1. Intranasal Medications in clinical practice

2. 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).
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

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. Why IN medications? 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 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

9. Lecture Outline Intranasal drug delivery: General principles
Intranasal drugs in clinical practice:
Pain control - opiates
Sedation - opiates, benzos, ketamine
Seizure Therapy - benzos
Nasopharyngeal procedures and epistaxis- anesthetics, vasoconstrictors
Opiate overdose - naloxone
Other

10. Understanding IN delivery: General principles
First pass metabolism
Nose brain pathway
Lipophilicity
Bioavailability

11. 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.

12. First pass metabolism

13. 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

14. 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

15. 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.

16. Bioavailability
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.

17. 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.

18. 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.

19. 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 over 1/2 to 1 ml per nostril are too large and may result in runoff out of the nostril.

20. 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 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.

21. Intranasal 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.

22. Intranasal 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.

23. 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.

24. 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.

25. Nasal Drug Delivery: What Medications?
Drugs of interest to Emergency Departments:
Pain control and Sedation- opiates, benzos, ketamine
Seizure Therapy - benzos
Nasopharyngeal procedures and epistaxis- anesthetics, vasoconstrictors
Opiate overdose - naloxone
Other

26. Pain control and sedation
Pain Medications Sedatives
• Diamorphine • Midazolam
• Fentanyl • Ketamine
• Sufentanil
• Meperidine

27. 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)

28. 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)
Titration allowed q 5 minutes
Results
Mean VAS score reductions of 18 mm at ten minutes
No negative side effects

29. 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 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.

30. 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
Conclusion: IN fentanyl is as effective as IV morphine for treating pain associated with broken extremities

31. 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
Conclusion: IN fentanyl is as effective as IV morphine for treating pain in adult EMS patients

32. Pain control and sedation
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

33. 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

34. 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”

35. Pre-operative pediatric sedation
Zedie: Comparison of intranasal midazolam and sufentanil premedication in pediatric outpatients. Clin Pharmacol Ther 1996
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.”

36. 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”

37. 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”

38. IN 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.

39. IN 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

40. Seizure Therapy
Anticonvulsants
Midazolam
Lorazepam??

41. 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.

42. 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%
Conclusion:
IN midazolam is more effective for controlling seizures than rectal diazepam and is more socially acceptable

43. 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.

44. 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
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)

45. 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.
83% “effective and easy to use.”
83% “preferred it to rectal diazepam.”

46. Seizure Therapy
Ahmad. 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 minutes
75% controlled with single dose IN lorazepam
61% controlled with IM paraldehyde
Conclusions: IN lorazepam is safe, non-invasive and effective in prehospital setting

47. Seizure Therapy Cost (March 7, 2004 Internet search):
Rectal diazepam (Diastat brand name)
10 mg: $171 - $194 (£94 - £106)
IN midazolam
10 mg: $4 - $17 (£2- £9)

48. 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).

49. Nasopharyngeal procedures and epistaxis
Topical anesthetics Topical vasoconstrictors
• Lidocaine • Oxymetazoline
• Benzocaine • Phenylephrine
• Tetracaine • Cocaine
• Cocaine
• Etc.

50. 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

51. 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

52. 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

53. 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

54. 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

55. 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.

56. 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!

57. 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.

58. 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

59. Prehospital 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

60. IN Naloxone by Paramedics

61. 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.

62. 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.

63. Treatment of opiate overdose with IN naloxone: My spin
Why not?
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.

64. 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?

65. IN drug delivery: Requirements
Appropriate Drug
Known to be bioavailable across the nasal mucosa
Appropriate Concentration
Most concentrated form available
Appropriate patient
Requires treatment
Nasal mucosa healthy, free of obvious severe bleeding, thick mucous, etc

66. IN drug delivery: Conclusions
IN drug delivery is:
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

67. Educational Web Links