Aspirin/Ketamine Combo Shows Promise in Pain Management

This transcript has been edited for clarity.

Robert Glatter, MD: Welcome. I'm Dr Robert Glatter, medical advisor for Medscape Emergency Medicine. Today we have a distinguished panel joining us to discuss an important advance in pain management in the emergency department using a specialized form of aspirin and oral ketamine.

Here to discuss this new study is Dr Sergey Motov, professor of emergency medicine and director of research in the Department of Emergency Medicine at Maimonides Medical Center in Brooklyn, New York. Also joining us is Dr Joseph Habboushe, assistant professor of emergency medicine at Weill Cornell Medical Center in New York City and co-founder of Vitalis Pharma.

Welcome, gentlemen. I really appreciate you taking the time to join us.

Sergey M. Motov, MD: Thanks so much.

Joseph Habboushe, MD: Thanks for having us.

Glatter: Joseph, I want to start with you. It's very interesting how this aspirin that you describe in your study, VTS-Aspirin, has a very integral role in terms of its actions with ketamine. I wanted to start off and let you describe what exactly VTS-Aspirin is, its mechanism and the rationale behind its use.

Habboushe: Thanks so much for having us, first of all. We were trying to solve a very well-known problem in medicine, which is that we don't have that many great pain medications out there. Ketamine has been approved for decades. We know that in low sub-dissociative dose, from some other studies that Sergey had done in the past, it is a very powerful pain medication. The problem is that ketamine is limited in a few ways.

Number one is that it doesn't work that well orally. It doesn't have good bioavailability. Number two is that whenever you do see good pain reduction, you typically see dissociation and sedation rates that would limit outpatient or more common use. The third is how long it lasts. A single dose of ketamine wears off after about an hour, so that's not great for oral use as well.

We wanted to find a way to address these three known issues in ketamine because, if so, maybe we're going to be able to unlock a really powerful new drug that doctors can use to help their patients.

We were trying to repurpose VTS-Aspirin, this aspirin formulation that we had come up with years ago. This aspirin formulation, which we're calling VTS-Aspirin, was originally developed to solve a totally different problem. If you remember, high-dose niacin for cholesterol — vitamin B3 in really high doses — we know does tremendous things for your cholesterol and used to be a very commonly used drug.

It had patient-centered side effects that really bothered folks. It caused this painful, bright-red burning of the skin. My father was on this drug and he wouldn't take it as often as he should because of the side effect. It bothered me so much because we already knew that taking an aspirin 30 or 60 minutes before would significantly reduce that flush, but getting that timing right was really hard.

Of course, people who are on cholesterol medications are on aspirin anyway. It seemed like a problem we should try to solve. Over a few iterations, we eventually came up with the formulation of aspirin you could take at the same time as the high-dose niacin, and it would lower the flush. Eventually, we found out that this was also helpful when combined with ketamine.

Glatter: Sergey, in terms of the action of aspirin, the specialized form with ketamine, how do these two interact? Is there a potentiation mechanism? From what I've read, there may be some effect on the NMDA receptors, and that could actually reduce the analgesic efficacy of ketamine. It's kind of a paradoxical approach from what I'm trying to understand here. Maybe you can clarify this for me.

Motov: Aspirin sort of modulates the NMDA receptor presence toward increasing it. At least in theory, one suspects that maybe, at some point, it can diminish the analgesic efficacy of ketamine. Results of the study showed a completely different entity.

To our great amusement, they seem to work synergistically very well. It could be possible that there are some anti-inflammatory properties or some antinociception that plays a different role in the synergy. I'm a firm believer that maybe for some unknown reason yet to be discovered, there is some great deal of synergy combining a COX-1/COX-2 enzyme inhibitor and an NMDA receptor antagonist.

Glatter: I want you to jump into the results of the trial, the study design, primary and secondary outcomes, need for rescue analgesia, and go through the study with me to let our audience understand what you found in this pilot trial.

Motov: I'd love to. Again, the idea was to put the pilot together. It was a single-arm, prospective interventional study, sort of proof-of-concept. As of right now, I don't believe that there are any studies ever done on oral ketamine at the scale that we've decided to do, especially in combination with proprietary VTS-Aspirin.

In all, 25 adult patients presented to the ED with a variety of acute musculoskeletal pathology. The reason we chose musculoskeletal pathology is that we frequently use NSAIDs and ketamine in my shop. It's one of the most common reasons patients can come in and require oral analgesia in comparison to parenteral.

The rationale was to look at the feasibility with respect to overall analgesic efficacy and tolerability, and, of course, the presence or absence of adverse effects. As Joe mentioned earlier, ketamine is notoriously known to cause a significant degree of dissociation and sedation.

Again, it was a single-arm, prospective interventional study. Patients received two capsules (324 mg; 162 mg per capsule) of VTS-Aspirin with a specific instruction to suck on the outer layer of the capsule for about 30-45 seconds and to subsequently swallow it. We used an injectable version of ketamine to administer it orally. Patients were instructed to sort of swish the liquid ketamine in their mouth for about 45 seconds or so and subsequently swallow it, which imitates the proprietary novel mechanism release of VTS-Aspirin and ketamine.

We used the research pharmacy to help us with the preparation of the medication. We added a little bit of sweetener to offset the bitter taste of ketamine and we used a dose of 0.5 mg/kg. The reason we had chosen this dose was that it was the minimally effective dose in a study by Lintner, who used oral ketamine for patients suffering from burns when they underwent burn wound dressing changes. That was shown to be the minimum effective dose. As you know, in my prior studies, I'm very big on using the lowest effective dose as potential to offset a great deal of adverse effects.

We enrolled 25 patients. Why? Because we used an effect size of 1.3 as a minimal clinically significant difference in the pain change score from baseline to 60 minutes. We used a standard deviation of 3. We used a one-sided thesis with a 97% confidence interval. That's how we came up with the number.

Here are the results. Of 25 patients, 20 achieved greater than 1.3-point change in pain score up to 60 minutes after medication administration. Overall, 60%, which is 15 out of 25, achieved greater than 4-point change from baseline to 60 minutes. Clinically, it translates to a 44.7% reduction in pain score from baseline. This is one of the largest we've had from the oral perspective. I've done studies on oral NSAIDs and we're talking about 1.7-2.2 points, somewhere around 30%. This was a whopping 45%.

More important, only one patient had a moderate degree of dizziness at 30 minutes and one patient had a moderate degree of sedation. The best part is that only 4% of patients, which is actually one patient, experienced moderate degree of feeling unreality, which can be equal to a dissociation, at 30 minutes, which basically resolved on its own at 60 minutes.

We've concluded that 80% of patients experienced greater than minimum appropriate effect in pain score change from baseline to 60 minutes. As I said, 60% of patients had a greater than 4-point relief from baseline to 60 minutes. The results were very, very encouraging.

Glatter: Because it's only 16% bioavailability orally, doesn't that, from the get-go, mean that you're giving someone a fractional dose of ketamine in the oral delivery route? How does that really play out? In other words, if it's such a small dose, how would that compare against an NSAID or simply another arm of the trial as a comparator?

Habboushe: That's a great question. When you take drugs orally, of course, often they act differently from if you get it IV or transmucosal, or what have you, because of first-pass metabolism. It actually happens for both of these drugs. Ketamine rapidly transforms into norketamine. Remember, norketamine is actually an active metabolite of ketamine. It just works a little bit differently.

The way we're giving it to patients is meant to have as much transmucosal absorption as possible. Sergey was describing that even the ketamine was swished around the mouth. The aspirin is also designed to do that, so there might be some avoidance of first-pass metabolism, which will help with this.

I think we are also most likely seeing some kind of synergistic effect of how aspirin, which is known to upregulate part of the NMDA receptor, could hurt the beneficial effects. There's probably something going on with that in terms of the ketamine and norketamine and the NMDA receptor, and how there is modulation of the NMDA receptor with aspirin.

Glatter: Is there research at a deeper, molecular level to try to figure this out receptor-wise? Is there anything at your company, Sergey, in terms of any further inquiry into the exact mechanism regarding the two synergistically?

Motov: Well, not at that level that you described because I'm primarily geared toward clinical research studies in humans. The potential study is to randomize subjects to different concentrations, different dosing regimens, and check the blood levels and compare it with existing ones. As you mentioned, if oral bioavailability is about 16%-17%, it would be interesting to see the C_max or T_max of the oral ketamine that is partially absorbed in the oral cavity and subsequently swallowed. You can maybe find healthy volunteers to do this, not necessarily patients, and measure the concentration at 15, 30, 60, and 90 minutes and compare.

It's all theoretical. I'm happy that we're having this conversation and that you're giving us great ideas. As of right now, that's where we stand. It's purely clinical and it's purely inpatients with acute pain in the ED.

Glatter: Right. In terms of throughput, looking at length of stay, in your experience from this pilot, do you see this as a reasonable approach that would adhere to guidelines in terms of quickly getting people managed, treated, and then discharged?

Motov: Yes. As I mentioned earlier, we were very encouraged by the results. We all have taken NSAIDs at some point in our lives and we know it takes somewhere between 45 minutes to maybe an hour to kick in and feel some sort of relief. Even if somebody comes in with a grade 2 sprain or B contusion, where I would consider giving NSAIDs plus ketamine, I need somewhere between 45 and 60 minutes to at least observe them in the ED for some mild to moderate efficacy of effect that they'll be comfortable to go home with.

What amazed us and really encouraged us is that adverse effects related to ketamine administration, specifically dizziness, were very short-lived and disappeared in most of the patients by 30 minutes. Those moderate-intensity adverse effects were gone by 60 minutes. None of the patients experienced severe side effects, such as abnormality in vital signs or altered mental status. They didn't go into a K-hole. They did not require rescue benzodiazepines.

These are things that set up the precedent that, maybe with future studies, a combination of oral ketamine with a novel mechanism of release and VTS-Aspirin will be a great analgesic alternative or the drug managing a variety of acute painful conditions in the ED, and outside of the ED, as you pointed out — let's say, fast-track, for instance.

Glatter: Right. As long as this doesn't delay throughput, and certainly if patients are responding, that's obviously a big positive. What about treating migraine headaches, other types of pain, or renal colic? Is there any thought about that at this point?

Habboushe: I think this is all hypothesis-generating, right? This is a pilot study. Really early days, for sure. We want to see this repeated in randomized controlled trials, but it is pretty exciting.

Another thing I'll add is that in Sergey's study, they measured pain for 120 minutes, or 2 hours, and you still had good pain reduction at 2 hours. There are a few oral ketamines that have been out in some other countries that are used in small procedures in clinics, where you see a little bit of pain reduction that wears off after an hour. That's also very promising, but we need to repeat these studies. We need to make them randomized.

I would love to see them — were talking to some folks — in postoperative pain, especially for some postoperative patients who need to be on aspirin anyway for VTE prophylaxis. It might line up really well with what they would potentially be doing.

Glatter: Maybe VTS-Aspirin alone might have an effect without ketamine. It would be interesting to study that in that separate arm, and obviously, in a larger study and play that out.

Motov: As you know, aspirin is the most commonly used over-the-counter medication for headaches. You're right; you have this type of formula with a partial rapid release that might be beneficial, and again, a hypothesis is a beautiful thing, but we need to have studies to prove it.

I have three take-home points and then, obviously, I defer to Joe. First is that synergy — for some unknown ways as of yet — between aspirin and ketamine is palpable. Even in the small pilot study, it was very encouraging.

Second, the ability of oral ketamine, being given in a way that part of it gets absorbed in the oral cavity, might have a great deal of faster analgesia, which could be very beneficial in a variety of acute painful presentations in the ED.

The last part, which is probably more important to me, is that the incidence of adverse effects by combining oral ketamine and VTS-Aspirin was significantly lower in direct comparison to all the studies in IV and even embolus ketamine that my team and I conducted at my shop in past decades. These are three points.

Glatter: Okay. Joe?

Habboushe: Thanks. What I get really excited about is trying to figure out how to use existing medications to solve problems. There are so many new medications coming through, which is great, and we need to push the boundaries of new medications. As a practicing doctor, I want what is safest for my patient. I love this idea that we've potentially been able to find a way to take a drug that already exists, that has some really great pain benefits, and then maybe address these known limitations. Again, making it work orally, having the side effects low but still having good pain reduction, and having it last a little longer.

It seems like those three things are getting addressed here, so to me, this is potentially very promising. There is a ton of work to do to really repeat this and prove that it's actually there because this is early days, as we talked about.

Glatter: Certainly, this is opioid sparing and that's obviously a big positive here. No one can argue that that's a big effect. Is there any addiction potential here — patients who feel a certain way and then come back or even request the medicine — that you see in the future as being an issue?

Motov: I have a decade worth of studying ketamine in different routes and for different groups of patients: pediatric, geriatric, adults, given intravenously, subcutaneously, and via short infusions. I have to tell you, I've had scores of patients through my research and my daily practices and I've yet to see patients who would come back to my emergency room and say, "I would like to get ketamine because I felt very good on this."

Again, we haven't measured a high. Don't get me wrong: Ketamine is associated with a high and that's why it's recreationally used — but on a dosage regimen that is almost three to five times higher than the one that we used for medicinal or research activity to that extent.

The fear is always there. Is it substantiated? Of course. I believe that there is another hypothesis that maybe having the VTS-Aspirin entity will offset that potential high associated with ketamine, and ultimately, the incidence of it would be so negligible that it's actually going to be very legit and a good medication or combination of such to treat patients.

Habboushe: Just adding to that, ketamine is a scheduled drug by the DEA [US Drug Enforcement Administration], so we take that very seriously. It's a lower schedule than opioids, for obvious reasons. It's very hard to overdose on ketamine.

Also, medicine's best understanding is that the addictive potential is related to the out-of-body feeling, the dissociation of ketamine. The hope is that if we're showing lower dissociation rates and we're also using a much lower dose than you typically see in recreational use, then maybe we have a safer alternative. Again, early days.

Glatter: Do you see that this one day might have some role in the outpatient realm, so to speak, as opposed to just ED, urgent care, or primary care settings?

Habboushe: I would say that if we can see that this works, that it has low side effects and it's safe, and the FDA agrees with that, then there are some use cases that could be really beneficial. That's why I mentioned postoperative pain earlier. We know that when we send patients home postoperatively, a few of them will take some opioids, and months later, some of them are still taking opioids. This is a problem that I think we can address if we have powerful, potentially less addicting medications.

Again, it’s early days here, but I could imagine that in those periods of high, acute postoperative pain, that's where I'd love to see this studied next. We're talking to some folks who are researchers in that space now.

Motov: If I can add to that, it's the same from the ED perspective, as all three of us are ED docs. Acute pain in the first 24, 48, up to 72 hours post-ED discharge — this is, I personally think, a great use of this combination, should it prove to be efficacious in larger-scale, randomized, double-blinded, two- or three-arm studies. That's what we primarily do as ED docs: We take care of patients in acute pain. If it can alleviate pain and suffering with a lower degree of adverse effects and a beneficial profile of analgesia and harms in comparison to opioids, everybody wins.

Glatter: Thank you both for taking time to discuss your research. It's very important and groundbreaking..

Robert Glatter, MD, is assistant professor of emergency medicine at Lenox Hill Hospital in New York City and at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is an editorial advisor and hosts the Hot Topics in EM series on Medscape. He is also a medical contributor for Forbes.

Sergey M. Motov, MD, is professor of emergency medicine and director of research in the Department of Emergency Medicine at Maimonides Medical Center in Brooklyn, New York. He is passionate about safe and effective pain management in the emergency department, and has numerous publications on the subject of opioid alternatives in pain management.

Joseph Habboushe, MD, is assistant professor of emergency medicine at Weill Cornell Medical Center in New York City and co-founder of Vitalis Pharma.

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