Annette M. Boyle
ROCKVILLE, MD — Morphine has met its match — and then some. After 200 years as the gold standard in battlefield analgesia, morphine is increasingly giving way to ketamine, a phencyclidine (PCP) derivative initially used in veterinary medicine.
Ketamine’s status has changed so rapidly that Army Col. Chester C. Buckenmaier III, MD, director, Defense and Veterans Center for Integrative Pain Management, has encountered some stiff resistance when using the drug. “I’ve twice had a nurse say, ‘You aren’t going to use that horse drug on my patient, are you?’”
|Army Col. Chester C. Buckenmaier III, MD, Director, Defense and Veterans Center for Integrative Pain Management, with a patient in Afghanistan in 2009.|
“That ‘horse drug’” is now one of the most effective tools available. Combat medics rate ketamine as more effective than morphine or fentanyl in providing rapid relief of severe pain, according to an ongoing survey conducted by the Naval Operational Medical Lessons Learned Center, Pensacola, FL.
Unlike morphine, ketamine does not cause hypotension or respiratory depression. It is “unique among anesthetics, because pharyngeal-laryngeal reflexes are maintained and cardiac function is stimulated rather than depressed,” said Air Force Lt. Col. John V. Gandy, MD, (ret.) in a Defense Health Board Decision Briefing.
In a March 8, 2012, memo to Jonathan Woodson, MD, assistant secretary of Defense (Health Affairs), the Defense Health Board (DHB) recommended adding ketamine to the Tactical Combat Casualty Care (TCCC) Guidelines as a battlefield analgesic. The memo noted that ketamine’s “clinical effects present within one minute of administration when given intravenously and within five minutes when given intramuscularly.”
“Four or five years ago, we would have had one or two patients on ketamine at Walter Reed; now about half are on ketamine on any given day. The use of ketamine in battlefield trauma has led the way to using it on wards — and even in civilian emergency departments,” Buckenmaier told U.S. Medicine.
Inhibits NMDA Receptors
Ketamine inhibits the action of the N-methyl d-aspartate (NMDA) receptors throughout the body and, at low doses, acts as a powerful analgesic and mild sedative and produces a sense of euphoria. At higher levels, it works as a dissociative anesthesia and provides moderate to deep sedation.
Ketamine also can cause hallucinations at higher doses, a problem seen particularly in its use in nonclinical settings as the street drug “angel dust” or “special K.” When used in surgical settings, especially for patients who have previously experienced hallucinations with ketamine, the International Committee of the Red Cross recommends using 10 mg of diazepam intravenously five minutes before and again at the conclusion of a procedure to minimize their incidence.
By blocking NMDA glutamate receptors, ketamine minimizes acute pain and decreases the wind-up pain caused by continual bombardment of the central nervous system. Wind-up amplifies incoming pain signals at the level of second-degree neurons in the spinal cord. Blocking these receptors also decreases tolerance to opioid medications.
“Inhibition of NMDA receptors in the acute phase is one of the few therapies that prevent development of chronic pain,” said Buckenmaier. Ketamine’s ability to reduce acute pain and short-circuit the development of chronic pain pathways makes it effective in any perioperative situation or trauma and can reduce post-operative and phantom-limb pain.No Longer Just a ‘Horse Drug,’ Ketamine Increasingly Used for Military Pain Management
Circumvents Opioid Tolerance
Ketamine addresses the significant problem with opioid tolerance in certain battlefield contexts, said Buckenmaier. “In Afghanistan, heroin was obviously a drug problem, particularly in indigenous personnel. Medics would give a standard dose of fentanyl, and it would barely faze them [because]they were so used to opium use and abuse. In situations like that, ketamine became an important tool. It’s a way around opioid addiction for an anesthesiologist.”
Patients who are hyperalgesic, whether from nerve damage or as a result of opioid use, might not respond to normal peripheral blocks. For them, ketamine can help them regain pain control so regular treatment plans can work, Buckenmaier explained. Small doses of the drug also can significantly boost the effectiveness of morphine and possibly prevent development of opioid hyperalgesia.
The drug works effectively to calm patients, as well.
“When I was in Afghanistan with the British at a Role III hospital, I didn’t pick up morphine one time; I always used ketamine. It works very quickly and is highly effective as a trauma anesthetic. When you have foreign nationals — we treat them just as we do U.S. soldiers — they are frightened, maybe they have a leg or an arm blown off. If we need to have them be still, 5 or 10 mg of ketamine works and won’t suppress respiration or cause greater problems with blood pressure,” said Buckenmaier. “At very low subanesthetic doses, it can create euphoria, which is not the worst problem to be having when you’re injured.”
Although effective, ketamine is not always seen as a first-line therapy. “There’s a sense that we need to use ketamine earlier,” Buckenmaier noted.
At Camp Bastion in Afghanistan, ketamine was introduced to flight medics and para-rescue jumpers (PJs), and special forces had begun to use the drug, he noted. “This is a drug that definitely should get out to medics.” Ketamine can be administered intramuscularly, intranasally, orally, rectally, intraosseously or intravenously.
Ketamine’s very favorable safety profile also makes it suitable for use in challenging environments. Gandy noted that the PCP derivative can be used as a single-agent surgical anesthesia in primitive settings where trained personnel and monitoring equipment might be unavailable.
The Food and Drug Administration (FDA) concurs with that view, stating, “ketamine has a wide margin of safety; several instances of unintentional administration of overdoses of ketamine (up to 10 times that usually required) have been followed by prolonged but complete recovery.”
Few deaths have been attributed to ketamine as a single agent, Gandy noted. Further, a study at Walter Reed National Military Medical Center, Bethesda, MD, showed that ketamine use on the wards, even with patient-controlled analgesia, was associated with no instances of issues requiring change in therapy, coding or transfer to a more intensive unit, according to Navy Cmdr. James S. Houston, MD, MC, director, Wounded Warrior Pain Management Initiative, and chief, Division of Pain Medicine, and director, Interventional Pain Clinic.
While ketamine poses less risk physically to patients, its psychosomatic effects have created some concerns about using the drug, though ongoing research may soon put those to rest.
“Ketamine does alter brain function and at high doses can make people exhibit signs of psychosis, but its clinical use is way below those levels. The question is: Might ketamine use contribute to post-traumatic stress injuries? Evidence shows that is not the case,” Buckenmaier said.
A 2008 U.S. Army Institute of Surgical Research (USAISR) study found that servicemembers with severe burns who received ketamine during surgery developed post-traumatic stress injury (PTSI) at lower rates than those who did not receive the drug, 27% vs. 46%, despite having more severe injuries and spending longer in the intensive-care unit. 5
Researchers trying to understand the effect of ketamine on PTSI are evaluating “changes in transcription in response to anesthetic exposure. Preliminary results suggest that ketamine may alter genes involved in memory formation,” according to USAISR. Researchers at Yale University, New Haven, CT, the Connecticut VAMC and New York’s Mount Sinai School of Medicine are conducting clinical trials to determine whether a single ketamine infusion can reduce core symptoms of PTSI.
Ketamine is contraindicated in patients with known or suspected schizophrenia, even if the condition is currently stable, and in infants under 3 months old. Previously, ketamine had been considered inappropriate in cases of increased intracranial pressure, but recent practice guidelines have removed this as a relative contraindication. The Defense Health Board recommended restricting use of ketamine in casualties with suspected traumatic brain injury and those with penetrating globe injuries of the eye.
In battlefield situations requiring silence, the random utterances and movement associated with emergency reactions from anesthetic levels of ketamine may be problematic. In addition, emergence reactions might require active restraint. According to the FDA, about 12% of patients experience emergence reactions. Severe reactions can be terminated by using a small dose of a short-acting barbiturate.4
“Ketamine’s been central in my practice for 10 years or more, but no drug is a panacea. Thinking that any drug is a silver bullet has hurt us. There is no one drug that everyone can use every time with no side effects. A multimodal approach to analgesia is better for patients, as it allows us to attack pain with different medications at lower doses and operating with different mechanisms,” Buckenmaier said.
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 Ketalar-ketamine hydrochloride injection. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/016812s039lbl.pdf
 Battlefield Pain Management. http://www.usaisr.amedd.army.mil/battle_pain_management.html
 Charney DS. Ketamine as a Rapid Treatment for Post-Traumatic Stress Disorder.
 Green SM, Roback MG, Kennedy RM, Krauss B. Clinical Practice Guideline for Emergency Department Ketamine Dissociative Sedation: 2011 Update. Ann of Emerg Med. 2011;57:449-463. http://www.ghdonline.org/uploads/Clinical_Guideline_on_Ketamine_Sedation_2011.pdf