intranasal meds

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pharmacology updateSection Editor: Kelly M. Smith, PharmD, BCPS, FASHP, FCCP

Use of Intranasal Medications in PediatricPatientsSusan E. Warrington, PharmD; Robert J. Kuhn, PharmD, FPPAG

Drs Warrington and Kuhn are from University of Kentucky HealthCare, Lexington, Kentucky.

Drs Warrington and Kuhn have no relevant nanci al relatio nships todisclose.

Correspondence should be addressed to: Susan E. Warrington, PharmD,800 Rose St, H110, Lexington, KY 40536-0293 ([email protected])

doi: 10.3928/01477447-20110427-20

Abstract : A growing body of evidence supports the intranasaladministration of atomized medications for a wide variety of

pediatric indications. This article describes their use applicableto orthopedic specialists in the areas of pediatric pain manage-ment, as well as pre- and intraoperative sedation. As a quick,painless alternative to more invasive routes of administration,intranasal drug delivery has shown similar time to clinical ef-fect compared to the intravenous route, while minimizing anxi-ety in both patients and their parents.

The administration of medications in pediatric

patients is not always an easytask. Barriers can be as simpleas poor palatability of oralmedications, or a patient whohas difculty swallowing pills.Rectal administration is an-other option, but this can oftenbe socially undesirable, espe-cially in older children. Moreinvasive routes of delivery,such as intramuscular, subcu-taneous, intravenous (IV), orintraosseous, provide optimal

drug delivery but often causeassociated pain and anxiety;therefore, an alternative routeof administration is often de-sired in the pediatric patientpopulation.

Intranasal drug administra-tion offers a quick, painless,noninvasive way to give medi-cations, with onset of actiongenerally comparable to thatof IV administration where thecentral nervous system is thesite of action. 1 An increasingbody of literature investigates

the applications of intrana-sal delivery for many indica-tions (eg, seizures, epistaxis,pretreatment for nasogastrictube insertion, and naloxoneadministration for narcoticoverdose reversal). This articledescribes their use applicableto orthopedic specialists in theareas of pediatric pain man-agement, as well as pre- andintraoperative sedation.

P HARMACOKINETICS

Delivery to the highly vas-cularized nasal mucosa allowsfor rapid transport of medica-tions into the bloodstream andacross the blood brain barrier.Intranasal administration hasfaster absorption comparedto oral. 2 Due to direct absorp-tion into the bloodstream, theintranasal delivery route alsobypasses rst-pass metabo-lism in the liver. In general,pharmacokinetic studies showthat the bioavailability of in-tranasal medications is lessthan that of IV administration,but direct absorption into thecentral nervous system andcomparable time to desired

clinical effect indicate thatthis route still achieves simi-lar outcomes regarding onsetof action. 3-5 It is importantto note, however, that due toincomplete absorption of in-tranasal administration, dosesfor intranasal medicationsare higher than those recom-mended for IV administration(Table).

DROPLETS VS ATOMIZED S PRAY

Studies have comparedthe use of atomized spray vsdroplet delivery into the nasalcavity. Drops into the nose arenoted to be primarily deposit-ed onto the ciliary surface withexcess runoff down the throat.In comparison, atomized par-ticles cover more surface areaand are better distributed intothe nasal mucosa, resulting inbetter bioavailability. 6,7 Fromthe perspective of patient ac-ceptance, administration of atomized spray has also beenshown to produce signicantlyless aversive behavior in youngchildren, making it a practicaloption. 8

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ADMINISTRATION

A key concept to considerfor intranasal drug delivery isselecting a formulation con-centration that allows for min-imization of volume. Volumesof 0.2 to 0.3 mL per nostril areideal, but volumes up to 1 mLper nostril can be used. Small

volumes divided between bothnostrils optimizes absorptionand reduces mucosal surfacesaturation and runoff downthe throat. However, this issueis more apparent in adults vschildren due to weight-baseddosing. 1

Another consideration forintranasal administration isthe patients mucosal environ-ment and potential barriers todrug delivery. Mucous, blood,and the use of vasoconstrictorsimpair absorption via intrana-sal route; therefore, alternativedelivery methods should beconsidered in these cases if na-sal suctioning is inadequate ornot possible.

Atomized intranasal admin-istration is achieved by usinga product known as a Muco-sal Atomizer Device (MAD;Wolfe Tory Medical, Inc, SaltLake City, Utah). 9 This latex-free device attaches directly toa luer-lock syringe and atomiz-es medications to a particle sizeof 30 to 100 . When drawingup medications to be given viaatomizer device, an additional0.1 mL of volume should be in-cluded to account for estimateddead space in the device. Costper atomizer device is approxi-mately $4 to $5.

P AIN CONTROL

Orthopedic fractures and joint dislocations are some

of the most painful pediatricemergencies, and time to ad-ministration of analgesics is of primary concern. Opiates viaIV administration for orthope-dic trauma pain provide rapidonset of analgesia and can betitrated to effect; however,other considerations regard-ing this route are additionalassociated pain and anxiety,as well as the time required togain IV access. The use of in-tranasal fentanyl in the emer-gency room setting has gainedfavor in recent years as a fast,painless alternative to IV ad-ministration. Intranasal opiatesalso appear to be most usefulfor acute pain management forwound-dressing changes, largeabrasions, and burns.

Fentanyl is an opiate anal-gesic with the most evidenceto support intranasal admin-istration. Use in pediatric pa-tients has shown comparableefcacy to IV fentanyl andIV morphine in postoperativepain management and acutefractures in the emergency de-partment, respectively. 4,10

A study by Saunders etal11 also shows efcacy in

pain control and overall pa-tient satisfaction with use fol-lowing traumatic orthopedicinjury. Lipophilic drugs withlow-molecular weight gen-erally achieve plasma levelssimilar to those from IV deliv-ery. Pharmacokinetic data forintranasal fentanyl suggestsapproximately 71% bioavail-ability, reecting ndingsthat relatively higher dosesare required for intranasalvs IV routes of administra-tion (ie, 1.5-2 /kg). As withIV administration, intranasalfentanyl also allows for titra-tion to effect while monitoringappropriately for potential re-spiratory depression and chestwall rigidity.

P RE- AND INTRAOPERATIVE S EDATION

Minimizing distress overparental separation and induc-tion of anesthesia are chal-lenges associated with pediat-ric patients in the preoperativeperiod. Therefore, the adminis-tration of a sedative/anxiolyticagent is common practice priorto IV cannulation and transferto the operating room. Oral

midazolam is one of the mostcommonly used agents forthis purpose, but only 70% of pediatric patients will acceptthis therapy. 12 Therefore, theuse of intranasal midazolam,intranasal dexmedetomidine,and intranasal ketamine havebeen investigated for pre- andintraoperative sedation.

Anxiety during medicalprocedures is also a commonscenario in pediatric patients,and procedures where intra-nasal sedation and anxiolysishave proven benecial in-clude: magnetic resonanceimaging and computed tomog-raphy scans, laceration repair,burn-dressing changes, dentalextractions, and venipuncture.

Midazolam is a water-sol-uble benzodiazepine knownto have a rapid onset and shortduration of action, as well asproperties of amnesia andanxiolysis. Administered in-tranasally, midazolam is aneffective option for conscioussedation. 13-16 When comparedto oral midazolam, intrana-sal administration has showna more rapid absorption andtime to onset of action due to

Table

Dosing of Intranasal Medications in Children

Medication DoseOnset of

Action, minDuration of Action, min Considerations

Dexmedetomidine 1-2 /kg 15-30 55-100 May be preferred when morethan mild sedation is desired;monitor for hypotension andbradycardia

Fentanyl 1.5-2 /kg 10-20 30 Monitor for hypoxia

Ketamine 5-8 mg/kg 5-10 Up to 60 Monitor for hypoxia

Midazolam(anxiolysis)

0.4-0.5 mg/kg 10-20 20-40 Use 5 mg/mL concentration;may cause nasal burning for30-45 seconds



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pharmacology update

systemic absorption via closecommunication between thevascular plexus cavity and thesubarachnoid space by way of the olfactory nerve. 2

Pharmacokinetic studieshave noted the bioavailabilityof intranasal midazolam to beapproximately 60%; however,similar outcomes for time toclinical effect are noted whencompared to IV midazolam.Intranasal midazolam hasbeen used since 1988 withrepeatable positive outcomes.The most commonly reportedadverse effects of intranasalmidazolam are nasal burningfor 30 to 45 seconds and bittertaste. In some instances, 10 of 10% lidocaine administeredintranasally to each nostril hasshown benet in reducing re-ported burning sensations. 17,18

Dexmedetomidine is a taste-less, colorless, and odorlessagent that acts as a selectivealpha-2 adrenergic agonist withboth sedative and analgesic ef-fects via actions in the centralnervous system. It is commer-cially available as a concentra-tion of 100 /mL, which makesit easy to administer in volumes 1 mL. A benet noted withthe use of this agent is that ithas minimal to no effect on re-spiratory rate or tidal volume.

Although time to effect isrelatively delayed when com-

pared to IV administration,pharmacological effects areconsidered comparable. 19 Themost notable adverse effectsthat occur with IV adminis-tration in pediatric patientsinclude dose-dependent hypo-tension and bradycardia. Withintranasal dexmedetomidine,moderate decreases in bloodpressure and heart rate havebeen noted in healthy childrenduring the rst hour after ad-ministration. 20,21

Talon et al 6 compared intra-nasal dexmedetomidine givenvia atomizer with oral mid-azolam in children youngerthan 18 years. Both productshad similar effects on preop-erative sedation and anxiolysisfor induction of general anes-thesia with no signicant ad-verse effects, and only modesthemodynamic effects. Yuen etal22 investigated time to onsetand duration of sedative effectsfor intranasal dexmedetomi-dine administered via dropletswith similar sedative efcacyand pharmacodynamic results(Table).

Ketamine is a dissocia-tive anesthetic that creates atrance-like state with proper-ties of sedation, amnesia, anal-gesia, and catalepsy. In a studyby Kazemia et al, 23 sedativeeffects of intranasal ketamine5 mg/kg were compared to

intranasal midazolam 0.2 mg/ kg. In 130 children aged 2 to5 years who received the studymedication 20 minutes preop-eratively, 89% of the ketaminegroup vs 90% of the midazol-am group vs 47.5% of placebogroup were sedated at the timeof separation from parents,and 80%, 86%, and 22.5%,respectively, were sedated atthe time of intravenous lineinsertion. Therefore, intrana-sal midazolam and intranasalketamine were deemed equal-ly effective for the purpose of easy parental separation andIV line placement.

Efcacy of intranasal ket-amine and midazolam werecompared by Gharde et al 24 inchildren with tetralogy of Fal-lot. Dosing up to 10 mg/kg of ketamine was used in this studyvs 0.2 mg/kg of midazolam, aswell as a mixture of ketamine7.5 mg/kg and midazolam 0.1mg/kg. Sedation was assessedat 30 minutes post-dose. In theketamine alone study group,sedation, separation, and ac-ceptance of IV cannulationwere all good, compared withgood sedation but poor sepa-ration and acceptance in themidazolam alone group. Over-all, the use of higher than typi-cally recommended intranasalketamine was deemed betterthan intranasal midazolam for

purposes of preparation forinduction in the preoperativeperiod. 24

Although the delivery of medications for pain and seda-tion via intranasal route doesnot have current approval bythe United States Food andDrug Administration, when

used in the proper patients andsettings, this route appears tobe a viable option for pediatricdrug delivery. As with any se-dation or narcotic analgesicuse in pediatric patients, theseprocedures should be donewith trained personnel whohave the expertise and equip-ment to monitor patients;therefore, it would seem pru-dent to make these agents partof standard protocols whenused. The ability to monitorpatients during the time peak effects of these agents are ob-tained is critical for both ef-cacy and safety. As an effectivecomponent of care, this meth-od of delivery not only helps toexpedite pain control and pre-or intraoperative sedation inpediatric patients, but alsohelps to alleviate anxiety inpediatric patients and theirparents.

REFERENCES

1. Wolfe TR, Braude DA. Intrana-sal medication delivery for chil-dren: a brief review and update[published online ahead of printAugust 9, 2010]. Pediatrics .2010; 126(3):532-537.

2. Rey E, Delaunay L, Pons G, et al.Pharmacokinetics of midazolamin children: comparative studyof intranasal and intravenous ad-ministration. Eur J Clin Pharma-col. 1991; 41(4):355-357.

3. Wermeling DP, Record KA, Ar-cher SM, Rudy AC. A pharma-cokinetic and pharmacodynam-ic study, in healthy volunteers,of a rapidly absorbed intranasal

THE BOTTOM LINE Intranasal medication administration is a practical option for pediatric patients as a noninvasive

alternative to the intravenous route. Atomized spray vs droplet delivery is noted to be superior in the literature due to better nasal

distribution and absorption. In the areas of pain control and pre- and intraoperative sedation, inhaled medications have shown

similar efcacy to intravenous options regarding time to onset of desired effect.



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midazolam formulation [pub-lished online ahead of printNovember 29, 2008]. Epilepsy

Res . 2009; 83(2-3):124-132.

4. Borland M, Jacobs I, King B,OBrien D. A randomized con-trolled trial comparing intrana-sal fentanyl to intravenous mor-phine for managing acute painin children in the emergencydepartment [published onlineahead of print October 25,2006]. Ann Emerg Med . 2007;49(3):335-340.

5. Lahat E, Goldman M, Barr J,Bistritzer T, Berkovitch M.Comparison of intranasal mid-azolam with intravenous diaz-epam for treating febrile sei-zures in children: prospectiverandomized study. BMJ . 2000;321(7253):83-86.

6. Talon MD, Woodson LC, Sher-wood ER, Aarsland A, McRaeL, Benham T. Intranasal dex-medetomidine premedication iscomparable with midazolam inburn children undergoing recon-structive surgery. J Burn Care

Res. 2009; 30(4):599-605.

7. Ljung B, Adreassen S. Compar-ison of midazolam nasal sprayto nasal drops for the sedationof children. J Nucl Med Tech-nol . 1996; 24(1):32-34.

8. Primosch RE, Guelmann M.Comparison of drops versus

spray administration of intra-nasal midazolam in two- andthree-year-old children fordental sedation. Pediatr Dent .2005; 27(5):401-408.

9. MAD Nasal Mucosal Atomiza-tion Device. Wolfe Tory Medical,Inc, Web site. http://www.wolfe-tory.com/MAD/MADNasal.aspx. Accessed March 12, 2011.

10. Manjushree R, Lahiri A, GhoshBR, Laha A, Handa K. Intrana-

sal fentanyl provides adequatepostoperative analgesia in pe-diatric patients. Can J Anesth .2002; 49(2):190-193.

11. Saunders M, Adelgais K, Nel-son D. Use of intranasal fen-tanyl for the relief of pediatricorthopedic trauma pain. Acad

Emerg Med . 2010; 17(11):1155-1161. doi: 10.1111/j.1553-2712.2010.00905.x.

12. Khalil SN, Vije HN, Kee SS,Farag A, Hanna E, Chuang AZ.A paediatric trial comparingmidazolam/Syrpalta mixturewith premixed midazolam syr-up (Roche). Paediatr Anaesth .2003; 13(3):205-209.

13. Wilton NC, Leigh J, Rosen DR,Pandit UA. Preanesthetic seda-tion of preschool children usingintranasal midazolam. Anesthe-siology . 1988; 69(6):972-975.

14. Lane RD, Schunk JE. Atomized

intranasal midazolam use forminor procedures in the pedi-atric emergency department.Pediatr Emerg Care . 2008;24(5):300-303.

15. Lloyd CJ, Alredy T, Lowry JC.Intranasal midazolam as an al-ternative to general anaesthesiain the management of childrenwith oral and maxillofacialtrauma. Br J Oral MaxillofacSurg . 2000; 38(6):593-595.

16. Yealy DM, Ellis JH, HobbsGD, Moscati RM. Intranasalmidazolam as a sedative forchildren during laceration re-pair. Am J Emerg Med . 1992;10(6):584-587.

17. Lugo RA, Fishbein M, NahataMC, Lininger B. Complicationof intranasal midazolam. Pedi-atrics . 1993; 92(4):638.

18. Chiaretti A, Barone G, RiganteD, et al. Intranasal lidocaineand midazolam for proceduralsedation in children [publishedonline ahead of print Octo-ber 27, 2010]. Arch Dis Child .2011; 96(2):160-163.

19. Iirola T, Vilo S, Manner T, et al.Bioavailability of dexmedeto-midine after intranasal adminis-tration. Eur J Clin Pharmacol .In press.

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tranasal dexmedetomidine andoral midazolam for premedi-cation in pediatric anesthesia:a double-blinded randomizedcontrolled trial. Anesth Analg .2008; 106(6):1715-1721.

21. Yuen VM, Irwin MG, Hui TW,Yuen MK, Lee LH. A double-blind, crossover assessment of the sedative and analgesic ef-fects of intranasal dexmedeto-midine. Anesth Analg . 2007;105(2):374-380.

22. Yuen VM, Hui TW, Irwin MG,Yao TJ, Wong GL, Yuen MK.Optimal timing for the admin-istration of intranasal dexme-detomidine for premedicationin children. Anaesthesia . 2010;65(9):922-929. doi: 10.1111/

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23. Kazemia AP, Kamalipour H,Seddighi M. Comparison of intranasal midazolam versusketamine as premedication in2-5 years old paediatric surgerypatients. Pak J Med Sci . 2005;21(4):460-464.

24. Gharde P, Chauhan S, Kiran U.Evaluation of efcacy of intra-nasal midazolam, ketamine andtheir mixture as premedicationand its relation with bispectralindex in children with tetralogyof fallot undergoing intracar-diac repair. Ann Card Anaesth .2006; 9(1):25-30.


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