Determination of equi-analgesic doses of inhaled methoxyflurane versus intravenous fentanyl using the cold pressor test in volunteers: a randomised, double-blinded, placebo-controlled crossover study.

BACKGROUND: Inhaled methoxyflurane for acute pain relief has demonstrated an analgesic effect superior to placebo. Data comparing methoxyflurane to an opioid are needed. The aim of this study was to determine the equi-analgesic doses of inhaled methoxyflurane vs i.v. fentanyl. Both drugs have an onset within minutes and an analgesic effect of 20-30 min. METHODS: Twelve subjects were included in a randomised, double-blinded, placebo-controlled crossover study with four treatments: placebo (NaCl 0.9%), fentanyl 25 µg i.v., fentanyl 50 µg i.v., or inhaled methoxyflurane 3 ml. The subjects reported pain intensity using the verbal numeric rating scale (VNRS) from 0 to 10 during the cold pressor test (CPT). The CPT was performed before (CPT 1), 5 min (CPT 2), and 20 min (CPT 3) after drug administration. RESULTS: Inhaled methoxyflurane and fentanyl 25 µg reduced VNRS scores significantly compared with placebo at CPT 2 (-1.14 [estimated difference in VNRS between treatment groups with 95% confidence interval {CI}: -1.50 to -0.78]; -1.15 [95% CI: -1.51 to -0.79]; both P<0.001) and CPT 3 (-0.60 [95% CI: -0.96 to -0.24]; -0.84 [95% CI: -1.20 to -0.47]; both P<0.001). There were no significant differences between the two drugs. Methoxyflurane had significantly higher VNRS scores than fentanyl 50 µg at CPT 2 (0.90 [95% CI: 0.54-1.26]; P<0.001) and CPT 3 (0.57 [95% CI: 0.21-0.94]; P<0.001). CONCLUSIONS: Inhaled methoxyflurane 3 ml was equi-analgesic to fentanyl 25 µg i.v. at CPT 2. Both resulted in significantly less pain than placebo. Fentanyl 50 µg i.v. demonstrated analgesia superior to methoxyflurane. CLINICAL TRIAL REGISTRATION: NCT03894800.

Multiple criteria decision analysis approach to consider therapeutic innovations in the emergency department: The methoxyflurane organizational impact in acute trauma pain.

BACKGROUND: Acute trauma pain is poorly managed in the emergency department (ED). The reasons are partly organizational: ED crowding and rare trauma care pathways contribute to oligoanalgesia. Anticipating the organizational impact of an innovative care procedure might facilitate the decision-making process and help to optimize pain management. METHODS: We used a multiple criteria decision analysis (MCDA) approach to consider the organizational impact of methoxyflurane (self-administered) in the ED, introduced alone or supported by a trauma care pathway. A MCDA experiment was designed for this specific context, 8 experts in emergency trauma care pathways (leading physicians and pharmacists working in French urban tertiary hospitals) were recruited. The study involved four steps: (i) Selection of organizational criteria for evaluating the innovation's impact; (ii) assessment of the relative weight of each criterion; (iii) choice of appropriate scenarios for exploring the organizational impact of MEOX under various contexts; and (iv) software-assisted simulation based on pairwise comparisons of the scenarios. The final outcome measure was the expected overall organizational impact of methoxyflurane on a 0-to-100 scale (score >50: positive impact). RESULTS: Nine organizational criteria were selected. "Mean length of stay in the ED" was the most weighted. Methoxyflurane alone obtained 59 as a total score, with a putative positive impact for eight criteria, and a neutral effect on one. When a trauma care pathway was introduced concomitantly, the impact of methoxyflurane was greater overall (score: 75) and for each individual criterion. CONCLUSIONS: Our model highlighted the putative positive organizational impact of methoxyflurane in the ED-particularly when supported by a trauma care pathway-and the relevance of expert consensus in this particular pharmacoeconomic context. The MCDA approach could be extended to other research fields and healthcare challenges in emergency medicine.

Service Evaluation of Methoxyflurane Versus Standard Care for Overall Management of Patients with Pain Due to Injury.

INTRODUCTION: Inhaled methoxyflurane is an analgesic used for the emergency relief of moderate to severe pain in conscious adult patients with trauma and associated pain that is increasingly being used in hospital emergency departments to provide rapid analgesia. It is widely accepted that effective pain relief can facilitate patient care and flow through the emergency department (ED). The main aim of this evaluation was to assess the impact of inhaled methoxyflurane on patient length of stay (LOS) in the ED compared with standard care. METHODS: Adult patients with moderate to severe trauma pain and Glasgow coma score of 15 were included in the evaluation. Evaluation forms were completed for 79 patients who received methoxyflurane and were matched with 80 patients who received standard care. RESULTS: Overall the mean time spent in the ED was reduced by 71 min in those patients who were administered methoxyflurane compared with patients who received standard care. Furthermore, analysis of LOS by injury type demonstrated a reduction in ED LOS by 183 min for patients with shoulder dislocation who were treated with methoxyflurane compared with patients who received standard care. There was no reduction in ED LOS for patients with lower limb, hip or pelvic injuries between the two treatment groups. CONCLUSION: Use of methoxyflurane in adult patients with trauma pain significantly reduced the ED LOS and may potentially improve patient flow through the ED.

[Acute pain management†: the role of inhaled methoxyflurane in clinical practice]. / Traitement de la douleur aiguë†: la place du méthoxyflurane inhalé dans la pratique clinique.

Since 2018, a new analgesic drug has been made available in Switzerland : methoxyflurane. This halogenated gas, controlled by the patient, offers a very effective analgesic effect comparable to opiates. Known since the 1960s and used mainly in pre-hospital emergency medicine in Australia and New Zealand, its use in Europe is increasing alongside standard analgesic treatments in the traumatic setting. Administered by inhalation, it does not require an intravenous access, which is ideal in prehospital emergency situations. This treatment could be used for the management of acute pain of various origins, such as renal lithiasis, or to facilitate different procedures, such as closed fracture reduction or chest tube insertion. Its indications are growing and its use will probably become commonplace with clinicians in a near future.

Depuis 2018, une nouvelle modalité antalgique est disponible en Suisse : le méthoxyflurane. Ce gaz halogéné, contrôlé par le·la patient·e, offre une antalgie très efficace, comparable aux opiacés. Utilisé depuis les années 1960 en médecine préhospitalière dans les régions d'Australie et de Nouvelle-Zélande, il fait ses preuves en Europe où on l'emploie avec les différents antalgiques habituels dans les situations traumatiques d'urgence. Par son administration inhalée, il ne nécessite aucune perfusion. Ce traitement pourrait être utilisé pour la gestion de douleurs aiguës d'origines diverses, telles que la colique néphrétique, ou encore faciliter différentes procédures, comme la réduction fermée de fracture ou la pose de drains. Son indication thérapeutique est croissante et son utilisation deviendra vraisemblablement commune.

Non-interventional study evaluating exposure to inhaled, low-dose methoxyflurane experienced by hospital emergency department personnel in France.

OBJECTIVES: Low-dose methoxyflurane is a non-opioid, inhaled analgesic administered via the Penthrox inhaler and was recently licensed in Europe for emergency relief of moderate-to-severe trauma-associated pain in conscious adults. This non-interventional study investigated occupational exposure to methoxyflurane in the hospital emergency department (ED) personnel during routine clinical practice. SETTING AND PARTICIPANTS: The study was conducted in two hospital ED triage rooms in France over a 2-week and 3-week period, respectively. Low-dose methoxyflurane analgesia was self-administered by patients via the inhaler under the supervision of nursing staff, per routine clinical practice. An organic vapour personal badge sampler was attached to the uniform of the nurses working in the treatment rooms throughout an 8-hour shift (total of 140 shifts during the study period). Seven-day ambient air monitoring of each treatment room was also performed. Methoxyflurane levels adsorbed in each badge sampler were measured by a central laboratory. The primary objective was to evaluate methoxyflurane exposure experience by the hospital ED nurses during an 8-hour shift. RESULTS: In 138 badge samplers, the median (range) concentration of methoxyflurane present following 8-hour nursing shifts was 0.017 (0.008, 0.736) ppm. This level was almost 900-fold lower than the previously reported 8-hour-derived maximal exposure level of 15 ppm; methoxyflurane exposure approaching this threshold was not documented in any badges. There was no correlation between the number of applications of low-dose methoxyflurane administered during a shift (range 0-5) and the vapour exposure measured on the personal badge samplers. CONCLUSIONS: This study indicates that nurses working in hospital EDs experience very low levels of occupational exposure to methoxyflurane vapour during routine clinical practice. These real-world data can provide reassurance to healthcare providers supervising patients receiving low-dose methoxyflurane analgesia via a Penthrox inhaler; further studies may inform exposure in other hospital ED settings.

Penthrox: a breath of PHEC air for the military?

Prehospital analgesia is vital to good clinical care and inhaled methoxyflurane (Penthrox) would be a valuable addition to the armed forces medical armoury. Penthrox would provide strong, fast-acting, self-administered and safe analgesia to patients with moderate to severe injuries. In addition, it would provide an option for strong analgesia which would not be subject to the regulations that govern controlled or accountable drugs which gives it a unique position as the military moves its focus from large enduring operations to small short-term training teams supported by lone combat medics in remote locations across the globe.

Inhaled Methoxyflurane Provides Greater Analgesia and Faster Onset of Action Versus Standard Analgesia in Patients With Trauma Pain: InMEDIATE: A Randomized Controlled Trial in Emergency Departments.

STUDY OBJECTIVE: The objective of the InMEDIATE study was to evaluate the change in intensity of traumatic pain over the first 20 min in adult patients treated with methoxyflurane versus standard analgesic treatment in Spain. This the first randomized, active-controlled, multicenter trial of methoxyflurane in the emergency setting in Europe. METHODS: This was a randomized, controlled study that enrolled adult patients with acute moderate to severe (score ≥4 on the 11-point Numeric Rating Scale) trauma-associated pain in 14 Spanish emergency departments. Patients were randomized 1:1 to methoxyflurane (up to 2×3 mL) or standard analgesic treatment. Coprimary endpoints were the change from baseline in Numeric Rating Scale pain intensity score during the first 20 minutes of treatment and time to first pain relief. RESULTS: Three hundred five patients were randomized (methoxyflurane 156; standard analgesic treatment 149). Most patients in the standard analgesic treatment group (70%) received intravenous first-step analgesics and 9.4% of patients were treated with opioids. Mean decrease from baseline in Numeric Rating Scale pain intensity score was greater for methoxyflurane than standard analgesic treatment at all points, with a significant treatment difference overall up to 20 minutes (repeated-measures model 2.47 versus 1.39; treatment difference 1.00; 95% confidence interval 0.84 to 1.32). Median time to first pain relief was significantly shorter for methoxyflurane than standard analgesic treatment (3 versus 10 minutes). Methoxyflurane achieved better patient and clinician ratings for pain control and comfort of treatment than standard analgesic treatment and exceeded patient and clinician expectations of treatment in, respectively, 77% and 72% of cases compared with 38% and 19% for standard analgesic treatment. CONCLUSION: These results support consideration of methoxyflurane as a nonnarcotic, easy-to-administer, rapid-acting, first-line alternative to currently available analgesic treatments for trauma pain.

Analgesic Efficacy, Practicality and Safety of Inhaled Methoxyflurane Versus Standard Analgesic Treatment for Acute Trauma Pain in the Emergency Setting: A Randomised, Open-Label, Active-Controlled, Multicentre Trial in Italy (MEDITA).

INTRODUCTION: Inhaled low-dose methoxyflurane is approved in Europe for emergency relief of moderate-to-severe trauma-related pain in adults, but data versus active comparators are sparse. The phase IIIb Methoxyflurane in Emergency Department in ITAly (MEDITA) trial investigated the analgesic efficacy, practicality and safety of methoxyflurane versus standard analgesic treatment (SAT) for acute trauma pain. METHODS: This was a randomised, active-controlled, parallel-group, open-label trial conducted in 15 Italian emergency units. Adults with limb trauma and pain score ≥ 4 on numerical rating scale (NRS) were randomised 1:1 to inhaled methoxyflurane 3 mL or SAT [intravenously administered (IV) morphine 0.1 mg/kg for severe pain (NRS ≥ 7); IV paracetamol 1 g or IV ketoprofen 100 mg for moderate pain (NRS 4-6)]. The primary endpoint was overall change in visual analogue scale (VAS) pain intensity from baseline (time of randomisation) to 3, 5 and 10 min. Non-inferiority and superiority of methoxyflurane versus SAT were concluded if the upper 95% confidence interval (CI) for the treatment comparison (methoxyflurane-SAT) was less than 1 and less than 0, respectively. RESULTS: Between 8 February 2018 and 8 February 2019, 272 patients were randomised (136 per treatment group). A total of 270 patients (mean age 51 years; 49% male; 34% with severe pain; mean baseline VAS 67 mm) were treated and analysed for efficacy and safety. Superiority of methoxyflurane was demonstrated for moderate-to-severe pain (adjusted mean treatment difference - 5.94 mm; 95% CI - 8.83, - 3.06 mm), moderate pain (- 5.97 mm; 95% CI - 9.55, - 2.39 mm) and severe pain (- 5.54 mm; 95% CI - 10.49, - 0.59 mm). Median onset of pain relief was 9 min for methoxyflurane and 15 min for SAT. Practicality of methoxyflurane treatment was rated "Excellent", "Very Good" or "Good" by 90% of clinicians vs. 64% for SAT. Adverse events (all non-serious) were reported by 17% of methoxyflurane-treated patients and 3% of SAT-treated patients. CONCLUSION: Methoxyflurane provided superior pain relief to SAT in patients with moderate-to-severe trauma pain and may offer a simple, fast, effective non-opioid treatment option. TRIAL REGISTRATION: Trial registered with EudraCT (2017-001565-25) on 2 March 2018 and ClinicalTrials.gov (NCT03585374) on 13 July 2018. FUNDING: Mundipharma Pharmaceuticals S.r.l.

Inhaled methoxyflurane (Penthrox®) versus placebo for injury-associated analgesia in children-the MAGPIE trial (MEOF-002): study protocol for a randomised controlled trial.

BACKGROUND: Pain from injuries is one of the commonest symptoms in children attending emergency departments (EDs), and this is often inadequately treated in both the pre-hospital and ED settings, in part due to challenges of continual assessment and availability of easily administered analgesic options. Pain practices are therefore a key research priority, including within the field of paediatric emergency medicine. Methoxyflurane, delivered via a self-administered Penthrox® inhaler, belongs to the fluorinated hydrocarbon group of volatile anaesthetics and is unique among the group in having analgesic properties at low doses. Despite over 30 years of clinical acute analgesia use, and a large volume of evidence supporting its safety and efficacy, there is a paucity of randomised controlled trial data for Penthrox®. METHODS: This is an international multi-centre randomised, double-blind, placebo-controlled phase III trial assessing the efficacy and safety of methoxyflurane delivered via the Penthrox® inhaler for the management of moderate to severe acute traumatic pain in children and young people aged 6-17 years. Following written informed consent, eligible participants are randomised to self-administer either inhaled methoxyflurane (maximum dose of 2 × 3 ml) or normal saline placebo (maximum dose 2 × 5 ml). Patients, treating clinicians and research nurses are blinded to the treatment. The primary outcome is the change in pain intensity at 15 min after the commencement of treatment, as measured by the Visual Analogue Scale (VAS) or the Wong-Baker FACES® Pain Rating scale, with the latter converted to VAS values. Secondary outcome measures include the number and proportion of responders who achieve a 30% reduction in VAS score compared to baseline, rescue medication requested, time and number of inhalations to first pain relief, global medication performance assessment by the patient, clinician and research nurse, and evaluation of adverse events experienced during treatment and during the subsequent 14 ± 2 days. The primary analysis will be by intention to treat. The total sample size is 110 randomised and treated patients per treatment arm. DISCUSSION: The Methoxyflurane AnalGesia for Paediatric InjuriEs (MAGPIE) trial will provide efficacy and safety data for methoxyflurane administered via the Penthrox® inhaler, in children and adolescents who present to EDs with moderate to severe injury-related pain. TRIAL REGISTRATION: EudraCT, 2016-004290-41 . Registered on 11 April 2017. ClinicalTrials.gov, NCT03215056 . Registered on 12 July 2017.

Inhaled methoxyflurane for the reduction of acute anterior shoulder dislocation in the emergency department.

OBJECTIVES: Methoxyflurane is an inhalation analgesic used in the emergency department (ED) but also has minimal sedative properties. The major aim of this study was to evaluate the success rate of methoxyflurane for acute anterior shoulder dislocation (ASD) reduction. The secondary aim was to assess the impact of methoxyflurane on ED patient flow compared to propofol. METHODS: A health record review was performed for all patients presenting with ASD who underwent reduction with either methoxyflurane or propofol over a 13-month period (December 2016 - December 2017). The primary outcome was reduction success for methoxyflurane, while secondary outcomes such as recovery time and ED length of stay (LOS) were also assessed compared to propofol. Patients with fracture dislocations, polytrauma, intravenous, or intramuscular opioids in the pre-hospital setting, no sedation for reduction, and alternative techniques of sedation or analgesia for reduction were excluded. RESULTS: A total of 151 patients presented with ASD during the study period. Eighty-two patients fulfilled our inclusion criteria. Fifty-two patients had ASD reduction with propofol while 30 patients had methoxyflurane. Successful reduction was achieved in 80% (95% CI 65.69% to 94.31%) patients who used methoxyflurane. The median recovery time and ED LOS were 30 minutes [19.3-44] and 70.5 minutes [49.3-105], which was found to be shorter for the methoxyflurane group, who had successful reductions compared to sedation with propofol. CONCLUSION: Methoxyflurane was used successfully in 30% of the 82 patients undergoing reduction for ASD, while potentially improving ED efficiency.

OBJECTIFS: Le méthoxyflurane en inhalation est un analgésique utilisé au service des urgences (SU), qui a de très faibles propriétés sédatives. L'étude avait pour objectif principal d'évaluer le taux de réussite de la réduction des luxations antérieures de l'épaule (LAE), en phase aiguë, au SU, à l'aide du méthoxyflurane et, pour objectif secondaire, d'évaluer l'effet du méthoxyflurane sur le flux des patients au SU, comparativement à celui du propofol. MÉTHODE: Il y a eu un examen des dossiers médicaux de tous les patients qui ont subi une réduction d'une LAE à l'aide du méthoxyflurane ou du propofol sur une période de 13 mois (décembre 2016 ­ décembre 2017). Le principal critère d'évaluation consistait en la détermination du taux de réussite des réductions réalisées à l'aide du méthoxyflurane, et les critères d'évaluation secondaires, en la comparaison de mesures comme le temps de rétablissement et la durée du séjour (DS) au SU, entre le méthoxyflurane et le propofol. Étaient exclus de l'étude les cas de fracture avec luxation de l'épaule, de polytrauma, d'administration intraveineuse ou intramusculaire d'opioïdes en phase préhospitalière, de réduction sans sédation d'une LAE ou de recours à d'autres techniques de sédation ou d'analgésie en vue de la réduction d'une LAE. RÉSULTATS: Au total, 151 patients ont été examinés au SU pour une LAE durant la période d'étude et, sur ce nombre, 82 satisfaisaient aux critères de sélection. Dans l'ensemble, 52 patients ont été traités par le propofol contre 30, par le méthoxyflurane pour la réduction d'une LAE. Le taux de réussite des réductions a atteint 80% (IC à 95% : 65,69% ­ 94,31%) chez les blessés traités par le méthoxyflurane. Les valeurs médianes du temps de rétablissement et de la DS au SU étaient de 30 minutes [19,3­44] et de 70,5 minutes [49,3-105], ce qui représente des valeurs plus faibles dans le groupe de traitement par le méthoxyflurane, dans les cas de réussite, que dans le groupe de sédation par le propofol. CONCLUSION: Le méthoxyflurane a atteint un taux de réussite de 30% chez les 82 patients qui ont subi une réduction d'une LAE et pourrait, de ce fait, accroître l'efficacité au SU.

Prospective, Multicentre Trial of Methoxyflurane for Acute Trauma-Related Pain in Helicopter Emergency Medical Systems and Hostile Environments: METEORA Protocol.

INTRODUCTION: The inhalational analgesic low-dose methoxyflurane has been widely used by Australian ambulance services since 1975 and is now approved in Europe for emergency relief of moderate-to-severe trauma-related pain in conscious adult patients. The use of methoxyflurane in hostile environments is of special interest given its portability, ease of use and rapid onset of action. This trial will investigate the efficacy, tolerability and practicality of use of inhaled methoxyflurane in patients with moderate-to-severe trauma-related pain rescued from hostile mountainous environments by the Helicopter Emergency Medical Service (HEMS) in Italy. METHODS: METEORA is a phase IIIb, prospective, single-arm, multicentre trial. Approximately 200 adult patients with a pain score of at least 4 on the numerical rating scale (NRS) due to limb trauma rescued by HEMS will be enrolled. Patients will receive up to 2 × 3 mL methoxyflurane, self-administered by the patient by inhalation under medical supervision. Rescue medication will be permitted if required. PLANNED OUTCOMES: Pain intensity will be measured using a 100-mm visual analogue scale (VAS) at baseline, at 5, 10, 15, 20, 30, 45 and 60 min after the start of methoxyflurane inhalation and when positioning the patient on a spinal board or stretcher; and also using the NRS at enrolment and at 10 min. Use of rescue medication (yes/no) will be recorded. The patient will rate efficacy and the healthcare professional will rate practicality of methoxyflurane treatment at 30 and 60 min using a 5-point Likert scale. Vital signs will be measured at baseline, 10, 30 and 60 min. Assessments after 30 min will only be performed for patients using a second inhaler. Adverse events will be recorded until safety follow-up at 3 ± 1 days. The primary endpoint is the percentage of patients achieving at least 30% improvement from baseline in VAS pain intensity within the first 10 min of methoxyflurane administration. TRIAL REGISTRATION: EudraCT number: 2017-004601-40. FUNDING: Mundipharma Pharmaceuticals, srl. Plain language summary available for this article.

Methoxyflurane Analgesia in Adult Patients in the Emergency Department: A Subgroup Analysis of a Randomized, Double-blind, Placebo-controlled Study (STOP!).

INTRODUCTION: Acute pain remains highly prevalent in the Emergency Department (ED) setting. This double-blind, randomized, placebo-controlled UK study investigated the efficacy and safety of low-dose methoxyflurane analgesia for the treatment of acute pain in the ED in the adult population of the STOP! trial. METHODS: Patients presenting to the ED requiring analgesia for acute pain (pain score of 4-7 on the Numerical Rating Scale) due to minor trauma were randomized in a 1:1 ratio to receive methoxyflurane (up to 6 mL) or placebo (normal saline), both via a Penthrox® (Medical Developments International Limited, Scoresby, Australia) inhaler. Rescue medication (paracetamol/opioids) was available immediately upon request. Change from baseline in visual analog scale (VAS) pain intensity was the primary endpoint. RESULTS: 300 adult and adolescent patients were randomized; data are presented for the adult subgroup (N = 204). Mean baseline VAS pain score was ~66 mm in both groups. The mean change from baseline to 5, 10, 15 and 20 min was greater for methoxyflurane (-20.7, -27.4, -33.3 and -34.8 mm, respectively) than placebo (-8.0, -11.1, -12.3 and -15.2 mm, respectively). The primary analysis showed a highly significant treatment effect overall across all four time points (-17.4 mm; 95% confidence interval: -22.3 to -12.5 mm; p < 0.0001). Median time to first pain relief was 5 min with methoxyflurane [versus 20 min with placebo; (hazard ratio: 2.32; 95% CI: 1.63, 3.30; p < 0.0001)]; 79.4% of methoxyflurane-treated patients experienced pain relief within 1-10 inhalations. 22.8% of placebo-treated patients requested rescue medication within 20 min compared with 2.0% of methoxyflurane-treated patients (p = 0.0003). Methoxyflurane treatment was rated 'Excellent', 'Very Good' or 'Good' by 77.6% of patients, 74.5% of physicians and 72.5% of nurses. Treatment-related adverse events (mostly dizziness/headache) were reported by 42.2% of patients receiving methoxyflurane and 14.9% of patients receiving placebo; none caused withdrawal and the majority were mild and transient. CONCLUSION: The results of this study support the evidence from previous trials that low-dose methoxyflurane administered via the Penthrox inhaler is a well-tolerated, efficacious and rapid-acting analgesic. FUNDING: Medical Developments International (MDI) Limited and Mundipharma Research GmbH & Co.KG. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01420159, EudraCT number: 2011-000338-12.

Derivation of an occupational exposure limit for an inhalation analgesic methoxyflurane (Penthrox(®)).

Methoxyflurane (MOF) a haloether, is an inhalation analgesic agent for emergency relief of pain by self administration in conscious patients with trauma and associated pain. It is administered under supervision of personnel trained in its use. As a consequence of supervised use, intermittent occupational exposure can occur. An occupational exposure limit has not been established for methoxyflurane. Human clinical and toxicity data have been reviewed and used to derive an occupational exposure limit (referred to as a maximum exposure level, MEL) according to modern principles. The data set for methoxyflurane is complex given its historical use as anaesthetic. Distinguishing clinical investigations of adverse health effects following high and prolonged exposure during anaesthesia to assess relatively low and intermittent exposure during occupational exposure requires an evidence based approach to the toxicity assessment and determination of a critical effect and point of departure. The principal target organs are the kidney and the central nervous system and there have been rare reports of hepatotoxicity, too. Methoxyflurane is not genotoxic based on in vitro bacterial mutation and in vivo micronucleus tests and it is not classifiable (IARC) as a carcinogenic hazard to humans. The critical effect chosen for development of a MEL is kidney toxicity. The point of departure (POD) was derived from the concentration response relationship for kidney toxicity using the benchmark dose method. A MEL of 15 ppm (expressed as an 8 h time weighted average (TWA)) was derived. The derived MEL is at least 50 times higher than the mean observed TWA (0.23 ppm) for ambulance workers and medical staff involved in supervising use of Penthrox. In typical treatment environments (ambulances and treatment rooms) that meet ventilation requirements the derived MEL is at least 10 times higher than the modelled TWA (1.5 ppm or less) and the estimated short term peak concentrations are within the MEL. The odour threshold for MOF of 0.13-0.19 ppm indicates that the odour is detectable well below the MEL. Given the above considerations the proposed MEL is health protective.

Self-administered methoxyflurane for procedural analgesia: experience in a tertiary Australasian centre.

Methoxyflurane, an agent formerly used as a volatile anaesthetic but that has strong analgesic properties, will soon become available again in the UK and Europe in the form of a small hand-held inhaler. We describe our experience in the use of inhaled methoxyflurane for procedural analgesia within a large tertiary hospital. In a small pilot crossover study of patients undergoing burns-dressing procedures, self-administered methoxyflurane inhalation was preferred to ketamine-midazolam patient-controlled analgesia by five of eight patients. Patient and proceduralist outcomes and satisfaction were recorded from a subsequent case series of 173 minor surgical and radiological procedures in 123 patients performed using inhaled methoxyflurane. The procedures included change of dressing, minor debridement, colonoscopy and incision-and-drainage of abscess. There was a 97% success rate of methoxyflurane analgesia to facilitate these procedures. Limitations of methoxyflurane include maximal daily and weekly doses, and uncertainty regarding its safety in patients with pre-existing renal disease.

Penthrox alone versus Penthrox plus periprostatic infiltration of local analgesia for analgesia in transrectal ultrasound-guided prostate biopsy.

BACKGROUND: The objective of this study was to compare pain intensity in patients undergoing transrectal ultrasound (TRUS)-guided biopsy of the prostate with Penthrox alone compared with Penthrox plus periprostatic infiltration of local analgesia (PILA). METHOD: Seventy-two subjects participated in this study after receiving appropriate education. Forty-two patients self-administered inhaled Penthrox (3 mL methoxyflurane) alone for analgesia (Group A), followed by 30 patients who self-administered Penthrox and received PILA with 5 mL of 2% lignocaine. All subjects had TRUS biopsy performed. Immediately after the procedure, patients were asked to rate their pain intensity using a numerical verbal rating scale from 0 to 10. RESULTS: Baseline characteristics of the two groups were similar. Patients in Group B reported significantly lower post TRUS biopsy median pain intensity of 2 (1-3) compared with Group A subjects who reported a median post TRUS biopsy pain intensity of 3 (2-5) (P = 0.014). A total of 72 men underwent TRUS-guided biopsy. All patients indicated they would be happy to have another TRUS-guided prostate biopsy in the future. CONCLUSION: Our study shows that Penthrox plus PILA shows promise as an efficacious and easily tolerated analgesic technique for outpatient TRUS biopsy, keeping resource use to a minimum. Planning for a multi-centre, double-blind randomized control trial comparing Penthrox plus PILA with PILA alone is presently underway.

Methoxyflurane: a review with emphasis on its role in dental practice.

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. Due to toxicity concerns, it lost favour in general anaesthesia and had been largely abandoned by the late 1970s. The manufacturer withdrew it in 1999, and the Food and Drug Administration in the United States did not renew its licence in 2005. It has also been 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 trauma. It has become attractive for use in dental practice, likely due to its effectiveness as an 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 reactions have been recorded. Practitioners should be well aware of risks associated with its use before considering administration, and carefully assess whether or not there are equally good alternative options that do not the carry the same risks. Methoxyflurane is reviewed below with an emphasis on its use in dental practice.

Penthrox inhaler analgesia in transrectal ultrasound-guided prostate biopsy.

BACKGROUND: Periprostatic injection of local anaesthetic (PILA) has been shown to significantly reduce pain in patients undergoing transrectal ultrasound-guided prostate biopsy (TRUSPB). However, this method does not address pain that is associated with ultrasound probe insertion, and the injection of local anaesthetic itself causes pain. The aim of this study was to explore the efficacy of methoxyflurane delivered by a Penthrox inhaler as a novel method of pain relief during TRUSPB. METHOD: From July 2012 to July 2013, 64 patients were scheduled at a single centre to undergo TRUSPB while receiving analgesia via Penthrox inhaler. Fifteen minutes after the biopsy procedure, these patients were asked to complete a pain score survey using a 10-cm visual analogue scale (VAS) to separately report the degree of pain experienced during digital rectal examination (DRE), ultrasound probe insertion and core biopsy. RESULTS: The median pain scores on a 10-cm VAS were 2.0, 2.4 and 3.0 during DRE, probe insertion and needle biopsy, respectively, while using the Penthrox inhaler. Of the 64 patients, 11 had undergone TRUSPB previously receiving PILA. In these patients, PILA was significantly better than the Penthrox inhaler for pain relief during needle biopsy (median pain score 2.0 versus 4.0; P = 0.012). CONCLUSION: The Penthrox inhaler appears to be a safe and effective method of analgesia for TRUSPB. Patients who had experienced both PILA and Penthrox reported pain scores that significantly favoured PILA over the Penthrox inhaler.

A randomised, double-blind, placebo-controlled study to assess the safety and efficacy of methoxyflurane for procedural pain of a bone marrow biopsy.

CONTEXT: Pain during bone marrow biopsy (BMB) under local anaesthesia (LA) is reported in 70% of patients, of whom 35% rate the pain as severe. Pain is experienced during both the biopsy and the marrow aspiration. Many medical centres use conscious sedation involving benzodiazepines and/or opioids administered orally or intravenously for BMB analgesia. Methoxyflurane (MEOF) is self-administered by a handheld device (the Penthrox inhaler), which is licensed in Australia for the relief of pain associated with short surgical procedures. OBJECTIVES: To evaluate the efficacy and safety of MEOF analgesia in patients with cancer undergoing BMB. METHODS: Patients received LA plus either MEOF or placebo. The primary endpoint was worst pain intensity measured with the Numerical Rating Scale. Anxiety was assessed with the State Trait Anxiety Inventory (STAI-Y-1). Patients, operators and the research nurse rated global medication performance using a 5-point Likert scale. RESULTS: Forty-nine of the 50 patients randomised to MEOF and 48 of the 50 patients randomised to placebo effectively received the allocated intervention. Mean±SD worst pain overall was 4.90±2.07 in MEOF group and 6.0±2.24 in placebo group (p=0.011). Worst pain during the aspiration was 3.3±2.0 in MEOF group and 5.0±2.4 in placebo group (p<0.001). 49% of patients treated with MEOF rated the medication as very good or excellent compared with 16.5% of the patients treated with placebo (p=0.005). 20.4% of patients treated with MEOF had an adverse event (AE) compared with 4.2% in the placebo arm (p=0.028). All AEs were grade 1. CONCLUSIONS: MEOF was safe and performed better than placebo for analgesia in BMB procedures.

Inhaled methoxyflurane for pain and anxiety relief during burn wound care procedures: an Australian case series.

Pain is a common and significant feature of burn injury. The use of intravenous opioids forms the mainstay of procedural burn pain management, but in an outpatient setting, the demand for novel agents that do not require parenteral access, are easy to administer and have a rapid onset are urgently needed. One such agent is the inhaled anaesthetic agent, methoxyflurane (MF). The aim of this study was to conduct a pilot investigation into the clinical effectiveness of MF inhaler on pain and anxiety scores in patients undergoing burn wound care procedures in an outpatient setting. A prospective case series involved recruiting patients undergoing a burn wound care procedure in an ambulatory burn care setting. Pain and anxiety were assessed using numerical rating scales. Overall, median numerical pain rating score was significantly higher post-dressing [pre-dressing: 2; interquartile range (IQR): 1-3 versus post-dressing: 3; IQR 1·5-4; P = 0·01], whereas median numerical anxiety score significantly reduced following the dressing (pre-dressing: 5; IQR 4-7 versus post-dressing: 2; IQR 1-2; P < 0·001). Our study suggests that there is a role for MF in the pain management armamentarium in those undergoing burn care procedures in the ambulatory care setting. However, there is an urgent need for larger case series and randomised controlled trials to determine its overall clinical effectiveness.

Patient-controlled analgesia with inhaled methoxyflurane versus conventional endoscopist-provided sedation for colonoscopy: a randomized multicenter trial.

OBJECTIVE: Inhaled methoxyflurane (Penthrox, Medical Device International, Melbourne, Australia) has been used extensively in Australasia (Australia and New Zealand) to manage trauma-related pain. The aim is to evaluate the efficacy, safety, and outcome of Penthrox for colonoscopy. DESIGN: Prospective randomized study. SETTING: Three tertiary endoscopic centers. PATIENTS: Two hundred fifty-one patients were randomized to receive either Penthrox (n = 125, 70 men, 51.4 ± 1.1 years old) or intravenous midazolam and fentanyl (M&F; n = 126, 72 men, 54.9 ± 1.1 years old) during colonoscopy. MAIN OUTCOME MEASUREMENT: Discomfort (visual analogue scale [VAS] pain score), anxiety (State-Trait Anxiety Inventory Form Y [STAI-Y] anxiety score), colonoscopy performance, adverse events, and recovery time. RESULTS: Precolonoscopy VAS pain and STAI-Y scores were comparable between the 2 groups. There were no differences between groups in (1) pain VAS or STAI Y-1 anxiety scores during or immediately after colonoscopy, (2) procedural success rate (Penthrox: 121/125 vs M&F: 124/126), (3) hypotension during colonoscopy (7/125 vs 8/126), (4) tachycardia (5/125 vs 3/126), (5) cecal arrival time (8 ± 1 vs 8 ± 1 minutes), or (6) polyp detection rate (30/125 vs 43/126). Additional intravenous sedation was required in 10 patients (8%) who received Penthrox. Patients receiving Penthrox alone had no desaturation (oxygen saturation [SaO(2)] < 90%) events (0/115 vs 5/126; P = .03), awoke quicker (3 ± 0 vs 19 ± 1 minutes; P < .001) and were ready for discharge earlier (37 ± 1 vs 66 ± 2 minutes; P < .001) than those receiving intravenous M&F. LIMITATIONS: Inhaled Penthrox is not yet available in the United States and Europe. CONCLUSIONS: Patient-controlled analgesia with inhaled Penthrox is feasible and as effective as conventional sedation for colonoscopy with shorter recovery time, is not associated with respiratory depression, and does not influence the procedural success and polyp detection.