Central Line
Episode Number: 138
Episode Title: New Findings re Ketamine
Recorded: July 2024
(SOUNDBITE OF MUSIC)
VOICE OVER:
Welcome to ASA’s Central
Line, the official podcast series of the American Society of Anesthesiologists,
edited by Dr. Adam Striker.
DR. ADAM STRIKER:
Welcome to Central Line.
I'm Dr. Adam Striker, your host and editor. Dr. Aaron Primm, from the editorial
board of Summaries of Emerging Evidence, more commonly known as SEE, is with me
today. And the topic on our minds today is ketamine. A few recent studies
included in the 40B issue of SEE shed new light on this old drug. So we're
going to dive in and explore what's new. Dr. Primm, thanks for returning to the
show.
DR. AAROM PRIMM:
Thank you. So great to
be back. It's been a little bit of time, but I'm excited to talk to you again
about SEE.
DR. STRIKER:
Fantastic. Let's start
by, if you don't mind telling us, our listeners, generally speaking, why this
topic warrants our time and attention.
DR. PRIMM:
Yeah. So today we're
going to focus on a couple of studies about ketamine. And you know, it has
really an interesting history and complex activity in the body. You know, we
use it for analgesia, for post-operative pain, acute and chronic pain
exacerbations, sedation even for RSIs. And there's more and more studies
looking at other chronic conditions that ketamine could affect.
I'll just give a little
bit of background on the drug itself. It is a cyclohexadiene. And the first one
in that class that was identified in 1956 was Phencyclidine or PCP. And in
1962, ketamine was compounded to try to possess some of those positive qualities
without that severe excitation and and profound psychosis, although there is
some psycho mimetic effect from ketamine, but mostly acts as an NMDA receptor
antagonist that gives its amnestic and amnestic dissociative effects. But
there's also a lot of other interactions in the body. Uh, it inhibits Enos
synthase, activates Gab receptors, interacts with, uh, nicotinic acetylcholine
receptors, dopamine, mu opioid receptors, all those things. And that's kind of
why we see all these unique interactions in our body. And there's some arguably
positive effects, of course, of the drug, which is why we use it. Uh, the
sympathomimetic and minimal respiratory effect can blunt central pain
sensitization. But there's also been a renewed interest in this drug, one with
the rise of the opioid epidemic, as people have been looking at this and
subanesthetic doses to, you know, reduce opioid tolerance, decrease
hyperalgesia following surgery. And now we're looking at it for a few different
niches. Um, talking about treating chronic depression and also headaches.
DR. STRIKER:
Well, you've already
gone over a number of uses of ketamine. As most of our listeners know, general
anesthesia, sedation, pain control, etc. But we do want to focus a little bit
on therapy for treatment resistant depression. It's not necessarily new to a
lot of our listeners, but recently, I mean, it's relatively new in the
specialty. And electroconvulsive therapy or ECT is also commonly used for
treatment resistant depression. Let's talk a little bit about a recent study
that sheds a little new light on the comparative effectiveness of of those two
treatments, the ketamine and ECT. And also just maybe include a little bit of
background about treatment resistant depression.
DR. PRIMM:
Sure. So a major
depressive disorder is is worldwide a cause of disability. And, uh, estimates
about 21 million adults in the United States, very prevalent. And more than a
third of the patients do not receive adequate treatment with antidepressant
medications alone. And this resistant depression really has no consensus
definition. But commonly it's thought of as depression with unsatisfactory
response to two or more adequate trials of antidepressants. And, you know,
talking about ECT. It's one of the most effective strategies for treatment
resistant depression for going on nearly 80 years, particularly effective for
late life and catatonic suicidal depression. And, you know, even though it
could be performed as an outpatient procedure, it's it's still relatively
underutilized just because it's limited availability. There's a social stigma
attached to it. Uh, there's concerns regarding cognitive impairment. Um, and
we're looking now at ketamine infusion might be more palatable and also
effective for patients.
DR. STRIKER:
So let's go over the
studies a little bit. Just talk a little bit about this specific study and the
methods used maybe.
DR. PRIMM:
Sure. Yeah. So this
first study that we're looking at is called the electroconvulsive therapy
versus ketamine in patients with treatment resistant depression, the elect D
study. This is a prospective randomized non-inferiority trial, uh, conducted at
five sites, and it compared a three week treatment of ketamine to ECT. And the
ketamine was done in two treatments per week, uh, 0.5mg/kg of ketamine that was
administered over 40 minutes, and the ECT was done three times per week using a
right unilateral lead placement. Um, the patients enrolled are 21 to 75 years
old. They had a diagnosis of major depression. And importantly, these are
patients that did not have psychotic features. And these patients had
inadequate response to two or more antidepressants and also had no contraindications
to ECT or ketamine, of course. And the primary outcome was showing a response
to treatment. And they defined that as having a 50% or greater decrease in
their depressive symptoms. And this was done by an inventory of depressive
symptomatology in the study. Um, all the patients that had an initial response
to treatment then received six months of follow up treatment. And then some
other outcomes they looked at were treatment response scale measurements,
memory function, cognitive symptoms, and just overall quality of life.
DR. STRIKER:
Okay, so let's talk a
little bit more about what ultimately this tells us as a specialty. What can we
glean from the results, the primary outcomes.
DR. PRIMM:
Yeah. So what they ended
up discovering is that a response to the treatment was present in 55% of the
ketamine patients and only 41% of the ECT patients, and that fell within that
noninferiority margin. And the dissociative events were more frequent in the
ketamine group, whereas there were some more musculoskeletal adverse effects in
the ECT group, which is probably to be expected. Um, and they concluded that,
you know, ketamine was noninferior to ECT as therapy for treatment resistant
major depression without psychosis. And, you know, I think that was kind of a
important step for, you know, the right patient needs treatment and they may
not be very excited about starting ECT therapy, this is potentially another
option if these patients meet the criteria. And of course, more studies need to
be done to address the comparative effectiveness in patients that are more
prone to be helped by ECT. So older patients, patients with bipolar depression,
inpatients, things like that. But overall very enlightning study.
DR. STRIKER:
Well, we've known about
this for a little while with ketamine and it's been used quite prevalently. So
talk a little bit about what has shifted here or what have we not known before.
What do we know now?
DR. PRIMM:
Right. So we did not
know that it would be a similar in the response rate. Right. And you know, in
the past there was a lot of assumptions that just doing Ketamine fusion
couldn't be as effective as ECT. And really what they set out to do was to say,
hey, at least this is noninferior for these patients. And in some respects they
are kind of choosing and picking which patients are going to respond. Um, but,
you know, I think the study is really proving that patients can potentially go
to an infusion center, have this done and still get a great response, and avoid
all the potential downsides of undergoing ECT therapy.
DR. STRIKER:
Great. Well, I want to
ask you a little bit about ketamine and migraines. Um, but let's take a short
patient safety break. So stay with me.
(SOUNDBITE OF MUSIC)
DR. DEBORAH SCHWENGEL:
Hi, this is Dr. Deborah
Schwengel. I'm chair of the ASA patient Safety editorial board.
Anesthesiologists need to be prepared to handle mass casualty incidents that we
call MCIs, but many anesthesiologists are not familiar with the protocols in
place to deal with MCIs. Every hospital should have incident command systems
that are activated to manage the dynamic and usually novel circumstances of
MCI. Every MCI is different. Incident command organizes teams into subteams
with clear and manageable scopes of responsibilities. The incident command
structure is designed to optimize communication to maximize patient and staff
safety. It's very important to remember that certain patient populations are at
higher risk during MCI, namely children, pregnant patients, the elderly, and
cognitively impaired patients who require careful triage and appropriate
referral. Care should also be taken to prevent inequities that affect people
with disabilities and people of color. Ongoing education on hospital policies
and procedures, as well as disaster preparedness exercises, rehearsals, and
simulations are needed to ensure that anesthesiology teams are ready. The time
to prepare is now.
VOICE OVER:
For more patient safety
content, visit asa.org/patient safety.
DR. STRIKER:
Well, we're back
discussing ketamine and summaries of emerging evidence with Dr. Aaron Primm and
the other study that I believe you want to talk about is regarding refractory
chronic migraine. Can you remind listeners a little bit about what this is and
how historically ketamine has been used to treat chronic migraines?
DR. PRIMM:
Yeah, sure. So
refractory chronic migraine is when there's inadequate response to to multiple
proven medications. And these have a significant impact on disability and
patients quality of life. And in 2018 there was some joint society consensus
guidelines published from ASRA and the American Academy of Pain Medicine and
the ASA, and they had five RCTs that described the benefits of IV infusions of
subanesthetic ketamine for headache. Just as an aside, you know, subanesthetic
is also not consistently defined as a lot of these things are. But many of the
studies used about 0.5mg/kg with an infusion rate of of less than 0.5mg/kg per
hour. And, you know, however beneficial the issue is that the IV Ketamine
required dose titration and adverse event monitoring by by pain specialists in
the hospital which could limit its use in the outpatient setting. And
practitioners who supervise the procedures or its administration should at a
minimum, you know, be ACLs certified, meet ASA requirements for moderate
sedation. And this is where we come across what's used in the next studies
intranasal ketamine.
There is some evidence
for intranasal ketamine in the treatment for headache disorders like migraine
and cluster headaches. But its role in treating this refractory chronic
migraine is not really been well described. Um, the intranasal ketamine, I
think maybe not everyone's really familiar with it. It's got a rapid systemic
absorption. Um, you bypass the first pass hepatic metabolism. Um, it's it's
about 25 to 50% bioavailable, which is actually higher than oral. But we should
be aware that this is actually an off label use for the medication. The
pharmacology and optimal dose delivery systems haven't really been fully
determined, and the ideal routes are still unknown. We don't really know the
time to onset, the bioavailability, which nasal passage to use, the spray
viscosity, all these details. But you know, it is preferable that the
medication be deposited higher in the nasal cavity to be better effective, better
absorption with that olfactory epithelium, lower clearance. And the FDA
recently approved esketamine, which is the uh s enantiomer, uh, for this
treatment resistant depression. And this is kind of the basis for why this
study was done using this medication.
DR. STRIKER:
Well, let's go ahead and
talk about the details of this study, how it's done. And let's outline it a
little bit.
DR. PRIMM:
Yeah. This study was
done by Yuan and colleagues published in Regional Anesthesia and Pain Medicine.
Um, they retrospectively reviewed the effectiveness and tolerability of
intranasal ketamine in 169 patients that had a refractory chronic migraine, and
these were patients that were outpatients at their tertiary headache center.
And it was the clinical practice of the center to offer intranasal ketamine to
patients after they had failed a standard anti-migraine medications, and they
compounded it as ten milligrams per 0.1ml, and the patients were instructed to
use 1 to 2 sprays in each nostril per dose every 15 minutes as needed, with up
to 20 sprays per day or 40 per week, at the discretion of the providers. And
they're also very careful to monitor them. All use of controlled substances and
alcohol and driving were all restricted while using the drug. The patients with
refractory chronic migraine who were prescribed this intranasal ketamine were
identified by looking at hospital records from 2019 and 2020, had a structured
telephone interview, and they collected a bunch of data related to pain relief,
pain scales, quality of life, adverse effects, Um, when they looked at the
population, all these patients had migraines, and two thirds of them had daily
headaches with some comorbid anxiety and depression, and most had failed three
preventative medications, were on at least two acute medications for migraine
management. So these were definitely, definitely patients that had a lot of
refractory disease.
DR. STRIKER:
All right. And what did
the researchers learn.
DR. PRIMM:
So, you know, in terms
of effectively treating the headaches, 49% and 39% of the patients, they rated
the intranasal ketamine as very effective or somewhat effective. And 78% of the
patients stated that the ketamine made their quality of life much better or
somewhat better. So a generally positive response, just based on these
interviews. And, you know, when they asked to compare this drug with other
acute headache medications, 43% rated as much better, 29% as somewhat better.
Only eight and 3% would say it was somehow inferior to their other medications.
And there was a lot of daily use that happened, about 13% of the patients, and
21% still used it more than 15 days per month. So a lot of continued use. But
what's interesting is that the the average daily intranasal ketamine dose was
only 60 to 80mg, which is much lower than the average infusion dose that the
patients were getting otherwise, which was almost 1000mg. About three quarters
of the patients reported less use of their other acute medications. But, you
know, there was 74% that had at least one adverse effect, which is something of
course, we should, you know, look into. Most commonly they were things like
fatigue, diplopia, blurred vision, uh, hallucinations, confusion, some vivid
dreams. But, you know, they were usually short lasting and did not necessitate
discontinuing the drug. And there were also about 7% that had some rise in
their transaminases, but without any rise in bilirubin. So, you know, all in
all, the authors concluded that on an as needed basis, this drug seems to have
mitigated their acute headache pain intensity and and reduced their other acute
medication use. So that was promising to see that just in this kind of
retrospective telephone interview, that there was a lot there to to work with.
And I'm sure that they're going to be using this study, you know, as a basis to
undergo other randomized controlled trials, try to really dial down on what can
be effective.
DR. STRIKER:
Do you have any insight
to the likelihood of or risk of dependence with ketamine? I mean, in this
particular circumstance.
DR. PRIMM:
I think there's always
the potential, which is the reason that there was a lot of coaching and and
teaching and monitoring. Um, you know, a large amount of these patients had
daily use and continued it way past the study date. Um, but what's promising, I
think, for at least intranasal s-ketamine is that, as we mentioned, that the
total dose per day was much lower than if they were getting treated with an
infusion, much less likely to have some sort of overdose, you know, especially
because with excessive sprays that that medication just ends up in the stomach
and that has poorer bioavailability than through the nasal passage. Um, is
there a concern for abuse? You know, I think so, and I think that's why they're
watching it. I don't think there's going to be some sort of epidemic of people
writing scripts for ketamine from infusion centers or anything like that. But I
think in terms of, you know, a drug that has these positive aspects to it, I
think we shouldn't shy away from exploring how we can use it.
DR. STRIKER:
Well, you selected these
items to include in in SEE. Do you mind telling our listeners why these
particular studies, and also why you think these are important? And then
ultimately, what would you like all the clinicians to take away from from the
information?
DR. PRIMM:
Yeah, I think since we
had these two studies in this issue about ketamine, it'd be interesting to talk
about them together and really try to kind of expand some horizons, draw some
interest into a drug that we, you know, some of us use every day, but maybe not
in these certain aspects or maybe not in our little subspecialty area. And both
of these studies show a lot of promise and what is possible. Um, and they
really suggest that in some selected patients that these subanesthetic doses,
whether it be intravenous or intranasal, they can really effectively manage,
you know, these resistant refractory neurologic disorders.
You know, we talked
about the potential for abuse. I think we always just need to, you know, with
any medication, we're going to weigh the risks and the benefits of using this
in our in our clinical practice. And the other factor that I think is important
to to discuss is that unlike ECT and some antidepressant medications, uh,
ketamine is generally not covered by insurance. And, you know, that can cost
around 4 to $500 per infusion. So ultimately, more studies needed for both. But
they they point to this larger role, uh, ketamine is going to have for
patients.
Another very interesting
aspect that recently was published in anesthesiology, the special article is
talking about ketamine and several other drugs, but they could contribute to a
possible overlap between anesthesiology and psychiatry. And because these drugs
are kind of bordering on this fine line between the two, and they really have
some synergy together, I think. Some of the highlights that they discuss about
things that they could pursue is understanding the role of depression in
perioperative outcomes, the the effects that routine anesthetic care can have
on patients with psychiatric illness. And what I also thought was different
idea was a proposal to have a subspecialty that would actually focus on
anesthetic neuropsychiatry, and then you would have quote unquote, bilingual
clinicians and scientists, you know, who could understand both areas and talk
to each other and collaborate and really advance the medicine and the science
in that direction. So, you know, I just think overall, really interesting topic,
really interesting drug and something to think about for everyone.
DR. STRIKER:
Yeah, that is a
fascinating thought bridging the gap between psychiatry and anesthesiology.
Well, before I let you go, I believe the 40 B issue that we were referring to
for SEE is out now, correct?
DR. PRIMM:
Yes, it is out.
DR. STRIKER:
Okay. And you can earn
up to 30 CME credits for this issue.
DR. PRIMM:
Yes.
DR. STRIKER:
Aside from the studies
we touched on here, were there any other studies that you would like to flag
for our listeners or something that might pique their interest to look into
this specific issue.
DR. PRIMM:
Yes, of course, many
great items in this issue. I'll give you just two snippets. The first is the
risk of a motor vehicle crash within 28 days after general surgery was similar
when compared to that in the Pre-surgical interview of 28 days in the overall
adult population. So a month before and after surgery, there's there's no
difference in risk of motor vehicle accidents. Um, the second one, um, a
randomized controlled trial demonstrated that the application of emla or
eutectic mixture of local anesthetics of emla cream to an endotracheal tube
cuff was associated with reduction in sore throat through the six postoperative
hour and a reduction in severe cough and hoarseness through the first 24 hours.
And I noticed a great amount of literature that typically shows no effect with
all these different things that we try to do to mitigate these adverse effects.
Um, but I thought it was really interesting that they really did show something
with emla cream. So, you know, all in all, two very interesting and applicable
studies that that you can dive more into with the issue 40B.
DR. STRIKER:
Yeah. Fascinating. Um,
really quite interesting. And SEE continues to be a great resource. And so I
highly encourage all our listeners to to check it out. It's always chock full
with a lot of great, pertinent, prescient information. Well, Dr. Primm, thanks
so much for joining us again. And, uh, giving us a little insight into a couple
really fascinating and unique studies. Love to have you on again to update us
some more.
DR. PRIMM:
Thank you, Dr. Striker.
It's my pleasure. It's great. Great speaking with you again.
(SOUNDBITE OF MUSIC)
DR. STRIKER:
And for those of you
interested in checking out the SEE platform, please go to asahq.org/see. Just
that simple. Again, to all our listeners, thanks for joining us on this episode
of Central Line, and please tune in again next time. Take care.
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