KNOWLEDGE SUMMARY

Keywords: BENZODIAZEPINES; CANINE; EPILESPY; INTRANASAL MIDAZOLAM; RECTAL DIAZEPAM; SEIZURES; STATUS EPILEPTICUS

Intranasal midazolam as an alternative to rectal diazepam for management of canine status epilepticus

Flora Foxx, BSc^1*

¹ Emergency Vets 24/7, 124 Anderson Street, Manunda, Queensland, Australia
* Corresponding author email: flora.foxx17@gmail.com

Vol 9, Issue 4 (2024)
Submitted: 16 Sep 2023; published: 10 Dec 2024; next review: 04 May 2026
DOI: https://doi.org/10.18849/ve.v9i4.689

PICO question

In canine patients in status epilepticus, is intranasal midazolam as effective as rectal diazepam for controlling seizures?

Clinical bottom line

Category of research

Treatment.

Number and type of study designs reviewed

One study was found—a multicentre randomised open-label clinical trial comparing intranasal midazolam and rectal diazepam in canine patients.

Strength of evidence

Weak.

Outcomes reported

The study critically appraised in this summary indicated that intranasal midazolam is effective in achieving seizure control in canine patients, with tolerable safety margins. Mild adverse effects associated with benzodiazepine administration such as sedation and drowsiness were noted, but there were no reports of serious adverse events related to the use of intranasal midazolam.

Conclusion

Intranasal midazolam appears to be safe and effective for achieving seizure control in canine patients, both in terms of efficacy and speed of onset, and is a suitable first-line treatment option for status epilepticus, especially when intravenous access is not rapidly available. Patients should be monitored after drug administration for development of adverse effects, including sedation, sneezing, and nasal irritation. A nasal mucosal atomisation device may be used to enhance bioavailability of the drug, improving efficacy.

How to apply this evidence in practice

The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources.

Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

Clinical scenario

A 4-year-old male neutered border collie previously diagnosed with idiopathic epilepsy presents to your practice in status epilepticus. Due to the severity of the seizure activity, you are unable to successfully place an intravenous catheter and must use another administration route to deliver emergency drugs. Would you choose intranasal midazolam or rectal diazepam as a first-line treatment to achieve cessation of the seizure activity?

The evidence

Literature searches identified only one paper directly comparing intranasal midazolam (IN-MDZ) and rectal diazepam (R-DZP) in canine patients experiencing status epilepticus (Charalambous, et al., 2017); this was a randomised multi-centre clinical trial.

Charalambous et al. (2017) found that IN-MDZ had a significantly higher success rate than R-DZP, with more rapid seizure control and fewer instances of seizure recurrence in canine patients. Whilst results from this study are promising, there were only 35 dogs included in the trial, reducing the overall statistical power. Furthermore, the researchers were not blinded to the treatment received by each dog, increasing the risk of observer bias when reporting data, especially when making subjective observations, such as whether tremors or other abnormal post-ictal behaviours count as new seizure activity (Hróbjartsson, et al., 2013).

Overall, the appraised study suggests that IN-MDZ is a safe and effective first-line treatment for status epilepticus in canine patients and may be a beneficial alternative to rectal diazepam in cases where intravenous access is not possible. Patients should be monitored after treatment for adverse effects, including excessive sedation, ataxia and nasal irritation. As there is only one clinical trial directly comparing IN-MDZ and R-DZP in dogs, the strength of the evidence is limited.

Summary of the evidence

Charalambous et al. (2017)

 

Appraisal, application and reflection

Status epilepticus is a life-threatening medical emergency requiring rapid and effective seizure control to reduce morbidity and mortality (Platt, 2014b; Charalambous et al., 2021; Charalambous et al., 2022). Benzodiazepines are frequently used as first-line medications in both human and canine patients due to their high potency and rapid onset of action (Charalambous, et al., 2021). These can be administered via various routes, with the intravenous (IV) route often preferred as it provides direct access to the circulation and 100% drug bioavailability (Schwartz, et al., 2013). However, in emergency situations establishing IV access may be difficult, requiring the use of alternative administration routes (Schwartz et al., 2013; Davis et al., 2021). Furthermore, these routes may be used outside of the clinical environment, including at home (Mula, 2017).

Rectal diazepam (R-DZP) is a commonplace first-line treatment for seizures, including status epilepticus, in both human and veterinary medicine (Platt, 2014a). However, rectal drug administration can be challenging in actively seizuring patients (De Haan et al., 2010). Furthermore, bioavailability of rectally administered drugs is variable, with limited maximum plasma concentrations and slow onset of action (Eagleson et al., 2012; Schwartz et al., 2013). Intranasal (IN) drug administration allows rapid drug absorption into the systemic circulation close to the brain, avoiding first-pass hepatic metabolism and encouraging accumulation of the drug within neurological tissue (Charalambous, 2018). In human patients, the IN route is more convenient and socially acceptable than rectal administration (Eagleson et al., 2012). A meta-analysis of studies investigating benzodiazepines for control of status epilepticus in human paediatric patients concluded that midazolam was superior for obtaining seizure control when compared to diazepam, with non-IV midazolam achieving the same efficacy as IV diazepam (McMullan et al., 2010). Furthermore, midazolam solutions are less irritant than diazepam solutions, reducing risk of irritation when administered intranasally (Schwartz et al., 2013; Platt, 2014a).

This Knowledge Summary seeks to appraise the evidence for use of intranasal midazolam (IN-MDZ) as an effective and safe alternative to R-DZP to control status epilepticus in canine patients. A literature search found a mixture of evidence, including two veterinary multi-centre open-label randomised clinical trials, a human open-label randomised clinical trial, and a human double-blinded placebo-controlled clinical trial. Few primary veterinary studies were found, indicating a need for further research to allow confident conclusions to be made. Only the study by Charalambous et al. (2017) directly related to all aspects of the PICO question, limiting the strengths of the conclusions that can be drawn, especially as the study was open-label and had a small sample size, reducing statistical power (Burmeister & Aitken, 2012). A follow-up study by Charalambous et al. (2019) compared IN-MDZ and IV-MDZ, further supporting the use of IN-MDZ in canine patients. However, as this paper did not directly compare IN-MDZ and R-DZP it did not meet the inclusion criteria for critical analysis. Whilst the conclusions from human clinical trials (Javadzadeh et al., 2012; Detyniecki et al., 2019) support those of the veterinary studies, care must be taken when applying results across species due to differences in pharmacokinetics (Potschka, et al. 2013; Uriarte & Maestro Saiz, 2016). A recent survey by Kähn et al. (2023) investigated dog owner perspectives on various out-of-hospital seizure control medications, including R-DZP and IN-MDZ. However, as this was not a clinical trial it does not meet the criteria for critical analysis.

When directly comparing IN-MDZ and R-DZP in canine patients, Charalambous et al. (2017) found that IN-MDZ was significantly more successful than R-DZP in achieving rapid seizure control and preventing further seizure activity. In this clinical trial, the time for administration of IN-MDZ was longer than for R-DZP, yet this did not affect overall drug efficacy. As explained by Kähn, et al. (2023), R-DZP is often administered from a pre-drawn syringe or suppository, whereas IN-MDZ administration requires several additional steps before the drug can be administered. Furthermore, unfamiliarity with the nasal mucosal atomisation device used for IN drug administration may increase the time taken for drug administration, as suggested by the authors of a similar human study (De Haan et al., 2010); trials performed after a period of regular use or training would allow a more accurate comparison. Despite being a multi-centre study, this investigation (Charalambous et al., 2017) had a small overall sample size and therefore limited statistical power to identify true differences between groups (Burmeister & Aitken, 2012). Furthermore, as noted by Packer et al. (2015), interpretation of seizure activity and paroxysmal events can be significantly different between clinicians; patients presenting to different hospitals may have been classified (and therefore treated) differently depending on clinician interpretation.

Additional papers indirectly supporting the findings of Charalambous et al. (2017) did not address all aspects of the PICO question and therefore did not meet the inclusion criteria for critical analysis. Relevant studies included a comparison of IN and intravenous midazolam (IV-MDZ) in canine patients in status epilepticus (Charalambous et al., 2019). Two human studies were also found; one was an open-label clinical trial comparing the efficacy of IN-MDZ and intravenous diazepam in controlling status epilepticus (Javadzadeh et al., 2012), and the other was a double-blinded randomised placebo controlled trial investigating the safety and efficacy of IN-MDZ for controlling cluster seizures (Detyniecki et al., 2019).

Detyniecki et al. (2019) investigated IN-MDZ as a treatment for cluster seizures in human patients, reporting this to be significantly more effective than a placebo for seizure control and preventing recurrence, with tolerable safety margins. In human patients, cluster seizures may progress to status epilepticus, but this has not been sufficiently investigated in veterinary patients (Platt, 2014b). Therefore, the results from Detyniecki et al. (2019) cannot be directly applied to canine patients or used to answer the PICO question.

When comparing IN-MDZ to intravenous midazolam (IV-MDZ) at the same dose in canine patients, Charalambous et al. (2019) found no significant difference in efficacy between treatment groups. Seizure cessation time was shorter in the IN-MDZ group, and this difference became statistically significant when accounting for the time taken to obtain IV access. These conclusions contrast with those of Javadzadeh et al. (2012), who compared IN-MDZ and IV-DZP in human children; intravenous diazepam (IV-DZP) achieved more rapid seizure control than IN-MDZ once the drug had been administered. However, obtaining IV access delayed drug administration, increasing the overall duration before seizure control was obtained in the IV-DZP group. Similarly, Mahmoudian & Mohammadi Zadeh (2004) found no significant difference in effectiveness between IN-MDZ and IV-DZP for controlling seizure activity in human patients. However, both of these studies found that seizure control was more rapid with IV-DZP than IN-MDZ once IV access was established, suggesting that this may be a preferred route of administration for patients with an IV catheter already in situ (Mahmoudian & Mohammadi Zadeh, 2004; Javadzadeh et al., 2012). This is clinically significant, as the prognosis for status epilepticus is time-dependent, with longer seizure duration associated with development of treatment-resistance and poor clinical outcomes (Charalambous, et al., 2019; Messahel et al., 2022). Therefore, finding an effective treatment option which can be rapidly administered is essential; these studies suggest that IN-MDZ better meets these criteria than trying to obtain IV access when patients are experiencing seizure activity prior to IV access being established. Due to species differences between humans and canine patients, the results from human studies cannot directly be extrapolated to the veterinary population. However, whilst the Mahmoudian & Mohammadi Zadeh (2004) and Javazadeh et al. (2012) studies do not directly compare IN-MDZ to R-DZP, their conclusions indirectly support those of Charalambous, et al., 2017; as IV drug administration is generally considered superior to rectal administration due to more rapid achievement of higher peak plasma concentrations (Eagleson et al., 2012), it is reasonable to extrapolate from these results that IN-MDZ is more clinically useful than rectal drug administration when IV access is not possible.

In many studies (Charalambous et al., 2017; Charalambous et al., 2019; Detyniecki et al., 2019), IN-MDZ was administered via a mucosal atomisation device; these devices create a fine mist of small particles, enhancing drug absorption, andtherefore bioavailability. Javadzadeh et al. (2012) did not use such a device in their study, instead administering IN-MDZ to human patients via a syringe. Detyniecki et al. (2019) used a novel combination product designed as a single-dose nasal spray for human patients; however, as the authors do not report the time taken for seizure control when using this product, results from this study cannot be directly compared to those of Javadzadeh et al. (2012) to determine the effect of the device. However, the canine studies (Charalambous et al., 2017; Charalambous et al., 2019) demonstrated faster times for seizure cessation with IN-MDZ administered via the mucosal atomisation device than those reported by Javadzadeh et al. (2012), where IN-MDZ was administered directly via a syringe, suggesting the device may improve efficacy of IN-MDZ. However, no study directly comapring the efficacy of IN-MDZ administered via a syringe to IN-MDZ administered via an atomisation device in canine patients was found; further research is warranted to determine the impact of such a device. Furthermore, as noted by Charalambous et al. (2019), no veterinary-specific devices are yet available; species- and breed-specific devices designed for veterinary patients would likely enhance the efficacy of IN-MDZ.

In all the reviewed studies, definitions of seizure activity and control were based on clinician interpretation of clinical signs rather than objective measurements of brain electrical activity. This is particularly significant in open-label trials, where observer bias may have influenced recording and reporting of data. Theoretically, double-blinded clinical trials relying on self-reporting by patients or their caregivers have a lower risk of bias; however, caregiver recognition, and reporting of seizure activity, and treatment efficacy may be unreliable (Akman et al., 2009). Furthermore, the data recorded by caregivers may be less accurate than that recorded by scientific and medical professionals, especially during a stressful situation (such as witnessing a seizure and administering a novel treatment (Cushner-Weinstein et al., 2008)).

IN-MDZ appears to be safe in human and veterinary patients; no significant adverse effects were reported in either of the veterinary trials (Charalambous et al., 2017; Charalambous et al., 2019) or in human patients by Javadzadeh et al. (2012). However, these studies were underpowered to detect rare adverse events, and single point in time trials cannot detect delayed adverse effects or those associated with chronic administration (Edwards et al., 1999). The double-blinded placebo-controlled trial by Detyniecki, et al. (2019) revealed a higher incidence of adverse effects in human patients receiving IN-MDZ when compared to a placebo group, including severe adverse reactions in 3% of IN-MDZ treated patients; no severe adverse reactions were reported in the placebo group. However, the authors did not report whether the difference in incidence of adverse reactions between the treatment groups was statistically significant (Detyniecki et al., 2019). In canine patients, common adverse effects appear to be related to benzodiazepine administration – including sedation, ataxia, and dysphoria – regardless of administration route (Charalambous, et al., 2017; Charalambous, et al., 2019). IN-MDZ was also associated with brief sneezing episodes in canine patients, suggesting nasal irritation (Charalambous et al., 2017; Charalambous et al., 2019). Human patients receiving intranasal administration of a placebo also reported nasal discomfort (Detyniecki et al., 2019), suggesting that this adverse effect may be related to the route of administration rather than the drug itself. Survey findings from Kähn et al. (2023) suggest that IN-MDZ is more successful than R-DZP for controlling seizures in dogs at home, with earlier seizure termination and less frequent repeat dosing for seizure control. Furthermore, the survey found owner compliance and satisfaction to be higher with IN-MDZ than R-DZP, suggesting this may be a preferable medication for recommendation for at-home use in canine patients with epilepsy.

Overall, there is little direct evidence that IN-MDZ is superior to R-DZP for controlling status epilepticus in canine patients, but extrapolation of results from human clinical trials and studies comparing IN-MDZ to other routes of administration suggest that it may be a superior first-line treatment option. Further large-scale randomised controlled trials in canine patients are needed to provide a stronger evidence base.

Methodology

Search strategy

 

Exclusion / inclusion criteria

 

Search outcome

 

Acknowledgements

The author would like to thank Evelyn O’Byrne for her help and support during the writing process.

ORCiD

Flora Foxx: https://orcid.org/0000-0002-8729-4982

Conflict of interest

The author declares no conflicts of interest.

References

1. Akman, C.I., Montenegro, M.A., Jacob, S., Eck, K., Chiriboga, C. & Gilliam, F. (2009). Seizure frequency in children with epilepsy: Factors influencing accuracy and parental awareness. Seizure. 18(7), 524–529. DOI: https://doi.org/10.1016/j.seizure.2009.05.009
2. Burmeister, E. & Aitken, L.M. (2012). Sample size: How many is enough? Australian Critical Care. 25(4), 271–274. DOI: https://doi.org/10.1016/j.aucc.2012.07.002
3. Charalambous, M., Bhatti, S.F.M., Van Ham, L., Platt, S., Jeffery, N.D., Tipold, A., Siedenburg, J., Volk, H.A., Hasegawa, D., Gallucci, A., Gandini, G., Musteata, M., Ives, E. & Vanhaesebrouck, A.E. (2017). Intranasal Midazolam versus Rectal Diazepam for the Management of Canine Status Epilepticus: A Multicenter Randomized Parallel-Group Clinical Trial. Journal of Veterinary Internal Medicine. 31(4), 1149–1158. DOI: https://doi.org/10.1111/jvim.14734
4. Charalambous, M. (2018). Controlling epileptic seizures at home with intranasal midazolam. Vet Times. 48(1), 4–5.  [Accessed 07 February 2023].
5. Charalambous, M., Volk, H.A., Tipold, A., Erath, J., Huenerfauth, E., Gallucci, A., Gandini, G., Hasegawa, D., Pancotto, T., Rossmeisl, J.H., Platt, S., De Risio, L., Coates, J.R., Musteata, M., Tirrito, F., Cozzi, F., Porcarelli, L., Corlazzoli, D., Cappello, R., Vanhaesebrouck, A., Broeckx, B.J.G., Van Ham, L. & Bhatti, S.F.M. (2019). Comparison of intranasal versus intravenous midazolam for management of status epilepticus in dogs: A multi-center randomized parallel group clinical study. Journal of Veterinary Internal Medicine. 33(6), 2709–2717. DOI: https://doi.org/10.1111/jvim.15627
6. Charalambous, M., Volk, H.A., Van Ham, L. & Bhatti, S.F.M. (2021). First-line management of canine status epilepticus at home and in hospital-opportunities and limitations of the various administration routes of benzodiazepines. BMC Veterinary Research. 17(1), 103. DOI: https://doi.org/10.1186/s12917-021-02805-0
7. Charalambous, M., Bhatti, S.F.M., Volk, H.A. & Platt, S. (2022). Defining and overcoming the therapeutic obstacles in canine refractory status epilepticus. The Veterinary Journal. 283–284 . DOI: https://doi.org/10.1016/j.tvjl.2022.105828
8. Cushner-Weinstein, S., Dassoulas, K., Salpekar, J.A., Henderson, S.E., Pearl, P.L., Gaillard, W.D. & Weinstein, S.L. (2008). Parenting stress and childhood epilepsy: The impact of depression, learning, and seizure-related factors. Epilepsy & Behavior. 13(1), 109–114. DOI: https://doi.org/10.1016/j.yebeh.2008.03.010
9. Davis, E.M., Feinsmith, S., Amick, A.E., Sell, J., McDonald, V., Trinquero, P., Moore, A., Gappmaier, V., Colton, K., Cunningham, A., Ford, W., Feinglass, J. & Barsuk, J.H. (2021). Difficult intravenous access in the emergency department: Performance and impact of ultrasound-guided IV insertion performed by nurses. The American Journal of Emergency Medicine. 46, 539–544. DOI: https://doi.org/10.1016/j.ajem.2020.11.013
10. De Haan, G.-J., Van Der Geest, P., Doelman, G., Bertram, E. & Edelbroek, P. (2010). A comparison of midazolam nasal spray and diazepam rectal solution for the residential treatment of seizure exacerbations. Epilepsia. 51(3), 478–482. DOI: https://doi.org/10.1111/j.1528-1167.2009.02333.x
11. Detyniecki, K., Van Ess, P.J., Sequeira, D.J., Wheless, J.W., Meng, T.C. & Pullman, W.E. (2019). Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters—a randomized, double-blind, placebo-controlled trial. Epilepsia. 60(9), 1797–1808. DOI: https://doi.org/10.1111/epi.15159
12. Eagleson, J.S., Platt, S.R., Strong, D.L.E., Kent, M., Freeman, A.C., Nghiem, P.P., Zheng, B. & White, C.A. (2012). Bioavailability of a novel midazolam gel after intranasal administration in dogs. American Journal of Veterinary Research. 73(4), 539–545. DOI: https://doi.org/10.2460/ajvr.73.4.539
13. Edwards, J.E., McQuay, H.J., Moore, R.A. & Collins, S.L. (1999). Reporting of Adverse Effects in Clinical Trials Should Be Improved: Lessons from Acute Postoperative Pain. Journal of Pain and Symptom Management. 18(6), 427–437. DOI: https://doi.org/10.1016/S0885-3924(99)00093-7
14. Hróbjartsson, A., Thomsen, A.S.S., Emanuelsson, F., Jeppesen, B.T, Hilden, J., Boutron, I., Ravaud, P. & Brorson, S. (2013). Observer bias in randomized clinical trials with measurement scale outcomes: a systematic review of trials with both blinded and nonblinded assessors. Canadian Medical Association Journal. 185(4), E201–E211. DOI: https://doi.org/10.1503/cmaj.120744
15. Javadzadeh, M., Sheibani, K., Hashemieh, M. & Saneifard, H. (2012). Intranasal midazolam compared with intravenous diazepam in patients suffering from acute seizure: a randomized clinical trial. Iranian Journal of Paediatrics. 22(1), 1–8.
16. Kähn, C., Bhatti, S.F.M., Meller, S., Meyerhoff, N., Volk, H.A. & Charalambous, M. (2023). Out-of-hospital rescue medication in dogs with emergency seizure disorders: an owner perspective. Frontiers in Veterinary Science. 10, 1278618. DOI: https://doi.org/10.3389/fvets.2023.1278618
17. Mahmoudian, T. & Mohammadi Zadeh, M. (2004). Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children. Epilepsy & Behavior. 5(2), 253–255. DOI: https://doi.org/10.1016/j.yebeh.2004.01.003
18. McMullan, J., Sasson, C., Pancioli, A. & Silbergleit, R. (2010). Midazolam Versus Diazepam for the Treatment of Status Epilepticus in Children and Young Adults: A Meta-analysis. Academic Emergency Medicine. 17(6), 575–582. DOI: https://doi.org/10.1111/j.1553-2712.2010.00751.x
19. Messahel, S., Bracken, L. & Appleton, R. (2022). Optimal Management of Status Epilepticus in Children in the Emergency Setting: A Review of Recent Advances. Open Access Emergency Medicine. 14, pp. 491–506. DOI: https://doi.org/10.2147/oaem.S293258
20. Mula, M. (2017). New Non-Intravenous Routes for Benzodiazepines in Epilepsy: A Clinician Perspective. CNS Drugs. 31(1), 11–17. DOI: https://doi.org/10.1007/s40263-016-0398-4
21. Packer, R.M., Berendt, M., Bhatti, S., Charalambous, M., Cizinauskas, S., De Risio, L., Farquhar, R., Hampel, R., Hill, M., Mandigers, P.J., Pakozdy, A., Preston, S.M., Rusbridge, C., Stein, V.M., Taylor-Brown, F., Tipold, A. & Volk, H.A. (2015). Inter-observer agreement of canine and feline paroxysmal event semiology and classification by veterinary neurology specialists and non-specialists. BMC Veterinary Research. 11(1), 39. DOI: https://doi.org/10.1186/s12917-015-0356-2
22. Platt, S. (2014a). Benzodiazepines. In: L. De Risio & S. Platt (eds). Canine and feline epilepsy: diagnosis and management. Wallingford: CABI International Publishing. 476–495.
23. Platt, S. (2014b). Pathophysiology and management of status epilepticus. In: L. De Risio & S. Platt (eds). Canine and feline epilepsy: diagnosis and management. Wallingford: CABI International Publishing. 519–536.
24. Potschka, H., Fischer, A., von Rüden, E.-L., Hülsmeyer, V. & Baumgärtner, W. (2013). Canine epilepsy as a translational model? Epilepsia. 54(4) 571-579. DOI: https://doi.org/10.1111/epi.12138
25. Schwartz, M., Muñana, K.R., Nettifee-Osborne, J.A., Messenger, K.M. & Papich, M.G. (2013). The pharmacokinetics of midazolam after intravenous, intramuscular, and rectal administration in healthy dogs. Journal of Veterinary Pharmacology and Therapeutics. 36(5), 471–477. DOI: https://doi.org/10.1111/jvp.12032
26. Uriarte, A. & Maestro Saiz, I. (2016). Canine versus human epilepsy: are we up to date? Journal of Small Animal Practice. 57(3), 115–121. DOI: https://doi.org/10.1111/jsap.12437