Opinion

The US military still lacks a safe and effective battlefield pain solution

Few battlefield pain management advances have been made since the Civil War.
battlefield pain solutions
A U.S. Air Force Special Tactics operator with the 23rd Special Tactics Squadron, Hurlburt Field, Florida, provides pain relief medication to a simulated patient at Eglin Range, Florida, Dec. 5, 2022. (SrA Christopher H. Stolze/U.S. Air Force).

Pain after traumatic injuries is among the most common reasons for combat casualties seeking medical care following initial injury.1 During recent conflicts, the U.S. military has had unprecedented casualty survival in excess of 95% if casualties arrive at a Military Treatment Facility (MTF) alive.2 While significant advancements have been made in hemorrhage control, resuscitation, and surgical interventions, few battlefield pain management advances have been made since the Civil War. 

As the U.S. military transitions into a posture of limited direct action, advancing, fielding, and training in battlefield medical developments will become a low priority, specifically for research and development of medical technology.3

The complexity of acute pain

Aside from the obvious in the acute phase, there are multiple long-term sequelae associated with inadequate pain control early after acute injury. The landmark study by Holbrook in 2010, highlighted the link between inadequate analgesia, namely morphine, and the development of posttraumatic stress disorder (PTSD). PTSD, along with traumatic brain injury (TBI), represents some of the most frequent signature long-term effects of injuries from recent conflicts.4 

Death by suicide continues to plague the U.S. military and often is preceded by multiple other common psychiatric disorders, including PTSD and chronic pain syndromes. While there is no data directly linking the two, one may transitively infer inadequate pain control contributes to suicide risk. Moreover, the cost to the U.S. government for PTSD and related diagnoses is massive and often continues for the lifetime of the service member through the Veterans Affairs system. The estimated cost is nearly $232 billion.5 

Cost aside, it has long-term detrimental effects on the quality of life for the service member.6

Morphine: The dinosaur looking for a tar pit

Morphine is a drug that has been in use since the Civil War and is largely considered to be an antiquated drug for major trauma, yet the U.S. military has a heavy reliance on outdated and poorly efficacious morphine intramuscular autoinjectors.7-10 

There have been adverse events in the field relating to morphine use dating back to World War II. This inadequate analgesia was ubiquitous for over a decade during the conflicts in Afghanistan and Iraq. Despite intramuscular (IM) morphine not being a recommended option under the Tactical Combat Casualty Care (TCCC) guidelines since the start of the conflicts, we continued to rely on this as our primary battlefield analgesia outside of special operations. 

The main problem with morphine lies in its pharmacokinetics, or how the body uses and moves drugs. Morphine, particularly in the IM route, requires upwards of 45 minutes to achieve maximal effect in healthy adults.11 Due to shock resulting from inadequate blood volume, medications may not circulate readily throughout the body, meaning that a severely wounded casualty may experience inadequate pain relief from a single dose, resulting in additional doses. 

When the casualty has been appropriately resuscitated, there will be a large amount of morphine that is now available in the body. This can compromise breathing and cardiovascular function. Consequently, the Committee on TCCC (CoTCCC) removed this option from the guidelines decades ago.12

The fentanyl “lollipop”

In search of a more effective and easily administered pain medication, the 75th Ranger Regiment began using oral transmucosal fentanyl citrate (OTFC). This option, more commonly known as the “fentanyl lollipop”, provides acute pain control13 and has since become a popular solution for acute pain control on the battlefield.9,14,15 

The advantage of the OTFC is rapid onset and self-administration. In other words, the medic can essentially “fire and forget” as the patient can control the drug received somewhat analogous to the current in-hospital technology that allows for on-demand pain medication doses. TCCC recommends taping it to the thumb or attaching it to a rubber band under tension, ensuring that if the casualty becomes unconscious, the lollipop falls out of their mouth. 

Despite the demonstrated efficacy of this medication, it carries significant challenges. First, the Food and Drug Administration (FDA) label does not include treatment of acute pain. Second, the drug carries an FDA black box warning against the use of this medication for opioid-naïve patients with acute pain, as it has a substantial risk of overdose in these patients due to limitations in titration. 

While off-label use of drugs is common practice in medicine, the prospect of off-label use of a controlled medication is concerning to many supervising physicians who ultimately control which medications medics may use. Because of this, we rarely see this medication dispensed to medics outside of special operations.8,16 While this eliminates the risk from the perspective of the supervising physician (e.g., brigade surgeon), this leaves medics without an effective option for controlling the pain of casualties in their care.

Fentanyl, like all opioids, can also decrease blood pressure, which is particularly risky if the casualty is experiencing significant blood loss. In addition to these labeling and safety challenges, there have also been cases of diversion and abuse in the deployed setting. Putting aside these drug-related concerns, for this medication to work, the casualty must be able to self-administer pain medications. This is not always feasible in the setting of significant polytrauma, especially if they have injuries to their hands. 

Intravenous fentanyl, unlike the OTFC delivery system, is FDA-approved for acute pain. Thus, this also represents an easy target for inclusion into a prefilled injector.

Ketamine

Ketamine has been available for use for several decades. It was initially investigated as a potential psychedelic medication; however, the drug developers quickly found the dissociative effects of the medication to be particularly useful when intravenous (IV) anesthesia is necessary.17 Thus, the only approved, labeled indication for racemic ketamine (the widely available IV formulation) per the FDA, is dissociative anesthesia. 

Since the 1990s there has been a growing number of studies evaluating low-dose – or sub-dissociative dose – ketamine for pain.18 Ketamine’s properties are ideal for a casualty experiencing substantial blood loss. Specifically, ketamine has neutral effects on blood pressure and may even raise the blood pressure transiently compared to morphine and fentanyl which lower it. However, there are concerns with both dose and rate of administration, namely the dissociative effects (awake but with no voluntary brain function), and hallucinations.19 Underdosing risks inadequate analgesia, while “over-dosing” risks dissociation.

Ketamine also has the same challenges as the fentanyl lollipop – off-label to treat acute pain. Moreover, ketamine typically comes in vials containing 500 mg, which is the equivalent of approximately 10 doses of the medication for pain. The multiuse vial is vulnerable to diversion and misuse. Because of this risk, the supervising physician, or medical director, of a prehospital or combat medic unit is often unwilling, or in some cases unable to, dispense ketamine to military teams.

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The development of an intramuscular ketamine auto-injector or prefilled injector has been proposed for over a decade as the solution for acute pain in the setting of significant bleeding, particularly for conventional force medics. 

An injector would alleviate nearly all the problems highlighted herein. First, the injectors have tamper-resistant features, making them very difficult to misuse or engage in diversion. Second, the injectors are trackable like other durable equipment on the hand receipt. Third, the device simplifies the administration process, removing the fine motor skills required to draw medication from a vial and administer it, particularly in the stressful and austere settings of combat. Accurate dosing from a multi-dose vial (the currently used vials) is fraught with risks of miscalculations, even in the controlled hospital setting.20 

While this solution is promising, the primary challenge remains in that a drug cannot be marketed and sold for an off-label indication. Thus, no company can develop and sell an intramuscular injector to the U.S. military for acute pain. To overcome this, studies meeting the stringent FDA requirements for label change need to occur. Such clinical trials will carry substantial costs. 

Outside of the  U.S. military (and likely coalition partners), there is limited use for a ketamine autoinjector. Therefore, it is unlikely that a private company will front the money for the clinical trials to gain the appropriate FDA labeling without a guaranteed market to recuperate the cost on the backend. There may be some interest for use in austere medicine settings and tactical EMS, but not in insufficient volumes to motivate a private company to push forward the development. Thus, the Department of Defense will have to lead the development if we want this solution to land in the medic’s aid bag.

Sufentanil (Dsuvia®)

The military recently funded the development of the novel oral sublingual sufentanil for battlefield use to address the gap in battlefield analgesia options.21,22 Seemingly, this drug represents a potentially ideal solution as the drugs are individually labeled, have anti-tamper delivery systems, and are easily tracked, similar to how other durable equipment is tracked on hand receipts. 

This drug is administered by way of a dispensing tool that comes attached to the drug. Responders place this tool into the casualty’s mouth for medication absorption under the tongue. While seemingly ideal, several issues come with this solution. 

First, the casualty must be able to cooperate to receive the drug off the dispensing tool and hold the medication under the tongue while it dissolves. The drug has little to no absorption once swallowed.23-25 Conversely, it is likely deadly if ground up and injected.26 While this drug shows efficacy in the postoperative setting, specifically in studies used to obtain FDA approval, the efficacy of this drug in the trauma population remains unclear.25,27 Moreover, compared to ketamine and fentanyl, U.S. military medical officers have relatively little experience with this drug reducing their enthusiasm for its use and slow adoption by the medical officers providing medical direction. 

Inhaled Anesthetics

Methoxyflurane is a volatile anesthetic that is delivered through a handheld inhaler and more commonly known as Penthrox® or colloquially named the “green whistle.”28 The use of this drug outside of the U.S. as an analgesic is well-described, with high-quality data supporting its use for analgesia.28-32 

It has a very rapid time of onset of analgesia of <1 minute, with doses lasting up to 30 minutes after 6-8 puffs. This drug is currently only approved and available in Australia, Canada, and Europe — many of the partner forces in the War on Terror, but it was previously available in the  U.S. and was removed from the market after case reports regarding renal and liver toxicity in repetitive dosing.28 Therefore, use of the drug for periods exceeding 3 hours is generally not recommended.33 

That said, the FDA has recently released the hold on the drug, allowing clinical trials for investigational drug application purposes (NCT05137184).34 The removal of the IND restrictions, and the manufacturing processes already in place in other countries, makes this an enticing near-term solution as many of the barriers to getting it into the medic’s aid bag are already addressed.

Recommendations for the way forward

To this end, we offer the following recommendations for the Department of Defense (DoD) to urgently pursue:

  1. The DoD should fund studies with academic and industry partners evaluating ketamine for an FDA label change to add an acute pain indication so it can be manufactured, sold, and used for this purpose.
  2. After obtaining the acute analgesia FDA indication for ketamine, the DoD should secure an industry partner that will provide both initial large-scale manufacturing of ketamine prefilled injectors and on-demand production.
  3. The DoD needs to secure an industry partner that will provide both initial large-scale manufacturing of fentanyl-prefilled injectors and provide on-demand production.
  4. The DoD needs to seek other novel non-opioid, analgesia solutions, such as the Penthrox® inhaler for prehospital use.

The military now faces a battlefield and prehospital analgesia capability gap for acute pain. While a ketamine intramuscular injector is currently the most promising materiel solution to that gap, developing and procuring these solutions will require an FDA label change and focused investment. This, in turn, threatens to be prohibitively expensive to approve this relatively inexpensive, generic medication in this manner. 

To overcome this dilemma, the U.S. military must partner with a commercial developer and academic researchers to meet the military’s unique battlefield medical care delivery mission. With the looming threats of large-scale combat operations, the need has become especially time-sensitive, or we risk failing our medics by leaving their aid bag devoid of effective pain solutions.

DISCLAIMER: The views expressed in this article are those of the authors and do not reflect the official policy or position of the U.S. Army Medical Department, Department of the Army, Department of Defense, or the U.S. Government.

References

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