nitrous oxide - happy gas - laughing gas - for pain relief in labor

Nitrous oxide – the Happy Gas

Nitrous oxide in labor

There are no properly designed studies on the role of nitrous oxide in labor. Nitrous oxide brings partial relief of labor pain. It takes about 50 seconds to achieve peak effect and its inhalation needs to be timed to the early start of uterine contraction. Nitrous oxide has potentially serious though rare side-effects.

Nitrous oxide was discovered by Joseph Priestley in 1786 when he noticed that ‘a candle burned in this air with a remarkably vigorous flame.’ He called it dephlogisticated air because of its ability to sustain combustion. Priestley assumed that the new gas had a propensity to absorb phlogiston that explained this observation. At the time phlogiston was thought to be the flammable part of any substance. In 1800 H.Davy published his tractate, “Researches, chemical and philosophical; chiefly concerning nitrous oxide, or dephlogisticated nitrous air, and its respiration.” He reported how the inhalation of three or four breaths of the gas greatly relieved his toothache. He went on to conclude that ‘As nitrous oxide in its extensive operation appears capable of destroying physical pain, it may probably be used with advantage during surgical operations in which no great effusion of blood takes place.’ 12

In December 1844 in Hartford, Connecticut, Horace Wells, a Boston-trained and discontented dentist, made a fool of himself on the stage of a ‘Grand Exhibition’ after inhaling nitrous oxide. That same evening, he observed that another participant, who had injured his leg while dancing on the stage, felt no pain until the effects of the nitrous oxide had worn off. Wells surmised that a person could probably ‘have a tooth extracted or a limb amputated and not feel any pain’. He then arranged for his wisdom tooth to be extracted under the influence of nitrous oxide on the following day by his former student John Riggs. ‘We knew not whether death or success confronted us’, said Riggs. ‘It was terra incognita we were bound to explore.’ Riggs later wrote of the experience: ‘Wells took the [N2O] bag in his lap, held the tube to his mouth and inhaled till insensibility relaxed the muscles of his arms – his hands fell on his breast – his head dropped on the head-rest and I instantly passed the forceps into the mouth, onto the tooth and extracted it’. When Wells awoke several minutes later and felt the empty space in his mouth he exclaimed ‘It is the greatest discovery ever made! I didn’t feel it so much as the prick of a pin!’

Ironically, first official demonstration of properties of nitrous oxide by Horace Wells in January 1845 was unsuccessful. Despite that inauspicious beginning, this gas was reintroduced after the establishment of ether anaesthesia, and was widely used from 1867 onwards. Since that time, its place in anaesthetic practice has been the subject of controversy.9

The use of volatile agents, or gases, for labor analgesia has a long history. James Simpson first used ether for vaginal delivery in 1847 in Scotland, months after its first anesthetic demonstration in Boston. However, clear acceptance of this technique occurred when John Snow administered chloroform to Queen Victoria during the birth of her eighth and ninth children in 1853 and 1857. The first use of nitrous oxide dates to 1881, when Stanislav Klikovich (Poland-Russia) studied the effects of premixed 80% nitrous oxide in oxygen on laboring women. In 1934, an apparatus for the self-administration of nitrous oxide in air was developed.

When inhaled, volatile anaesthetic agents diffuse into the blood and are carried by the bloodstream to the organs, including the brain. Despite the fact that anaesthetic gasses are used on millions of patients around the world every year and their effects have been studied in depth, we don’t know the precise biochemical mechanism by which these agents work.

Many volatile agents have been developed in the course of the twenties century and many of them have been tested for relieving pain in labor. However, only nitrous oxide is used to great extent in obstetric practice. In my opinion, the reasons for it are fairly obvious. Nitrous oxide is unique in that it does not cause unconsciousness, the property other gasses have. Also, unlike other gasses, it has analgesic property, or the ability to reduce pain, the feature most other anaesthetic gasses lack. It is does not have a pungent odor, minimally affects cardiovascular and respiratory system and does not affect the function of the uterus during labor. It is easy to use, relatively cheap and safe, including the fact that it is not flammable. Though exact data for the frequency of use of nitrous oxide are not available, it has been estimated that in the United Kingdom, nitrous oxide is used by approximately 50% to 75% and in Finland by approximately 60% women in labor1. It is considered to be safe in many parts of the world including Canada, Australia, and New Zealand, when used properly trained physicians, nurses, or midwives.

Nitrous oxide is administered mixed with oxygen. In the United Kingdom and elsewhere, 50% nitrous oxide in 50% oxygen is premixed in a single cylinder and is called Entonox, first described in 1961 by M.Tunstall and introduced into practice in 1965. Alternatively, nitrous oxide and oxygen are blended to deliver a fixed concentration of 50% nitrous oxide and 50% oxygen by a special device activated by the patient.

Nitrous oxide, like other inhalational anaesthetics, is administered either intermittently, when a woman starts inhaling the gas during a contraction, or continuously. Both techniques are currently used, and both have advantages and problems. Nitrous oxide can be used for many hours during both labor and delivery, or as a temporizing measure until an epidural can be started.

The main problem when administering the nitrous oxide intermittently is the time lag of approximately 50 seconds after the onset of administration before full analgesic effect can be expected. Though, because the respiratory system of pregnant woman a term undergoes certain physiological changes, the gas may work faster. Pregnant women are also more sensitive to the effects of anaesthetic gasses. It is advised to start inhaling the gas before the contraction, which requires very close attention to contraction timing, but is difficult for many patients in labor for obvious reasons.

The continuous technique of Entonox administration also can be problematic. Continuing breathing nitrous oxide between contractions may lead to excessive drowsiness, dizziness, lightheadedness and nausea.

Surprisingly, despite of the use of nitrous oxide in labor for decades, there are not many formal, properly conducted studies regarding its efficiency and side-effects. Recent systematic review of existing studies included 11 properly conducted trials for assessing the efficacy and nineteen were considered for discussing side-effects and complications regarding nitrous oxide in labor.1

Only one trial considered in the review compared nitrous oxide administration with placebo.2 Twenty six women were randomly assigned to receive either nitrous oxide or compressed air for labor pain. After a while they were allowed to change to another option. Over 5 successive contractions there were no differences in terms of pain relief between the two gas mixtures, yet most subjects were able to distinguish nitrous oxide and chose to continue using it. The authors described many limitations of their study. Nitrous oxide was used in early labor in the study, though in clinical practice it is used more often either in the late first stage or second stage of labor. Moreover, women were included for this study on voluntary basis, so that there is some bias regarding selection of patients. Also, the authors used an intermittent technique with initiation at the onset of contraction, not in anticipation of contraction to synchronize peak nitrous oxide concentrations with the peak of the pain of contraction, which is essential for effective use, and probably a poorly controlled aspect of most other studies. Nevertheless, most women clearly differentiated the two gases and chose to continue the use of nitrous oxide for at least a while.

One study gives some idea regarding the efficacy of nitrous oxide in labor. It was conducted in 1987 and compared four ways of pain relief in childbirth: transcutaneous electrical nerve stimulation (TENS), nitrous oxide, pethidine, or epidural analgesia.4 Approximately 90% of the women who chose either TENS or nitrous oxide reported “partial pain relief,” 88% of those who chose epidural anesthesia reported “complete relief,” but only 54% of those who chose opioids (pethidine) reported “partial pain relief.” In other words, the women judged nitrous oxide to be as efficacious as TENS, more effective than opioids, but less effective than epidural analgesia. The data suggested to the authors that nitrous oxide was a method useful for women who wished to cope with the earlier part of labor “drug free.”

The conclusion of the review stated: “taken together, these studies do not provide clear, quantitative, objective evidence of the analgesic efficacy of nitrous oxide for relief of labor pain. Despite its use for more than 100 years, we do not appear to be any closer to quantifying nitrous oxide’s analgesic effects in labor”. The same opinion was expressed in the older review.3

Nitrous oxide is a drug, however, and its side-effects are well documented. The most convincing evidence that nitrous oxide may be detrimental to those to whom it is administered has been gathered by investigators concerned with the effects of the gas on bone marrow. In 1978 it was demonstrated that exposure to nitrous oxide for 24 hours interfered with synthesis of DNA.5 This confirmed the earlier study6 that showed that nitrous oxide converts the cobalt in vitamin B12 from the monovalent form to the bivalent form and thus inactivates it. This, in turn, irreversibly inactivates the enzyme methionine synthase and may lead to the depression of the function of the bone marrow, leading to megaloblastic anaemia, as well as subacute degeneration of the spinal cord. Vitamin B12 deficient patients are more susceptible to this effect of nitrous oxide.

Inactivation of methionine synthase may also lead to an increase in plasma homocysteine. Homocysteine is an independent risk factor for cardiovascular disease, but the significance of its short-term increase in unclear. But it may facilitate the development of depression. Recently published case report describes a 41 year old female dentist who developed major depression about ten years ago. After questioning the patient about possible risk factors it turned out that she treated a lot of children in her clinic using nitrous oxide. Blood tests showed marked increase in plasma homocysteine. The patient was successfully treated with vitamin B12 and folic acid and recovered within weeks.

It is the prolonged exposure to nitrous oxide that leads to subacute combined degeneration of the spinal cord, however there has recently been a report of a patient who developed this condition after a single exposure lasting 8 hours.7

There is also some evidence that nitrous oxide may affect immune system, however at this stage it is controversial. Some studies demonstrated that nitrous oxide may affect neutrophils, the cells responsible for attacking bacteria, others have not been able to show the same effect. Significance of this effect is not clear and is not likely to be important when this gas is used labor.

Prolonged exposure to high concentrations of nitrous oxide causes birth defects in rats, although no conclusive results have been shown in humans. Studies in pregnant women receiving N2O early in pregnancy have not demonstrated any increase in fetal loss or fetal abnormalities.9 Exposure in the workplace is more controversial, and the possibility remains that workplace exposure to nitrous oxide may have an adverse effect on the outcome of pregnancy. In a study of dental assistants, an increased risk of spontaneous abortion was seen among women who worked with nitrous oxide for three or more hours per week in the absence of scavenging equipment.10 In midwives involved in more than 30 deliveries per month when N2O was used, there was a significant reduction in fertility.11

The evidence of harmful effects of nitrous oxide has been sufficient for some clinicians to comment that drugs have been withdrawn from the market on much less convincing evidence than that available for teratogenic effects of nitrous oxide and suggested that it should be avoided and other anaesthetic techniques used where possible.

Another property that has been hotly debated is the ability of nitrous oxide to cause nausea and vomiting. If this is important in labor is not clear. Several studies reported that from 5% to 36% of women in labor experience nausea and vomiting. But all these studies did not have control group that did not receive medication. It is important because nausea and vomiting are common during labor, and at this time we cannot say if nitrous oxide makes it worse.1

Overall, however, it appears that nitrous oxide provides benefit for many women in labor. Many women insist that nitrous oxide brings considerable relief of labor pain and state that they would choose it again for their next labor. Nitrous oxide has been established in obstetric practice, and conducting properly designed randomized study is difficult for ethical reasons. The fact that it has been used for decades with only a few reports of significant complications indicates its safety. As the duration of exposure to this gas is what determines the risk of complications, it seem that the staff of labor wards is at more risk of developing adverse effects due to this agent. Even though the ability of nitrous oxide to relieve labor pain is nowhere near that of epidural analgesia, it does brings partial relief for some women and may be suitable for patients who for some reason want to have their labor drug free.

References: 

1. Rosen M. Nitrous oxide for relief of labor pain: A systematic review. Am J Obstet Gynecol 2002;186:S110-26.

2. Carstoniu J, Levytam S, Norman P, Daley D, Katz J, Sandler AN. Nitrous oxide in early labor. Safety and analgesic efficacy assessed by a double-blind, placebo-controlled study. Anesthesiology 1994;80:30-5.

3. Irestedt I. Current status of nitrous oxide for obstetric pain relief. Acta Anaesthesiol Scand 1994;38:771-2.

4. Harrison R, Shore M, Woods T, et al. A comparative study of transcutaneous electrical nerve stimulation (TENS), entonox, pethidine + promazine and lumbar epidural for pain relief in labor. Acta Obstet Gynecol Scand 1987;66:9-14.

5. Amess JAL, Burman JF, Rees GM, Nancekievill DG, Mollin DL. Megaloblastic haemopoiesis in patients receiving nitrous oxide. Lancet 1978; 2: 339-42.

6. Banks RGS, Henderson RJ, Pratt JM. Reactions of gases in solution. Part III. Some reactions of nitrous oxide with transition-metal complexes. Journal of the Chemical Society (A) 1968; 3: 2886-9.

7. Hadzic A, Glab K, Sauborn KV, Thys DM. Severe neurologic deficit after nitrous oxide anesthesia. Anesthesiology 1995; 83: 863-6.

8. Frohlich D, Rothe G, Wittmann S, Schmitz G, Schmidt P, Taeger K, Hobbhahn J. Nitrous oxide impairs the neutrophil oxidative response. Anesthesiology 1998; 88:1281 – 1290.

9. James M. Nitrous oxide: still useful in the year 2000? Review Article. Volume 12(4), August 1999, pp 461-466.

10. 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; 141:531-538.

11. Ahlborg GJ, Axelsson G, Bodin L. Shift work, nitrous oxide exposure and subfertility among Swedish midwives. Int J Epidemiol 1996; 25:783-790.

12. Shaw AD, Morgan M. Nitrous oxide: time to stop laughing? [editorial] Anaesthesia 1998; 53:213-215.

13. Litman RS. Nitrous oxide: the passing of a gas? Current Opinion in Anaesthesiology 2004, 17:207–209.

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Dr. Eugene Smetannikov is a practicing anesthesiologist with the interest in obstetric anesthesia. He is the author of the most comprehensive book on the subject, The Truth About Labor Epidural