Intranasal Drug Delivery

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Intranasal Drug Delivery Clinical Implications
for Pre-hospital care
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Lecture outline

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

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Why do I think nasal drug delivery is important
in prehospital care?

• Efficacy, speed and ease of delivery
• No delivery delays (no IV)
• Can deliver to anyone with an exposed nose
• Rapid onset of action (Pain control, Sedation,
  seizure, overdose)
• As effective and fast as IV drugs in most
  situations
• Safety
• No needle stick risk
• Lower risk of respiratory depression (compared to
  IV)
• Easier to proceed with additional care
• Start IV in children or agitated adult
• Calm the agitated patient

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Understanding IN delivery General principles

• First pass metabolism
• Nose brain pathway
• Bioavailability / Drug absorption
• 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.
• Offers a rapid, direct route for drug delivery to
  the brain (skipping the blood brain barrier).

Brain CSF
Highly vascular nasal mucosa
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Nose brain pathway
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Bioavailability/ Drug absorption

• 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 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
• Beware of abnormal nasal mucosal characteristics
• Mucous, blood and vasoconstrictors may reduce
  absorption
• Suction nose or consider alternate delivery route
  if present

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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 Prehospital
care?
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Nasal Drug Delivery What Medications?

• Pain control Opiates, other
• Fentanyl, ketamine?
• Sedation- Benzodiazepines
• Midazolam, lorazepam
• Seizure Therapy Benzodiazepines
• Midazolam, lorazepam
• Opiate overdose - Naloxone

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Intranasal Medication Cases
Pain Control
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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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Case Pediatric Hand burn

• A 5 year old burned her hand on the stove
• Clinical Needs Pain control, Transport for wound
  care
• 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
• She is transported to a nearby medical facility
• 15 minutes later the patient easily tolerates
  cleansing of the burn and dressing application.

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Literature to support these cases - pediatrics
Nasal
Intravenous
Borland, Ann Emerg Med 2007
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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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Pain control Literature support

• Prehospital and wounded soldier literature
• Rickard 07 (MAD) IN fentanyl equal to IV
  morphine for pain control in adults. No IV
  needed.
• McLean 09 (MAD) IN fentanyl very effective for
  adult ski trauma victims with onset of action on
  less than 5 minutes
• Johnstone 09 (MAD) IN fentanyl in ambulance is
  very effective for visceral non-traumatic pain
  in adults.
• U.S. Military Ketamine 50 mg IN is as
  good/better than morphine 7.5 mg IV for acute
  pain and the soldier can self administer and
  potentially continue his mission.

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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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IN opiates for Pain control My insights

• I use nasal opiates in my practice - daily.
• Our statewide ambulance services IN fentanyl is
  the first line pain treatment in all children,
  adult option. ?Nasal ketamine soon?
• Generic concentrations available in U.S. work
  fine and are
• inexpensive (1-4/vial)
• Efficacy Very effective and it can be
  titrated.
• Segway to IV therapy in the appropriate
  situation (fear, agitation)

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Intranasal Medication Cases
Sedation
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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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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 in kids, 10 mg straight dose in adults)
• 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

• The EMS literature is just emerging Many cases
  reported, few good actual studies
• Timing Sedation onset with midazolam at about
  5-10 minutes, maximal at 10-20 and starts to wear
  off at 25-30.
• Efficacy Sedation is not deep but it takes the
  edge off and can make further care less stressful
  or dangerous
• Lorazepam? More data needs to be obtained for
  lorazepam. My experience lasts longer, 75
  effective.
• Ketamine? Mixed results, doses of at least 5
  mg/kg needed, more data needs to be obtained in
  prehospital and ER environment before conclusions
  can be made.

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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 and
  less need for airway management that either IV or
  rectal drugs
• 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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Seizure Therapy - expenses

• Cost Average wholesale price
• Rectal diazepam
• (Diastat brand name)
• 10 mg 120/dose
• IN midazolam
• 10 mg 3.20

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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 prehospital
  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 MAD nasal
  to deliver naloxone on all these patients.

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Case Methadone induced coma

• A mother enters her daughters room to find her
  unconscious, barely breathing, blue color. Since
  her daughter is on methadone maintenance, the
  family was trained to deliver rescue naloxone
  (see photo of kit above).
• The mother quickly delivers the naloxone
  intranasally.
• She provides 2-3 minutes of rescue breathing
  until her daughter begins to arouse. She
  gradually awakens over 10 minutes.
• The patient is transferred to the emergency room
  for observation due to the long half life of
  naloxone, but makes an uneventful recovery.

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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 time
  of onset and 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 is safe, has saved many lives and
  reduces medical resource consumption

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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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Drug doses
Scenario Drug and Dose Important Reminders
Pain Control Fentanyl 2 mcg/kg ? Ketamine 1 mg/kg Titration is possible Half up each nostril
Sedation Midazolam 0.5 mg/kg 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 waiting
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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?

• Educational Web site
• www.intranasal.net