Intranasal Drug Delivery – Clinical Implications for Pre-hospital care

Lecture outline Why use intranasal medications? Intranasal drug delivery: General concepts Intranasal drugs indications with clinical cases and personal insights: • Pain Control • Sedation • Seizures • Opiate overdose Drug doses Resources

Why do I think nasal drug delivery is important in prehospital care? Efficacy, speed and ease of delivery No delivery delays (no IV) Can deliver to anyone with an exposed nose Rapid onset of action (Pain control, Sedation, seizure, overdose) As effective and fast as IV drugs in most situations Safety No needle stick risk Lower risk of respiratory depression (compared to IV) Easier to proceed with additional care Start IV in children or agitated adult Calm the agitated patient

Understanding IN delivery: General principles First pass metabolism Nose brain pathway Bioavailability / Drug absorption Safety vs IV drugs

First pass metabolism Nasal Mucosa: No first pass metabolism Gut mucosa: Subject to first pass metabolism 5

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. Offers a rapid, direct route for drug delivery to the brain (skipping the blood brain barrier). Brain CSF Highly vascular nasal mucosa 6

Nose brain pathway 7

Bioavailability/ Drug absorption 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 depending on molecule, pH, etc Midazolam 75+% Fentanyl and Sufentanil 80+% Naloxone 90+% Lorazepam, ketamine, Romazicon, etc

Optimizing Bioavailability of IN drugs Critical Concept Minimize volume - Maximize concentration 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 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 may reduce absorption Suction nose or consider alternate delivery route if present 9

Dropper vs Atomizer Absorption Usability / acceptance Drops = runs down to pharynx and swallowed Atomizer = sticks to broad mucosal surface and absorbs Usability / acceptance Drops = Minutes to give, cooperative patient, head position required Atomizer = seconds to deliver, better accepted

Dropper vs Atomizer Merkus 2006

Safety of Nasal drugs

Safety and onset of Nasal drugs

Intranasal Medications What IN medications can we use in Prehospital care?

Nasal Drug Delivery: What Medications? Pain control – Opiates, other Fentanyl, ketamine? Sedation- Benzodiazepines Midazolam, lorazepam Seizure Therapy – Benzodiazepines Opiate overdose - Naloxone 15

Intranasal Medication Cases Pain Control

Case: MVC pinned in car A 35 year old male pinned in a car following an MVC. Bilateral upper arm fractures, femur fracture, likely other injuries. Screaming in pain. Clinical Needs: Pain control, sedation, rapid extraction, then IV access (cannot do so now). Treatment: 1.5 mcg/kg of intranasal fentanyl plus 5 mg IN midazolam In 7 minutes his pain is much better controlled and he is calmer Extraction requires 20 minutes, then full trauma assessment and care proceeds. 17

Case: Pediatric Hand burn A 5 year old burned her hand on the stove Clinical Needs: Pain control, Transport for wound care Treatment: 2.0 mcg/kg of intranasal fentanyl (40 mcg – 0.8 ml of generic “IV” fentanyl) Within 3-5 minutes her pain is improved She is transported to a nearby medical facility 15 minutes later the patient easily tolerates cleansing of the burn and dressing application. 18

Literature to support these cases - pediatrics Nasal Intravenous Borland, Ann Emerg Med 2007 19

Pain control – Literature support Over a decade of prehospital and ER literature exists for burn, orthopedic trauma and visceral pain in both adults and children showing the following: Faster drug delivery (no IV start needed) so faster onset Equivalent to IV morphine Superior to IM morphine Care givers are more likely to treat pediatric severe pain Highly satisfied patients and providers Safe

Pain control – Literature support Prehospital and wounded soldier literature Rickard 07 (MAD): IN fentanyl equal to IV morphine for pain control in adults. No IV needed. McLean 09 (MAD): IN fentanyl very effective for adult ski trauma victims with onset of action on less than 5 minutes Johnstone 09 (MAD): IN fentanyl in ambulance is very effective for “visceral” non-traumatic pain in adults. U.S. Military: Ketamine 50 mg IN is as good/better than morphine 7.5 mg IV for acute pain and the soldier can self administer and potentially continue his mission.

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.

Nasal The Doubters: Surely IN drugs can’t be as good as an injection for pain control! Intravenous ACTUALLY – They are equivalent or better (in these settings) Borland 2007 – IN fentanyl onset of action and quality of pain control was identical to IV morphine in patients with broken legs and arms Borland 2008, Holdgate 2010, Crellin 2010 - time to delivery of IN opiates was half that of IV and more patients get treated Kendal 2001 – IN opiate superior to IM opiate for pain control Conclusions IN opiates are just as good as IV IN opiates are delivered in half the waiting time as IV IN opiate are preferred by patients, providers and parents over injections 23

IN opiates for Pain control – My insights I use nasal opiates in my practice - daily. Our statewide ambulance services –IN fentanyl is the first line pain treatment in all children, adult option. ?Nasal ketamine soon? Generic concentrations available in U.S. work fine and are inexpensive ($1-4/vial) Efficacy: Very effective – and it can be titrated. Segway to IV therapy in the appropriate situation (fear, agitation)

Intranasal Medication Cases Sedation

Case: Excited Delirium A 27-year old male is apprehended by police and paramedics for extremely violent, out of control behavior following use of crystal meth. He is at significant risk of injuring himself and others. It is too dangerous (needle stick risk) to give him an injection of sedatives. The paramedic administers 10 mg of IN midazolam and 7 minutes later he is calm and can be transported safely to the hospital. 26

Sedation – Literature support Hundreds of articles dating back into the 1980’s. Most used midazolam. Effective only if adequate dose is given (0.4 to 0.5 mg/kg in kids, 10 mg straight dose in adults) Effective in children and adults (even exited delirium in EMS) Safe – no reports of respiratory depression

IN Benzos for sedation – my insights The EMS literature is just emerging: Many cases reported, few good actual studies Timing: Sedation onset with midazolam at about 5-10 minutes, maximal at 10-20 and starts to wear off at 25-30. Efficacy: Sedation is not deep but it takes the edge off and can make further care less stressful or dangerous Lorazepam?: More data needs to be obtained for lorazepam. My experience – lasts longer, 75% effective. Ketamine?: Mixed results, doses of at least 5 mg/kg needed, more data needs to be obtained in prehospital and ER environment before conclusions can be made. 28

Intranasal Medication Cases Seizure Control

Case: Seizing child The ambulance is transporting a 13 y.o. girl suffering a grand mal seizure. Despite trying, no IV can be successfully established. Rectal diazepam is unsuccessful at controlling the seizure. IV attempts in the clinic / hospital are also unsuccessful. However, on patient arrival a dose of nasal midazolam (Versed, Dormicum) is given and within 3 minutes of drug delivery the child stops seizing. 30

Seizure Therapy - Literature support Lahat 2000; Fisgin 2002; Holsti 2006; Ahmad 2006; Arya 2011; Holsti 2011; Javadzadeh 2012; Thakker 2012: IN midazolam is superior to rectal diazepam for seizure control and is preferred by care givers IN midazolam is superior to intramuscular injection of paraldehyde IN midazolam/lorazepam is equivalent to intravenous delivery for stopping seizures, much faster at stopping them due to no IV start needed and it leads to less respiratory depression and less need for airway management that either IV or rectal drugs IN midazolam can be delivered by family at home safely and effectively

Onset of nasal vs buccal seizure drugs (Time of onset matters) Anderson 2011: IN vs buccal lorazepam

Seizure Therapy - expenses Cost: Average wholesale price Rectal diazepam (Diastat brand name) 10 mg: $120/dose IN midazolam 10 mg: $3.20

The Doubters: Surely IN drugs can’t be as good as IV for seizures! ACTUALLY – They are equivalent or better (in these settings) 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 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. 34

IN benzodiazepines for seizures – My insights Very effective, very fast: Rapid seizure resolution without IV access. Should be first line therapy in ALL prolonged acute seizures while IV access is being established (if at all) Effective and safe at home, in prehospital setting, in hospital More effective, less expensive and preferred by providers when compared to alternative (rectal diazepam).

Intranasal Medication Cases Opiate Overdose

Case: Heroin Overdose The ambulance responds to an unconscious, barely breathing patient with obvious intravenous drug needle marks on both arms – consistent with heroin overdose After an IV is established, naloxone (Narcan) is administered and the patient is successfully resuscitated. Unfortunately, the medic suffers a contaminated needle stick while establishing the IV. The patient admits to being infected with both HIV and hepatitis C. He remains alert for 2 hours with no further therapy in the ED (i.e.- no need for an IV) and is discharged.

Case: Heroin Overdose The medic now needs treatment - HIV prophylaxis The next few months will be difficult for him: Side effects that accompany HIV medications Personal life is in turmoil due to issues of safe sex with his spouse Mental anguish of waiting to see if he develops HIV or hepatitis C. He wonders why his system is not using MAD nasal to deliver naloxone on all these patients.

Case: Methadone induced coma A mother enters her daughters room to find her unconscious, barely breathing, blue color. Since her daughter is on methadone maintenance, the family was trained to deliver rescue naloxone (see photo of kit above). The mother quickly delivers the naloxone intranasally. She provides 2-3 minutes of rescue breathing until her daughter begins to arouse. She gradually awakens over 10 minutes. The patient is transferred to the emergency room for observation due to the long half life of naloxone, but 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: IN naloxone is at least 80-90% effective at reversing opiate overdose When compared directly it is equivalent in time of onset and 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 is safe, has saved many lives and reduces medical resource consumption

IN naloxone for opiate overdose – my insights Why not? Is there a downside? High risk population for HIV, HCV, HBV Difficult IV to establish due to scarring of veins Elimination of needle eliminates needle stick risk They awaken more gently than with IV naloxone New epidemiology shows prescription drugs (methadone, etc) are causing many deaths that naloxone at home could reverse. Simple enough that lay public can administer and not even call ambulance 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 ? Ketamine 1 mg/kg Titration is possible Half up each nostril Sedation Midazolam: 0.5 mg/kg Use concentrated formula Seizures Midazolam: 0.2 mg/kg Lorazepam 0.1 mg/kg Support breathing while waiting Opiate Overdose Naloxone: 2 mg

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 site: www.intranasal.net