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TABLE 2 Select Concomitant Pain Medications severely injured casualties. Second, the available data do not
Medication No (%) of recipients* provide sufficient granularity on who administered the med-
Fentanyl 1 (5) ication, so we cannot accurately discuss the clinical practice
guidelines under which they may be operating. Third, this data
Hydromorphone 1 (5) is derived solely from the setting of irregular warfare, and how
Ketamine 1 (5) such an intervention would apply to future large-scale combat
Morphine 9 (41) operations remains unclear. Last, DODTR relies on documen-
*This includes casualties that received more than one medication. tation in austere settings, so accurate data collection remains
an ongoing challenge. 36,43
of care. Previous studies from the U.S. found that 22%–29%
of casualties receive multiple medications, including OTFC, In conclusion, we described the use of methoxyflurane in the
morphine, fentanyl, and ketamine. 38,39 Given the limited avail- deployed combat setting. The use of methoxyflurane for anal-
ability of methoxyflurane in the theater and only among select gesia suggests both feasibility and usability. Our findings may
Coalition forces, we assume that a Coalition force medical inform future drug development for non-opioid pain solutions.
team must have been involved in their chain of care; however,
the registry lacks sufficient granularity to determine who ad- Author Contributions
ministered the medication. SGS conceptualized the study, analyzed the data, and drafted
the manuscript. ADF and MDA provided subject matter exper-
We noted a median drop in pain score by 3 points; however, tise and critical revisions. All authors contributed substantially
this was only among three casualties, so the extrapolation of to this manuscript. The authors would like to thank the Joint
this finding remains quite limited. Extensive high-quality data Trauma System Data Analysis Branch for their efforts with
demonstrate the efficacy of this agent for pain control in the ci- data acquisition.
vilian setting. 23–25 Given the improved pain scores among those
with documented pain assessments and the lack of required Disclaimer
concomitant pain medications among half of the casualties, it The U.S. Army Institute of Surgical Research Regulatory Com-
is reasonable to suggest that the agent had efficacy. pliance Office reviewed protocol H-23-004x and determined
that our study met exempt category #4 criteria, so institutional
While the volume of casualties is low within our data set, this review board approval was not required. We requested and
study provides proof-of-concept, demonstrating both feasibil- were granted HIPAA waiver M-11013. The data were trans-
ity and usability in this setting. Methoxyflurane represents a ferred under Defense Health Agency data sharing agreement
potentially ideal agent for the U.S. Military to develop. The 23-2977.
drug is already available for manufacture for the analgesia
indication. This opportunity is a clear advantage over ket- The views expressed in this article are those of the authors and
amine, which has no analgesia indication or administration do not reflect the official policy or position of the U.S. Army
tool (such as an auto-injector) available, and none is expected Medical Department, Department of the Army, Department of
2
in the near term. Moreover, the FDA recently released the Defense, or the U.S. Government.
hold on methoxyflurane for investigational new drug appli-
cation purposes; this opens the door to the studies required to Disclosures
bring it to market, and a phase 3 study is already underway All authors have received grant funding to their institutions
(NCT05137184). The U.S. Military could leverage this near- from the Department of Defense for unrelated studies. We
ready solution through the special military-use pathway at the have no other disclosures.
FDA to help expedite the approval of the drug. The design of
the inhaler allows for easier control of the drug throughout the Funding
theater. More recent inhaler technology can come with dose No funding was received for this work.
measurements (equivalent to the inhaler version of an odom-
eter), allowing for better monitoring of controlled substances Public Affairs Approval
than reusable ketamine vials. While this does not eliminate This manuscript was approved for public dissemination.
misuse potential, it does improve our tracking capabilities.
Moreover, the inhaler design allows for self-administration, References
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doi:10.1080/10903127.2021.1907491.
2. Bebarta GE, Bebarta VS, Fisher AD, et al. An analysis of ketamine
Conclusion doses administrated to nonintubated casualties prehospital. Mil
Med. Published online 4 December, 2021. doi:10.1093/milmed/
Our study has several limitations. First, for inclusion within the usab511.
DODTR, casualties must arrive at a location with surgical ca- 3. Glare PA, Walsh TD. Clinical pharmacokinetics of morphine.
pabilities (e.g., FRSD, field support hospital) alive or with on- Ther Drug Monit. 1991;13(1):1–23. doi:10.1097/00007691-
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unlikely that any gravely injured casualties would receive this special operations. Mil Med. 1996;161 Suppl:3–16.
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MD. Trends in prehospital analgesia administration by US forces
gesting that only moderately injured casualties received this from 2007 through 2016. Prehosp Emerg Care. 2019;23(2):271–
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