = Minutes to give,
cooperative patient, head
position required
 Atomizer = seconds to
deliver, better accepted
Dropper vs Atomizer
Merkus 2006
Safety of Nasal drugs
Safety and onset of Nasal drugs
Intranasal Medications
What IN medications can we use in
emergency medicine?
Nasal Drug Delivery:
What Medications?
 Pain control – Opiates
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Fentanyl, sufentanil, ? ketamine
 Sedation- Benzodiazepines, ά-2 Agonists
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Midazolam, dexmedetomidine
 Seizure Therapy – Benzodiazepines
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Midazolam, Lorazepam
 Opiate overdose - Naloxone
 Nasopharyngeal procedures and epistaxis
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Anesthetics, vasoconstrictors
Intranasal Medication Cases
Pain Control
Case: Pediatric
Hand burn
A 5 year old burned her hand on the stove
 Clinical Needs: Pain control, debride and clean
wound.
 Treatment: 2.0 mcg/kg of intranasal fentanyl (40
mcg – 0.8 ml of generic “IV” fentanyl)
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Within 3-5 minutes her pain is improved
15 minutes later the patient easily tolerates cleansing of
the burn and dressing application.
She is discharged with an oral pain killer one hour post
triage.
Case: Injured ankle
A 25 year old injured his ankle and has significant
ankle swelling, bruising and pain.
 Clinical Needs: Pain control, x-ray, splint.
 Treatment: 0.5 mcg/kg of intranasal sufentanil (45
mcg – 0.9 ml of generic “IV” sufentanil)
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5-10 minutes later the pain is gone and he is calm
He is taken off to x-ray for diagnostic evaluation of his
ankle, followed by a splint and referral to an orthopedist.
Case: MVC
pinned in car
A 35 year old male pinned in a car following an MVC.
Bilateral upper arm fractures, femur fracture, likely
other injuries. Screaming in pain.
 Clinical Needs: Pain control, sedation, rapid
extraction, then IV access (cannot do so now).
 Treatment: 1.5 mcg/kg of intranasal fentanyl plus 5
mg IN midazolam
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In 7 minutes his pain is much better controlled and he is
calmer
Extraction requires 20 minutes, then full trauma
assessment and care proceeds.
Literature to support this case - pediatrics
Nasal
Intravenous
Borland, Ann Emerg Med 2007
Literature to support this case - adults
Steenblik, Am J Emerg Med 2012
Intranasal Ketamine for pain ?:
Literature support
US Army IN
ketamine data
 Compared IN
ketamine to IV
morphine for
severe pain
 IN ketamine (50
mg) as fast and as
good as IV
morphine (7.5 mg)
w/o side effects.
The Doubters: Surely IN drugs
can’t be as good as an injection
for pain control!
Nasal
Intravenous
ACTUALLY – They are equivalent or better (in these settings)
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Borland 2007 – IN fentanyl onset of action and quality of pain control
was identical to IV morphine in patients with broken legs and arms
Borland 2008, Holdgate 2010, Crellin 2010 - time to delivery of IN
opiates was half that of IV and more patients get treated
Kendal 2001 – IN opiate superior to IM opiate for pain control
Conclusions
 IN opiates are just as good as IV
 IN opiates are delivered in half the waiting time as IV
 IN opiate are preferred by patients, providers and parents over
injections
Pain control –
Literature support
Over a decade of prehospital and ER literature exists for
burn, orthopedic trauma and visceral pain in both adults
and children showing the following:
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Faster drug delivery (no IV start needed) so faster onset
Equivalent to IV morphine
Superior to IM morphine
Care givers are more likely to treat pediatric severe pain
Highly satisfied patients and providers
Safe
IN opiates for Pain control – My
insights
• This is the most common use of IN drugs in my practice - daily.
• Generic concentrations available in U.S. work fine and are
inexpensive ($1-4/vial)
• Great patient and parent satisfier: Rapid pain resolution with no
need for a painful injection.
• Efficacy: Very effective – and it can be titrated.
• Use a pulse oximeter with sufentanil:
• Sufentanil is especially potent and must be treated with
respect.
• Fentanyl seems fine and can safely be given with minimal
risk
• Give an oral pain killer as well: It kicks in as IN drug wears off
Intranasal Medication Cases
Sedation
Case: CT scan child
A 5-year old boy requires a CT scan (computed
tomography) of his head due to head injury.
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He does not have an IV in place and mildly agitated.
He will not remain still enough to obtain quality images.
The clinician administers topical lidocaine followed by 0.5
mg/kg of IN midazolam (or 2 ug/kg dexmedetomidine if
longer duration of sedation is needed for MRI) and 10
minutes later he is dozing off and remains calm and still
for the ct scan.
Case: Abscess Drainage
A 40 year old male complains of redness, swelling and
pain on his thigh. Exam reveals a large pus filled
abscess.
 Clinical Needs: Pain control, sedation, incision and
drainage of the abscess
 Treatment:
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40 mcg of IN sufentanil then 10 mg intranasal midazolam
15 minutes later he is asleep, mildly sedated
The abscess is injected with lidocaine, incised, drained
and packed and patient is discharged when awake.
Case: Excited Delirium
A 27-year old male is apprehended by police and
paramedics for extremely violent, out of control
behavior following use of crystal meth.
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He is at significant risk of injuring himself and others.
It is too dangerous (needle stick risk) to give him an
injection of sedatives.
The paramedic administers 10 mg of IN midazolam and
7 minutes later he is calm and can be transported safely
to the hospital.
Literature to support this case - pediatrics
Klein, Ann Emerg Med 2011
Sedation –
Literature support
Hundreds of articles dating back into the 1980’s. Most
used midazolam.
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Effective only if adequate dose is given (0.4 to 0.5 mg/kg)
Burns upon application – pretreat with lignocaine
Effective in children and adults (even exited delirium in EMS)
Safe – no reports of respiratory depression
IN Benzos for sedation – my insights
 Nasal Midazolam burns on application: Pretreat with
lignocaine, warn the parents, this lasts 30-45 seconds then
dissipates
 Timing: Children become sedated at about 5-10 minutes,
maximal at 10-20 and starts to wear off at 25-30 so be
ready to do prep and suture or do procedure in this time
frame.
 Efficacy: Sedation is not deep. OK for minor procedures,
CT, ?MRI, not good enough for complex face laceration.
More data needs to be obtained for lorazepam.
Intranasal Medication Cases
Seizure Control
Case: Seizing child
The ambulance is transporting a 13 y.o. girl suffering a grand
mal seizure.
 Despite trying, no IV can be successfully established.
 Rectal diazepam is unsuccessful at controlling the seizure.
 IV attempts in the clinic / hospital are also unsuccessful.
 However, on patient arrival a dose of nasal midazolam
(Versed, Dormicum) is given and within 3 minutes of drug
delivery the child stops seizing.
Seizure Therapy Literature support
Lahat 2000; Fisgin 2002; Holsti 2006; Ahmad 2006; Arya 2011;
Holsti 2011; Javadzadeh 2012; Thakker 2012:
 IN midazolam is superior to rectal diazepam for seizure control and
is preferred by care givers
 IN midazolam is superior to intramuscular injection of paraldehyde
 IN midazolam/lorazepam is equivalent to intravenous delivery for
stopping seizures, much faster at stopping them due to no IV start
needed and it leads to less respiratory depression
 IN midazolam can be delivered by family at home safely and
effectively
Onset of nasal vs buccal seizure drugs
(Time of onset matters)
Anderson 2011: IN vs buccal lorazepam
The Doubters: Surely IN drugs
can’t be as good as IV for seizures!
ACTUALLY – They are equivalent or better (in these settings)
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Lahat 00, Mahmoudian 04, Arya 11, Thakker 12, Javadzadeh
12 – IV and IN are equivalent for stopping seizures rapidly,
but IN works faster due to no delays
Holsti 2007, Fisgin 2002 – IN is superior to rectal
Holsti 2011 – IN is safe at home with immediate results
Conclusions
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IN seizure medication are just as good as IV, better than rectal
IN seizure medication are delivered much more rapidly so seizure stops
sooner.
Anyone (Parents, care givers, nursing home staff, ambulance driver,
etc.) can administer the medication so seizure length is shorter.
IN benzodiazepines for
seizures – My insights
Very effective, very fast: Rapid seizure resolution
without IV access.
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Should be first line therapy in ALL prolonged acute
seizures while IV access is being established (if at all)
Effective and safe at home, in EMS setting, in hospital
More effective, less expensive and preferred by
providers when compared to alternative (rectal
diazepam).
Intranasal Medication Cases
Opiate Overdose
Case: Heroin
Overdose
The ambulance responds to an unconscious, barely breathing
patient with obvious intravenous drug needle marks on both
arms – consistent with heroin overdose
 After an IV is established, naloxone (Narcan) is
administered and the patient is successfully resuscitated.
 Unfortunately, the medic suffers a contaminated needle stick
while establishing the IV.
 The patient admits to being infected with both HIV and
hepatitis C. He remains alert for 2 hours with no further
therapy in the ED (i.e.- no need for an IV) and is discharged.
Case: Heroin Overdose
 The medic now needs treatment - HIV prophylaxis
 The next few months will be difficult for him:
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Side effects that accompany HIV medications
Personal life is in turmoil due to issues of safe sex with
his spouse
Mental anguish of waiting to see if he develops HIV or
hepatitis C.
 He wonders why his system is not using LMAMAD nasal to deliver naloxone on all these patients.
Opiate overdose –
Literature support
Intranasal naloxone literature
 Barton 02, 05; Kelly 05; Robertson 09; Kerr 09; Merlin 2010;
Doe Simkins 09; Walley 12:
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IN naloxone is at least 80-90% effective at reversing opiate
overdose
When compared directly it is equivalent in efficacy to IV or IM
therapy.
IN naloxone results in less agitation upon arousal
IN naloxone is lay person approved in many places. It safe and
has saved many lives.
IN naloxone for opiate overdose
– my insights
Why not? Is there a downside?
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High risk population for HIV, HCV, HBV
Difficult IV to establish due to scarring of veins
Elimination of needle eliminates needle stick risk
They awaken more gently than with IV naloxone
New epidemiology shows prescription drugs (methadone, etc)
are causing many deaths that naloxone at home could reverse.
 Simple enough that lay public can administer and not even call
ambulance
Every ambulance system, police agency and many clinics and
families with high risk patients should be utilizing this
approach.
Intranasal medication cases
Nasopharyngeal procedures and epistaxis
Topical anesthetics
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Lidocaine
Benzocaine
Tetracaine
Cocaine
• Etc.
Topical vasoconstrictors
• Oxymetazoline
• Phenylephrine
• Cocaine
Case: Epistaxis
(Bloody nose)
An elderly male arrives at the emergency room with profuse
epistaxis from his anterior left nares.
 Treatment: Atomized oxymetazoline (Afrin) plus 4% lidocaine
into the nostril, and insertion of an oxymetazoline soaked cotton
pledget.
 15 minutes later his nasal mucosa is dry due to oxymetazoline
induced vasoconstriction.
 One large vessel is cauterized (he is numb from the lidocaine).
 He is discharged with instructions to use oxymetazoline for 3
days, and to self treat in the future if possible.
 No packing is needed, no expensive clotting factors are required
Nasopharyngeal procedures and
epistaxis – Literature support
Extensive literature in the past 40 years
documents efficacy of topical anesthesia
 Wolfe 00 (MAD): IN lidocaine markedly
reduces pain during nasogastric tube
placement. Many similar studies since.
 National Center for patient safety 06:
Online PDF review of the literature –
recommends nasal/oral lidocaine
 Kremple 95, Doo 99: IN oxymetazoline
excellent single therapy for epistaxis
(bloody nose).
IN anesthetics and
vasoconstrictors – my insights
Nasal instrumentation: Do it every time
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Proven by multiple studies to improve
procedural comfort.
Epistaxis: Very effective, very simple
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Inexpensive and easy
Drug doses
Scenario
Drug and Dose
Important Reminders
Pain Control
Fentanyl: 2 mcg/kg
Sufentanil: 0.5 mcg/kg
Ketamine 1 mg/kg?
•Titration is possible
•Sufentanil – use pulse ox
•Half up each nostril
Sedation
Midazolam: 0.5 mg/kg
(combination w/ pain)
•Use lidocaine to prevent burning
•Use concentrated formula
Seizures
Midazolam: 0.2 mg/kg
Lorazepam 0.1 mg/kg
•Support breathing while waiting
•Use concentrated formula
Opiate Overdose
Naloxone: 2 mg
•Support breathing while awaiting onset
Epistaxis
Oxymetazoline or
Phenylephrine +
Lidocaine
•Blow nose prior to application
•Spray, then apply soaked cotton ball
•Pinch nose for 10 minutes
Nasal Procedures
Oxymetazoline or
Phenylephrine +
Lidocaine
•Wait 3 full minutes for anesthetic effect
Intranasal medications summary
 Another tool for drug delivery to
supplement standard IV, IM, PO–very
useful when appropriate
 Supported by extensive literature
 Inexpensive
 Speeds up care in many situations
 Safe
Questions?
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www.intranasal.net