Intranasal Medications
in Hospice
A Novel method of pain,
dyspnea, seizure and anxiety
control.
Disclosures
 Off Label Medications will be discussed
(all the indications are “on label” but the delivery
method is “off label”)
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
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.
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.
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
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.
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%.
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
Understanding IN delivery:
Key concepts
First pass metabolism
Nose brain pathway
Bioavailability
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
Brain
CSF
Highly vascular nasal mucosa
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
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
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

Minor comments
Seizure Therapy – Benzodiazepines

Minor comments
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
Mercadante
2009
33% pain reduction
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
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
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%
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
Good 2009
Dose Titration of opiates
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
Intranasal Ketamine for pain:
Why ketamine?
 NMDA receptor blocker – different site than
opiates
 Doses 10-15 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)
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
Carr 2004
Intranasal
Ketamine:
 Meaningful
pain reduction
in 10 minutes
 Low dose
 No side effects
 Alternative
therapy when
opiate failing
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.
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 www.palliativedrugs.com)
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
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
Contact and Educational
Information
 Educational web site(s) with extensive
literature on this topic:
www.intranasal.net


http://palliative.info/IncidentPain.htm
www.palliativedrugs.com