Methoxyflurane, sold under the brand namePenthrox (the "green whistle") among others, is an inhaled medication primarily used to reduce pain following an injury.[9][10] It may also be used to reduce pain associated with minor medical procedures.[11] Onset of pain relief is rapid and a standard dose typically lasts for up to 30 minutes.[11] Use is only recommended with direct medical supervision.[9]
It was firstmade in 1948 byWilliam T. Miller and came into medical use in the 1960s.[13] It was used as ageneral anesthetic from its introduction in 1960 until the late 1970s.[14] In 1999, the manufacturer discontinued methoxyflurane in the United States, and in 2005 theFood and Drug Administration withdrew it from the market, due to reports of nephrotoxicity and hepatotoxicity.[14][15] As of April 2025, it is used in New Zealand, Australia, Ireland, and the United Kingdom for acute pain.[9][16][17]
Methoxyflurane handheld inhalerPatient self-administering penthrox at the Royal Melbourne Hospital
Methoxyflurane is used for relief of moderate or severe pain as a result of trauma.[10][9] It may also be used for short episodes of pain as a result of procedures.[11]
Each dose lasts approximately 30 minutes.[18] Pain relief begins after 6–8 breaths and continues for several minutes after stopping inhalation.[19] The maximum recommended dose is 6 milliliters per day or 15 milliliters per week because of the risk of kidney problems, and it is not recommended to be used on consecutive days.[11] Despite the potential for kidney problems when used at anesthetic doses, no significant adverse effects have been reported when it is used at the lower doses (up to 6 milliliters) used for pain relief.[20][21][22] Due to the risk of kidney toxicity, methoxyflurane iscontraindicated in people with pre-existingkidney disease ordiabetes mellitus, and is not recommended to be administered in conjunction with tetracyclines or other potentially nephrotoxic orenzyme-inducing drugs.[21]
It is self-administered to children and adults using a hand-held inhaler device.[23][20][24][21] A non-opioid alternative tomorphine, it is also easier to use thannitrous oxide.[11] A portable, disposable, single-use inhaler device, along with a single 3 milliliter brown glass vial of methoxyflurane allows people who are conscious andhemodynamically stable (including children over the age of 5 years) to self-administer the medication, under supervision.[11]
Inprehospital care Penthrox offers an alternative toEntonox, it being smaller, lighter and not contraindicated with chest injuries.[25]
An association between methoxyflurane andacute kidney injury was first reported in a 1964 case study of three patients.[29] Another report was published in 1966, in which 17 of 95 patients (18%) who received methoxyflurane as a general anaesthetic developedvasopressin and fluid challenge-resistanthigh-output kidney failure (production of large volumes of poorly concentrated urine) and deranged serum electrolytes. Most of these cases resolved within 2–3 weeks, but evidence of renal dysfunction persisted in some patients for more than one year.[30]
Compared withhalothane, methoxyflurane produces dose-dependent abnormalities in kidney function. The authors showed thatsubclinical nephrotoxicity occurred following methoxyflurane atminimum alveolar concentration (MAC) for 2.5 to 3 hours (2.5 to 3 MAC hours), while overt toxicity was present in all patients at dosages greater than 5 MAC hours.[26] This study provided a model that would be used for the assessment of the nephrotoxicity of volatile anesthetics for the next two decades.[31] Furthermore, the concurrent use oftetracyclines and methoxyflurane has been reported to result in fatal renal toxicity.[32]
The biodegradation of methoxyflurane begins immediately. Thekidney andliver toxicity observed after anesthetic doses is attributable to one or moremetabolites produced by O-demethylation of methoxyflurane. Products of thiscatabolic process include methoxyfluoroacetic acid (MFAA), dichloroacetic acid (DCAA), and inorganic fluoride.[27] Methoxyflurane nephrotoxicity is dose dependent[30][35][36] and irreversible, resulting from O-demethylation of methoxyflurane to fluoride and DCAA.[11] It is not entirely clear whether the fluoride itself is toxic—it may simply be asurrogate measure for some othertoxic metabolite.[37] The concurrent formation of inorganic fluoride and DCAA is unique to methoxyfluranebiotransformation compared with other volatile anesthetics, and this combination is more toxic than fluoride alone. This may explain why fluoride formation from methoxyflurane is associated with nephrotoxicity, while fluoride formation from other volatile anesthetics (such asenflurane andsevoflurane) is not.[38]
Methoxyflurane has a very high lipid solubility, which gives it very slowpharmacokinetics[34] (induction and emergence characteristics); this being undesirable for routine application in the clinical setting. Initial studies performed in 1961 revealed that inunpremedicated healthy individuals, induction of general anesthesia with methoxyflurane-oxygen alone or with nitrous oxide was difficult or even impossible using the vaporizers available at that time. It was found to be necessary to administer anintravenous anesthetic agent such assodium thiopental to ensure a smooth and rapid induction. It was further found that after thiopental induction, it was necessary to administer nitrous oxide for at least ten minutes before a sufficient amount of methoxyflurane could accumulate in thebloodstream to ensure an adequate level of anesthesia. This was despite using high flow (litres per minute) of nitrous oxide and oxygen, and with the vaporizers delivering the maximum possible concentration of methoxyflurane.[39]
Similar to its induction pharmacokinetics, methoxyflurane has very slow and somewhat unpredictable emergence characteristics. During initial clinical studies in 1961, the average time to emergence after discontinuation of methoxyflurane was 59 minutes after administration of methoxyflurane for an average duration of 87 minutes. The longest time to emergence was 285 minutes, after 165 minutes of methoxyflurane administration.[39]
Unlike diethyl ether, methoxyflurane is a significant respiratory depressant. In dogs, methoxyflurane causes adose-dependent decrease inrespiratory rate and a marked decrease inrespiratory minute volume, with a relatively mild decrease intidal volume. In humans, methoxyflurane causes a dose-dependent decrease in tidal volume and minute volume, with respiratory rate relatively constant.[40] The net effect of these changes is profound respiratory depression, as evidenced byCO2 retention with a concomitant decrease in arterialpH (this is referred to as arespiratory acidosis) when anesthetized subjects are allowed to breathe spontaneously for any length of time.[39]
Although the high blood solubility of methoxyflurane is often undesirable, this property makes it useful in certain situations—it persists in thelipid compartment of the body for a long time, providingsedation and analgesia well into the postoperative period.[45][40] There is substantial data to indicate that methoxyflurane is an effective analgesic and sedative agent at subanesthetic doses.[23][20][46][47][48][49][50][51][52][53][54][55][56] Supervisedself-administration of methoxyflurane in children and adults can briefly lead to deep sedation,[20] and it has been used as apatient controlled analgesic for painful procedures in children in hospitalemergency departments.[24] Duringchildbirth, administration of methoxyflurane produces significantly better analgesia, lesspsychomotor agitation, and only slightly moresomnolence than trichloroethylene.[48]
Penthrox, commonly known as the "green whistle", has been offered in hospital to women for painfulintrauterine device procedures (insertion and removal).[57]
The carbon–fluorine bond, a component of all organofluorine compounds, is the strongestchemical bond in organic chemistry. Furthermore, this bond becomes shorter and stronger as more fluorine atoms are added to the same carbon on a given molecule. Because of this,fluoroalkanes are some of the mostchemically stable organic compounds.[70]
Obstacles had to be overcome in the handling of both fluorine and UF6. Before theK-25 gaseous diffusion enrichment plant could be built, it was first necessary to developnon-reactivechemical compounds that could be used ascoatings, lubricants and gaskets for the surfaces which would come into contact with the UF6 gas (a highly reactive andcorrosive substance). William T. Miller, professor oforganic chemistry atCornell University, was co-opted to develop such materials, because of his expertise in organofluorine chemistry. Miller and his team developed several novel non-reactivechlorofluorocarbonpolymers that were used in this application.[82]
Miller and his team continued to develop organofluorine chemistry after the end of World War II and methoxyflurane was made in 1948.[83]
In 1968, Robert Wexler ofAbbott Laboratories developed the Analgizer, a disposableinhaler that allowed the self-administration of methoxyflurane vapor in air foranalgesia.[84] The Analgizer consisted of apolyethylene cylinder 5 inches long and 1 inch in diameter with a 1 inch long mouthpiece. The device contained a rolledwick ofpolypropylenefelt which held 15 milliliters of methoxyflurane. Because of the simplicity of the Analgizer and thepharmacological characteristics of methoxyflurane, it was easy for patients to self-administer the drug and rapidly achieve a level ofconscious analgesia which could be maintained and adjusted as necessary over a period of time lasting from a few minutes to several hours. The 15 milliliter supply of methoxyflurane would typically last for two to three hours, during which time the user would often be partlyamnesic to the sense of pain; the device could be refilled if necessary.[51] The Analgizer was found to be safe, effective, and simple to administer in obstetric patients during childbirth, as well as for patients withbone fractures andjoint dislocations,[51] and for dressing changes onburn patients.[50] When used for labor analgesia, the Analgizer allows labor to progress normally and with no apparentadverse effect onApgar scores.[51] Allvital signs remain normal in obstetric patients, newborns, and injured patients.[51] The Analgizer was widely utilized for analgesia and sedation until the early 1970s, in a manner that foreshadowed the patient-controlled analgesia infusion pumps of today.[48][49][52][53] The Analgizer inhaler was withdrawn in 1974, but use of methoxyflurane as a sedative and analgesic continues in Australia and New Zealand in the form of the Penthrox inhaler.[23][20][24][21] During 2020 trials of methoxyflurane as an analgesic in emergency medicine were held in the UK.[85]
Methoxyflurane has a varied legal status worldwide depending on its use. It was initially used as a general anesthetic in the 1960s and 1970s; however, its anesthetic application was discontinued due to risks of nephrotoxicity and hepatotoxicity at high doses.[86] At lower doses, it has been approved as an analgesic for moderate-to-severe pain in many countries.[87] In Australia and New Zealand, methoxyflurane has been widely used for over 40 years in emergency medicine and minor procedures.[86] It is also authorized in the European Union, including the United Kingdom and Ireland, for trauma-related pain relief via a self-administered inhaler device (Penthrox).[86] Methoxyflurane was withdrawn from the United States market in 2005, due to safety concerns but is now undergoing clinical trials for reintroduction as an analgesic.[88] In Canada, it is approved for pain relief under strict guidelines.[89] Its use remains prescription-only in most regions, reflecting ongoing caution regarding potential side effects like kidney and liver toxicity.[90][88]
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