pISSN 2383-9309❚eISSN 2383-9317 Review Article J Dent Anesth Pain Med 2020;20(1):1-8❚https://doi.org/10.17245/jdapm.2020.20.1.1

Midazolam use in pediatric dentistry: a review

Shreyans Aditya Jain, Nilesh Rathi, Nilima Thosar, Sudhindra Baliga

Department of Paedodontics and Preventive Dentistry, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Medical Sciences, Sawangi, India

Behaviour management and dental procedures performed in very young, pre-cooperative, highly anxious, or medically disabled children are challenging tasks. Various drugs and methods have, however, been introduced to facilitate treatment for this patient population. Midazolam is a benzodiazepine used as an adjunct to behavior management techniques in the dental treatment of pediatric patients. Midazolam can be used as a safe and effective drug for conscious sedation, general anesthetic premedication, and treatment of seizures during dental procedures. Nevertheless, further research involving pediatric patients would be beneficial.

Keywords: Benzodiazepines; Conscious Sedation; Midazolam; Pediatric Dentistry.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

INTRODUCTION turates, can be administered by various routes including oral, transmucosal (intranasal, buccal, or sublingual), intravenous, intramuscular, and rectal. Its advantageous Reducing the level of anxiety and pain in child patients role in the management of child dental patients will be undergoing dental procedures has been an issue for discussed and reviewed in detail [2]. pediatric dentists. The majority of child patients can be managed using conventional behavior management MIDAZOLAM: CLASS, PHARMACOKINETICS, AND methods; nevertheless, many require pharmacological PHARMACODYNAMICS intervention. Various drugs―namely, sedatives―have been studied to overcome this problem, for which benzodiazepines are commonly used. Midazolam is a Benzodiazepines exert their effects on the central benzodiazepine that has been available since 1983 [1]. nervous system. Specific benzodiazepine receptors are It has a fast and short duration of action, exerting anxi- located in neurons in the brain. All benzodiazepine olytic, anticonvulsive, muscular relaxant, and amnesic molecules have a common core shape, which binds to effects [1]. Hangover effects are decreased by its short these receptors and, in turn, alter an existing physiological half-life when used as a sedative agent, making filter. Normal passage of information from the peripheral midazolam a possible sedative drug for use in pediatric senses to the brain is filtered by the gamma-aminobutyric patients undergoing dental procedures. acid (GABA) system [2]. GABA is an inhibitory neuro- Sedative drugs, such as benzodiazepines and barbi- transmitter released from sensory nerve endings as a

Received: January 15, 2019•Revised: February 6, 2020•Accepted: February 8, 2020 Corresponding Author: Shreyans Aditya Jain, Department of Paedodontics and Preventive Dentistry, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Medical Sciences, Sawangi, Maharashtra-442001, India Tel: +91 9762745168 E-mail: [email protected] Copyrightⓒ 2020 Journal of Dental Anesthesia and Pain Medicine

http://www.jdapm.org 1 Shreyans Aditya Jain, et al result of nerve stimuli passing from one neuron to another tation, especially in younger child patients, although [2]. GABA binds to receptors on the cell membrane of accounting for only 1.4% of reactions [4,9,10]. Certain the post-synaptic neuron and stabilizes it by increasing drugs may interact with midazolam, which usually the threshold for firing. As a result, the number of sensory manifest as impeding its metabolism in the liver and messages perceived by the brain is reduced. When increasing or prolonging plasma concentrations. Inter- administered, benzodiazepines prolong the effect of acting drugs include erythromycin and clarithromycin, GABA, which reduces the number of stimuli reaching fluconazole and ketoconazole, and some antivirals such higher centers and results in sedation, muscle relaxation, as efavirenz, fosamprenavir, and nelfinavir [2,7,10]. anxiolysis, amnesia, and anticonvulsant effects [2,3]. Midazolam may also enhance the hypotensive effects of Benzodiazepines need to cross the blood-brain barrier to calcium channel blockers [9,11]. These effects should be reach their receptors. Midazolam can reach the brain very considered before administering midazolam to patients. quickly due to its high lipophilic property [4]. It is a The main side effect of benzodiazepines, which may water-soluble, non-irritant benzodiazepine with a distri- also lead to complications, is occasional marked respi- bution half-life of 6–15 min and an elimination half-life ratory depression. Therefore, it is vital that oxygen and of 1.5–2 h [4]. Therefore, it is a safe and effective all required equipment for the management of respiratory medicament in children because its elimination half-life depression using positive pressure ventilation are makes it especially suitable for short-duration procedures available [9]. Decreases in mean arterial pressure, cardiac [5-7]. It has been shown that children under midazolam output, systemic vascular resistance, and stroke volume conscious sedation have no recollection that of difficult may also occur, with only a small fall in arterial blood or unpleasant treatment [8]. pressure immediately after drug administration [3]. Flumazenil is the drug used to reverse over-sedation, USES OF MIDAZOLAM IN PEDIATRIC DENTAL respiratory depression, and/or paradoxical reactions PRACTICE caused by benzodiazepines. No pediatric dose has been recommended by the manufacturer nor is it licensed for use in children. The adult dose is 0.2 mg (intravenous Midazolam is used for two main purposes in child [IV]), administered over 15 s, and additional 0.1 mg IV patients: conscious sedation, and premedication to relieve doses at 60 s intervals if required, up to a maximum of anxiety before induction of general anesthesia (GA) [4,9]. 1 mg. Proportional dosage reduction in children has been It can also be used as an emergency drug to control recommended with the dose of IV flumazenil as 0.01 seizure attacks [9]. In general, the use of midazolam is mg/kg [9]. It is noteworthy that the half-life of flumazenil indicated in children who cannot cope with dental is shorter than that of midazolam; therefore, sedation may treatment due to high levels of anxiety, young age, recur when the patient has returned home [3]. learning difficulties, and/or an underlying medical 1. Conscious sedation for dental treatment condition. However, midazolam is contraindicated in children with hypersensitivity to benzodiazepines. It is Conscious sedation has been defined as a technique in relatively contraindicated in patients with acute or chronic which the use of a drug or drugs produces a state of pulmonary disease, pulmonary and/or cardiac insuffi- depression of the central nervous system enabling ciency, and myasthenia gravis [9]. A major drawback of treatment to be administered, but during which verbal midazolam sedation is the possibility of paradoxical contact with the patient is maintained throughout the reactions, which include disinhibition, hallucinations, period of sedation [12]. During conscious sedation, no agitation, inconsolable crying, restlessness, and disorien- interventions are required to maintain a patent airway,

2 J Dent Anesth Pain Med 2020 February; 20(1): 1-8 Midazolam in pediatric dentistry spontaneous ventilation is adequate, and cardiovascular difficult because some of the solution may be spat out function is usually maintained [13,14]. The drugs and [9]; moreover, no oral preparation (i.e., liquid form) is techniques used to provide conscious sedation for dental available. Therefore, the IV solution is mixed with juice treatment should carry a margin of safety sufficiently to mask the strong, bitter taste and improve acceptability wide to render loss of consciousness unlikely [15]. in child patients. For optimal sedation, the drug should Conscious sedation is used as an adjunct to behavior be administered 10–20 min before commencement of management techniques for treating child patients in the dental treatment. One study compared cola (PepsiCo, dental setting. It avoids the major risks associated with Harrison, NY, USA), 10% sodium citrate, pomegranate GA and aims for behavior improvement, apprehension juice, and grapefruit juice as mixtures with midazolam and anxiety reduction, and an increase in amnesia [1]. for oral intake, and concluded that drug ingestion was In a Cochrane systematic review addressing conscious simpler and sedation was more effective when midazolam sedation in anxious pediatric dental patients, the authors was added to sodium citrate because it reduced gastric were not able to draw a conclusion regarding the most pH, which facilitated better absorption of the drug [20]. effective drug or method of sedation for anxious children Another study investigating the use of oral midazolam [16]. However, the use of midazolam is a possible option for sedation of child patients reported that the technique for conscious sedation in pediatric dentistry. Children was well tolerated by children and accepted by parents required to undergo conscious sedation with midazolam [21]. Oral midazolam sedation has been reported to be should be carefully selected. American Society of safe and effective, although some patients became Anesthesiologists (ASA) class I or class II patients may agitated during or after treatment [21]. be candidates for conscious sedation as outpatients. Wilson et al. [22] performed a randomized, controlled However, ASA class III and IV patients must undergo cross-over trial to investigate the effectiveness of 0.5 conscious sedation in hospital settings along with mg/kg oral midazolam sedation for orthodontic extraction consultation with their medical doctor [12,13]. of permanent teeth. They concluded that oral sedation As mentioned above, various routes of administration using midazolam was safe and acceptable in patients 10– can be considered for the use of midazolam in conscious 16 years of age. In another study, involving 5-10-year-old sedation. The oral route of administration is the most children, oral midazolam was compared with nitrous widely used in children. It is easy to administer and has oxide inhalation sedation. Oral sedation proved to be safe decreased the risks for allergic reaction. However, when and effective but was not the method of choice for all taken orally, the onset and duration of action of mida- patients [23]. This may have been due to the unpleasant zolam is prolonged, gastric absorption is unpredictable, taste of the oral solution or the emergence of paradoxical and a stable sedative level is attained 30 min following reactions. Transmucosal, intranasal route of administ- drug intake [17-19]. The bioavailability of midazolam is ration is another effective method in child patients. The decreased when it passes the portal circulation to reach sedative effect is observed within 5 min of administration systemic circulation. Therefore, a higher oral dosage of 0.1–0.2 mg/kg midazolam intranasally or transmucosal (0.3-0.5 mg/kg up to 12 mg maximum) is required [9]. (sublingual). Preparations used via the nasal route are The oral route of administration is useful in needle-phobic made to order and administered using a metered nasal young children who cannot cope with dental treatment, spray. Studies have demonstrated the rapid onset (5–10 as well as patients with learning difficulties or other min) of intranasal midazolam sedation, as well as the medical conditions. However, oral intake of the drug is short recovery time following administration [17-19, 24]. completely dependent on the compliance of the child Intranasal midazolam is rapidly absorbed from the nasal patient and determination of the appropriate dosage is mucosa into the circulation and the peak effect occurs

http://www.jdapm.org 3 Shreyans Aditya Jain, et al sooner compared with the oral route. Therefore, the nasal patients, with an onset of action as short as 5 min [29,30]. route could be a better option in children. Despite rapid However, interruption of absorption by defecation and onset and ease of administration, large volumes of the lack of patient and parent acceptance are major disadvan- solution can cause coughing, sneezing, and expulsion of tages of rectally administered midazolam [24]. Patient the drug [9]. The use of intranasal midazolam is sedation using midazolam via any of the above-mentioned associated with nasal irritation and unacceptability in routes of administration should be monitored for vital children with nasal discharge [25] and could lead to signs, including respiration and blood pressure, especially occasional respiratory depression [26]. Karl et al. [27] when midazolam is administered via the oral or IV route compared intranasal and sublingual routes of administ- [2,24,29,30]. Using pulse oximetry throughout sedation ration of midazolam in child patients 6 months to 10 years is mandatory in case of any complication. Oxygen of age. Their results revealed that sublingual administration saturation levels < 90% should be investigated and the of midazolam was as effective as the intranasal route. cause corrected. However, the sublingual route was better accepted by 2. Premedication for induction of GA child patients. The compliance of the 6-month-old patients with sublingual lozenges was not clearly Induction of GA may be challenging in a highly anxious addressed in this study. The IV route is one of the most or a pre-cooperative patient, as well those with a common routes of administration of midazolam. The medically compromising condition or learning difficulty. general advantages of IV midazolam sedation include Various medications have been advocated to ease rapid onset (3–4 min) with adequate patient cooperation, child-separation anxiety from parents and to mitigate ability to titrate the dose, and good amnesia of the anxiety during different phases of the perioperative procedure [28]. In pediatric dentistry, however, it may period. The ideal premedication agent for children should only serve as a possible option in anxious adolescents have an acceptable and atraumatic route of adminis- [28]. The fact that cannulation must be performed may tration, a rapid and reliable onset, minimal side effects, make it a less favorable route of administration in very and rapid elimination [31]. It has been reported that young children. The recommended dosage for IV midazolam fulfills these criteria and, therefore, can be midazolam in children is 0.25–1.5 μg/kg/min. The drug used as a premedication in child patients undergoing must be administered slowly so that its effects are dental treatment under GA [6,32,33]. Wilton et al. [34] assessed and overdosage is avoided [4]. Robb et al. [28] first described the use of intranasal midazolam as reported 18 cases of conscious sedation with IV premedication for GA. In a prospective randomized midazolam in children 11–15 years of age. No loss of double-blind clinical trial, Weber et al. [35] used the consciousness or fall in oxygen saturation levels was intranasal route of administration for midazolam and observed, which suggested the safe use of this drug for concluded that it was an appropriate premedication in conscious sedation. The intramuscular (IM) route of preschool children. administration has not been extensively studied in A placebo-controlled trial investigated the reaction time pediatric patients. In children, however, the disadvantages and psycho-motor coordination of children undergoing of this technique outweigh its advantages. A stable level GA before discharge and at 48 h when premedicated with of sedation is attained 30 min following drug 0.2 mg/kg buccal mucosa injection of midazolam to a administration [17-19] and administering IM injection to maximum dose of 10 mg [36]. Premedication with mida- a child patient is unpleasant and most probably not zolam requires a low dose (0.2 mg/kg) for anxiolysis; acceptable. Rectal administration of midazolam has been however, for oral sedation, a higher dose (0.5 mg/kg) is demonstrated to be effective and safe for sedating child required for anxiolysis as well as sedation. A total of 179

4 J Dent Anesth Pain Med 2020 February; 20(1): 1-8 Midazolam in pediatric dentistry children participated in this study, each receiving buccal CONTROL OF ACUTE SEIZURES IN EPILEPTIC midazolam or placebo before induction of GA. Results CHILDREN IN THE DENTAL SETTING revealed that reaction time was significantly slower and psychomotor coordination was also significantly impaired in the midazolam group. Midazolam was also associated A prolonged convulsive seizure is the most common with anterograde amnesia before discharge and at 48 h neurological medical emergency with poor outcome. An [36]. This indicates that impairment of children’s ideal anticonvulsant should be easy to administer, cognitive function and amnesia lasting for up to 48 h effective, and safe, as well as having a long-lasting effect. post-GA should be expected when midazolam is used for IV or rectally administered benzodiazepines have generally premedication. been used as first-line drugs. In young children, however, A more recent study, however, demonstrated that 0.2 gaining IV access on the dental chair and during a seizure mg/kg buccal midazolam reduced anxiety in most patients attack is exceedingly difficult, if not impossible. but did not have an effect on psychological morbidity, Transmucosal midazolam has recently been suggested induction behavior, and subsequent dental attendance as a possible drug for the management of seizure attacks [37]. Kain et al. [38] reported that children premedicated on the dental chair and at home [42]. Transmucosal with oral midazolam exhibited less negative behavioral (intranasal and buccal) route of administration has mainly changes during the first postoperative week compared to been studied and compared with IV or rectal diazepam. those in the placebo group. It has been suggested that In a prospective randomized study involving 358 patients, high levels of trait anxiety could be a contraindication Holsti et al. [43] compared the use of intranasal to the use of oral midazolam as a premedication for GA. midazolam with rectal diazepam at home for the treatment In addition, the use of midazolam before GA for a child of seizures in children with epilepsy. There was no with low state baseline anxiety is deemed unnecessary difference among the two drugs in terms of efficacy as [39]. Regarding recovery and discharge times, Viitanen a rescue medication. However, ease of administration and et al. [40] reported that the use of oral midazolam as overall satisfaction was higher with intranasal midazolam. premedication for propofol-induced GA in 1–3-year-old Another recent study involving 98 participants compared children delayed early recovery but did not affect the use of buccal midazolam with rectal diazepam. discharge time. The authors also concluded that oral Results revealed that midazolam was as effective as midazolam did not improve the quality of recovery. A diazepam. However, midazolam was less time consu- literature review of available randomized controlled trials ming, and more parents were satisfied with the buccal investigating midazolam oral premedication studied the route of administration [42]. The buccal administration effects of midazolam on separation anxiety, induction dose of 0.3 mg/kg (Epistat) has been recommended and anxiety, emergence agitation, recovery times, long-term the effects are observed within 5 min [36]. A Cochrane outcomes, and dose and timing of the drug. The authors review concluded that buccal midazolam was successful concluded that premedication with oral midazolam in the treatment of seizures at a rate almost double that reduced anxiety in children at separation from parents and for rectal diazepam. The authors reported that intranasal anesthesia induction. However, there appeared to be no midazolam was as effective as IV diazepam in the evidence supporting the moderation of emergence agitation, treatment of prolonged febrile convulsions, suggesting and awakening times were slightly delayed, although no that when IV access is unavailable, buccal midazolam is serious side effects were reported [41]. Finally, mida- the treatment of choice [44]. It is noteworthy that only zolam could be used as an emergency drug in the dental four studies were included in this systematic review. setting. However, more studies have been performed since then,

http://www.jdapm.org 5 Shreyans Aditya Jain, et al and the use of midazolam for seizures has been proven uses and toxicity. J Emerg Med 1997; 15: 357-65. to be effective [45]. 3. Craig D, Skelly M. Practical conscious sedation. London: Midazolam can be used to help child patients cope with Quintessence publishing; 2004. dental treatment and undergo GA, as well as being a 4. Folayan MO, Faponle A, Lamikanra A. Seminars on life-saving drug in case of a seizure attack. Midazolam, controversial issues. A review of the pharmacological similar to any other drug, has its own side effects that approach to the management of dental anxiety in children. could lead to very serious complications such as Int J Paediatr Dent 2002; 12: 347-54. respiratory depression. Therefore, clinicians should be 5. Payne K, Mattheyse FJ, Liebenberg D, Dawes T. The familiar with the administration of midazolam and pharmacokinetics of midazolam in paediatric patients. Eur management of its complications in case of an J Clin Pharmacol 1989; 37: 267-72. emergency. Monitoring vital signs at all times during 6. McMillan CO, Spahr-Schopfer IA, Sikich N, Hartley E, sedation is vital so that appropriate action can be taken Lerman J. Premedication of children with oral midazolam. to reverse over-sedation. The midazolam reversal drug Can J Anaesth 1992; 39: 545-50. flumazenil should always be present in dental settings 7. Weldon BC, Watcha MF, White PF. Oral midazolam in where midazolam sedation is performed. children: effect of time and adjunctive therapy. Anesth Analg 1992; 75: 51-5. AUTHOR ORCIDs 8. Merritt P, Hirshman E, Hsu J, Berrigan M. Metamemory Shreyans Aditya Jain: https://orcid.org/0000-0002-2819-7242 without the memory: are people aware of midazolam- Nilesh Rathi: https://orcid.org/0000-0003-0595-5191 induced amnesia? Psychopharmacol 2005; 177: 336-43. Nilima Thosar: https://orcid.org/0000-0003-3339-781X 9. Hosey MT, Fayle S. Pharmaceutical prescribing for Sudhindra Baliga: https://orcid.org/0000-0002-4799-8205 children. Part 5. Conscious sedation for dentistry in children. Prim Dent Care 2006; 13: 93-6. AUTHOR CONTRIBUTIONS 10. Massanari M, Novitsky J, Reinstein LJ. Paradoxical Shreyans Aditya Jain: Conceptualization, Data curation, Methodology, reactions in children associated with midazolam use during Resources, Software, Supervision, Validation, Visualization, Writing endoscopy. Clin Pediatr (Phila) 1997; 36: 681-4. – original draft, Writing – review & editing 11. British National Formulary. 2014. Available from: Nilesh Rathi: Supervision, Writing – review & editing http://www.bnf.org. Nilima Thosar: Writing – review & editing 12. Hallonsten AL, Jensen B, Raadal M, Veerkamp J, Hosey Sudhindra Baliga: Supervision, Writing – review & editing MT, Poulsen S. European Academy of Paediatric Dentistry guidelines on conscious sedation in paediatric dentistry. DECLARATION OF INTEREST: No potential conflict of 2003. interest was reported by the authors. 13. UK national clinical guidelines in paediatric dentistry. managing anxious children: the use of conscious sedation REFERENCES in paediatric dentistry. Int J Paediatr Dent 2002; 12: 359-72. 14. National Clinical Guideline Centre. Sedation in children and young people: sedation for diagnostic and therapeutic 1. Torres-Pérez J, Tapia-García I, Rosales-Berber MA, procedures in children and young people. London: Royal Hernández-Sierra JF, Pozos-Guillén Ade J. Comparison College of Physicians (UK); 2010. of three conscious sedation regimens for pediatric dental 15. Standing dental advisory committee. Conscious sedation patients. J Clin Pediatr Dent 2007; 31: 183-6. in the provision of dental care: report of an expert group 2. Nordt SP, Clark RF. Midazolam: a review of therapeutic for sedation in dentistry. London: UK Department Of

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