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The Pharmacology, Physiology and Clinical Application in Dentistry of Nitrous Oxide

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Abstract

Nitrous oxide (N2O) is the nearly ‘ideal’ clinical sedative. For Paediatric Dentistry, it is almost as important as local anaesthesia. Many children (as well as children with special needs) would have been obliged to undergo deep sedation or general anaesthesia if it wasn’t available. N2O has been used for well over 150 years in clinical dentistry for its analgesic and anxiolytic properties. In this chapter, the way it is being used in Dentistry will be discussed. This small and simple inorganic chemical molecule has simultaneously effects of analgesia, anxiolysis, and anaesthesia that are of great clinical interest. Recent studies have helped to clarify the analgesic mechanisms of N2O, but the mechanisms involved in its anxiolytic and anaesthetic actions remain less clear. Research indicates that the analgesic effect of N2O is opioid in nature, while the anxiolytic effect resembles that of benzodiazepines and may be initiated at selected subunits of the gamma-aminobutyric acid type A (GABAA) receptor. Similarly, the anaesthetic effect of N2O may involve actions at GABAA receptors and possibly at N-methyl-D-aspartate receptors as well.

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References

  1. Emmanouil D, Kupietzky A. Nitrous oxide/oxygen inhalation sedation in children. In: Behav. Manag. Dent. Child. Chichester: John Wiley & Sons; 2014. p. 145–58.

    Google Scholar 

  2. Wright AJ. History of anesthesia: early use of nitrous oxide. Bull Anesth Hist. 1999;17:10–1.

    Article  CAS  PubMed  Google Scholar 

  3. Wilson S, Alcaino EA. Survey on sedation in paediatric dentistry: a global perspective. Int J Paediatr Dent. 2011;21(5):321–32.

    Article  PubMed  Google Scholar 

  4. Langa H. Relative analgesia in dental practice; inhalation analgesia with nitrous oxide. Philadelphia: Saunders; 1968.

    Google Scholar 

  5. Emmanouil D. Mechanism of action of nitrous oxide. In: Nitrous oxide in pediatric dentistry. Cham: Springer; 2020.

    Google Scholar 

  6. Gillman MA, Lichtigfeld FJ. Pharmacology of psychotropic analgesic nitrous oxide as a multipotent opioid agonist. Int J Neurosci. 1994;76:5–12.

    Article  CAS  PubMed  Google Scholar 

  7. Roberts GJ. Inhalation sedation (relative analgesia) with oxygen/nitrous oxide gas mixtures: 1. Principles. Dent Update. 1990;17:139–42, 145–6.

    CAS  PubMed  Google Scholar 

  8. Galeotti A, Garret Bernardin A, D’Antò V, Ferrazzano GF, Gentile T, Viarani V, Cassabgi G, Cantile T. Inhalation conscious sedation with nitrous oxide and oxygen as alternative to general anesthesia in precooperative, fearful, and disabled pediatric dental patients: a large survey on 688 working sessions. Biomed Res Int. 2016:1–6.

    Google Scholar 

  9. Coté CJ, Wilson S. Guidelines for monitoring and management of pediatric patients before, during, and after sedation for diagnostic and therapeutic procedures: update. Pediatr Dent. 2016;38:13–39.

    PubMed  Google Scholar 

  10. Jastak JT, Orendurff D. Recovery from nitrous sedation. Anesth Prog. 1975;22:113–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Gupta K, Ritwik P. Clinical application of nitrous oxide in pediatric dentistry. In: Nitrous oxide in pediatric dentistry. Cham: Springer; 2020.

    Chapter  Google Scholar 

  12. Babl FE, Oakley E, Seaman C, Barnett P, Sharwood LN. High-concentration nitrous oxide for procedural sedation in children: adverse events and depth of sedation. Pediatrics. 2008;121:528–32.

    Article  Google Scholar 

  13. Klein U, Robinson TJ, Allshouse A. End-expired nitrous oxide concentrations compared to flowmeter settings during operative dental treatment in children. Pediatr Dent. 2011;33(1):56–62.

    PubMed  Google Scholar 

  14. Hammond NI, Full CA. Nitrous oxide analgesia and children’s perception of pain. Pediatr Dent. 1984;6:238–42.

    CAS  PubMed  Google Scholar 

  15. Gupta K, Ritwik P. Rationale for using nitrous oxide in pediatric dentistry. In: Nitrous oxide in pediatric dentistry. Cham: Springer; 2020. p. 29–32.

    Chapter  Google Scholar 

  16. Lockwood AJ, Yang YF. Nitrous oxide inhalation anaesthesia in the presence of intraocular gas can cause irreversible blindness. Br Dent J. 2008;204:247–8.

    Article  CAS  PubMed  Google Scholar 

  17. Lindstedt G. Nitrous oxide can cause cobalamin deficiency. Vitamin B12 is a simple and cheap remedy. Lakartidningen. 1999;96(44):4801–5.

    CAS  PubMed  Google Scholar 

  18. Lacassie HJ, Nazar C, Yonish B, Sandoval P, Muir HA, Mellado P. Reversible nitrous oxide myelopathy and a polymorphism in the gene encoding 5,10 methylenetetrahydrofolate reductase. Br J Anaesth. 2006;96:222–5.

    Article  CAS  PubMed  Google Scholar 

  19. Arab AH, Elhawary NA. Methylenetetrahydrofolate reductase gene variants confer potential vulnerability to autism spectrum disorder in a Saudi community. Neuropsychiatr Dis Treat. 2019;15:3569–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Selzer RR, Rosenblatt DS, Laxova R, Hogan K. Adverse effect of nitrous oxide in a child with 5,10-methylenetetrahydrofolate reductase deficiency. N Engl J Med. 2003;349:45–50.

    Article  PubMed  Google Scholar 

  21. Fleming P, Walker PO, Priest JR. Bleomycin therapy: a contraindication to the use of nitrous oxide-oxygen psychosedation in the dental office. Pediatr Dent. 1988;10(4):345–6.

    CAS  PubMed  Google Scholar 

  22. Onody P, Gil P, Hennequin M. Safety of inhalation of a 50% nitrous oxide/oxygen premix. Drug Saf. 2006;29:633–40.

    Article  CAS  PubMed  Google Scholar 

  23. Kupietzky A, Tal E, Shapira J, Ram D. Fasting state and episodes of vomiting in children receiving nitrous oxide for dental treatment. Pediatr Dent. 2008;30:414–9.

    PubMed  Google Scholar 

  24. Dundee JW, Moore J. Alterations in response to somatic pain associated with anaesthesia. IV. The effect of subanaesthetic concentrations of inhalation agents. Br J Anaesth. 1960;32:453–9.

    Article  CAS  PubMed  Google Scholar 

  25. Gillmam M. Minimal sedation required with nitrous oxide-oxygen treatment of the alcohol withdrawal state. Br J Psychiatry. 1986;148:604–6.

    Article  Google Scholar 

  26. Chapman WP, Arrowood JG, Beecher HK. The analgetic effects of low concentrations of nitrous oxide compared in man with morphine sulphate. J Clin Invest. 1943;22(6):871–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Berkowitz BA, Ngai SH, Finck AD. Nitrous oxide “analgesia”: resemblance to opiate action. Science. 1976;194:967–8.

    Article  CAS  PubMed  Google Scholar 

  28. Berkowitz BA, Finck AD, Ngai SH. Nitrous oxide analgesia: reversal by naloxone and development of tolerance. J Pharmacol Exp Ther. 1977;203:539–47.

    CAS  PubMed  Google Scholar 

  29. Gillman MA, Kok L, Lichtigfeld FJ. Paradoxical effect of naloxone on nitrous oxide analgesia in man. Eur J Pharmacol. 1980;61:175–7.

    Article  CAS  PubMed  Google Scholar 

  30. Lawrence D, Livingston A. Opiate-like analgesic activity in general anaesthetics. Br J Pharmacol. 1981;73(2):435–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yang JC, Clark WC, Ngai SH. Antagonism of nitrous oxide analgesia by naloxone in man. Anesthesiology. 1980;52(5):414–7.

    Article  CAS  PubMed  Google Scholar 

  32. Quock RM, Kouchich FJ, Tseng LF. Does nitrous oxide induce release of brain opioid peptides? Pharmacology. 1985;30(2):95–9.

    Article  CAS  PubMed  Google Scholar 

  33. Sanders RD, Weimann J, Maze M. Biologic effects of nitrous oxide: a mechanistic and toxicologic review. Anesthesiology. 2008;109:707–22.

    Article  CAS  PubMed  Google Scholar 

  34. Emmanouil DE, Quock RM. Advances in understanding the actions of nitrous oxide. Anesth Prog. 2007;54:9–18.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Emmanouil DE, Quock RM. Modification of nitrous oxide analgesia by benzodiazepine receptors. Anesth Prog. 1989;36:5–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Okuda T, Wakita K, Tsuchiya N, Hatsuoka K, Koga Y. Yohimbine and flumazenil: effect on nitrous oxide-induced suppression of dorsal horn neurons in cats. J Anesth. 1997;11:198–201.

    Article  PubMed  Google Scholar 

  37. Fujinaga M, Doone R, Davies MF, Maze M. Nitrous oxide lacks the antinociceptive effect on the tail flick test in newborn rats. Anesth Analg. 2000;91:6–10.

    Article  CAS  PubMed  Google Scholar 

  38. Sawamura S, Kingery WS, Davies MF, Agashe GS, Clark JD, Kobilka BK, Hashimoto T. Antinociceptive action of nitrous oxide is mediated by stimulation of noradrenergic neurons in the brainstem and activation of α2B- adrenoreceptors. J Neurosci. 2000;20:9242–925.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Orii R, Ohashi Y, Guo T, Nelson LE, Hashimoto T, Maze M, Fujinaga M. Evidence for the involvement of spinal cord α1-adrenoreceptors in nitrous oxide-induced antinociceptive effects in Fischer rats. Anesthesiology. 2002;97:1458–65.

    Article  CAS  PubMed  Google Scholar 

  40. Zhang C, Davies MF, Guo TZ, Maze M. The analgesic action of nitrous oxide is dependent on the release of norepinephrine in the dorsal horn of the spinal cord. Anesthesiology. 1991;91:1401–7.

    Article  Google Scholar 

  41. Guo TZ, Poree L, Golden W, Fujinaga M, Maze M. Antinociceptive response to nitrous oxide is mediated by supraspinal opiate and spinal alpha2- adrenergic receptors in the rat. Anesthesiology. 1996;85:846–52.

    Article  CAS  PubMed  Google Scholar 

  42. Dawson C, Ma D, Chow A, Maze M. Dexmedetomidine enhances analgesic action of nitrous oxide. Anesthesiology. 2004;100:894–904.

    Article  CAS  PubMed  Google Scholar 

  43. Guo TZ, Davies F, Kingery WS, Patterson AJ, Limbird LE, Maze M. Nitrous oxide produces antinociceptive response via α 2B-and/or α 2C-adrenoreceptor subtypes in mice. Anesthesiology. 1999;90:470–6.

    Article  CAS  PubMed  Google Scholar 

  44. Mueller JL, Quock RM. Contrasting influences of 5-hydroxytryptamine receptors in nitrous oxide antinociception in mice. Pharmacol Biochem Behav. 1992;41:429–32.

    Article  CAS  PubMed  Google Scholar 

  45. Fitzgerald M, Koltzenburg M. The functional development of descending inhibitory pathways in the dorsolateral funiculus of the newborn rat spinal cord. Brain Res. 1986;389:261–70.

    Article  CAS  PubMed  Google Scholar 

  46. Fitzgerald M, Shaw A, Macintosh N. Postnatal development of the cutaneous flexor reflex: comparative study of preterm infants and newborn rat pups. Dev Med Child Neurol. 1988;30:520–6.

    Article  CAS  PubMed  Google Scholar 

  47. Ohashi Y, Stowell JM, Nelson LE, Hashimoto T, Maze M, Fujinaga M. Nitrous oxide exerts age-dependent antinociceptive effects in Fischer rats. Pain. 2002;100:7–18.

    Article  CAS  PubMed  Google Scholar 

  48. Georgiev SK, Kohno T, Ikoma M, Yamakura T, Baba H. Nitrous oxide inhibits glutamatergic transmission in spinal dorsal horn neurons. Pain. 2008;134:24–31.

    Article  CAS  PubMed  Google Scholar 

  49. Prast H, Philippu A. Nitric oxide as modulator of neuronal function. Prog Neurobiol. 2001;64:51–68.

    Article  CAS  PubMed  Google Scholar 

  50. McDonald CE, Gagnon MJ, Ellenberger EA, Hodges BL, Ream JK, Tousman SA, Quock RM. Inhibitors of nitric oxide synthesis antagonize nitrous oxide antinociception in mice and rats. J Pharmacol Exp Ther. 1994;269(2):601–8.

    CAS  PubMed  Google Scholar 

  51. Henry ED, Ohgami Y, Li S, Chung E, Quock RM. Correlation of inbred mouse sensitivity to nitrous oxide antinociception with brain nitric oxide synthase activity following exposure to nitrous oxide. Pharmacol Biochem Behav. 2005;81:764–8.

    Article  CAS  PubMed  Google Scholar 

  52. Ishikawa M, Quock RM. N2O stimulates NOS enzyme activity in C57BL/6 but not DBA/2 mice. Brain Res. 2003;976:262–3.

    Article  CAS  PubMed  Google Scholar 

  53. Quock RM, Mueller JL, Vaughn LK, Belknap JK. Nitrous oxide antinociception in BXD recombinant inbred mouse strains and identification of quantitative trait loci. Brain Res. 1996;725:23–9.

    Article  CAS  PubMed  Google Scholar 

  54. Mueller JL, Ellenberger EA, Vaughn LK, Belknap JK, Quock RM. Detection and mapping of quantitative trait locithat determine responsiveness of mice to nitrous oxide antinociception. Neuroscience. 2004;123:743–9.

    Article  CAS  PubMed  Google Scholar 

  55. Lee CGL, Gregg AR, O’Brien WE. Localization of the neuronal form of nitric oxide synthase to mouse chromosome 5. Mamm Genome. 1995;6:56–7.

    Article  CAS  PubMed  Google Scholar 

  56. Tseng LF, Higgins MJ, Hong JS, Hudson PM, Fujimoto JM. Release of immunoreactive met-enkephalin from the spinal cord by intraventricular β-endorphin but not by morphine in anesthetized rats. Brain Res. 1985;343:60–9.

    Article  CAS  PubMed  Google Scholar 

  57. Tseng LF. Intracerebroventricular administration of β-endorphin releases immunoreactive met-enkephalin from the spinal cord in cats, guinea pigs and mice. Neuropharmacology. 1989;28:1333–9.

    Article  CAS  PubMed  Google Scholar 

  58. Hara S, Kuhns WR, Ellenberger EA, Mueller JL, Shibuya T, Endo T, Quock RM. Involvement of nitric oxide in intracerebroventricular β-endorphin-induced neuronalrelease of methionine-enkephalin. Brain Res. 1995;675:190–4.

    Article  CAS  PubMed  Google Scholar 

  59. Ohgami Y, Li S, Chung E, Quock RM. Exposure to nitrous oxide [N2O] causes a nitric oxide [NO]-dependent release of β-endorphin in the rat arcuate nucleus. Proc West Pharmacol Soc. 2007;50:194.

    Google Scholar 

  60. Zelinski M, Ohgami Y, Quock RM. Exposure to nitrous oxide stimulates a nitric oxide-dependent neuronal release of β-endorphin in ventricular-cisternally-perfused rats. Brain Res. 2009;1300:37–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cope JL, Chung E, Ohgami Y, Quock RM. Antagonism of the antinociceptive effect of nitrous oxide by inhibition of enzyme activity expression of neuronal nitric oxide synthase in mouse brain and spinal cord. Eur J Pharmacol. 2010;626:234–8.

    Article  CAS  PubMed  Google Scholar 

  62. Emmanouil DE, Dickens AS, Heckert RW, Ohgami Y, Chung E, Han S, Quock RM. Nitrous oxide-antinociception is mediated by opioid receptors and nitric oxide in the periaqueductal gray region of the brain. Eur Neuropsychopharmacol. 2008;18:194–9.

    Article  CAS  PubMed  Google Scholar 

  63. Zuniga JR, Joseph SA, Knigge KM. The effects of nitrous oxide on the secretory activity of pro-opiomelanocortin peptides from basal hypothalamic cells attached to cytodex beads in a superfusion in vitro system. Brain Res. 1987;420:66–72.

    Article  CAS  PubMed  Google Scholar 

  64. Rupreht J, Dworacek B, Bonke B, Dzoljic MR, Van Eijndhoven JH, De Vlieger M. Tolerance to nitrous oxide in volunteers. Acta Anaesthesiol Scand. 1985;29:635–8.

    Article  CAS  PubMed  Google Scholar 

  65. Berkowitz BA, Finck AD, Hynes MD, Ngai SH. Tolerance to nitrous oxide analgesia in rats and mice. Anesthesiology. 1979;51:309–12.

    Article  CAS  PubMed  Google Scholar 

  66. Emmanouil DE, Quock RM. Effects of benzodiazepine agonist, inverse agonist and antagonist drugs in the mouse staircase test. Psychopharmacology. 1990;102:95–7.

    Article  CAS  PubMed  Google Scholar 

  67. Quock RM, Emmanouil DE, Vaughn LK, Pruhs RJ. Benzodiazepine receptor mediation of behavioral effects of nitrous oxide in mice. Psychopharmacology. 1992;107:310–4.

    Article  CAS  PubMed  Google Scholar 

  68. Emmanouil DE, Johnson CH, Quock RM. Nitrous oxide anxiolytic effect in mice in the elevated plus maze: mediation by benzodiazepine receptors. Psychopharmacology. 1994;115:167–72.

    Article  CAS  PubMed  Google Scholar 

  69. Czech DA, Green DA. Anxiolytic effects of nitrous oxide in mice in the light-dark and holeboard exploratory tests. Psychopharmacology. 1992;109:315–20.

    Article  CAS  PubMed  Google Scholar 

  70. Li S, Quock RM. Comparison of N2O- and chlordiazepoxide-induced behaviors in the light/dark exploration test. Pharmacol Biochem Behav. 2001;68:789–96.

    Article  CAS  PubMed  Google Scholar 

  71. Li S, Ohgami Y, Dai Y, Quock RM. Antagonism of nitrous oxide-induced anxiolytic-like behavior in the mouse light/dark exploration procedure by pharmacologic disruption of endogenous nitric oxide function. Psychopharmacology. 2003;166:366–72.

    Article  CAS  PubMed  Google Scholar 

  72. Li S, Quock RM. Effects of a nitric oxide donor on behavior and interaction with nitrous oxide in the mouse light/dark exploration test. Eur J Pharmacol. 2002;447(1):75–8.

    Article  CAS  PubMed  Google Scholar 

  73. Hornbein TF, Eger EI, Winter PM, Smith G, Wetstone D, Smith KH. The minimum alveolar concentration of nitrous oxide in man. Anesth Analg. 1982;61:553–6.

    Article  CAS  PubMed  Google Scholar 

  74. Epstein RM, Rackow H, Salanitre E, Wolf GL. Influence of the concentration effect on the uptake of anesthetic mixtures: the second gas effect. Anesthesiology. 1964;25:364–71.

    Article  CAS  PubMed  Google Scholar 

  75. Jevtović-Todorović V, Todorović SM, Mennerick S, Powell S, Dikranian K, Benshoff N, Zorumski CF, Olney JW. Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med. 1998;4(4):460–3.

    Article  PubMed  Google Scholar 

  76. Jevtovic-Todorovic V, Benshoff N, Olney JW. Ketamine potentiates cerebrocortical damage induced by the common anaesthetic agent nitrous oxide in adult rats. Br J Pharmacol. 2000;130:1692–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Biersner RJ. Selective performance effects of nitrous oxide. Hum Factors. 1972;14:187–94.

    Article  CAS  PubMed  Google Scholar 

  78. Block RL, Ghoneim MM, Hinrichs JV, Kumar V, Pathak D. Effects of a subanaesthelic concentration of nitrous oxide on memory and subjective experience: influence of assessment procedures and types of stimuli. Hum Psychopharmacol J. 1998:257–65.

    Google Scholar 

  79. Ramsay DS, Leonesio RJ, Whitney CW, Jones BC, Samson HH, Weinstein P. Paradoxical effects of nitrous oxide on human memory. Psychopharmacology. 1992;106:370–4.

    Article  CAS  PubMed  Google Scholar 

  80. Culley DJ, Raghavan SD, Baxter MG, Yukhananov R, Deth RC, Crosby G. Nitrous oxide decreases cortical methionine synthase transiently but produces lasting memory impairment in aged rats. Anesth Analg. 2007;105:83–8.

    Article  CAS  PubMed  Google Scholar 

  81. Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, et al. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell. 1994;79:59–68.

    Article  CAS  PubMed  Google Scholar 

  82. Emmanouil D, Klein ED, Chen K, Brewer AL, Zhang Y, Quock RM. Nitrous oxide-induced impairment of spatial working memory requires activation of GABAergic pathways. Current Psychopharmacology, 2020;9:68–78.

    Google Scholar 

  83. Maze M, Fujinaga M. Recent advances in understanding the actions and toxicity of nitrous oxide. Anaesthesia. 2000;55:311–4.

    Article  CAS  PubMed  Google Scholar 

  84. Rowland AS, Baird DD, Shore DL, Weinberg CR, Savitz DA, Wilcox AJ. Nitrous oxide and spontaneous abortion in female dental assistants. Am J Epidemiol. 1995;141(6):531–7.

    Article  CAS  PubMed  Google Scholar 

  85. American Academy of Pediatric Dentistry. Use of nitrous oxide for pediatric dental patients. Pediatr Dent. 2018;REF MAN:293–8.

    Google Scholar 

  86. American Academy of Pediatric Dentistry. Policy on minimizing occupational health hazards associated with nitrous oxide. Pediatr Dent. 2018;40(6):104–5.

    Google Scholar 

  87. Malamed SF. Inhalation sedation: techniques of administration. In: Sedation: a guide to patient management. 6th ed. St. Louis: Mosby Elsevier; 2018. p. 227–52.

    Google Scholar 

  88. Rademaker AM, McGlothlin JD, Moenning JE, Bagnoli M, Carlson G, Griffin C. Evaluation of two nitrous oxide scavenging systems using infrared thermography to visualize and control emissions. J Am Dent Assoc. 2009;140(2):190–9.

    Article  CAS  PubMed  Google Scholar 

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Emmanouil, D. (2021). The Pharmacology, Physiology and Clinical Application in Dentistry of Nitrous Oxide. In: Mason, MD, K.P. (eds) Pediatric Sedation Outside of the Operating Room. Springer, Cham. https://doi.org/10.1007/978-3-030-58406-1_12

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