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.

Methoxyflurane toxicity: historical determination and lessons for modern patient and occupational exposure.

AIM: Historically methoxyflurane was used for anaesthesia. Evidence of nephrotoxicity led to abandonment of this application. Subsequently, methoxyflurane, in lower doses, has re-emerged as an analgesic agent, typically used via the Penthrox inhaler in the ambulance setting. We review the literature to consider patient and occupational risks for methoxyflurane. METHOD: Articles were located via PubMed, ScienceDirect, Google Scholar, Anesthesiology journal and the Cochrane Library. RESULTS: Early studies investigated pharmacokinetics and considered the resulting effects to pose minimal risk. Pre-clinical rodent studies utilised a species not vulnerable to the nephrotoxic fluoride metabolite of methoxyflurane, so nephrotoxicity was not identified until almost a decade after its introduction, and was initially met with scepticism. Further evidence of nephrotoxicity led to abandonment of methoxyflurane use for anaesthesia. Subsequent research suggested there are additional risks potentially relevant to recurrent patient or occupational exposure. Specifically, greater than expected fluoride production after repeated low-dose exposure, increased fluoride production due to medication-caused hepatic enzyme induction, fluoride deposition in bone potentially acting as a slow-release fluoride compartment, which suggests a risk of skeletal fluorosis, and hepatotoxicity. Gestational risk is unclear. CONCLUSIONS: Methoxyflurane poses a potentially substantial health risk in high (anaesthetic) doses, and there are a number of pathways whereby repeated exposure to methoxyflurane in lower doses may pose a risk. Single analgesic doses in modern use generally appear safe for patients. However, the safety of recurrent patient or occupational healthcare-worker exposure has not been confirmed, and merits further investigation.

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.

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.

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.

Effect of anesthetics on pathogenesis of experimentally induced murine pneumococcal pneumonia.

BACKGROUND AND PURPOSE: To define the effects of three commonly used anesthetic agents--sodium pentobarbital given intraperitoneally, and inhaled halothane and methoxyflurane--on the pathogenesis of pneumococcal pneumonia and bacteremia in an experimental murine model. METHODS: Swiss outbred mice were anesthetized with either sodium pentobarbital, halothane, or methoxyflurane before intranasal infection with Streptococcus pneumonia. At defined times after infection, bacterial numbers in lungs and blood, markers of acute lung injury, and lung cytokine levels were compared. RESULTS: Mice anesthetized with inhaled halothane or methoxyflurane prior to intranasal inoculation with type-2 Streptococcus pneumoniae developed pneumonia and bacteremia distinctly different from that in mice anesthetized by intraperitoneal (IP) administration of sodium pentobarbital. Mice having brief exposure to inhaled halothane or methoxyflurane had significantly greater numbers of bacteria in lungs and blood 48 hours after inoculation, compared with mice anesthetized by IP administration of pentobarbital. Also, mice inhaling halothane had significantly decreased activities of pro-inflammatory cytokines interleukin 6 and tumor necrosis factor-alpha in lung homogenates at 24 hours after inoculation, compared with those given pentobarbital IP. CONCLUSION: Effects of anesthesia on murine models of pneumonia should be considered in the design and interpretation of studies of pneumococcal pathogenesis.

Maternal and perinatal risk factors for Wilms' tumor: a nationwide nested case-control study in Sweden.

This report describes maternal and perinatal risk factors for Wilms' tumor analyzed in a case-control study nested in a nationwide cohort in Sweden. The Swedish National Cancer Registry ascertained 110 cases from among successive birth cohorts from 1973 through 1984, identified by the Swedish Medical Birth Registry, the latter based on medical records. From the Birth Registry, we matched 5 controls without cancer to each case by sex and date of birth. Wilms'-tumor children were more likely to have mothers who had been exposed to penthrane (methoxyflurane) anesthesia during delivery than mothers of controls (odds ratio (OR) = 2.4; 95% confidence interval (CI) 1.1 to 5.1); this excess risk was higher in females than males and increased with age at diagnosis. Wilms'-tumor cases were also more likely to have had physiologic jaundice (OR = 2.3; 95% CI 1.1 to 5.0). Higher parity of the mother decreased the risk of Wilms' tumor among females (OR = 0.7; 95% CI 0.5 to 1.0). We were unable to confirm the reported increased risks of Wilms' tumor for those with high birth weights or with a maternal history of hypertension or fluid retention during pregnancy, nor did we find any association with mother's age at delivery, previous stillbirth, previous live birth, gestational length or height of the child.

Enflurane hepatotoxicity. A clinicopathologic study of 24 cases.

Analysis of 24 cases of enflurane anesthesia-associated hepatic injury shows that the clinical, biochemical, and histologic features are similar to those seen with halothane- and methoxyflurane-related hepatitis. Postoperative fever was the presenting symptom in 19 patients. Jaundice occurred in 19 patients after a mean latent period of 8 days. Sixteen patients had been previously exposed to enflurane or halothane, and the latent period from exposure to the onset of symptoms or jaundice was shortened in these patients. There were five fatalities among the entire group. Liver biopsy most characteristically showed centrilobular necrosis, occasionally with ballooning degeneration and fatty change. The presumed mechanism of injury is metabolic idiosyncracy, and prior exposure to a haloalkane anesthetic may increase the risk of hepatic injury after enflurane administration.

Hepatitis and renal tubular acidosis after anesthesia with methoxyflurane.

A 69-year-old man operated for acute cholecystitis under methoxyflurane anesthesia developed postoperatively a hepatic insufficiency syndrome and renal tubular acidosis. Massive bleeding appeared during surgery which lasted for six hours. Postoperative evolution under supportive therapy was favourable. Complete recovery was confirmed by repeated controls performed over a period of one year after surgery.

Pathophysiology of renal concentrating defects.

A number of advances which took place during the last decade have increased our understanding of the physiology and pathophysiology of urinary concentrating defects. The development of a highly sensitive radioimmunoassay for plasma vasopressin concentration has shed new light on vasopressin control mechanisms. The cellular action of vasopressin in biological membranes has been studied by various techniques. The role of adenylate cyclase, cyclic adenosine monophosphate (cAMP), microtubules, and microfilaments, in the response of vasopressin-sensitive membranes is now partially understood. New models of countercurrent multiplication systems, in which urea plays a prominent role, offer a better explanation of certain experimental facts. Such advances had permitted a better understanding of clinical conditions characterized by concentrating defects, including hyperkalemia, hypercalcemia, parenchymal renal disease, obstructive renal disease, and polyuria induced by certain drugs.

Energy metabolism in anesthetized children with burns.

Energy dynamics in 10 burned children were studied to determine cause and effect relationships between rates of heat production, heat loss and plasma catecholamine concentrations when thermoregulatory responses were depressed by methoxyflurane anesthesia. Rapid cooling of the burned children was due to increased heat loss during the period of anesthesia. Heat production increased significantly, although not enough to counterbalance the increased heat loss reflecting a block in central thermoregulation by general anesthesia. Mean plasma catecholamine concentrations decreased during general anesthesia as compared with baseline values. Heat production attempted to track heat loss during a period in which plasma catecholamine levels declined. An increased rate of heat loss is concluded to be primary stimulus for increased metabolic acitvity after thermal injury.

Thermoregulatory defect in rats during anesthesia.

Male rats of the Fischer 344, Sprague-Dawley, Brattleboro, and Wistar strains, balb/C mice, and Hartley guinea pigs were divided into 2 treatment groups. One group drank tap water while the other group drank water containing 1 mg/ml of phenobarbital. Animals were exposed to sevoflurane, enflurane, methoxyflurane, isoflurane, or halothane in a closed chamber. In some of the experiments, soda lime was included and in other the chamber was heated to 39 degrees C with a water blanket. Eighty-six percent (43/50) of Fischer 344 rats treated with phenobarbital and esposed to either sevoflurane or enflurane, in the presence of either soda lime or exogenous heat, died within a few hours after exposure. Fischer 344 rats and rats of other strains drinking phenobarbital water and exposed to methoxyflurane were affected, but to a lesser degree. Rats drinking ordinary tap water and phenobarbital-treated rats not exposed to either soda lime or exogenous heat were unaffected. Guinea pigs and mice also were unaffected. We postulate that the toxic response represents a species-specific thermoregulatory defect, precipitated by heat and occurring in rats treated with phenobarbital in combination with sevoflurane, endlurane, or methoxyflurane.