Morphine has been the mainstay for treating pain since the Civil War. Although doctors recognized long ago that prolonged use of morphine can lead to addiction, nothing changed for 150 years. That’s because there were no practical alternatives. The good news is that an effective non-opioid pain medicine exists. The bad news is that the FDA has not yet approved the medication’s use for this purpose.
Opioid abuse is ravaging families and communities across the United States. More than 81,000 opioid overdose deaths occurred in 2022, six times the number recorded in 1999. President Trump first declared the opioid crisis a public health emergency in 2017. His declaration was officially renewed in 2024. Although overdose deaths have declined somewhat in the past two years, they remain the leading cause of death among Americans aged 18-44. More must be done.
Ketamine: An Old Drug With New Uses
Ketamine, an anesthetic, was first approved by the FDA 50 years ago. Its low cost and wide safety margin quickly made it a popular choice for surgery worldwide. The WHO classified it as an essential medicine in 1985.
Recently, ketamine has also shown promise in treatment-resistant depression. Unfortunately, media coverage of that development, along with the rapid proliferation of “ketamine clinics,” online prescribing and a celebrity death overshadowed another, equally promising use for ketamine: as an non-opioid alternative to treat acute pain.
Ketamine’s pain-relieving properties at doses far below those required for anesthesia have been recognized for years. And unlike morphine, ketamine tends to preserve blood pressure and breathing, even when administered to unstable patients.
Military Medicine Leads The Way
When the U.S. military entered Afghanistan in 2001 and Iraq in 2003, morphine was its primary drug for treating pain on the battlefield. It was soon supplemented by even more potent opioids, including fentanyl lozenges and hydromorphone. Near the end of the decade, growing concern about the opioids led military doctors to consider ketamine as an alternative.
When used to treat wounded soldiers, ketamine provides excellent pain relief. Some who receive it report little or no recall of their acute event. Based on this success, the military developed guidelines for ketamine’s use, trained its medics and corpsmen to administer it and supplied the medication to units deploying for combat.
Civilian Interest Grows
When word got out of the military’s favorable experience, several civilian EMS services and hospital ERs started using ketamine “off-label” to treat pain. Prescribing FDA-approved medications for non-FDA-approved purposes is more common than many people realize. Nearly 40% of U.S. prescriptions are written “off-label,” according to the Congressional Research Service.
Over the next several years, numerous clinical trials in civilian ERs and EMS services confirmed that low-dose ketamine works faster than morphine and is as safe and effective. Based on this evidence, five emergency care organizations, ten specialty societies endorsed its use to treat severe pain in emergency care settings. So did the military’s Committee on Tactical Combat Casualty Care.
Is Ketamine Safe?
Allowing medics and other emergency care professionals to administer small, fixed doses under medical supervision is safe. Using ketamine as a “party drug” or to self-treat depression at home is not. On top of that, two heavily publicized deaths put ketamine in a bad light. Both involved highly unusual circumstances and much larger doses of ketamine than those used to treat pain.
In 2019, Elijah McClain, a young, unarmed Black man, was violently tackled by three police officers, twice put in chokeholds, and pinned to the ground. When paramedics arrived shortly thereafter, they administered a large dose of ketamine for presumed “agitated delirium.” Shortly thereafter, Mr. McClain went into cardiac arrest. The contract medical examiner retained for the case concluded that McClain’s death was “most likely the result of ketamine toxicity.” Four years later, a Colorado jury found both paramedics guilty of negligent homicide.
In 2023, Hollywood actor Matthew Perry consumed a large quantity of ketamine and then climbed into his hot tub. Because no one was with him at the time, he drowned. Two months later, the L.A. County coroner ruled that Perry’s death was caused by “acute effects of ketamine.” Drowning, along with coronary artery disease and concurrent use of an opioid, buprenorphine, were listed as “contributing factors.”
In contrast to the annual toll of opioid-related deaths, deaths due to ketamine are rare. CDC recently analyzed four years of data on fatal drug overdoses reported by 44 states and the District of Columbia. A total of 228,668 deaths were identified. Ketamine was detected among other drugs in 912 (0.4%) of these fatalities, listed as “involved” in 440 (0.2%), and was the only substance involved in 24 (0.01%) deaths—an average of six per year. To put this number in perspective, overdoses with acetamenophen account for about 500 deaths per year in the U.S.
“Off-Label” Use Is Not Ideal
Because the FDA has only approved ketamine as an anesthetic, manufacturers produce it in multidose vials of three different strengths. In high-stress emergencies, calculating the correct dose to withdraw from a vial takes time and increases the risk of error. This is why, for more than a decade, the U.S. military has sought FDA approval of ketamine to treat severe pain in combat and other time-urgent emergency care settings.
If (or more likely, when) the FDA finally grants approval, military and civilian teams should be able to acquire prepackaged doses of ketamine or better yet, preloaded automatic injectors that will enable them to relieve the pain experienced by seriously injured patients more quickly and safely. Additionally, pre-loaded injectors are more difficult to divert than multi-dose vials.
The Only Remaining Hurdle Is The FDA
Rather than accept the large body of real-world evidence of the safety and efficacy of low-dose ketamine as an analgesic, the FDA wants additional studies done to pinpoint the best dose and to prove to its satisfaction that this battle-tested drug is effective at reducing or relieving pain. This will take time and money. If the FDA does not reconsider its position, I hope that the U.S. military quickly sponsors the needed research so its medics, corpsmen and doctors, as well as civilian EMS and ER staff, can reduce their longstanding reliance on morphine, fentanyl, and other opioid analgesics to treat severe pain.
The authors views are his own.
