German Version

Methoxyflurane in Tactical Medicine: A Green Whistle in a Green Environment

Sebastian Weber^a, Florent Josse^a

^a Bundeswehr Hospital Ulm – Department of Anesthesiology, Intensive Care, Emergency Medicine, and Pain Management

Summary

Methoxyflurane is a safe, fast-acting, and effective medication (“proof-of-concept”) for patient-controlled analgesia in acute, trauma-associated, moderate to severe pain (NRS ≥ 4). Foreign armed forces already utilize Methoxyflurane, and it is increasingly appreciated and applied by civilian mobile rescue teams (including mountain, air, and ski patrols, expedition teams) in so-called “Austere/Remote Environments” and in “Wilderness Medicine.” The advantages of this drug lie in its practical and patient-controlled application, as well as its rapid onset of action paired with a favorable safety profile. With appropriate training and consideration of specific characteristics, Methoxyflurane has the potential to complement and significantly enhance pain management in tactical medicine.

Keywords: Methoxyflurane, analgesic, patient-controlled analgesia, emergency medicine, tactical medicine

Introduction and Background

Pain treatment and relief are a core task of medical personnel. Sufficient pain management is not only ethically necessary but is also a critical quality feature of our treatment and facilitates dealing with the injured. Pain is a common symptom of injuries, and rapid and sufficient pain management in tactical settings is challenging. The requirements for the ideal analgesic in tactical medicine are even higher: It

• maintains combat effectiveness or does not compromise it,
• provides efficient pain relief,
• is simple to administer,
• requires no special knowledge/skills or equipment,
• has a low side effect profile without significant impact on vital functions,
• is easily controllable with a rapid onset and quick elimination,
• has low potential for abuse and dependency,
• offers a good safety profile with minimal risk of overdose and severe reactions,
• and imposes no special requirements for storage and transport.

Methoxyflurane, an inhalational non-opioid analgesic, meets some of these requirements and has the potential to complement pain management concepts in tactical medicine meaningfully. This article does not provide a comprehensive overview of tactical medicine’s various pain management options. Instead, it introduces methoxyflurane and its application and classification in tactical medicine.

What is Methoxyflurane – the “Green Whistle”?

Methoxyflurane (International Union of Pure and Applied Chemistry, IUPAC: 2,2-Dichloro-1,1-difluoro-1-methoxyethane) is a compound from the group of inhalational anesthetics. It is a clear, colorless, volatile liquid with a sweet, fruity odor. During the 1960s-1970s, it was used for conducting clinical anesthesia. A benefit compared to other inhalational anesthetics (e.g., Halothane, Isoflurane, Desflurane, Sevoflurane, and others) was its analgesic component, which extended into the postoperative phase, reducing the need for opioids [20][23][26].

At the time, the most significant concerns regarding Methoxyflurane use were its nephrotoxic side effects. Case studies reported that postoperative acute renal failure correlated with the use of methoxyflurane as a general anesthetic. It was shown that this nephrotoxicity is caused by the release of inorganic fluoride ions (serum fluoride concentration ≥ 40 µmol/L ≙ Methoxyflurane exposure ≥ 2.0 MAC1-hours) during biotransformation and is dose-dependent. Even at sub-anesthetic doses (max. 6 ml/day and 15 ml/week ≙  0.59 MAC-hours), the analgesic effect can be achieved, and there is no evidence of nephrotoxicity in this range [12][14][21][27].

Tab. 1: Side Effects of Methoxyflurane According to the Professional Information

Since 1975 in Australia and 2002 in New Zealand, Methoxyflurane has been used in sub-anesthetic doses for pain management in emergency medical services, with more than 5 million doses administered without noteworthy side effects [2][4][9][19]. The “STOP!” approval study by Coffey et al. in 2014 confirmed that Methoxyflurane is a safe and effective medication [10]. Furthermore, it demonstrated significant pain reduction and less need for rescue medication. Pain reduction occurs at a median of 4 minutes, significantly earlier than with conventional agents (intranasal Fentanyl 11 minutes, oral mucosal Fentanyl 16 minutes, intravenous Morphine 5 minutes) [10]. Several prospective randomized controlled studies from Italy (MEDITA Trial 2019), Spain (InMEDIATE Trial 2020), France (PenASAP Study 2020), and Australia (RAMPED Trial 2020) have reinforced the effectiveness and safety of Methoxyflurane in in-hospital emergency departments [5][7][25][29].

Figure 1: Example of a Methoxyflurane Application Algorithm as an Analgesia Option in the Tactical Environment (the “reverse side” is shown in Figure 4)

Another promising randomized controlled Phase 3 study (PreMeFen), examining the non-inferiority of Methoxyflurane for prehospital analgesia compared to intranasal Fentanyl and intravenous Morphine, is currently underway [33].

In 2018, Methoxyflurane was approved by the European Medicines Agency (EMA) in Europe for patient-controlled analgesia of trauma-associated pain. Internationally, it is known and available under the trade name Penthrox^® (colloquially “Green Whistle”). It is currently offered by the pharmaceutical companies Galen Limited from Ireland and Medical Developments International Limited from Australia. Until 2019, it was also distributed by Mundipharma International Corporation Limited from the United Kingdom. The approval (since 04/2018) of Penthrox^® in Germany was revoked on July 16, 2024. According to § 31 paragraph 4 of the German Medicines Act, “the medication may continue to be marketed for two years, starting from the first of January or July following the announcement of the revocation per § 34” [8]. For continued use in Germany beyond this date, a joint interagency solution similar to that of the U.S. armed forces must be developed [31].

Mundipharma’s market launch in Germany was halted due to approval and application restrictions and issues arising from Brexit [1]. In Austria, it has been marketed under the trade name Penthrop^® by Mundipharma GmbH since 2018. Methoxyflurane is self-administered by the injured individual as vapor through the so-called Penthrox^® inhaler system.

Figure 2: In-Hospital Application Algorithm for Penthrox^® at the Bundeswehr Hospital Ulm

Why is Methoxyflurane Suitable for Tactical Medicine?

Pain Management Without Access

Methoxyflurane can effectively be used for analgesia in hemodynamically stable injured individuals with trauma-associated moderate to severe pain (Numeric Rating Scale ≥ 4). It allows medical teams to treat the injured without needing intravenous medication administration, which is advantageous in tactical and adverse environments. It can thus bridge and even replace the time gap until or during transport or until the establishment of an intravenous access and the onset of action of an intranasal/intramuscular/intravenous analgesic.

Tab. 2: Contraindications of Methoxyflurane

Logistics

Methoxyflurane is relatively easy to procure through an international pharmacy and can be used in many countries. The set, consisting of a 3ml medication vial and an inhaler with an activated charcoal filter, is small and lightweight (approx. 59 g) and can be easily packed and transported in the equipment of operational forces or medical personnel.

Methoxyflurane does not require special temperature storage conditions and can thus be used in all climate zones and altitudes. It is not stored in pressurized gas containers nor classified as hazardous material, thereby not subject to national and international transport regulations (e.g., by aviation authorities). It is also not subject to narcotics laws and is therefore much easier to manage and distribute.

Simplicity and Practicality

The injured individual self-administers methoxyflurane through an inhaler. This requires no complex medical equipment or training, and users also do not need to learn weight-based dosages. This makes the application simple, quick, and resistant to stress.

Fast Action and Elimination

Methoxyflurane acts quickly (after approximately 6–10 inhalations), which is crucial in tactical situations where it is essential to calm, stabilize, and transport the injured individual within the shortest time possible. The duration of action lasts about 30–45 minutes, depending on inhalation intensity (intermittent > continuous inhalation for prolonged effect). The substance is also quickly eliminated and exhaled. Possible side effects subside quickly, the injured individual remains potentially self-reliant, and the neurological status can still be well assessed.

Legal Aspects

Methoxyflurane is not subject to narcotics laws. Thus, non-medical medical personnel can use it after appropriate training without significant legal hurdles, expanding their operational scope. Furthermore, the cumbersome administration documentation required for opioids is not necessary.

Low Side Effects

Compared to opioid-containing pain medications, Methoxyflurane has fewer severe side effects and a lower dependency potential. The most common side effects are dizziness and an initial cough, which subsides after 2–3 breaths; others include headaches and drowsiness (Table 1). However, these also depend on how much and quickly the injured individual inhales Methoxyflurane. The injured individual titrates and controls their therapy.

Application of Methoxyflurane/Recommendations for Action

Methoxyflurane has not only found its way into in-hospital emergency medicine but is increasingly being used in the pre-hospital setting by (non-)medical personnel. In Germany and internationally, various civilian land—and air-based emergency services use methoxyflurane [6][22][34][35][38].

The Australian, British, French, New Zealand, and U.S. armed forces use Methoxyflurane in the military environment [11][24][31]. However, in the current 2024 guidelines for tactical casualty care (Tactical Combat Casualty Care), Methoxyflurane is not yet mentioned. Still, it could establish itself as a non-opioid solution within the existing analgesic concept of 4 options (Figure 1) [13][31].

Of particular interest in tactical medicine is the mass casualty incident (MASCAL). Life-saving immediate measures have the highest priority, yet they involve harrowing injuries, so adequate pain management should be anticipated promptly. An analysis of ten military MASCALs by U.S. forces in Afghanistan showed that pain management is a neglected prehospital measure, carried out only 17% of the time [32]. In the civilian sector, the percentage is even lower. Only 3.2% of all medications administered by emergency personnel during a civilian MASCAL were pain medications [16]. Methoxyflurane can fill the time gap until classic pain management, such as intravenous analgesia, can be performed by appropriate personnel [36].

In situations where access to the injured and thus the feasibility of medical measures or access to medical facilities is difficult (e.g., extreme environmental conditions or adverse environments, so-called “austere/remote environments”), Methoxyflurane has been recognized as a valuable option. It is successfully and satisfactorily used by rescue teams from mountain and ski patrols [3][15][17][30][37][39].

The recent acknowledgment in this field came with Methoxyflurane’s mention in the 2024 stepwise treatment recommendations for acute pain in “austere environments” by the Wilderness Medical Society [18]. The authors have successfully used Penthrox for over three years in the Central Interdisciplinary Emergency Department at the Bundeswehr Hospital Ulm and in pre-hospital settings. They can only confirm the positive reports, studies, and effects (see Figure 2).

Figure 2 exemplifies the action algorithm used at the Center for Emergency Medicine at the Bundeswehr Hospital Ulm.

Challenges and Considerations

Contraindications

Like any medication, Methoxyflurane has specific contraindications and should be used with caution in certain patient groups (e.g., hemodynamically unstable injured individuals) (see Table 2).

Training and Education

Methoxyflurane can only be used safely and effectively if users receive appropriate training in handling the drug and monitoring the injured. This can be relatively simple, for example, in the form of digital training (e.g., the Bundeswehr’s “Link and Learn” training platform, podcast, ...) or conventional training by superior medical personnel. Figures 3 and 4 show examples of a part of such training in the form of a so-called One Minute Wonder.

Figure 3: One Minute Wonder “Drug Profile Methoxyflurane”

Figure 4: One Minute Wonder “Application of Penthrox^®” According to Professional Information (also usable as the reverse side for the algorithm in Figure 1)

Regular training and continuing education are essential to uncover training deficits on time, convey new scientific findings, and improve operational security in the tactical environment [28].

Legal and Regulatory Issues

Military forces, government agencies, and NGOs fulfill their missions worldwide. In some countries, there may be legal restrictions on the use of Methoxyflurane. Operational troops and medical personnel who use Methoxyflurane must familiarize themselves with the regional regulations beforehand.

The Bundeswehr was able to reauthorize methoxyflurane through the Central Pharmaceutical Commission of the Bundeswehr, and a corresponding proposal is currently under review by the Federal Ministry of Health. It is highly likely that it will soon be included as part of the Individual First Aid Kit (IFAK) for soldiers of the Bundeswehr.

The Bundeswehr was able to reauthorize Methoxyflurane through the Central Pharmaceutical Commission of the Bundeswehr (ZAMKBw), and a corresponding proposal is currently under review by the Federal Ministry of Health. It is highly likely that Methoxyflurane will soon become part of the Individual First Aid Kit (IFAK) for Bundeswehr soldiers.

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Manuscript Data

Citation

Weber S, Josse F: Methoxyflurane in Tactical Medicine: a Green Whistle in a Green Environment. WMM 2025; 69(6E): 8.

DOI: https://doi.org/10.48701/opus4-503

For the Authors

Lieutenant Colonel (MC) Dr. Florent Josse, MD

Bundeswehr Hospital Ulm

Department of Anesthesiology, Intensive Care, Emergency Care, Pain Treatment

Oberer Eselsberg 40, D-89081 Ulm

E-Mail: florentjosse@me.com