Transcript Nasal Drug Delivery in EMS

Advances in pain management:
Atomized intra-nasal opiate and
sedative drug delivery:
A Novel method of pain and anxiety
control.
End of life pain and anxiety
control: Problems
 Pain medication requirements increase in
final days.

Hinkka, Support care cancer 2001.
 Breakthrough pain, requiring immediaterelease analgesics is common and difficult to
control.
Miller, Am Fam physician 2001.
 Fine, J Pain Symtom Manage 1998
 Portenoy, Pain 1990

End of life pain and anxiety
control: Problems
 Pain and anxiety medications are
increasingly difficult to deliver:


Oral medications ineffective or too slow.
Patients often can’t swallow, have N/V or GI
obstruction eliminating oral drug delivery option.
Letizia, Hosp J 2000.
 Takala, Acta Anaesthesiol Scand 1997.

End of life pain and anxiety
medication delivery: Options
 Oral



Appropriate for baseline pain control.
Often too slow for breakthrough pain.
Ineffective once patient cannot swallow.
 Transdermal


Appropriate for baseline pain control.
Too slow for breakthrough pain.
 Rectal


Relatively slow for breakthrough pain.
Socially unacceptable to many patients and families.
End of life pain and anxiety
medication delivery: Options
 Subcutaneous/Intramuscular –.







Suboptimal/inappropriate for baseline pain control over
long periods.
OK for breakthrough pain, but delivery method is
painful.
Slower onset than IV or Transmucosal.
Invasive.
Slight infection risk.
Difficult for family members to manage.
Needle stick risks.
End of life pain and anxiety
medication delivery: Options
 Intravenous therapy.






Gold standard for severe pain control.
Appropriate for baseline as well as breakthrough pain
management.
Invasive.
Mild to moderate infection risk.
Difficult for family members to manage.
Needle stick risks.
End of life pain and anxiety
medication delivery: Options
 Transmucosal (Nasal, sublingual, buccal).







Appropriate for baseline as well as breakthrough pain
management.
Titratable.
Non-invasive.
No infection risk.
Easy for family members to manage.
No needle stick risks.
No need to swallow.
Transmucosal medication
delivery
 Is this really a novel idea?
 Commercially available transmucosal drugs:







Actiq oral (transmucosal fentanyl lollipop)
Nitroglycerin – Sublingual.
Stadol (butorphanol) - Intranasal opiate.
Fentora - Transmucosal fentanyl tablet
DDAVP - Intranasal delivery route.
Migraine medications - Intranasal meds available.
Influenza Vaccine - Intranasal system on the horizon.
 Active area of pharm research
Transmucosal Drug Delivery
 Many IV medications, including analgesics
and sedatives, can be delivered
transmucosally, though not available for that
indication commercially:



Large literature base to support their use.
No need to wait for R&D of new forms.
In some cases, generic drugs are available,
cutting costs significantly.
Intranasal Medication
Administration
 Needleless: Intranasal Medication administration
offers a truly “Needleless” solution to drug delivery.
 Superior: Intranasal medication administration
generally results in superior drug delivery to the
blood stream compared to other transmucosal
routes.
The remainder of this slide show will surround the
topic of intranasal drug delivery issues.
Nasal Drug Delivery for Analgesia
and Sedation: What Medications?
Drugs of interest in end of life care:

Analgesics: Intranasal Opiates
Fentanyl
 Sufentanil
 Others


Sedatives: Intranasal Benzodiazepines
Midazolam (Versed)
 Diazepam (Valium)
 Lorazepam (Ativan)

Intranasal Opiates: Literature
support
Zeppetella, J Pain Symptom Manage 2000.
 Assessed IN fentanyl (20 µg total) in 12 hospice
cancer patients with breakthrough pain.
 Results:



Two thirds had pain relief in 10 minutes or less.
Three quarters wanted to continue use.
One-quarter (that did not have good experience) had
higher opiate baseline needs.
 Conclusion: Dosing studies needed.
Intranasal Opiates: Literature
support
Zeppetella, J Pain Symptom Manage 2000.

Problems:



Dose - Too low when compared to other similar studies in postoperative pain patients and recommend IV doses.
 Manufactured recommended dosing for acute pain: 0.5 - 1.5
µ/kg/hr infusion IV.
 Effective intranasal fentanyl post-op pain dose: 1.5 µg/kg
 Opiate dependent patients - may need even higher doses than
post-operative patients.
No titration- Due to rapid onset of action intranasal pain meds can
be titrated to effect. The single dose given in this study is inadequate.
Sample size - makes any conclusions difficult.
Intranasal Opiates: Literature
support
Jackson, J Pain Symptom Manage 2002
 Sufentanil PCINA (Patient Controlled Intra-nasal
analgesia) for breakthrough pain.


Dose: 4.5 µg to 36 µg q 10 minutes up to 3 doses per
event (dose titrated up daily if needed, sufentanil is 8
times more potent than fentanyl)
Preliminary data
“Patients who achieved good pain relief rated IN
sufentanil as much better than their usual opioid
breakthrough, both in speed of onset and efficacy.”
Intranasal Opiates: Literature
support
Striebel, Anesth Analg 1996
Toussaint, Can J Anaesth 2000
Schwagmeier, Anaesthesist 1996
 Compared IV Fentanyl PCA to Fentanyl PCINA
(Patient controlled intranasal analgesia)
 Prospective, Randomized trials
 Results:



No difference in pain intensity
PCINA provided relief of postoperative pain as
effectively as IV PCA
Similar Patient satisfaction
Intranasal Opiates: Literature
support
Striebel, J Clin Anesth 1996
Schwagmeier, Anaesthesist 1996
 Compared Fentanyl PCINA (25 µg, lock out 6
minutes) to customary ward-provided pain control
therapy.
 Prospective, Randomized trials.
 Results:


PCINA provided better pain control
PCINA provided much higher patient satisfaction
Intranasal Opiates: Literature
support
Kendall, BMJ 2001
 Compared nasal diamorphine to IM morphine in
404 ER patients with bony fractures.
 Compared to IM morphine, the nasal medication
had the advantages of



Faster onset of pain relief
No discomfort with administration
More acceptable
IN Fentanyl
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
Intranasal Opiates: Literature
support
Manjushree, Can J Anesth 2002:

IN fentanyl (mean dose 1.43 µg/kg) provides
good pain relief postoperatively.
Hallett, Anaesthesia 2000:

IN diamorphine provides good pain relieve post
operatively.
Wilson, J Accid Emerg Med 1997:

IN diamorphine equivalent to IM morphine
Intranasal Opiates: Literature
support
Striebel, Can J Anaesth 1995:

IN meperidine (Demerol) better than SQ
meperidine for post-op pain.
Strieble, Anaesthesia 1993:

IN fentanyl equivalent to IV fentanyl for post-op
pain
Intranasal Opiates: Web based
support
Sublingual/IN sufentanil protocol for
breakthrough pain:

http://palliative.info/incidentpain.htm
Pain Management abstracted references:


http://www.amedeo.com/medicine/pai/JPAINSY
M.HTM
www.intranasal.net
IN Opiate Bioavailability
 Morphine: 10%
 Morphine plus Chitosan: 31-60%
 Diamorphine: High
 Fentanyl: 70-80% - very lipid soluble
 Sufentanil: 78% - very lipid soluble
 Alfentanil: 65%
 Oxycodone: 46%
Intranasal Sedatives: Literature
support
Benzodiazepines represent the most commonly
studied intranasal sedatives.
 Intra-nasal benzodiazepines studied:



Midazolam (Versed®): Huge literature base
Lorazepam (Ativan®): Small literature base
Diazepam (Valium®): Small literature base
IN Midazolam for 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”
Lloyd, Br J OMFS 2000: IN midazolam prior to oral
and maxillofacial surgery

“Intranasal midazolam is a safe and effective alternative
to general anesthesia in the definitive treatment of
children with oral and maxillofacial injuries”
IN Midazolam for sedation
Bjorkman, Br J Anaesth: Pharmacokinetics of IN midazolam
in adult surgical patients
 “Uptake of Midazolam was rapid and bioavailability was
83%”.
Weber, J Nurse Care Qual: IN midazolam prior to
radiographic procedures.
 In midazolam as followup agent for failure to sedate with
chloral hydrate was 82% effective.
Yealy, Am J Emerg Med 1992:
 “Intranasal midazolam is a safe and effective for sedative
for laceration repair.”
IN Midazolam for sedation
Fukuta, J Clin Pediatr Dent 1993: IN midazolam
for highly combative, mentally disabled dental
patients

Patients “showed a marked improvement in behavioral
patterns after administration of intranasal midazolam.”
Malinovsky, Br J Anaesth 1993:


IN midazolam peaked sooner and 3 times higher than
rectal midazolam.
Sedation occurred sooner with IN meds (7.7min vs. 12.5
min rectal)
IN Benzodiazepine
Pharmacokinetics
 Midazolam




Bioavailability: 60% (drops) to 85% (Atomized)
Clinical onset of action: 5-10 minutes
Peaks: 10-15 minutes
Offset: 30 - 40 minutes
 Lorazepam: 77% bioavailable, single study
 Diazepam: 34% to 50% bioavailable, few
studies
Conclusions
Medications:

Multiple Opiates, Benzodiazepines and other
drugs designed for IV administration are highly
bioavailable via the nasal mucosal membranes.
Dosing:

Needs to be higher than IV forms
Titration:

Due to the rapid CNS and serum penetration,
adequate pain control and/or sedation can be
rapidly achieved.
Conclusions
Research data:



Currently available data for IN analgesics and
sedatives in the hospice setting is limited.
Data from other settings (post-operative,
anesthesia, emergency, radiology and dental) is
more extensive.
Randomized controlled trials to determine the
optimal dosing and quantify any unknown
problems are warranted in hospice setting.
Web Links
 http://palliative.info/IncidentPain.htm
 www.intranasal.net