Aims: Acute oral pain is a leading cause of presentations to emergency care. Methoxyflurane (MTXF) is a halogen gas with significant analgesic properties at low doses. MTXF administration was reported for dental pain with controversial results. The safety and simplicity of using a recently approved hand-held inhaler represent encouraging evidence for its application for dental pain. Thus, a systematic review was conducted with the following objectives: to determine the efficacy of MTXF in the management of acute dental pain, and to highlight the most effective procedure. Methods: This literature review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) methodology. Results: Overall, 62 publications were identified, from which 5 articles were selected for this work. The overall quality of the included studies was low with a fairly high risk of bias. In the vast majority of studies, the level of pain experienced by patients using MTXF was low to very low. However, in some circumstances, injection of an additional local anesthetic was required for complete pain relief. The occurrence of adverse effects was low. Conclusion: All of the publications highlighted the promising properties of inhaled MTXF at low doses for acute dental pain relief.

Pain management with methoxyflurane (Penthrox®) in Swedish ambulance care – An observational pilot study

Background: Methoxyflurane (MF), a volatile anaesthetic agent is known for its analgesic properties in sub anaesthetic concentrations. It has been used as an analgesic agent for short procedures in both adults and children in the prehospital setting and in the emergency department. We conducted a pilot study to investigate the use of MF for burn dressing changes in children. Methods: A prospective case series was conducted in the paediatric burns ward amongst children aged 4–9 years. During burns dressing changes MF was administered using a hand-held patient-controlled device. An investigator monitored vital signs together with pain scores, sedation levels and levels of satisfaction of staff. Results: Twelve patients were enrolled for the study. The majority of the burn wounds were classified as partial-thickness wounds. Methoxyflurane was used as the sole agent for analgesia and sedation for the procedure. No major adverse events were noted. Analgesia and sedation levels were sufficient and appropriate respectively for the majority of the patients during the initial exposure of the wound and the application of the new dressing. However, during the scrubbing of the burn wound analgesia and sedation proved insufficient in four and seven of the patients respectively. Conclusion: In our setting the use of MF for inpatient burn wound dressing changes may be insufficient as a sole agent in the paediatric patient. We suggest it may be used as an adjunct to current practice. Further, larger studies are required to delineate the appropriate role MF can play in the paediatric burns setting.

Introduction: Inhaled low dose methoxyflurane (MEOF) was recently approved in Canada for the short-term relief of moderate to severe acute pain associated with trauma or interventional medical procedures in conscious adult patients. ADVANCE-ED is an ongoing phase IV, prospective open label study undertaken to generate real-world evidence to complement the global clinical development program through evaluation of the effectiveness of low dose MEOF in Canadian emergency departments (EDs). Methods: This multi-centre study is enrolling adult (≥18 yrs) patients with moderate to severe acute pain (NRS0-10 ≥ 4) associated with minor trauma. To address limitations from the pivotal study, this study allows patients who were excluded in the pivotal trials: namely, those with severe (≥7) pain, and those using OTC or stably dosed analgesics for other conditions, including chronic pain. Eligible patients receive a single treatment of up to 2 x 3 mL MEOF (2nd 3 mL to be provided only upon request), self-administered by the patient under medical supervision. Rescue medication is permitted at any time, if required. Results: Here we describe the patient demographics and treatment satisfaction (Global Medication Performance, GMP) at 50% enrolment (n = 49). Mean (SD) patient age is 48.0 (17.1) yrs and 55.1% are female. Mean pain (SD) reported at enrolment is 8.3 (1.5), with 73.4% of patients with NRS0-10 ≥ 8. Injuries are overwhelmingly limb trauma (87.8%). The most common type is sprain/strain (40.8%), followed by fracture (32.7%). At 5 minutes post-start of administration (STA) of MEOF, 80.4% of patients reported pain relief; this increased to 91.3% at 15 minutes, and 100% of patients reported pain relief by 30 minutes post-STA. GMP was assessed as “good”, “very good” or “excellent” by ≥80% of patients both 20 minutes post-start of administration (STA) of MEOF (83.3%) and at discharge (85.8%). When asked to what extent their expectation of pain relief had been met, 32.7% responded good, 26.5% responded “very good” and 22.4% responded “excellent”. Three quarters of enrolled patients (75.5%) did not require rescue medication. The most common (≥5%) treatment-related adverse events were dizziness (n = 14, 28.6%) and euphoric mood (n = 4, 8.2%). No serious adverse events have been reported. Conclusion: Based on 50% of the patients enrolled in this prospective, open label study, responses to inhaled low-dose MEOF are within expectation for both effectiveness and tolerability.

Introduction: Pain is a significant driver of demand in emergency care and 65% of adult patients with trauma also report moderate to severe pain. Inhaled low dose methoxyflurane (MEOF) a rapid-acting patient administered inhalational analgesic was recently approved in Canada for the short-term relief of moderate to severe acute pain associated with trauma or interventional medical procedures in conscious adult patients. This study will generate real-world evidence to complement the global clinical development program through evaluation of the effectiveness of MEOF in Canadian emergency departments. Methods: This is a phase IV, prospective open label, multi-centre study. Approximately 100 adult (≥18 yrs) patients with moderate to severe acute pain (NRS0-10≥4) associated with single system trauma will be enrolled at 5-10 EDs across Canada. Patients will receive a single treatment of up to 2 x 3 mL MEOF (2nd 3 mL to be provided only upon request), self-administered by the patient under medical supervision. Rescue medication will be permitted at any time, if required. Results: Planned Assessments and Outcome Measures: Pain will be assessed using the NRS0-10 at 4 time points: screening/triage, 5 minutes and 20 minutes post-start of administration (STA) of MEOF, and when ready for discharge. Secondary assessments will include the speed of action of analgesia (from STA of MEOF); patient and physician satisfaction with treatment (as assessed through Global Medical Performance (GMP) at 20 minutes post-STA and when ready for discharge); patient and physician fulfilment of pain relief expectations (assessed when ready for discharge); use of rescue medication and treatment-emergent adverse events. Exploratory outcomes will include the time to disposition, time to readiness for discharge and responder analysis. The primary outcome measure will be the change in pain intensity over 20 minutes from the start of administration of MEOF as measured on the NRS0-10. Conclusion: We report on the methodology of a phase IV, prospective open label, multi-centre study, evaluating the use of MEOF for the management of acute traumatic pain in Canadian Emergency Departments.

POSTER ABSTRACTThe intramuscular administration of onabotulinumtoxinA (onabotA) has been well established as an effective preventative treatment for chronic migraines (CM). Though generally well tolerated, the procedure-related pain can be a large limitation of the treatment for patients with comorbidities such as fibromyalgia.Inhaled low-dose methoxyflurane (MEOF) is a proven analgesic that has been used for over 30 years with more than 5.6 million administrations worldwide. MEOF was recently approved in Canada for moderate-severe pain related to trauma or interventional medical procedures in adults. MEOF as an analgesic for onabotA injections for CM has not been previously reported.This case series describes the use of MEOF as a procedural analgesic during intramuscular onabotA injections for CM.Ten patients who previously experienced significant pain (NRS >8) and associated moderate-severe anxiety with onabotA injections were treated with MEOF. Immediately post-procedure, patients rated their pain and anxiety. Adverse events (AE) were recorded andpatient satisfaction was assessed by asking “Are you satisfied with the treatment?” and “Would you use MEOF again?”.Post-procedure, average reported pain score was 3 and the average anxiety level was “mild”. All patients were “satisfied” with MEOF and confirmed that they would use it again. Most common AEs were dizziness and somnolence and AEs were transient (resolved within 5 minutes post administration). To our knowledge, this is the first report of the use of MEOF to facilitate intramuscular onabotA injections.

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.

ContextPain 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...

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.

ObjectiveThis study analysed the analgesic effect and changes in vital signs associated with administration of inhaled Methoxyflurane (MTX) and/or intranasal Fentanyl (INF) for prehospital management of visceral pain.MethodA retrospective, observational...

Methoxyflurane (MF), a potent volatile anesthetic, can be used as an analgesic in subanesthetic concentrations. In Australia, MF is extensively used in children and adults as an analgesic in the prehospital setting via a hand-held inhaler device. We conducted a pilot study to explore its use as a patient controlled analgesic for painful procedures in children in the emergency department (ED). This is a prospective observational case series of children aged 5 years and older requiring procedural analgesia for brief painful procedures. Pain scores, depth of sedation, adverse events and patient, parent and staff satisfaction were assessed as well as consumption of MF measured. Fourteen patients (aged 6-13 years) received MF mainly for extremity injuries. Amount of MF consumed ranged from 0.36 to 3.06 g per patient inhaled over 4-25 min. There were no serious adverse events. No patient was deeply sedated. Five patients had mild brief self-resolving adverse events including agitation, euphoria, blurry vision, dizziness and cough. Four patients with fractures with initial high pain scores (> or =6) received MF for bridging analgesia with large drops in pain scores. Four patients who required fracture reductions with initial low scores did not achieve adequate analgesia. The remaining six patients had painful procedures undertaken with satisfactory analgesia. On the basis of this small pilot study of MF use in children in the ED, this agent appears to be a powerful analgesic. MF seems most useful as a self-titrated bridging analgesic agent in patients after extremity trauma. It appears less useful as a procedural agent when patients are unable to anticipate and achieve a sufficient level of analgesia before painful stimulus infliction. Pre- and intraprocedure coaching is an important aspect of its use especially if initial pain scores are low.

Tail biopsies are routinely taken to genotype genetically modified mice. However, the effect of this procedure on the wellbeing of the animals has rarely been investigated. Thus, it has not yet been clearly demonstrated to what extent the mice suffer from tail biopsy (TB) and for how long. The aim of our study was to assess the impact of a single TB on the physiological and behavioural parameters of adult mice and to investigate whether or not anaesthesia can be beneficial. Body weight (BW) curves, daily food/water consumption and telemetric measurements of heart rate, body core temperature, and locomotor activity were recorded for three days following TB, both with and without anaesthesia with methoxyflurane (MOF) or diethylether (ether). Additionally, the impact of anaesthesia alone was characterized. TB without anaesthesia induced an increase in heart rate and locomotor activity for 1 h. Body core temperature was elevated for 2 h. In contrast, heart rate was increased for up to 4 h after anaesthesia. Body core temperature remained altered for up to 20 h after exposure to ether and for 44 h after exposure to MOF. BW was slightly reduced after MOF. Cases of death occurred exclusively under ether at a rate of 7%. Our results indicate a short-lived impact of a TB, whereas anaesthesia with either MOF or ether induced remarkable alterations in the parameters analysed. In conclusion, these types of anaesthesia did not improve mouse wellbeing following tail biopsy.

Edjtehadi, M. and Mehrabani, D. 2005. Prevention of epinephrine-induced arrhythmias with lidocaine during thiopental and methoxy flurane anesthesia in sheep. J Appl. Anim. Res., 27: 55–59. The present experiment was designed to evaluate efficacy of lidocaine for prevention of epinephrine induced arrhythmias in sheep. The results indicated that lidocaine alone could prevent these arrhythmias in non-anesthetized and thiopental and methoxyflurane anesthetized animals. The results from electrocardiogram parameters indicated hat lidocaine could not prevent the decrease in P wave, PR, QT, ST intervals and, an increase in T amplitude induced with epinephrine in such animals. Nevertheless, T amplitude in all groups increased significantly more than control value. In conclusion, we suggest that lidocaine could be safely used clinically to prevent the lethal arrhythmias, due to catecholamine-anesthetic interaction, in non-anesthetized and thiopental and methoxyflurane anesthetized animals.

To evaluate the effect of various anesthetic agents on hyperosmolar blood-brain barrier disruption (BBBD), Sprague-Dawley rats were given pentobarbital (PB), ketamine-xylazine (KX), isoflurane (IF), methoxyflurane (MF), or fentanyl-droperidol (FD) before intracarotid infusion of mannitol or saline. Physiological monitoring showed that the effects of mannitol infusion differed significantly from those of saline infusion and were associated with transient bradycardia, hypotension, metabolic acidosis, and electroencephalographic depression. With PB, KX, or IF anesthesia, we obtained excellent BBBD as evidence by 3+ Evans blue staining of the mannitol-infused cerebral hemisphere. FD anesthesia was associated with tachycardia and MF anesthesia resulted in hypotension; both showed poor Evans blue staining. Radioisotope delivery to the disrupted hemisphere averaged 0.80% of the administered 125I-albumin compared to 0.03% in the contralateral and 0.06% in control (saline-infused) hemispheres. 99mTc-glucoheptonate delivery measured 0.49% of the administered dose after BBBD, 0.03% contralaterally, and 0.05% in control hemispheres. Pharmacological manipulation to normalize the cardiac index in the FD and MF groups resulted in 3+ Evans blue staining and significantly increased delivery of albumin and glucoheptonate. This study suggests that the cardiovascular changes of these specific anesthetic agents are important in obtaining optimal hyperosmolar BBBD.

Pharmacokinetics of methoxyflurane after its intra-dermal injection as lecithin-coated microdroplets

Cardiopulmonary effects of prolonged, constant-alveolar-dose halothane (HAL) and methoxyflurane (MOF) in O2 anesthesia on spontaneously breathing dogs were determined. One hour after anesthetic induction, end-tidal concentration was set at 1.04% HAL or 0.28% MOF [each representing 1.2 minimum alveolar concentration (MAC) for dogs] and maintained for 7 h. No time-related changes were associated with MOF. However, HAL significantly (P less than 0.05) elevated cardiac output (Q) from 2 to 7 h by increasing stroke volume; mean aortic pressure (MAP) also increased with time (P less than 0.05 beginning at 5 h). Four of these dogs were studied again at least 3 wk later at a constant end-tidal dose of 1.48% HAL in O2 (1.7 MAC). Q and MAP were lower initially during 1.7 MAC than during 1.2 MAC but not after 2 h of anesthesia. The greater HAL dose initially depressed ventilation and elevated arterial partial pressure of CO2 (PaCO2) compared with the lower dose. PaCO2 continued to increase with duration of 1.7 MAC HAL, as did results of ventilatory gas volume and flow measurements.

Applied anatomy and physiology of the kidney are briefly reviewed. This includes an account of renal blood flow, glomerular filtration rate, juxtaglomerular apparatus, renal autoregulation and intra-renal blood flow distribution, tubular transport mechanisms, solute handling in proximal tubule, function of loop of Henle and distal tubule system. This section concludes with a summary of changes in tubule fluid along the length of the nephron. Acute effects of anaesthesia are reviewed in detail. Indirect effects include those on circulatory and sympathetic nervous systems, autoregulation, endocrine systems such as those involving anti-diuretic hormone, adrenaline and noradrenaline, renin-angiotensin and aldosterone. Direct effects of anaesthesia on renal function have now been confirmed both in vitro and in vivo. Delayed direct nephrotoxicity of anaesthetics relates predominantly to methoxyflurane (MOF) and its metabolism to inorganic fluoride. Other factors are MOF dose, genetics, age, enzyme induction, obesity, other nephrotoxic drugs. Clinical implications are presented. Enflurane nephrotoxicity is rare but aetiologic factors are similar to the foregoing. Isoflurane and halothane are not nephrotoxic. A consideration of the influence of anaesthetic management on the incidence and severity of postoperative acute renal failure concludes the review.

Concentrations of Methoxyf Lurane and Nitrous Oxide in Veterinary Operating Rooms

Inorganic fluoride (F-) production and renal function were assessed in six groups of Fischer 344 rats administered either methoxyflurane (MOF) or deuterated methoxyflurane (d4-MOF). One untreated and one phenobarbital (PB)-treated group were exposed for two hours to either air, 0.5 per cent (V/v) MOF, or 0.5 per cent (v/v) d4-MOF. Serum and urinary F- and serum urea nitrogen and creatinine were measured. Urine volume and urinary F- excretion were only slightly greater among MOF than among d4-MOF exposed animals. Pretreatment with PB, however, greatly enhanced F- production in MOF-exposed animals leading to marked renal impairment but only slightly enhanced F- production in d4-MOF animals leading to mild renal impairment. Thus, only in PB-pretreated animals could a biologically significant difference in nephrotoxicity be demonstrated for MOF and d4-MOF.

We have compared the combined effects of halothane, enflurane, isoflurane and methoxyflurane on caffeine-induced contractures of normal and malignant hyperthermia susceptible (MHS) skeletal muscle fascicles. We have found that caffeine contractures without and with the addition of any of these four anaesthetics are higher in MHS than in normal muscle. The differences between the normal and MHS muscle are about the same for all drug combinations. For all four anaesthetics the degree of increase of the contracture is about the same in the normal as in the MHS muscle. For both the MHS and the normal muscle the caffeine contractures are from greatest to least: halothane > isoflurane > enflurane > methoxyflurane. Examination of the relationships among the caffeine specific concentrations in the presence of the various anaesthetics shows significant differences for the comparisons of halothane with the other three anaesthetics but, for the most part, the comparisons among methoxyflurane, enflurane and isoflurane are not meaningful statistically. On a compare les effets potentialisateurs de ľhalothane, de ľenflurane, de ľisofiurane et du methoxyflurane sur la reponse a la stimulation par cafeine du muscle normal et du muscle de sujets susceptibles a ľhyperthermie maligne. La reponse a la cafeine s’est averee plus importante chez les sujets susceptibles a ľhyperthermie que chez ceux presentant un muscle normal, et ceci independamment de la presence ou de ľabsence de ľun des anesthesiques compares. La difference entre la reponse du muscle normal et celle du muscle de sujets anormaux etait a peu pres la mame avec les quatre agents etudies. Lapotentialisation de ľeffet de la cafeine etait a peu pres la mcme avec les quatre anesthesiques pour le muscle normal et ľanormal, ľhalothane etant le plus actif, suivi de ľisofiurane, de ľenflurane et du methoxyflurlane. Ľexamen des rapports entre les concentrations specifiques de cafeine en presence des quatre anesthesiques montre des differences significatives entre ľhalothane et les trois autres, mais non entre les trois autres.