Intranasal Drug Delivery – Clinical
Implications for Hospice
Lecture outline
 Why use intranasal medications?
 Intranasal drugs indications with clinical cases
and personal insights:
• Pain Control
• Sedation
• Opiate overdose
• Episodic breathlessness
• Seizures
 Optimizing delivery & Drug doses
 Resources
Why do I think nasal drug delivery is
important to this audience (Hospice)?
 Ease of delivery
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Anyone can be trained quickly to deliver nasal medication, to
themselves or their family member
Works even if patient cannot swallow, has N/V
 Speed of delivery
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No delays in pain control, seizure therapy, sedation
Faster, higher levels than sublingual (OTFC), titratable to effect
 Safety
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No needle stick risk, low risk of respiratory depression
 Painless, compassionate delivery method – no injection
 Cost effective
Potential indications for intranasal
medications in Hospice:
Breakthrough pain control – Opiates, ketamine
Episodic breathlessness – Opiates
Sedation- Benzodiazepines, ketamine,
dexmedetomidine
Seizure Therapy – Benzodiazepines
Opiate Overdose – Naloxone
Intranasal Medication Cases
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.
Pain control –
Literature support
Hospice / Chronic pain literature –
Breakthrough pain data
 Taylor 09, Mercadante 09, Palliativecare.org: IN fentanyl
is superior in terms of onset of action, effectiveness of pain
control compared to OTMF (Actiq, Fentora, etc)
 Kress 09, Good 09: Patients prefer IN fentanyl/sufentanil to
standard breakthrough pain regimen
 Carr 04, Huge 09: IN ketamine effective for breakthrough
pain, especially neuropathic pain. Has different mechanism
than opiates so may be good added treatment.
 Many more recent articles (2010-2012) with same
conclusions
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)
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IN fentanyl worked faster
More patients achieved meaningful pain control
77% preferred nasal to Actiq lollipops
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
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)
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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 8-10 times as potent as fentanyl)
 Prospective trial
 Results: (see next slide)
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IN sufentanil worked fast and was safe at home
94% preferred IN sufentanil to prior methods
Good 2009
Literature to support IN opiates- adults
Steenblik, Am J Emerg Med 2012
Safety of Nasal drugs
Dose Titration of opiates
IN opiates for Pain control – My
insights
• This is the most common use of IN drugs in my ER practice.
• The hospice literature on the topic has exploded in the last 2
years and essentially confirms superior efficacy for breakthrough
pain compared to buccal and oral options.
• Generic concentrations available in U.S. work fine and are
inexpensive ($1-4/vial)
• Great patient satisfier: Rapid pain resolution with no
need for a painful injection.
• Efficacy: Very effective – and it can be titrated.
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.
Sitte et al 2008
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
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
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)
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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.
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.
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 Benzos for sedation – my insights
 Generic concentrations of midazolam are fairly dilute – if
they are not effective, try lorazepam 0.1 mg/kg
 Timing: Sedation onset at about 10 minutes, maximal at
10-20 and starts to wear off at 25-30 so if you plan a
procedure, be ready to do procedure in this time frame.
 Efficacy: Sedation is not deep. OK for minor procedures,
 Burning: there is some mild burning for 30 seconds with
this drug– forewarn the patient or pretreat children with
lignocaine.
Case 5: 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%.
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 RCT studies and extensive clinical
experience demonstrate successful, safe home, EMS
and ER therapy for seizures.
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This is now standard of care in Australia/NZ and
becoming very common in USA
Onset of nasal vs buccal seizure drugs
(Time of onset matters)
Anderson 2011: IN vs buccal lorazepam
The Doubters: Surely IN drugs
can’t be as good as IV for seizures!
ACTUALLY – They are equivalent or better (in these settings)
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Lahat 00, Mahmoudian 04, Arya 11, Thakker 12, Javadzadeh
12 – IV and IN are equivalent for stopping seizures rapidly,
but IN works faster due to no delays
Holsti 2007, Fisgin 2002 – IN is superior to rectal
Holsti 2011 – IN is safe at home with immediate results
Conclusions
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IN seizure medication are just as good as IV, better than rectal
IN seizure medication are delivered much more rapidly so seizure stops
sooner.
Anyone (Parents, care givers, nursing home staff, ambulance driver,
etc.) can administer the medication so seizure length is shorter.
IN benzodiazepines for
seizures – My insights
Very effective, very fast: Rapid seizure resolution
without IV access.
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Should be first line therapy in ALL acute seizures while
IV access is being established (if at all)
Effective and safe at home, in EMS setting, in hospital
More effective, less expensive and preferred by
providers when compared to alternative (rectal
diazepam).
Final Case: Oral morphine,
fentanyl patch induced coma
A daugheter enters her chronically ill mothers room to find her
unconscious, barely breathing, blue color. Since her mother is
on powerful opiates, the family was trained to deliver rescue
naloxone (see photo of kit above).
 The daughter quickly delivers the naloxone intranasally.
 She provides 2-3 minutes of rescue breathing until her mother
begins to arouse. She gradually awakens over 10 minutes.
 The patient makes an uneventful recovery.
Opiate overdose –
Literature support
Intranasal naloxone literature
 Barton 02, 05; Kelly 05; Robertson 09; Kerr 09; Merlin 2010;
Doe Simkins 09; Walley 12:
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IN naloxone is at least 80-90% effective at reversing opiate
overdose
When compared directly it is equivalent in efficacy to IV or IM
therapy.
IN naloxone results in less agitation upon arousal
IN naloxone is lay person approved in many places. It safe and
has saved many lives.
IN naloxone for opiate overdose
– my insights
Why not? Is there a downside?
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No need for an IV
Elimination of needle – no pain, eliminates needle stick risk
They awaken more gently than with IV naloxone.
Simple enough that lay public can administer and not even call
ambulance – extensive supporting evidence
Every ambulance system, police agency and many clinics and
families with high risk patients should be utilizing this
approach.
Drug doses
Scenario
Drug and Dose
Important Reminders
Pain Control
Fentanyl: 2 mcg/kg
Sufentanil: 0.5 mcg/kg
•Titration is possible
•Sufentanil – use pulse ox
•Half up each nostril
Sedation
Midazolam: 0.5 mg/kg
(combination w/ pain)
•Lidocaine prevents burning
•Use concentrated formula
Seizures
Midazolam: 0.2 mg/kg
Lorazepam 0.1 mg/kg
•Support breathing while waiting
•Use concentrated formula
Opiate Overdose Naloxone: 2 mg
•Support breathing while waiting
Optimizing absorption of IN
drugs
Critical
 Minimize volume - Maximize concentrationConcept
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0.2 to 0.3 ml per nostril ideal, 1 ml is maximum
Most potent (highly concentrated) drug should be used
 Maximize total absorptive mucosal surface area
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Use BOTH nostrils (doubles your absorptive surface area)
 Use a delivery system that maximizes mucosal
coverage and minimizes run-off.
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Atomized particles across broad surface area
Dropper vs Atomizer
Absorption
 Drops = Oral drug via the
nasal passage
 Atomizer = nasal mist onto
broad mucosal surface
Usability / acceptance
 Drops = Minutes to give,
cooperative patient, head
position critical
 Atomizer = seconds to
deliver, better accepted
Intranasal medications summary
 Another tool for drug delivery to
supplement standard IV, IM, PO–very
useful when appropriate
 Supported by extensive literature
 Inexpensive
 Speeds up care in many situations
 Safe
Questions?
Educational Web sites:
 www.intranasal.net
 Doctorsevidence.com/LMA
 http://palliative.info/IncidentPain.htm
 www.palliativedrugs.com