Transcript Nasal Drug Delivery in EMS

Intranasal Medications in clinical
practice
Scenario 1: Broken arm
A 12 year old fell off his bicycle and fractured her
distal arm.
 She is in significant pain.
 ED protocols call for IN administration of
sufentanil (0.75 mcg/kg).
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10 minutes later the child’s pain gone and she is calm
She is taken off to x-ray for diagnostic evaluation of his
fracture
Scenario 2: Frightened child
A 3-year old boy requires head CT scan (or a
number of other procedures).
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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.
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.
Scenario 4: Epistaxis
 A 60 y.o male arrives at the A & E with his third episode of
epistaxis in 3 days.
 He was cauterized and packed in another A & E 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.
Scenario 5: Heroin Overdose
 An unkempt male is dumped in your ambulance bay. 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 nurse 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 (i.e.- no need for an IV) and is discharged.
Scenario 5: Heroin Overdose
 The nurse 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.
Why IN medications?
 This delivery route has several advantages:
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Its easy and convenient
Almost everyone has a nose
The nose is a very easy access point for medication
delivery - even easier to access than IM or IV sites
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 the medical
provider
Lecture Outline
 Intranasal drug delivery: General principles
 Intranasal drugs in clinical practice:
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Pain control - opiates
Sedation - opiates, benzos, ketamine
Seizure Therapy - benzos
Nasopharyngeal procedures and epistaxis- anesthetics,
vasoconstrictors
Opiate overdose - naloxone
Other
Understanding IN delivery:
General principles
First pass metabolism
Nose brain pathway
Lipophilicity
Bioavailability
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 body’s
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.
First pass metabolism
Nose brain pathway
 The olfactory mucosa (smelling
Olfactory mucosa, nerve
area in nose) is in direct contact
with the brain and CSF.
 Medications absorbed across the
Brain
olfactory mucosa directly enter
CSF
the CSF.
 This area is termed the nose brain
pathway and offers a rapid, direct
route for drug delivery to the
brain.
Highly vascular nasal mucosa
Lipophilicity
“Lipid Loving”
Non-lipophilic molecules
Lipophilic molecules
 Cellular membranes
are composed of
layers of lipid
material.
Cell Membrane
 Drugs that are
lipophilic are easily
and rapidly absorbed
across the mucous
membranes.
Blood stream
Bioavailability
 How much of the administered medication
actually ends up in the blood stream.
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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
Naloxone Serum Concentration
1000
Naloxone conc
 Graph demonstrating
naloxone serum
concentrations when
given via IV and IN
routes.
 Note that IV and IN
serum levels are
similar after about 2-3
minutes.
100
Intravenous
Intranasal
10
1
Time
Intranasal Medication
Administration: Bioavailability
 Not all drugs can be delivered via the nasal mucosa.
 Factors affecting bioavailability:
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Medication characteristics.
Medication volume and concentration.
Nasal mucosal characteristics.
Delivery system characteristics.
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Mucosal surface area coverage.
Medication particle size.
Intranasal Medication Administration:
Factors Affecting Bioavailability
Medication Characteristics:
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Drug characteristics that affect bioavailability
via the nasal mucosa include:
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Molecular size.
Lipophilicity.
pH.
Drug concentration.
Properties of the solution the drug is solubilized
within.
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 over 1/2 to 1 ml per nostril are too large and
may result in runoff out of the nostril.
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Intranasal Medication Administration:
Factors Affecting Bioavailability
Nasal mucosal characteristics:
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If there is something wrong with the nasal mucosa it
may not absorb medications effectively.
Examples:
Vasoconstrictors such as Afrin 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:
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Larger surface area delivery = higher
bioavailability.
Particle size:
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Particle size 10-50 microns adheres best to the
nasal mucosa.
Smaller particles pass on to the lungs, larger
particles form droplets and run-out of the nose.
Intranasal Medication Administration:
Factors Affecting Bioavailability
Bioavailability and Particle size: Henry, Ped Dent
1998.
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Study: Compared IV, IN drops and IN atomization in animal
model. Measured Serum and CSF concentrations.
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Results:
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Serum levels: IV >Atomization > Drops.
CSF levels: Atomization>>Drops>IV.
Conclusion:
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Atomization results in higher serum bioavailability than drops
and higher CSF bioavailability than IV.
Bioavailability and Particle size
 Compared to drops,
atomized medication
results in:
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Larger surface area of
coverage.
Smaller liquid particle
size allowing thin layer
to cover mucosa.
Less run-off out the
nasal cavity.
Intranasal Medication Administration:
Factors Affecting Bioavailability
 Points:
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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.
Nasal Drug Delivery:
What Medications?
Drugs of interest to Emergency Departments:
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Pain control and Sedation- opiates, benzos, ketamine
Seizure Therapy - benzos
Nasopharyngeal procedures and epistaxis- anesthetics,
vasoconstrictors
Opiate overdose - naloxone
Other
Pain control and sedation
Pain Medications
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Diamorphine
Fentanyl
Sufentanil
Meperidine
Sedatives
• Midazolam
• Ketamine
Pain control and sedation
Bates et al: A comparison of intranasal sufentanil and
midazolam to intramuscular meperidine, promethazine,
and chlorpromazine for conscious sedation in children.
Ann Emerg Med, 1994
 Both methods equally effective in achieving sedation
 IN sufentanil and midazolam superior in:
 Better tolerated by the patients
 13 minutes faster onset to time of laceration injection
(20 vs 33 minutes)
 27 minute faster discharge (54 vs 81 minutes)
Pain control and sedation
Borland et al: Intranasal fentanyl reduces acute pain in
children in the emergency department: a safety and
efficacy study. Emerg Med (Fremantle), 2002
 45 Children in acute pain given IN Fentanyl (20 to
40 ug)
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Titration allowed q 5 minutes
Results
 Mean VAS score reductions of 18 mm at ten minutes
 No negative side effects
Pain control and sedation
Kendall et al: Multicentre randomised controlled trial of nasal
diamorphine for analgesia in children and teenagers with
clinical fractures. BMJ, 2001.
 Randomized trial - 204 IN diamorphine, 200 IM morphine.
 Results:
 IN medication achieved superior pain control at 5, 10 and 20 minutes.
Equal at 30 minutes.
 IN much better tolerated.
 IN better accepted by parents and staff.
 Conclusion: Nasal opiates should be the prefered method of pain relief in
children with painful conditions presenting to the emergency department.
Pain control and sedation
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
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Conclusion: IN fentanyl is as effective as IV morphine
for treating pain associated with broken extremities
Pain control and sedation
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
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Conclusion: IN fentanyl is as effective as IV morphine
for treating pain in adult EMS patients
Pain control and sedation
Caveats:
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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
Pain control and sedation
Louon et al: Nasal midazolam and ketamine for paediatric
sedation during computerised tomography. Acta
Anaesthesiol Scand, 1994
 30 children < 16 kg requiring CT
 Dose: Midazolam 0.6 mg/kg, Ketamine 5 mg/kg mixed
 Results:
 83% effective sedation
 Rapid onset
 No complications or desaturations
Pre-operative pediatric sedation
Saint-Maurice: The use of midazolam in
diagnostic and short surgical procedures in
children. Acta Anaesthesiol Scand Suppl
1990
“a relatively safe, adaptable, non-invasive method
of inducing sedation in children”
Pre-operative pediatric sedation
Zedie: Comparison of intranasal midazolam and
sufentanil premedication in pediatric
outpatients. Clin Pharmacol Ther 1996
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Pre-operative sedation 30 minutes prior to
anesthesia induction with Midazolam or
Sufentanil
“Both intranasal midazolam and sufentanil
provide rapid, safe, and effective sedation in small
children before anesthesia for ambulatory
surgery.”
Post-operative pain control
Manjushree: Intranasal fentanyl provides
adequate postoperative analgesia in pediatric
patients. Can J Anaesth 2002
“The intranasal route provides a good alternative
for administration of fentanyl in pediatric
surgical patients”
Post-operative pain control
Finkel: The effect of intranasal fentanyl on the
emergence characteristics after sevoflurane
anesthesia in children undergoing surgery for
bilateral myringotomy tube placement. Anesth
Analg 2001
“nasally administered fentanyl … was found to
reduce the incidence of agitation in these
patients”
IN opiates and benzos - My
spin
IN opiates and benzos are clearly effective
HOWEVER:
 Still in its infancy due to:
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Variable doses in the published studies.
Variable delivery devices effecting mucosal coverage.
Drug concentrations tend to be too dilute.
Lack of titration in most studies.
 Opiates and benzos have considerable interindividual
variations in effect making titration and mixing of two
agents necessary for best effect.
IN opiates and benzos - My
spin
We need:
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Dosing studies that include titration as part of the
administration protocol.
Combination drug studies due to interindividual
variations in drug response.
More concentrated medications.
Standardization of delivery method to optimize
mucosal coverage and improve bioavailability.
My personal experience with sufentanil is that it
is the ideal ED opiate for IN delivery
Seizure Therapy
Anticonvulsants
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Midazolam
Lorazepam??
Seizure Therapy
Lahat et al:Comparison of intranasal midazolam with
intravenous diazepam for treating febrile seizures in
children: prospective randomised study. BMJ, 2000
 Prospective study: IN midazolam versus IV diazepam for
prolonged seizures (>10 minutes) in children.
 Similar efficacy in stopping seizures (app. 90%).
 Time to seizure cessation:
 IV Valium: 8.0 minutes.
 IN Versed: 6.1 minutes.
 Conclusions: IN midazolam controls seizures more rapidly
because there is no delay in establishing an IV.
Seizure Therapy
Fisgin et al:Effects of intranasal midazolam and rectal
diazepam on acute convulsions in children: prospective
randomized study. J Child Neurol, 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%
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Conclusion:
 IN midazolam is more effective for controlling seizures than
rectal diazepam and is more socially acceptable
Seizure Therapy
Scheepers et al: Is intranasal midazolam an effective rescue
medication in adolescents and adults with severe
epilepsy? 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.
Seizure Therapy
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
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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)
Seizure Therapy
Wilson, M. et al: Nasal/buccal midazolam use
in the community. Arch Dis Child 2004.
 Survey of families with epileptic patients
who were prescribed IN midazolam.
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83% “effective and easy to use.”
83% “preferred it to rectal diazepam.”
Seizure Therapy
Ahmad. et al: Seizure therapy - IN lorazepam vs
IM paraldehyde in rural Africa. Lancet 2006.
 RCT of 160 children with status epilepticus.
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Mean seizure duration 128 minutes
75% controlled with single dose IN lorazepam
61% controlled with IM paraldehyde
 Conclusions: IN lorazepam is safe, noninvasive and effective in prehospital setting
Seizure Therapy
Cost (March 7, 2004 Internet search):
 Rectal diazepam (Diastat brand name)
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10 mg: $171 - $194 (£94 - £106)
 IN midazolam
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10 mg: $4 - $17 (£2- £9)
IN Benzodiazepines for
seizures: My spin
 IN benzos are very effective for seizure therapy both in
children and in adults.
 If a seizing patient needs to be treated and does not have
an IV established, then administration of IN midazolam
should be done without delay.
 Ideal setting will be home treatment by family and in
EMS settings.
 Midazolam concentration (5 mg/ml) is marginal and a
higher concentration would be preferred.
 Other medications such as lorazepam need to be
investigated more thoroughly. (I find lorazepam IN to be
quite sedating when compared to midazolam).
Nasopharyngeal procedures
and epistaxis
Topical anesthetics
• Lidocaine
• Benzocaine
• Tetracaine
• Cocaine
• Etc.
Topical vasoconstrictors
• Oxymetazoline
• Phenylephrine
• Cocaine
Nasopharyngeal procedures
and epistaxis
Singer et al:Comparison of topical anesthetics and
vasoconstrictors vs lubricants prior to nasogastric
intubation: a randomized, controlled trial. Acad Emerg
Med, 1999
 Topical nasal and oral anesthetics with nasal
vasoconstrictors result in markedly reduced pain and
gagging compared to placebo during NGT placement
 Pain VAS: 28.6 mm vs 57.5 mm
 Gagging VAS: 24.1 mm vs 50.9 mm
Nasopharyngeal procedures
and epistaxis
Wolfe et al:Atomized lidocaine as topical anesthesia for
nasogastric tube placement: A randomized, double-blind,
placebo-controlled trial. Ann Emerg Med, 2000
 Topical nasal and oral anesthetics result in markedly reduced
pain compared to topical intranasal 2% lidocaine jelly alone
during NGT placement.
 Pain VAS: 37.4 mm vs 64.5 mm
Nasopharyngeal procedures
and epistaxis
Krempl et al: Use of oxymetazoline in the management of
epistaxis. Ann Otol Rhinol Laryngol, 1995
 Retrospective ED study
 60 patients with epistaxis
 Results:
 65% controlled with oxymetazoline alone
 83% success with oxymetazoline plus silver nitrate
 Only 17% needed packing
Nasopharyngeal procedures
and epistaxis
Doo et al: Oxymetazoline in the treatment of posterior
epistaxis. Hawaii Med J, 1999
 Retrospective study
 36 patients with posterior epistaxis
 Results:
 75% controlled with oxymetazoline alone
 Remaining 25% treated non-surgically with
recurrent oxymetazoline therapy
Nasopharyngeal procedures
and epistaxis
Katzet al: A comparison of cocaine, lidocaine with
epinephrine, and oxymetazoline for prevention of
epistaxis on nasotracheal intubation. J Clin Anesth 1990
 3 groups of 14 pateints pretreated with the study drug
 Following NT intubation, amount of epistaxis scored
 Lidocaine with epi:
No bleeding in 29%
 Cocaine:
No bleeding in 57%
 Oxymetazoline:
No bleeding in 86%
 Vitals: Slightly higher SBP with cocaine, o/w no changes
IN anesthetics and
vasocontrictors: My Spin
Nasal instrumentation: Do it every time
 Proven by multiple RCT’s to reduce pain and
bleeding associated with nasal procedures such as
NGT placement and nasal intubation.
Epistaxis: Probably effective, very simple
 Nasal oxymetazoline for the treatment of epistaxis
is intriguing and appears to be effective
 Better quality studies are needed.
Treating Opiate overdose
The problem! NEEDLESTICKS
 Nasal drug delivery of naloxone for opiate overdose
is attractive not because it is BETTER than
injectable therapy……
BUT
 …Because it is SAFER!
..No needle
NO needle stick risk!
Treating Opiate overdose
Hussain et al: Nasal absorption of naloxone and
buprenorphine in rats. Int J Pharm, 1984
 Naloxone bioavailability is 100% for both IN and IV
delivery.
Loimer et al: (1994). Nasal administration of naloxone is as
effective as the intravenous route in opiate addicts. Int J
Addict 1994
 Nasal naloxone was as effective as IV naloxone in
eliciting opiate withdrawal.
Treating Opiate overdose
Barton et al: Intranasal administration of naloxone
by paramedics. Prehosp Emerg Care, 2002
 Prospective prehospital study investigating the efficacy
of IN naloxone in treating opiate overdoses
 100 patients entered, 52 determined to have opiate
overdose
 Results:
 43/52 (83%) = “IN Naloxone Responders.”
 Conclusions:
 IN naloxone is effective most of the time
 Routine use may reduce needle stick injuries
Prehospital IN Naloxone
 Results (cont.).
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43/52 (83%) = “IN Naloxone Responders.”
Mean time = 3.9 minutes (range 1-11 min.).
 Median time = 3 min.
 Mean time from first contact = 9.9 min.
 Median time from first contact = 8 min.
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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
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IN Naloxone by Paramedics
Other Naloxone Studies…
 IV vs. SQ Naloxone:
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Wanger et al, Acad Emer Med, 1998.
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196 patients in Vancouver, BC.
IV naloxone (0.4mg) vs. SQ (0.8mg).
Response time = crew arrival to RR > 10.
 Median response time IV = 9.3 min.
 Median response time SQ = 9.6 min.
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Conclusions = No significant difference.
 Delay in SQ response offset by time for IV insertion.
*Median response time IN naloxone = 8.0 min.
What if IN naloxone had been
available here?
 Opiate is gas used at theater
By Judith Ingram
ASSOCIATED PRESS
MOSCOW — Russia's top health official said
yesterday that the gas used in the storming of a
Moscow theater held by Chechen gunmen was
based on fentanyl, a fast-acting opiate with medical
applications, Russian news agencies reported.
Treatment of opiate overdose
with IN naloxone: My spin
Why not?
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High risk population for HIV, HCV, HBV
Difficult IV to establish due to scarring of veins
Elimination of needle reduces needle stick risk
IV unnecessary for any other therapy in majority of cases
IN works as fast or faster than IV naloxone
If the treatment is unsuccessful, one can always proceed to
injectable naloxone and no untoward effects should occur
(may need 3 minutes of bag ventilation while waiting)
 Every EMS system should be utilizing this approach.
Other potential IN medications
 IN glucagon for hypoglycemia
 IN lidocaine for cluster headaches
 IN saline for severe sinus congestion
 IN hydroxycobalamine for cyanide treatment?
 IN antiemetics for N/V, headaches?
IN drug delivery: Requirements
 Appropriate Drug
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Known to be bioavailable across the nasal mucosa
 Appropriate Concentration
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Most concentrated form available
 Appropriate patient
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Requires treatment
Nasal mucosa healthy, free of obvious severe bleeding,
thick mucous, etc
IN drug delivery: Conclusions
 IN drug delivery is:
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Convenient, easy and effective for selected
situations
May result in reduced needlestick risk
Is not always effective
Will NOT replace the need for injections
Can improve and simplify your practice and your
patients experience
Educational Web Links
www.intranasal.net