2Scenario 1: Broken armA 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).10 minutes later the child’s pain gone and she is calmShe is taken off to x-ray for diagnostic evaluation of his fracture
3Scenario 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.
4Scenario 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.
5Scenario 4: EpistaxisA 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.
6Scenario 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.
7Scenario 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.
8Why IN medications? This delivery route has several advantages: Its easy and convenientAlmost everyone has a noseThe nose is a very easy access point for medication delivery - even easier to access than IM or IV sitesNo special training is required to deliver the medicationNo shots are neededIt is painlessIt eliminates any risk of a needle stick to the medical provider
9Lecture Outline Intranasal drug delivery: General principles Intranasal drugs in clinical practice:Pain control - opiatesSedation - opiates, benzos, ketamineSeizure Therapy - benzosNasopharyngeal procedures and epistaxis- anesthetics, vasoconstrictorsOpiate overdose - naloxoneOther
10Understanding IN delivery: General principles First pass metabolismNose brain pathwayLipophilicityBioavailability
11First pass metabolismMolecules 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.
13Nose brain pathwayThe 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, nerveBrainCSFHighly vascular nasal mucosa
14Lipophilicity “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 moleculesCell MembraneBlood stream
15BioavailabilityHow 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.
16BioavailabilityGraph 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.
17Intranasal 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.
18Intranasal 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.
19Volume and concentration: Intranasal Medication Administration: Factors Affecting BioavailabilityVolume 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.
20Intranasal 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 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.
21Intranasal Medication Administration: Factors Affecting Bioavailability Delivery system characteristics:Nasal mucosal surface area coverage:Larger surface area delivery = higher bioavailability.Particle size:Particle size microns adheres best to the nasal mucosa.Smaller particles pass on to the lungs, larger particles form droplets and run-out of the nose.
22Intranasal Medication Administration: Factors Affecting Bioavailability Bioavailability and Particle size: Henry, Ped Dent 1998.Study: Compared IV, IN drops and IN atomization in animal model. Measured Serum and CSF concentrations.Results:Serum levels: IV >Atomization > Drops.CSF levels: Atomization>>Drops>IV.Conclusion:Atomization results in higher serum bioavailability than drops and higher CSF bioavailability than IV.
23Bioavailability 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.
24Intranasal 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.
25Nasal Drug Delivery: What Medications? Drugs of interest to Emergency Departments:Pain control and Sedation- opiates, benzos, ketamineSeizure Therapy - benzosNasopharyngeal procedures and epistaxis- anesthetics, vasoconstrictorsOpiate overdose - naloxoneOther
26Pain control and sedation Pain Medications Sedatives• Diamorphine • Midazolam• Fentanyl • Ketamine• Sufentanil• Meperidine
27Pain 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, 1994Both methods equally effective in achieving sedationIN sufentanil and midazolam superior in:Better tolerated by the patients13 minutes faster onset to time of laceration injection (20 vs 33 minutes)27 minute faster discharge (54 vs 81 minutes)
28Pain 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), 200245 Children in acute pain given IN Fentanyl (20 to 40 ug)Titration allowed q 5 minutesResultsMean VAS score reductions of 18 mm at ten minutesNo negative side effects
29Pain 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 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.
30Pain control and sedation Borland, Ann Emerg Med, 2007.IN fentanyl versus IV morphine for treatment of pediatric orthopedic fractures - Randomized, double blind, placebo controlled trialResults:Pain scores identical for IV morphine and IN fentanyl at 5, 10, 20 and 30 minutesLess time to delivery of medication via nasal routeConclusion: IN fentanyl is as effective as IV morphine for treating pain associated with broken extremities
31Pain 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 trialResults:Pain scores identical for IV morphine and IN fentanyl by the time the hospital was reachedLess time to delivery of medication via nasal routeConclusion: IN fentanyl is as effective as IV morphine for treating pain in adult EMS patients
32Pain control and sedation Caveats:Borland and Rickard used concentrated fentanyl (150 to 300 mcg/ml)U.S. generic fentanyl comes in 50 mcg/ml concentrationsThis lower concentration will likely reduce efficacy leading to the need to titrate doseIdea - Sufentanil is more potent than fentanyl and is very effective in adults for controlling pain
33Pain control and sedation Louon et al: Nasal midazolam and ketamine for paediatric sedation during computerised tomography. Acta Anaesthesiol Scand, 199430 children < 16 kg requiring CTDose: Midazolam 0.6 mg/kg, Ketamine 5 mg/kg mixedResults:83% effective sedationRapid onsetNo complications or desaturations
34Pre-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”
35Pre-operative pediatric sedation Zedie: Comparison of intranasal midazolam and sufentanil premedication in pediatric outpatients. Clin Pharmacol Ther 1996Pre-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.”
36Post-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”
37Post-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”
38IN opiates and benzos - My spin IN opiates and benzos are clearly effective HOWEVER:Still in its infancy due to: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.
39IN opiates and benzos - My spin We need: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
41Seizure TherapyLahat et al:Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study. BMJ, 2000Prospective 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.
42Seizure TherapyFisgin et al:Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study. J Child Neurol, 2002IN midazolam versus rectal diazepam for treatment of pediatric seizure. Prospective trialResults:IN midazolam effective in 87% of seizures.Rectal diazepam effective in 60%Conclusion:IN midazolam is more effective for controlling seizures than rectal diazepam and is more socially acceptable
43Seizure TherapyScheepers et al: Is intranasal midazolam an effective rescue medication in adolescents and adults with severe epilepsy? Seizure, 2000IN 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.
44Seizure Therapy Holsti, Pediatr Emerg Care, 2007. IN midazolam versus rectal diazepam (PR) for treatment of pediatric seizure in EMS setting - before an after trialResults:IN midazolam - 19 minutes less seizure activity on average (11 min IN vs 30 min PR)Rectal diazepamMore 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)
45Seizure TherapyWilson, 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.83% “effective and easy to use.”83% “preferred it to rectal diazepam.”
46Seizure TherapyAhmad. et al: Seizure therapy - IN lorazepam vs IM paraldehyde in rural Africa. Lancet 2006.RCT of 160 children with status epilepticus.Mean seizure duration 128 minutes75% controlled with single dose IN lorazepam61% controlled with IM paraldehydeConclusions: IN lorazepam is safe, non-invasive and effective in prehospital setting
48IN 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).
49Nasopharyngeal procedures and epistaxis Topical anesthetics Topical vasoconstrictors• Lidocaine • Oxymetazoline• Benzocaine • Phenylephrine• Tetracaine • Cocaine• Cocaine• Etc.
50Nasopharyngeal 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, 1999Topical nasal and oral anesthetics with nasal vasoconstrictors result in markedly reduced pain and gagging compared to placebo during NGT placementPain VAS: 28.6 mm vs 57.5 mmGagging VAS: 24.1 mm vs 50.9 mm
51Nasopharyngeal 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, 2000Topical 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
52Nasopharyngeal procedures and epistaxis Krempl et al: Use of oxymetazoline in the management of epistaxis. Ann Otol Rhinol Laryngol, 1995Retrospective ED study60 patients with epistaxisResults:65% controlled with oxymetazoline alone83% success with oxymetazoline plus silver nitrateOnly 17% needed packing
53Nasopharyngeal procedures and epistaxis Doo et al: Oxymetazoline in the treatment of posterior epistaxis. Hawaii Med J, 1999Retrospective study36 patients with posterior epistaxisResults:75% controlled with oxymetazoline aloneRemaining 25% treated non-surgically with recurrent oxymetazoline therapy
54Nasopharyngeal procedures and epistaxis Katzet al: A comparison of cocaine, lidocaine with epinephrine, and oxymetazoline for prevention of epistaxis on nasotracheal intubation. J Clin Anesth 19903 groups of 14 pateints pretreated with the study drugFollowing NT intubation, amount of epistaxis scoredLidocaine 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
55IN anesthetics and vasocontrictors: My Spin Nasal instrumentation: Do it every timeProven by multiple RCT’s to reduce pain and bleeding associated with nasal procedures such as NGT placement and nasal intubation.Epistaxis: Probably effective, very simpleNasal oxymetazoline for the treatment of epistaxis is intriguing and appears to be effectiveBetter quality studies are needed.
56Treating Opiate overdose The problem! NEEDLESTICKSNasal 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!
57Treating Opiate overdose Hussain et al: Nasal absorption of naloxone and buprenorphine in rats. Int J Pharm, 1984Naloxone 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 1994Nasal naloxone was as effective as IV naloxone in eliciting opiate withdrawal.
58Treating Opiate overdose Barton et al: Intranasal administration of naloxone by paramedics. Prehosp Emerg Care, 2002Prospective prehospital study investigating the efficacy of IN naloxone in treating opiate overdoses100 patients entered, 52 determined to have opiate overdoseResults:43/52 (83%) = “IN Naloxone Responders.”Conclusions:IN naloxone is effective most of the timeRoutine use may reduce needle stick injuries
59Prehospital IN Naloxone Results (cont.).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.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
61Other 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.
62What 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.
63Treatment of opiate overdose with IN naloxone: My spin Why not?High risk population for HIV, HCV, HBVDifficult IV to establish due to scarring of veinsElimination of needle reduces needle stick riskIV unnecessary for any other therapy in majority of casesIN works as fast or faster than IV naloxoneIf 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.
64Other potential IN medications IN glucagon for hypoglycemiaIN lidocaine for cluster headachesIN saline for severe sinus congestionIN hydroxycobalamine for cyanide treatment?IN antiemetics for N/V, headaches?
65IN drug delivery: Requirements Appropriate DrugKnown to be bioavailable across the nasal mucosaAppropriate ConcentrationMost concentrated form availableAppropriate patientRequires treatmentNasal mucosa healthy, free of obvious severe bleeding, thick mucous, etc
66IN drug delivery: Conclusions IN drug delivery is:Convenient, easy and effective for selected situationsMay result in reduced needlestick riskIs not always effectiveWill NOT replace the need for injectionsCan improve and simplify your practice and your patients experience