Skip to main content
PMC home page
Neurotherapeutics logoLink to Neurotherapeutics
. 2009 Apr;6(2):352–358. doi: 10.1016/j.nurt.2009.01.002

Intranasal delivery of antiepileptic medications for treatment of seizures

Daniel P Wermeling 1,✉
PMCID: PMC5084214  PMID: 19332330

Summary

Acute isolated seizure, repetitive or recurrent seizures, and status epilepticus are all deemed medical emergencies. Mortality and worse neurologic outcome are directly associated with the duration of seizure activity. A number of recent reviews have described consensus statements regarding the pharmacologic treatment protocols for seizures when patients are in pre-hospital, institutional, and home-bound settings. Benzodiazepines, such as lorazepam, diazepam, midazolam, and clonazepam are considered to be medications of first choice. The rapidity by which a medication can be delivered to the systemic circulation and then to the brain plays a significant role in reducing the time needed to treat seizures and reduce opportunity for damage to the CNS. Speed of delivery, particularly outside of the hospital, is enhanced when transmucosal routes of delivery are used in place of an intravenous injection.

Intranasal transmucosal delivery of benzodiazepines is useful in reducing time to drug administration and cessation of seizures in the pre-hospital setting, when actively seizing patients arrive in the emergency room, and at home where care-givers treat their dependents. This review summarizes factors to consider when choosing a benzodiazepine for intranasal administration, including formulation and device considerations, pharmacology and pharmacokinetic/pharmacodynamic profiles. A review of the most relevant clinical studies in epilepsy patients will provide context for the relative success of this technique with a number of benzodiazepines and relatively less sophisticated nasal preparations. Neuropeptides delivered intranasally, crossing the blood-brain barrier via the olfactory system, may increase the availability of medications for treatment of epilepsy. Consequently, there remains a significant unmet medical need to serve the pharamcotherapeutic requirements of epilepsy patients through commercial development and marketing of intranasal antiepileptic products.

Key Words: Intranasal, drug delivery, antiepileptic medications, treatment of seizures, emergency pharmacotherapy, benzodiazepines, blood-brain barrier

References

  • 1.Lowenstein DH, Alldredge BK. Status epilepticus. N Eng J Med. 1998;338:970–976. doi: 10.1056/NEJM199804023381407. [DOI] [PubMed] [Google Scholar]
  • 2.Lowenstein DH, Bleck T, Macdonald RL. It’s time to revise the definition of status epilepticus. Epilepsia. 1999;40:120–122. doi: 10.1111/j.1528-1157.1999.tb02000.x. [DOI] [PubMed] [Google Scholar]
  • 3.Wang HC, Chang WN, Chang HW, et al. Factors predictive of outcome in posttraumatic seizures. J Trauma. 2008;64:883–888. doi: 10.1097/TA.0b013e31804a7fa4. [DOI] [PubMed] [Google Scholar]
  • 4.Stavem K, BJornaes H, Langmoen IA. Long-term seizures and quality of life after epilepsy surgery compared with matched controls. Neurosurgery. 2008;62:326–334. doi: 10.1227/01.neu.0000315999.58022.1c. [DOI] [PubMed] [Google Scholar]
  • 5.Logroscino G, Hessdorffer DC, Cascino G, et al. Time trends in incidence, mortality, and case-fatality after first episode of status epilepticus. Epilepsia. 2001;42:1031–1035. doi: 10.1046/j.1528-1157.2001.0420081031.x. [DOI] [PubMed] [Google Scholar]
  • 6.Feen ES, Bershad EM, Suarez JI. Status Epilepticus. South Med J. 2008;101:400–406. doi: 10.1097/SMJ.0b013e31816852b0. [DOI] [PubMed] [Google Scholar]
  • 7.Pang T, Hirsch L. Treatment of convulsive and nonconvulsive status epilepticus. Cur Treat Options Neurol. 2005;7:247–259. doi: 10.1007/s11940-005-0035-x. [DOI] [PubMed] [Google Scholar]
  • 8.Smith B. Treatment of status epilepticus. Neurol Clin. 2001;19:347–369. doi: 10.1016/S0733-8619(05)70022-0. [DOI] [PubMed] [Google Scholar]
  • 9.Ericksson K, Kalviainen R. Pharmacologic management of convulsive status epilepticus in childhood. Expert Rev Neurotherapeutics. 2005;5:777–783. doi: 10.1586/14737175.5.6.777. [DOI] [PubMed] [Google Scholar]
  • 10.Wolfe T, Macfarlane T. Intranasal midazolam therapy for pediatric status epilepticus. Am J Emerg Med. 2006;24:343–346. doi: 10.1016/j.ajem.2005.11.004. [DOI] [PubMed] [Google Scholar]
  • 11.Meierkord H, Engelsen B, Gocke K, et al. EFNS guideline on the management of status epilepticus. Eur J Neurol. 2006;13:445–450. doi: 10.1111/j.1468-1331.2006.01397.x. [DOI] [PubMed] [Google Scholar]
  • 12.Prasad K, Krishman P, Al-Roomi K, et al. Anticonvulsant therapy for status epilepticus. Br J Clin Pharmacol. 2007;63:640–647. doi: 10.1111/j.1365-2125.2007.02931.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Illum L. Nasal Clearance in Health and Disease. J Aerosol Med. 2006;19:92–99. doi: 10.1089/jam.2006.19.92. [DOI] [PubMed] [Google Scholar]
  • 14.Merkus P, Ebbens FA, Muller B, Fokkens WJ. Influence of anatomy and head position on intranasal drug deposition. Eur Arch Otorhinolaryngol. 2006;263:827–832. doi: 10.1007/s00405-006-0071-5. [DOI] [PubMed] [Google Scholar]
  • 15.Illum L. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci. 2000;11:1–18. doi: 10.1016/S0928-0987(00)00087-7. [DOI] [PubMed] [Google Scholar]
  • 16.Illum L. Is nose to brain transport of drugs a reality? JPP. 2004;56:3–17. doi: 10.1211/0022357022539. [DOI] [PubMed] [Google Scholar]
  • 17.Merkus F, van den Berg MP. Can nasal drug delivery bypass the blood-brain barrier? Questioning the direct transport theory. Drugs. 2007;8:133–144. doi: 10.2165/00126839-200708030-00001. [DOI] [PubMed] [Google Scholar]
  • 18.Constantino HR, Illum L, Brandt G, et al. Intl J Pharmaceutics. 2007;337:1–24. doi: 10.1016/j.ijpharm.2007.03.025. [DOI] [PubMed] [Google Scholar]
  • 19.Davis GA, Rudy AC, Archer SA, Wermeling DP, McNamara PJ. Effect of fluticasone propionate nasal spray on bioavailability of hydromorphone hydrochloride in patients with allergic rhinitis. Pharmacotherapy. 2004;24:26–32. doi: 10.1592/phco.24.1.26.34810. [DOI] [PubMed] [Google Scholar]
  • 20.Davis GA, Rudy AC, Archer SM, Wermeling DP, McNamara PJ. Bioavailability and pharmacokinetics of intranasal hydromorphone in patients experiencing vasomotor rhinitis. Clin Drug Invest. 2004;24:1–7. doi: 10.2165/00044011-200424110-00002. [DOI] [PubMed] [Google Scholar]
  • 21.Holsti M, Sill B, Firth S, et al. Prehospital intranasal midazolam for the treatment of pediatric seizures. Ped Emerg Care. 2007;23:148–153. doi: 10.1097/PEC.0b013e3180328c92. [DOI] [PubMed] [Google Scholar]
  • 22.Rudy AC, Coda BA, Archer SM, Wermeling DP. A multiple dose phase 1 study of intranasal hydromorphone hydrochloride in healthy volunteers. Anesth Analg. 2004;99:1379–1386. doi: 10.1213/01.ANE.0000132927.47528.8B. [DOI] [PubMed] [Google Scholar]
  • 23.Van den Donk HJ, van den Huervel AG, Zuidema J, Merkus FW. The effects of nasal drops and their additives on human nasal mucociliary clearance. Rhinology. 1982;20:127–137. [PubMed] [Google Scholar]
  • 24.Kubek MJ, Domb AJ, Veronesi MC. Attenuation of kindled seizures by intranasal delivery of neuropeptide-loaded nanoparticles. Neurotherapeutics. 2009;6:359–371. doi: 10.1016/j.nurt.2009.02.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Loftsson T, Gudmundsdottir H, Sigurjonsdottir JF, et al. Cyclodextrin solubilization of benzodiazepines: formulation of midazolam nasal spray. Int J Pharm. 2001;212:29–40. doi: 10.1016/S0378-5173(00)00580-9. [DOI] [PubMed] [Google Scholar]
  • 26.Knoester PD, Jonker DM, Van Der Hoeven RT, et al. Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers. Br J Clin Pharmacol. 2002;53:501–507. doi: 10.1046/j.1365-2125.2002.01588.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Gudmundsdottir H, Sigurjonsdottir JF, Masson M, et al. Intranasal administration of midazolam in a cyclodextrin based formulation: bioavailability and clinical evaluation in humans. Pharmazie. 2001;56:963–966. [PubMed] [Google Scholar]
  • 28.Dale O, Nilsen T, Loftsson T. Intranasal midazolam: a comparison of two delivery devices in human volunteers. J Pharmacy Pharmacol. 2006;58:1311–1318. doi: 10.1211/jpp.58.10.0003. [DOI] [PubMed] [Google Scholar]
  • 29.Burstein AH, Modica R, Hatton M, et al. Pharmacokinetics and pharmacodynamics of midazolam after intranasal administration. J Clin Pharmacol. 1997;37:711–718. doi: 10.1002/j.1552-4604.1997.tb04358.x. [DOI] [PubMed] [Google Scholar]
  • 30.Wermeling D, Record K, Kelly T, et al. Pharmacokinetics and pharamcodynamics of a new intranasal midazolam formulation in healthy volunteers. Anesth Analg. 2006;103:344–349. doi: 10.1213/01.ane.0000226150.90317.16. [DOI] [PubMed] [Google Scholar]
  • 31.Schols-Hendriks MWG, Lohman JJHM, Janknegt R, et al. Absorption of clonazepam after intranasal and buccal administration. Br J Clin Pharmacol. 1995;39:449–451. doi: 10.1111/j.1365-2125.1995.tb04476.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Lindhardt K, Gizurarson S, Stefansson SB, et al. Electroencephalographic effects and serum concentrations after intranasal and intravenous administration of diazepam to healthy volunteers. Br J Clin Pharmacol. 2001;52:521–527. doi: 10.1046/j.0306-5251.2001.01486.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Lau SWJ, Slattery JT. Intl J Pharmaceutics. Absorption of diazepam and lorazepam following intranasal administration. Int J Pharmaceutics. 1989;54:171–174. doi: 10.1016/0378-5173(89)90337-2. [DOI] [Google Scholar]
  • 34.Wermeling DP, Miller JL, Archer SM, et al. Bioavailability and pharmacokinetics of lorazepam after intranasal, intravenous, and intramuscular administration. J Clin Pharmacol. 2001;41:1225–1231. doi: 10.1177/00912700122012779. [DOI] [PubMed] [Google Scholar]
  • 35.Greenblatt D, Gan L, Harmatz, et al. Pharmacokinetics and pharmacodynamics of single-dose triazolam: EEG compared with digital symbol substitution test. Br J Clin Pharmacol. 2005;60:244–248. doi: 10.1111/j.1365-2125.2005.02409.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.O’Regan M, Brown J, Clarke M. Nasal rather than rectal benzodiazepines in the management of acute childhood seizures. Develop Med and Child Neurol. 1996;38:1037–1045. doi: 10.1111/j.1469-8749.1996.tb15064.x. [DOI] [PubMed] [Google Scholar]
  • 37.Mittal P, Manohar R, Rawat A. Comparative study of intranasal midazolam and intravenous diazepam sedation for procedures and seizures. Ind J Pediatrics. 2006;73:975–978. doi: 10.1007/BF02758299. [DOI] [PubMed] [Google Scholar]
  • 38.Mahmoudian T, Zadeh M. Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children. Epilepsy Behav. 2004;5:253–255. doi: 10.1016/j.yebeh.2004.01.003. [DOI] [PubMed] [Google Scholar]
  • 39.Lahat E, Goldman M, Barr J, et al. Comparison of intranasal midazolam with intravenous diazepam in treating febrile seizures in children: prospective randomized study. BMJ. 2000;321:83–87. doi: 10.1136/bmj.321.7253.83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Bhattacharyya M, Kalra V, Gulati S. Intranasal midazolam vs rectal diazepam in acute childhood seizures. Pediatric Neurology. 2006;34:355–359. doi: 10.1016/j.pediatrneurol.2005.09.006. [DOI] [PubMed] [Google Scholar]
  • 41.Wilson MT, Macleod S, O’Regan ME. Nasal/buccal midazolam use in the community. Arch Dis Child. 2004;89:50–51. doi: 10.1136/adc.2002.019836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Harbord MG, Kyrkou NE, Kyrkou MR, Kay D, Coulthard KP. Use of intranasal midazolam to treat acute seizures in paediatric community settings. J Paediatr Child Health. 2004;40:556–558. doi: 10.1111/j.1440-1754.2004.00463.x. [DOI] [PubMed] [Google Scholar]
  • 43.Jeannet PY, Roulet E, Maeder-Ingvar M, Gehri M, Jutzi A, Deonna T. Home and hospital treatment of acute seizures in children with nasal midazolam. Eur J Paediatr Neurol. 1999;3:73–77. doi: 10.1016/S1090-3798(99)80016-6. [DOI] [PubMed] [Google Scholar]
  • 44.Ahmad S, Ellis J, Kamwendo H, Molyneux E. Efficacy and safety of intranasal lorazepam versus intramuscular paraldehyde for protracted convulsions in children: an open label trial. Lancet. 2006;367:1591–1597. doi: 10.1016/S0140-6736(06)68696-0. [DOI] [PubMed] [Google Scholar]

Articles from Neurotherapeutics are provided here courtesy of Elsevier

RESOURCES