Discussion

Nitrous oxide (N2O) is widely used within dentistry, in combination with oxygen, as a form of inhalation sedation. Its properties lend itself well to dental treatment, allowing for rapid onset of sedation at titratable levels and rapid recovery to allow patients to continue normal activities following treatment. As a drug, N2O has a wide margin of safety, with a generally low potency, reflected by its minimum alveolar concentration of 105%. Its use and evidence base within dentistry to manage anxiety is extensive, proving effective for both adult and paediatric patients alongside appropriate behavioural management techniques.1,2

Sustainability and the environmental impact of dentistry has become a growing topic in recent years.3 Recognition of the impact we can have has become common knowledge and in turn, practices are slowly changing. Indeed, sustainability is being incorporated into undergraduate curricula to ensure new generations of dental professionals are more environmentally conscious within their clinical practice.4

Concerns have been raised regarding the environmental impact of N2O which is a known anthropogenic greenhouse gas, causing ozone depletion and contributing to climate change.5 Main sources of N2O being released into the atmosphere come from agriculture but we must recognise emissions from medical N2O. In line with current guidance, scavenging is recommended to minimise potential side effects of N2O on clinical staff through occupational exposure; however, this results in the N2O being released directly into the atmosphere.6 New technology, in the form of N2O destruction units have been developed. These units allow exhaled N2O to be broken down to regular air which can be safely returned to the atmosphere. However, this equipment is expensive and somewhat cumbersome. With N2O being a reliable and well-established sedative agent within the dental field, its potential withdrawal from use for environmental or health concerns would be deeply impactful. While its withdrawal is not yet being considered, we must be aware that its use has been suspended in some hospital settings.7 Indeed, N2O has now also been classified as a Class C drug, which may bring about regulations regarding storage and access.8 Therefore, the consideration of alternative drugs and methods of inhalation sedation would be beneficial, with one such alternative being methoxyflurane.

Methoxyflurane was originally an anaesthetic agent used in the 1960s and early 1970s. It is a colourless, volatile liquid with a distinct fruity odour. At low concentrations it is chemically stable and non-flammable at normal room temperature. Supplied as a methoxyflurane inhaler (Pethrox, Galen Limited, Craigavon, Northern Ireland), a 3 ml liquid vial is opened and poured onto a wick within the inhaler. The patient can then inhale the vapour via a mouthpiece. A dilutor valve, to which a chamber of activated carbon is attached, allows for the concentration to be changed, with 0.2-0.4% inhaled with the dilutor valve uncovered and 0.5-0.7% with the dilutor valve closed by occlusion with a finger. The activated carbon chamber reduces atmospheric release of the drug on exhalation. Figure 1 shows these features. A maximum dose of 6 ml (two vials) can be used within 24 hours. At present, the use of the Penthrox inhaler is not licenced for those under the age of 18. Common side effects as reported by the manufacturer are dizziness, euphoric mood, headaches, somnolence and nausea.9 Contraindications for the use of methoxyflurane can be seen in Box 1. Regarding occupational exposure, evidence suggests this is minimal; nurses undertaking bone marrow biopsy lists showed exposure levels far below the maximum calculated exposure limit of 15 ppm.10

Fig. 1
figure 1

Penthrox inhaler (a = mouthpiece; b = dilutor valve; c = activated carbon chamber; d = removable cap, where methoxyflurane can be poured onto wick). Image courtesy of Galen

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With regard to more concerning side effects, methoxyflurane's use as an anaesthetic agent was suspended due to inducing dose-dependent renal and hepatic toxicity.11 Despite this, its use has continued at lower doses for its potent analgesic and anxiolytic effects. Methoxyflurane has established itself well mainly within Australia and New Zealand within emergency medicine, mainly in pre-hospital and trauma settings for the above properties. When used at sub-anaesthetic doses, methoxyflurane is able to produce rapid, effective, and importantly, lasting analgesia, owing to its high blood-gas partition co-efficient.12,13,14 It is also highly soluble in lipids, thus allowing its diffusion into fatty tissue. This may also act as a reservoir, allowing for lasting analgesia.15 We unfortunately do not know the length of its sedative effects. Following on from this, methoxyflurane has started to be used within outpatient settings to allow for various invasive procedures, for example, in burns dressings, prostate biopsy and colonoscopy.11 It was proven equally effective for use in outpatient colonoscopies when compared to intravenous sedation.16 However, in this study, a small number of patients did require additional intravenous sedation on top of the Penthrox inhaler to complete the procedure. With an evidence base established for its analgesic properties, there is recognition of its sedative effects too. However, there are limited studies within the literature specifically assessing the drugs anxiolytic effects.

Other aspects of the drug can also present drawbacks when considering its use within dentistry. Methoxyflurane is not licenced for those aged under 18 in the UK, thus preventing its use in a large part of the patient population. N2O is arguably one of the biggest tools in the treatment of paediatric patients. Being unable to use Penthrox inhalers with children will clearly be a large barrier for finding alternatives to N2O. Encouragingly, it is licenced for use in paediatric patients in Australia and proven effective in management of analgesia.17 This gives precedent for its use in paediatric patients in the UK.

Additionally, there are no guidelines for its safe use in out-patient settings. If this drug were to be introduced in dental practice, would an escort be needed? Would the patient be able to drive home following the appointment? These questions can only be answered with more research and agreement among the profession. From the evidence available, it does seem minimal recovery time would be needed, and patients should be able to return to normal daily activities quickly.11 Indeed, vital signs monitoring is not needed when using this drug.10 When consulting the British National Formulary, maximum doses cannot exceed 6 ml per day (two vials), 15 ml per week (five vials), avoiding use on consecutive days. This will require consideration for patients who may need treatment over multiple visits. Lastly, the inhalation of the drug requires putting the inhaler to the mouth; this would naturally stop dental treatment. More issues may be created where restorative treatment is taking place, such as maintaining moisture control or using rubber dam.

With the above data, it can be appreciated how methoxyflurane could lend itself well within the dental field to aid with analgesia and anxiety management, with some disadvantages. Unfortunately, there is limited evidence regarding its use within dentistry specifically, with only one recent study comparing its use in third molar extractions to N2O. In this study, methoxyflurane was shown to be as effective as N2O for inhalation sedation.18 The use of inhaled methoxyflurane in dentistry in certain countries still prevails, however, despite the lack of a well-rounded evidence base.19

From the available data and information regarding methoxyflurane, we can see it acts as a potent analgesic drug with recognised anxiolytic/sedative properties. It is rapidly acting, with a relatively quick recovery time as well. It has a good margin of safety, with doses provided by the Penthrox inhaler being far below those needed to produce any renal or hepatic toxicity, and it is used safely within other health care settings. The inhaler design is simple and would not require adaptation of existing dental clinics for its use. Regarding environmental concerns, the activate carbon chamber should prevent environmental release of the drug. No sedative agent is perfect, however, and the disadvantages discussed here must also be considered. More research needs to be undertaken to establish its efficacy in managing dental pain and anxiety to allow for its use alongside dental treatment. Should it be proven effective, methoxyflurane could be a useful and environmentally friendly alternative to N2O.