Clonazepam Versus Lorazepam in the Treatment of Methamphetamine-Poisoned Children: A Pilot Clinical Trial

Background: To evaluate the ecacy of oral clonazepam versus oral lorazepam following initial parenteral benzodiazepine administration to control methamphetamine-induced agitation in children. Methods: In a single-center clinical trial, intravenous diazepam (0.2 mg/Kg) was initially administered to all methamphetamine-poisoned pediatric patients to control their agitation, followed by a single dose of oral clonazepam (0.05 mg/Kg; n = 15) or oral lorazepam (0.05 mg/Kg; n = 15) to prevent relapse of toxicity. Results: The median age [IQR] (range) was 15 [10, 36] (6-144) months. The source of poisoning was methamphetamine exposure from oral ingestion in 23 (76.7%) and passive inhalation in 7 (23.3%) patients. The most common symptoms/signs were agitation (23; 96.7%), mydriatic pupils (26; 86.7%), and tachycardia (20; 66.6%). Four patients (13.3%) needed re-administration of IV diazepam due to persistent agitation. There was no report of benzodiazepine complications in either group. Conclusions: Although both benzodiazepines were effective, considering the similar administered doses of oral clonazepam and lorazepam as well as the higher potency of clonazepam, it seems that lorazepam is a better suited oral benzodiazepine for the maintenance treatment of methamphetamine-induced agitation in children and can be used with minimal complications.

and tachycardia (20; 66.6%). Four patients (13.3%) needed re-administration of IV diazepam due to persistent agitation. There was no report of benzodiazepine complications in either group.
Conclusions: Although both benzodiazepines were effective, considering the similar administered doses of oral clonazepam and lorazepam as well as the higher potency of clonazepam, it seems that lorazepam is a better suited oral benzodiazepine for the maintenance treatment of methamphetamine-induced agitation in children and can be used with minimal complications.
Trial registration: IRCT20180610040036N2, April 18th 2020. Retrospectively registered Background In recent years, Iran has seen a rise in the prevalence of stimulant abuse, including from methamphetamine, methylphenidate, and ecstasy [1,3,4]. The hidden nature of stimulant abuse among family members has also resulted in a dramatic increase in the frequency of accidental stimulant toxicity in children. Even though accidental opioid poisonings remain more common in Iranian children [1], this change in adult drug use patterns presents a challenge for clinical practice, since no appropriate antidote exists for stimulant poisoning [2]. The most common signs and symptoms of stimulant toxicity in children are irritability, agitation, hyperactivity, ataxia, seizure, inconsolable or constant body movements, roving eye movements, cortical blindness, hyperthermia, tachycardia, hypertension, vomiting, respiratory distress, and rhabdomyolysis [2].
Benzodiazepines (BZOs) are the rst-line medications in the treatment of toxicity from stimulants, including methamphetamine. Management of agitation is the cornerstone in the treatment of methamphetamine poisoning, which can prevent further complications including hyperthermia, hypertension, hallucination, delirium, and rhabdomyolysis.
BZO treatment can control methamphetamine-induced agitation and prevent seizures simultaneously.
BZOs bind to the GABA receptors, which increase chlorine release into the neurons and result in anti-anxiety, anti-convulsive, and sedative effects [12]. They are generally intravenously administered until the patient becomes symptom-free and calm.
However, in pediatric patients, access to and maintenance of the intravenous (IV) line is a major concern, especially in younger children and in busy wards. A child may not cooperate with the treating team, and the IV line may be lost during the treatment process due to the child's movements. IV administration of BZOs in children needs to be slow and requires respiratory monitoring, as rapid administration of BZOs may induce respiratory depression and apnea [5; 13-15]. This risk is not common with oral BZOs [5].
Early administration of oral BZOs has been advocated in adult patients with methamphetamine poisoning [11]. However, the role of oral BZOs in the treatment stimulant-poisoned children after initial emergency department (ED) management is unclear, as literature on this subject is sparse. In clinical practice, we have observed that initial IV administration of BZOs does not sedate the child or that it can lead to a recurrence of stimulant toxicity. We hypothesize that the combination of two BZOs may have greater e cacy and safety, in which IV administration acts like a loading dose for oral treatment.
The aim of the current study was thus to evaluate the e cacy of oral BZOs in the treatment of methamphetamine poisoning in children referring to the only pediatric poisoning center in Tehran (Iran) after they were initially managed by administration of IV diazepam. For this purpose, we assigned the patients to two groups of oral clonazepam and oral lorazepam and compared the two treatments in their e cacy in terms of reducing agitation and other manifestations of stimulant toxicity.

Methods
Thirty methamphetamine-poisoned children who had been referred to Loghman-Hakim Poison Center in Tehran (Iran) between January 2017 and January 2018 were enrolled in this pilot clinical trial adhering to CONSORT guidelines (Iranian Registry of Clinical Trials ID: IRCT20180610040036N2).
Patients were eligible for inclusion in the study if they were below the age of 12 and met diagnostic criteria for methamphetamine poisoning.
Diagnosis of methamphetamine poisoning was based on three criteria: the history given by the child's parents, a positive urine methamphetamine, and clinical presentation. Patients with mixed poisoning (i.e. methamphetamine and other substance) or those whose urine was negative for methamphetamine were excluded from the study. Normal vital signs were determined based on pre-de ned measures for each patient's respective age group [12].

BZO treatment
All thirty patients were initially administered IV diazepam (0.2 mg/Kg) and then consecutively (on a weekly basis) assigned to either the oral clonazepam or the oral lorazepam group (1:1 allocation ratio, 15 patients each, 0.05 mg/Kg [routine dose of oral BZO in children]). After the initial IV diazepam treatment, oral BZOs were only given once to prevent return of stimulant toxicity by one of three of co-authors on shift. They were given when the patient was calm, and could be switched to oral regimen.

Data collection
Records were kept on the patients' demographic characteristics, urine drug screen results, route of methamphetamine exposure (inhalation versus ingestion), time elapsed between methamphetamine use and hospital presentation, vital signs and signs/symptoms on presentation, type and total dose of the oral BZO administered (clonazepam versus lorazepam), need for re-administration of the IV BZOs after initial management of the patient, time elapsed between BZO administration and resolution of the signs and symptoms, duration of hospital stay, and side effects of treatment (respiratory depression, deep sedation, and paradoxical agitation).

Patient monitoring
Patients were continuously monitored for pulse rate, respiratory rate, and cardiac rhythm. However, since they were irritable and using pressure cuffs for blood pressure check could agitate them, blood pressure was only checked every six hours. During the post-treatment observation period, the nurses would call the attending physician if they detected agitation or any changes in the patient's vital signs or cardiac rhythm. Patients' monitoring continued till discharge.

Data analysis
The data were analyzed using IBM Statistical Package for Social Sciences (SPSS) version 21. For qualitative variables, percentage of frequency was reported. Mann-Whitney U-test and chi-square test were used to evaluate the association between continuous and categorical variables. A P value of less than 0.05 was considered to be statistically signi cant.
Twenty-three patients (76.7%) had ingested methamphetamine, either in the form of crystal powder (16 patients; 53.3%) or as water from a methamphetamine pipe (7 patients; 23.3%). Seven (23.3%) had been passively exposed to methamphetamine smoked by their parents (i.e. fathers, based on patient history).
The median elapsed time [IQR] between ingestion and development of methamphetamine toxicity was one hour [1,2] (30 minutes to 24 hours), and the median [IQR] time between ingestion and hospital presentation was ve hours [3,6] (one hour to 72 hours; Table 1), according to parental report. Urine methamphetamine was positive in all cases.

Discussion
In our study, treatment with oral clonazepam and oral lorazepam had the same e cacy in the resolution of the signs and symptoms of methamphetamine toxicity in children. Limited access to parenteral lorazepam (as a good substitute for parenteral BZOs such as diazepam and midazolam) in Iran had made us look for safer oral alternatives, and our results show that most of our pediatric patients were sedated adequately with the combination treatment of only 0.2-mg/Kg IV diazepam as loading dose followed by oral BZO administration (clonazepam or lorazepam at 0.05 mg/Kg). This combination treatment was well tolerated, as none of the patients in our sample experienced any complications. Oral lorazepam and clonazepam were both administered at an average dose of 1.1 mg. Considering the BZO equivalency table [20], it thus seems that lorazepam is a safer option for the treatment of agitation in methamphetamine-poisoned children because it is less potent.
To the best of our knowledge, this pilot study is the rst to investigate the e cacy of oral BZOs in pediatric methamphetamine poisoning.
Literature on the management of stimulant-poisoned children has been limited to reports of IV BZO treatment to date. For instance, Van Rijwijk (10-mg diazepam), Duffy MR (5-mg diazepam and 2-mg IV lorazepam), Campbell (Diazepam and IV lorazepam), Cooper (IV diazepam), and Bedford Russel (2.5 mg/kg IV diazepam) have previously evaluated the effectiveness of IV BZOs for the treatment of ecstasy-poisoned children [6][7][8][9][10]. Kung and colleagues reported on a 5-year-old MDMA-poisoned patient with hypertension, tachycardia, hyperthermia, and mydriasis. An initial IV dose of 2.5 mg of diazepam was administered followed by other divided doses in 20-minute intervals which recovered the patient. The patient was discharged home after four days of ICU admission completely symptom-free [17]. Strommen and colleagues reported a 17-month-old infant with methamphetamine poisoning who referred with acute irritability, muscle twitching, and severe perspiration whose agitation was controlled within 30 to 40 minutes after administration of parenteral BZOs [16]. Matteucci et al. retrospectively evaluated 47 pediatric cases (age 0-6 years) of methamphetamine poisoning who had been referred to poisoning control centers in the USA between 2004-07, with agitation as most common symptom. Parenteral BZO had been administered to more than half of them, and the mean time to resolution of their signs and symptoms was 22 hours. No death was reported [18]. Ruha and Yarema reported 18 children poisoned with methamphetamine who were admitted to a critical care unit between 1997 and 2004. They were all treated with BZOs, and haloperidol was also administered to 12. They all improved with no important side effect [19].
Our ndings thus support our hypothesis that treatment with oral clonazepam or lorazepam following only an initial IV diazepam loading dose is e cacious and may reduce the burden for healthcare workers, for whom establishing access to and maintenance of the intravenous line is a major concern in pediatric patients.
Compared to the aforementioned pediatric studies, we managed to enroll a substantial sample of 30 patients. Replication of our ndings would lend further support to the concept of the combination treatment of IV and oral BZO as a practical, novel and cost-e cient intervention. However, further studies to evaluate different BZOs in the setting of acute methamphetamine poisoning in children are also warranted. These may include a comparison of the non-IV administration of different BZOs, e.g. by the intranasal (diazepam, midazolam), buccal and intramuscular (both midazolam) routes, which have already been tested in the management of epileptic seizures in children and shown similar e cacy as IV diazepam for this indication [21].
The generalizability of our ndings is limited by the fact that all patients were recruited at a single center in Tehran, and the external validity may be questionable. Moreover, patients were not randomly assigned to their treatment condition, and we cannot rule out the possibility of clinician bias. Future research could compare the treatment regimens more systematically in a blinded RCT.

Conclusion
This study demonstrates that oral lorazepam and clonazepam are effective and safe adjunct medications to IV diazepam in the treatment of methamphetamine poisoning and its agitation syndrome in children. Considering the higher potency of clonazepam and the similar administered doses of lorazepam and clonazepam, it seems although both treatments were effective, but oral lorazepam might be a better option in maintenance treatment of methamphetamine-induced agitation in children. Oral BZOs are effective to control methamphetamine induced agitation in children. Consent to publish:

List Of Abbreviations
Available.