American Association for Clinical Chemistry
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Nitrous Oxide (N2O)

This molecule is an anesthetic commonly used in dentistry. Abusers are mainly found among healthcare workers and employees in the restaurant and catering business.

Discovered in 1772 by English scientist Joseph Priestley, N2O was made by heating ammonium nitrate in the presence of iron filings and then passing the gas that came off (NO) through water to remove toxic by-products. Following Priestley's discovery, Humphry Davy of the Pneumatic Institute in Bristol, England, experimented with the gas, even administering it to visitors to the institute. After watching the amusing effects on people who inhaled it, he coined the term “laughing gas.” Early on, N2O was primarily used for recreation at traveling public shows but eventually found a more scientific use as an anesthetic in clinical dentistry and medicine. As the story goes, in 1844 a medical school dropout named Gardner Quincy Colton put on a nitrous oxide exhibition in Hartford, Connecticut. In the audience was a local dentist named Horace Wells. Dr. Wells watched with interest as one of the volunteers inhaled the gas then injured his leg when he staggered into some nearby benches. When he went back to his seat, he appeared to be unaware of the injury until the effects of the gas wore off. Dr.Wells immediately realized that N2O might possess painkilling qualities. Wells approached Colton and invited him to participate in an experiment the next day. Colton agreed and administered nitrous oxide to Wells while another local dentist extracted one of Wells' molars. Dr. Wells experienced no pain during the procedure, and the birth of N2O as a dental and medical painkiller had arrived. Nitrous oxide is a very safe and popular agent still utilized by dentists today. It is much less toxic than alternatives such as chloroform, with far less risk of explosion than ether. The main use for N2O is usually as a mild sedative and analgesic. It helps to allay anxiety that many patients may have toward dental treatment, and it offers some degree of painkilling ability.

N2O is a nonflammable gas present in the atmosphere in a concentration of ~0.3 ppm (4). It is water soluble and colorless and has a slightly sweet smell. Bacteriostatic properties and the lack of influence on food flavor make it a useful agent in the food industry (3). An important property of N2O for medicinal purposes is its low oil:gas partition coefficient of 1.4 at atmospheric pressure. This low partition coefficient produces a minimal alveolar concentration (MAC) of 1.05 atmospheres for anesthesia. Its low blood:gas partition coefficient (0.47 at 37 °C), quickly increases its partial pressure in blood, and results in a rapid induction of anesthesia. The low blood:gas coefficient also causes N2O to diffuse readily into enclosed air-filled body cavities, replacing nitrogen. N2O enters the cavity 35 times as rapidly as nitrogen exits, thereby expanding the cavity or increasing pressure. Therefore, use of N2O is not recommended in patients with occlusion of the middle ear, pneumothorax, obstructed intestine, or air emboli in the bloodstream (5).

Pharmacology and Kinetics

N2O interacts with opioid receptors of the m- and k-subtypes to produce analgesia. N2O can act both as an antagonist that reduces the effect of morphine in humans and as an agonist that acts synergistically with the opioid-receptor–mediated anesthetic effect of ketamine. Therefore, N2O is considered a partial agonist at these receptors (6). Tolerance occurs for the nociceptive effect of N2O, which develops between 45 and 150 min, possibly because of a decrease in opioid-receptor density (7). N2O may also interact with the d- and s-receptors (6, 8).

Besides these direct effects on opiate receptors, indirect effects of N2O have been reported. It can cause the release of endogenous opioids, such as met-enkephalin and b-endorphin, and thereby indirectly activate opioid receptors (6).

The mechanism of action for gaseous anesthetics is still poorly understood. Anesthetic potency is correlated to drug lipophilicity. Lipophilic molecules enter the lipid bilayer and expand and impede the opening of ion channels in the membrane and thereby the generation and propagation of action potentials. Another hypothesis is that anesthetic molecules bind to lipid portions of the ion channels and inhibit proper functioning (5).

N2O is not biotransformed. It enters and exits the body unchanged, almost entirely through the lungs (2).

Clinical Use

Because N2O is a gas, effects depend on its partial pressure in the administered gas mixture, and the partial pressure is directly proportional to the percentage of N2O in the mixture. Concentrations are therefore expressed in percentages. Clinical responses to different concentrations of N2O are as follows (5):

• 20% analgesia

• 40% behavioral disinhibition

• 60% amnesia

• 80% unconsciousness

The analgesic effect of 20 percent N2O is comparable to that of 15 mg subcutaneous morphine (2). In 1991, the gas was used in more than half (2) of U.S. dental offices in concentrations of less than 50 percent in combination with oxygen to provide conscious sedation. The average concentration of N2O used for dental procedures is 40 percent (9). In higher concentrations, N2O f unctions as an anesthetic. Because of its low potency (high MAC value), it is not used as a sole general anesthetic. However, it is often combined with more potent anesthetics to provide general anesthesia with analgesia, rapid recovery, and a limited complication incidence (9). To distinguish between analgesic and anesthetic use of N2O, the former is also called psychotropic analgesic nitrous oxide (PAN). PAN has been used successfully to reduce craving in people who are withdrawing from alcohol, cannabis, and nicotine and may therefore be able to prevent relapses in these patients (10).

Other contraindications for the use of N2O include respiratory infections and chronic obstructive pulmonary diseases (COPD). Patients with respiratory infections contaminate tubing and the breathing apparatus and place other patients at risk. N2O with oxygen should not be used in patients with COPD because these patients depend partly on a low blood oxygen concentration to initiate a breathing stimulus. Pregnancy is not a contraindication if sedation is required; N2O with oxygen may even be recommended (2).

Side Effects

Because N2O is a weak anesthetic agent, it is generally considered a safe drug. Although N2O may be safe for acute effects of exposure, including nausea, hypoxia, and claustrophobia (1), chronic, occupation-related, low-dose exposure to N2O can cause serious side effects. N2O oxidizes components of the vitamin B12 complex. The result is a decreased availability of the vitamin, decreased activity of the vitamin B12 -dependent enzyme methionine synthetase, and a subsequent decrease in protein and nucleic acid synthesis, megaloblastic anemia, and other symptoms of vitamin B12 deficiency (5).

Other side effects related to chronic exposure to N2O are (11):

  • Decreased fertility
  • Increased incidence of cervical cancer
  • Reduced sperm motility
  • Kidney and liver disease
  • Adverse effects on bone marrow function
  • Diminished immune response

Chronic abusers of high concentrations of N2O can develop central nervous system myeloneuropathy with symptoms of numbness, equilibrium and coordination problems, muscle weakness, and headaches (11). Neuropsychiatric symptoms such as depression, impaired memory, confusion, and delusions have also been described (14). Recovery from these side effects can occur once the exposure ends. Treatment with steroids and vitamin B12 is of questionable value (15).

With more than 200,000 healthcare workers potentially exposed to the drug (3), it is important to keep N2O concentrations low in the workplace. The American Conference of Governmental Industrial Hygienists recommends a threshold value for N2O of 50 ppm for an eight-hour average exposure. The National Institute for Occupational Safety and Health recommends a limit of 25 ppm per anesthetic operation (12, 13).

There are no reports of allergic reactions to the gas or of irritation of the bronchial mucosa ( 2 ).

Abuse

Although abuse of and addiction to N2O can occur, it is generally thought to have a low abuse potential because of its partial agonism and fast-developing tolerance. Abusers are mainly found among healthcare workers and employees in the restaurant and catering business. It is estimated that as many as 20% of medical and dental students have tried N2O to get high, although very few have continued to use the drug. N2O is usually one element of a polydrug addiction. The effects of the recreational use of N2O are euphoria and a sense of well-being, sometimes combined with fantasies; dysphoria is produced in some individuals (16). These effects are short-lived (14).

One method of administering the gas is through a breathing apparatus attached to a commercially available tank of N2O. Another method is to re-breathe the gas from a plastic bag. Without supplemental oxygen, however, this method can lead to hypoxia, syncope, and death. Medical examiners report that recreational use of N2O is responsible for less than 0.1 percent of drug-abuse-related deaths in the United States (3). Postmortem blood concentrations of 46–180 mL/L have been documented. Concentrations during anesthesia are 170–220 mL/L (17).

Analysis

N 2 O analysis can be accomplished with gas chromatography using a molecular sieve or Porapak Q column (17). Detection methods include electron capture (sensitivity increases with the detector temperature), flame ionization, infrared analysis (18), mass spectrometry, and thermal conductivity. Exposure to N 2 O can be determined by analysis of air samples collected with a pump-bag sampling system (4). Commercial passive dosimeters for N2O are also available (13).

Because of its high volatility and rapid elimination, N2O is difficult to detect with traditional screening procedures (1). Head-space analysis of urine provides the best method, although blood and breath may also be analyzed. Measurement of N2O in arterial blood accurately reflects N2O exposure, whereas venous blood concentrations are poorly correlated. However, measurement in repeated arterial blood samples is impractical (4). Biological effects of exposure to N2O can be tested with the deoxyuridine suppression test. This is a sensitive biochemical way to detect temporary inactivation of the enzyme methionine synthetase (11).

References

  1. Sandoval VA. Nitrous oxide: a serious look at laughing gas. Tex Dent J 1993;110(5):13–6.
  2. Stach DJ. Nitrous oxide sedation: understanding the benefits and risks. Am J Dent 1995;8(1):47–50.
  3. Suruda AJ, McGothlin JD. Fatal abuse of nitrous oxide in the workplace. J Occup Med 1990;32(8):682–4.
  4. Sonander H, Stenqvist O, Nilsson K. Exposure to trace amounts of nitrous oxide. Br J Anaesth 1983;55:1225–9.
  5. Sung Y-F, Holtzman SG. General anesthetics. In: Brody TM, Larner J, Minneman KP, Neu HC, eds. Human pharmacology molecular to clinical, 2nd ed. St. Louis: Mosby-Year Book, 1994:401–22.
  6. Gillman MA, Lichtigfeld FJ. Opioid properties of psychotropic analgesic nitrous oxide (laughing gas). Perspect Biol Med 1994;38:125–38.
  7. Rupreht J, Dworacek B, Bonke B, Dzoljic MR, Eijndhoven JHM van, Vlieger M de. Tolerance to nitrous oxide in volunteers. Acta Anaesthesiol Scand 1985;29:635–8.
  8. Gillman MA. Nitrous oxide, an opioid addictive agent, review of the evidence. Am J Med 1986;81:97–102.
  9. Jastak JT, Donaldson D. Nitrous oxide. Anesth Prog 1991;38:142–53.
  10. Daynes G, Gillman MA. Psychotropic analgesic nitrous oxide prevents craving after withdrawal for alcohol, cannabis and tobacco. Int J Neurosci 1994;76:13–6.
  11. Henry RJ. Assessing environmental health concerns associated with nitrous oxide. J Am Dent Assoc 1993;124(5):12–4.
  12. Yagiela JA. Health hazards and nitrous oxide: a time for reappraisal. Anesth Prog 1991;38:1–11.
  13. Donaldson D, Meechan JG. The hazards of chronic exposure to nitrous oxide: an update. Br Dent J 1995;178:95–100.
  14. Gillman MA. Nitrous oxide abuse in perspective. Clin Neuropharmacol 1992;15(4):297–306.
  15. Ellenhorn MJ, Barceloux DG. Medical toxicology— diagnosis and treatment of human poisoning. New York : Elsevier, 1988:840–4,876–7.
  16. Dohrn CS, Lichtor JL, Coalson DW, Uitvlugt A, Wit H de, Zacny JP. Reinforcing effects of extended inhalation of nitrous oxide in humans. Drug Alcohol Depend 1993;31:265–80.
  17. Baselt RC. Disposition of toxic drugs and chemicals in man, 2nd ed. Davis, CA: Biomedical Publications, 1982:565–6.
  18. Walder B, Lauber R, Zbinden AM. Accuracy and cross-sensitivity of 10 different anesthetic gas monitors. J Clin Monit 1993;9:364–73.