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 immediate-release 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 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 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.

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/JPAINSYM.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: Dosing: Titration: 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