Narrator - Dr. Abel  00:00
Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions.

Narrator - ?  00:11
This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy.

Narrator - Dr. Abel  00:17
This podcast contains general information for educational purposes only. This is not professional advice, and should not be used in lieu of obtaining advice from a qualified health care provider.

Narrator - ?  00:27
And now on to the show.

Dr. Sean Kane  00:31
Welcome to Episode 95 I'm your co host, Dr. Kane. I'm Dr. Schuman, and I'm Dr. Patel, and today's title of our episode is the ultimate guide to NSAIDs, an in depth drug class review where we'll be talking about NSAIDs, everything from, when are they indicated? What are some of the toxicity profiles of those? And really, what are some of the differences between a drug class that has over 20 different drugs in its category?

Speaker 1  00:55
So if for our listeners, setting up the background will be nice. And so we can talk about, maybe how the NSAIDs actually work, and looking at the detailed pharmacology. So as we know, it's an anti inflammatory works on the inflammatory pathway that triggers the release of arachidonic acid. And this arachidonic acid is then further acted by cyclooxygenase enzymes, and eventually they are then converted into prostaglandins, prostacyclins and thromboxanes. And these are compounds. They play an important role in, you know, mounting fever and causing pain and inflammation, but they are also important in certain non inflammatory pathways to carry out daily functions of bodily organs, right?

Speaker 2  01:38
And there are really two different types of COX enzymes. So you have Cox one or cyclooxygenase one, that's the one that's always expressed as part of your routine cellular maintenance and function. One of the big things we know about that is responsible for the protection of the gastric epithelial cells. So that's one of the reasons why, from blocking it, we see gastrointestinal toxicities with our NSAIDs. And it'll be something we'll be talking about plenty, but it's also involved in producing thromboxane A2 which increases platelet activation. So again, it's a reason why we have aspirin as an antiplatelet drug, as a medication that can interfere with platelet function. It's also why we can see NSAIDs having issues, or NSAIDs and aspirin having issues with bleeding. Again, an important consideration for counseling points, and I'm always a believer in instead of memorizing side effects by understanding the mechanisms of action, and then the side effects become more intuitive there. And so then Cox two is only expressed, or is a response to inflammation and cellular damage produces compounds such as part of the inflammatory response. So again, blocking it has an anti inflammatory effect.

Dr. Sean Kane  02:38
So really, the pain, inflammation, fever component is a Cox two mediated thing where you have arachidonic acid. Cox two works on arachidonic acid to produce these compounds that will, in turn, cause fever, inflammation and pain. So if you think about it really like if we were to design the perfect drug, we would design a Cox two inhibitor that would inhibit this pathway. But most of the NSAIDs in the market do both. They do Cox one and Cox two inhibition. And as we'll talk about later, chemists did think about, well, maybe we just want the Cox two effects in terms of blocking that pathway. And it turns out that actually didn't work out so well. And we'll talk about why that was as well, right?

Speaker 2  03:16
So I think one of the things that Dr. Kane pointed out was there's over 20 different NSAIDs in the US that are approved. So when we look at these with the what are some that come to mind of the US, kind of the main, the Mainstays, the one you think about the most.

Speaker 1  03:27
So I mean, there are some of these that are available over the counter too. But if you break down the usage based on how many prescriptions were filled, you know, we get to see things such as Meloxicam (Mobic) and ibuprofen (Advil or Motrin). We're looking at like 21 million prescriptions per year in the United States.

Dr. Sean Kane  03:50
And then my personal favorite, for a variety of different reasons, naproxen (Aleve) — prescription brand Naprosyn, that one has 11 million diclofenac goes through a bunch of different brand names like Zorvolex, Zipsor, Voltaren has topicals. It has oral products, things like that. We're at about 10 million for that one, yeah.

Speaker 2  04:09
And then we've got a Celebrex or celecoxib at about 6 million, and then a whole host of other ones. And kind of in that 1 million or more, ketorolac (Toradol), which is often used as an IM or IV injection, so probably not captured as part of that million. So may actually be a little bit more — Etodolac (Lodine), not seen as much in practice; nabumetone (Relafen), which I felt like had some use, but not seeing that much. And then indomethacin (Indocin), which I think is a really interesting one, but still around that 1 million per year.

Dr. Sean Kane  04:39
Just to put a number to it, roughly around 1 million prescriptions per year. Puts it within striking distance of the top 300 drug category in the US in terms of outpatient fills for prescriptions. So, you know, we've gone through a number of NSAIDs that do fulfill that, like top 300 drug category in terms of commonness of prescriptions. So, so. Is it to say these are incredibly commonly used drugs within this NSAID drug class,

Speaker 1  05:05
and then there are some combination products available with acetaminophen and aspirin, and, you know, they're commonly, kind of combined into this NSAID categories. And those two are different beasts to handle all together. You know, talking about aspirin, you know, we use it a low dose for anti platelet effects, for cardiovascular risk reduction, and then Tylenol, which is the acetaminophen. You know, we always kind of compare and contrast. Are you taking NSAIDs, or are you taking Tylenol for pain or even fever control? And then the mechanism of action, as well as the side effect profile there, is completely different, but we're not going to go into detail of those two.

Dr. Sean Kane  05:40
So in terms of, you know, you have a drug class with 20 plus drugs in it, we have really important considerations in terms of, why might we pick one instead over the other? And that's really part of today's podcast is to help the listeners understand why might you pick ibuprofen over naproxen or Meloxicam over a Celebrex. So what are some things that we think about when comparing and contrasting these agents.

Speaker 2  06:02
I think one thing to think about right off the bat again is me, what is the efficacy data? Do we have anything looking at comparative efficacy among these agents that would maybe allow one of them to rise above the pack?

Dr. Sean Kane  06:11
When we talk about efficacy, we have to think about, well, what indication Are we even thinking about? So for the most part, most of the comparative evidence is going to be with pain, especially with arthritis and gout, those are two very common indications, knowing that we'll also see it for headache and kind of inflammatory conditions, like musculoskeletal conditions that commonly are associated with pain as well. So we're kind of encompassing all of that in today's podcast.

Speaker 1  06:38
And what's the finding, then? Is one superior in treating osteoarthritis or gout, per se, over the others.

Speaker 2  06:44
So yeah, the Agency for Healthcare Research and Quality, AHRQ, put out a really nice NSAID guideline in 2012 looking at osteoarthritis, and found that really, there's not a preferred NSAID among all the data on that they all seem to do equally well. And I

Speaker 1  06:59
think this evidence is also backed up by the 2012 American College of Rheumatology guidelines for osteoarthritis treatment as well,

Dr. Sean Kane  07:07
and gout is basically the same way. So if you look at the 2017 American College of Physicians gout guidelines, they do not have a preferred NSAID, which was actually kind of surprising to me, because when I think gout NSAID, I think of indomethacin, and really they recognize that that is the go‑to NSAID in gout, but they also comment, and they basically say, there's no reason for that. This is what we've always done. There's no evidence that indomethacin is better for gout than any other NSAID on the market. It tends to be the one that we use historically, but without really good evidence saying that it's better for any other reason.

Speaker 1  07:39
But I do know, Dr. Schuman, you want to point out indomethacin is used somewhere else. So what do you got there?

Speaker 2  07:44
Yeah, let me crack my knuckles real quick. So one thing I like is that found out there's actually an entire class of headaches called indomethacin‑responsive headaches, in which this agent, compared to others, has a very potent effect in certain types of headaches, and a lot of that, it's thought because it has a similar chemical structure, an indole group that looks a lot like melatonin as well as triptans and ergotamine. And so because of that, as well as some increased lipophilicity, it seems to do a really good job of penetrating the CNS compared to a lot of the other NSAIDs and these other agents, which may be used for headaches as well. It lends it to this exquisite response that you really get from that medication. And so again, you have this whole classification that's simply based upon if it responds to indomethacin, then it kind of fits into this one headache group. So we've had a few patients that will fail many different medications; you give them indomethacin and, all of a sudden, it does what nowhere else would. So that's my little soap box about some exquisite use of indomethacin.

Dr. Sean Kane  08:41
And what's really interesting about that, which you pointed out, is that within these 20 plus NSAIDs, chemically, these are not always similar. There's a lot of different chemical structures that play a role in NSAIDs. It's not like one category with a side chain that is modified 20 times. We see a lot of different chemical structures and compounds that make up this larger drug class, which is just fascinating. So really, if we're trying to summarize here, then from an efficacy standpoint, aside from kind of this niche, indomethacin‑responsive headache, for gout, for osteoarthritis, for pain, as long as you dose the NSAID at an equipotent level, you're going to see equal efficacy among all NSAIDs.

Speaker 1  09:23
Then, yeah, then what does really the choice boils down to is, how many times do you want your patients to take it? Right? So we have NSAIDs available. They are variable in their half‑lives. So depending on the half life, then we're going to have patients take it either every four hours up to every 24 hours too. We have some of those longer acting ones available.

Dr. Sean Kane  09:43
And again, commercials like for naproxen or Aleve really take advantage of this, and they show you how many pills you're going to have to take if you take their comparator over the counter product, and how often you're going to take it. And you know, absolutely this is a concern for patients in terms of pill burden, right?

Speaker 2  09:59
Absolutely. Yeah, so then another factor to look at is going to be the safety aspect of it. So we kind of already talked about differences in Cox one versus Cox two selectivity. So by blocking Cox one again, you got some of those concerns with the lining of the GI tract and risk for ulceration or bleeding. And then with Cox two, you potentially have a concern that we've learned, if focusing on it too much you may have some some concerns about cardiovascular safety. And so that balance between Cox one and Cox two, I think, has to be considered as well. And we'll

Dr. Sean Kane  10:27
definitely get more into why that cardiovascular safety thing cropped up later in the podcast.

Speaker 1  10:33
Yeah, so taking a look at kinetic based differences, and you know, frequency of administration throughout the day, we have some very short acting NSAIDs that are dosed two to four times a day. The examples are ibuprofen — that's the most common one available over the counter — indomethacin and diclofenac that kind of fit there. But then we have some moderately long acting NSAIDs there are Ketorolac and celecoxib dosed. You know, Ketorolac can be dosed up to four times a day, versus celecoxib one to two times a day. And then there are some that are longer acting. That's 10 plus hours of half life. And we're looking at that naproxen like Dr. Kane said, you know, they really capture the marketing there. Dose twice a day. Meloxicam available via prescription, usually prescribed once a day. And then nabumetone (Relafen) is also taken once a day.

Dr. Sean Kane  11:21
And what's interesting here is that many of these NSAIDs are renally eliminated, so as the patient gets older, or they have some degree of chronic kidney disease, typically your dosing frequency will also be diminished, where you won't have to take it as often per day. And to be honest, if you take it more often, then you're going to be at a higher risk for side effects, because your NSAID levels are going to be higher,

Speaker 2  11:39
all right. So I think next, then we kind of to delve in a little bit more into that, that Cox one, Cox two. Unfortunately, Dr. Kane, we don't have that cool time machine again this week, but I do want to kind of get back in the history of it. So the Cox two selective medications were really developed because of that knowledge that blocking Cox one, and some of the GI issues and concerns about bleeding, stomach aches, pain there. So again, what if we can focus on that Cox two piece, really hit the anti inflammatory aspect, and can we avoid some side effects? So they they really wanted to avoid the event the gastric mediated pathway of Cox one. And the only problem with that, though, is we added a whole kind of the law of unintended consequences. So we avoided a lot of the Cox one issues with the gastric system, but ended up with new Cardiovascular toxicity. So Dr. Kane, where did that come from? Why would that be such a problem?

Dr. Sean Kane  12:26
So it turns out that we think that blocking Cox one may have some degree of a cardiovascular protective role, because we do know that with aspirin, the way it has this antiplatelet effect is that it blocks COX‑1 mediated thromboxane A2 production, and thromboxane A2 is a prostaglandin involved in activation of platelets. So you take aspirin, you don't make thromboxane a two, then you don't activate as many platelets. But if you have a Cox two selective drug like celecoxib or Celebrex, what can happen is that you get zero antiplatelet effect, and maybe you even shunt some of the prostaglandins that are produced to that Cox one pathway to promote more platelet aggregation, because you have all of these arachidonic acid products hanging around that aren't converted by Cox two into something so they get converted by Cox one. So the lack of that platelet inhibition is the thought of why we might see worse cardiovascular toxicities. And this got to the point where a number of Cox two selective drugs were actually removed from the market. And the one that comes to my mind is Vioxx, or rofecoxib. This is a Cox two selective drug that I saw tons of drug commercials when I was growing up or in pharmacy school, where, you know, it was those lawyer commercials of did you take Vioxx and did you have a heart attack? If so, call our number and we'll get you all this money for a claim. Really, at this point in the game, the only Cox two selective drug in the market anymore is Celebrex or celecoxib. And as we'll talk about later, the data supports that probably celecoxib or Celebrex is similar in cardiovascular toxicity to other NSAIDs that are on the market, whereas with Vioxx and some of these other Cox two selective drugs that are no longer in the market, they were probably worse from a cardiovascular standpoint.

Speaker 1  14:12
So I guess Celebrex was a really good example of how they could be Cox one or Cox two. Specific. Vast majority of the NSAIDs are fairly balanced between the Cox one and Cox two inhibition, but we do have some that favorite Cox one or the Cox two inhibition, so we're looking at more of the Cox one inhibition. Again. These are the ones that put higher risk of Gi toxicities versus the other. NSAIDs are ketorolac and indomethacin versus the COX‑2 ones such as diclofenac, meloxicam, and celecoxib (Celebrex).

Dr. Sean Kane  14:45
and some people will even claim that meloxicam (Mobic) is kind of preferentially COX‑2 versus a true COX‑2 selective drug, and diclofenac is just a little bit below Meloxicam in terms of its Cox two preference or selectivity. And again, this is very theoretical. What I mean by that is that this is test tube data of how well it binds to Cox one or Cox two. Most of the data does not support a strong difference in GI bleeding risk between indomethacin versus diclofenac, for example. And that's

Speaker 1  15:14
exactly what we're going to look at. Now kind of dive into what are the safety differences? And that probably is the the end of all game, if you're really applying it to, I guess, special population, per se, right?

Speaker 2  15:26
So I think one of the first things you look at is going to be that, that dreaded boxed warning. And so with with NSAIDs, you do have three of them to account for and patients to be aware of. So first, something I already mentioned about, is the GI toxicity. So risk of bleeding, risk of ulcerations and risk of perforation more common in the elderly, but it's even there. Surprisingly, for celecoxib, Celebrex does have a lower risk versus the non‑selective NSAIDs, but it's still on there.

Dr. Sean Kane  15:52
And another box warning for all NSAIDs is that they increase your risk of cardiovascular thrombotic events, specifically heart attacks and strokes, and this risk is going to be higher with with prolonged use of NSAIDs, typically probably also a larger dose of the NSAID and also, specifically in patients who are at higher risk of cardiovascular disease, are also going to be at a higher risk for this event to happen.

Speaker 1  16:17
And I guess the third warning is very specific to those high cardiovascular risk patients who are undergoing CABG (coronary artery bypass graft) surgery. So that's a specific surgery that requires, or we call it open heart surgery, too. And really the warning comes from as we talked about the Cox two specific inhibitors that were previously studied and were found to be harmful. If we look at Cox one and the aspirin, you know it's good to inhibit the thrombox and a two production and and decrease the plate aggregation. Turns out Ketorolac, which is more Cox, one leaning NSAID, also has this warning. But again, the data suggests, and the mechanism suggests that it shouldn't really and

Dr. Sean Kane  16:58
this actually surprised me a little bit. So we do use ketorolac in our open heart surgery patients. I think that the FDA may have been a bit aggressive and labeling all NSAIDs to have this warning on the basis of Cox, two drugs that are no longer on the market, but theoretically, all NSAIDs do carry this warning, and the ketorolac data hasn't, kind of been challenged to remove that as a boxed warning for CABG surgery patients.

Speaker 1  17:23
Yeah, and the outpatient side, you know what I normally see for those who are undergoing this kind of surgeries, the recommendation is to stop all NSAIDs seven days before, except if they're taking 81 milligram aspirin for cardiovascular protection, they can still undergo CABG and be taking the small‑dose aspirin.

Speaker 2  17:41
So kind of a sum of all this and these toxicities. So something that mirroring the language on medications like benzodiazepines now and opioids, is going back to the idea about using the lowest effective dose for the shortest duration of possible use. And so again, thinking about all the other non pharmacologic interventions that can be done for pain, just like and just like we would if we're talking opioids or benzodiazepines, is really looking at the risk versus benefit. And if you don't need to use the medication, don't. If you can do a dose de escalation, do that too, and I

Dr. Sean Kane  18:08
just want to highlight here. So we have over the counter drugs that have now three box warnings for gi perforation, bleeding and ulcer and heart attacks and stroke. That's crazy to me that we allow some of these to be over the counter products and leave it up to the consumer, the patient, to kind of dose it and decide how long they want to continue it and things like that. So I think it's really important as pharmacists, that we educate patients about some of the safety issues with NSAIDs. And I think probably the biggest one is going to be the GI toxicity.

Speaker 1  18:39
And give you an example. Takes me back to my fourth year rotation at UIC. You know, we saw four major hospitalization ER visits due to overuse of NSAIDs. One caused renal failure and the other had caused, you know, GI bleeding.

Dr. Sean Kane  18:54
What's interesting about GI bleeding is that when GI bleeding happens, only about one in five patients will actually have symptoms before the ulcer turns into a bleed, meaning that many patients will have asymptomatic ulcerations, and they won't actually have symptoms prior to the serious event happening where they actually have that bleeding or perforation. So sometimes this can actually be silent in a really bad way, right?

Speaker 1  19:16
And then I believe some of the underlying risk factor can exacerbate this, chances of NSAIDs induced ulcer and bleeding too, right? So some of some of the examples is, if they, if they have peptic ulcer disease, or they had a history of Gi bleeds, you know, they're gonna, it's gonna put you at a 10 times higher risk of having bleed with NSAID use.

Dr. Sean Kane  19:36
And hopefully that makes sense. If it's happened before, it's more likely to happen on an NSAID and

Speaker 2  19:40
a few of the other ones. So looking at the highest, higher dose, longer duration of therapy. Again, going back to the idea about minimizing the overall exposure when you can other things that are interesting, looking at concomitant medications, and this makes sense, other medications that can have anti inflammatory properties. So again, the NSAID, meaning non‑steroidal. So the steroidal piece, adding that on as well. And. Aspirin and anticoagulants and then potentially SSRIs. This is an area that's been a hot topic number of conferences we've gone to, and it's one that, yeah, in some individuals, it may be clinically meaningful. Large population, it's it's not always something you can make a blanket actionable statement, but for certain individuals that that may be an issue, and you have to really look at the risk versus benefit for every one of the patients.

Dr. Sean Kane  20:22
Just to put a number to it, if you have someone who's taking warfarin versus Warfarin plus an NSAID, that addition of the NSAID, increases the risk of GI bleeding by about three to six times. That's an incredibly high risk. And again, this isn't just for warfarin. We're not just picking on that one. This is any anticoagulant, so the DOACs — things like that, to have an NSAID plus an anticoagulant that dramatically increases that risk, right?

Speaker 1  20:45
And that, that is why it's so much more important for us to educate the patient on, you know, unopposed use of over-the-counter NSAIDs along with prescription ones.

Dr. Sean Kane  20:56
So other risk factors also include smokers, those with alcohol use and abuse. And then anyone with advanced liver disease or coagulopathies, again, that kind of makes sense, that they're going to be at a higher risk for bleeding. And then finally, kind of older people. So this would be anyone above 60, that's a risk factor for inset induced GI bleeding, as well as just poor general health status. So more comorbid, more debilitated, more elderly, those patients typically are going to have lower gfrs. They're typically not going to be aware of some of their symptoms. They're going to have many other competing drug interactions that increases their bleeding risk. Just to put a number to it, if you're not including some of these risk factors for someone who starts an NSAID, about 1% of patients will have a serious upper GI event that would typically be a GI bleed or a perforation about 1% over three to six months from starting NSA therapy, and then at one year, the risk of an NSA induced serious upper GI event is about two to 4% that's a pretty high percentage for again an over the counter medication,

Speaker 1  21:58
absolutely so what do We do to mitigate some of the risk, you know, how can we fend it off?

Dr. Sean Kane  22:04
So one option that we have is considering Celebrex or celecoxib, because of its Cox two selectivity, and from the class study at nine months, they found that those who received Celebrex, as opposed to a non selective NSAID, had a lower risk of GI events, mostly GI bleeding. The difference, though, was this was only in those who were not taking aspirin, so the risk was point 44% versus 1.27% with a non selective NSAID. However, if a patient was on aspirin, the protective effects or the lack of harmful effects from celecoxib was not apparent. Basically, both groups had about a 2% risk of a serious upper GI event, such as GI bleeding. So if you're on aspirin, Celebrex is not helpful. If you are not on aspirin, it can reduce your risk of a GI event.

Speaker 1  22:53
That's pretty interesting finding to consider another agent you said it's leaning Cox two, or pretty much a Cox two without being advertised as meloxicam, so something like that can be used in comparison to some of the mixed Cox one Cox two inhibitors. Yeah.

Speaker 2  23:11
And then another thing again, is always, you know, kind of cringe a little bit about adding a medication to fix the side effect of another medication, but considering adding a PPI or an H2 blocker, or misoprostol, something like that, to kind of mitigate that risk. And so we think PPIs, a lot of times, is probably the most effective one. So the ulcer rate, again, similar to the numbers you mentioned before, about 60% reduction from adding something like omeprazole compared to h2 blocker for something like Ranitidine, reducing your ulcer rate by about 45% so still in that same ballpark range. And then another medication that doesn't come up as much, least in my practice, misoprostol (Cytotec), another one that can reduce the ulcer rate by about 65% — that medication is a prostaglandin E analog. And so again, looking at blocking Cox one. And so when you do that, it affects prostaglandin. So this medication produces or gives back some of that prostaglandin effect that that isn't being produced, dosing frequency is going to be an issue with it. So it's a medication has to be given four times a day. There is a combo product — Arthrotec (diclofenac + misoprostol). I don't see that used in practice, really at all, but that is something. And then for a medication that, again, affects the GI tract, unfortunately, you're also going to see other new GI side effects, so things like diarrhea, abdominal discomfort may be noted there. It's probably not as well tolerated as a ppi. And then lastly, the idea is that it is an abortifacient medication, so it's really not one you can use in pregnancy or of women of child bearing age. Obviously, a box warning on there for that reason.

Speaker 1  24:46
And I believe the bottle of Arthrotec says, you know, even, like, do not handle if you are pregnant or you know about to conceive.

Dr. Sean Kane  24:53
So, so I really view this as a no brainer. Like, would you rather take a PPI or an h2 blocker that has almost no side effect? Per. Profile, or would you rather take misoprostol that you have to take four times a day that causes diarrhea, abdominal pain, and you can't take it if you're of childbearing age? I think it's pretty clear that a PPI is going to be most effective and most tolerated, and if a patient isn't a candidate for a PPI niche, two blocker does confer a pretty good benefit as well. So the Gastrointestinal Toxicity is by far the most common toxicity that we worry about with NSAIDs, but especially in the news on the on the tail of these Cox, two selective drugs being removed from the market, we worry about cardiovascular toxicity, specifically increased risk of stroke and heart attack with taking an NSAID

Speaker 2  25:38
so one of the things we know about that is that NSAIDs compete with aspirin, and so therefore, because of that, the anti platelet effect of aspirin can be reduced when it's taken with NSAIDs, maybe some competitive binding there.

Dr. Sean Kane  25:48
What's really fascinating about aspirin is its half life versus its pharmacodynamic properties. So if you look up the half life of aspirin, it's just measured in minutes. It's like 15 to 20 minutes, but the actual duration of anti platelet effect is really, really long, and the reason for that is that aspirin covalently binds to Cox one, whereas all of the other NSAIDs don't do that. So the anti platelet effect of aspirin lasts until the platelet goes away, which is about five to seven days in the anti platelet effect of any NSAID is only based on its half life. So naproxen, for example, has a fairly long half life, it has a fairly long duration of antiplatelet effect. Where it gets goofy, though, is that if you take your naproxen first, aspirin isn't able to bind to that Cox one site. Therefore aspirin doesn't covalently bind, and it doesn't have its antiplatelet effect of five to seven days, it just falls off the platelet and will never bind to it. So there's this really interesting drug interaction where if you take a short acting NSAID before you take aspirin, aspirin will not have its antiplatelet effect for that five to seven day period.

Speaker 1  26:50
Some NSAIDs increase the risk of cardiovascular events by about 1.5×. The COX‑2 selective agent celecoxib (Celebrex) has a risk similar to other NSAIDs. We talked about Vioxx being recalled because of cardiovascular risk; celecoxib's CV profile is similar to other available NSAIDs.

Dr. Sean Kane  27:21
and that was huge for the makers of Celebrex or celecoxib to basically prove that they were not worse than NSAIDs, because many of the other Cox two inhibitors were removed from the market because of this increased risk. I do

Speaker 1  27:33
remember something about naproxen and its cardiovascular per se, not really benefit, but lack of harmful effect. What's the evidence there? Yeah, there

Speaker 2  27:43
was some interesting data that came out that said that it actually may not have that same increased risk of cardiovascular effects of the use of naproxen. And so I remember when that data first came out, actually, one of the manufacturers over the counter, elite said, you know, can we Great? Can we put in our packaging that says we have lower risk? And the FDA was kind of like, no, no, you you can't. You can't do that. There's not they felt in 2014 they put out their ruling that said all NSA didn't get that box warning you can't have anything saying otherwise, we don't feel the data is compelling enough to really to say that you guys truly are better. But it was interesting because there was a signal in some, in some overall data showing that.

Dr. Sean Kane  28:18
And if you think about it, who is going to be taking NSAIDs. Typically, these are patients, especially with osteoarthritis, that are going to be a little bit older. Those with gout, a little bit older, they're going to have a higher risk of cardiovascular MI and stroke down the road. So it's very common that these patients will require NSAIDs for quality of life and for pain management, but they also are likely to be at higher cardiovascular risk and maybe even on aspirin. So what are some of the ways that we mitigate this cardiovascular risk in someone who has to take an NSAID in order to get through the day?

Speaker 1  28:49
And you talked about that interaction before, how aspirin binds to the platelets, you know, covalently, versus the NSAIDs are there only until they're half life. So what makes sense to me is that taking aspirin 30 minutes before taking any NSAIDs can help mitigate this interaction, and so this helps the aspirin covalently bind to the platelets to exert its anti platelet effect without really having to compete with that NSAID for the binding site on the platelets.

Speaker 2  29:16
Another interesting point is we have to look at the outside of the thrombotic risk of cardiovascular disease, and think of the potentially by some of their effects on the renal system. And otherwise, I'm seeing some salt and water retention as well. And so potentially chronic heart failure and hypertension could, in theory, be affected as well. And so we do have to be aware of those considerations.

Dr. Sean Kane  29:37
So again, these are over the counter medications. We've covered only two of the boxed warnings, and yet, there are a number of other toxicities that are absolutely important for every healthcare provider to know about. Nephrotoxicity is one, especially for an ICU clinician, I see a ton of acute kidney injury, so NSAIDs will cause pre renal acute kidney injury, where they reduce blood flow to the kidney. And this. More likely if a patient gets dehydrated, more likely if they're on other drugs that also cause pre renal, acute kidney injury, like diuretics, ACE inhibitors, ARBs, things like that. So absolutely, we don't use a lot of NSAIDs in the ICU because we see so much acute kidney injury. So that's something that providers should be aware of, absolutely.

Speaker 1  30:17
And I think this is probably an eye opening, but there is, you know, some toxicities listed for hepatic tissues as well. I mean, this is very rare. One in 100,000 all NSAIDs carry the risk. But some of the particular ones that have higher risk are diclofenac and sulindac, yes.

Speaker 2  30:35
And then another thing to consider is that you hear, every now and then, it's debated about the rash and allergic reaction as well as worsening asthma. So about 5% of children and one in five or 20% of adults with asthma having, you know, we call a, quote, allergy to NSAIDs. And it's interesting. It's again, looking at that pathway, and how it comes about is shunting it from that arachidonic acid, from the Cox pathway and towards a leukotriene pathway. And if you remember, from medications like montelukast (Singulair) which work on that leukotriene system, we know that those leukotrienes can cause bronchoconstriction in patients who reactive early disease. So that's actually a target in asthma. And so by increasing more of it, could increase the risk of having that occur.

Dr. Sean Kane  31:15
And what's really interesting about that is that, I mean, based on the mechanism that makes sense that all NSAIDs would kind of fall in that category. Commonly. When we think about allergic reactions, we assume that similar chemical structure is what matters in terms of that allergic reaction happening. But if a patient is allergic in terms of rash, respiratory symptoms, anything like that, if they're allergic to any NSAID or aspirin, we assume that they're allergic to the entire category of aspirin and NSAIDs. So someone says I'm allergic to ibuprofen, and they just had a heart attack, you're going to be really, really cautious to even consider them for aspirin because of this cross reactivity to this allergy or hypersensitivity,

Speaker 2  31:52
which is interesting because, again, as you mentioned, structurally, they're also very different. So it's kind of different than other classes where it has to do with the chemical structure and cross reactivity.

Dr. Sean Kane  32:01
So one thing that I wanted to get out of this podcast episode is really appreciating Why would a provider pick any given NSA over any other NSAID, and we've gone through considerations like half life, mechanism, efficacy, safety profile among some of the more common agents. What are characteristics that stand out to you guys in terms of why a provider might pick or not pick any of these NSAIDs?

Speaker 1  32:23
Well, I'm gonna go with the ibuprofen (Advil or Motrin) are the brand names. You know, despite all these risks out there, they are available over the counter. They are taken a few more times a day. As far as the frequency is concerned, the maximum dose recommendation if they're OTC versus prescription are different. So OTC label says, you know, no more than 1200 milligrams, but the RX prescription can go up to 3200 milligrams per day, and this is the max daily dose we're talking about. And the good thing about Ibuprofen is it's available in liquid form, so it's available for using kids over the counter products that starting at two years old, obviously for fever or pain reduction, and then prescription products starting at six months old.

Speaker 2  33:07
So Meloxicam Mobic is another one that I think gets a fair amount of use in our primary care clinics because the longer half life, allowing for once daily dosing, so not having to worry as much, maybe about breakthrough pain or for missing doses. So for individuals have a high pill burden or concerns with remember to take the medication. That's a nice thing as well as it's probably considered one of the, if not the most Cox too selective of the non selective NSAIDs. And so because of that, in theory, it may have less of a GI effect than the other ones.

Dr. Sean Kane  33:35
And then another NSAID is naproxen (Aleve). This is available prescription and over the counter. And one of the reasons why people might select naproxen versus ibuprofen over the counter is because of its half life. So typically, this is dosed twice a day versus ibuprofen every four to six hours. The max dose here for over the counter use is 600 milligrams. The max dose for prescription is 1000 milligrams per day. And one of the chinks in the armor of naproxen is the age restriction. So basically, this is really indicated if you're 12 years or older, regardless of whether it's over the counter or prescription. Really, there's a lack of data using Naproxen in children less than 12 years of age, so it's not even like a prescription versus over the counter thing. It's just it hasn't really been studied that well, because ibuprofen kind of corners the market there. With respect to naproxen, as we mentioned, if you're trying to mitigate some of that cardiovascular risk, naproxen appears to be the best agent, based on the best available data that we have to have the lowest risk of cardiovascular events versus the other NSAIDs. Obviously not having an NSAID period is going to be better. But if you had to pick an NSAID, it would appear that naproxen is the way to go, although the FDA, as we mentioned, would disagree with that, and they kind of labeled all NSAIDs equally regarding cardiovascular risk.

Speaker 1  34:48
You know, diclofenac is another generic product that is available in many different brand names like Zorvolex or Voltaren. It's again, closer to the COX‑2 selective side of things, just like meloxicam is. But unlike meloxicam, this has a shorter half life, which means it has to be dosed multiple times a day. And another good thing about this particular NSAID is that it's available in a topical form. So if you were thinking about more of the diverting the GI pathway and then just, you know, having patient apply it topically, this form is

Speaker 2  35:19
valuable, yeah. So I think another one again, we talked about already a celecoxib or Celebrex. So that's really the only currently standing Cox two selective NSA on the market. And definitely see that better gastrointestinal profile versus non selective NSA than, as we said, fortunately, does not appear that it has any higher rate of cardiovascular events than the less selected ones, which is fortunate for the product, as well as for overall people using it. And then another one doesn't come up as much an nabumetone (Relafen), which I think for a while seemed to have a better GI profile. But the only one claim to fame is a really, really, really long half life with this one. But again, it doesn't appear that it separates itself from a GI perspective.

Speaker 1  36:01
And what we learned about indomethacin is that, surprisingly, this is not the preferred NSAID in gout. Any NSAIDs are equally efficacious in gout. But as Dr. Schuman mentioned earlier, there is some niche use in indomethacin‑responsive headaches,

Speaker 2  36:18
yeah, and unfortunately, we've seen some GI issues with that. You have to keep in mind, but yeah, if possible, it does seem to have a nice niche.

Dr. Sean Kane  36:24
Then the last one, which is more in my neck of the woods, is ketorolac (Toradol). This is available IM and IV, which is why we typically will use it more in the hospital setting. It does come available orally as well, although that's a pretty uncommon medication for use orally. And what's interesting about this is this might win the award for the most box warnings. I was amazed to see how many boxed warnings ketorolac has versus the other NSAIDs. So we've already covered the three boxed warnings that all NSAIDs must have. Ketorolac has another handful of boxed warnings as well. So one, you can't use ketorolac for more than five days total — that includes IV, IM and PO; combined duration must be less than five days. And the reason that they pick that is that this has a really serious potency to it. So it's a really potent NSAID, which means that it has a lot of side effects that come along with it. So it's more likely to have the GI toxicities, more likely to see bleeding events, acute kidney injury, things like that. Number two, box warning is again higher risk of renal impairment, bleeding and hypersensitivity or allergic reaction. Number three, you should not inject this into a spine intrathecal or epidural, because it contains alcohol, and alcohol is not good for your tissues, especially in your spine. Number four, you should not use this for labor and delivery, because ketorolac adversely affects fetal circulation. It also inhibits uterine contraction so that baby's not going to come out as quickly. So giving this is going to be detrimental. Number five, don't use this with other NSAIDs again, because this is such a potent, such a toxic NSAID. If you combine this with other NSAIDs, you're more likely to see that toxicity profile of acute kidney injury, bleeding and GI events. Then the last one is that you should pick a smaller dose. If your patient is older, so more than 65 years of age, smaller, less than 50 kilograms, or if they have an elevated serum creatinine value. What's fascinating about this is that there's a lot of data that says that there's a dose cap or a ceiling effect to the dose of ketorolac, and that cap happens about 10 milligrams. Theoretically, you can give doses of 15–30, even 60 milligrams. So what I take away from that, again, is use the smallest dose that you need to and if the smallest dose is closer to 10 to 15, even if it's a younger, healthy person, I'm typically never recommending the higher doses of ketorolac.

Speaker 1  38:41
so lot of food for thought for inpatient or ICU practitioner, but I think one take home point for outpatient practitioners or pharmacist or pharmacy student is that if you're receiving a prescription for Toradol PO, make sure it's not more than five days, because you should be questioning the duration otherwise Absolutely.

Dr. Sean Kane  39:00
So that covers a lot of the NSAIDs. I think it's a good idea to kind of review some of the key points here. One key point for me that I was surprised about is that as long as you use an equipotent dose, all of the NSAIDs have similar efficacy for pain, inflammation, in terms of gout, osteoarthritis, things like that. And again, I was surprised to see that indomethacin did not corner the market of gout. There's nothing special about indomethacin for gout.

Speaker 1  39:25
All NSAIDs have these three boxed warnings related to GI toxicities (GI bleeds, ulceration and perforation), cardiovascular thrombotic events such as heart attack and stroke, and the third warning (peri‑operative use) applies to patients undergoing CABG (coronary artery bypass graft) surgery.

Speaker 2  39:50
So another thing that I didn't really think about as much, but is that idea about because of the the way it can interact with aspirin and the increased risk of cardiovascular effect from. Really getting and competing for some of that that binding to platelets, you can mitigate it by taking the aspirin about 30 minutes before the first NSAID dose of the day, and then potentially by favoring a naproxen over these other NSAIDs. And the

Dr. Sean Kane  40:12
last thing is that all of these agents are well associated with GI toxicities, like gi ulcers, bleeding and perforation. And you can mitigate some of that risk by adding more medication if the patient must have that NSAID so. Proton pump inhibitors have the best efficacy and probably are most tolerated. H2 blockers, like famotidine or ranitidine, have moderate efficacy and they're also well tolerated. The misoprostol has really good efficacy, similar to PPIs, but they're very poorly tolerated in terms of diarrhea, abdominal discomfort, and you can't use this in women of childbearing age, so there's a lot of limitations to that. So I think that wraps up episode 95 quite well. If you want to see show notes, including some of the references, it's available at HelixTalk.com episode 95 we are on Twitter, and for every episode that we release, we occasionally release out these clinical pearls from all of our episodes. So if you want to kind of catch those in your Twitter feed, you can, you can follow us on Twitter at HelixTalk. And then finally, we love the five star reviews in iTunes. And actually, today's episode on NSAIDs was recommended by a reviewer who emailed us asking for this very episode. So if you want to hear about a drug class review or new guidelines or disease state, email us or contact us through Twitter, and we'll add that to our episode queue as well. So with that, I'm Dr. Kane, I'm Dr. Schuman, and

Unknown Speaker  41:31
I'm Dr. Patel, and as always, study hard.

Narrator - Dr. Abel  41:35
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