Inhaled analgesics for the treatment of prehospital acute pain-A systematic review.

BACKGROUND: Many prehospital emergency patients receive suboptimal treatment for their moderate to severe pain. Various factors may contribute. We aim to systematically review literature pertaining to prehospital emergency adult patients with acute pain and the pain-reducing effects, adverse events (AEs), and safety issues associated with inhaled analgetic agents compared with other prehospital analgesic agents. METHODS: As part of an initiative from the Scandinavian Society of Anaesthesia and Intensive Care Medicine, we conducted a systematic review (PROSPERO CRD42018114399), applying the PRISMA guidelines, Grading of Recommendations Assessment, Development, and Evaluation (GRADE), and Cochrane methods, searching the Cochrane Library, Epistemonikos, Centre for Reviews and Dissemination, PubMed, and EMBASE databases (updated March 2024). Inclusion criteria were the use of inhaled analgesic agents in adult patients with acute pain in the prehospital emergency care setting. All steps were performed by minimum of two individual researchers. The primary outcome was pain reduction; secondary outcomes were speed of onset, duration of effect, and relevant AEs. RESULTS: We included seven studies (56,535 patients in total) that compared inhaled agents (methoxyflurane [MF] and nitrous oxide [N2O]) to other drugs or placebo. Study designs were randomized controlled trial (1; n = 60), randomized non-blinded study (1; n = 343), and randomized open-label study (1; n = 270). The remaining were prospective or retrospective observational studies. The evidence according to GRADE was of low or very low quality. No combined meta-analysis was possible. N2O may reduce pain compared to placebo, but not compared to intravenous (IV) paracetamol, and may be less effective compared to morphine and MF. MF may reduce pain compared to paracetamol, ketoprofen, tramadol, and fentanyl. Both agents may be associated with marked but primarily mild AEs. CONCLUSION: We found low-quality evidence suggesting that both MF and N2O are safe and may have a role in the management of pain in the prehospital setting. There is low-quality evidence to support MF as a short-acting single analgesic or as a bridge to IV access and the administration of other analgesics. There may be occupational health issues regarding the prehospital use of N2O.

Inhaled Analgesia in Dermatologic Settings: A Comprehensive Overview of Methoxyflurane.

Pain management is an important aspect of dermatologic procedures, which are typically performed on awake patients in outpatient settings. The first-line modalities for procedural analgesia during most dermatologic procedures are topical and injectable local anesthetics, such as lidocaine. However, in some medical and cosmetic dermatologic procedures, pain cannot be effectively managed with local anesthetics due to procedure-specific lack of efficacy, large treatment surface areas, high dosage requirements, allergies, or other contraindications. In these circumstances, methoxyflurane inhalers may be highly beneficial. Methoxyflurane (Penthrox®) has demonstrated efficacy for providing pain relief in randomized controlled trials in patients who presented to emergency departments with acute trauma-related pain, as well as in patients undergoing painful procedures for other medical indications. The limited side effect profile, ease of patient self-administration, rapid onset and quick resolution of central nervous system effects following cessation makes methoxyflurane an ideal choice for analgesia during outpatient dermatologic procedures. This review provides an overview of the supporting evidence for methoxyflurane inhalers and clinical commentary on potential indications for methoxyflurane use in dermatology.

Methoxyflurane analgesia for outpatient hysteroscopy: A double-blind, randomised, controlled trial.

BACKGROUND: Despite clinical and economic benefits, pain during outpatient hysteroscopy (OPH) remains a barrier to use. There is a lack of evidence to support routine use of one analgesic over another versus no analgesic. AIMS: To study the efficacy and safety of methoxyflurane analgesia during OPH. MATERIALS AND METHODS: A single-centre, randomised, double-blind, placebo-controlled experiment was performed; 90 patients were randomly assigned (1:1). Participants allocated to the treatment group (cases) received 3 mL of methoxyflurane through an inhaler. The control group received a placebo. The primary outcome was a mean difference in pain, via a change in Visual Analog Scale (VAS) score from baseline at diagnostic hysteroscopy. Secondary outcomes were a mean difference in VAS score with any subsequent operative procedures; a mean difference in VAS score at 15 min post-procedure; participant and clinician-reported adverse effects and events; and participant-reported procedure acceptability, adjuvant nitrous oxide (N2O2) use and a composite of 'distress'. RESULTS: During diagnostic hysteroscopy, there was a mean difference of 11.5 mm/100 (95% confidence interval (CI) 0.08-22.95), P = 0.05, with the lower score in the cases, compared with controls. During subsequent operative procedures, there was a mean difference of 15 mm/100 (95% CI 2.71-28.22), P = 0.02, with the lower pain score in the cases, compared with controls. There was no significant difference in pain 15 min post-procedure, participant- and clinician- reported adverse effects and events, procedure acceptability and the 'distress' composite. CONCLUSIONS: Methoxyflurane significantly reduced pain during OPH compared with placebo, for diagnostic as well as operative procedures. Furthermore, methoxyflurane was well tolerated, with no adverse events.

Literature review on the use of methoxyflurane in the management of pain in cancer-related procedures.

INTRODUCTION: Self-administered methoxyflurane, also known as Penthrox, at a sub-anesthetic dose is a short-term, fast-acting, and safe analgesic that may provide suitable pain relief for cancer patients. This review aims to compile the existing evidence on methoxyflurane and its efficacy in reducing pain during cancer-related procedures. METHODS: A literature search was conducted through OVID Medline and Embase. The search was limited to articles published between 2012 and 2021 and studies were included if they assessed the efficacy of methoxyflurane to reduce pain in cancer-related procedures. All types of cancer were included. RESULTS: The literature search yielded seven studies published between 2012 and 2021. The studies analyzed assessed methoxyflurane use in prostate biopsy, colonoscopy, removal of brachytherapy rods, and bone marrow biopsy. Various research designs were employed, including three randomized controlled trials, two prospective observational studies, one retrospective, and one non-randomized controlled trial. In all, methoxyflurane has a demonstrated ability to reduce pain in these procedures. CONCLUSION: In the limited studies available in evaluating the efficacy of methoxyflurane for reducing procedural pain during cancer-related procedures, all have demonstrated clinical equivalency or superiority. Pain relief appears to be equivalent however methoxyflurane overcomes the standard limitations of respiratory sedation and has demonstrated quicker procedural recovery times than traditional sedation methods. The accumulated data to date supports the use of methoxyflurane which can supplement or supplant current methods of analgesia in cancer-related procedures.

How I Do It: Penthrox in Urology.

Penthrox is a portable handheld inhaler that delivers a low dose of methoxyflurane - an anesthetic with analgesic effects, rapid onset of action, and a favorable side-effect profile. It has been widely used for acute pain management in Australia for the past 40 years. Currently, it is approved for use in over 55 countries, including Canada. Prospective randomized studies highlight Penthrox analgesic effectiveness and safety profile for emergency, prehospital and outpatient settings. In addition, the use of multimodal analgesia, specifically Penthrox, can play an important role in the analgesic management of urological procedures, such as prostatic biopsies and office-based minimally invasive surgical therapies. Herein readers will familiarize themselves with Penthrox, significant studies, and technique used for outpatient urological procedures.

Time to Reconsider Analgesia in Mass Casualty Incidents.

The provision of analgesia in mass casualty incidents has traditionally been viewed as low-priority and reserved for later stages of care. Poor pain management is commonplace in trauma victims, and inadequate acute pain management can hinder evacuation efforts and may lead to the development of chronic pain and posttraumatic stress disorder. New, safe, and simple methods for administering quality analgesia have proven to be safe and effective in the prehospital setting and, as such, could easily be implemented into mass casualty incident protocols and allow for analgesia at earlier stages in such incidents, thereby improving patient care.

'Pain-free TRUS B': a phase 3 double-blind placebo-controlled randomized trial of methoxyflurane with periprostatic local anaesthesia to reduce the discomfort of transrectal ultrasonography-guided prostate biopsy (ANZUP 1501).

OBJECTIVE: To determine whether the addition of inhaled methoxyflurane to periprostatic infiltration of local anaesthetic (PILA) during transrectal ultrasonography-guided prostate biopsies (TRUSBs) improved pain and other aspects of the experience. PATIENTS AND METHODS: We conducted a multicentre, placebo-controlled, double-blind, randomized phase 3 trial, involving 420 men undergoing their first TRUSB. The intervention was PILA plus a patient-controlled device containing either 3 mL methoxyflurane, or 3 mL 0.9% saline plus one drop of methoxyflurane to preserve blinding. The primary outcome was the pain score (0-10) reported by the participant after 15 min. Secondary outcomes included ratings of other aspects of the biopsy experience, willingness to undergo future biopsies, urologists' ratings, biopsy completion, and adverse events. RESULTS: The mean (SE) pain scores 15 min after TRUSB were 2.51 (0.22) in those assigned methoxyflurane vs 2.82 (0.22) for placebo (difference 0.31, 95% confidence interval [CI] -0.75 to 0.14; P = 0.18). Methoxyflurane was associated with better scores for discomfort (difference -0.48, 95% CI -0.92 to -0.03; P = 0.035, adjusted [adj.] P = 0.076), whole experience (difference -0.50, 95% CI -0.92 to -0.08; P = 0.021, adj. P = 0.053), and willingness to undergo repeat biopsies (odds ratio 1.67, 95% CI 1.12-2.49; P = 0.01) than placebo. Methoxyflurane resulted in higher scores for drowsiness (difference +1.64, 95% CI 1.21-2.07; P < 0.001, adj. P < 0.001) and dizziness (difference +1.78, 95% CI 1.31-2.24; P < 0.001, adj. P < 0.001) than placebo. There was no significant difference in the number of ≥ grade 3 adverse events. CONCLUSIONS: We found no evidence that methoxyflurane improved pain scores at 15 min, however, improvements were seen in patient-reported discomfort, overall experience, and willingness to undergo repeat biopsies.

Efficacy and safety of methoxyflurane (Penthrox) for pain control during water vapor thermal therapy (Rezum) for benign prostatic enlargement.

INTRODUCTION: The safety and efficacy of low dose methoxyflurane disposable inhaler (Penthrox) was assessed in this study of men undergoing Rezum water vapor thermal therapy (WVTT). MATERIAL AND METHODS: An open-labeled, single-center study was conducted to demonstrate the safety and efficacy of using methoxyflurane inhaler during a Rezum procedure. Patients assessed current pain intensity using a 10-point Visual Analog Scale (VAS) of Pain at 4 timepoints including (1) before any medication, (2) initially after insertion of the rigid cystoscope and before any Rezum treatment, (3) immediately after final injection of Rezum treatment and (4) at discharge. Patients were asked to fill out the Treatment Satisfaction Questionnaire for Medication (TSQM 1.4) and one question about pain relief at discharge. Treating physician also completed the TSQM 1.4. RESULTS: Ten patients were recruited. Median prostate volume was 53.4 cc (range 24-158 cc). Patients received a median of 10.5 Rezum injections, with a median procedure time of 4.5 minutes. Median VAS scores were 0, 0.1, 0 (primary efficacy outcome) and 0 (out of scale of 10) at the 4 timepoints, respectively. TSQM scores on effectiveness, side effects, convenience and global median satisfaction rated by patients were respectively 69.4, 100.0, 77.8 and 82.1 (out of scale of 100). Treatment satisfaction on pain relief was rated as 4.0 (very good). There were no observed adverse events. CONCLUSIONS: Methoxyflurane inhaler (Penthrox) was low cost, rapid, feasible and easy to administer as a pain management strategy for Rezum therapy. Further data from a larger comparative study will be conducted.

Evaluation of the effectiveness and costs of inhaled methoxyflurane versus usual analgesia for prehospital injury and trauma: non-randomised clinical study.

BACKGROUND: We aimed to investigate clinical benefits and economic costs of inhaled methoxyflurane when used by ambulance staff for prehospital emergency patients with trauma. Comparison is to usual analgesic practice (UAP) in the UK in which patient records were selected if treatment had been with Entonox® or intravenous morphine or intravenous paracetamol. METHODS: Over a 12-month evaluation period, verbal numerical pain scores (VNPS) were gathered from adults with moderate to severe trauma pain attended by ambulance staff trained in administering and supplied with methoxyflurane. Control VNPS were obtained from ambulance database records of UAP in similar patients for the same period. Statistical modelling enabled comparisons of methoxyflurane to UAP, where we employed an Ordered Probit panel regression model for pain, linked by observational rules to VNPS. RESULTS: Overall, 96 trained paramedics and technicians from the East Midlands Ambulance Service NHS Trust (EMAS) prepared 510 doses of methoxyflurane for administration to a total of 483 patients. Comparison data extracted from the EMAS database of UAP episodes involved: 753 patients using Entonox®, 802 patients using intravenous morphine, and 278 patients using intravenous paracetamol. Modelling results included demonstration of faster pain relief with inhaled methoxyflurane (all p-values < 0.001). Methoxyflurane's time to achieve maximum pain relief was estimated to be significantly shorter: 26.4 min (95%CI 25.0-27.8) versus Entonox® 44.4 min (95%CI 39.5-49.3); 26.5 min (95%CI 25.0-27.9) versus intravenous morphine 41.8 min (95%CI 38.9-44.7); 26.5 min (95%CI 25.1-28.0) versus intravenous paracetamol 40.8 (95%CI 34.7-46.9). Scenario analyses showed that durations spent in severe pain were significantly less for methoxyflurane. Costing scenarios showed the added benefits of methoxyflurane were achieved at higher cost, eg versus Entonox® the additional cost per treated patient was estimated to be £12.30. CONCLUSION: When administered to adults with moderate or severe pain due to trauma inhaled methoxyflurane reduced pain more rapidly and to a greater extent than Entonox® and parenteral analgesics. Inclusion of inhaled methoxyflurane to the suite of prehospital analgesics provides a clinically useful addition, but one that is costlier per treated patient.

Usability and effectiveness of inhaled methoxyflurane for prehospital analgesia - a prospective, observational study.

BACKGROUND: Pain relief in the prehospital setting is often insufficient, as the administration of potent intravenous analgesic drugs is mostly reserved to physicians. In Australia, inhaled methoxyflurane has been in routine use by paramedics for decades, but experience in Central European countries is lacking. Thus, we aimed to assess whether user friendliness and effectiveness of inhaled methoxyflurane as sole analgesic match the specific capabilities of local ground and air-based EMS systems in Austria. METHODS: Observational study in adult trauma patients (e.g. dislocations, fracture or low back pain following minor trauma) with moderate to severe pain (numeric rating scale [NRS] ≥4). Included patients received a Penthrop® inhaler containing 3 mL of methoxyflurane (maximum use 30 min). When pain relief was considered insufficient (NRS reduction < 3 after 10 min), intravenous analgesics were administered by an emergency physician. The primary endpoint was effectiveness of methoxyflurane as sole analgesic for transport of patients. Secondary endpoints were user friendliness (EMS personell), time to pain relief, vital parameters, side effects, and satisfaction of patients. RESULTS: Median numeric pain rating was 8.0 (7.0-8.0) in 109 patients. Sufficient analgesia (reduction of NRS ≥3) was achieved by inhaled methoxyflurane alone in 67 patients (61%). The analgesic effect was progressively better with increasing age. Side effects were frequent (n = 58, 53%) but mild. User satisfaction was scored as very good when pain relief was sufficient, but fair in patients without benefit. Technical problems were observed in 16 cases (14.7%), mainly related to filling of the inhaler. In every fifth use, the fruity smell of methoxyflurane was experienced as unpleasant. No negative effects on vital signs were observed. CONCLUSION: In prehospital use, inhaled methoxyflurane as sole analgesic is effective for transport of trauma patients (62%) with moderate to severe pain. Older patients benefit especially from inhaled methoxyflurane. Side effects are mild and vital parameters unaffected. Thus, inhaled methoxyflurane could be a valuable device for non-physician EMS personnel rescue services also in the central Europe region.

[Volatile anesthetics for prehospital analgesia by paramedics-An overview]. / Volatile Anästhetika zur präklinischen Analgesie durch Rettungssanitäter ­ Eine Übersicht.

Treatment of acute pain is a central task in emergency medicine. Yet, prehospital pain relief is often insufficient or delayed since the administration of potent intravenous analgesic drugs (such as opioids) is mostly limited to physicians due to legal restrictions or training deficiencies in Germany and Austria. Frequently, prehospitally operating emergency physicians have to be demanded later for anguished patients limiting disposability of physicians for patients who are in a potentially life-threatening condition. Thus, inhaled analgesics could represent an interesting alternative.A mixture of 50% nitrous oxide and 50% oxygen (N2O, Livopan®) has been available in Germany and Austria for several years; however, prehospital use of Livopan has been merely realized and only one trial has been published. In addition, methoxyflurane (Penthrop®), a volatile anesthetic from the group of the dialkyl esters (2-dichloro-1:1-difluoroethyl-methyl-ester) was approved for the treatment of moderate to severe pain following trauma in adults in many European countries in recent years and was brought onto the market in Austria in 2018. Several in-hospital trials demonstrated high effectiveness in this setting.This article discusses the effects and prehospital areas of application of both substances in the light of the existing literature. We provide a narrative overview of the current study situation and report on a recently performed prehospital application study of methoxyflurane (Penthrop®) from Austria.The need for pressurized gas cylinders for the use of N2O represents a certain limitation in prehospital use. Furthermore, in certain injuries such as of the inner ear or a pneumothorax N2O should not be used and the risk of diffusion hypoxemia has to be addressed. Users should be particularly careful and limit the use in alcohol addicts and vegans. The advances of N2O are that it is odorless, has a fast onset of action, the usability in patients over 1 month old and has stabilizing effects on the circulation. Plenty of literature regarding prehospital as well as in-hospital use of nitrous oxide in emergency, obstetric and pediatric settings show its effectiveness as a single drug as well as in combination with other analgesics, such as paracetamol or various opioids. Its long tradition in Anglo-American countries is also based on its safety and low rate of side effects.Methoxyflurane is easier to store and handle and may be slightly more effective in severe pain after trauma; however, its approval is restricted to adults, where it works significantly better with increasing age, based on the declining minimal alveolar concentration (MAC) of all inhaled anesthetics with increasing age. Furthermore, decades of use of inhaled methoxyflurane in Australia have shown the drug is effective, safe and low in side effects and has a broad spectrum of applications. The use of methoxyflurane is limited in patients with severe hepatic or renal insufficiency and the characteristic odor has been described as unpleasant by some patients. In Europe, three large in-hospital trials showed strong pain relief in trauma patients, even comparable to opioids.Overall, based on the current evidence, the use of nitrous oxide and even more of methoxyflurane may be recommended also for prehospital use by skilled paramedics.

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.

Frequency and duration of ambulance officer exposure to nitrous oxide and methoxyflurane in New Zealand.

OBJECTIVE: Nitrous oxide (Entonox®) and methoxyflurane (Penthrox®) are inhaled analgesics administered in paramedicine. Occupational exposure to nitrous oxide has been associated with negative health effects, and may inhibit professional capability. The effect of occupational exposure to methoxyflurane has not yet been clearly determined. This study identifies the frequency and duration of ambulance officer (AO) occupational exposure to nitrous oxide and methoxyflurane to provide a foundation for future assessments of occupational toxicity risk. METHODS: A retrospective database review of Patient Report Forms (PRFs) in 11 months between February 2016 and February 2018 was conducted. Nitrous oxide was available for the first 5 months studied, followed by 6 months methoxyflurane availability. AO-specific measures of attendance, rate of inhaled analgesic use, and duration of analgesic use were determined. Subgroup analysis by AO qualification and rostered work hours was undertaken. RESULTS: A total of 46,759 PRFs were examined, identifying 1,033 cases of nitrous oxide administration and 1456 cases of methoxyflurane was administration. There was a significant increase in the proportion of cases where inhaled analgesia was administered following the replacement of nitrous oxide with methoxyflurane. Relative risk of exposure to methoxyflurane compared with nitrous oxide was 1.22, while median duration of each exposure remained unchanged (32 vs. 33 min). CONCLUSIONS: Methoxyflurane via the Penthrox® inhaler was more likely to be administered than nitrous oxide. Most AOs are infrequently exposed to inhaled analgesics and are exposed for durations slightly greater than previously reported. Relative risk of exposure was greatest for lower-qualified AOs. Peak number of exposures and duration values suggest a subset of AOs with higher occupational health risk.

[Use of methoxyflurane on acute pain during burn dressing in adult consultation]. / Utilisation du méthoxyflurane sur la douleur aiguë lors du pansement en consultation des brûlés adultes.

INTRODUCTION: The objective was to compare the short-term efficacy of methoxyflurane vs. MEOPA on acute pain during burn dressing in consultation, the secondary outcome was to assess the patient's comfort and the quality of the dressing performed. MATERIALS AND METHODS: Monocentric, prospective study from April 2018 to January 2019. Men and women>18 years presenting acute burn on<10% SCT were included. A pain≥4 on the numerical scale (from 0 to 10) at the beginning of the treatment established the indication of methoxyflurane or MEOPA, with randomization done by a nurse. The following data were collected: burn description, performed debridement, pain assessment by numerical scale: on arrival, at the beginning of care, after 6 to 10 inhalations for methoxyflurane or 3 to 4minutes of inhalation for MEOPA and at the end of care. RESULTS: Sixty patients were included, 30 in each group. There was a decrease of -2.47 points of numerical scale when initiating methoxyflurane against -1.53 points for MEOPA (P=0.08). Patients were significantly less painful when stopping treatment in the methoxyflurane group -4 points vs -2 points (P=0.001). Methoxyflurane significantly improved the debridement of the burn (P=0.018). CONCLUSION: Methoxyflurane is more effective than MEOPA in acute pain in burn dressing, improved patient comfort, and improved dressing quality.

A review of the safety and efficacy of inhaled methoxyflurane as an analgesic for outpatient procedures.

Methoxyflurane delivered via a hand-held inhaler is a proven analgesic which has been used in Australasia for emergency relief of trauma associated pain since the 1970s. The agent is self-administered by the patient under the supervision of trained personnel. More than 5 million patients have received inhaled methoxyflurane without significant side effects. Methoxyflurane is also licensed in Australasia for the relief of pain in monitored conscious patients requiring analgesia for minor surgical procedures. Recent clinical studies undertaken in a variety of outpatient settings, including colonoscopy, prostate biopsy, dental procedures, bone marrow biopsy, and the management of burns dressings, indicate that inhaled methoxyflurane has significant analgesic activity, without producing deep sedation or respiratory depression. Return to full psychomotor activity is rapid. Thus, methoxyflurane may be a suitable and well-tolerated alternative to traditional i.v. sedative agents for outpatient medical and surgical procedures. There are direct advantages to the patient in terms of rapid recovery and an early return to normal activities, and significant benefits for outpatient departments in terms of cost saving and rate of throughput. Further randomised controlled trials comparing the efficacy, safety, and cost-effectiveness of inhaled methoxyflurane against traditional i.v. sedative techniques are currently in progress.

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.

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.

Skeletal fluorosis secondary to methoxyflurane use for chronic pain.

Skeletal fluorosis is rare and occurs secondary to chronic high amounts of fluoride consumption, manifesting as diffuse osteosclerosis, skeletal pain, connective tissue calcification, and increased fracture risk. Methoxyflurane is a volatile, fluorinated hydrocarbon-inhaled analgesic, and the maximum recommended dose is 15 mL (99.9 % w/w) per wk. A rodent study found increased skeletal fluoride after methoxyflurane exposure. However, skeletal fluorosis secondary to methoxyflurane use in humans has rarely been reported. We present the case of a 47-yr-old female with diffuse osteosclerosis secondary to fluorosis from methoxyflurane use for chronic pain, presenting with 3 yr of generalized bony pain and multiple fragility fractures. Lumbar spine BMD was elevated. CT and radiographs demonstrated new-onset marked diffuse osteosclerosis, with calcification of interosseous membranes and ligaments, and a bone scan demonstrated a grossly increased uptake throughout the skeleton. Biochemistry revealed an elevated alkaline phosphatase and bone turnover markers, mild secondary hyperparathyroidism with vitamin D deficiency, and mild renal impairment. Zoledronic acid, prescribed for presumed Paget's disease, severely exacerbated bony pain. Urinary fluoride was elevated (7.3 mg/L; reference range < 3.0 mg/L) and the patient revealed using methoxyflurane 9 mL per wk for 8 yr for chronic pain. A decalcified bone biopsy revealed haphazardly arranged cement lines and osteocytes lacunae and canaliculi, which was consistent with an osteosclerotic process. Focal subtle basophilic stippling around osteocyte lacunae was suggestive of fluorosis. Although fluorosis is not a histological diagnosis, the presence of compatible histology features was supportive of the diagnosis in this case with clinical-radiological-pathological correlation. Skeletal fluorosis should be considered as a cause of acquired diffuse osteosclerosis. Methoxyflurane should not be recommended for chronic pain. The risk of repeated low-dose exposure to fluoride from methoxyflurane use as analgesia may be greater than expected, and the maximum recommended dose for methoxyflurane may require re-evaluation to minimize skeletal complications. Abbreviated abstract: Skeletal fluorosis is rare and occurs secondary to chronic high amounts of fluoride consumption, manifesting as diffuse osteosclerosis, skeletal pain, connective tissue calcification, and increased fracture risk. We present the case of a 47-yr-old female with skeletal fluorosis secondary to long-term methoxyflurane for chronic pain. The risk of repeated low-dose exposure to fluoride from methoxyflurane use for analgesia may be greater than expected, and the maximum recommended dose for methoxyflurane may require re-evaluation to minimize skeletal complications.

MethOxyfluraNe in InTerventiOnal Radiology (MONITOR): A randomised controlled trial.

INTRODUCTION: Procedural sedation and pain management in interventional radiology (IR) are of critical importance to successful outcomes but remain under-researched. Methoxyflurane has been previously used in some minor procedures with several advantages including rapid onset and offset and a good safety profile. The purpose of this study was to evaluate methoxyflurane for procedures in IR. METHODS: A randomised, double-blind, placebo-controlled trial was performed between October 2021 and November 2022. Patients presenting for portacath insertion, portacath removal or solid organ biopsy were randomised to either methoxyflurane or placebo. Three hundred and fourteen patients were enrolled in total. Patients were supplied with one Penthrox inhaler containing either 3 mL methoxyflurane or placebo. The primary endpoints of the study were change in pain and anxiety scores compared with baseline, measured on a standardised visual analogue scale (VAS) pre-procedure, at 5-min intervals during the procedure and post-procedure. Baselines scores were controlled for in the statistical analysis. Safety analysis was also performed. RESULTS: One hundred and sixty-nine patients received methoxyflurane and 145 received placebo. Baseline characteristics were similar between the two groups. The methoxyflurane group had lower pain and anxiety scores throughout the procedure (P < 0.001) with 2.5 times less pain (VAS 1.08/10) and 1.6 times less anxiety (VAS 0.97/10) on average. Lower post-procedure pain (mean 0.72 vs 1.44; P < 0.001) and anxiety (mean 0.55 vs 1.13; P = 0.008) were also observed with methoxyflurane. There were no drug or major procedure-related adverse events. CONCLUSION: The results of this study suggest that methoxyflurane provides safe and effective analgesia and anxiolysis for some procedures in IR.