Table 5.

Evidence supporting alternative routes of benzodiazepines administration.

Intranasal and Rectal Formulation Trials
Author/Year	Design (Type of Seizure)	Setting	Sample	Interventions	Results
Jain et al. 2016 [65]	Systematic review and meta-analysis (no specific type of seizure)	Emergency department	Adult and pediatric; two randomized open-label trials (N = 91)	IN midazolam (0.2 mg/kg) Rectal diazepam (0.3–0.5 mg/kg)	IN midazolam is superior to rectal diazepam in terminating seizures within 10 min (RR 1.14; 95% CI, 1.05–1.25)
Holsti et al. 2010 [16]	Randomized single-blind trial (no specific type ofseizure)	Outpatient	Pediatrics (N = 92)	IN midazolam (0.2 mg/kg) Rectal diazepam (0.3–0.5 mg/kg)	Time to seizure cessation after drug administration was not significantly different between IN midazolam and rectal diazepam (3 vs. 4.3 min, p = 0.09)
Haan et al. 2010 [66]	Cross-sectional (no specific type ofseizure)	Residential epilepsy center	Adults (N = 21)	IN midazolam (10 mg) Rectal diazepam (10 mg)	Both have similar success rate (82% vs. 89%, p = 0.57) and time to seizure termination (4.6 vs. 4.3 min, p = 0.6)
Intramuscular and Rectal Formulation Trials
Author	Design (Type of Seizure)	Settings	Sample	Doses	Results
Momen et al. 2015 [67]	Randomized open-label trial (status epilepticus)	Emergency department	Pediatrics (N = 100)	IM midazolam (0.3 mg/kg) Rectal diazepam (0.5 mg/kg)	Both have a similar success rate in seizure control, but midazolam is faster to achieve seizure cessation after drug administration (2.17 vs. 1.1 min, p < 0.001)
Lamson et al. 2011 [39]	Pharmacokinetic study (healthy subjects)	-	Adults (N = 48)	-	Similar bioavailability, but rectal diazepam had a faster time to maximum concentration (0.17–1.00 h vs. 0.25–2.00 h)
Buccal and Rectal Formulation Trials
Author	Design (Type of Seizure)	Settings	Sample	Doses	Results
Jain et al. 2016 [65]	Systematic review and meta-analysis (no specific type of seizure)	Mostly in the emergency department	Pediatric and adult patients of 7 randomized clinical trials	Buccal midazolam (0.25–0.5 mg/kg) Rectal diazepam (0.5 mg/kg)	Buccal midazolam has a significantly higher rate of seizure cessation within 10 min compared to rectal diazepam (RR 1.14; 95% CI, 1.06–1.24; p = 0.0008)
Nakken and Lossius, 2011 [68]	Quasi-randomized trial (status epilepticus)	Residential institution	Adults (N = 22)	Buccal midazolam (mean 15.5 mg) Rectal diazepam (mean 26 mg)	Buccal midazolam has a significantly shorter time to convulsive status epilepticus control (2.8 vs. 5 min, p = 0.012)
Rogawski et al. 2020 [69]	Pharmacokinetic study (no specific type of seizure)	-	Adults (N = 28)	-	Buccal diazepam is less variable in reaching the maximum concentration compared to rectal diazepam (buccal geometric SD [GSD] 136.12–306.49 and rectal GSD 87.71–508.63), but the time buccal formulation takes to reach maximum concentration is longer than the rectal formulation (1.0 and 0.52 h, p < 0.05)
Other Oral Formulations Trials
Author	Design (Type of Seizure)	Settings	Sample	Doses	Results
Troester et al. 2010 [70]	Cross-sectional home response from caregivers (no specific type of seizure)	Outpatient	Pediatrics (N = 38)	Clonazepam oral disintegrating tablet (0.25–2 mg)	Clonazepam achieved seizure control within 10 min for all the patients (74% within 5 min), and 69% of the patients who used rectal diazepam previously felt oral clonazepam was as equal or more effective than rectal diazepam
Conry et al. 2009 [71]	Randomized, double-blind multicenter trial (drop vs. nondrop seizures, repetitive seizures were recorded)	Outpatient	Adults and pediatrics (N = 68)	Clobazam oral tablet (0.25 mg/kg/day vs. 1 mg/kg/day)	Patients received daily doses of clobazam. In both drop and nondrop seizures, high-dose significantly reduced seizure frequency compared to low-dose (p = 0.0001 and p = 0.0222, respectively)
Feely et al. 1982 [72]	Placebo-controlled cross-over (repetitive seizures and catamenial epilepsy)	Outpatient	Adolescent (N = 14)	Clonazepam, did not specify the dosage form (20–30 mg/day)	Patients received daily doses of clobazam for 10 days around menstruation time. Thirteen patients responded favorably to clobazam. Three of them have been successfully treated to be seizure free for 3–3.5 years. No evidence of tolerance was observed
Malu et al. 2014 [73]	Randomized open-label multicenter trial (status epilepticus)	Emergency department	Pediatrics (N = 436)	Sublingual lorazepam (0.1 mg/kg) Rectal diazepam (0.5 mg/kg)	Sublingual lorazepam is less effective in stopping seizures within 10 min compared to rectal diazepam (56–79%, p < 0.001), and the treatment failure was higher in the lorazepam group (OR = 2.95, 95% CI = 1.91–4.55)
Intravenous and Intramuscular Trials
Author	Design (Type of Seizure)	Settings	Sample	Doses	Results
Welch et al. 2015 [74]	Randomized double-blind multicenter trial (status epilepticus)	Emergency department	Pediatrics (N = 120)	IM midazolam (0.5 mg/kg) IV lorazepam (0.1 mg/kg)	IM midazolam have similar efficacy to IV lorazepam in stopping seizure before emergency department arrival (68.3% in IM midazolam vs. 71.6% in lorazepam) and (risk difference = −3.3%; 99% CI −24.9% to 18.2%)
Portela et al. 2015 [75]	Randomized open-label trial (no specific type of seizure)	Emergency department	Pediatrics (N = 32)	IM midazolam (0.5 mg/kg) IV diazepam (0.5 mg/kg)	The time from admission to seizure termination was shorter in the IM midazolam group (7.3 vs. 10.6 min; p = 0.006), and IV placement was unsuccessful in 25% of patients in the IV group
Silbergleit et al. (RAMPART) 2012 [12]	Randomized double-blind multicenter trial (status epilepticus)	Emergency department	Adults and pediatrics (N = 893)	IM midazolam (5–10 mg) IV lorazepam (2–4 mg)	IM midazolam was noninferior to IV lorazepam with regard to the rate of seizure control without the need for rescue therapy (73.4% vs. 63.4% [95% CI, 4.0–16.1; p < 0.001]), and the total time to seizure cessation from randomization was similar between both groups
Intravenous and Intranasal Trials
Author	Design (Type of Seizure)	Settings	Sample	Doses	Results
Inokuchi et al. 2015 [76]	Retrospective cohort study (status epilepticus)	Emergency department	Adults (N = 19)	IN diazepam (10 mg) IV diazepam (10 mg)	IN diazepam demonstrated a significantly shorter time to seizure termination than IV diazepam (3 vs. 9.5 min, p = 0.003)
Jain et al. 2016 [65]	Systematic review and meta-analysis (no specific type of seizure)	Emergency department	Pediatric patients of 4 randomized clinical trials	IN midazolam (0.2 mg/kg) IV diazepam (0.2–0.3 mg/kg)	IN midazolam is similar to IV diazepam in seizure cessation within 10 min (RR 1.00; 95% CI, 0.93–1.06). However, the time to seizure control after the presentation to the emergency department was shorter in the IN midazolam group (mean difference −5.23 min; 95% CI, −9.55 to −0.90)
Intravenous and Buccal Formulation Trials
Author	Design (Type of Seizure)	Settings	Sample	Doses	Results
Tonekaboni et al. 2012 [77]	Randomized open-label trial (status epilepticus)	Emergency department	Pediatrics (N = 92)	Buccal midazolam (6–12 mo: 2.5 mg; 1–4 yrs: 5 mg; 5–9 yrs: 7.5 mg; ≥10 yrs: 10 mg) IV Diazepam (0.3 mg/kg)	Both medications have similar efficacy in seizure control within 10 min (68.8% vs. 70%, p = 0.09)
Talukdar and Chakrabarty, 2009 [78]	Randomized open-label trial (no specific type of seizure)	Emergency department	Pediatrics (N = 120)	Buccal midazolam (0.2 mg/kg) IV diazepam (0.3 mg/kg)	Buccal midazolam and IV diazepam have similar efficacies in controlling any type of seizure within 5 min of drug administration (85% vs. 93.3%, p = 0.142). However, it took buccal midazolam a shorter time to control the seizure after the presentation to the emergency department compared to IV diazepam (p = 0.004)