Considering ketamine

Hospitalists may think they know all the options for inpatient pain management, but they might want to take a look at low-dose ketamine, some experts say.

The drug, which works on various receptors including the N-methyl-D-aspartate (NMDA) glutamate receptor, can be used during anesthesia. But it's also being prescribed, at far lower, or subanesthetic, doses, as an adjunct to opioids for some patients with unrelenting pain from sickle cell disease, advanced cancer, and other conditions.

Hospitals vary in whether they have developed guidance for low-dose ketamine, however, as well as on specifics such as who can prescribe the drug, where in the hospital it can be administered, and how patients are monitored.

One challenge is the limited evidence support. Consensus guidelines on the use of IV ketamine infusions for chronic pain, published in 2018 by the American Society of Anesthesiologists among other groups, cited the paucity of studies about using ketamine for acute pain.

Most research in the field has focused on the perioperative environment and a few painful disease states, such as sickle cell pain crises, the guideline authors said. A Cochrane review in 2017, which looked at patients with refractory cancer pain, determined that data were insufficient to assess ketamine's benefits and harms.

Even so, emerging evidence and some experts support the benefits of ketamine for certain hospital patients.

“I'm a proponent for ketamine as I believe everyone deserves a chance to minimize suffering and have their pain better controlled,” said Jennifer McEntee, MD, MPH, MEd, who helped lead the development of a ketamine policy for acute pain at the University of North Carolina Medical Center in Chapel Hill, where she is an associate professor of medicine and pediatrics.

Potential candidates

Case reports, among other evidence, have indicated that ketamine can help some patients when opioids alone aren't sufficient or they can't tolerate opioid-related side effects, such as severe constipation or nausea, reported Dr. McEntee.

Ketamine appears to work particularly well in treating neuropathic pain, such as when patients require painful wound care or a tumor has impinged on adjacent nerves, added Emily Martin, MD, MS, an assistant professor of clinical medicine and an associate director of palliative care at the University of California, Los Angeles (UCLA), David Geffen School of Medicine. “It's that sharp, shooting pain that opioids are not as effective with,” she said.

Dr. Martin, who was the physician lead on an update of UCLA Health's low-dose ketamine policy, said that more physicians and hospital leaders have taken a closer look at the drug as they've searched for alternatives in recent years to further escalating opioids.

“There's a lot of fear and concern about the opioid epidemic,” she said. “I think that, in light of that culture, ketamine has risen as an opioid-sparing medication, which is very appealing to many providers.”

Dr. McEntee, who presented at SHM Converge earlier this year about the use of ketamine in hospitalized patients, listed an array of potential indications, including neuropathic pain, pain related to vaso-occlusive crises in sickle cell disease, and acute or chronic severe pain not relieved by opioids and other medications. She strongly encourages earlier use of ketamine on a trial basis for many of the aforementioned conditions.

Patients who experience a traumatic injury also may benefit from the drug as part of their pain management, said Melissa Weimer, DO, MCR, an associate professor of medicine at Yale School of Medicine in New Haven, Conn. Dr. Weimer, who specializes in internal medicine and addiction medicine, recalled an example of a patient who was prescribed ketamine after trauma surgery; she had fallen some 30 feet and had multiple fractures, including of the arms and face.

Other potential candidates include those patients who have already developed a high opioid tolerance, among them survivors of opioid overdoses, Dr. Weimer said. These individuals may have been found after lying immobile for some time and thus can develop compartment syndrome in a limb, which may require multiple painful surgeries to debride damaged tissue and muscle. The hospitalist may be called to collaborate with the orthopedist or trauma surgeon on how best to manage the patient's pain, she said.

Ketamine, which is prescribed for treatment-resistant depression, can provide relief for patients with advanced cancer or other types of pain that involve some degree of existential suffering, noted Rabia Atayee, PharmD, BCPS, a professor of clinical pharmacy at the University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences.

This type of pain, she said, is “both physical and psychosocial. Whether the patient can tell that about themselves is irrelevant. Sometimes patients can't separate their suffering.”

Variable guidance

The 2018 consensus guidelines include some details about subanesthetic prescribing, but Dr. Atayee wanted to develop more targeted guidance to assist hospital clinicians developing their facilities' policies. After surveying 15 health systems, she discovered that there wasn't sufficient consensus to do so. Only nine of the studied systems both had ketamine guidelines and were able to share them.

“What we found was that there was a lot of variation in dosing but also who could prescribe it,” said Dr. Atayee, lead author of the resulting study, published online on April 19 in the Journal of Palliative Medicine.

Dr. Martin found similar variations, including in who could order the drug, when she reached out to colleagues at other hospitals while developing UCLA Health's policy. At UCLA, low-dose ketamine is typically used for refractory pain or as an adjunct to opioids, she said. Under the policy, any physician can order the drug, but this should be done in consultation with a palliative care physician or an anesthesiologist.

Hospitalists shouldn't prescribe the drug without consulting with a specialist, such as an anesthesiologist or a pain medicine team, agreed David Dickerson, MD, chair of the Committee on Pain Medicine at the American Society of Anesthesiologists. Such experts can assist with dosing and other considerations, including how the drug will interact with existing pain medications, said Dr. Dickerson, section chief of pain medicine at NorthShore University HealthSystem in Evanston, Ill.

Also, he asked, “When you start someone on ketamine, and it's not working, what do you do next? Now, do you call that consulting physician? It would have been better to have them involved earlier.”

At UC San Diego, prescribing was initially limited to pain medicine and palliative care clinicians, with the patients typically being monitored in the ICU or intermediate care unit, said Dr. Atayee, noting that the institution's guideline was approved by the pharmacy and therapeutics committee. Under that guideline, ketamine can be administered as an IV between 0.1 mg/kg per hour and 0.5 mg/kg per hour.

Most commonly, patients start at 0.1 mg/kg per hour, and their pain is reassessed daily to determine if the ketamine should be increased another 0.1 mg/kg, Dr. Atayee said. When administered as a continuous infusion, the drug “works fast—usually within 12 to 15 hours you are getting the full benefit of the medication.”

To determine if the ketamine is working, Dr. Atayee checks whether patients' pain has eased, whether their functioning has improved, and if they require fewer opioids for pain control. “The patients that have made me a believer in ketamine for pain,” she said, “their opioid requirement was cut in half.”

Other considerations

Precisely how ketamine impacts the body physiologically is difficult to sort out, as many of the studies to date have involved the doses used for anesthesia, which are typically 1.5 to 2 mg/kg or higher given as a bolus, the authors of the 2018 consensus guidelines noted. Moreover, “there is no standard definition of what dose is considered ‘subanesthetic,’” they wrote.

While the drug is metabolized by the liver and excreted by the kidney, “in the vast majority of cases, prolonged effects on hepatic or renal function have not been noted with subanesthetic doses,” according to the consensus authors. But physicians should be aware of the drug's potential effects on the cardiovascular system, and subanesthetic prescribing should likely be avoided in patients with unstable angina, a rapid heart rate, abnormally low blood pressure, or other cardiac risk factors, Dr. Weimer said.

She also suggests caution in patients with an underlying psychosis or unstable mental health disorder. If ketamine is prescribed, such patients should be closely monitored for dissociative symptoms, including hallucinogenic effects, she said.

Given ketamine's role as an alternative for more difficult-to-treat pain, candidates for treatment will include those with a history of substance use disorder, Dr. Weimer said. Physicians may be reluctant to prescribe ketamine to such patients because of concern about substance use disorder, but she does not see it that way.

“I completely disagree with that,” she said. “The option if it's not used is that you increase opioids, which causes other harms, or you allow the patient to suffer with severe pain.”

As patients on subanesthetic ketamine near discharge, hospitalists should pay close attention to their outpatient pain control plan and should ideally work with a pain management team if one is available, Dr. Dickerson said. Otherwise, patients could potentially return to the hospital seeking re-administration of the drug, he said.

He recommends that physicians be cautious in the use of subanesthetic ketamine for patients with a substance use disorder, due to the potential for abuse or misuse. Ketamine is a schedule III drug and can be misused for its hallucinatory effects, according to the Drug Enforcement Agency.

Overall, though, the drug remains underutilized to ease refractory pain, Dr. Martin said. Hospital physicians should have a lower threshold to recommend ketamine on a trial basis, with a plan to discontinue the drug if it doesn't prove to be effective, she said.

That can be determined after several days, Dr. Martin said, adding that 12 to 15 hours of a steady infusion is typically needed to determine if the current rate works. The dose can be slowly increased upwards. But, she added, if there has been no improvement in the patient's pain once a rate of 0.5 mg/kg per hour has been reached, in her experience it is unlikely the patient will benefit from further increasing the dose.

“There are some patients who seem to respond extraordinarily well to ketamine such that it is absolutely life-changing—it shifts the entire course of their hospitalization,” Dr. Martin said. “And then there are some patients that you think would respond well, or you think that this would be a good agent, and they just don't seem to have the response.”