Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Medical Developments UK Limited, c/o Price Bailey LLP, Causeway House, 1 Dane Street, Bishops Stortford, Herts CM23 3BT, United Kingdom
Pharmacotherapeutic group: Analgesics, other analgesics and antipyretics
ATC code: N02BG09
The mechanism by which methoxyflurane exerts its analgesic activity has not been fully elucidated.
Methoxyflurane belongs to the fluorinated hydrocarbon group of volatile anaesthetic agents and provides analgesia when inhaled at low concentrations in conscious patients. At analgesic therapeutic doses pain relief, some decrease in blood pressure may occur, which may be accompanied by bradycardia, the cardiac rhythm is usually regular, although drowsiness may occur. The myocardium is only minimally sensitised to adrenaline by methoxyflurane.
The efficacy and safety of PENTHROX was demonstrated in a randomised, double-blind, multi-centre, placebo controlled study in the treatment of acute pain in patients with minor trauma presenting to an Emergency Department. 300 patients were recruited (151 received methoxyflurane and 149 received placebo in a 1:1 ratio). Patients with a pain score of ≥4 to ≤7 on the Numerical Rating Scale were eligible for the study. The mean pain scores (Visual Analogue Scale (VAS)) observed at baseline were similar in the methoxyflurane (64.8) and placebo (64.0) groups. The primary efficacy variable, the estimated mean change in VAS pain from Baseline to 5 min, 10 min, 15 min and 20 min, was greater for the methoxyflurane group (-23.1, -28.9, -34.0 and -35.0 respectively) when compared to the placebo group (-11.3, -14.8, -15.5 and -19.0 respectively). Overall, there was a highly significant difference between the methoxyflurane and placebo group (estimated treatment effect -15.1; 95% CI -19.2 to -11.0; p<0.0001). The greatest treatment effect was seen at 15 minutes (estimated treatment effect of -18.5). An analysis was undertaken where a responder was defined as a patient who experienced at least a 30% improvement from baseline VAS pain score. Results of this analysis indicated that percentage of responders at 5, 10, 15 and 20 mins was significantly greater for the methoxyflurane group (51.0%, 57.7%, 63.8%, 63.8%) when compared to the placebo group (23.5%, 30.9%, 33.6%, 37.6%), with p<0.0001 at each time-point. A total of 126 patients (84.6%) in the methoxyflurane group experienced their first pain relief after 1-10 inhalations in comparison to 76 patients (51%) in the placebo group.
Methoxyflurane has the following partition coefficients:
Methoxyflurane enters the lungs in the form of a vapour and is rapidly transported into the blood, therefore there is a rapid onset of analgesic action.
Methoxyflurane has a high oil/gas coefficient hence methoxyflurane is highly lipophilic. Methoxyflurane has great propensity to diffuse into fatty tissues where it forms a reservoir from which it is released slowly over days.
Biotransformation of methoxyflurane occurs in man. Methoxyflurane is metabolised by dechlorination and o-demethylation in the liver, mediated by CYP 450 enzymes particularly CYP 2E1 and CYP 2A6. Methoxyflurane is metabolised to free fluoride, oxalic acid, difluoromethoxyacetic acid, and dichloroacetic acid. Both free fluoride and oxalic acid can cause renal damage at concentrations higher than those achievable with single analgesic dose use. Methoxyflurane is more susceptible to metabolism than other halogenated methyl ethyl ethers and has greater propensity to diffuse into fatty tissues. Hence methoxyflurane is released slowly from this reservoir and becomes available for biotransformation for many days.
Approximately 60% of methoxyflurane uptake is excreted in the urine as organic fluorine, fluoride and oxalic acid; the remainder is exhaled unaltered or as carbon dioxide. Higher peak blood fluoride levels may be obtained earlier in obese than in non-obese people, and in the elderly.
Methoxyflurane is not considered mutagenic as indicated in an in vitro Ames study and an in vivo micronucleus study in rats. There is no clear evidence that methoxyflurane has carcinogenic properties. Furthermore, the potential risk is reduced by the fact that PENTHROX is intended for single administration or short-term intermittent use.
Methoxyflurane does not affect sperm cells in mice. In studies in mice and rats, methoxyflurane crossed the placenta but demonstrated no evidence of embryotoxic or teratogenic properties. However, delayed fetal development (reduced fetal body weight and decreased ossification) was observed following repeated dosing over 9 days. The no observed adverse effect level (NOAEL) for embryo-fetal development was 0.006% - 4h/day in mice and close to 0.01% - 8 h/day in rats. The NOAELs in mouse and rat represent a 1- to 2-fold margin on a mg/kg basis and a 0.1- to 0.3-fold margin on a mg/m² basis versus the proposed maximum clinical dose. As PENTHROX is not intended for daily use, the risk of delayed fetal development is considered to be very low.
Repeated intermittent or continuous administration of subanaesthetic concentrations of methoxyflurane has been associated with limited and commonly reversible hepatic changes (fatty metamorphosis, elevated ALT/AST) in several species. A NOAEL has not been established. These effects were seen at exposures considered sufficiently in excess of those anticipated through normal clinical use of the product.
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