Methoxyflurane (Penthrox®) is a non-opioid analgesic and muscle relaxant that had been utilized in anesthesia until its fallout due to concerns for nephrotoxicity. Despite this, its use continued, at lower doses than utilized in anesthesia, for pain relief of traumatic injuries in countries outside of the United States (US) for decades. As an inhaled analgesic, its use in the pre-hospital Emergency Medical Services (EMS) setting has been well established since the 1970s throughout Australia, with more recent studies exploring its utility in the emergency department (ED). With its availability now in more than 40 countries worldwide, will the Food and Drug Administration (FDA) approve its use in the US? In 2005, the FDA reviewed and determined methoxyflurane was associated with serious and irreversible nephrotoxicity and hepatotoxicity in humans, ultimately determining that the risks of toxicity outweighed potential benefits. However, in 2022, the FDA announced it would lift the previous hold on methoxyflurane allowing for phase 3 clinical trials to commence.
The United Nations designates analgesia as a human right, posing an ethical consideration in addition to a clinical obstacle to safely and in a timely manner provide pain relief and, ultimately, definitive care. Untreated pain could pose a risk of ineffective trauma treatment both from physiologic effects (increased heart rate, increased blood pressure, delayed recovery, inability to sleep) as well as patients may be unable or unwilling to provide a history or cooperate with an exam, and might be agitated, frustrated, or aggressive due to inadequate pain management.
Chemical structure of methoxyflurane (PubChem)
The ideal agent to provide analgesia is one with a rapid onset, adequate duration for the situation at hand, and with limited alterations in vitals and mental status. Typically, a short duration is ideal because stabilization and immobilization of traumatic injuries provide relief. However, an agent with a longer duration may be necessary if there is a prolonged evacuation time or an inability to adequately immobilize an injury in a wilderness environment. Available options, depending on the setting, include but are not limited to opioids, non-steroidal anti-inflammatories (NSAIDs), acetaminophen, ketamine, and nitrous oxide. With the exception of nitrous oxide, which is an inhalation, all these drugs have routes of administration including oral, intravenous (IV), intramuscular (IM), or intranasal (IN). Even though nitrous oxide is inhaled, its use in the wilderness environment is non-existent due to the logistics required for its administration. The oral route is not preferred for analgesia due to a prolonged onset of action. Routes such as IV, IM, or IN would be useful in the austere setting; each has advantages and disadvantages.
Methoxyflurane is available in a disposable 3 mL portable inhaler commonly referred to as the “Green Whistle”. It is self-administered by the patient and has a rapid onset of action providing a 5-point drop on the Visual Analogue Scale (VAS) for pain, in less than 60 seconds. To use, the patient inhales through the mouthpiece and exhales through an activated charcoal chamber connected to the device, so that bystanders are not exposed. Generally, pain relief occurs within 6-10 inhalations. Patients are able to titrate the amount of medication inhaled and should be instructed to inhale intermittently to achieve adequate analgesia. Continuous inhalation of a bottle containing 3 mL provides analgesic relief for up to 25-30 minutes; intermittent inhalation may provide longer analgesic relief. Patients should be advised to use the lowest possible dose to achieve pain relief. Use should be limited to two 3 mL inhalers within 24 hours. In addition to these advantages, the inhaler is lightweight, making it appealing for use in the wilderness setting. Additionally, it can be administered to patients when IV, IM, or IN routes are not ideal or possible.
Inhalation and exhalation of methoxyflurane through activated charcoal chamber (penthrox.co.uk)
Several studies show a favorable safety profile of inhaled methoxyflurane. Side effects to be aware of include non-serious adverse reactions such as dizziness, somnolence, headache, dry mouth, and nausea which are all easily reversible with withdraw of the medication. Treatment with methoxyflurane has not shown to have clinically significant effects on cardiovascular or respiratory parameters, and although methoxyflurane causes significant nephrotoxicity at high doses. clinical trials have not revealed evidence of nephrotoxicity. Even though the safety profile is favorable, there are some patient populations in which methoxyflurane use should be avoided: known history of malignant hyperthermia, significant renal impairment, clinically evident cardiovascular instability or respiratory depression and some patients in which caution should be taken when used: hepatic dysfunction, elderly; those taking isoniazid, rifampicin, carbamazepine, efavirenz, nevirapine or in those who are under the influence of alcohol due to drug interactions.
Is the “Green Whistle” (methoxyflurane) the next big med in wilderness medicine in the US? Maybe. There are several studies evaluating the efficacy of methoxyflurane when compared to placebo or standard of care. Routinely, methoxyflurane performs favorably compared to the standard of care with a greater reduction in pain on the pain scale as well as a faster reduction in pain. Available studies have largely been in pre-hospital EMS or ED settings without much evidence in the austere environment. One study evaluated the safety and efficacy of use at altitude (in Machermo, Nepal, at 4470 meters) during a suprapubic aspiration for urinary retention. The authors concluded that methoxyflurane provided rapid, effective analgesia for both visceral and procedural pain. They noted it was easy to use, and the patient remained responsive to voice, and maintained adequate oxygen saturation throughout the procedure. Additional studies have discussed methoxyfluranes usefulness in pain management by ski patrollers for the reduction of dislocated shoulders.
With a promising efficacy and safety profile coupled with an extensive history of use throughout the pre-hospital community worldwide, a crossover of use by the wilderness medicine community is plausible. Until the FDA approval is granted, use of methoxyflurane in the US will remain a dream. Further studies of use in the extremes of environment encountered in the austere setting are needed, however, in order to make specific recommendations for its use within wilderness medicine.