Advances%20in%20pain%20management:

1
Advances in pain management

• Atomized intra-nasal opiate and sedative drug
  delivery
• A Novel method of pain and anxiety control.

2
End of life pain and anxiety control Problems

• Pain medication requirements increase in final
  days.
• Hinkka, Support care cancer 2001.
• Breakthrough pain, requiring immediate-release
  analgesics is common and difficult to control.
• Miller, Am Fam physician 2001.
• Fine, J Pain Symtom Manage 1998
• Portenoy, Pain 1990

3
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 cant swallow, have N/V or GI
  obstruction eliminating oral drug delivery
  option.
• Letizia, Hosp J 2000.
• Takala, Acta Anaesthesiol Scand 1997.

4
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.

5
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.

6
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.

7
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.

8
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

9
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 RD of new forms.
• In some cases, generic drugs are available,
  cutting costs significantly.

10
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.

11
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)

12
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.

13
Intranasal Opiates Literature support

• Zeppetella, J Pain Symptom Manage 2000.
• Problems
• Dose - Too low when compared to other similar
  studies in post-operative 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.

14
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.

15
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

16
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

17
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

18
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

19
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

20
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

21
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/JPAINSYM.HTM
• www.intranasal.net

22
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

23
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

24
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

25
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.

26
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)

27
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

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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.

29
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.

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Web Links

• http//palliative.info/IncidentPain.htm
• www.intranasal.net