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 6

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 Olfactory mucosa, nerve 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. 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 Seizure Therapy – Benzodiazepines

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 Intranasal vs buccal: 33% pain reduction 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 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) 24

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 25

Carr 2004 Intranasal Ketamine: Meaningful pain reduction in 10 minutes Low dose No side effects Alternative therapy when opiate failing 26

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. 27

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