1. Intranasal Medications in Hospice
A Novel method of pain, dyspnea, seizure and anxiety control.

2. Disclosures Off Label Medications will be discussed
(all the indications are “on label” but the delivery method is “off label”)

3. IN medications and off-label use
What is “off-label” use
Use other than FDA approved specific indications in specific subpopulations by specific route of delivery
Is it OK to use drugs “off-label”
Yes – in fact is is expected this will occur and this actually helps advance medical care – supported by FDA, supreme court, standards of care practice, etc
We all do it and its not only legal, it is expected to occur.
In fact – about 80% of critically ill children and 40% of adults are treated with “off label” medications (Hospice?)
Failure to provide off label can result in malpractice
Example - N-acetylcysteine for Tylenol overdose

4. Case 1: Patient with bony metastasis with breakthrough pain
A 65 year old female with metastatic breast CA to her spine
Every time she gets up to use the toilet, she suffers severe pain. She also has spontaneous spells of severe pain even at rest (despite baseline opiate therapy).
Solution: Prior to movement and/or during spontaneous breakthrough pain she self administers 30 mcg of intranasal sufentanil (30 mcg – 0.6 ml of generic IV sufentanil)
Within 5 minutes her pain is improved
At 15 minutes the patient easily tolerates movement to go to the toilet or conduct other activities.

5. Case 2: Episodic breathlessness
A 73 y.o. man with metastatic carcinoma to
lungs complains of severe dyspnea and cough.
RR = 30, O2 saturation 62%, air hunger.
Solution: You administer 50 to 150 mcg of intranasal fentanyl – (Fentanyl compounded to 500mcg/ml).
In 3 minutes he has improved symptomatically
At 7 minutes his RR = 12, O2 saturation = 94%.
He self delivers 100 mcg IN fentanyl on an as needed basis for the remainder of his care – using it about 7 times/day
He dies comfortably within one week, having no further severe dyspnea/air hunger issues.

6. Case 3: Neuropathic pain
A 59 y.o. man with ALS who suffers extreme neuropathic pain with any contact to his skin.
Is already on high doses of opiates to point of sedation and inability to interact with family
Family cannot touch him due to exacerbation of his pain
Solution: You administer 50 mg of intranasal ketamine – (100 mg/ml – 0.5 ml total).
In 10 minutes he can be touched
He is able to back off the opiates and be somewhat more alert so he can interact more and touch his loved ones for the last weeks of his life 6

7. Case 4: Dementia with spells of severe agitation
An 86-year old man with dementia, end stage cardiovascular disease suffers intermittent spells of agitation and violent behavior not amendable to pain medication.
He is agitated, powerful and dangerous to home assistants and to himself.
Solution: You administer 5-10 mg of IN midazolam (titrate) and 10 minutes later he is calm.

8. Last case: Seizing patient
55 y.o. with metastatic melanoma – has brain metastasis and seizures.
Suffers from recurrent seizures that often progress to status epilepticus.
Has been transported to ER multiple times simply to control seizures
Rectal diazepam is unsuccessful at controlling the seizure.
Solution: Intranasal midazolam is given and within 3 minutes of drug delivery he stops seizing. This is implemented as home therapy and his EMS/ER trips drop off 80%.

9. Advantages of IN medications in Hospice
Ease of use and convenience
Rapidly effective - onset within 3-10 minutes
Short acting – no long side effects from drug
No special training is required to deliver the medication
No shots are needed – Totally Painless
No needle stick risk, no infection risk
Patients (and family) really like this approach
Works even if patient cannot swallow or has N/V
Socially acceptable (no rectal drugs)
Better than sublingual (faster onset, higher drug levels)
Titratable to effect – can re-dose every 5-15 minutes
Inexpensive –use generic or compounded drug

10. Understanding IN delivery: Key concepts
First pass metabolism
Nose brain pathway
Bioavailability

11. First pass metabolism Nasal Mucosa: No first pass metabolism
Gut mucosa: Subject to first pass metabolism

12. Nose brain pathway Olfactory mucosa, nerve
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.
Brain
CSF
Highly vascular nasal mucosa

13. 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:
Midazolam 75+%
Fentanyl and Sufentanil 80+%
Naloxone 90+%
Lorazepam, ketamine, Romazicon, etc, etc

14. Optimizing Bioavailability of IN drugs
Critical
Concept
Minimize volume - Maximize concentration
0.2 to 0.4 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
Beware of abnormal nasal mucosal characteristics
Mucous, blood and vasoconstrictors reduce absorption
Suction nose or consider alternate delivery route if present

15. Potential indications for intranasal medications in Hospice:
Breakthrough pain control – Opiates, ketamine
This will be the main focus
Episodic breathlessness – Opiates
Minor comments
Sedation- Benzodiazepines, ketamine, dexmedetomidine
Seizure Therapy – Benzodiazepines

16. Intranasal Opiates for pain: Literature support
Mercadante, Current Med Res Opinion 2009
Compared IN Fentanyl (compounded) to OTFC (Actiq) for cancer breakthrough pain
Prospective, Randomized, crossover trial
Results: (see next slide)
IN fentanyl worked faster
More patients achieved meaningful pain control
77% preferred nasal to Actiq lollipops

17. Mercadante 2009 Intranasal vs buccal:
33% pain reduction
Mercadante 2009
Intranasal vs buccal:
Meaningful pain reduction 11 minutes vs 16 minutes
Preferred by 77%
Much faster onset of pain control on VAS for 33% and 50% drop in pain scores
50% pain reduction

18. Intranasal Opiates for pain : Literature support
Kress, Clinical Therapeutics 2009
Compared IN Fentanyl (compounded) to placebo plus standard therapy for cancer breakthrough pain
Prospective, Blinded, Randomized, crossover trial
Results: (see next slide)
IN fentanyl showed significant pain reduction by 5 minutes
More INF patients achieved meaningful pain control
Only 14% of INF used rescue drug, while 45% of control group used rescue drug

19. Kress, 2009 Intranasal Fentanyl vs standard therapy:
Much faster onset of pain control on VAS
Well tolerated
Impression of pain control “good to very good” in 75% vs 31%

20. Intranasal Opiates for pain : Literature support
Good, Palliative Med 2009
Investigated efficacy of generic IN sufentanil for cancer breakthrough pain
(Sufentanil is 10 times as potent as fentanyl)
Prospective trial
Results: (see next slide)
IN sufentanil worked fast and was safe at home
94% preferred IN sufentanil to prior methods

21. Good 2009

22. Dose Titration of opiates

23. Intranasal Opiates for dyspnea: Literature support
Sitte, Intranasal fentanyl for episodic breathlessness, J Pain & Symptom Management 2008
Case series describing their experience with IN fentanyl for breathlessness
Their pharmacy compounds the drug for them
Have used in over 200 patients successfully
Have not seen patients overuse or significant side effects

24. Intranasal Ketamine for pain:
Why ketamine?
NMDA receptor blocker – different site than opiates
Doses times less than anesthetic dose are all that is needed for pain control (analgesia)
Side effects are dose dependent – so rare side effects
Alternative option to opiates, ideal for neuropathic pain (common in cancer, radiation injury to nerves, MS, ALS, etc) 24

25. Intranasal Ketamine for pain: Literature support
Carr, Pain 2004
Compared IN Ketamine (generic 100 mg/ml) to placebo for breakthrough pain
Prospective, Randomized, crossover trial
1 atomized spray (10 mg) q 90 sec to 5 doses max
Results: (see next slide)
VAS drop in pain 26.5 mm vs 8 mm
Onset of pain relief 10 minutes
No side effects at this dose 25

26. Carr 2004 Intranasal Ketamine: Meaningful pain reduction in 10 minutes
Low dose
No side effects
Alternative therapy when opiate failing 26

27. 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. 27

28. IN Midazolam for adult sedation
Hundreds of articles showing efficacy in sedation in children and in some adult studies outside the hospice setting.
No actual published literature in hospice
Many discussions demonstrating sublingual benzodiazepines work – so nasal should work as well or better (see

29. IN Midazolam for adult sedation
Hollenhorst, AJR 2001: IN midazolam for MR imaging in adults
Resulted in “sizable reduction in MR imaging related anxiety and improved MR image quality”
Tschirch,Eur Radiology 2007: IN midazolam prior to MRI in adults
97% success rate in anxiolysis
Manley, Brit Dental 2008: IN midazolam prior to dental therapy in agitated, mentally disabled adults
93% success rate in sedation prior to oral procedures

30. IN Midazolam for adult seizures
Scheepers, Seizure 2000: Is intranasal midazolam an effective rescue medication in adolescents and adults with severe epilepsy?
84 adult seizures treated, 79 successfully
Much preferred to rectal and more effective
Other: Numerous studies demonstrate successful, safe home, EMS and ER therapy for seizures.
This is now standard of care in Australia/NZ and becoming very common in USA

31. Contact and Educational Information
Educational web site(s) with extensive literature on this topic: