Choosing a nonsteroidal anti-inflammatory drug for pain

[Music] Welcome to the Australian Prescriber Podcast. An independent, no-nonsense podcast for busy health professionals.

Nonsteroidal anti-inflammatories are often maligned medicines despite their usefulness in many conditions. So today on the Australian Prescriber Podcast, I'm speaking with 2 authors of a great new article which outlines how clinicians can approach choosing a nonsteroidal anti-inflammatory drug for pain.

I'm Dr Laura Beaton, a GP in Melbourne, and my guests are Dr Stephanie Hopkins, a rheumatology advanced trainee, and Dr David Liew, a rheumatologist and clinical pharmacologist, you may also recognise as a host of this very podcast. Thank you very much for coming on the show.

SH: Thank you for having us. It's lovely to be here.

DL: Thanks so much, Laura.

I remember the adverse effects of NSAIDs [nonsteroidal anti-inflammatory drugs] being emphasised a lot in medical training, particularly all of those that land people in hospital from serious cardiovascular, renal, and gastrointestinal side effects. And so I'm actually wondering if we start today talking about balancing out the messaging a little bit. What are NSAIDs really great at treating?

SH: That's a great question. In this paper, we did focus quite a lot on balancing those risks and benefits, focusing on the individual patient. We know that NSAIDs are particularly effective at managing mild to moderate pain, especially where there's that inflammatory component. So thinking about conditions like rheumatic or musculoskeletal disorders or in the postoperative setting for example. We did run through a few particular examples where they play an important role. Those are osteoarthritis, rheumatoid arthritis, and axial spondyloarthropathy.

Osteoarthritis, they play a particularly important role there in reducing pain in knee, hip, and hand osteoarthritis, which was interestingly greater in studies than either paracetamol or opioids. And that's obviously important because osteoarthritis is a common but often quite inappropriate indication for opioid prescription.

In axial spondyloarthropathy, including ankylosing spondylitis, NSAIDs combined with physical therapy are considered first line for management, slowing disease progression, and also reducing pain.

And in rheumatoid arthritis, NSAIDs are often really helpful in that early sort of disease phase, providing symptom relief when we're starting a disease modifying anti-rheumatic drug, which can take weeks to months to take full effect. And we also can't forget about some of those really common indications for NSAIDs, including headaches, acute musculoskeletal injury, dysmenorrhea, and dental pain as well.

DL: I think there's actually a lot to be lost from not utilising NSAIDs in the way that we would like to. We can look back to what happened in the mid-2000s and see how our reflexive prescribing at that time potentially had real harm. If you go back to then, seasoned listeners might remember rofecoxib (Vioxx), and the issues that came about with that, especially in the US. We saw that this COX-2 inhibitor, that nonsteroidal anti-inflammatory had enormous promises as far as gastrointestinal safety was concerned, but actually had really serious cardiovascular events associated with it.

And there was a black box warning and I think people at that time really were very concerned about the side effects from nonsteroidal anti-inflammatories as they should have done. But if you look at that time, that really was the start of the opioid crisis in the US. Now it's very hard to point to causality, but really there's an equipoise. There's a balance that was required. And I think now at this time when we are really trying to rationalise our opioid use and we're realising that, in fact, chronic non-cancer pain is really badly treated with opioids and, actually, nonsteroidal anti-inflammatories have an enormous role to play, it's really useful for us to really understand how to navigate the NSAID landscape, really identify, mitigate risk where we can so that we can harness the benefit of NSAIDs and really get benefit for individual patients without the risks of things like opioids.

I certainly found your article really helpful. And I think our listeners probably all remember being told about COX-2 selective NSAIDs. They're going to be a lot safer, much more protective for the GI [gastrointestinal] tract, thus to have that shattered a little bit for some medicines. But that being said, the COX-2s are still on the market and they're really advantageous in certain situations. But their advantage as far as analgesic effect seems actually quite minimal.

And so I guess I was wondering when you're thinking about when you choose a selective NSAID, so a COX-2 selective NSAID, what are the factors that really make you say, �Look, this is someone who is going to benefit mostly from a COX-2 inhibitor over a nonselective NSAID�? Or is it more that you're just trying to avoid the side effects of a nonselective NSAID?

SH: As you mentioned, those COX-2 selective NSAIDs were really developed to try and reduce the gastrointestinal risk that is associated with NSAIDs. And they have reduced that risk, but it's not absent. So the risk with the COX-2 selective NSAIDs is around half in terms of gastrointestinal adverse effects when compared to nonselective NSAIDs like ibuprofen or naproxen. And we'd be really leaning towards selecting a COX-2 specific NSAID in individuals that are considered high gastrointestinal risk just to try to mitigate that. So thinking about people that are in an older age group or particularly if they have a past history of peptic ulcer disease, we might be leaning more towards a COX-2 selective agent.

DL: If I can add in, I think selectivity gives us this false reassurance sometimes and people might be wondering why we still get side effects, gastrointestinal side effects in COX-2 inhibitors. And it's fair to say that very few agents are purely selective. And this idea of COX-2 selectivity is a relative thing and that COX-2 isn't completely irrelevant when it comes to gastrointestinal health either.

We know that COX-2 is important for maintaining the gastric and intestinal mucosa. And I think one thing that gets forgotten about in terms of gastrointestinal side effects from NSAIDs really is about non-upper GI side effects, which are substantially represented and relevantly aren't affected by PPIs [proton pump inhibitors].

That takes us to one of your great practice points in the article around thinking about mitigating these GI side effects and the controversy as to who really needs a PPI to be routinely co-prescribed if we're going to prescribe an NSAID. And I wonder, in your practice, who are those patient categories that you think this person really does need to have a PPI prescribed at the same time if we're talking about having an NSAID for more than a couple of days?

SH: PPIs really shouldn't be routinely co-prescribed with NSAIDs, but should be selected in particular individuals. I guess you highlighted those that are only taking NSAIDs for a very short period are in that lower risk group. So those who are likely to take them for a longer duration, we'd really consider co-prescription with a PPI. And then also those who have risk factors for gastrointestinal adverse effects, we would be considering a PPI alongside their NSAID.

Maybe we could move now to cardiovascular risk. Which nonsteroidal anti-inflammatory drugs have the lowest cardiovascular risk?

SH: So it seems that naproxen and low-dose celecoxib have the lowest cardiovascular risk, but they are all associated with an increased risk of cardiovascular events. And there is that clear dose�response relationship. So higher daily doses of NSAIDs are associated with an increased overall risk, but naproxen and low dose celecoxib seem to be the lowest risk.

DL: We've got a beautiful table in the article where we do compare the relative cardiovascular gastrointestinal risks for different agents. It's not necessarily straightforward because there aren't that many comparative studies. There are certainly some comparative randomised controlled trials, but trying to pare apart the pharmacoepidemiological data and make some comparisons, it's become very clear over the course of time that there are some higher risk NSAIDs, lower risk NSAIDs. I think for both gastrointestinal and cardiovascular risk, it's worthwhile thinking about the individual patient in front of you and thinking about their relative gastrointestinal and cardiovascular risk.

Turning now to the kidneys, what renal factors should we consider when choosing an NSAID for pain?

SH: We do need to be a little bit cautious with the NSAIDs, particularly amongst those who already have chronic kidney disease or who are at risk of an acute kidney injury. And those particular risks would be things like older age, volume depletion, or if they're already using nephrotoxins.

In terms of the chronic kidney disease, we'd be cautious and monitor renal function after NSAID commencement in someone with an eGFR [estimated glomerular filtration rate] in that 30 to 60 sort of range. And the recommendation is really to avoid NSAIDs altogether in someone with an eGFR that sits less than 30.

As well as GI bleeding, NSAID use also increases the risk of other major bleeding but also thrombosis. How do we understand this?

DL: Yeah, look, I think it's a difficult thing to navigate. And we've tried to outline that a little bit in the article in a section on bleeding and thrombosis. I think many people are aware about the antiplatelet effect from low-dose aspirin. We do think that comes about from inhibiting COX-1. We see that a lot less clearly from any other NSAIDs including nonselective NSAIDs.

On the other side, we do see an increased risk of thrombosis. We know especially with COX-2 inhibition, they would get imbalance and thromboxane�prostacyclin signalling and we do see an incremental risk of thrombosis. But once again, I don't think this is something that we should be overly scared of. This is an incremental risk of what's at baseline, or low risk for patients who might be at high risk of thrombosis, especially a venous thromboembolism. That might be something to think about. It might give us a little bit of caution about NSAIDs. But at the same time, I'd hate to be in a situation where we are giving people this really long shopping list of risks when their baseline risk is already quite low.

Like a lot of the risks that we talk about today, this actually better reflects people's background risk rather than an absolute risk from NSAIDs. This applies really to the discussions we're having today about cardiovascular risk in particular, but also a little bit to gastrointestinal risk. Really, one of the biggest predictors of how these people do is their background cardiovascular risk, their background thrombosis risk. So I don't think we necessarily need to reflexively steer away from NSAIDs and patients with low cardiovascular risk, low thrombosis risk, or necessarily even scare them unnecessarily by pushing firmly on them about these risks when their absolute risk is low. But it's our responsibility as prescribers, as clinicians, to keep all of this in mind as we select agents and, where relevant, that we take the appropriate considerations. And I think particularly when we're talking about longer term NSAID use, that we look to mitigate these risk factors, especially cardiovascular risk, where it's relevant in long-term use.

And as a prescriber, it's really great to have some guidance like this article to turn to. For example, I was interested to learn about the relative risk of different NSAIDs in hepatic impairment. Steph, would you mind taking us through just briefly what we should think about for NSAIDs and the liver?

SH: Yeah, absolutely. So it's certainly something that we think about less than some of those other risks with NSAIDs, but it is an important consideration because most of the NSAIDs do undergo metabolism in the liver, and they can result in the production of these reactive intermediaries that can cause liver damage.

As David flagged, much of this as a consideration is related to the patient's background risk. And we'd be particularly thinking about those with a background of hepatic cirrhosis and really wanting to avoid NSAIDs in those individuals. There does seem to be variable risk with the different NSAIDs, and diclofenac has been flagged as probably the highest risk in terms of liver injury.

Moving now to some interesting immunology � hypersensitivity reactions to NSAIDs. I was interested to read about non-allergic hypersensitivity reactions. Can you talk us through these so that our prescribers can have a little bit more of a broad understanding of what can go on?

SH: Yeah, absolutely. So it's certainly disconcerting thinking about the possibility of some of these non-allergic hypersensitivity reactions, which can present in a very similar way to hereditary angioedema where individuals can develop urticaria and angioedema. And it's thought that's really related to COX-1 inhibition and then that downstream production of leukotrienes, which does mean that those COX-2 selective inhibitors are a little bit less likely to have that as an adverse effect.

DL: That's not of course to say that NSAIDs can't cause IgE-mediated anaphylaxis (true anaphylaxis). It certainly is the case. There are some differences but, fundamentally, you look to treat IgE-mediated anaphylaxis and anaphylactoid non�IgE-mediated anaphylaxis in the same type of way in the first instance. You would not give adrenaline because you thought it was an anaphylactoid reaction.

But there are some important differences. We know that the time of onset after exposure is different. Anaphylaxis is usually within short minutes, whereas anaphylactoid reactions, usually longer between 30 minutes out to a few hours.

Testing. There's a big difference in that IgE-mediated reactions can give you a skin test reaction where we don't see the non-IgE-mediated reactions. But probably one of the most pertinent implications is the fact that for non�IgE-mediated reactions, we do expect to see that that would affect all nonsteroidal anti-inflammatories. So that would rule out essentially the use of all NSAIDs for that patient. But if we are satisfied that it is an IgE-mediated anaphylaxis, a true anaphylaxis, then there's not the same likelihood of cross-reactivity. And often we can use a different nonsteroidal anti-inflammatory. We're blessed with a number of different NSAIDs. And often the clinical utility is really strong. So it's an important distinction to make potentially really in combination with your local allergist, immunologist.

As a GP, I've essentially steered well clear of NSAIDs in pregnancy and breastfeeding, but there are some specific situations where actually the benefits might outweigh the risks. Can we talk through those?

SH: Yeah, so I guess the first thing to consider is really the timing of NSAID use during the pregnancy and in particular thinking about the first trimester and the third trimester as being higher risk zones.

So in the first trimester, there is an increased risk of miscarriage associated with NSAID use. And in the third trimester, especially later in pregnancy after 30 weeks, there is a risk of premature closure of the fetal ductus arteriosus and also of oligohydramnios. Those are the particular areas where we would suggest avoiding NSAIDs where possible. But as you flagged, you'd be considering the individual in front of you and whether the benefits might outweigh the risks for them.

I was reassured also to read that short-acting NSAIDs are considered safe to use in breastfeeding. We're not using high-dose aspirin, but standard dosing, short-acting NSAIDs are considered safe in breastfeeding.

SH: Yeah. Simple things like ibuprofen, our most common short-acting NSAID, is considered safe for breastfeeding as well.

DL: I mean, in fact, other NSAIDs probably are safe, but out of abundance of caution, we really do lean towards those short-acting NSAIDs.

So after we said that we didn't want to spend the entire podcast thinking about all of the adverse effects of NSAIDs, they are really helpful. And we do have to decide which one to prescribe if we are going to prescribe. And so, if they've got similar efficacy for analgesia, it's going to be down to patient factors. Thinking about their efficacy, David, would you mind talking to us a little bit about what evidence there is out there?

DL: Yes. It's one of those situations where the pharmacological properties, especially the pharmacokinetics, also to some extent the pharmacodynamics, are important in agent selection. I think over time we've realised that maybe COX-2 inhibition, selective inhibition, isn't the panacea of all the problems that we thought might be the case, but there are some relative benefits in different situations. And so, keeping in mind relative COX-2 selectivity is important when we think about gastrointestinal risk and thinking about the people who are at increased gastrointestinal risk, and thinking especially about those older patients, patients with established gastrointestinal risk, or I guess thinking about those patients who might have more to lose from gastrointestinal adverse events, if they're already on an anticoagulant like warfarin or direct-acting oral anticoagulant, for example.

I think the pharmacokinetics is also really important. There are times when we do want a shorter half-life and there are times when we want a long half-life. It's really hard to remember to take medicines 3 times a day on a long-term basis. But being able to wash out quickly or potentially in different situations be able to mitigate adverse events is also really important.

We're lucky we've got a variety of different nonsteroidal anti-inflammatories to be able to service those needs. It should also be said as well, different modes of administration. While we don't use them as frequently now as we maybe previously did, it's worthwhile keeping in mind that there are other types of agents apart from oral agents. There are of course topical nonsteroidal anti-inflammatories as well, but they really do have limited efficacy outside the direct effect. That's something to think about when you need something really targeted and limited.

Beyond that, there are some situations where there are a few little quirks. For example, we know that with these very specific situations, paroxysmal hemicrania and hemicrania continua, these are 2 headache syndromes. And specifically, they only seem to respond to indometacin. That's one to keep in mind as well.

And of course we are leaving out of this the potential benefits of low-dose aspirin. I think high-dose aspirin is, as far as NSAIDs for pain are concerned, well and truly in the history books. Low-dose aspirin of course, we use in very different situations that won't have the same effects.

The final thing I'll say is that sometimes one NSAID just won't work for one patient, but another NSAID will. And so, this idea of NSAID rotation in the face of primary inefficacy is certainly something which is valid as well.

I wanted to also ask you about not just the common misconceptions, but your practice points. One of the most common questions I get asked as a GP, �Do I need to take this with food or not?� What's the evidence around taking our NSAIDs with food?

DL: This is surprisingly controversial. We thought we should mention it in the article because it clearly does come up a lot. So taking an NSAID with food we do think probably does slow down the absorption of the NSAID. And so that might be disadvantageous. In acute pain, we're trying to get acute relief.

Clearly also though, it does reduce, at least we think from animal models, and it does seem likely based on human data, that it does reduce gastric adverse events specifically, and potentially might also reduce small bowel damage as well. So I think generally depends on what you're trying to achieve and thinking about how things might sit with chronic musculoskeletal indications. Often where we're reaching steady state and we're trying to get the longer term benefits of NSAIDs so, for example, in an ankylosing spondylitis patient, then in that case I'd be suggesting NSAIDs with food. But then in a situation where we need more rapid relief, for example, some of those situations like headache syndromes or period pain, then with food might actually do the opposite of what we're trying to do.

Having said all that, these are small incremental differences. And I think we sometimes panic more about these things than we should. I hope that by discussing NSAIDs more, that we all have greater confidence of how to navigate the situation because I think NSAIDs are with us for the indefinite future. And using them well is actually of real benefit to our patients. There's a reason why this is a core part of general practice. And I hope that other specialties, craft groups, professions, all can see the benefit of that as well. I think we've almost come to the point where we undervalue them and it's now time to revalue nonsteroidal anti-inflammatories.

Thanks, David. And thanks, Steph. It's been great to speak with you today. I do actually feel a bit more confident. I feel like I've got my head a little bit more around why I'm choosing this one for this person at this time. It's been great to speak with you. And it's been great to read the article.

DL: You flatter us, Laura. Thank you for having a chat to us today.

SH: Yes, thank you.

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I'll remind our listeners that the full article is available for free on the Australian Prescriber website.

If you're a GP, it is now even easier to record your CPD with Australian Prescriber. After reading the article online, you can follow the links. There's some reflective questions and then you'll have 1 hour of Educational Activities and 1 hour of Reviewing Performance hours uploaded for you.

The views of the hosts and the guests on this podcast are their own and may not represent Australian Prescriber or Therapeutic Guidelines. David Liew is a member of the Pharmaceutical Benefits Advisory Committee Drug Utilisation Subcommittee and a podcast host for Australian Prescriber.