Intranasal Medications in the Prehospital Setting

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Intranasal Medications in the Prehospital Setting
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Scenario 1 Broken arm

• A 12 year old fell off his bicycle and fractured
  his distal arm.
• He is in significant pain.
• EMS protocols call for IN administration of
  fentanyl (2 mcg/kg).
• 10 minutes later the childs pain is improved but
  still substantial.
• After a second dose of IN fentanyl he is
  comfortable.

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Scenario 2 Frightened child

• A 3-year old boy requires head CT scan (or a
  number of other procedures).
• He does not have an IV in place and is terrified
  of needles.
• He will not relax and clings to his parent.
• You administer 0.5 mg/kg of IN midazolam and 10
  minutes later he is dozing off and is easily
  separated from his parent and taken over for his
  testing.

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Scenario 3 Seizing child

• EMS is enroute with a 3 y.o. girl suffering a
  grand mal seizure for at least 15 minutes.
• No IV can be established.
• Rectal diazepam (Valium) is unsuccessful at
  controlling the seizure.
• IV attempts in the ED 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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Scenario 4 Epistaxis

• A 60 y.o male arrives at the ED with his third
  episode of epistaxis in 3 days.
• He was cauterized and packed in another ED the
  day prior, but started bleeding 5 hours after the
  packing was removed.
• You administer 1 ml of oxymetazoline (Afrin) into
  the nostril, and insert an oxymetazoline soaked
  cotton pledget.
• 15 minutes later his nasal mucosa is dry.
• You discharge him with instructions to use
  oxymetazoline TID for 3 days, and to self treat
  in the future if possible.

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Scenario 5 Heroin Overdose

• EMS responds to an unconscious male. He has slow
  respirations, pinpoint pupils, cool dusky skin
  and obvious intravenous drug abuse needle track
  marks on both arms.
• After an IV is established, naloxone (Narcan) is
  administered and the patient is successfully
  resuscitated.
• Unfortunately, the paramedic 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
  in the ED with no further therapy (i.e.- no need
  for an IV) and is discharged.

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Scenario 5 Heroin Overdose

• The paramedic is given his first dose of HIV
  prophylactic medications. No treatment for hep C
  prophylaxis exists.
• The next few months will be difficult He faces
  the substantial side effects that accompany HIV
  medications and his personal life is in turmoil
  due to issues of safe sex with his wife and the
  mental anguish of waiting to see if he will
  contract HIV or hepatitis C.
• A friend informs him that new evidence suggests
  that naloxone is effective at reversing heroin
  overdose if it is given intranasally with no
  risk of a needle stick.

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The problem! NEEDLESTICKS

• Nasal drug delivery is attractive not because it
  is BETTER than injectable therapy
• BUT
• Because it is SAFER!
• ..No needle NO needle stick risk!

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The problem! NEEDLESTICKS

• The CDC estimates
• 600,000 percutaneous injuries each year involving
  contaminated sharps in the U.S. A..
• Technological developments can increase
  protection.

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in the field! Very high risk

• High risk patients
• HIV patients 4.1-8.3/100 transports
• Marcus et al, Ann Em Med, 1995
• High risk environments
• Altered patients, combative
• Scene control issues
• Moving ambulance

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Intranasal Medication Administration

• Intranasal Medication administration offers a
  truly Needleless solution to drug delivery.
• The remainder of this slide show will surround
  the topic of intranasal drug delivery issues.

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Intranasal Medication Administration Basic
Concepts

• This delivery route has several advantages
• Its easy and convenient
• Almost everyone has a nose
• The nose is a very easy access point for
  medication delivery (even easier than the arm,
  especially in winter)
• No special training is required to deliver the
  medication
• No shots are needed
• It is painless
• It eliminates any risk of a needle stick to you,
  the medical provider

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Understanding IN delivery Definitions

• First pass metabolism
• Nose brain pathway
• Lipophilicity
• Bioavailability

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First pass metabolism

• Molecules absorbed through the gut, including all
  oral medications enter the portal circulation
  and are transported to the liver.
• Liver enzymes then break down most of these drug
  molecules and only a small fraction enter the
  bodys circulation as active drug.
• This process is called First Pass Metabolism.
• POINT Nasally delivered medications avoid the
  gut so do not suffer first pass metabolism.

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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
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Lipophilicity
Non-lipophilic molecules

• Lipid Loving
• Cellular membranes are composed of layers of
  lipid material.
• Drugs that are lipophilic are easily and rapidly
  absorbed across the mucous membranes.

Lipophilic molecules
Cell Membrane
Blood stream
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Bioavailability

• How much of the administered medication actually
  ends up in the blood stream.
• Examples
• IV medications are 100 bioavailable.
• Most oral medications are about 5-10
  bioavailable due to destruction in the gut and
  liver.
• Nasal medications vary, but nasal Narcan
  approaches 100 - the same as when given
  intravenously.

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Bioavailability

• Table demonstrating naloxone serum concentrations
  when given via IV and IN routes.
• Note that IV and IN serum levels are identical
  after about 2-3 minutes.

How long does it take you to start an IV in a
heroin user?
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Intranasal Medication Administration
Bioavailability

• Not all drugs can be delivered via the nasal
  mucosa.
• Factors affecting bioavailability
• Medication characteristics.
• Medication volume and concentration.
• Nasal mucosal characteristics.
• Delivery system characteristics.
• Mucosal surface area coverage.
• Medication particle size.

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Intranasal Medication Administration Factors
Affecting Bioavailability

• Medication Characteristics
• Drug characteristics that affect bioavailability
  via the nasal mucosa include
• Molecular size.
• Lipophilicity.
• pH.
• Drug concentration.
• Properties of the solution the drug is
  solubilized within.

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Intranasal Medication Administration Factors
Affecting Bioavailability

• Volume and concentration
• Low volume - High concentration.
• Too large a volume or too weak a concentration
  may lead to failure because the drug cannot be
  absorbed in high enough quantity to be effective.
• Volumes over1 ml per nostril are too large and
  may result in runoff out of the nostril.
• 1/3 to 1/2 ml is ideal in an adult

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Intranasal Medication Administration Factors
Affecting Bioavailability

• Nasal mucosal characteristics
• If there is something wrong with the nasal mucosa
  it may not absorb medications effectively.
• Examples
• Vasoconstrictors such as cocaine prevent
  absorption.
• Bloody nose, nasal congestion, mucous discharge
  all prevent mucosal contact of drug.
• Destruction of nasal mucosa from surgery or past
  cocaine abuse no mucosa to absorb the drug.

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Intranasal Medication Administration Factors
Affecting Bioavailability

• Delivery system characteristics
• Nasal mucosal surface area coverage
• Larger surface area delivery higher
  bioavailability.
• Particle size
• Particle size 10-50 microns adheres best to the
  nasal mucosa.
• Smaller particles (nebulized) pass on to the
  lungs, larger particles form droplets and run-out
  of the nose.

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Bioavailability and Particle size

• Compared to drops, atomized medication results
  in
• Larger surface area of coverage.
• Smaller liquid particle size allowing thin layer
  to cover mucosa.
• Less run-off out the nasal cavity.

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Intranasal Medication Administration Factors
Affecting Bioavailability

• Points
• Nasal drug delivery is convenient and easy, but
  it may not always be effective.
• Nasal drug delivery cannot completely replace the
  need for injections.
• Being aware of the limitations and using the
  correct equipment and drug concentrations will
  assist you in predicting times when nasal drug
  delivery may not be effective.

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Nasal Drug Delivery in EMS What Medications?

• Drugs of interest to EMS systems
• Intranasal naloxone (Narcan)
• Intranasal midazolam (Versed)
• Intranasal fentanyl
• Others

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Intranasal (IN) Naloxone

• Background
• Absorption of IN naloxone almost as fast as IV in
  both animal and human models
• Hussain et al, Int J Pharm, 1984
• Loimer et al, Int J Addict, 1994
• Loimer et al, J Psychiatr Res, 1992
• Atomized spray of medications show much better
  absorption via the IN route
• Bryant et al, Nucl Med Comm, 1999
• Daley-Yates et al, Br J Clin Pharm 2001
• Henry et al, Ped Dent 1998

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Intranasal Administration of Naloxone by
Paramedics

• Prospective clinical trial
• Preliminary study February, 2001
• Barton et al, Prehosp Emer Care 2002
• Final study completed
• Barton et al, J Emerg Med 2005
• Kelly et al, Med J Aust 2005 (a study in
  Australia)
• Study design
• Required all patients to get an IV and IV
  naloxone (standard care) however nasal naloxone
  was administered first and if the patient awoke
  prior to IV therapy they could stop.

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IN Naloxone by Paramedics
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Prehospital IN Naloxone

• Results
• 43/52 (83) IN Naloxone Responders.
• Median time to awaken from drug delivery 3 min.
• Median time from first contact 8 min.
• 9/52 (17) IN Non-responders.
• 4 patients noted to have epistaxis, trauma,
  or septal abnormality.
• Note no one waited for them to respond, once IV
  started they got IV naloxone so some cases were
  given IV naloxone before the nasal drug could
  absorb.

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Prehospital IN Naloxone

• Conclusions
• IN naloxone is effective
• 83 response in the field
• Potentially higher if one waits a few minutes for
  its effect prior to giving IV naloxone.
• Inexpensive device
• Syringe driven atomizer
• May decrease prehospital blood exposures
• 29 no IV in the field (woke up before one could
  be started.) Potential for at least 83 with no
  IV.

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Other Naloxone Studies

• IV vs. SQ Naloxone
• Wanger et al, Acad Emer Med, 1998.
• 196 patients in Vancouver, BC.
• IV naloxone (0.4mg) vs. SQ (0.8mg).
• Response time crew arrival to RR gt 10.
• Median response time IV 9.3 min.
• Median response time SQ 9.6 min.
• Conclusions No significant difference.
• Delay in SQ response offset by time for IV
  insertion.
• Median response time IN naloxone 8.0 min.
• Point IN responses from time of arrival to RR gt
  10 are same as those for IV and SQ.

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Prehospital IN Naloxone

• Take away lessons for nasal naloxone
• Dose and volume higher concentration preferred
  so use 1mg/ml IV solution.
• Delivery immediately on decision to treat
  inject naloxone into nose with atomizer, then
  begin standard care.
• Successful awakening eliminates the need for any
  IV or further ALS care.
• Awakening is gradual-patient doesnt jump off the
  bed, but adequate respiratory efforts occur as
  fast or faster than IV naloxone due to no delays
  with IV start.
• Not 100 effective so failures with IN naloxone
  need to be followed with IV naloxone.

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What if intranasal naloxone does not work?

• 1st - Continue ABCs to support breathing and
  circulation.
• 2nd Administer Naloxone IM or IV.
• 3rd - Consider other causes for coma
• AEIOU-TIPPS
• Is there anything you can do for these processes?

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Protocol Dosing for IN naloxone

• Inspect nostrils for mucus, blood or other
  problems which might inhibit absorption.
• (If these are present, consider other routes and
  be aware of increased risk of failure.)
• Draw 2mg of 1mg/ml solution for delivery by
  atomizer device.
• Give ½ of volume in each nostril.
• Support ventilations for 3 to 4 minutes, if no
  response proceed to IV therapy and consider other
  causes for coma.

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Midazolam

• What is it?
• Benzodiazepine related to Valium (diazepam)
• Benzodiazepines act on the GABA receptor to
  stabilize neural membrane and reduce neuronal
  irritation.
• Water soluble, pH 3.5 (Valium thick, alkalotic)
• Side effects
• Sedation
• Respiratory depression
• Amnesia

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Prehospital IN Midazolam

• Why intranasal midazolam in the EMS setting?
• Seizures
• No needles, no need for an IV in a seizing
  patient.
• Rapid delivery No delays in IV attempts.
• Socially acceptable No need for rectal drug
  administration.
• As effective as IV therapy, more effective than
  rectal therapy, faster onset than either.
• Sedation
• Agitation/combative patient

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IN Midazolam

• Supporting data
• Nasal midazolam has been extensively studied for
  over a decade with hundreds of studies published
  regarding its effectiveness for sedation
  children.
• Very effective for treating acute seizures and
  status epilepsy.

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IN Midazolam

• Seizures.
• Lahat et al, BMJ, 2000.
• Prospective study IN midazolam versus IV
  diazepam for prolonged seizures (gt10 minutes) in
  children.
• Similar efficacy in stopping seizures (app. 90).
• Time to seizure cessation
• IV Valium 8.0 minutes.
• IN Versed 6.1 minutes.

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IN Midazolam

• Lahat et al, BMJ, 2000 (cont)
• Conclusions
• IV diazepam and IN midazolam have similar
  efficacy at controlling prolonged seizures in
  children.
• IN midazolam controls seizures more rapidly
  because there is no delay in establishing an IV.

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IN Midazolam

• Sheepers et al, Seizure, 2000.
• IN midazolam for treatment of severe epilepsy in
  adults.
• Results IN midazolam effective in 94 of
  seizures.
• Conclusion IN midazolam an effective method for
  controlling seizures and is a more acceptable
  and dignified route than rectal diazepam.

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IN Midazolam

• Fisgin, J Child Neur, 2002.
• IN midazolam versus rectal diazepam for treatment
  of pediatric seizure. Prospective trial
• Results
• IN midazolam effective in 87 of seizures.
• Rectal diazepam effective in 60
• Conclusion
• IN midazolam is more effective for controlling
  seizures than rectal diazepam.
• IN midazolam will be very useful in the
  emergency setting

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IN Midazolam

• Holsti, Pediatr Emerg Care, 2007.
• IN midazolam versus rectal diazepam (PR) for
  treatment of pediatric seizure in EMS setting -
  before an after trial
• Results
• IN midazolam - 19 minutes less seizure activity
  on average (11 min IN vs 30 min PR)
• Rectal diazepam
• More likely to re-seize (O.R. 8.4)
• More likely to need intubation (O.R. 12.2)
• More likely to require admission to hospital
  (O.R. 29.3)
• More likely to require admission to ICU (O.R.
  53.5)

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IN Midazolam

• Take away lessons for nasal midazolam
• Dose and volume Higher concentration required -
  use 5mg/ml IV solution.
• Dosing calculations are difficult Use a
  predefined age or weight based table to determine
  dose.
• Deliver immediately on decision to treat Spray
  into nose with atomizer, then begin standard
  care.
• Efficacy Not quite 100 effective so failures
  with nasal may need follow-up with IV therapy.

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Fentanyl

• What is it?
• Synthetic opiate pain killer
• Fentanyl is 50 to 100 times more potent than
  morphine
• It is 1/2 to 1/3 as long lasting as morphine
• Water soluble
• Side effects
• Sedation
• Respiratory depression
• Amnesia

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Prehospital IN Fentanyl

• Why intranasal fentanyl in the EMS setting?
• Pain control
• No needles, no need for an IV
• Rapid delivery No delays in IV attempts.
• As effective as IV morphine in children adults
• Allows adequate pain control without need to
  establish an IV in patients that likely do not
  need IV access (minor orthopedic trauma and burns)

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IN Fentanyl

• Borland, Ann Emerg Med, 2007.
• IN fentanyl versus IV morphine for treatment of
  pediatric orthopedic fractures - Randomized,
  double blind, placebo controlled trial
• Results
• Pain scores identical for IV morphine and IN
  fentanyl at 5, 10, 20 and 30 minutes
• Less time to delivery of medication via nasal
  route
• Conclusion IN fentanyl is as effective as IV
  morphine for treating pain associated with broken
  extremities

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IN Fentanyl

• Rickard, Am J Emerg Med, 2007.
• IN fentanyl versus IV morphine for treatment of
  adult patients with non-cardiac pain in the
  prehospital setting - Randomized, open label
  trial
• Results
• Pain scores identical for IV morphine and IN
  fentanyl by the time the hospital was reached
• Less time to delivery of medication via nasal
  route
• Conclusion IN fentanyl is as effective as IV
  morphine for treating pain in adult EMS patients

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IN Fentanyl

• Caveats
• Borland and Rickard used concentrated fentanyl
  (150 to 300 mcg/ml)
• U.S. generic fentanyl comes in 50 mcg/ml
  concentrations
• This lower concentration will likely reduce
  efficacy leading to the need to titrate dose
• Idea - Sufentanil is more potent than fentanyl
  and is very effective in adults for controlling
  pain

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Other IN Medications

• ALS Drugs
• Glucagon
• ?Hydroxycobalamine for cyanide
• ??others

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Conclusions

• Multiple drugs can be given IN
• Rapid
• Immediate access
• Can be given to almost anyone
• Exception Nasal mucosal abnormalities.
• Delivery method and drugs (generic) are
  inexpensive

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Conclusions

• Intranasal drug delivery is a true needleless
  system!
• Reduce blood borne exposure risks
• HIV
• Hepatitis B, C
• Decrease IV placements in the field
• Improve care in situations where an IV cannot be
  established.
• Equivalent results to IV in many cases, superior
  to rectal

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Educational Web Links

• www.intranasal.net