Intranasal Medications in the Prehospital Setting

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 child’s pain is improved but still substantial. After a second dose of IN fentanyl he is comfortable.

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.

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 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.

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.

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.

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!

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.

…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

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.

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

Understanding IN delivery: Definitions 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.

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

Lipophilicity “Lipid Loving” Non-lipophilic molecules 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

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.

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?

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.

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.

Volume and concentration: 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

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.

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.

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.

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.

Nasal Drug Delivery in EMS: What Medications? Drugs of interest to EMS systems: Intranasal naloxone (Narcan) Intranasal midazolam (Versed) Intranasal fentanyl Others

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

“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.

IN Naloxone by Paramedics

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.

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.

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 > 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 > 10 are same as those for IV and SQ.

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 doesn’t 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.

What if intranasal naloxone does not work? 1st - Continue ABC’s 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?

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.

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

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

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.

IN Midazolam Seizures. Lahat et al, 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.

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.

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.

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

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)

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.

Fentanyl What is it? Synthetic opiate pain killer Water soluble 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

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)

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

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

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

Other IN Medications ALS Drugs Glucagon ?Hydroxycobalamine for cyanide ??others

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

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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