Effective management of pain and anxiety in pediatric emergency room is crucial for ensuring both the physical and emotional well-being of young patients. Analgosedation, a combination of analgesia and sedation, is commonly used to facilitate various procedures in children. However, selecting the optimal agent and administration route remains challenging due to the unique pharmacological profiles and side effects of available drugs. This scoping review aims to provide a comprehensive analysis of the pharmacological agents used for procedural analgosedation in pediatric emergency settings, focusing on their efficacy, safety, administration routes, and potential side effects. A systematic review of the literature was conducted, focusing on key agents such as ketamine, midazolam, dexmedetomidine, fentanyl, and nitrous oxide. Studies were included based on their relevance to pediatric procedural sedation, particularly in emergency settings. Literature analysis showed that ketamine and fentanyl are effective for managing moderate to severe pain, with a rapid onset of action. Fentanyl is preferred for acute pain management following fractures and burns, while ketamine and midazolam are commonly used for emergency analgosedation. Dexmedetomidine, which induces sedation similar to natural sleep, is particularly effective in preventing pain and agitation during procedures and is well tolerated in children, especially those with developmental disorders. Nitrous oxide, when used in a 50% oxygen mixture, offers a valuable option for conscious sedation during mildly to moderately painful procedures, maintaining respiratory and airway reflexes. No single drug is ideal for all pediatric patients and procedures and the choice of agent should be tailored to the specific clinical scenario, considering both the sensory and affective components of pain. Future research should prioritize large-scale comparative studies, the exploration of combination therapies, and the development of no Fentanyl is preferred for acute pain management following fractures and burns, while ketamine and midazolam are commonly used for emergency analgosedation. Dexmedetomidine, which induces sedation similar to natural sleep, is particularly effective in preventing pain and agitation during procedures and is well tolerated in children, especially those with developmental disorders. Nitrous oxide, The NICE guidelines suggest that combining INF with midazolam may be a safe and effective strategy for procedural sedation in pediatric patients undergoing minor procedures, such as laceration repair or orthopedic manipulation, especially in urgent care settings [ 27 , 53 , 54 ]. 6. Nitrous Oxide Nitrous oxide is an anesthetic gas naturally present in the atmosphere, known for its sedative, anxiolytic, moderately analgesic, and amnesic properties. Although its precise mechanism of action remains unclear, it is believed that its analgesic effects are mediated through modulation of opioid receptors. Inhalation of a 50% nitrous oxide/50% oxygen mixture induces a state of conscious sedation, where the patient experiences a depressed level of consciousness while maintaining independent breathing, protective airway reflexes, and the ability to respond to verbal stimuli. This allows for its use without the need for fasting or intravenous access [ 57 ]. Outside the operating room, nitrous oxide is commonly used in a 50–50 mixture, providing sufficient analgesic and anxiolytic effects for moderately painful procedures. This dosage has been shown to be highly effective and safe in numerous pediatric studies, making it a preferred agent for short procedures that involve mild to moderate pain. Notably, it can be safely administered by adequately trained nursing staff [ 58 ]. Administration of nitrous oxide can be continuous or on-demand using a facial mask, with the latter activated by the patient through deep inspiration, making it suitable only for cooperative children [ 59 , 60 ]. Side effects are rare and typically resolve quickly once administration is stopped. Minor side effects, reported in approximately 5% of patients, include disinhibition, disorientation, dizziness, headache, euphoria, restlessness, nausea, and vomiting. Major side effects are extremely rare (0.3%) and are more likely to occur when nitrous oxide is used in concentrations above 50% or in combination with benzodiazepines or opioids. These more serious side effects include desaturation, apnea, airway obstruction, bradycardia, and loss of verbal contact [ 61 , 62 ]. The contraindications for nitrous oxide use are relatively few but are important to consider, especially in conditions where inhaled gas can rapidly diffuse into air-filled spaces, leading to increased pressure. The study found that patient behavior was rated as “good/very good” in 79.7% of cases, with no significant differences based on the type of procedure performed. Adverse effects were recorded in 7.9% of cases, most commonly dizziness and headache. The medical team found the administration process easy in 96.6% of cases, and 92.7% of parents indicated they would accept the use of nitrous oxide in similar future situations for their child. 7. Conclusions While no single drug possesses all the ideal characteristics for analgesia and sedation, optimizing the choice of an analgesic requires a comprehensive understanding of both the sensory and affective components of pain. These studies should also explore optimal dosing strategies for intranasal and other non-invasive routes of administration to minimize side effects while maximizing therapeutic benefits. Second, further investigation into the use of combination therapies is essential, particularly in understanding the interactions between drugs like ketamine, midazolam, dexmedetomidine, and nitrous oxide. These studies should aim to establish clear guidelines on which combinations offer the best balance of efficacy and safety for specific procedures.

<h4>Background</h4>Depression remains a global public health challenge, prompting interest in translational targets which allow for more effective and rapidly acting interventions. Nitrous oxide (N2O), an N-methyl-d-aspartate receptor antagonist, has demonstrated potential as a rapid-acting antidepressant. This study synthesised existing data on the efficacy and safety of N2O in depressive disorders.<h4>Methods</h4>We systematically reviewed clinical trials, exploratory studies, and protocol papers evaluating N2O for the treatment of depression, including major depressive disorder (MDD), treatment-resistant depression (TRD), and bipolar depression, following PRISMA guidelines. Meta-analysis was completed where possible. Primary outcomes were change in depressive symptoms and adverse events (AEs). Pooled mean differences (MD) and relative risk ratios were calculated using random- or fixed-effects models. Evidence mapping described trial characteristics across completed and ongoing studies.<h4>Findings</h4>Seven clinical trials involving 247 participants with depressive disorders, and four protocol papers were reviewed. N2O was administered via inhalation at 25% or 50%, as single or repeated sessions, with comparators including air, oxygen, or midazolam. Pooled results from three trials administering 50% N2O in a single session showed significant reductions in depressive symptoms at 2 h (pooled MD -2.74, 95% Confidence Interval (CI): -4.72 to -0.76; p = 0.007) and 24 h (MD -3.32, 95% CI: -5.09 to -1.55; p < 0.0001), but not at 1 week post-inhalation (MD -1.52; 95% CI: -4.07 to 1.03; p = 0.24). AEs were mild and transient, with 25% N2O generally being better tolerated. Evidence mapping showed that most trials are early-phase and focused on short-term outcomes in adults with MDD and TRD.<h4>Interpretation</h4>N2O demonstrates rapid, reproducible antidepressant effects in early-phase trials. Its future clinical value depends on whether these effects can be sustained over time through optimised dosing and extended/repeated use. Improved trial design, outcome standardisation, and population diversity is required to clarify its full potential for the treatment of depression.<h4>Funding</h4>The funder had no role in study design, data collection, analysis, interpretation, or writing.

Nitrous oxide (N₂O) misuse represents a growing public health issue, particularly among adolescents and young adults, who use it recreationally. This scoping review investigates recent and foundational studies on the long-term neuropsychiatric effects associated with prolonged and frequent use of this volatile gas. Various clinical databases and journal archives, such as those of the Journal of Addiction Medicine, Journal of Child Psychiatry, Journal of Anesthesiology, Science Direct, and National Survey of Drug Use and Health, were queried for clinical trials, case reports, and public health surveys. Emphasis was placed on studies exploring the neurobiological mechanisms, epidemiological trends, clinical manifestations, and treatment strategies associated with chronic N₂O exposure. The search revealed epidemiological factors like low socioeconomic status, peer influence, and concurrent use of alcohol or cannabis increased the likelihood of N₂O misuse. Biomechanically, N₂O acts via N-methyl-D-aspartate receptor (NMDA) receptor antagonism and endogenous opioid release, altering neurotransmitter dynamics and leading to potential dependence. Chronic use disrupts vitamin B12 metabolism by oxidizing methylcobalamin, impairing myelin production,n and leading to subacute combined degeneration of the spinal cord. Neuroimaging studies reveal deactivation of the hippocampus and visual cortices, aligning with observed memory and sensory processing deficits. Psychiatric complications such as depression, delusions, and agitation are frequently reported in adolescent users. Early intervention through cessation, vitamin B12 supplementation, and emerging pharmacologic agents such as naltrexone and aripiprazole can mitigate adverse outcomes. Public health initiatives such as educational campaigns, legislative control, and school-based prevention programs are critical to curbing ongoing misuse. Despite increasing attention, significant gaps remain in understanding long-term outcomes, 2757 cureus Cureus Cureus Cureus Inc. PMC12324979 12324979 12324979 40772002 10.7759/cureus.89448 Impact of Nitrous Oxide on Neuropsychiatric Impairment in Adolescents: A Scoping Review Cornelio Vanessa C 1 2 3 ✉ Lail Gary 1 Go Kimberly 1 4 Kaur Kiran 1 Slowik Piotr 1 Muacevic Alexander Adler John R 1 Psychiatry, St. John's Episcopal Hospital, Far Rockaway, USA 2 Gastroenterology and Hepatology, St. John's Episcopal Hospital, Far Rockaway, USA 3 Anatomical Sciences, William Carey University College of Osteopathic Medicine, Hattiesburg, USA 4 Internal Medicine, American University of the Caribbean School of Medicine, Cupecoy, SXM ✉ Vanessa C. Cornelio vcornelio96@gmail.com ✉ Corresponding author. 5 8 2025 17 8 e89448 e89448 6 8 2025 Copyright © 2025, Cornelio et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Nitrous oxide (N₂O) misuse represents a growing public health issue, particularly among adolescents and young adults, who use it recreationally. This scoping review investigates recent and foundational studies on the long-term neuropsychiatric effects associated with prolonged and frequent use of this volatile gas. Keywords: addiction medicine, inhalant use among adolescents, inhalant use disorder, longterm complication of nitrous oxide, nitrous oxide toxicity, treatment for nitrous oxide status released display-pdf yes is-olf no is-manuscript no is-preprint no is-journal-matter no is-scanned no is-retracted no Received 2025 Apr 6; Accepted 2025 Aug 5; Collection date 2025 Aug. Introduction and background Nitrous oxide (N 2 O) is a colorless, non-irritating gas with a sweet aroma that has therapeutic roles in alleviating pain and anxiety in medical and dental procedures, as well as in the management of treatment-resistant depression. There are multiple purported mechanisms by which N 2 O exerts its analgesic effect, including via activation of the endogenous opioid system and induction of a preventative blockade of pain hypersensitivity by interrupting nociceptive inputs [ 1 ]. To demonstrate the efficacy of N 2 O in pain reduction, a randomized Since its discovery and debut for analgesic and anesthetic properties in 1844, N 2 O pressure cylinders have been a staple for dental and minimally invasive medical procedures in the field of obstetrics, pediatrics, and chronic pain therapy, to safely administer the inhalant to patients [ 12 ]. In recent years, N 2 O has also been shown to be efficacious in treating refractory depression. Patients who received a mean duration of N 2 O treatment of 55.6 minutes at a median inspiratory concentration of 44% report a sustained improvement in mood and associated symptoms, days after treatment [ 3 , 13 ]. These processes are dramatically affected by nitrous oxide misuse, affecting the synthesis and processing of BH4. Many case studies have indicated a low level of vitamin B12 in N 2 O users. It has been postulated that N 2 O inactivates methylcobalamin by oxidizing the cobalt ion from 1+ to 3+ valence states [ 21 , 23 ]. By doing so, methionine synthase cannot convert the amino acid homocysteine into methionine, thereby causing a decrease in myelin production. There is also an impaired ability to convert 5-methyltetrahydrofolate to tetrahydrofolate, negatively affecting the production of DNA synthesis. This can enhance myelin inflammation, causing damage to the posterior columns and the corticospinal tract of the spinal cord. Neuropsychiatric effects of nitrous oxide Human behavioral studies have depicted impairments in psychomotor function and cognitive performance with the chronic use of N 2 O. A study conducted by Gylai et al. using positron emission tomography (PET) and regional cerebral blood flow indicated areas of the brain that were affected by N 2 O [ 26 ].

Nitrous oxide and epinephrine-induced arrhythmias. We asked whether the sympathomimetic effect of nitrous oxide (N2O) predisposed patients receiving N2O to arrhythmias in response to epinephrine administration. We also asked whether aging contributed to the development of arrhythmias, with or without N2O. One hundred patients having transsphenoidal hypophysectomy were randomly assigned to receive anesthesia including (n = 49) or excluding (n = 51) N2O. All patients were given an injection of epinephrine 1:200,000, with 0.5% lidocaine to produce hemostasis. Using intermittent 12-lead and continuous lead II electrocardiography, we determined the incidence of premature ventricular contraction, isorhythmic atrioventricular (AV) dissociation, and changes in T-wave morphology. Patients given N2O had a significantly higher incidence of isorhythmic AV dissociation (61.2% vs 41.2%). A trend toward a higher incidence of multiple premature ventricular contractions (16.3% vs 7.8%) was not statistically significant. Both anesthetic groups had a high incidence of postoperative changes in T-wave morphology (46.9% in the N2O group vs 50.9% in the group not given N2O).

similar to those of other dissociative anesthetics such as ketamine, nitrous oxide, and phencyclidine. It was patented in 1949 and approved for medical use Dextromethorphan is a cough suppressant used in many cough and cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropion to serve as a rapid-acting antidepressant in people with major depressive disorder. It is in the morphinan class of medications with dissociative and stimulant properties (at lower doses). Dextromethorphan does not hav Dextromethorphan is a cough suppressant used in many cough and cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropion to serve as a rapid-acting antidepressant in people with major depressive disorder. It is in the morphinan class of medications with dissociative and stimulant properties (at lower doses). Dextromethorphan does not have a significant affinity for the mu-opioid receptor activity typical of morphinan compounds and exerts its therapeutic effects through several other receptors. In its pure form, dextromethorphan occurs as a white powder. When exceeding approved dosages, dextromethorphan acts as a dissociative hallucinogen. It has multiple mechanisms of action, including actions as a nonselective serotonin–norepinephrine reuptake inhibitor and a sigma-1 receptor agonist. Dextromethorphan and its major metabolite dextrorphan also block the NMDA receptor at high doses, producing effects similar to those of other dissociative anesthetics such as ketamine, nitrous oxide, and phencyclidine. It was patented in 1949 and approved for medical use in 1953. In 2023, the combination with promethazine was the 252nd most commonly prescribed medication in the United States, with more than 1 million prescriptions; and the combination with brompheniramine and pseudoephedrine was the 281st most commonly prescribed medication in the United States, with more than 700,000 prescriptions.

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