ACCEPTED VERSION "This is the peer reviewed version of the following article: Angus Kingon, Tami Yap, Carmelo Bonanno, Paul Sambrook, and Michael McCullough Methoxyflurane: a review with emphasis on its role in dental practice Australian Dental Journal, 2016; 61(2):157-162 © 2016 Australian Dental Association which has been published in final form at http://dx.doi.org/10.1111/adj.12346 This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving." 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Authors may transmit, print and share copies of the accepted version with colleagues, provided that there is no systematic distribution, e.g. a posting on a listserve, network or automated delivery. There is no obligation upon authors to remove preprints posted to not for profit preprint servers prior to submission. 2 June 2017 http://hdl.handle.net/2440/95495 Article Type: Review Article (non-solicited) e Methoxyflurane: a review with emphasis on its role in dental practice l c Angus Kingon1, Tami Yap2, Carmelo Bonanno3, Paul Sambrook4 and Michael McCullough2* i t 1 – Willendon, 45 Grandview Street, Pymble, NSW 2073 r 2 – Melbourne Dental School, The University of Melbourne, 720 Swanston Street, Carlton, VIC, 3010 A 3 – 1/48 Corinna St., Phillip, ACT 2606 4 – School of Dentistry, North Terrace Campus, The University of Adelaide, SA 5005 *Corresponding Author, Michael McCullough, Melbourne Dental School, The d University of Melbourne, 720 Swanston Street, Carlton VIC. Ph: + 61 (0)3 93411490: Fax: +61 (0)3 934115959: Email: [email protected] e Running Title: Methoxyflurane - role in dentistry review t Abstract p Methoxyflurane was developed as an anaesthetic agent and introduced into clinical practice in 1960. It soon became evident that it possessed analgesic properties that other drugs did not. e Due to toxicity concerns, it lost favour in general anaesthesia and had been largely abandoned c by the late 1970's. The manufacturer withdrew it in 1999, and the Food and Drug Administration in the United States did not renew its license in 2005. It has also been c withdrawn by the European Union. However, it continues to be used in Australasia, primarily as an inhaled self-administered analgesic by emergency services immediately following A This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/adj.12346 This article is protected by copyright. All rights reserved. trauma. It has become attractive for use in dental practice, likely due to its effectiveness as an e analgesic and its additional sedative qualities. Its acceptance is controversial as its use in dentistry is largely elective. Despite its good safety record in analgesic doses, adverse l reactions have been recorded. Practitioners should be well aware of risks associated with its c use before considering administration, and carefully assess whether or not there are equally i good alternative options that do not the carry the same risks. Methoxyflurane is reviewed t below with an emphasis on its use in dental practice. r A Keywords: analgesic, dentistry, inhalation, Methoxyflurane, safety Background d The principle for methoxyflurane development initially occurred when methyl alcohol was added to Fluoroethylenes.1 Described as the first "modern" halogenated ether, it was e introduced in 1959,2 and clinical evaluation in 100 patients was reported in 1960.3 It was t described as a second-generation halogenated inhaled anaesthetic but was withdrawn from use in many countries due to case reports of renal impairment.4 Its use in anaesthetics p declined in the 1970's due to adverse effects. Despite this, it continued to be used in some parts of the world as a self-administered inhalational preparation, for example “the e Analgizer”.5 In 1999, the manufacturers, Abbott Laboratories, voluntarily withdrew c methoxyflurane from US market. FDA later revoked its license in 2005. However, it remains licensed for use in Australia (Therapeutic Goods Administration) and New Zealand c (Pharmaceutical Management Agency). A This article is protected by copyright. All rights reserved. The analgesic qualities of methoxyflurane were recognised shortly after its introduction for e clinical use,6 and this view was supported a few years later.7 An assessment of six inhalation anaesthetic agents used at sub-anaesthetic concentrations found that methoxyflurane and l nitrous oxide possessed both analgesic and hypnotic actions, which halothane, enflurane, c isoflurane and sevoflurane did not.8 A role for methoxyflurane was suggested in situations i where general anaesthesia was a significant hazard or regional anaesthesia was deemed t impractical or contraindicated.9 In a small cohort pilot study, in children, it was deemed r effective as an analgesic, with no serious adverse events, and found most useful as a bridging A analgesic agent post extremity trauma.10 Methoxyflurane as a Penthrox (Medical Developments International, Springvale, Victoria, Australia) inhaler was approved under the PBS for prescription by medical practitioners.11,12 d Pharmacology e Methoxyflurane is 2,2-dichloro-1,1-difluoro-ethyl methyl ether. It is a clear, almost colourless liquid with a characteristic odour. At its recommended concentrations, it is non- t flammable and chemically stable in the presence of light, oxygen, moisture and carbon p dioxide absorbents. Methoxyflurane vapour provides analgesia when inhaled at low concentrations. Once absorbed, 50-70% is metabolized to free fluoride, oxalic acid, e difluoromethoxyacetic acid, and dichloroacetic acid. The high blood gas partition coefficient of methoxyflurane was found to be of considerable benefit ensuring pain relief for a c prolonged period after administration was ceased.13 Its propensity to diffuse into fatty tissues c creates a slow release reservoir for days post administration.14 This is of particular concern in the dental setting as many anxious patients may also be obese and if they are promptly A discharged they are likely to retain the drug for release over a considerable time after treatment. This article is protected by copyright. All rights reserved. Clinical Use e The pre-hospital setting: Methoxyflurane is as a self administered inhalational analgesic in pre-hospital settings in l which the patient is intentioned towards a full medical service and primary attention is c allocated to monitor and assist the sedated patient. Although there are no published i controlled trials of use of methoxyflurane in sub-anaesthetic doses, available data suggests t that it is effective as an analgesic, particularly in the pre-hospital post-trauma setting15-17 with r its strength lying in the rapidity of pain relief onset.18 This facilitates patient comfort prior to A treatment in a hospital setting where more potent intravenous medications can be administered by personnel with appropriate training with the availability of monitoring and resuscitation facilities. It is, however, reported to be less effective in overall pain relief than fentanyl and morphine in both adults and children.19 20 Further, there is insufficient d information to support its use for procedural pain. 21 The incidence of adverse events has been reported in the literature as low/insignificant when the recommended doses are not e exceeded, although deep sedation has been reported in children less than five years old.16,21 Aside from trials of its use in pre-hospital settings, there has been minimal data on the use of t methoxyflurane in the last 30 years. p Dressings for burns: Methoxyflurane was found to be useful as an analgesic for burns' dressings.22,23 e Patient acceptance was good, and advantages included no undue sedation, no need for c preoperative starvation, and venepuncture being avoided. Use in burn dressings for children has been variably reported, with one study of patients under five years reporting that it c provided unsatisfactory analgesia,24 while a separate study25 reported that analgesia was deemed good or better in approximately two thirds of cases aged between four months and 13 A years. This article is protected by copyright. All rights reserved. Obstetric practice: e Methoxyflurane was used extensively in obstetric practice when it became initially available. It was described as drug of choice in obstetric anaesthesia.26 A review of 645 cases in 1962 l found methoxyflurane to be a safe anaesthetic and analgesic agent, without side-effects, c because only low concentrations were needed.27 When self-administered, methoxyflurane i was deemed a more effective analgesic, with less nausea and vomiting, when compared to t nitrous oxide,28 and another study found in the same year (1969) methoxyflurane similarly r satisfactory, noting there were no ill effects upon the foetus.29 Pain relief was reported up to A 36-48 hours post-partum but also some drowsiness.30 It was suggested that there was no evidence of renal dysfunction after self-administered use during labour.31 However, a subsequent study in 1977 reported dose dependent changes in renal markers of both mothers and neonates.32 Methoxyflurane is no longer a drug of use in obstetric practice. d Dental practice: e The use of methoxyflurane in dentistry was recommended due to its analgesic and sedative t properties.33 Safety and simplicity of administration were noted in two other reports.34,35 An p early (1960) blinded trial on methoxyflurane in dental anaesthesia did not demonstrate any particular advantage in its use.38 A study from 1975 showed that nitrous oxide caused e significantly less uncooperative behaviour than methoxyflurane.36 In a recent study, the Penthrox inhaler provided comparable sedation to nitrous oxide when third molars were c removed under local anaesthesia. 37 This study was completed on a group of healthy individuals aged between 18-30 in an oral and maxillofacial clinic with full resuscitation c facilities available. A This article is protected by copyright. All rights reserved. Adverse effects e In the 1960s, an emphasis on development of improved analgesics and anaesthetic drugs saw published data on fluorinated anaesthetic compounds, initially predominantly animal l studies,39-42 and proceeding into human clinical trials.43,44 The results from one large series c was encouraging,45 with the main adverse effect in most reports appearing to be respiratory i depression. As discussed above, methoxyflurane has a propensity to diffuse into fatty tissues t creating a slow release reservoir for days post administration.14 In the dental setting, if used r with obese patients, this has the potential for prolonged respiratory depression for days after A discharge. Nephrotoxicity Changes in renal function, and the potential for nephrotoxicity, were being monitored if not at d the time of, then shortly after, the introduction of methoxyflurane into clinical practice.46-48 Limitations on concentration and duration of exposure were suggested.49 Deaths due to renal e failure at analgesic doses via a penthrane analgiser have also been reported.50 The t mechanism of renal toxicity of methoxyflurane is unknown. There has been a suggested role p of intrarenal generation of nephrotoxic metabolites, in particular inorganic fluoride ions.51 More recently a new hypothesis of methoxyflurane nephrotoxicity proposed that it may result e from O-demethylation which forms both fluoride and dichloroacetic acid.52 The formation of the two compounds is unique to methoxyflurane compared to other volatile anaesthetics. c c An earlier laboratory study in rats suggested that the predominant factors leading to methoxyflurane nephrotoxicity appeared to be dosage of the agent, and serum inorganic A fluoride concentration. Secondary factors included the high rate of methoxyflurane This article is protected by copyright. All rights reserved. metabolism, sensitivity of the kidney to inorganic fluoride toxicity, concurrent treatment with e other nephrotoxic drugs, pre-existing renal disease, repeat administration, and concurrent treatment with enzyme-inducing drugs such as phenobarbital.53 l c Hepatotoxicity i There have been a number of reports of hepatotoxicity, some non-fatal54-57 and some fatal.58- t 60 Repeated exposure,61 even in sub-anaesthetic concentrations,62 may be a risk factor. One r conclusion drawn in a further report of two obstetric cases was that idiosyncratic hepatitis A will continue to occur unpredictably in a very few patients.63 In 2008, a review of adverse drug reactions with halogenated anaesthetics, focused on adverse organ effects (including hepatic and renal) that were attributable to anaesthetic metabolism and/or degradation. It was stated that none of the currently available halogenated anaesthetics cause clinically d significant changes in renal function2 but the licence for the use of methoxyflurane had been withdrawn64 in the USA by the time this article was published. A manufacturer-funded study e (which indicated there was no conflict of interest) found no difference in event rates for t cardiac/renal/hepatic/disease plus diabetes and cancer, between those who received p Methoxyflurane, and those who did not, in the pre-hospital setting.65 e Illicit use and occupational hazards There are a number of papers documenting diverse medical problems as a result of c methoxyflurane abuse: renal57, psychiatric66, multisystem67, and ocular.68 Attention to the c potential for occupational hazards for anaesthetists was drawn,69 and rare but significant occupational exposure problems have been reported including hepatic and renal effects; A specifically, these were significantly elevated levels of blood urea nitrogen, serum uric acid, serum glutamic oxaloacetic transaminases (SGOT) and serum glutamic pyruvic This article is protected by copyright. All rights reserved. transaminases (SGPT) three days after exposure to Methoxyflurane, emphasising the need for e good scavenging.32 Exacerbation of subclinical myasthenia (reversible lethargy, muscular weakness and ptosis) in a nurse anaesthetist has also been reported.70 l c Access and Availability of Information i t Availability of methoxyflurane is not limited to ambulance and Emergency Department but r available for purchase by health professionals. According to an Australian manufacturer’s website, it can be purchased by a dentist with provision of a “Dental Registration A Certificate/Card”. 71 The available product information guide contains comprehensive information. 72 Contraindications include patients with renal impairment and failure, hypersensitivity to fluorinated anaesthetics, cardiovascular instability, respiratory depression, d head injury or loss of consciousness. Caution is highlighted for those with liver disease and diabetes, the elderly and the obese and patients on enzyme inducing drugs. Additionally, e health care workers regularly exposed to patient using methoxyflurane inhalers are encouraged to be aware of relevant occupation health and safety guidelines for use of t inhalational agents. Dental use is analogous to other usages. The maximum stated daily dose p of 2 bottles x 3ml and no more than 15ml (5 bottles) in a week for all patients. Regarding operation of a vehicle after administration, this is suggested to be at the discretion of the e treating doctor, however a minimum of 24 hours would seem prudent. 72 c Guidelines for the use of methoxyflurane in Dental Practice c 1. Safety in the use of methoxyflurane can only be possible if used in accordance with the A manufacturer’s instructions and anxiolysis guidelines of the Dental Board of Australia. A sound knowledge of potential adverse events should precede embarkation of its use. This article is protected by copyright. All rights reserved. 2. Although the product is readily available, it should be known that the use of e methoxyflurane is governed under the anxiolysis guidelines of the Dental Board of Australia. There is a clear requirement for training on the correct use of methoxyflurane with the need l for oxygen, airway management skills and life support skills. c 3. Patient selection requires that a full and current patient medical history be taken by the i clinician with particular relevance to strict and relative contraindications. t 4. Prior to use, dentists should carefully consider whether or not there are alternatives to r methoxyflurane that do not carry the same risk of adverse reactions. A 5. Should the procedure require anything more than simple anxiolysis or analgesia, methoxyflurane is not indicated, and the patient should be referred. 6. A clear and concise discussion on its intended use should be had with the patient prior to d its use. This should not occur at the same appointment that this is intending to be used. 7. Methoxyflurane should not be used with any other sedative medication, as it is likely that e this will be both harmful and illegal if dentist is not an endorsed Dental Sedationists. t 8. Extreme care should be taken to not allow misuse of methoxyflurane. It is not appropriate p to override patient control by holding the device to the patient’s mouth during administration. 9. Patients should be monitored after administration of methoxyflurane and should not e operate machinery or drive a vehicle until they have completely recovered from the effects of the drug, and it is recommended that this be at least 24 hours. c 10. Dentists and patients must be well informed of the possibility of developing late c complication. A 11. Similar to that recommended for the use of methoxyflurane in the ambulance setting to reduce the risk of occupational exposure to methoxyflurane, no single Dentist should This article is protected by copyright. All rights reserved.