Nitrous oxide in oxygen (50:50) is analgesic that requires optimal inhalation procedure

1 The powerful context sensitive therapeutic effect

Anna-Maria Kuivalainen and her co-workers should be complimented for trying to compare inhalation of 50% N₂O in oxygen with 50% oxygen in nitrogen. This study design attempts to have a similar context-sensitive therapeutic effect with the two gas mixtures. The context is always a powerful factor in any treatment attempting to reduce the total experience of a painful condition [2].

Anna-Maria Kuivalainen and her co-workers were not able to document that this method of administering 50% N₂O in oxygen improves the painful experience of bone marrow aspiration and biopsy in adult patients, at least not more than inhalation of 50% nitrogen in oxygen. This is unfortunate because it contributes to a faulty impression that N₂O in oxygen is useless as a non- invasive analgesic procedure. This contributes to scepticism among health care personnel towards using nitrous oxide even in children. Another double blind trial in adults using 50% N₂O in oxygen for pain during prostate biopsy concluded that N₂O inhalation was successful and should be the analgesic of choice for that painful procedure [3].

2 Nitrous oxide inhalation for painful procedures in children

Mask-inhalation of 50% N₂O in oxygen has had an encouraging renaissance during the last decade for painful procedures in children, such as lumbar puncture, venous cannulation, repairs of lacerations, and even in fibreoptic bronchoscopy [4-6]. Experience shows that this is successful only if the persons administering the nitrous oxide are able to create a calm, trustful atmosphere that allows uninterrupted inhalation of the gas-mixture for 3–5 min [6]. Shorter or interrupted inhalation of 50% N₂O gas mixture will not bring enough N₂O to the brain to cause sufficient concentrations for analgesia. An anxious child who does not feel comfortable with the mask and does not trust the person administering N₂O will not be able to inhale the gas mixture for long enough to have any analgesic effect. Pedersen and co-workers’ thorough systematic review [6] concluded with a strong statement that N₂O is effective, safe and underused in Denmark, as I am sure it is in Norway as well. They confirm the important observation that non-anaesthesia personnel can learn how to administer N₂O to children in a safe and effective manner. With modern equipment for scavenging and destruction of any exhaled N₂O from the patients, the low risk of any adverse effects on the health care providers is abolished.

3 Nitrous oxide inhalation for painful procedures in adult patients

In adult patients, 50% N₂O in oxygen is helpful for anxious patients having painful dental treatment, for urologic procedures, for painful obstetric procedures, painful procedures in the emergency department, and even in ambulances-for references see [7]. The original 50% N₂O in oxygen, Entonox®, has been used in the UK for several decades [7]. In the Nordic countries, we were afraid of possible separation of N₂O and oxygen in the Entonox^® cylinders during transport in low ambient temperatures in our subarctic regions. Therefore, Entonox^® was not marketed in this cold corner of the world. For a few years now, we have had the same gas mixture marketed as Livopan® from Germany for use in hospitals. EMONO® is available in Southern Europe, at least in France and Spain [4].

4 Nitrous oxide for labour pain (for references see [7])

In the delivery rooms we have had N₂O available as part of the hospitals N₂O central gas system. However, due in part to weakly founded worries about N₂O’s possible adverse effects on health personnel, and even worries about unfounded long-term adverse effects on children after intrauterine exposure to N₂O, this non- invasive analgesic procedure for pain during vaginal deliveries has gradually become less popular in the Nordic countries. The most important reason for the declining use of N₂O for delivery analgesia, beside beliefs about N₂O as an occupational risk, is lack of knowledge of how to administer N₂O correctly, leading to a faulty impression among midwives that “N₂O does not work anyway - so why risk the adverse environmental effects”.

When midwives compare the extremely effective pain relief from epidural or subarachnoid (“spinal”) analgesia, they are of course correct in interpreting inhalation of 50% N₂O as a weak analgesic method. Epidural analgesia has been increasingly available in Nordic obstetric departments, concomitant with the declining popularity of 50% N₂O. This has even caused removal of equipment for inhalation of N₂O/oxygen from delivery rooms in major hospitals in Norway.

An opposite development is occurring in the USA; N₂O for pain during deliveries is increasing in popularity after the FDA approved equipment for it use in 2011 [8]. More mothers can afford about $100 for N₂O. The cost of an epidural is about $ 3000 (News from the American Pain Society on January 28, 2014).

5 Optimal administration of 50% N₂O inhalation analgesia

Inhalation of N₂O has been used for more than 170 years. The analgesic effect of N₂O in the brain is caused by inhibition of NMDA- receptors (like ketamine), inhibition of GABA_a receptors, and via a number of other putative mechanisms [7,9,10]. For this to occur it is critical that the inhalation of the N₂O-oxygen gas mixture goes on long enough to wash nitrogen out of the alveolar gas and create a high enough alveolar gas/alveolar blood gradient for absorption of N₂O into alveolar blood and transport via arterial blood to the brain. The higher the N₂O concentration in the inspired gas, the quicker a sufficient concentration (or partial pressure) of N₂O in the brain is obtained. Even with 66% inhaled N₂O, this takes between 5 and 10min for an equilibrium state [11]. Inhaling 50% N₂O for 5 min secures a sufficient N₂O partial pressure in the brain to create analgesia, but this is only half of the N₂O concentration needed to induce a complete anaesthetic state, which is possible only under hyperbaric conditions! [7,11]. This also requires that there is a good, tight mask fit so that the patient does not inhale room air and dilutes the already low concentration N₂O. If there are interruptions, because the patient feels uncomfortable, is anxious and afraid, the whole procedure has to start anew.

This was the problem of the unfortunate dentist Horace Wells, who had used N₂O successfully in his dental practice. When he demonstrated N₂O inhalation at Massachusetts General Hospital in 1845, the patient was sedated by N₂O, but when he remove the administration equipment and let the surgeon John C. Warren proceed, the patient complained of pain. Horace Wells was hissed out of the room as a fraud. Less than one year later, on October 16th, 1846 ether was successfully demonstrated by the dentist William Morton in the operating theatre, later named the “Ether Dome”, where the same surgeon Warren exclaimed: “This is no humbug”. This was the start of modern anaesthesia and all the advances in surgery and medicine made possible by pain-free surgery [12].

6 More positive effects of N₂O: reduced risk of persistent postoperative pain, beneficial effect on neuropathic pain, beneficial effect on treatment-resistant major depression

Many hospitals unfortunately have stopped using N₂O after the famous multicentre ENIGMA study that indicated that 70% N₂O as part of general anaesthesia could have untoward postoperative cardiac outcomes [7]. However, the two groups in the ENIGMA study did not receive equal concentrations of oxygen, a serious fault in the study design. And a large single-centre study subsequently documented beneficial effects of N₂O on the occurrence of postoperative morbidities and mortalities [7].

In addition, the ENIGMA study documented one unexpected but important benefit for the patients: N₂O halved the risk of new, persistent pain after surgery [13,14]. This may be connected with the observation that inhalation of N₂O may have beneficial effects on chronic neuropathic pain - see [7]. At subanaesthetic doses of ketamine it is known to provide prolonged relief of major depression that has not responded to ordinary antidepressive drugs, and as N₂O also has a ketamine-like anti-NMDA-receptor blocking effect, it was expected that inhalation of N₂O by patients with treatment- resistant major depression would have a beneficial effect on their mental state [10].

I refer to Schallner and Goebel [7] for a balanced review of these studies.

7 Toxic effects of long term high concentrations of N₂O-inhalation

Long-term high exposure of N₂O by dentists before effective scavenging was introduced, and by persons addicted to N₂O is well known to cause serious central nervous and haematological complications. N₂O can oxidize Vitamin B12, inhibiting its coenzyme function for the synthesis of DNA, RNA, and myelin [7,9]. This is why these persons developed severe neuropathy and megaloblastic anaemia - for references and a balanced discussion see [7]. A large study with 7800 paediatric patients could not document any toxic effects by inhalation of N₂O via nasal masks for repeated dental procedures [15], confirming its high safety record in clinical use.

8 Conclusions

Inhalation of N₂O in at least 50% concentration in oxygen with modern equipment is a blessing for children and adults who are in need of having painful procedures, provided the administration of the gas is optimal. The complications are few and hardly clinically relevant when well-trained and experienced persons administer nitrous oxide. The renaissance of this almost 200 years old laughing gas should be welcomed and encouraged. It is cheap, has a rapid onset of analgesic effect, it is safe, and it is quickly removed from the patients body when exposure is stopped.