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 • Opiate overdose

• Sedation • Epistaxis

• Seizures • Nasopharyngeal procedures

Drug doses Resources

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

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

BrainCSF

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

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

Critical Concept

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 Fentanyl, sufentanil, ? ketamine

Sedation- Benzodiazepines, ά-2 Agonists Midazolam, dexmedetomidine

Seizure Therapy – Benzodiazepines Midazolam, Lorazepam

Opiate overdose - Naloxone

Nasopharyngeal procedures and epistaxis 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) 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) 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 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!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

Nasal

Intravenous

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

Pain control – Literature support

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. 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: 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. 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.

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)

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.

IN benzodiazepines for seizures – My insightsVery 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).

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:

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.

Opiate overdose – Literature supportIntranasal 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.

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

ambulanceEvery ambulance system, police agency and many clinics and families

with high risk patients should be utilizing this approach.

Intranasal medication cases

Topical anesthetics Topical vasoconstrictors

• Lidocaine • Oxymetazoline

• Benzocaine • Phenylephrine

• Tetracaine • Cocaine

• Cocaine

• Etc.

Nasopharyngeal procedures and epistaxis

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 Proven by multiple studies to improve

procedural comfort.

Epistaxis: Very effective, very simple Inexpensive and easy

Drug dosesScenario Drug and Dose Important Reminders

Pain Control Fentanyl: 2 mcg/kgSufentanil: 0.5 mcg/kgKetamine 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/kgLorazepam 0.1 mg/kg

•Support breathing while waiting •Use concentrated formula

Opiate Overdose Naloxone: 2 mg •Support breathing while awaiting onset

Epistaxis Oxymetazoline orPhenylephrine +Lidocaine

•Blow nose prior to application•Spray, then apply soaked cotton ball•Pinch nose for 10 minutes

Nasal Procedures Oxymetazoline orPhenylephrine +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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