Intranasal Drug Delivery

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Intranasal Drug Delivery Clinical Implications
for Emergency Medicine and EMS
2
Lecture outline

• Why use intranasal medications?
• Intranasal drug delivery General concepts
• Intranasal drugs indications with clinical cases
  and personal insights
• Pain Control Opiate overdose
• Sedation Epistaxis
• Seizures Nasopharyngeal procedures
• Drug doses
• Resources

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Advantages of Nasal drugs

• 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

4
Understanding IN delivery General principles

• First pass metabolism
• Nose brain pathway
• Bioavailability
• Safety vs IV drugs

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First pass metabolism
Nasal Mucosa No first pass metabolism
Gut mucosa Subject to first pass metabolism
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Nose brain pathway
Olfactory mucosa, nerve

• 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.

Brain CSF
Highly vascular nasal mucosa
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Nose brain pathway
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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

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Optimizing Bioavailability of IN drugs
Critical Concept

• Minimize volume - Maximize concentration
• 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
• Use BOTH nostrils (doubles your absorptive
  surface area)
• Use a delivery system that maximizes mucosal
  coverage and minimizes run-off.
• Atomized particles across broad surface area

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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

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Dropper vs Atomizer
Merkus 2006
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Safety of Nasal drugs
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Safety and onset of Nasal drugs
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Intranasal Medications
What IN medications can we use in emergency
medicine?
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Nasal Drug Delivery What Medications?

• Pain control Opiates
• Fentanyl, sufentanil, ? ketamine
• Sedation- Benzodiazepines, ?-2 Agonists
• Midazolam, dexmedetomidine
• Seizure Therapy Benzodiazepines
• Midazolam, Lorazepam
• Opiate overdose - Naloxone
• Nasopharyngeal procedures and epistaxis
• Anesthetics, vasoconstrictors

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Intranasal Medication Cases
Pain Control
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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)
• 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.

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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)
• 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.

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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
• In 7 minutes his pain is much better controlled
  and he is calmer
• Extraction requires 20 minutes, then full trauma
  assessment and care proceeds.

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Literature to support this case - pediatrics
Nasal
Intravenous
Borland, Ann Emerg Med 2007
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Literature to support this case - adults
Steenblik, Am J Emerg Med 2012
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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.

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The Doubters Surely IN drugs cant be as good as
an injection for pain control!
Nasal
Intravenous

• ACTUALLY They are equivalent or better (in
  these settings)
• 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

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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
• 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

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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

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Intranasal Medication Cases
Sedation
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Case CT scan child

• A 5-year old boy requires a CT scan (computed
  tomography) of his head due to head injury.
• 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.

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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
• 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.

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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.
• 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.

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Literature to support this case - pediatrics
Klein, Ann Emerg Med 2011
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Sedation Literature support

• Hundreds of articles dating back into the 1980s.
  Most used midazolam.
• 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

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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.

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Intranasal Medication Cases
Seizure Control
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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.

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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

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Onset of nasal vs buccal seizure drugs(Time of
onset matters)
Anderson 2011 IN vs buccal lorazepam
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The Doubters Surely IN drugs cant be as good as
IV for seizures!

• ACTUALLY They are equivalent or better (in
  these settings)
• 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
• 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.

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IN benzodiazepines for seizures My insights

• Very effective, very fast Rapid seizure
  resolution without IV access.
• 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).

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Intranasal Medication Cases
Opiate Overdose
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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.

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Case Heroin Overdose

• The medic now needs treatment - HIV prophylaxis
• The next few months will be difficult for him
• 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 LMA-MAD
  nasal to deliver naloxone on all these patients.

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Opiate overdose Literature support

• Intranasal naloxone literature
• Barton 02, 05 Kelly 05 Robertson 09 Kerr 09
  Merlin 2010 Doe Simkins 09 Walley 12
• 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.

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IN naloxone for opiate overdose my insights

• Why not? Is there a downside?
• 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.

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Intranasal medication cases
Nasopharyngeal procedures and epistaxis
Topical anesthetics Topical vasoconstrictors
Lidocaine Oxymetazoline
Benzocaine Phenylephrine
Tetracaine Cocaine Cocaine
Etc.
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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

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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).

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IN anesthetics and vasoconstrictors my insights

• Nasal instrumentation Do it every time
• Proven by multiple studies to improve procedural
  comfort.
• Epistaxis Very effective, very simple
• Inexpensive and easy

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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
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Intranasal medications summary

• Another tool for drug delivery to supplement
  standard IV, IM, POvery useful when appropriate
• Supported by extensive literature
• Inexpensive
• Speeds up care in many situations
• Safe

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Questions?

• www.intranasal.net