Penthrox Mechanism of Action

Pharmacotherapeutic Class: Analgesic. ATC code: N02BG09.
Pharmacology: Pharmacodynamics: Methoxyflurane vapour provides analgesia when inhaled at low concentrations. The precise mechanism of action whereby methoxyflurane produces analgesia at sub-anaesthetic doses is unknown, although a reduction in substance P and β-endorphine-like immunoreactivity in the brain has been suggested.
After methoxyflurane administration, drowsiness may occur. During methoxyflurane administration, the cardiac rhythm is usually regular. The myocardium is only minimally sensitised to adrenaline by methoxyflurane. At analgesic therapeutic doses pain relief may lead to some decrease in blood pressure. This may be accompanied by bradycardia.
Clinical efficacy and safety: The efficacy and safety of PENTHROX was demonstrated in a clinical study in the treatment of acute pain in patients ≥12 years with minor trauma presenting to an Emergency Department. 300 patients were randomised in a 1:1 ratio to receive methoxyflurane or placebo. 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) 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.
Pharmacokinetics: Absorption: Methoxyflurane has the following partition coefficients: a water/gas coefficient of 4.5, a blood/gas coefficient of 13 and an oil/gas coefficient of 825.
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. In a pharmacokinetic (PK) study in healthy volunteers, the mean plasma concentration-time curves showed an extremely rapid rise in methoxyflurane plasma concentrations. Following a single dose of 3 mL methoxyflurane inhaled intermittently over an hour, the arterial profile is demonstrated by a t_max at 0.25 hours (range 0.08-0.75 hours), C_max of 32.39 μg/mL (SD 13.546 μg/mL, CV 41.8%) and the AUC of 28.95 h.μg/mL (range 12.3-52.6 h.μg/mL).
Distribution: 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: 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, CYP 2B6 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.
Elimination: In the PK study in healthy volunteers who inhaled 3 mL of methoxyflurane over 1 hour, there was an early peak in methoxyflurane plasma concentration-time curves followed by a rapid elimination from the plasma, with methoxyflurane concentrations returning to baseline by 24 hours after administration. Concentrations of the metabolite, inorganic fluoride, rose less quickly than methoxyflurane (median t_max of 1.5 hours) and were gradually eliminated from the plasma, with significant concentrations measured in plasma 48 hours after methoxyflurane administration. Following a single dose of 3 mL methoxyflurane inhaled intermittently over an hour, the venous median half-life for methoxyflurane is 3.16 hours (range 1.06-7.89 hours), and that for inorganic fluoride is 33.30 hours (range 23.50-51.20 hours). The PK profiles for methoxyflurane and inorganic fluoride exhibited high inter-subject variability.
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.
Toxicology: Preclinical safety data: Genotoxicity and carcinogenicity: Methoxyflurane is not considered mutagenic as indicated in an in vitro Ames study and an in vivo micronucleus study in rats.
There is no evidence that methoxyflurane has carcinogenic properties.
Reproductive and developmental toxicity: 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% (104 mg/kg) - 4h/day in mice and close to 0.01% (245 mg/kg) - 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.
Renal and hepatic effects: Continuous administration of higher anaesthetic doses of methoxyflurane to rats has been associated with renal tubular necrosis and mitochondrial swelling. 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.
After 6 hours of continuous inhalation of methoxyflurane for 14 consecutive days in rats, kidney findings were limited to minimal vacuolation of cortical tubules and in the liver, there was minimal/mild centrilobular vacuolation expansion of cytoplasm (centrilobular hepatocytes) lending the cytoplasm a frothy appearance.
After 90 minutes of continuous inhalation of methoxyflurane for 14 consecutive days in dogs, no salient kidney findings were noted and in the liver, there was minimal/mild centrilobular glycogen accumulation.
NOAELs of 396 mg/kg and 153 mg/kg were reported for the previously mentioned rat and dog studies respectively. These renal and hepatic effects were however seen with prolonged and repeat administrations over 14 days therefore the total exposures are in excess of those anticipated through normal clinical use of the product.