Presentation on theme: "Intranasal Drug Delivery – Clinical Implications for Pre-hospital care"— Presentation transcript:
1 Intranasal Drug Delivery – Clinical Implications for Pre-hospital care
2 Lecture outline Why use intranasal medications? Intranasal drug delivery: General conceptsIntranasal drugs indications with clinical cases and personal insights:• Pain Control• Sedation• Seizures• Opiate overdoseDrug dosesResources
3 Why do I think nasal drug delivery is important in prehospital care? Efficacy, speed and ease of deliveryNo delivery delays (no IV)Can deliver to anyone with an exposed noseRapid onset of action (Pain control, Sedation, seizure, overdose)As effective and fast as IV drugs in most situationsSafetyNo needle stick riskLower risk of respiratory depression (compared to IV)Easier to proceed with additional careStart IV in children or agitated adultCalm the agitated patient
4 Understanding IN delivery: General principles First pass metabolismNose brain pathwayBioavailability / Drug absorptionSafety vs IV drugs
5 First pass metabolism Nasal Mucosa: No first pass metabolism Gut mucosa: Subject to first pass metabolism5
6 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).BrainCSFHighly vascular nasal mucosa6
8 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, etcMidazolam 75+%Fentanyl and Sufentanil 80+%Naloxone 90+%Lorazepam, ketamine, Romazicon, etc
9 Optimizing Bioavailability of IN drugs CriticalConceptMinimize volume - Maximize concentration0.2 to 0.3 ml per nostril ideal, 1 ml is maximumMost potent (highly concentrated) drug should be usedMaximize total absorptive mucosal surface areaUse BOTH nostrils (doubles your absorptive surface area)Use a delivery system that maximizes mucosal coverage and minimizes run-off.Atomized particles across broad surface areaBeware of abnormal nasal mucosal characteristicsMucous, blood and vasoconstrictors may reduce absorptionSuction nose or consider alternate delivery route if present9
10 Dropper vs Atomizer Absorption Usability / acceptance Drops = runs down to pharynx and swallowedAtomizer = sticks to broad mucosal surface and absorbsUsability / acceptanceDrops = Minutes to give, cooperative patient, head position requiredAtomizer = seconds to deliver, better accepted
17 Case: MVC pinned in carA 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 midazolamIn 7 minutes his pain is much better controlled and he is calmerExtraction requires 20 minutes, then full trauma assessment and care proceeds.17
18 Case: Pediatric Hand burn A 5 year old burned her hand on the stoveClinical Needs: Pain control, Transport for wound careTreatment: 2.0 mcg/kg of intranasal fentanyl (40 mcg – 0.8 ml of generic “IV” fentanyl)Within 3-5 minutes her pain is improvedShe is transported to a nearby medical facility15 minutes later the patient easily tolerates cleansing of the burn and dressing application.18
19 Literature to support these cases - pediatrics NasalIntravenousBorland, Ann Emerg Med 200719
20 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 onsetEquivalent to IV morphineSuperior to IM morphineCare givers are more likely to treat pediatric severe painHighly satisfied patients and providersSafe
21 Pain control – Literature support Prehospital and wounded soldier literatureRickard 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 minutesJohnstone 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.
22 Intranasal Ketamine for pain ?: Literature support US Army IN ketamine dataCompared IN ketamine to IV morphine for severe painIN ketamine (50 mg) as fast and as good as IV morphine (7.5 mg) w/o side effects.
23 NasalThe Doubters: Surely IN drugs can’t be as good as an injection for pain control!IntravenousACTUALLY – 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 armsBorland 2008, Holdgate 2010, Crellin time to delivery of IN opiates was half that of IV and more patients get treatedKendal 2001 – IN opiate superior to IM opiate for pain controlConclusionsIN opiates are just as good as IVIN opiates are delivered in half the waiting time as IVIN opiate are preferred by patients, providers and parents over injections23
24 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 areinexpensive ($1-4/vial)Efficacy: Very effective – and it can be titrated.Segway to IV therapy in the appropriate situation (fear, agitation)
26 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
27 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
28 IN Benzos for sedation – my insights The EMS literature is just emerging: Many cases reported, few good actual studiesTiming: Sedation onset with midazolam at about 5-10 minutes, maximal at and starts to wear off atEfficacy: Sedation is not deep but it takes the edge off and can make further care less stressful or dangerousLorazepam?: 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
30 Case: Seizing childThe 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
31 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 giversIN midazolam is superior to intramuscular injection of paraldehydeIN 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 drugsIN midazolam can be delivered by family at home safely and effectively
32 Onset of nasal vs buccal seizure drugs (Time of onset matters) Anderson 2011: IN vs buccal lorazepam
34 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 delaysHolsti 2007, Fisgin 2002 – IN is superior to rectalHolsti 2011 – IN is safe at home with immediate resultsConclusionsIN seizure medication are just as good as IV, better than rectalIN 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
35 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 hospitalMore effective, less expensive and preferred by providers when compared to alternative (rectal diazepam).
37 Case: Heroin OverdoseThe ambulance responds to an unconscious, barely breathing patient with obvious intravenous drug needle marks on both arms – consistent with heroin overdoseAfter 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.
38 Case: Heroin Overdose The medic now needs treatment - HIV prophylaxis The next few months will be difficult for him:Side effects that accompany HIV medicationsPersonal life is in turmoil due to issues of safe sex with his spouseMental 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.
39 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.
40 Opiate overdose – Literature support Intranasal naloxone literatureBarton 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 overdoseWhen compared directly it is equivalent in time of onset and in efficacy to IV or IM therapy.IN naloxone results in less agitation upon arousalIN naloxone is lay person approved in many places. It is safe, has saved many lives and reduces medical resource consumption
41 IN naloxone for opiate overdose – my insights Why not? Is there a downside?High risk population for HIV, HCV, HBVDifficult IV to establish due to scarring of veinsElimination of needle eliminates needle stick riskThey awaken more gently than with IV naloxoneNew 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 ambulanceEvery ambulance system, police agency and many clinics and families with high risk patients should be utilizing this approach.
42 Drug doses Scenario Drug and Dose Important Reminders Pain Control Fentanyl: 2 mcg/kg? Ketamine 1 mg/kgTitration is possibleHalf up each nostrilSedationMidazolam: 0.5 mg/kgUse concentrated formulaSeizuresMidazolam: 0.2 mg/kgLorazepam 0.1 mg/kgSupport breathing while waitingOpiate OverdoseNaloxone: 2 mg
43 Intranasal medications summary Another tool for drug delivery to supplement standard IV, IM, PO–very useful when appropriateSupported by extensive literatureInexpensiveSpeeds up care in many situationsSafe