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K. or Nay?

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Ketamine is currently enjoying a surge in popularity. Though the year 2017 is still young, a PubMed search of articles with “ketamine” in the title limited to 2017 showed that there’ve already been 106 such publications released this year. Practical Pain Management named oral ketamine for pain management as their Practical Clinical Advance of 2016.

Earlier this year, I delivered a webinar called “What’s So Special about Ketamine? A Review of Its Uses at the End of Life” to a national audience of our hospice partners. Judging by both the volume of attendees and questions and comments I’ve received, it’s clear to me that many end-of-life practitioners are indeed very interested in ketamine, but why?

Ketamine, brand name Ketalar, or “Special K” as it’s known when used illicitly (along with many other creative nicknames), is more than 50 years old. Although originally synthesized in 1962, it wasn’t until 1970 that the FDA approved its use as a disassociative anesthetic, which remains its only labeled indication today.

Ketamine, for who and why?

When a drug is used for an indication that’s non-FDA approved, it’s being used in an “off-label” manner. Ketamine has been studied for a variety of these off-label uses, including many different types of pain, psychological conditions such as depression, anxiety and PTSD, and less commonly for other refractory symptoms like seizures and asthma. Besides the wide variety of uses, there are also different ways to administer ketamine other than the FDA-approved IV/IM routes, including oral, subcutaneous, rectal, intranasal, inhaled and topical administration.

I think the primary reason for the intrigue surrounding ketamine is that all of us who work in the hospice landscape hate to see patients suffer—physically, emotionally or otherwise. Ketamine has the potential to allow some of our patients to avoid this suffering. Therefore, I believe it is incumbent on us to learn as much as possible about it in order to answer questions like: Who’s the ideal candidate for use? How should it be dosed? What issues (i.e., adverse effects, contraindications) do I need to look out for?

Let’s start with that first question—Who’s the ideal candidate for ketamine use? Ketamine isn’t, and probably won’t ever be, first-line therapy for any of the off-label indications mentioned above. Therefore, we need to frame its use in terms of when it should be considered. Take refractory pain for example: despite the many other drug therapies available, including opioid and non-opioid analgesics and all sorts of adjuvants, unfortunately, we still run across patients with poorly controlled pain.

Knowledge about ketamine’s purported mechanism of analgesic effect sheds some light on when to consider its use. Ketamine is a potent N-methyl-D-aspartate (NMDA) receptor antagonist, but what exactly does that mean? The precise workings of this receptor system are still not fully known, but blocking it seems to have a number of effects, including curbing opioid tolerance, reducing neuropathic pain, as well as changing the ways pain is processed (specifically, inhibiting aspects of central sensitization such as the “wind-up” effect).

Ketamine can also be beneficial for particularly difficult to manage pain types, including allodynia and hyperalgesia, both of which are potential adverse effects associated with opioid-induced neurotoxicity (OIN). Although myoclonus is perhaps the most easily recognized feature of OIN, more troubling is the potential that the very opioids we’re using to treat pain may, in fact, be causing it in some patients.

Considering the above, you could make an argument that ketamine should especially be considered for pain management in patients with some combination of neuropathic pain / high opioid tolerance / OIN. Also of interest: some researchers have found what they term “use dependence,” where the higher the opioid dose a patient is on when they start ketamine, the more likely it is that ketamine will be beneficial.

Wouldn’t it be great if ketamine could allow for both better pain control and opioid dose reduction? Though hospice is often considered a “carve out,” some prescribers I work with have let me know that they too are feeling the heat (e.g., the oft-criticized Centers for Disease Control and Prevention (CDC) opioid prescribing guidelines) in terms of reducing opioid prescribing, particularly at very high doses. I’m sure many would welcome a non-opioid adjuvant, particularly one that allows them to reduce opioid prescribing.

While pain management is a cornerstone of hospice care, it may be ketamine’s use in the treatment of depression that’s the primary factor driving interest in ketamine. Its antidepressant mechanism(s) are still being elucidated, but they may be less related to its NMDA receptor-blocking effect and instead involve one or more of ketamine’s metabolites acting at a separate AMPA receptor system, with ketamine itself acting as a prodrug. Long-term upregulation of these receptors in response to activation by these metabolites may explain why the antidepressant effects of single-dose ketamine typically persist for several days after ketamine has cleared systemic circulation.

How does ketamine work?

While we don’t know exactly how it works to treat depression, there is little doubt that most who take ketamine (interestingly, unipolar or bipolar) will respond positively, quickly, and unfortunately, transiently. Ketamine has even been found to be beneficial in suicidal patients, who perhaps represent the pinnacle of suffering. The beneficial effects are often realized within hours and typically persist for about a week after a single dose.

In my opinion, the importance of this rapid benefit cannot be understated. According to the National Hospice and Palliative Care Organization’s (NHPCO) most recent facts and figures, the median life expectancy of a hospice patient is about 17 days. In other words, if we started all of our depressed hospice patients on conventional antidepressants, which take weeks for their full effect (if they work for the patient at all), about half would die before the antidepressant took full effect.

One might argue that we could instead use methylphenidate if we’re hoping for relatively immediate antidepressant actions. It may be preferential for some, such those who also suffer from apathy or fatigue, but it’s not appropriate for all patients. Also, be mindful that pain and depression frequently coexist. Undertreated pain can contribute to depressive symptoms, and conversely, depressed patients’ pains are often more difficult to treat. Therefore, add patients who are both in pain and depressed to our list of ketamine candidates.

Administering and dosing ketamine for EOL patients

So, if you have a patient who may benefit from ketamine, how do you dose it? Although the optimal dosing and route of ketamine administration for either pain or depression is thus far not universally agreed upon, a number of straightforward dosing strategies have been proposed. The oral route is the least invasive and, in my experience, the most agreeable to both patients and prescribers. It’s also the most studied route in the hospice setting. Even at the end of life, where many experience dysphagia, most are still able to take either the solution for injection or concentrated compounded solutions orally.

Ten to 25mg given orally three to four times daily can be considered a starting dose for pain. It can be titrated rapidly by 5mg per dose (or 20mg per day). Most patients will likely require about 100mg per day, although some will need several hundred milligrams per day and doses as high as 900mg/day have been reported. I usually recommend to titrate as tolerated until an effective dose is reached. If ketamine is completely ineffective despite titration to a few hundred milligrams per day, I believe it’s unlikely that ketamine is going to provide much benefit and discontinuation should be considered.

The American Psychiatric Association (APA) recently released a consensus statement on the use of ketamine in the treatment of mood disorders, and avoiding at-home, self-administration was a point of emphasis. However, applicability of this statement to the terminally ill population is debatable, particularly since hospice doctors and nurses could closely monitor their patients.

Importantly, ketamine dosing for depression differs from its analgesic dosing. The most commonly recommended oral dose for depression is 0.5mg/kg given either as a single dose or once daily. I typically recommend a one-time dose to start with because even though most patients who respond do so within hours, some respond a day or two after the dose and ongoing use isn’t always necessary.

To my knowledge, off-label dosing in the settings of renal or hepatic impairment hasn’t been studied. Despite this, because ketamine is both hepatically metabolized and renally eliminated, a more conservative dosing approach is reasonable. In addition, since ketamine likely works as prodrug to provide its antidepressant benefits, hepatic conversion to its metabolites is essential for its antidepressant effects.

Monitoring for effect/side-effects

Like with any other drug, if ketamine is commenced, close monitoring of adverse effects and efficacy is essential. The adverse effects are dose-related, but the exact incidences of individual side effects when it’s used off-label are unknown. When used for depression, most hospice patients don’t experience clinically significant adverse effects. When they do occur, they’re typically mild and transient, subsiding within a few hours. When used for pain, where doses are often higher and more frequent, about one half of patients experience side effects, but these do not always lead to discontinuation.

Ketamine can potentially cause psychomimetic, cardiovascular, gastrointestinal and urinary adverse effects. Psychomimetic effects consist of decreased cognition, psychosis and “emergence phenomena,” which are adverse effects such as delirium, nightmares or sensory misperceptions experienced as ketamine is wearing off. Importantly, patients do not always find these emergence phenomena distressful and some may even find them to be pleasant. In the future, pharmacogenetics may play a role in predicting which patients are more likely to experience these effects.

As far as cardiovascular adverse effects, both hypertension and tachycardia have been reported. Gastrointestinal disturbances including hypersalivation, nausea/vomiting and diarrhea are also possible. Cystitis is an uncommon but severe side effect most commonly associated with total daily doses of 400mg per day or more. Ketamine should be discontinued if this occurs. This effect is common in long-term street users of ketamine and is referred to as “K-cramps.”

What’s missing from the above list of adverse effects? Respiratory depression. It’s very uncommon, even at anesthetic doses, and especially at subanasthetic doses. In fact, some authors have reported that if CNS depression occurs with use, reduce the opioid (due to ketamine’s opioid-sparing effect), not the ketamine. At this year’s American Academy of Hospice and Palliative Medicine (AAHPM) assembly, I met an anesthesiologist and of course had to pick his brain on ketamine. I mentioned to him I thought many were deterred from prescribing ketamine due to the perception of dangerous adverse effects. He laughed out loud and said, “I don’t know why they would be—they write for opioids and benzodiazepines on a daily basis and they’re a heck of a lot more dangerous than ketamine.”

Even if intolerable adverse effects occur with use, that’s not necessarily the end of the story. If the benefits of ketamine are such that continued use is desired, the adverse effects can potentially be mitigated with other medications, some of which patients probably already have orders for. Antipsychotics or benzodiazepines have been used for psychomimetic side effects. Anticholinergics can be used if hypersalivation occurs. Various cardiovascular drugs are available if hypertension are tachycardia become problematic enough to warrant treatment.

Contraindications to ketamine relate closely to its adverse effect profile, and unfortunately they’re unclear and inconsistent from source to source. Many have been reported, including: increased intracranial pressure (ICP), seizure disorder, uncontrolled hypertension or tachycardia, prior severe reactions to ketamine (or to prior illicit hallucinogenic drugs) and other severe psychiatric disorders. Of these, most have at least some evidence to refute them. For example, ketamine has been safely used in patients with ICP and has actually been used as a treatment for refractory seizures. Generally, I’d avoid ketamine in patients with severe psychiatric disorders like schizophrenia, but beyond that I question whether absolute contraindications exist in the hospice setting.

Monitoring ketamine’s analgesic effect can be done with a number of pain rating scales. In terms of its antidepressant efficacy, it’s also preferable to use a structured tool, such as the Montgomery-Åsberg Depression Rating Scale (MADRS). If a partial response is observed, increasing to daily dosing seems to be a rational next step. Rarely, some patients find it beneficial to dose more frequently.

Stopping ketamine

When ketamine is effective, we have another question to answer: How long should it be used? Long-term ketamine use for medical reasons has not been studied. Long-term illicit use has been linked to severe urologic symptoms, cirrhosis and even brain damage. Unlike most medications, ketamine’s effects can persist in some patients for weeks to months after stopping, so ideally it shouldn’t be continued any longer than necessary. In patients with prognoses of several weeks or more, some recommend to discontinue it once it’s effective with the hope that the benefits persist and the fallback plan that it can be restarted if needed. The argument could also be made that when using in hospice patients, use will not typically be “long-term.” Being that it’s not typically used as first-line therapy, I can imagine that both patients and prescribers alike will be reluctant to stop it if it’s an overwhelming success.

If discontinuation is attempted, conflicting recommendations exist. There have been case reports of worsening pain involving hyperalgesia and allodynia if ketamine is abruptly stopped, so some recommend a tapered discontinuation over several weeks. Conversely, others have reported that it can be stopped without withdrawal effects.

To conclude, ketamine can likely be of benefit to a subset of hospice patients who suffer from pain or depression that’s resistant to conventional treatments or when those treatments would take too long to work. More and more information on off-label use of ketamine continues to be published each day, so keep your eyes peeled, because if you haven’t already, I think at some point you probably will take care of a patient who could benefit from ketamine.

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Written by Joseph Solien, PharmD, BCPP, CGP. Joe is the Senior Clinical Pharmacist for OnePoint Patient Care and based in Tempe, Arizona.

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