• Rapid Reviews: Start picking your nose! Intranasal delivery of medications

    by Alan Batt. Last modified: 02/10/14

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    It seems like everyone wants to give medications through the nose these days. Recently the Pre-Hospital Emergency Care Council of Ireland released the 2014 edition Clinical Practice Guidelines which include intranasal (IN) administration of naloxone for Emergency Medical Technicians. This mode of delivery and medication is now being rolled out to all responder levels in Ireland in order to combat the large number of opioid related deaths in Ireland. IN fentanyl has also recently been added to the analgesia options for Advanced Paramedics in Ireland.

    Based on these developments, we began to wonder what other medications could be administered safely through the IN route, resulting in

    1. quicker care for patients
    2. reduced sharps related injuries
    3. ability to safely administer medications in high-risk settings (flight, aggressive situations, moving vehicles)

    A study by McDermott & Collins (2012) concluded that the IN route of medication administration is significantly faster, better accepted, and perceived to be safer than using an IV route of administration.

    What we found was surprising – many medications can be administered through the IN route – some which you wouldn’t have thought of!

    Some key concepts in administering any medication IN are:

    1. Increase the dose
    2. Decrease the volume
    3. Use both nostrils
    4. Use a MAD

    Below you will find medications commonly used in the prehospital setting that have been administered successfully through the IN route, along with references to abstracts and articles where available. There are other medications that can be given IN, but they aren’t in most EMT or Paramedic formularies worldwide, so we’ve left them out.

    If you’d like to read more than you ever thought possible on IN medication administration, Dr. Tim Wolfe, one of the original designers of the Mucosal Atomiser Device (MAD) used in IN administration runs a great website detailing further medications and resources regarding IN medication administration. Find it at http://www.intranasal.net

    If you have experience delivering any of these medications through the IN route we’d love to hear your thoughts – leave a comment below! Usual obvious disclaimers apply to this post – always operate to your scope of practice and local protocols etc.

    Atropine

    Intranasal atropine use has been reported in the treatment of organophosphate poisoning (OP) in one animal study (Pravin et al 2001), and is commonly used in humans for treating rhinorrhea and postnasal drip (Baroody et al 1996). One paper from Ozyurt et al (2003) details the successful use of aerosolised atropine administered through the IN route in the management of three patients with OP poisoning – however, all of these patients also received IV doses of atropine. No literature exists as yet on the use of IN atropine in human subjects with symptomatic bradycardia.

     
    Baroody FM1, Driscoll PV, Moylan B, Fleming L, Shilstone J, Naclerio RM. Duration of action of intranasal atropine on methacholine-induced nasal secretions. Arch Otolaryngol Head Neck Surg. 1996 Mar;122(3):321-3. PMID: 8607961.

    Pravin K, VIJAYARAGHAVAN R, Singh M (2001) EFFICACY OF ATROPINE NASAL AEROSOL SPRAY AGAINST ORGANOPHOSPHOROUS POISONING Indian Journal of Pharmacology 2001; 33: 431-436 – openaccess

    Özyurt G, Bilgin H, Kutsal M (2003) ATROPINE AEROSOL SPRAY (AAS) BY NASAL APPLICATION IN ORGANOPHOSPHATE POISONING J Med Chem Def 1(1) – openaccess

    Fentanyl

    IN fentanyl has been shown to have a rapid onset and efficiency similar to that of IV, is easier to administer in children who may be in severe pain, and is quicker to administer than establishing an IV and administering an IV analgesic. Borland et al. (2002 & 2007) found that IN fentanyl was better than morphine for pain relief in children, however Rickard (2007) found no difference between the two medications. A systematic review by Mudd in 2011 concluded that INF is a safe and effective method of pain management for children in a variety of clinical settings. Gausche et al (2014) also recommend IN fentanyl in their Evidence-based Guideline for prehospital analgesia in trauma. However, Hansen & Dahl (2013) argue that there is limited evidence for IN fentanyl in the prehospital setting and that further research is required, a view that was shared by Dale et al in 2002.

     
    Borland M1, Jacobs I, King B, O'Brien D. A randomized controlled trial comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department. Ann Emerg Med. 2007 Mar;49(3):335-40. PMID: 17067720.

     

     
    Borland ML1, Jacobs I, Geelhoed G. Intranasal fentanyl reduces acute pain in children in the emergency department: a safety and efficacy study. Emerg Med (Fremantle). 2002 Sep;14(3):275-80. PMID: 12487045.

     

     
    Rickard C1, O'Meara P, McGrail M, Garner D, McLean A, Le Lievre P. A randomized controlled trial of intranasal fentanyl vs intravenous morphine for analgesia in the prehospital setting. Am J Emerg Med. 2007 Oct;25(8):911-7. PMID: 17920976.

     

     
    Dale O1, Hjortkjaer R, Kharasch ED. Nasal administration of opioids for pain management in adults. Acta Anaesthesiol Scand. 2002 Aug;46(7):759-70. PMID: 12139528.

     
    Hansen MS1, Dahl JB. Limited evidence for intranasal fentanyl in the emergency department and the prehospital setting--a systematic review. Dan Med J. 2013 Jan;60(1):A4563. PMID: 23340187.
    openaccess (free full text available here)

     
    Mudd S. Intranasal fentanyl for pain management in children: a systematic review of the literature. J Pediatr Health Care. 2011 Sep-Oct;25(5):316-22. PMID: 21867860.

     
    Gausche-Hill M, Brown KM, Oliver ZJ, Sasson C, Dayan PS, Eschmann NM, Weik TS, Lawner BJ, Sahni R, Falck-Ytter Y, Wright JL, Todd K, Lang ES. An Evidence-based Guideline for prehospital analgesia in trauma. Prehosp Emerg Care. 2014;18 Suppl 1:25-34. PMID: 24279813.
    – openaccess (free full text available from author on ResearchGate)

    A study investigating the efficacy of IN fentanyl is ongoing in Ireland at present (See http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3414794/)

    The PICHFORK trial ongoing in Australia at present is comparing IN fentanyl with IN ketamine for pain relief (See http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3716920/)

    Flumazenil

    The evidence is sparse for IN administration of flumazenil. Heard et al (2009) describe a case of over-sedation of a 3 year old child with IN sulfentanil and midazolam which was successfully reversed by IN administration of naloxone and flumazenil. A study carried out by Sheepers et al in 2000 showed that plasma concentrations of flumazenil were similar between IN and IV administration, concluding that this route of administration (IN) may be useful when the intravenous route is not readily available.

     
    Heard C1, Creighton P, Lerman J. Intranasal flumazenil and naloxone to reverse over-sedation in a child undergoing dental restorations. Paediatr Anaesth. 2009 Aug;19(8):795-7; discussion 798-9. PMID: 19624367.
    – openaccess (free full text available here)

     
    Scheepers LD1, Montgomery CJ, Kinahan AM, Dunn GS, Bourne RA, McCormack JP. Plasma concentration of flumazenil following intranasal administration in children. Can J Anaesth. 2000 Feb;47(2):120-4. PMID: 10674504.
    – openaccess (free full text available here)

    MAD100 (Small)

    Glucagon

    Intranasal glucagon has been shown to be effective in treating hypoglycaemia in a number of case reports and studies. Sibley et al (2013) published a case report detailing the successful administration of IN glucagon to a female hypoglycaemic patient in the prehospital setting. Pontiroli et al., as far back as 1989 suggested that IN glucagon could be a potential emergency solution to hypoglycaemic episodes. Stenninger & Aman (1993) found that IN glucagon resulted in a slower plasma glucose rise, but was associated with less side-effects.  Rosenfalck found between treatment with 2mg IN and 1mg IM that IN results in a lower overall plasma glucose level 40 minutes after administration, and that 80% of the patients treated with IN glucagon had some localised side effects such as rhinitis. There is a lack of recent, robust clinical trials in favour of IN glucagon, and this is an area that warrants further research.

     
    Sibley T1, Jacobsen R, Salomone J. Successful administration of intranasal glucagon in the out-of-hospital environment. Prehosp Emerg Care. 2013 Jan-Mar;17(1):98-102. PMID: 22971130.

     
    Pontiroli AE1, Calderara A, Pajetta E, Alberetto M, Pozza G. Intranasal glucagon as remedy for hypoglycemia. Studies in healthy subjects and type I diabetic patients. Diabetes Care. 1989 Oct;12(9):604-8. PMID: 2676430.
    –  openaccess (free full text available from author on ResearchGate)

     
    Stenninger E1, Aman J. Intranasal glucagon treatment relieves hypoglycaemia in children with type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1993 Oct;36(10):931-5. PMID: 8243872.
    – openaccess (free full text available here)

     
    Rosenfalck AM1, Bendtson I, Jørgensen S, Binder C. Nasal glucagon in the treatment of hypoglycaemia in type 1 (insulin-dependent) diabetic patients. Diabetes Res Clin Pract. 1992 Jul;17(1):43-50. PMID: 1511660.

     

    A study investigating the safety and efficacy of intranasal glucagon is completing this month in the US (See http://clinicaltrials.gov/show/NCT01994746)

    Ketamine

    IN ketamine can be used for sedation and analgesia purposes. However, doses need to be increased (as they do with most medications if administering via the IN route). Tsze et al (2012) found the a dose of 9mg/kg of IN ketamine produced successful sedation (when compared with 3mg/kg and 6mg/kg doses). Johanssen et al (2013) describe a series of nine cases treated with IN ketamine in which all patients achieved analgesia with little side-effects, with their conclusion being that IN ketamine may reduce the time spent on the scene of the accident and most likely reduces the need to expose the patient to the environment in especially challenging cases of prehospital analgesia. Reid et al (2013) also present a case report of successful analgesia with IN ketamine in a paediatric burn victim. Yeaman et al (2013) concluded that an average dose of 1.0 mg/kg IN ketamine provided adequate analgesia by 30 min for most of the 28 paediatric patients in the study with isolated limb injuries, and in a further study of adult patients in 2014 found that 56% of the 72 patients studied had adequate pain relief from doses of approximately 1 mg/kg.

     
    Tsze DS1, Steele DW, Machan JT, Akhlaghi F, Linakis JG. Intranasal ketamine for procedural sedation in pediatric laceration repair: a preliminary report. Pediatr Emerg Care. 2012 Aug;28(8):767-70. PMID: 22858745.
    – openaccess (free full text available from author on ResearchGate)

     
    Johansson J1, Sjöberg J, Nordgren M, Sandström E, Sjöberg F, Zetterström H. Prehospital analgesia using nasal administration of S-ketamine--a case series. Scand J Trauma Resusc Emerg Med. 2013 May 14;21:38. PMID: 23672762.
    – openaccess

     
    Reid C1, Hatton R, Middleton P. Case report: prehospital use of intranasal ketamine for paediatric burn injury. Emerg Med J. 2011 Apr;28(4):328-9. PMID: 21292791.

     

     
    Yeaman F1, Oakley E, Meek R, Graudins A. Sub-dissociative dose intranasal ketamine for limb injury pain in children in the emergency department: a pilot study. Emerg Med Australas. 2013 Apr;25(2):161-7. PMID: 23560967.

     

     
    Yeaman F1, Meek R, Egerton-Warburton D, Rosengarten P, Graudins A. Sub-dissociative-dose intranasal ketamine for moderate to severe pain in adult emergency department patients. Emerg Med Australas. 2014 Jun;26(3):237-42. PMID: 24712757.

     

    The PRECINKT trial in Alberta and BC in Canada is set to investigate the efficacy of IN ketamine as an analgesia option in the prehospital setting. (See http://clinicaltrials.gov/show/NCT02033434)

    The PICHFORK trial ongoing in Australia at present is comparing IN fentanyl with IN ketamine for pain relief (See http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3716920/)

    Lorazepam

    In 2011, Arya et al published a very interesting paper which showed that IN lorazepam was as effective as IV lorazepam for controlling seizures – and was administered much quicker in the population studied. A BestBET topic by Allan & Cullen (2013) concluded that intranasal lorazepam appears to be an acceptable intervention for the termination of seizures, demonstrating both efficacy and safety.

     
    Arya R1, Gulati S, Kabra M, Sahu JK, Kalra V. Intranasal versus intravenous lorazepam for control of acute seizures in children: a randomized open-label study. Epilepsia. 2011 Apr;52(4):788-93. PMID: 21275979.

     
    Allan A1, Cullen J. Best BETs from the Manchester Royal Infirmary. BET 1: intranasal lorazepam is an acceptable alternative to intravenous lorazepam in the control of acute seizures in children. Emerg Med J. 2013 Sep;30(9):768-9. PMID: 23943640.
    – openaccess (free full text available here)

    Metoclopramide

    Metoclopramide is an effective anti-emetic agent, and has been successfully administered through the IN route by Ormrod & Goa (1999), who found that an 80mg IN dose reduced the frequency of acute vomiting in chemotherapy patients. However, Wagner at al (1996) in a double-blind, placebo-controlled evaluation of intranasal metoclopramide in the prevention of postoperative nausea and vomiting (PONV) found that a 20mg dose was ineffective in preventing the occurrence of PONV – they do however recognise these results may be due to an inadequate dose.

     
    Wagner BK1, Berman SL, Devitt PA, Halvorsen MB, O'Hara DA. A double-blind, placebo-controlled evaluation of intranasal metoclopramide in the prevention of postoperative nausea and vomiting. Pharmacotherapy. 1996 Nov-Dec;16(6):1063-9. PMID: 8947980.

     
    Ormrod D1, Goa KL. Intranasal metoclopramide. Drugs. 1999 Aug;58(2):315-22; discussion 323-4. PMID: 10473023.

    Midazolam

    Rainbow et al. (2002) found that intranasal midazolam can control seizures as effectively as diazepam in the prehospital setting. Intranasal midazolam can also result in a comparable time to cessation of seizures to that of intravenous diazepam (Lahat et al., 2000). Wolfe & Macfarlane (2006) found that intranasal midazolam can provide better seizure control than PR diazepam, and is easier for paramedics to administer to a patient who is actively seizing. A number of authors (Scott et al, 1999; Wilson et al., 2004; Humphries & Eiland, 2013) also found that patients and caregivers found intranasal midazolam to be more socially acceptable than per rectum administration of diazepam, as well as re-confirming the view it was more convenient for paramedics to access the intranasal route than the per rectum route. Fisgin et al (2002) compared intranasal midazolam to rectal diazepam and found midazolam was more effective than diazepam. A prehospital study by Holsti et al (2007), found that IN midazolam showed better prehospital seizure control, less need for need for emergent intubation and less need for hospital admission in the intranasal midazolam group compared with the rectal diazepam group. Bhattacharyya (2006) in a randomised study of 46 children (188 seizure episodes) concludes intranasal midazolam is preferable to rectal diazepam in the treatment of acute seizures in children.

     
    Scott RC1, Besag FM, Neville BG. Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet. 1999 Feb 20;353(9153):623-6. PMID: 10030327.

     

     
    Humphries LK1, Eiland LS. Treatment of acute seizures: is intranasal midazolam a viable option? J Pediatr Pharmacol Ther. 2013 Apr;18(2):79-87. PMID: 23798902.

     

     
    Rainbow J1, Browne GJ, Lam LT. Controlling seizures in the prehospital setting: diazepam or midazolam? J Paediatr Child Health. 2002 Dec;38(6):582-6. PMID: 12410871.

     
    Lahat E1, Goldman M, Barr J, Bistritzer T, Berkovitch M. Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study. BMJ. 2000 Jul 8;321(7253):83-6. PMID: 10884257.
    – openaccess (free full text available here)

     
    Wolfe TR1, Macfarlane TC. Intranasal midazolam therapy for pediatric status epilepticus. Am J Emerg Med. 2006 May;24(3):343-6. PMID: 16635708.

     
    Wilson MT1, Macleod S, O'Regan ME. Nasal/buccal midazolam use in the community. Arch Dis Child. 2004 Jan;89(1):50-1. PMID: 14709505.
    – openaccess

     
    Fişgin T1, Gurer Y, Teziç T, Senbil N, Zorlu P, Okuyaz C, Akgün D. Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study. J Child Neurol. 2002 Feb;17(2):123-6. PMID: 11952072.

     
    Holsti M1, Sill BL, Firth SD, Filloux FM, Joyce SM, Furnival RA. Prehospital intranasal midazolam for the treatment of pediatric seizures. Pediatr Emerg Care. 2007 Mar;23(3):148-53. PMID: 17413428.
    openaccess (free full text available here)

     
    Bhattacharyya M1, Kalra V, Gulati S. Intranasal midazolam vs rectal diazepam in acute childhood seizures. Pediatr Neurol. 2006 May;34(5):355-9. PMID: 16647994.
    – openaccess (free full text available here)

    Morphine

    Christensen et al (2008) studied 225 patients post dental surgery with randomisation to either IN morphine, IV morphine, PO morphine or placebo, and concluded that IN morphine offers a noninvasive alternative to IV morphine for postoperative analgesia. Stoker et al (2008) found that IN morphine-chitosan solution provided sustained analgesia in postsurgical patients and thus may offer a safe and less invasive alternative to IV morphine.

     
    Christensen KS1, Cohen AE, Mermelstein FH, Hamilton DA, McNicol E, Babul N, Carr DB. The analgesic efficacy and safety of a novel intranasal morphine formulation (morphine plus chitosan), immediate release oral morphine, intravenous morphine, and placebo in a postsurgical dental pain model. Anesth Analg. 2008 Dec;107(6):2018-24. PMID: 19020153.
    – openaccess (free full text available from the author on ResearchGate)

     
    Stoker DG1, Reber KR, Waltzman LS, Ernst C, Hamilton D, Gawarecki D, Mermelstein F, McNicol E, Wright C, Carr DB. Analgesic efficacy and safety of morphine-chitosan nasal solution in patients with moderate to severe pain following orthopedic surgery. Pain Med. 2008 Jan-Feb;9(1):3-12. PMID: 18254761.

    Naloxone

    Naloxone is routinely administered in the prehospital setting through IV and IM routes, but many studies have shown its efficacy when administered IN. Kerr et al (2009) in a study of 172 patients in the pre-hospital setting found intranasal naloxone reversed heroin overdose successfully in 82% of patients, with a similar time of response to IM naloxone. Barton et al (2005) also came to similar conclusions. Kelly (2005) found that IN naloxone was effective at treating opioid induced respiratory depression, but not as effective as IM. Bystanders with no medical training used naloxone to successfully reverse opioid overdose in 74 times in a take-home naloxone study by Doe-Simkins et al (2009). A BestBET by Ahston & Hassan (2006) concluded it is likely that intranasal naloxone is a safe and effective first line prehospital intervention in reversing the effects of an opioid overdose and helping to reduce the risk of needle stick injury, but that a large, well conducted trial into it’s usage is required.

     
    Kerr D1, Kelly AM, Dietze P, Jolley D, Barger B. Randomized controlled trial comparing the effectiveness and safety of intranasal and intramuscular naloxone for the treatment of suspected heroin overdose. Addiction. 2009 Dec;104(12):2067-74. PMID: 19922572.

     
    Kelly AM1, Kerr D, Dietze P, Patrick I, Walker T, Koutsogiannis Z. Randomised trial of intranasal versus intramuscular naloxone in prehospital treatment for suspected opioid overdose. Med J Aust. 2005 Jan 3;182(1):24-7. PMID: 15651944.
     – openaccess

     
    Doe-Simkins M1, Walley AY, Epstein A, Moyer P. Saved by the nose: bystander-administered intranasal naloxone hydrochloride for opioid overdose. Am J Public Health. 2009 May;99(5):788-91. PMID: 19363214.
    – openaccess

     
    Barton ED1, Colwell CB, Wolfe T, Fosnocht D, Gravitz C, Bryan T, Dunn W, Benson J, Bailey J. Efficacy of intranasal naloxone as a needleless alternative for treatment of opioid overdose in the prehospital setting. J Emerg Med. 2005 Oct;29(3):265-71. PMID: 16183444.

     
    Ashton H1, Hassan Z. Best evidence topic report. Intranasal naloxone in suspected opioid overdose. Emerg Med J. 2006 Mar;23(3):221-3. PMID: 16498165.
    – openaccess

    Salbutamol

    Weksler et al (1999) describe three cases where salbutamol was successfully administered through the IN route after the patients were found to be unresponsive to conventional therapy. The only other available literature is an animal study by Hussain et al (2004) which showed albuterol (salbutamol) to be equally effective when administered either intranasally or intratracheally.

     
    Weksler N1, Brill S, Tarnapolski A, Gurman GM. Intranasal salbutamol instillation in asthma attack. Am J Emerg Med. 1999 Nov;17(7):686-8. PMID: 10597090.

     

     
    Hussain AA1, Dakkuri A, Lai YL, Traboulsi A, Hussain MA. Nasal administration of albuterol: an alternative route of delivery. J Pharm Pharmacol. 2004 Oct;56(10):1211-5. PMID: 15482634.

    Tranexamic Acid

    While not technically intranasal in the sense we have been discussing, the new kid on the block for many EMS providers, TXA applied to a pledget was better than anterior nasal packing in the initial treatment of idiopathic anterior epistaxis in a study by Zahed et al in 2013. There’s not much evidence to support it’s widespread use though, further studies are needed.

     
    Zahed R1, Moharamzadeh P, Alizadeharasi S, Ghasemi A, Saeedi M. A new and rapid method for epistaxis treatment using injectable form of tranexamic acid topically: a randomized controlled trial. Am J Emerg Med. 2013 Sep;31(9):1389-92. PMID: 23911102.

    Additional Resources & References

     
    Collopy KT1, Snyder SR. Intranasal drug administration: an innovative approach to traditional care. EMS World. 2011 May;40(5):45-50. PMID: 21650113.
    – free full text at http://www.emsworld.com/article/10251608/intranasal-drug-administration

     
    Del Pizzo J1, Callahan JM. Intranasal medications in pediatric emergency medicine. Pediatr Emerg Care. 2014 Jul;30(7):496-501; quiz 502-4. PMID: 24987995.

     
    McDermott C1, Collins NC. Prehospital medication administration: a randomised study comparing intranasal and intravenous routes. Emerg Med Int. 2012;2012:476161. PMID: 22953064.
    – openaccess

    Dr. Tim Wolfe, one of the original designers of the Mucosal Atomiser Device (MAD) used in IN administration runs a great website detailing further medications and resources regarding IN medication administration. Find it at http://www.intranasal.net

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    Alan Batt

    Alan Batt

    Paramedic, educator, researcher
    Alan is a critical care paramedic, paramedic educator and prehospital researcher, currently working around the world as an educator and researcher. He has previously worked and studied across Europe, North America and the Middle East. He holds a Graduate Certificate in Intensive Care Paramedic Studies, and an MSc in Critical Care. His main interests are in care of the elderly, end-of-life care, patient safety, professionalism (including role and identity), and paramedic education.

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